regulatory-strategy-memo-velonatib-psoriasis.docx

1018-00005 · Penterra Pharmaceuticals Corp · Memoranda & Analysis

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CALDERWOOD & HARKNESS LLP 1301 Avenue of the Americas, 42nd Floor New York, New York 10019 Telephone: (212) 558-4000 Facsimile: (212) 558-3588

PRIVILEGED & CONFIDENTIAL — ATTORNEY-CLIENT COMMUNICATION ATTORNEY WORK PRODUCT

MEMORANDUM

I. EXECUTIVE SUMMARY

This memorandum outlines Calderwood & Harkness LLP's ("C&H") recommended regulatory strategy for the preparation and submission of a supplemental New Drug Application ("sNDA") seeking approval of velonatib hydrochloride (VELONATIB®) for the treatment of moderate-to-severe chronic plaque psoriasis in adults who are candidates for systemic therapy or phototherapy. Velonatib hydrochloride is a selective Janus kinase-1 ("JAK-1") inhibitor, available as oral tablets in 5 mg and 10 mg dosage strengths. The drug was originally approved by the U.S. Food and Drug Administration ("FDA") on June 14, 2019, under NDA No. 215-847, for the treatment of moderate-to-severe rheumatoid arthritis ("RA") in adults with an inadequate response or intolerance to one or more disease-modifying antirheumatic drugs ("DMARDs"). NDA No. 215-847 is held by Penterra Pharmaceuticals Corp. ("PPC" or "Penterra").

Our strategy is informed by three principal inputs: (a) the written minutes and informal guidance obtained from the Type B Pre-sNDA meeting held on May 4, 2022 (Meeting ID: FDA-2022-M-1743) with the Division of Dermatology and Dentistry ("DDD"), Office of Immunology and Inflammation, Center for Drug Evaluation and Research ("CDER"); (b) the clinical data generated to date under the CLARION clinical development program, which includes the completed Phase II dose-ranging study (CLARION-1), the completed Phase III pivotal study (CLARION-2), and the ongoing Phase III confirmatory study (CLARION-3); and (c) the applicable statutory and regulatory framework governing supplemental new drug applications under the Federal Food, Drug, and Cosmetic Act ("FD&C Act") and its implementing regulations.

Based on our analysis, we recommend a phased submission strategy targeting a Q1 2023 sNDA filing date, contingent upon receipt of positive top-line results from CLARION-3, which are expected in Q4 2022. Assuming a standard ten-month review timeline under the Prescription Drug User Fee Act ("PDUFA"), this would yield a projected PDUFA goal date in Q4 2023. To maximize the probability of a timely filing and minimize the interval between CLARION-3 data availability and sNDA submission, we recommend that parallel labeling development — including a draft United States Prescribing Information ("USPI"), Patient Package Insert, and Medication Guide — begin immediately, with a target first complete draft USPI by September 2022 and a target Rev. 3 for internal review by mid-October 2022. CLARION-3 data placeholders would be populated upon receipt of final results. This parallel-track approach will enable Penterra to move rapidly to final sNDA assembly if CLARION-3 results are positive.

It is important to note the commercial significance of this regulatory initiative. Velonatib currently generates fiscal year 2022 U.S. net sales of approximately $1.47 billion, representing approximately 67.4% of PPC's $2.18 billion total revenue. PPC's current market capitalization is approximately $6.3 billion. The psoriasis indication represents a significant commercial expansion opportunity for Penterra's flagship asset, potentially broadening velonatib's addressable patient population substantially. The moderate-to-severe chronic plaque psoriasis population in the United States is estimated at approximately 3.6 million adults, with a growing proportion of patients seeking oral systemic therapies as alternatives to injectable biologics. Accordingly, the regulatory strategy for this sNDA warrants careful and comprehensive planning.

This memorandum addresses the regulatory framework, key takeaways from the FDA Type B Pre-sNDA meeting, the clinical data supporting the sNDA, the proposed labeling strategy, the timeline and key milestones, risks and contingencies, and coordination with outside advisors. Separate C&H memoranda addressing (i) the REMS assessment and (ii) PREA pediatric deferral obligations are forthcoming and are expected in September 2022.

II. REGULATORY FRAMEWORK

A. Statutory and Regulatory Basis

The sNDA for the psoriasis indication will be submitted under Section 505(b) of the Federal Food, Drug, and Cosmetic Act, 21 U.S.C. § 355(b). Because velonatib is already approved under NDA No. 215-847, the submission will take the form of a supplemental application to the existing NDA rather than a new stand-alone application. This approach is both procedurally required and strategically advantageous, as it preserves the existing RA labeling while adding the new psoriasis indication to the approved product labeling.

The sNDA will be classified as an Efficacy Supplement — Type 10 (new indication) under 21 C.F.R. § 314.70(b). Under this regulation, the addition of a new therapeutic indication constitutes a "major change" to approved labeling that may not be placed into distribution until the supplement has been approved by FDA. Accordingly, a prior-approval supplement — rather than a "changes being effected" (CBE-0 or CBE-30) supplement — is required. This classification is consistent with FDA's guidance in "Guidance for Industry: Changes to an Approved NDA or ANDA" (April 2004, as revised), which identifies the addition of a new indication as a change requiring prior approval.

The sNDA filing will be submitted in electronic Common Technical Document ("eCTD") format in accordance with FDA's current technical specifications for electronic submissions. The submission will include, at a minimum, updated Modules 1 (administrative information and prescribing information), 2 (overviews and summaries, including a clinical overview and clinical summary), and 5 (clinical study reports) of the CTD. Module 3 (quality) updates are not expected to be required, as the drug substance and drug product specifications remain unchanged from the approved RA indication. Module 4 (nonclinical study reports) may require limited updates if any new nonclinical studies have been conducted to support the psoriasis indication, but this is not anticipated at present.

B. PDUFA Review Timeline

Under the Prescription Drug User Fee Act, as most recently reauthorized by PDUFA VII (effective October 1, 2022), the standard review clock for an efficacy supplement is ten months from the filing date. For purposes of timeline planning, we assume a Q1 2023 filing date — specifically, a target submission in February or March 2023 — which would yield a projected PDUFA goal date in Q4 2023, likely November or December 2023.

It is important to note that the PDUFA review clock does not begin on the date of submission but rather on the date FDA "files" the application, which occurs after a preliminary completeness review. FDA may issue a refuse-to-file ("RTF") letter within 60 days of receipt of the sNDA if the submission is determined to be incomplete or otherwise insufficient for filing. An RTF determination would delay the review timeline by at least several months and could require substantial reworking of the submission. To mitigate this risk, we recommend that the team prepare a comprehensive pre-submission readiness checklist, modeled on FDA's "Guidance for Industry: Refuse to File" checklist, to verify the completeness and quality of all sNDA components prior to submission. C&H and Callendar Baines Group LLC ("CBG") will collaborate on the development and execution of this checklist.

We also note that Penterra may, in appropriate circumstances, request Priority Review designation for the sNDA, which would shorten the review timeline to six months. However, Priority Review is reserved for applications for products that treat serious conditions and, if approved, would provide a significant improvement in safety or effectiveness. Given that the psoriasis indication, while important, involves a therapeutic area with multiple approved systemic therapies — including biologic agents with high PASI-90 response rates — we do not believe that Priority Review designation is likely to be granted in this instance. We do not recommend pursuing a Priority Review request at this time, but we will reassess if CLARION-3 results demonstrate a particularly compelling efficacy or safety profile that could support such a request.

C. Coordination with Existing NDA

Because the sNDA supplements the existing NDA No. 215-847, the resulting approved labeling must be internally consistent across both the RA and psoriasis indications. This coordination requirement applies to all sections of the USPI but is most critical with respect to the following:

First, the boxed Warning (currently addressing serious infections, malignancies, major adverse cardiovascular events ("MACE"), and thrombosis, consistent with FDA's September 2021 class-wide JAK-inhibitor labeling update) must be consistent across both indications. Any modification to the boxed Warning for the psoriasis indication — which we do not anticipate at this time — would necessarily apply to the RA indication as well.

Second, the Warnings and Precautions section (Section 5 of the USPI) must harmonize any psoriasis-specific safety language with the existing RA-specific language. As discussed in Section V.B.3 below, FDA's Type B meeting feedback calls for enhanced hepatotoxicity monitoring language specific to the psoriasis population, which must be drafted in a manner that is consistent with — and does not create confusion relative to — the existing hepatotoxicity language applicable to the RA indication.

Third, the Adverse Reactions section (Section 6 of the USPI) will need to present psoriasis-specific adverse event data in a manner that is clearly delineated from the existing RA adverse event data, while maintaining a unified and coherent presentation across the full label.

Fourth, any changes to safety-related labeling sections that result from the CLARION safety data — even if those changes relate primarily to the psoriasis population — may have implications for the RA labeling and should be evaluated accordingly.

The Penterra Regulatory Affairs team, under Dr. Hessler's direction, will serve as the central coordination point for ensuring labeling consistency across both indications. C&H will provide legal and regulatory review of all labeling language to confirm consistency and compliance with applicable FDA requirements.

III. FDA MEETING FEEDBACK — KEY TAKEAWAYS FROM TYPE B PRE-sNDA MEETING

On May 4, 2022, representatives of Penterra Pharmaceuticals Corp., Calderwood & Harkness LLP, and Callendar Baines Group LLC participated in a Type B Pre-NDA/BLA Meeting with the Division of Dermatology and Dentistry, Office of Immunology and Inflammation, CDER (Meeting ID: FDA-2022-M-1743). The meeting was conducted by teleconference, consistent with FDA's prevailing meeting format. The purpose of the meeting was to discuss the regulatory requirements and clinical data expectations for the planned sNDA submission for the velonatib psoriasis indication.

The meeting was productive and yielded substantive guidance from FDA on several critical issues. The written minutes of the meeting, received by Penterra on June 2, 2022, have been reviewed by C&H and are reflected in the analysis below. We summarize the key points of FDA feedback as follows:

1. Two Adequate and Well-Controlled Trials Required. FDA confirmed that two Phase III, adequate and well-controlled clinical trials demonstrating efficacy will be expected to support the sNDA submission for the psoriasis indication. This is consistent with the standard evidentiary requirement under Section 505(d) of the FD&C Act for new efficacy claims, as well as with FDA's longstanding practice in the dermatology therapeutic area. CLARION-2, completed in April 2022, constitutes the first pivotal trial. CLARION-3, currently ongoing, is designed as the confirmatory study. FDA did not indicate that a single pivotal trial, even with highly persuasive results, would be sufficient to support the sNDA. Accordingly, successful completion of CLARION-3 is an absolute prerequisite for filing.

2. Active Comparator Arm. FDA strongly recommended the inclusion of an active comparator arm in at least one of the Phase III studies, in order to contextualize velonatib's efficacy within the current psoriasis competitive landscape, which is increasingly dominated by biologic therapies — particularly interleukin-17 ("IL-17") inhibitors and interleukin-23 ("IL-23") inhibitors — that have set a high efficacy bar in terms of PASI-90 and PASI-100 response rates. While FDA did not characterize the active comparator arm as a formal regulatory requirement, the recommendation was made with sufficient emphasis that compliance is advisable both for regulatory purposes and for the benefit-risk assessment that FDA will conduct during review. CLARION-3 includes an adalimumab biosimilar arm as an active comparator, which satisfies this recommendation. We note that the selection of adalimumab — a TNF-alpha inhibitor — rather than an IL-17 or IL-23 inhibitor as the active comparator was discussed at the Type B meeting. FDA did not object to the use of adalimumab, recognizing that it remains a widely prescribed comparator in dermatology clinical trials, although FDA noted that the prescribing community may place greater weight on comparisons with newer biologic agents. The inclusion of the adalimumab arm provides a meaningful reference point while avoiding the complexities of a head-to-head comparison with a product that may have a higher absolute response rate.

3. Co-Primary Endpoints for CLARION-3. FDA stated that the co-primary endpoints of PASI-75 at Week 16 and static Physician Global Assessment ("sPGA") 0/1 at Week 16 were acceptable endpoints for the psoriasis indication, consistent with FDA's Draft Guidance for Industry: "Psoriasis: Developing Drugs for Treatment" (September 2020). However, FDA also expressed a clear preference for the inclusion of PASI-90 at Week 16 as a co-primary endpoint in the confirmatory study (CLARION-3), citing evolving standards in the psoriasis therapeutic area and the higher efficacy bar established by newer biologic therapies. FDA's rationale was that PASI-75, while historically the standard primary endpoint in psoriasis trials, may no longer adequately differentiate new therapies from established treatments in the current treatment landscape, and that PASI-90 more closely approximates the level of skin clearance that patients and prescribers now expect from a psoriasis therapy.

Penterra agreed during the meeting to designate PASI-90 at Week 16 and sPGA 0/1 at Week 16 as co-primary endpoints for CLARION-3, with PASI-75 at Week 16 reclassified as a key secondary endpoint. This agreement was reflected in the written meeting minutes. It is critical to note that both co-primary endpoints must be met in CLARION-3 to support filing of the sNDA. Failure to achieve statistical significance on either co-primary endpoint would render the confirmatory study inadequate for regulatory purposes and would preclude filing.

4. 12-Month Safety Database. FDA requested that 12-month safety data from both Phase III studies (CLARION-2 and CLARION-3) be included in the sNDA submission. This request is consistent with the International Council for Harmonisation ("ICH") E1 Guideline, "The Extent of Population Exposure to Assess Clinical Safety for Drugs Intended for Long-Term Treatment of Non-Life-Threatening Conditions," which recommends that for chronic-use products, the safety database include at least 100 patients exposed for a minimum of 12 months and a total safety database of at least 1,500 patients. Because psoriasis is a chronic condition requiring long-term treatment, FDA's request for 12-month safety data is expected and appropriate.

Both CLARION-2 and CLARION-3 include 12-month open-label safety extension periods. The CLARION-2 extension is currently underway, with 12-month data expected to be available in time for sNDA submission. The CLARION-3 extension timeline is dependent on the CLARION-3 enrollment and randomization schedule, and the team should confirm with CBG that 12-month CLARION-3 safety data will be available in time for the Q1 2023 filing target. If 12-month CLARION-3 safety data are not available by the filing date, Penterra may need to submit the data as a post-filing amendment, which could complicate the review process and potentially delay the PDUFA goal date. We will monitor this issue closely and advise accordingly.

5. Hepatotoxicity Monitoring. FDA flagged the need for enhanced hepatotoxicity monitoring language in the proposed labeling for the psoriasis indication, given known JAK-1 class effects on liver enzymes. Specifically, FDA recommended that the USPI Warnings and Precautions section (Section 5) include language recommending baseline and periodic liver enzyme testing (alanine aminotransferase, or ALT, and aspartate aminotransferase, or AST) for patients receiving velonatib for the psoriasis indication. FDA suggested a testing frequency of baseline, followed by testing at 4 to 8 weeks after initiation of therapy, and then periodically thereafter. This recommendation is consistent with the hepatotoxicity monitoring language included in the approved labeling for certain other JAK inhibitors in the dermatology space, including the approved labeling for upadacitinib in atopic dermatitis.

FDA's focus on hepatotoxicity reflects the general class-level concern regarding JAK inhibitors and liver injury, as well as specific observations from the CLARION clinical program. While no clinically significant hepatotoxicity signal has been identified in the CLARION data to date, elevated liver enzymes (Grade 1 and Grade 2 ALT elevations) were observed at a numerically higher rate in velonatib-treated patients than in placebo-treated patients in CLARION-2. The enhanced monitoring language is therefore a precautionary measure that will need to be carefully drafted to balance appropriate safety communication with avoidance of unduly restrictive language that could hinder commercial uptake. Coordination between the psoriasis-specific hepatotoxicity language and the existing RA label language on hepatotoxicity will be necessary to ensure internal consistency within the USPI.

6. REMS Assessment. FDA indicated during the Type B meeting that it would conduct a Risk Evaluation and Mitigation Strategy ("REMS") assessment in connection with the sNDA review for the psoriasis indication. FDA noted that the current NDA for velonatib does not include a REMS for the RA indication, but that the addition of a new indication — particularly in a therapeutic area with a potentially broader patient population — warrants a fresh assessment of whether a REMS is necessary to ensure that the benefits of velonatib outweigh its risks. FDA requested that Penterra address the potential need for a REMS in the sNDA submission, including an analysis of whether existing labeling elements (including the boxed Warning and Medication Guide) are sufficient to manage the known risks of velonatib, or whether additional REMS elements (such as a Communication Plan, Elements to Assure Safe Use ("ETASU"), or an Implementation System) may be warranted.

C&H will prepare a separate memorandum analyzing the REMS issue in detail, including an assessment of the likelihood and potential scope of REMS imposition and a recommended approach for addressing the REMS question in the sNDA submission. This memorandum is expected in September 2022.

7. Pediatric Written Request. FDA issued a Written Request under the Pediatric Research Equity Act ("PREA") for pediatric studies of velonatib in psoriasis patients ages 12 to 17. The Written Request contemplates a pharmacokinetic and efficacy study in adolescent patients with moderate-to-severe chronic plaque psoriasis. Penterra has requested and obtained a deferral of the pediatric study obligation until 18 months after approval of the adult psoriasis indication, which is consistent with FDA's standard practice for pediatric deferrals under PREA. The terms of the deferral, including required pediatric study milestones and reporting obligations, will be addressed in a separate C&H memorandum expected in September 2022.

IV. CLINICAL DATA OVERVIEW

A. Summary Table

The following table summarizes the clinical studies comprising the CLARION development program for velonatib in chronic plaque psoriasis:

B. CLARION-1 (Phase II)

CLARION-1 was a Phase II, randomized, double-blind, placebo-controlled, dose-ranging study designed to evaluate the efficacy, safety, and tolerability of velonatib hydrochloride at two dose levels (5 mg and 10 mg once daily) compared with placebo in adults with moderate-to-severe chronic plaque psoriasis. The study enrolled 287 patients at approximately 48 clinical sites in the United States and Canada.

Patients were randomized in a 1:1:1 ratio to receive velonatib 5 mg once daily, velonatib 10 mg once daily, or matching placebo for a 12-week double-blind treatment period, followed by an optional 40-week open-label extension period. The primary efficacy endpoint was the proportion of patients achieving PASI-75 (i.e., at least a 75% reduction from baseline in the Psoriasis Area and Severity Index) at Week 12.

The 10 mg dose met the primary endpoint with a statistically significant and clinically meaningful treatment effect: 68.2% of patients in the velonatib 10 mg group achieved PASI-75 at Week 12, compared with 12.4% of patients in the placebo group (p < 0.001). The 5 mg dose did not reach statistical significance for PASI-75 at Week 12, with a response rate of approximately 34.7% (p = 0.07 vs. placebo). These results supported the selection of 10 mg once daily as the dose for Phase III development, as the 10 mg dose demonstrated a substantially higher response rate than the 5 mg dose without a meaningfully different safety profile.

The safety profile observed in CLARION-1 was consistent with the known velonatib safety data from the approved RA indication. The most common adverse events in the velonatib 10 mg group were upper respiratory tract infections, nasopharyngitis, headache, and nausea. No serious infections, malignancies, MACE events, or thromboembolic events were observed during the 12-week double-blind treatment period, although the study was not powered to detect differences in these low-frequency safety events.

The principal role of CLARION-1 in the sNDA will be as dose-selection justification and as supportive efficacy and safety data. CLARION-1 is not designated as a pivotal study and, standing alone, would not be sufficient to support the sNDA.

C. CLARION-2 (Phase III, Pivotal No. 1)

CLARION-2 was a Phase III, randomized, double-blind, placebo-controlled study designed to evaluate the efficacy and safety of velonatib 10 mg once daily compared with placebo in adults with moderate-to-severe chronic plaque psoriasis who are candidates for systemic therapy or phototherapy. The study enrolled 742 patients at approximately 126 clinical sites in the United States, Canada, and Europe.

Patients were randomized in a 2:1 ratio to receive velonatib 10 mg once daily or matching placebo for a 16-week double-blind treatment period, followed by a 36-week open-label extension period in which all patients received velonatib 10 mg once daily. Key eligibility criteria included: age 18 years or older; a diagnosis of chronic plaque psoriasis for at least 6 months prior to screening; moderate-to-severe disease severity defined as body surface area ("BSA") involvement of at least 10%, a PASI score of at least 12, and an sPGA score of at least 3 (moderate); and candidacy for systemic therapy or phototherapy. Patients with prior exposure to more than two biologic therapies for psoriasis were excluded, consistent with the design of a broad-population study.

The study met both co-primary endpoints with robust statistical significance:

• PASI-75 at Week 16: 71.5% of patients in the velonatib group achieved PASI-75 at Week 16, compared with 9.1% of patients in the placebo group (p < 0.001). The treatment difference of 62.4 percentage points was both statistically significant and clinically meaningful.

• sPGA 0/1 at Week 16: 58.3% of patients in the velonatib group achieved an sPGA score of 0 (clear) or 1 (almost clear) at Week 16, compared with 5.7% of patients in the placebo group (p < 0.001). The treatment difference of 52.6 percentage points was both statistically significant and clinically meaningful.

Key secondary endpoints also demonstrated statistically significant improvements in the velonatib group compared with placebo, including PASI-90 at Week 16, Dermatology Life Quality Index ("DLQI") response, and itch numerical rating scale ("NRS") reduction.

The safety profile observed in CLARION-2 was generally consistent with the known velonatib safety data from the approved RA indication. No new safety signals were identified during the 16-week double-blind treatment period. The most common adverse events (≥ 5% incidence) in the velonatib group were nasopharyngitis (8.1%), upper respiratory tract infection (6.7%), headache (5.9%), and nausea (5.2%). Serious adverse events were observed in 3.4% of velonatib-treated patients and 2.8% of placebo-treated patients. There were no cases of active tuberculosis, opportunistic infections, or gastrointestinal perforation. Grade 1 and Grade 2 ALT elevations were observed at a numerically higher rate in the velonatib group (4.8%) than in the placebo group (2.0%); no Grade 3 or Grade 4 ALT elevations were reported. One venous thromboembolic event (deep vein thrombosis) was observed in the velonatib group; the event occurred in a patient with pre-existing risk factors and was considered possibly related to study drug. No MACE events were reported during the double-blind period.

The 12-month safety extension of CLARION-2 is ongoing, and data from this extension are expected to be available in time for inclusion in the sNDA submission, consistent with FDA's 12-month safety data request.

CLARION-2 constitutes the first adequate and well-controlled Phase III trial for purposes of the sNDA and provides the primary evidence of velonatib's efficacy in the psoriasis indication.

D. CLARION-3 (Phase III, Confirmatory — Ongoing)

CLARION-3 is a Phase III, randomized, double-blind, placebo- and active-comparator-controlled study designed to serve as the confirmatory efficacy and safety trial for the sNDA. The study has enrolled 698 patients (target enrollment met) at approximately 138 clinical sites in the United States, Canada, Europe, and Australia.

The study employs a three-arm design: velonatib 10 mg once daily, adalimumab biosimilar (active comparator, administered by subcutaneous injection per the approved adalimumab labeling), and matching placebo. The inclusion of an active comparator arm is consistent with FDA's strong recommendation at the Type B Pre-sNDA meeting, as discussed in Section III above. The adalimumab biosimilar arm provides a clinically relevant reference point for contextualizing velonatib's efficacy relative to an established biologic therapy, while the placebo arm ensures the internal validity of the study.

Consistent with the agreement reached at the Type B Pre-sNDA meeting, the co-primary endpoints for CLARION-3 are PASI-90 at Week 16 and sPGA 0/1 at Week 16. This represents an elevation of the efficacy bar relative to CLARION-2 (which used PASI-75 at Week 16 as a co-primary endpoint) and reflects FDA's expectation that new psoriasis therapies should demonstrate high levels of skin clearance. The key secondary endpoint is PASI-75 at Week 16.

Top-line results from CLARION-3 are expected in Q4 2022. These results will be determinative of the sNDA filing strategy. Both co-primary endpoints must be met for the study to serve as the confirmatory trial. If either co-primary endpoint is not met, the sNDA cannot be filed, and the development strategy will need to be reassessed, as discussed in Section VII below.

The 12-month safety extension of CLARION-3 is also ongoing and is expected to provide critical long-term safety data for the sNDA submission. As noted in Section III.4 above, the team should confirm with CBG that 12-month CLARION-3 safety data will be available in time for the Q1 2023 filing target.

E. Integrated Safety Database

Callendar Baines Group LLC is coordinating the preparation of an integrated safety analysis across all three CLARION studies (CLARION-1, CLARION-2, and CLARION-3). The integrated safety analysis is a critical component of the sNDA and will be central to FDA's benefit-risk assessment of velonatib for the psoriasis indication. Dr. Priya Sundaram, Managing Director, and Dr. Neil Oxborough, Principal Consultant, are leading this effort on behalf of CBG.

The integrated safety database must include 12-month safety data from both Phase III studies (CLARION-2 and CLARION-3), consistent with FDA's request at the Type B meeting and with ICH E1 guidance for chronic-use products. The total psoriasis safety database across the three CLARION studies will include approximately 1,727 patients exposed to velonatib at various dose levels and durations, which is expected to meet or exceed the ICH E1 population exposure thresholds.

Key safety topics that will be addressed in the integrated safety analysis, reflecting both the JAK-inhibitor class profile and FDA's specific guidance, include the following:

• Serious infections: Including herpes zoster, opportunistic infections, and tuberculosis, consistent with the boxed Warning for serious infections.

• Malignancies: Including lymphoma and non-melanoma skin cancer, consistent with the boxed Warning.

• Major adverse cardiovascular events (MACE): Including myocardial infarction, stroke, and cardiovascular death, consistent with the September 2021 class-wide JAK-inhibitor boxed Warning update.

• Thrombosis: Including deep vein thrombosis, pulmonary embolism, and arterial thrombosis, consistent with the September 2021 class-wide JAK-inhibitor boxed Warning update.

• Hepatotoxicity: Including drug-induced liver injury, ALT and AST elevations, and cases meeting Hy's Law criteria, per FDA's specific guidance at the Type B meeting.

The integrated safety analysis will also address laboratory abnormalities (including lipid elevations, neutropenia, lymphopenia, and anemia), gastrointestinal perforations, and any other adverse events of special interest identified during the course of the CLARION program. CBG will prepare the integrated safety summary and individual clinical study reports in accordance with ICH E3 and FDA's current guidance on the format and content of clinical study reports.

V. PROPOSED LABELING STRATEGY

A. General Approach

To enable a rapid finalization of labeling upon receipt of positive CLARION-3 top-line data, we recommend that preparation of draft labeling documents — including the USPI, Patient Package Insert, and Medication Guide — begin immediately and proceed in parallel with the CLARION-3 trial. This parallel development approach will allow the team to address the substantial labeling work required for the sNDA without waiting for CLARION-3 results, thereby minimizing the interval between data availability and sNDA submission. CLARION-3-specific data placeholders will be incorporated into the draft labeling and populated upon receipt of final clinical results.

Labeling development will be a multi-party collaborative effort. C&H will provide legal and regulatory review of all labeling language, with a particular focus on regulatory compliance, consistency with FDA guidance and meeting minutes, and alignment with the statutory labeling requirements under 21 U.S.C. § 352 and 21 C.F.R. Part 201. Penterra Regulatory Affairs, under the direction of Dr. Karen Hessler, SVP of Regulatory Affairs, will lead the overall labeling development process and serve as the primary interface with FDA on labeling matters. Penterra Medical Affairs, under the direction of Dr. Tomás Becerra, will provide clinical and medical review of the labeling language to ensure accuracy and clinical appropriateness. CBG will provide clinical data presentation, including formatting of efficacy and safety tables, figures, and patient demographic summaries for inclusion in the USPI.

In addition, Whitfield & Grange LLP ("W&G"), Penterra's patent and intellectual property counsel, will review the labeling language for consistency with the scope of existing and pending patent claims. Dr. Eleanor Cassidy and Brian Takata of W&G will lead this review. Of particular importance, a provisional patent application for a method-of-treatment claim covering the use of velonatib for psoriasis was filed in August 2022 (U.S. Provisional Application No. 63/XXX,XXX). The labeling language in Sections 1.2 (Indications and Usage — Psoriasis) and 14.2 (Clinical Studies — Psoriasis) of the USPI should be reviewed carefully by W&G to ensure that the language does not inadvertently narrow the scope of the method-of-treatment claims in the provisional application or its anticipated non-provisional counterpart. C&H will coordinate with W&G on this review prior to finalizing the USPI.

B. Key USPI Sections Requiring Modification

The following sections of the existing USPI for velonatib (NDA No. 215-847) will require modification to incorporate the psoriasis indication:

1. Section 1 — Indications and Usage.

A new subsection, Section 1.2 (Chronic Plaque Psoriasis), will be added to the USPI to describe the approved psoriasis indication. The proposed language for Section 1.2 is as follows (subject to revision based on CLARION-3 results and FDA feedback during review):

1.2 Chronic Plaque Psoriasis

VELONATIB is indicated for the treatment of moderate-to-severe chronic plaque psoriasis in adults who are candidates for systemic therapy or phototherapy.

The existing Section 1.1, which describes the approved RA indication, will be maintained unchanged. The overall structure of Section 1 will be reorganized as necessary to accommodate the addition of Section 1.2.

The team should also consider whether a limitation-of-use statement is appropriate for the psoriasis indication. For example, a limitation-of-use statement could specify that velonatib has not been studied in combination with biologic therapies for psoriasis, or that velonatib is not recommended for use in combination with other JAK inhibitors, biologic immunomodulators, or potent immunosuppressants such as cyclosporine. Such limitation-of-use statements are common in JAK-inhibitor labeling and may be expected by FDA. We recommend including a draft limitation-of-use statement in the initial USPI draft for discussion with FDA during the review process.

2. Section 2 — Dosage and Administration.

Section 2 will be updated to include the recommended dosage for the psoriasis indication. Based on the CLARION clinical program data, the recommended dose for chronic plaque psoriasis will be 10 mg once daily, administered orally. This dose differs from the approved RA dose of 5 mg once daily, which reflects the different dose-response relationships observed in the two disease populations (CLARION-1 demonstrated that the 5 mg dose did not achieve statistical significance for PASI-75, while the 10 mg dose showed robust efficacy).

The existing RA dosing information (5 mg once daily) will be maintained unchanged. The dosage and administration section will be organized by indication to clearly delineate the different dosing recommendations for RA and psoriasis.

The team should also address whether dose adjustment recommendations differ for the psoriasis population compared with the RA population, including adjustments for renal impairment, hepatic impairment, drug interactions (particularly with strong CYP3A4 inhibitors), and lymphopenia. To the extent practicable, dose adjustment recommendations should be harmonized across both indications to avoid clinical confusion. If clinical data support different dose adjustment recommendations for the psoriasis population, these differences should be clearly explained in the labeling.

3. Section 5 — Warnings and Precautions.

The most substantive labeling change in Section 5 relates to Section 5.5 (Hepatotoxicity), which will require enhanced hepatotoxicity monitoring language specific to the psoriasis indication, consistent with FDA's Type B meeting guidance. We recommend the following approach:

• Update Section 5.5 to include a recommendation for baseline liver enzyme testing (ALT and AST) prior to initiation of velonatib for the psoriasis indication.

• Include a recommendation for periodic liver enzyme testing at 4 to 8 weeks after initiation of therapy, and then periodically thereafter (e.g., every 3 months or as clinically indicated).

• Include guidance on dose modification or discontinuation in the event of clinically significant liver enzyme elevations (e.g., ALT > 5× ULN, confirmed on repeat testing).

• Coordinate this language with the existing hepatotoxicity language in the RA label to ensure consistency and avoid conflicting recommendations.

The existing boxed Warning for serious infections and malignancies will be maintained as currently approved, consistent with FDA's September 2021 class-wide JAK-inhibitor labeling update. The boxed Warning elements addressing MACE and thrombosis will also be maintained without modification. No changes to Sections 5.1 through 5.4 (Serious Infections, Malignancy and Lymphoproliferative Disorders, Major Adverse Cardiovascular Events, Thrombosis) or Sections 5.6 through 5.11 are anticipated at this time, subject to review of CLARION-3 safety data. If CLARION-3 safety data reveal any new or unexpected safety signals, additional modifications to Section 5 may be required, and we will advise the team accordingly upon receipt of the data.

4. Section 6 — Adverse Reactions.

Section 6 will be updated to include psoriasis-specific adverse reaction data from the CLARION clinical program. The updated section will include:

• A new subsection (e.g., Section 6.1.2 or Section 6.2) presenting adverse reactions observed in clinical trials of velonatib for the psoriasis indication.

• A tabular summary of adverse events occurring at ≥ 2% incidence in velonatib-treated psoriasis patients and at a higher rate than in placebo-treated patients, derived from the pooled CLARION-2 and CLARION-3 double-blind treatment periods.

• A narrative summary of clinically significant adverse events, including serious infections, malignancies, MACE, thromboembolic events, hepatotoxicity, and laboratory abnormalities, specific to the psoriasis population.

• The existing RA adverse reaction data will be preserved in a separate subsection, with clear labeling to delineate the two indication-specific datasets.

Placeholders for CLARION-3 adverse event data will be included in the initial USPI draft and populated upon availability of the CLARION-3 safety data.

5. Section 14 — Clinical Studies.

A new subsection, Section 14.2 (Chronic Plaque Psoriasis), will be added to describe the pivotal and confirmatory efficacy results from CLARION-2 and CLARION-3. This section will include:

• Study design descriptions for CLARION-2 and CLARION-3, including randomization scheme, treatment arms, and study duration.

• Patient demographic and baseline disease characteristic summaries.

• Primary and key secondary endpoint results, presented as proportions with confidence intervals and p-values.

• Response over time figures (e.g., PASI-75 and PASI-90 response rates by study visit).

• Subgroup analyses, as appropriate, by baseline disease severity, prior therapy history, body weight, and other relevant demographic characteristics.

CLARION-3 data placeholders will be incorporated into the initial Section 14.2 draft and populated upon availability of the CLARION-3 efficacy results.

6. Medication Guide.

The existing Medication Guide will be updated to reflect the new psoriasis indication. Key updates will include:

• Addition of a plain-language description of the psoriasis indication, including a brief explanation of what chronic plaque psoriasis is and how velonatib is used to treat it.

• Addition of enhanced hepatotoxicity monitoring language, consistent with the updated USPI Section 5.5, presented in patient-friendly terms (e.g., "Your doctor should do blood tests to check your liver before you start taking VELONATIB for psoriasis and regularly while you take it").

• Review and update of the entire Medication Guide to ensure that all safety information is accurate, current, and consistent with the updated USPI.

C. boxed Warning

The current USPI for velonatib carries a boxed Warning addressing four categories of serious risks: (1) serious infections, including tuberculosis, invasive fungal infections, and opportunistic infections; (2) malignancies, including lymphoma; (3) major adverse cardiovascular events, including myocardial infarction and stroke; and (4) thrombosis, including deep vein thrombosis and pulmonary embolism. This boxed Warning was updated in September 2021 to add the MACE and thrombosis warnings, consistent with FDA's class-wide labeling update for all JAK inhibitors following the completion of the ORAL Surveillance post-marketing safety study for tofacitinib.

The psoriasis label will carry the same boxed Warning. No revisions to the boxed Warning are anticipated at this time, as the risks addressed by the boxed Warning are considered class effects that apply across all JAK-inhibitor indications. However, we will confirm with FDA during the sNDA review process whether any additional boxed Warning elements are required specifically for the psoriasis population. In particular, if CLARION-3 safety data reveal any increase in the rates of MACE, thromboembolic events, or malignancies in the psoriasis population relative to the RA population or the general psoriasis population, FDA may require additional or modified boxed Warning language. We will monitor this issue and advise the team as appropriate.

D. Orange Book and Patent Considerations

Whitfield & Grange LLP has confirmed, based on its review of the existing Orange Book-listed patents for velonatib, that the proposed psoriasis indication does not require new Orange Book patent listings at this time. The existing listed patents are:

• U.S. Patent No. 10,412,XXX (compound patent, covering the velonatib compound itself; expiration date: February 2034)

• U.S. Patent No. 10,891,XXX (formulation patent, covering the oral tablet formulation; expiration date: August 2036)

Both patents are currently listed in the Orange Book in connection with NDA No. 215-847 and will continue to provide patent protection for velonatib regardless of the addition of the psoriasis indication.

As noted above, Penterra filed a provisional patent application in August 2022 (U.S. Provisional Application No. 63/XXX,XXX) for a method-of-treatment claim covering the use of velonatib for the treatment of psoriasis. If a non-provisional patent application is filed and ultimately issues as a patent, the method-of-treatment patent could be listed in the Orange Book in connection with the psoriasis indication. W&G is evaluating the strategy for converting the provisional application to a non-provisional application and will advise on the timing and scope of claims.

It is important that the USPI labeling language — particularly the Indications and Usage (Section 1.2) and Clinical Studies (Section 14.2) sections — be reviewed by W&G prior to finalization to ensure that the language does not inadvertently narrow the scope of the method-of-treatment patent claims. In future Hatch-Waxman Act paragraph IV certification proceedings involving generic challengers, the content of the approved labeling may be relevant to claim construction and infringement analyses. C&H will coordinate with W&G on this review in October 2022, as reflected in the timeline below.

E. Draft Labeling Timeline

The proposed timeline for labeling development is as follows:

• Target first complete draft USPI incorporating the psoriasis indication: September 2022

• Target Rev. 3 for internal review (Penterra, C&H, CBG, W&G): Mid-October 2022

• Target final USPI for sNDA submission: Q1 2023 (contingent on positive CLARION-3 results and incorporation of CLARION-3 data)

This timeline is designed to allow sufficient time for multiple rounds of review and revision, including the W&G patent/labeling review, prior to finalization of the USPI for inclusion in the sNDA submission. The Medication Guide and Patient Package Insert will be developed on a parallel track, with a target draft completion in late October 2022.

VI. TIMELINE AND MILESTONES

The following table sets forth the key milestones and target dates for the sNDA regulatory strategy:

All dates are targets and are subject to adjustment based on the timing of CLARION-3 results, FDA interactions, and other factors. The critical-path item is the receipt of positive CLARION-3 top-line data in Q4 2022. If CLARION-3 results are delayed or negative, the timeline will require substantial revision, as discussed in Section VII below.

VII. RISKS AND CONTINGENCIES

The sNDA strategy is subject to a number of risks and contingencies, which we summarize below along with our assessment and recommended mitigation approaches.

1. CLARION-3 Failure to Meet Co-Primary Endpoints. This is the single most significant risk to the sNDA strategy. If CLARION-3 does not meet both co-primary endpoints — PASI-90 at Week 16 and sPGA 0/1 at Week 16 — the sNDA cannot be filed. FDA was unambiguous at the Type B meeting that both co-primary endpoints must be met in the confirmatory study, and that the sNDA must be supported by two adequate and well-controlled Phase III trials. A failure on either endpoint would render CLARION-3 inadequate as the second pivotal study. In such a scenario, Penterra would need to consider several alternative paths: (a) conducting a redesigned confirmatory study with different co-primary endpoints (subject to further FDA input); (b) evaluating whether the key secondary endpoint (PASI-75 at Week 16) was met and whether a single-study sNDA supported by CLARION-2 alone could be justified under the "exceptional circumstances" provision of Section 505(d); or (c) reassessing the commercial viability of the psoriasis development program in light of the clinical data. We note that option (b) is highly unlikely to succeed given FDA's clear guidance that two adequate and well-controlled trials are required. The probability of this risk materializing cannot be estimated with precision at this time, but the CLARION-2 results (71.5% PASI-75 response rate, 58.3% sPGA 0/1 response rate) and the CLARION-1 dose-response data provide a reasonable basis for optimism regarding CLARION-3 outcomes.

2. FDA Request for Additional Studies or Data. Even if CLARION-3 meets its co-primary endpoints, FDA may request additional safety or efficacy data beyond what the CLARION program provides. This could include requests for longer-term safety follow-up (e.g., 24-month or 36-month safety data), mechanistic studies addressing specific safety concerns (e.g., hepatotoxicity mechanism), or post-marketing commitments for additional studies. While such requests would not necessarily prevent approval, they could add complexity and cost to the regulatory program and may result in post-marketing study requirements or labeling commitments that affect the commercial profile of the product. We recommend proactively preparing a robust integrated safety analysis and safety narrative to address anticipated FDA questions and minimize the likelihood of requests for additional pre-approval data.

3. Evolving JAK-Inhibitor Class Labeling Requirements. FDA's approach to JAK-inhibitor labeling continues to evolve in the wake of the September 2021 class-wide labeling update, which added boxed Warning elements for MACE and thrombosis and imposed a limitation-of-use statement requiring prior biologic failure for certain JAK inhibitors in the RA indication. It is possible that FDA could impose similar or additional labeling restrictions for the psoriasis indication, including: (a) a limitation-of-use statement requiring that velonatib be reserved for patients who have failed or are intolerant to one or more biologic therapies for psoriasis; (b) additional Warnings and Precautions language addressing specific risks in the psoriasis population; or (c) additional boxed Warning elements. Such restrictions could significantly affect the addressable patient population and commercial uptake of velonatib for psoriasis. The team should closely monitor FDA advisory committee proceedings, guidance documents, and labeling actions for other JAK inhibitors in the dermatology therapeutic area to anticipate potential labeling restrictions.

4. Competitive Landscape. The psoriasis therapeutic area is increasingly dominated by biologic therapies with high efficacy. IL-17 inhibitors (e.g., secukinumab, ixekizumab, brodalumab) and IL-23 inhibitors (e.g., guselkumab, risankizumab, tildrakizumab) have demonstrated PASI-90 response rates of 60% to 75% or higher in clinical trials, setting a high efficacy bar for new entrants. FDA's benefit-risk assessment will likely consider velonatib's efficacy relative to available biologic alternatives, even though head-to-head comparison data with IL-17 and IL-23 inhibitors are not available. Velonatib's principal competitive advantage — oral dosing with no injection requirement — is a significant differentiator that may influence both FDA's benefit-risk assessment and commercial positioning. However, if CLARION-3 PASI-90 response rates are substantially lower than those reported for IL-17 and IL-23 inhibitors, FDA may scrutinize the benefit-risk profile more closely and could require additional labeling language contextualizing velonatib's efficacy relative to biologic alternatives.

5. REMS Imposition. Although our preliminary assessment is that a full REMS with Elements to Assure Safe Use is unlikely for the psoriasis indication — given that velonatib is approved for the RA indication without a REMS and the safety profile in the psoriasis population appears consistent with the RA profile — FDA could impose REMS elements that affect the commercial launch strategy and timeline. Potential REMS elements could include a Communication Plan directed to healthcare providers and/or patients, enhanced Medication Guide requirements, or, in a less likely scenario, ETASU elements such as prescriber certification or patient enrollment. Any REMS requirement would add complexity to the commercial launch and could delay market access. C&H's forthcoming REMS assessment memorandum (expected September 2022) will provide a detailed analysis of the likelihood and scope of potential REMS imposition and will recommend an approach for addressing the REMS question in the sNDA submission.

6. Hepatotoxicity signal. If CLARION-3 safety data reveal a higher-than-expected rate of hepatotoxicity events in the psoriasis population — including serious drug-induced liver injury, Grade 3 or Grade 4 ALT/AST elevations, or cases meeting Hy's Law criteria — FDA could require additional monitoring requirements beyond what has been discussed at the Type B meeting, more restrictive labeling language (e.g., contraindication in patients with pre-existing hepatic impairment), or REMS elements specifically addressing hepatotoxicity risk. This risk is considered moderate given the numerical imbalance in ALT elevations observed in CLARION-2 (4.8% velonatib vs. 2.0% placebo) and the known JAK-1 class effect on liver enzymes. The integrated safety analysis, coordinated by CBG, will provide a comprehensive characterization of the hepatotoxicity signal across the CLARION program, which will be essential for addressing this risk in the sNDA submission.

7. Patent and intellectual Property Risks. Although the labeling language is not expected to require new Orange Book patent listings, the content of Sections 1.2 (Indications and Usage — Psoriasis) and 14.2 (Clinical Studies — Psoriasis) of the USPI could be relevant in future Hatch-Waxman Act paragraph IV certification proceedings involving abbreviated new drug applications ("ANDAs") filed by generic challengers. Specifically, the labeling language could be cited by generic applicants or courts in claim construction proceedings to construe the scope of method-of-treatment patent claims. Overly narrow or overly specific labeling language could limit the scope of patent protection or create arguments for non-infringement. Coordination with W&G patent counsel is therefore essential to ensure that the USPI language is consistent with and supportive of the broadest reasonable construction of the pending method-of-treatment patent claims.

VIII. COORDINATION WITH OUTSIDE ADVISORS

The sNDA regulatory strategy involves coordination among several outside advisory firms, each of which plays a distinct role in the overall effort. C&H will serve as lead coordinating counsel for the regulatory submission, with Penterra Regulatory Affairs (Dr. Karen Hessler) serving as the primary client point of contact for all matters relating to the sNDA.

Whitfield & Grange LLP (Dr. Eleanor Cassidy, Partner; Brian Takata, Associate). W&G serves as Penterra's patent and intellectual property counsel and plays a critical role in the sNDA strategy with respect to three issues: (a) review of labeling language for consistency with the scope of existing and pending patent claims, particularly the provisional method-of-treatment patent application filed in August 2022; (b) confirmation that the proposed psoriasis indication does not require new Orange Book patent listings; and (c) ongoing method-of-treatment patent strategy, including the anticipated conversion of the provisional application to a non-provisional application. C&H will coordinate with W&G on labeling language review beginning in October 2022, with a target completion prior to finalization of the USPI.

Callendar Baines Group LLC (Dr. Priya Sundaram, Managing Director; Dr. Neil Oxborough, Principal Consultant). CBG serves as Penterra's clinical development and regulatory affairs consultant and is responsible for several critical elements of the sNDA strategy: (a) clinical trial design consultation and oversight for the CLARION program; (b) preparation for and participation in FDA meetings, including the Type B Pre-sNDA meeting; (c) coordination of the integrated safety data analysis across all three CLARION studies; and (d) assembly and quality review of the sNDA submission in eCTD format. CBG's role is central to the sNDA effort, and close coordination between C&H, CBG, and Penterra Regulatory Affairs will be essential throughout the submission preparation process.

Thornfield Lewis LLP (Richard Croydon, CPA). Thornfield Lewis serves as Penterra's external auditor and tax advisor. The firm's role in the sNDA strategy is limited to the extent that PPC's 10-K and 10-Q disclosures reference the sNDA pipeline, development milestones, or contingent events related to the psoriasis indication. Thornfield Lewis does not have an active role in the sNDA filing itself but should be kept informed of material developments (e.g., CLARION-3 results, sNDA filing, PDUFA goal date) that may affect PPC's financial disclosures and reporting obligations under the Securities Exchange Act of 1934. Any communications with Thornfield Lewis regarding the sNDA should be coordinated through PPC's General Counsel to preserve attorney-client privilege where applicable.

C&H will maintain primary responsibility for the regulatory legal strategy and will coordinate the contributions of all outside advisors to ensure consistency and quality across all elements of the sNDA submission. Regular coordination calls among C&H, Penterra, CBG, and W&G will be scheduled beginning in September 2022 and continuing through the sNDA submission.

IX. RECOMMENDATION

Based on our analysis of the regulatory framework, FDA meeting feedback, clinical data, labeling requirements, and risk factors, C&H recommends the following course of action:

1. Proceed with parallel labeling development. Preparation of draft labeling documents (USPI, Patient Package Insert, and Medication Guide) should begin immediately and proceed in parallel with the ongoing CLARION-3 trial. This parallel-track approach is essential to enable a rapid sNDA filing upon receipt of positive CLARION-3 top-line data and to avoid unnecessary delays in the submission timeline.

2. Prepare first complete draft USPI. A first complete draft USPI incorporating the psoriasis indication should be prepared for internal review by September 2022, with a target of Rev. 3 by mid-October 2022. CLARION-3 data placeholders should be included in the initial draft and populated upon receipt of final results.

3. Prepare Medication Guide update. The Medication Guide update should be prepared on a parallel track, with a target draft completion in late October 2022.

4. Prepare C&H supporting memoranda. C&H will prepare a REMS assessment memorandum and a pediatric deferral analysis memorandum in September 2022. These memoranda will address, respectively, the likelihood and scope of potential REMS imposition and the terms and obligations of the PREA pediatric study deferral.

5. Coordinate with Whitfield & Grange on patent/labeling interface. C&H will coordinate with W&G on the review of USPI labeling language for patent claim scope consistency in October 2022. This review should be completed prior to finalization of the USPI for sNDA submission.

6. Maintain contingency planning. All work described above is contingent on positive CLARION-3 top-line data, which are expected in Q4 2022. If CLARION-3 fails to meet both co-primary endpoints, the sNDA strategy will need to be reassessed in its entirety. C&H will advise the team promptly upon receipt of CLARION-3 results regarding any necessary adjustments to the regulatory strategy.

7. Target Q1 2023 sNDA filing. Assuming positive CLARION-3 results, C&H and CBG stand ready to support a rapid sNDA assembly timeline, with a target filing in Q1 2023 and a projected PDUFA goal date in Q4 2023.

We are available to discuss this memorandum and its recommendations at your convenience. Please do not hesitate to contact Joel Strauss at (212) 558-4120 or joel.strauss@calderwoodharkness.com, or Sean Morrissey at (212) 558-4287 or sean.morrissey@calderwoodharkness.com, with any questions or to schedule a follow-up discussion.

This memorandum is a privileged and confidential attorney-client communication and attorney work product prepared by Calderwood & Harkness LLP for the exclusive use of Penterra Pharmaceuticals Corp. It is not intended for distribution to, or reliance upon by, any third party. The information contained herein is based on facts and circumstances as of the date of this memorandum and may be affected by subsequent developments. This memorandum does not constitute legal advice on any specific matter and should not be relied upon as such without further consultation with counsel.

CALDERWOOD & HARKNESS LLP 1301 Avenue of the Americas, 42nd Floor	New York, NY 10019 T: (212) 558-4000	F: (212) 558-3588 Matter No.: 1018-00005
TO:	Lisa Moritani, Esq., General Counsel & Corporate Secretary, Penterra Pharmaceuticals Corp.

Dr. Karen Hessler, SVP, Regulatory Affairs, Penterra Pharmaceuticals Corp.

FROM:

Sean Morrissey, Associate, Calderwood & Harkness LLP

DATE:	August 12, 2022
RE:	Regulatory Strategy for sNDA — Velonatib (NDA No. 215-847) for Chronic Plaque Psoriasis
Matter No.:	1018-000

CALDERWOOD & HARKNESS LLP 1301 Avenue of the Americas, 42nd Floor New York, New York 10019 Telephone: (212) 558-4000 Facsimile: (212) 558-3588
PRIVILEGED & CONFIDENTIAL — ATTORNEY-CLIENT COMMUNICATION ATTORNEY WORK PRODUCT
MEMORANDUM
I. EXECUTIVE SUMMARY
This memorandum outlines Calderwood & Harkness LLP's ("C&H") recommended regulatory strategy for the preparation and submission of a supplemental New Drug Application ("sNDA") seeking approval of velonatib hydrochloride (VELONATIB®) for the treatment of moderate-to-severe chronic plaque psoriasis in adults who are candidates for systemic therapy or phototherapy. Velonatib hydrochloride is a selective Janus kinase-1 ("JAK-1") inhibitor, available as oral tablets in 5 mg and 10 mg dosage strengths. The drug was originally approved by the U.S. Food and Drug Administration ("FDA") on June 14, 2019, under NDA No. 215-847, for the treatment of moderate-to-severe rheumatoid arthritis ("RA") in adults with an inadequate response or intolerance to one or more disease-modifying antirheumatic drugs ("DMARDs"). NDA No. 215-847 is held by Penterra Pharmaceuticals Corp. ("PPC" or "Penterra").
Our strategy is informed by three principal inputs: (a) the written minutes and informal guidance obtained from the Type B Pre-sNDA meeting held on May 4, 2022 (Meeting ID: FDA-2022-M-1743) with the Division of Dermatology and Dentistry ("DDD"), Office of Immunology and Inflammation, Center for Drug Evaluation and Research ("CDER"); (b) the clinical data generated to date under the CLARION clinical development program, which includes the completed Phase II dose-ranging study (CLARION-1), the completed Phase III pivotal study (CLARION-2), and the ongoing Phase III confirmatory study (CLARION-3); and (c) the applicable statutory and regulatory framework governing supplemental new drug applications under the Federal Food, Drug, and Cosmetic Act ("FD&C Act") and its implementing regulations.
Based on our analysis, we recommend a phased submission strategy targeting a Q1 2023 sNDA filing date, contingent upon receipt of positive top-line results from CLARION-3, which are expected in Q4 2022. Assuming a standard ten-month review timeline under the Prescription Drug User Fee Act ("PDUFA"), this would yield a projected PDUFA goal date in Q4 2023. To maximize the probability of a timely filing and minimize the interval between CLARION-3 data availability and sNDA submission, we recommend that parallel labeling development — including a draft United States Prescribing Information ("USPI"), Patient Package Insert, and Medication Guide — begin immediately, with a target first complete draft USPI by September 2022 and a target Rev. 3 for internal review by mid-October 2022. CLARION-3 data placeholders would be populated upon receipt of final results. This parallel-track approach will enable Penterra to move rapidly to final sNDA assembly if CLARION-3 results are positive.
It is important to note the commercial significance of this regulatory initiative. Velonatib currently generates fiscal year 2022 U.S. net sales of approximately $1.47 billion, representing approximately 67.4% of PPC's $2.18 billion total revenue. PPC's current market capitalization is approximately $6.3 billion. The psoriasis indication represents a significant commercial expansion opportunity for Penterra's flagship asset, potentially broadening velonatib's addressable patient population substantially. The moderate-to-severe chronic plaque psoriasis population in the United States is estimated at approximately 3.6 million adults, with a growing proportion of patients seeking oral systemic therapies as alternatives to injectable biologics. Accordingly, the regulatory strategy for this sNDA warrants careful and comprehensive planning.
This memorandum addresses the regulatory framework, key takeaways from the FDA Type B Pre-sNDA meeting, the clinical data supporting the sNDA, the proposed labeling strategy, the timeline and key milestones, risks and contingencies, and coordination with outside advisors. Separate C&H memoranda addressing (i) the REMS assessment and (ii) PREA pediatric deferral obligations are forthcoming and are expected in September 2022.
II. REGULATORY FRAMEWORK
A. Statutory and Regulatory Basis
The sNDA for the psoriasis indication will be submitted under Section 505(b) of the Federal Food, Drug, and Cosmetic Act, 21 U.S.C. § 355(b). Because velonatib is already approved under NDA No. 215-847, the submission will take the form of a supplemental application to the existing NDA rather than a new stand-alone application. This approach is both procedurally required and strategically advantageous, as it preserves the existing RA labeling while adding the new psoriasis indication to the approved product labeling.
The sNDA will be classified as an Efficacy Supplement — Type 10 (new indication) under 21 C.F.R. § 314.70(b). Under this regulation, the addition of a new therapeutic indication constitutes a "major change" to approved labeling that may not be placed into distribution until the supplement has been approved by FDA. Accordingly, a prior-approval supplement — rather than a "changes being effected" (CBE-0 or CBE-30) supplement — is required. This classification is consistent with FDA's guidance in "Guidance for Industry: Changes to an Approved NDA or ANDA" (April 2004, as revised), which identifies the addition of a new indication as a change requiring prior approval.
The sNDA filing will be submitted in electronic Common Technical Document ("eCTD") format in accordance with FDA's current technical specifications for electronic submissions. The submission will include, at a minimum, updated Modules 1 (administrative information and prescribing information), 2 (overviews and summaries, including a clinical overview and clinical summary), and 5 (clinical study reports) of the CTD. Module 3 (quality) updates are not expected to be required, as the drug substance and drug product specifications remain unchanged from the approved RA indication. Module 4 (nonclinical study reports) may require limited updates if any new nonclinical studies have been conducted to support the psoriasis indication, but this is not anticipated at present.
B. PDUFA Review Timeline
Under the Prescription Drug User Fee Act, as most recently reauthorized by PDUFA VII (effective October 1, 2022), the standard review clock for an efficacy supplement is ten months from the filing date. For purposes of timeline planning, we assume a Q1 2023 filing date — specifically, a target submission in February or March 2023 — which would yield a projected PDUFA goal date in Q4 2023, likely November or December 2023.
It is important to note that the PDUFA review clock does not begin on the date of submission but rather on the date FDA "files" the application, which occurs after a preliminary completeness review. FDA may issue a refuse-to-file ("RTF") letter within 60 days of receipt of the sNDA if the submission is determined to be incomplete or otherwise insufficient for filing. An RTF determination would delay the review timeline by at least several months and could require substantial reworking of the submission. To mitigate this risk, we recommend that the team prepare a comprehensive pre-submission readiness checklist, modeled on FDA's "Guidance for Industry: Refuse to File" checklist, to verify the completeness and quality of all sNDA components prior to submission. C&H and Callendar Baines Group LLC ("CBG") will collaborate on the development and execution of this checklist.
We also note that Penterra may, in appropriate circumstances, request Priority Review designation for the sNDA, which would shorten the review timeline to six months. However, Priority Review is reserved for applications for products that treat serious conditions and, if approved, would provide a significant improvement in safety or effectiveness. Given that the psoriasis indication, while important, involves a therapeutic area with multiple approved systemic therapies — including biologic agents with high PASI-90 response rates — we do not believe that Priority Review designation is likely to be granted in this instance. We do not recommend pursuing a Priority Review request at this time, but we will reassess if CLARION-3 results demonstrate a particularly compelling efficacy or safety profile that could support such a request.
C. Coordination with Existing NDA
Because the sNDA supplements the existing NDA No. 215-847, the resulting approved labeling must be internally consistent across both the RA and psoriasis indications. This coordination requirement applies to all sections of the USPI but is most critical with respect to the following:
First, the boxed Warning (currently addressing serious infections, malignancies, major adverse cardiovascular events ("MACE"), and thrombosis, consistent with FDA's September 2021 class-wide JAK-inhibitor labeling update) must be consistent across both indications. Any modification to the boxed Warning for the psoriasis indication — which we do not anticipate at this time — would necessarily apply to the RA indication as well.
Second, the Warnings and Precautions section (Section 5 of the USPI) must harmonize any psoriasis-specific safety language with the existing RA-specific language. As discussed in Section V.B.3 below, FDA's Type B meeting feedback calls for enhanced hepatotoxicity monitoring language specific to the psoriasis population, which must be drafted in a manner that is consistent with — and does not create confusion relative to — the existing hepatotoxicity language applicable to the RA indication.
Third, the Adverse Reactions section (Section 6 of the USPI) will need to present psoriasis-specific adverse event data in a manner that is clearly delineated from the existing RA adverse event data, while maintaining a unified and coherent presentation across the full label.
Fourth, any changes to safety-related labeling sections that result from the CLARION safety data — even if those changes relate primarily to the psoriasis population — may have implications for the RA labeling and should be evaluated accordingly.
The Penterra Regulatory Affairs team, under Dr. Hessler's direction, will serve as the central coordination point for ensuring labeling consistency across both indications. C&H will provide legal and regulatory review of all labeling language to confirm consistency and compliance with applicable FDA requirements.
III. FDA MEETING FEEDBACK — KEY TAKEAWAYS FROM TYPE B PRE-sNDA MEETING
On May 4, 2022, representatives of Penterra Pharmaceuticals Corp., Calderwood & Harkness LLP, and Callendar Baines Group LLC participated in a Type B Pre-NDA/BLA Meeting with the Division of Dermatology and Dentistry, Office of Immunology and Inflammation, CDER (Meeting ID: FDA-2022-M-1743). The meeting was conducted by teleconference, consistent with FDA's prevailing meeting format. The purpose of the meeting was to discuss the regulatory requirements and clinical data expectations for the planned sNDA submission for the velonatib psoriasis indication.
The meeting was productive and yielded substantive guidance from FDA on several critical issues. The written minutes of the meeting, received by Penterra on June 2, 2022, have been reviewed by C&H and are reflected in the analysis below. We summarize the key points of FDA feedback as follows:
1. Two Adequate and Well-Controlled Trials Required. FDA confirmed that two Phase III, adequate and well-controlled clinical trials demonstrating efficacy will be expected to support the sNDA submission for the psoriasis indication. This is consistent with the standard evidentiary requirement under Section 505(d) of the FD&C Act for new efficacy claims, as well as with FDA's longstanding practice in the dermatology therapeutic area. CLARION-2, completed in April 2022, constitutes the first pivotal trial. CLARION-3, currently ongoing, is designed as the confirmatory study. FDA did not indicate that a single pivotal trial, even with highly persuasive results, would be sufficient to support the sNDA. Accordingly, successful completion of CLARION-3 is an absolute prerequisite for filing.
2. Active Comparator Arm. FDA strongly recommended the inclusion of an active comparator arm in at least one of the Phase III studies, in order to contextualize velonatib's efficacy within the current psoriasis competitive landscape, which is increasingly dominated by biologic therapies — particularly interleukin-17 ("IL-17") inhibitors and interleukin-23 ("IL-23") inhibitors — that have set a high efficacy bar in terms of PASI-90 and PASI-100 response rates. While FDA did not characterize the active comparator arm as a formal regulatory requirement, the recommendation was made with sufficient emphasis that compliance is advisable both for regulatory purposes and for the benefit-risk assessment that FDA will conduct during review. CLARION-3 includes an adalimumab biosimilar arm as an active comparator, which satisfies this recommendation. We note that the selection of adalimumab — a TNF-alpha inhibitor — rather than an IL-17 or IL-23 inhibitor as the active comparator was discussed at the Type B meeting. FDA did not object to the use of adalimumab, recognizing that it remains a widely prescribed comparator in dermatology clinical trials, although FDA noted that the prescribing community may place greater weight on comparisons with newer biologic agents. The inclusion of the adalimumab arm provides a meaningful reference point while avoiding the complexities of a head-to-head comparison with a product that may have a higher absolute response rate.
3. Co-Primary Endpoints for CLARION-3. FDA stated that the co-primary endpoints of PASI-75 at Week 16 and static Physician Global Assessment ("sPGA") 0/1 at Week 16 were acceptable endpoints for the psoriasis indication, consistent with FDA's Draft Guidance for Industry: "Psoriasis: Developing Drugs for Treatment" (September 2020). However, FDA also expressed a clear preference for the inclusion of PASI-90 at Week 16 as a co-primary endpoint in the confirmatory study (CLARION-3), citing evolving standards in the psoriasis therapeutic area and the higher efficacy bar established by newer biologic therapies. FDA's rationale was that PASI-75, while historically the standard primary endpoint in psoriasis trials, may no longer adequately differentiate new therapies from established treatments in the current treatment landscape, and that PASI-90 more closely approximates the level of skin clearance that patients and prescribers now expect from a psoriasis therapy.
Penterra agreed during the meeting to designate PASI-90 at Week 16 and sPGA 0/1 at Week 16 as co-primary endpoints for CLARION-3, with PASI-75 at Week 16 reclassified as a key secondary endpoint. This agreement was reflected in the written meeting minutes. It is critical to note that both co-primary endpoints must be met in CLARION-3 to support filing of the sNDA. Failure to achieve statistical significance on either co-primary endpoint would render the confirmatory study inadequate for regulatory purposes and would preclude filing.
4. 12-Month Safety Database. FDA requested that 12-month safety data from both Phase III studies (CLARION-2 and CLARION-3) be included in the sNDA submission. This request is consistent with the International Council for Harmonisation ("ICH") E1 Guideline, "The Extent of Population Exposure to Assess Clinical Safety for Drugs Intended for Long-Term Treatment of Non-Life-Threatening Conditions," which recommends that for chronic-use products, the safety database include at least 100 patients exposed for a minimum of 12 months and a total safety database of at least 1,500 patients. Because psoriasis is a chronic condition requiring long-term treatment, FDA's request for 12-month safety data is expected and appropriate.
Both CLARION-2 and CLARION-3 include 12-month open-label safety extension periods. The CLARION-2 extension is currently underway, with 12-month data expected to be available in time for sNDA submission. The CLARION-3 extension timeline is dependent on the CLARION-3 enrollment and randomization schedule, and the team should confirm with CBG that 12-month CLARION-3 safety data will be available in time for the Q1 2023 filing target. If 12-month CLARION-3 safety data are not available by the filing date, Penterra may need to submit the data as a post-filing amendment, which could complicate the review process and potentially delay the PDUFA goal date. We will monitor this issue closely and advise accordingly.
5. Hepatotoxicity Monitoring. FDA flagged the need for enhanced hepatotoxicity monitoring language in the proposed labeling for the psoriasis indication, given known JAK-1 class effects on liver enzymes. Specifically, FDA recommended that the USPI Warnings and Precautions section (Section 5) include language recommending baseline and periodic liver enzyme testing (alanine aminotransferase, or ALT, and aspartate aminotransferase, or AST) for patients receiving velonatib for the psoriasis indication. FDA suggested a testing frequency of baseline, followed by testing at 4 to 8 weeks after initiation of therapy, and then periodically thereafter. This recommendation is consistent with the hepatotoxicity monitoring language included in the approved labeling for certain other JAK inhibitors in the dermatology space, including the approved labeling for upadacitinib in atopic dermatitis.
FDA's focus on hepatotoxicity reflects the general class-level concern regarding JAK inhibitors and liver injury, as well as specific observations from the CLARION clinical program. While no clinically significant hepatotoxicity signal has been identified in the CLARION data to date, elevated liver enzymes (Grade 1 and Grade 2 ALT elevations) were observed at a numerically higher rate in velonatib-treated patients than in placebo-treated patients in CLARION-2. The enhanced monitoring language is therefore a precautionary measure that will need to be carefully drafted to balance appropriate safety communication with avoidance of unduly restrictive language that could hinder commercial uptake. Coordination between the psoriasis-specific hepatotoxicity language and the existing RA label language on hepatotoxicity will be necessary to ensure internal consistency within the USPI.
6. REMS Assessment. FDA indicated during the Type B meeting that it would conduct a Risk Evaluation and Mitigation Strategy ("REMS") assessment in connection with the sNDA review for the psoriasis indication. FDA noted that the current NDA for velonatib does not include a REMS for the RA indication, but that the addition of a new indication — particularly in a therapeutic area with a potentially broader patient population — warrants a fresh assessment of whether a REMS is necessary to ensure that the benefits of velonatib outweigh its risks. FDA requested that Penterra address the potential need for a REMS in the sNDA submission, including an analysis of whether existing labeling elements (including the boxed Warning and Medication Guide) are sufficient to manage the known risks of velonatib, or whether additional REMS elements (such as a Communication Plan, Elements to Assure Safe Use ("ETASU"), or an Implementation System) may be warranted.
C&H will prepare a separate memorandum analyzing the REMS issue in detail, including an assessment of the likelihood and potential scope of REMS imposition and a recommended approach for addressing the REMS question in the sNDA submission. This memorandum is expected in September 2022.
7. Pediatric Written Request. FDA issued a Written Request under the Pediatric Research Equity Act ("PREA") for pediatric studies of velonatib in psoriasis patients ages 12 to 17. The Written Request contemplates a pharmacokinetic and efficacy study in adolescent patients with moderate-to-severe chronic plaque psoriasis. Penterra has requested and obtained a deferral of the pediatric study obligation until 18 months after approval of the adult psoriasis indication, which is consistent with FDA's standard practice for pediatric deferrals under PREA. The terms of the deferral, including required pediatric study milestones and reporting obligations, will be addressed in a separate C&H memorandum expected in September 2022.
IV. CLINICAL DATA OVERVIEW
A. Summary Table
The following table summarizes the clinical studies comprising the CLARION development program for velonatib in chronic plaque psoriasis:
B. CLARION-1 (Phase II)
CLARION-1 was a Phase II, randomized, double-blind, placebo-controlled, dose-ranging study designed to evaluate the efficacy, safety, and tolerability of velonatib hydrochloride at two dose levels (5 mg and 10 mg once daily) compared with placebo in adults with moderate-to-severe chronic plaque psoriasis. The study enrolled 287 patients at approximately 48 clinical sites in the United States and Canada.
Patients were randomized in a 1:1:1 ratio to receive velonatib 5 mg once daily, velonatib 10 mg once daily, or matching placebo for a 12-week double-blind treatment period, followed by an optional 40-week open-label extension period. The primary efficacy endpoint was the proportion of patients achieving PASI-75 (i.e., at least a 75% reduction from baseline in the Psoriasis Area and Severity Index) at Week 12.
The 10 mg dose met the primary endpoint with a statistically significant and clinically meaningful treatment effect: 68.2% of patients in the velonatib 10 mg group achieved PASI-75 at Week 12, compared with 12.4% of patients in the placebo group (p < 0.001). The 5 mg dose did not reach statistical significance for PASI-75 at Week 12, with a response rate of approximately 34.7% (p = 0.07 vs. placebo). These results supported the selection of 10 mg once daily as the dose for Phase III development, as the 10 mg dose demonstrated a substantially higher response rate than the 5 mg dose without a meaningfully different safety profile.
The safety profile observed in CLARION-1 was consistent with the known velonatib safety data from the approved RA indication. The most common adverse events in the velonatib 10 mg group were upper respiratory tract infections, nasopharyngitis, headache, and nausea. No serious infections, malignancies, MACE events, or thromboembolic events were observed during the 12-week double-blind treatment period, although the study was not powered to detect differences in these low-frequency safety events.
The principal role of CLARION-1 in the sNDA will be as dose-selection justification and as supportive efficacy and safety data. CLARION-1 is not designated as a pivotal study and, standing alone, would not be sufficient to support the sNDA.
C. CLARION-2 (Phase III, Pivotal No. 1)
CLARION-2 was a Phase III, randomized, double-blind, placebo-controlled study designed to evaluate the efficacy and safety of velonatib 10 mg once daily compared with placebo in adults with moderate-to-severe chronic plaque psoriasis who are candidates for systemic therapy or phototherapy. The study enrolled 742 patients at approximately 126 clinical sites in the United States, Canada, and Europe.
Patients were randomized in a 2:1 ratio to receive velonatib 10 mg once daily or matching placebo for a 16-week double-blind treatment period, followed by a 36-week open-label extension period in which all patients received velonatib 10 mg once daily. Key eligibility criteria included: age 18 years or older; a diagnosis of chronic plaque psoriasis for at least 6 months prior to screening; moderate-to-severe disease severity defined as body surface area ("BSA") involvement of at least 10%, a PASI score of at least 12, and an sPGA score of at least 3 (moderate); and candidacy for systemic therapy or phototherapy. Patients with prior exposure to more than two biologic therapies for psoriasis were excluded, consistent with the design of a broad-population study.
The study met both co-primary endpoints with robust statistical significance:
• PASI-75 at Week 16: 71.5% of patients in the velonatib group achieved PASI-75 at Week 16, compared with 9.1% of patients in the placebo group (p < 0.001). The treatment difference of 62.4 percentage points was both statistically significant and clinically meaningful.
• sPGA 0/1 at Week 16: 58.3% of patients in the velonatib group achieved an sPGA score of 0 (clear) or 1 (almost clear) at Week 16, compared with 5.7% of patients in the placebo group (p < 0.001). The treatment difference of 52.6 percentage points was both statistically significant and clinically meaningful.
Key secondary endpoints also demonstrated statistically significant improvements in the velonatib group compared with placebo, including PASI-90 at Week 16, Dermatology Life Quality Index ("DLQI") response, and itch numerical rating scale ("NRS") reduction.
The safety profile observed in CLARION-2 was generally consistent with the known velonatib safety data from the approved RA indication. No new safety signals were identified during the 16-week double-blind treatment period. The most common adverse events (≥ 5% incidence) in the velonatib group were nasopharyngitis (8.1%), upper respiratory tract infection (6.7%), headache (5.9%), and nausea (5.2%). Serious adverse events were observed in 3.4% of velonatib-treated patients and 2.8% of placebo-treated patients. There were no cases of active tuberculosis, opportunistic infections, or gastrointestinal perforation. Grade 1 and Grade 2 ALT elevations were observed at a numerically higher rate in the velonatib group (4.8%) than in the placebo group (2.0%); no Grade 3 or Grade 4 ALT elevations were reported. One venous thromboembolic event (deep vein thrombosis) was observed in the velonatib group; the event occurred in a patient with pre-existing risk factors and was considered possibly related to study drug. No MACE events were reported during the double-blind period.
The 12-month safety extension of CLARION-2 is ongoing, and data from this extension are expected to be available in time for inclusion in the sNDA submission, consistent with FDA's 12-month safety data request.
CLARION-2 constitutes the first adequate and well-controlled Phase III trial for purposes of the sNDA and provides the primary evidence of velonatib's efficacy in the psoriasis indication.
D. CLARION-3 (Phase III, Confirmatory — Ongoing)
CLARION-3 is a Phase III, randomized, double-blind, placebo- and active-comparator-controlled study designed to serve as the confirmatory efficacy and safety trial for the sNDA. The study has enrolled 698 patients (target enrollment met) at approximately 138 clinical sites in the United States, Canada, Europe, and Australia.
The study employs a three-arm design: velonatib 10 mg once daily, adalimumab biosimilar (active comparator, administered by subcutaneous injection per the approved adalimumab labeling), and matching placebo. The inclusion of an active comparator arm is consistent with FDA's strong recommendation at the Type B Pre-sNDA meeting, as discussed in Section III above. The adalimumab biosimilar arm provides a clinically relevant reference point for contextualizing velonatib's efficacy relative to an established biologic therapy, while the placebo arm ensures the internal validity of the study.
Consistent with the agreement reached at the Type B Pre-sNDA meeting, the co-primary endpoints for CLARION-3 are PASI-90 at Week 16 and sPGA 0/1 at Week 16. This represents an elevation of the efficacy bar relative to CLARION-2 (which used PASI-75 at Week 16 as a co-primary endpoint) and reflects FDA's expectation that new psoriasis therapies should demonstrate high levels of skin clearance. The key secondary endpoint is PASI-75 at Week 16.
Top-line results from CLARION-3 are expected in Q4 2022. These results will be determinative of the sNDA filing strategy. Both co-primary endpoints must be met for the study to serve as the confirmatory trial. If either co-primary endpoint is not met, the sNDA cannot be filed, and the development strategy will need to be reassessed, as discussed in Section VII below.
The 12-month safety extension of CLARION-3 is also ongoing and is expected to provide critical long-term safety data for the sNDA submission. As noted in Section III.4 above, the team should confirm with CBG that 12-month CLARION-3 safety data will be available in time for the Q1 2023 filing target.
E. Integrated Safety Database
Callendar Baines Group LLC is coordinating the preparation of an integrated safety analysis across all three CLARION studies (CLARION-1, CLARION-2, and CLARION-3). The integrated safety analysis is a critical component of the sNDA and will be central to FDA's benefit-risk assessment of velonatib for the psoriasis indication. Dr. Priya Sundaram, Managing Director, and Dr. Neil Oxborough, Principal Consultant, are leading this effort on behalf of CBG.
The integrated safety database must include 12-month safety data from both Phase III studies (CLARION-2 and CLARION-3), consistent with FDA's request at the Type B meeting and with ICH E1 guidance for chronic-use products. The total psoriasis safety database across the three CLARION studies will include approximately 1,727 patients exposed to velonatib at various dose levels and durations, which is expected to meet or exceed the ICH E1 population exposure thresholds.
Key safety topics that will be addressed in the integrated safety analysis, reflecting both the JAK-inhibitor class profile and FDA's specific guidance, include the following:
• Serious infections: Including herpes zoster, opportunistic infections, and tuberculosis, consistent with the boxed Warning for serious infections.
• Malignancies: Including lymphoma and non-melanoma skin cancer, consistent with the boxed Warning.
• Major adverse cardiovascular events (MACE): Including myocardial infarction, stroke, and cardiovascular death, consistent with the September 2021 class-wide JAK-inhibitor boxed Warning update.
• Thrombosis: Including deep vein thrombosis, pulmonary embolism, and arterial thrombosis, consistent with the September 2021 class-wide JAK-inhibitor boxed Warning update.
• Hepatotoxicity: Including drug-induced liver injury, ALT and AST elevations, and cases meeting Hy's Law criteria, per FDA's specific guidance at the Type B meeting.
The integrated safety analysis will also address laboratory abnormalities (including lipid elevations, neutropenia, lymphopenia, and anemia), gastrointestinal perforations, and any other adverse events of special interest identified during the course of the CLARION program. CBG will prepare the integrated safety summary and individual clinical study reports in accordance with ICH E3 and FDA's current guidance on the format and content of clinical study reports.
V. PROPOSED LABELING STRATEGY
A. General Approach
To enable a rapid finalization of labeling upon receipt of positive CLARION-3 top-line data, we recommend that preparation of draft labeling documents — including the USPI, Patient Package Insert, and Medication Guide — begin immediately and proceed in parallel with the CLARION-3 trial. This parallel development approach will allow the team to address the substantial labeling work required for the sNDA without waiting for CLARION-3 results, thereby minimizing the interval between data availability and sNDA submission. CLARION-3-specific data placeholders will be incorporated into the draft labeling and populated upon receipt of final clinical results.
Labeling development will be a multi-party collaborative effort. C&H will provide legal and regulatory review of all labeling language, with a particular focus on regulatory compliance, consistency with FDA guidance and meeting minutes, and alignment with the statutory labeling requirements under 21 U.S.C. § 352 and 21 C.F.R. Part 201. Penterra Regulatory Affairs, under the direction of Dr. Karen Hessler, SVP of Regulatory Affairs, will lead the overall labeling development process and serve as the primary interface with FDA on labeling matters. Penterra Medical Affairs, under the direction of Dr. Tomás Becerra, will provide clinical and medical review of the labeling language to ensure accuracy and clinical appropriateness. CBG will provide clinical data presentation, including formatting of efficacy and safety tables, figures, and patient demographic summaries for inclusion in the USPI.
In addition, Whitfield & Grange LLP ("W&G"), Penterra's patent and intellectual property counsel, will review the labeling language for consistency with the scope of existing and pending patent claims. Dr. Eleanor Cassidy and Brian Takata of W&G will lead this review. Of particular importance, a provisional patent application for a method-of-treatment claim covering the use of velonatib for psoriasis was filed in August 2022 (U.S. Provisional Application No. 63/XXX,XXX). The labeling language in Sections 1.2 (Indications and Usage — Psoriasis) and 14.2 (Clinical Studies — Psoriasis) of the USPI should be reviewed carefully by W&G to ensure that the language does not inadvertently narrow the scope of the method-of-treatment claims in the provisional application or its anticipated non-provisional counterpart. C&H will coordinate with W&G on this review prior to finalizing the USPI.
B. Key USPI Sections Requiring Modification
The following sections of the existing USPI for velonatib (NDA No. 215-847) will require modification to incorporate the psoriasis indication:
1. Section 1 — Indications and Usage.
A new subsection, Section 1.2 (Chronic Plaque Psoriasis), will be added to the USPI to describe the approved psoriasis indication. The proposed language for Section 1.2 is as follows (subject to revision based on CLARION-3 results and FDA feedback during review):
1.2 Chronic Plaque Psoriasis
VELONATIB is indicated for the treatment of moderate-to-severe chronic plaque psoriasis in adults who are candidates for systemic therapy or phototherapy.
The existing Section 1.1, which describes the approved RA indication, will be maintained unchanged. The overall structure of Section 1 will be reorganized as necessary to accommodate the addition of Section 1.2.
The team should also consider whether a limitation-of-use statement is appropriate for the psoriasis indication. For example, a limitation-of-use statement could specify that velonatib has not been studied in combination with biologic therapies for psoriasis, or that velonatib is not recommended for use in combination with other JAK inhibitors, biologic immunomodulators, or potent immunosuppressants such as cyclosporine. Such limitation-of-use statements are common in JAK-inhibitor labeling and may be expected by FDA. We recommend including a draft limitation-of-use statement in the initial USPI draft for discussion with FDA during the review process.
2. Section 2 — Dosage and Administration.
Section 2 will be updated to include the recommended dosage for the psoriasis indication. Based on the CLARION clinical program data, the recommended dose for chronic plaque psoriasis will be 10 mg once daily, administered orally. This dose differs from the approved RA dose of 5 mg once daily, which reflects the different dose-response relationships observed in the two disease populations (CLARION-1 demonstrated that the 5 mg dose did not achieve statistical significance for PASI-75, while the 10 mg dose showed robust efficacy).
The existing RA dosing information (5 mg once daily) will be maintained unchanged. The dosage and administration section will be organized by indication to clearly delineate the different dosing recommendations for RA and psoriasis.
The team should also address whether dose adjustment recommendations differ for the psoriasis population compared with the RA population, including adjustments for renal impairment, hepatic impairment, drug interactions (particularly with strong CYP3A4 inhibitors), and lymphopenia. To the extent practicable, dose adjustment recommendations should be harmonized across both indications to avoid clinical confusion. If clinical data support different dose adjustment recommendations for the psoriasis population, these differences should be clearly explained in the labeling.
3. Section 5 — Warnings and Precautions.
The most substantive labeling change in Section 5 relates to Section 5.5 (Hepatotoxicity), which will require enhanced hepatotoxicity monitoring language specific to the psoriasis indication, consistent with FDA's Type B meeting guidance. We recommend the following approach:
• Update Section 5.5 to include a recommendation for baseline liver enzyme testing (ALT and AST) prior to initiation of velonatib for the psoriasis indication.
• Include a recommendation for periodic liver enzyme testing at 4 to 8 weeks after initiation of therapy, and then periodically thereafter (e.g., every 3 months or as clinically indicated).
• Include guidance on dose modification or discontinuation in the event of clinically significant liver enzyme elevations (e.g., ALT > 5× ULN, confirmed on repeat testing).
• Coordinate this language with the existing hepatotoxicity language in the RA label to ensure consistency and avoid conflicting recommendations.
The existing boxed Warning for serious infections and malignancies will be maintained as currently approved, consistent with FDA's September 2021 class-wide JAK-inhibitor labeling update. The boxed Warning elements addressing MACE and thrombosis will also be maintained without modification. No changes to Sections 5.1 through 5.4 (Serious Infections, Malignancy and Lymphoproliferative Disorders, Major Adverse Cardiovascular Events, Thrombosis) or Sections 5.6 through 5.11 are anticipated at this time, subject to review of CLARION-3 safety data. If CLARION-3 safety data reveal any new or unexpected safety signals, additional modifications to Section 5 may be required, and we will advise the team accordingly upon receipt of the data.
4. Section 6 — Adverse Reactions.
Section 6 will be updated to include psoriasis-specific adverse reaction data from the CLARION clinical program. The updated section will include:
• A new subsection (e.g., Section 6.1.2 or Section 6.2) presenting adverse reactions observed in clinical trials of velonatib for the psoriasis indication.
• A tabular summary of adverse events occurring at ≥ 2% incidence in velonatib-treated psoriasis patients and at a higher rate than in placebo-treated patients, derived from the pooled CLARION-2 and CLARION-3 double-blind treatment periods.
• A narrative summary of clinically significant adverse events, including serious infections, malignancies, MACE, thromboembolic events, hepatotoxicity, and laboratory abnormalities, specific to the psoriasis population.
• The existing RA adverse reaction data will be preserved in a separate subsection, with clear labeling to delineate the two indication-specific datasets.
Placeholders for CLARION-3 adverse event data will be included in the initial USPI draft and populated upon availability of the CLARION-3 safety data.
5. Section 14 — Clinical Studies.
A new subsection, Section 14.2 (Chronic Plaque Psoriasis), will be added to describe the pivotal and confirmatory efficacy results from CLARION-2 and CLARION-3. This section will include:
• Study design descriptions for CLARION-2 and CLARION-3, including randomization scheme, treatment arms, and study duration.
• Patient demographic and baseline disease characteristic summaries.
• Primary and key secondary endpoint results, presented as proportions with confidence intervals and p-values.
• Response over time figures (e.g., PASI-75 and PASI-90 response rates by study visit).
• Subgroup analyses, as appropriate, by baseline disease severity, prior therapy history, body weight, and other relevant demographic characteristics.
CLARION-3 data placeholders will be incorporated into the initial Section 14.2 draft and populated upon availability of the CLARION-3 efficacy results.
6. Medication Guide.
The existing Medication Guide will be updated to reflect the new psoriasis indication. Key updates will include:
• Addition of a plain-language description of the psoriasis indication, including a brief explanation of what chronic plaque psoriasis is and how velonatib is used to treat it.
• Addition of enhanced hepatotoxicity monitoring language, consistent with the updated USPI Section 5.5, presented in patient-friendly terms (e.g., "Your doctor should do blood tests to check your liver before you start taking VELONATIB for psoriasis and regularly while you take it").
• Review and update of the entire Medication Guide to ensure that all safety information is accurate, current, and consistent with the updated USPI.
C. boxed Warning
The current USPI for velonatib carries a boxed Warning addressing four categories of serious risks: (1) serious infections, including tuberculosis, invasive fungal infections, and opportunistic infections; (2) malignancies, including lymphoma; (3) major adverse cardiovascular events, including myocardial infarction and stroke; and (4) thrombosis, including deep vein thrombosis and pulmonary embolism. This boxed Warning was updated in September 2021 to add the MACE and thrombosis warnings, consistent with FDA's class-wide labeling update for all JAK inhibitors following the completion of the ORAL Surveillance post-marketing safety study for tofacitinib.
The psoriasis label will carry the same boxed Warning. No revisions to the boxed Warning are anticipated at this time, as the risks addressed by the boxed Warning are considered class effects that apply across all JAK-inhibitor indications. However, we will confirm with FDA during the sNDA review process whether any additional boxed Warning elements are required specifically for the psoriasis population. In particular, if CLARION-3 safety data reveal any increase in the rates of MACE, thromboembolic events, or malignancies in the psoriasis population relative to the RA population or the general psoriasis population, FDA may require additional or modified boxed Warning language. We will monitor this issue and advise the team as appropriate.
D. Orange Book and Patent Considerations
Whitfield & Grange LLP has confirmed, based on its review of the existing Orange Book-listed patents for velonatib, that the proposed psoriasis indication does not require new Orange Book patent listings at this time. The existing listed patents are:
• U.S. Patent No. 10,412,XXX (compound patent, covering the velonatib compound itself; expiration date: February 2034)
• U.S. Patent No. 10,891,XXX (formulation patent, covering the oral tablet formulation; expiration date: August 2036)
Both patents are currently listed in the Orange Book in connection with NDA No. 215-847 and will continue to provide patent protection for velonatib regardless of the addition of the psoriasis indication.
As noted above, Penterra filed a provisional patent application in August 2022 (U.S. Provisional Application No. 63/XXX,XXX) for a method-of-treatment claim covering the use of velonatib for the treatment of psoriasis. If a non-provisional patent application is filed and ultimately issues as a patent, the method-of-treatment patent could be listed in the Orange Book in connection with the psoriasis indication. W&G is evaluating the strategy for converting the provisional application to a non-provisional application and will advise on the timing and scope of claims.
It is important that the USPI labeling language — particularly the Indications and Usage (Section 1.2) and Clinical Studies (Section 14.2) sections — be reviewed by W&G prior to finalization to ensure that the language does not inadvertently narrow the scope of the method-of-treatment patent claims. In future Hatch-Waxman Act paragraph IV certification proceedings involving generic challengers, the content of the approved labeling may be relevant to claim construction and infringement analyses. C&H will coordinate with W&G on this review in October 2022, as reflected in the timeline below.
E. Draft Labeling Timeline
The proposed timeline for labeling development is as follows:
• Target first complete draft USPI incorporating the psoriasis indication: September 2022
• Target Rev. 3 for internal review (Penterra, C&H, CBG, W&G): Mid-October 2022
• Target final USPI for sNDA submission: Q1 2023 (contingent on positive CLARION-3 results and incorporation of CLARION-3 data)
This timeline is designed to allow sufficient time for multiple rounds of review and revision, including the W&G patent/labeling review, prior to finalization of the USPI for inclusion in the sNDA submission. The Medication Guide and Patient Package Insert will be developed on a parallel track, with a target draft completion in late October 2022.
VI. TIMELINE AND MILESTONES
The following table sets forth the key milestones and target dates for the sNDA regulatory strategy:
All dates are targets and are subject to adjustment based on the timing of CLARION-3 results, FDA interactions, and other factors. The critical-path item is the receipt of positive CLARION-3 top-line data in Q4 2022. If CLARION-3 results are delayed or negative, the timeline will require substantial revision, as discussed in Section VII below.
VII. RISKS AND CONTINGENCIES
The sNDA strategy is subject to a number of risks and contingencies, which we summarize below along with our assessment and recommended mitigation approaches.
1. CLARION-3 Failure to Meet Co-Primary Endpoints. This is the single most significant risk to the sNDA strategy. If CLARION-3 does not meet both co-primary endpoints — PASI-90 at Week 16 and sPGA 0/1 at Week 16 — the sNDA cannot be filed. FDA was unambiguous at the Type B meeting that both co-primary endpoints must be met in the confirmatory study, and that the sNDA must be supported by two adequate and well-controlled Phase III trials. A failure on either endpoint would render CLARION-3 inadequate as the second pivotal study. In such a scenario, Penterra would need to consider several alternative paths: (a) conducting a redesigned confirmatory study with different co-primary endpoints (subject to further FDA input); (b) evaluating whether the key secondary endpoint (PASI-75 at Week 16) was met and whether a single-study sNDA supported by CLARION-2 alone could be justified under the "exceptional circumstances" provision of Section 505(d); or (c) reassessing the commercial viability of the psoriasis development program in light of the clinical data. We note that option (b) is highly unlikely to succeed given FDA's clear guidance that two adequate and well-controlled trials are required. The probability of this risk materializing cannot be estimated with precision at this time, but the CLARION-2 results (71.5% PASI-75 response rate, 58.3% sPGA 0/1 response rate) and the CLARION-1 dose-response data provide a reasonable basis for optimism regarding CLARION-3 outcomes.
2. FDA Request for Additional Studies or Data. Even if CLARION-3 meets its co-primary endpoints, FDA may request additional safety or efficacy data beyond what the CLARION program provides. This could include requests for longer-term safety follow-up (e.g., 24-month or 36-month safety data), mechanistic studies addressing specific safety concerns (e.g., hepatotoxicity mechanism), or post-marketing commitments for additional studies. While such requests would not necessarily prevent approval, they could add complexity and cost to the regulatory program and may result in post-marketing study requirements or labeling commitments that affect the commercial profile of the product. We recommend proactively preparing a robust integrated safety analysis and safety narrative to address anticipated FDA questions and minimize the likelihood of requests for additional pre-approval data.
3. Evolving JAK-Inhibitor Class Labeling Requirements. FDA's approach to JAK-inhibitor labeling continues to evolve in the wake of the September 2021 class-wide labeling update, which added boxed Warning elements for MACE and thrombosis and imposed a limitation-of-use statement requiring prior biologic failure for certain JAK inhibitors in the RA indication. It is possible that FDA could impose similar or additional labeling restrictions for the psoriasis indication, including: (a) a limitation-of-use statement requiring that velonatib be reserved for patients who have failed or are intolerant to one or more biologic therapies for psoriasis; (b) additional Warnings and Precautions language addressing specific risks in the psoriasis population; or (c) additional boxed Warning elements. Such restrictions could significantly affect the addressable patient population and commercial uptake of velonatib for psoriasis. The team should closely monitor FDA advisory committee proceedings, guidance documents, and labeling actions for other JAK inhibitors in the dermatology therapeutic area to anticipate potential labeling restrictions.
4. Competitive Landscape. The psoriasis therapeutic area is increasingly dominated by biologic therapies with high efficacy. IL-17 inhibitors (e.g., secukinumab, ixekizumab, brodalumab) and IL-23 inhibitors (e.g., guselkumab, risankizumab, tildrakizumab) have demonstrated PASI-90 response rates of 60% to 75% or higher in clinical trials, setting a high efficacy bar for new entrants. FDA's benefit-risk assessment will likely consider velonatib's efficacy relative to available biologic alternatives, even though head-to-head comparison data with IL-17 and IL-23 inhibitors are not available. Velonatib's principal competitive advantage — oral dosing with no injection requirement — is a significant differentiator that may influence both FDA's benefit-risk assessment and commercial positioning. However, if CLARION-3 PASI-90 response rates are substantially lower than those reported for IL-17 and IL-23 inhibitors, FDA may scrutinize the benefit-risk profile more closely and could require additional labeling language contextualizing velonatib's efficacy relative to biologic alternatives.
5. REMS Imposition. Although our preliminary assessment is that a full REMS with Elements to Assure Safe Use is unlikely for the psoriasis indication — given that velonatib is approved for the RA indication without a REMS and the safety profile in the psoriasis population appears consistent with the RA profile — FDA could impose REMS elements that affect the commercial launch strategy and timeline. Potential REMS elements could include a Communication Plan directed to healthcare providers and/or patients, enhanced Medication Guide requirements, or, in a less likely scenario, ETASU elements such as prescriber certification or patient enrollment. Any REMS requirement would add complexity to the commercial launch and could delay market access. C&H's forthcoming REMS assessment memorandum (expected September 2022) will provide a detailed analysis of the likelihood and scope of potential REMS imposition and will recommend an approach for addressing the REMS question in the sNDA submission.
6. Hepatotoxicity signal. If CLARION-3 safety data reveal a higher-than-expected rate of hepatotoxicity events in the psoriasis population — including serious drug-induced liver injury, Grade 3 or Grade 4 ALT/AST elevations, or cases meeting Hy's Law criteria — FDA could require additional monitoring requirements beyond what has been discussed at the Type B meeting, more restrictive labeling language (e.g., contraindication in patients with pre-existing hepatic impairment), or REMS elements specifically addressing hepatotoxicity risk. This risk is considered moderate given the numerical imbalance in ALT elevations observed in CLARION-2 (4.8% velonatib vs. 2.0% placebo) and the known JAK-1 class effect on liver enzymes. The integrated safety analysis, coordinated by CBG, will provide a comprehensive characterization of the hepatotoxicity signal across the CLARION program, which will be essential for addressing this risk in the sNDA submission.
7. Patent and intellectual Property Risks. Although the labeling language is not expected to require new Orange Book patent listings, the content of Sections 1.2 (Indications and Usage — Psoriasis) and 14.2 (Clinical Studies — Psoriasis) of the USPI could be relevant in future Hatch-Waxman Act paragraph IV certification proceedings involving abbreviated new drug applications ("ANDAs") filed by generic challengers. Specifically, the labeling language could be cited by generic applicants or courts in claim construction proceedings to construe the scope of method-of-treatment patent claims. Overly narrow or overly specific labeling language could limit the scope of patent protection or create arguments for non-infringement. Coordination with W&G patent counsel is therefore essential to ensure that the USPI language is consistent with and supportive of the broadest reasonable construction of the pending method-of-treatment patent claims.
VIII. COORDINATION WITH OUTSIDE ADVISORS
The sNDA regulatory strategy involves coordination among several outside advisory firms, each of which plays a distinct role in the overall effort. C&H will serve as lead coordinating counsel for the regulatory submission, with Penterra Regulatory Affairs (Dr. Karen Hessler) serving as the primary client point of contact for all matters relating to the sNDA.
Whitfield & Grange LLP (Dr. Eleanor Cassidy, Partner; Brian Takata, Associate). W&G serves as Penterra's patent and intellectual property counsel and plays a critical role in the sNDA strategy with respect to three issues: (a) review of labeling language for consistency with the scope of existing and pending patent claims, particularly the provisional method-of-treatment patent application filed in August 2022; (b) confirmation that the proposed psoriasis indication does not require new Orange Book patent listings; and (c) ongoing method-of-treatment patent strategy, including the anticipated conversion of the provisional application to a non-provisional application. C&H will coordinate with W&G on labeling language review beginning in October 2022, with a target completion prior to finalization of the USPI.
Callendar Baines Group LLC (Dr. Priya Sundaram, Managing Director; Dr. Neil Oxborough, Principal Consultant). CBG serves as Penterra's clinical development and regulatory affairs consultant and is responsible for several critical elements of the sNDA strategy: (a) clinical trial design consultation and oversight for the CLARION program; (b) preparation for and participation in FDA meetings, including the Type B Pre-sNDA meeting; (c) coordination of the integrated safety data analysis across all three CLARION studies; and (d) assembly and quality review of the sNDA submission in eCTD format. CBG's role is central to the sNDA effort, and close coordination between C&H, CBG, and Penterra Regulatory Affairs will be essential throughout the submission preparation process.
Thornfield Lewis LLP (Richard Croydon, CPA). Thornfield Lewis serves as Penterra's external auditor and tax advisor. The firm's role in the sNDA strategy is limited to the extent that PPC's 10-K and 10-Q disclosures reference the sNDA pipeline, development milestones, or contingent events related to the psoriasis indication. Thornfield Lewis does not have an active role in the sNDA filing itself but should be kept informed of material developments (e.g., CLARION-3 results, sNDA filing, PDUFA goal date) that may affect PPC's financial disclosures and reporting obligations under the Securities Exchange Act of 1934. Any communications with Thornfield Lewis regarding the sNDA should be coordinated through PPC's General Counsel to preserve attorney-client privilege where applicable.
C&H will maintain primary responsibility for the regulatory legal strategy and will coordinate the contributions of all outside advisors to ensure consistency and quality across all elements of the sNDA submission. Regular coordination calls among C&H, Penterra, CBG, and W&G will be scheduled beginning in September 2022 and continuing through the sNDA submission.
IX. RECOMMENDATION
Based on our analysis of the regulatory framework, FDA meeting feedback, clinical data, labeling requirements, and risk factors, C&H recommends the following course of action:
1. Proceed with parallel labeling development. Preparation of draft labeling documents (USPI, Patient Package Insert, and Medication Guide) should begin immediately and proceed in parallel with the ongoing CLARION-3 trial. This parallel-track approach is essential to enable a rapid sNDA filing upon receipt of positive CLARION-3 top-line data and to avoid unnecessary delays in the submission timeline.
2. Prepare first complete draft USPI. A first complete draft USPI incorporating the psoriasis indication should be prepared for internal review by September 2022, with a target of Rev. 3 by mid-October 2022. CLARION-3 data placeholders should be included in the initial draft and populated upon receipt of final results.
3. Prepare Medication Guide update. The Medication Guide update should be prepared on a parallel track, with a target draft completion in late October 2022.
4. Prepare C&H supporting memoranda. C&H will prepare a REMS assessment memorandum and a pediatric deferral analysis memorandum in September 2022. These memoranda will address, respectively, the likelihood and scope of potential REMS imposition and the terms and obligations of the PREA pediatric study deferral.
5. Coordinate with Whitfield & Grange on patent/labeling interface. C&H will coordinate with W&G on the review of USPI labeling language for patent claim scope consistency in October 2022. This review should be completed prior to finalization of the USPI for sNDA submission.
6. Maintain contingency planning. All work described above is contingent on positive CLARION-3 top-line data, which are expected in Q4 2022. If CLARION-3 fails to meet both co-primary endpoints, the sNDA strategy will need to be reassessed in its entirety. C&H will advise the team promptly upon receipt of CLARION-3 results regarding any necessary adjustments to the regulatory strategy.
7. Target Q1 2023 sNDA filing. Assuming positive CLARION-3 results, C&H and CBG stand ready to support a rapid sNDA assembly timeline, with a target filing in Q1 2023 and a projected PDUFA goal date in Q4 2023.
We are available to discuss this memorandum and its recommendations at your convenience. Please do not hesitate to contact Joel Strauss at (212) 558-4120 or joel.strauss@calderwoodharkness.com, or Sean Morrissey at (212) 558-4287 or sean.morrissey@calderwoodharkness.com, with any questions or to schedule a follow-up discussion.
This memorandum is a privileged and confidential attorney-client communication and attorney work product prepared by Calderwood & Harkness LLP for the exclusive use of Penterra Pharmaceuticals Corp. It is not intended for distribution to, or reliance upon by, any third party. The information contained herein is based on facts and circumstances as of the date of this memorandum and may be affected by subsequent developments. This memorandum does not constitute legal advice on any specific matter and should not be relied upon as such without further consultation with counsel.
CALDERWOOD & HARKNESS LLP 1301 Avenue of the Americas, 42nd Floor | New York, NY 10019 T: (212) 558-4000 | F: (212) 558-3588 Matter No.: 1018-00005
TO: | Lisa Moritani, Esq., General Counsel & Corporate Secretary, Penterra Pharmaceuticals Corp.
Dr. Karen Hessler, SVP, Regulatory Affairs, Penterra Pharmaceuticals Corp.
FROM: | Joel Strauss, Partner, Calderwood & Harkness LLP
Sean Morrissey, Associate, Calderwood & Harkness LLP
DATE: | August 12, 2022
RE: | Regulatory Strategy for sNDA — Velonatib (NDA No. 215-847) for Chronic Plaque Psoriasis
Matter No.: | 1018-000

MEMORANDUM

I. EXECUTIVE SUMMARY

II. REGULATORY FRAMEWORK

IV. CLINICAL DATA OVERVIEW

V. PROPOSED LABELING STRATEGY

VI. TIMELINE AND MILESTONES

VII. RISKS AND CONTINGENCIES

VIII. COORDINATION WITH OUTSIDE ADVISORS

IX. RECOMMENDATION

Record

Parties

Dates

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