Contract analysis

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 selec

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 procedura

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

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 t

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 te

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Global Assessment ("sPGA") 0/1 at Week 16 were acceptable endpoints for the psoriasis indication, consistent with FDA's Draft Guidance for Industry: "Psoriasis: Developing Drugs for Treatment" (September 2020).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

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 amino

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 popul

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

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 o

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

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 i

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

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

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 hi

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. • Pr

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, pres

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 su

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-control

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 add

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

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

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 ele

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., contraind

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. Sp

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

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 Morriss