1018-00005 · Penterra Pharmaceuticals Corp · Memoranda & Analysis

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CALDERWOOD & HARKNESS LLP Attorneys at Law

PRIVILEGED & CONFIDENTIAL — ATTORNEY-CLIENT COMMUNICATION ATTORNEY WORK PRODUCT

MEMORANDUM

I. INTRODUCTION

This memorandum analyzes whether the U.S. Food and Drug Administration ("FDA") is likely to require a Risk Evaluation and Mitigation Strategy ("REMS") in connection with the supplemental New Drug Application ("sNDA") for velonatib (velonatib hydrochloride) for the treatment of moderate-to-severe chronic plaque psoriasis in adults, and recommends a strategy for how Penterra Pharmaceuticals Corp. ("Penterra" or the "Company") should address REMS considerations in the sNDA submission. This analysis is informed by the regulatory record to date, the applicable statutory and regulatory framework, and the specific guidance FDA provided at the Type B Pre-sNDA meeting held on May 4, 2022.

Background. At the Type B Pre-sNDA meeting (Meeting ID: FDA-2022-M-1743), FDA's Division of Dermatology and Dentistry, within the Office of Immunology and Inflammation, Center for Drug Evaluation and Research ("CDER"), indicated that a REMS assessment would be required in connection with the sNDA for the psoriasis indication. The Division's feedback was communicated in the official meeting minutes provided to Penterra on May 27, 2022, and the specific language used was that FDA "anticipates that the sNDA submission will include a thorough assessment of the need for a REMS for the proposed psoriasis indication, taking into account the expanded patient population and the known class-wide safety concerns associated with JAK inhibitors." This direction was not unexpected, given the evolving regulatory landscape for Janus kinase ("JAK") inhibitors, but it requires careful strategic analysis to determine the appropriate scope of the REMS assessment and the substantive position Penterra should advance in the submission.

Drug Background. Velonatib (velonatib hydrochloride) is a selective JAK-1 inhibitor formulated as oral tablets in 5 mg and 10 mg strengths. Velonatib was originally approved under NDA No. 215-847 on June 14, 2019, for the treatment of moderate-to-severe rheumatoid arthritis ("RA") in adults who have had an inadequate response or intolerance to one or more disease-modifying antirheumatic drugs ("DMARDs"). Velonatib is currently marketed in the United States under the trade name Velonara. At the time of original approval, and in the period since, FDA has not required a REMS for velonatib for the RA indication. The approved labeling includes a boxed Warning addressing serious infections and malignancies, a required Medication Guide, and detailed prescribing information addressing the known safety profile of the drug.

Proposed New Indication. The proposed sNDA seeks to add an indication for the treatment of moderate-to-severe chronic plaque psoriasis in adults who are candidates for systemic therapy or phototherapy. The proposed dosing regimen for the psoriasis indication is 10 mg once daily. The sNDA is being submitted as an Efficacy Supplement — Type 10 (new indication) under Section 505(b) of the Federal Food, Drug, and Cosmetic Act ("FD&C Act"), 21 U.S.C. § 355(b), and the applicable regulations at 21 C.F.R. § 314.70(b).

Current REMS Status. As noted above, velonatib is not currently subject to a REMS for the RA indication. FDA determined at the time of original NDA approval that the existing labeling, including the boxed Warning and the Medication Guide, was sufficient to ensure that the benefits of velonatib outweighed its risks in the approved RA population. No REMS has been subsequently imposed, notwithstanding the September 2021 class-wide JAK-inhibitor labeling update that expanded the boxed Warning to include major adverse cardiovascular events ("MACE") and thrombosis.

Coordination with Callendar Baines Group. This memorandum has been prepared in coordination with Callendar Baines Group LLC ("CBG"), a regulatory and clinical strategy consultancy retained by Penterra to assist with the sNDA submission. CBG's Managing Director, Dr. Priya Sundaram, and Principal Consultant, Dr. Neil Oxborough, are providing strategic support on the integrated safety data presentation and clinical narrative for the REMS assessment section of the sNDA. CBG's work product has informed certain of the clinical and epidemiological analyses discussed herein, and CBG will be primarily responsible for the preparation of integrated safety data tables and analyses to be included in the REMS assessment section of the submission.

II. LEGAL FRAMEWORK

A. Statutory Authority — Section 505-1 of the FD&C Act

The principal statutory authority governing REMS is Section 505-1 of the FD&C Act, codified at 21 U.S.C. § 355-1. This provision was added by the FDA Amendments Act of 2007 ("FDAAA"), Pub. L. No. 110-85, § 901, 121 Stat. 823, 926-43 (2007), and has been subsequently amended. Section 505-1 grants FDA the authority to require a REMS if the agency determines that such a strategy is "necessary to ensure that the benefits of the drug outweigh the risks of the drug." 21 U.S.C. § 355-1(a)(1).

The statute contemplates the imposition of REMS requirements at several junctures. For new applications and supplements, FDA may require a REMS at the time of approval. 21 U.S.C. § 355-1(a)(1). This authority extends to supplemental applications, including sNDAs of the type Penterra intends to submit. With respect to sNDAs specifically, the statute provides that FDA may require a REMS or modifications to an existing REMS "if new safety information becomes available." 21 U.S.C. § 355-1(a)(2). The concept of "new safety information" is defined broadly in the statute and encompasses, among other things, information derived from clinical trials, post-marketing surveillance, active surveillance systems, epidemiological studies, and analyses of adverse event reports. 21 U.S.C. § 355-1(b)(3).

In the context of the velonatib psoriasis sNDA, the relevant statutory pathway is Section 355-1(a)(1), because the REMS assessment would be conducted in connection with the initial approval of the drug for a new indication. However, to the extent that safety data from the CLARION clinical program or post-marketing experience with velonatib in RA constitute "new safety information," Section 355-1(a)(2) may also be implicated. The practical effect of either statutory pathway is the same: FDA will evaluate whether a REMS is necessary to ensure that the benefits of velonatib outweigh its risks in the proposed psoriasis population.

B. Factors FDA Considers Under 21 U.S.C. § 355-1(a)(1)

The statute enumerates six factors that FDA must consider in determining whether a REMS is necessary. These factors are set forth in 21 U.S.C. § 355-1(a)(1) and apply to both new applications and supplements:

1. Estimated size of the population likely to use the drug. FDA considers the number of patients who are expected to be prescribed and use the drug if the application or supplement is approved. A larger anticipated patient population generally increases FDA's concern about population-level exposure to safety risks and may weigh in favor of requiring a REMS, particularly where the safety profile includes rare but serious adverse events whose absolute incidence would increase with broader use.

2. Seriousness of the disease or condition that is to be treated. The statute directs FDA to consider the gravity of the disease or condition for which the drug is indicated. Drugs indicated for serious, life-threatening conditions may receive a more favorable benefit-risk calculus — that is, FDA may be willing to tolerate a higher level of risk for a drug that treats a life-threatening disease than for one that treats a less serious condition. This factor is particularly significant in the velonatib psoriasis context, as discussed in Section III.B.2 below.

3. Expected benefit of the drug. FDA evaluates the magnitude and clinical significance of the therapeutic benefit demonstrated by the drug. A drug that provides substantial efficacy — particularly where unmet medical need exists — may be viewed more favorably in the benefit-risk calculus, potentially reducing the perceived need for a REMS. Conversely, marginal efficacy in the context of serious safety risks may strengthen the case for risk mitigation.

4. Expected or actual duration of treatment. The duration of anticipated drug exposure is relevant because chronic, long-term use increases cumulative exposure to drug-related risks. For conditions requiring indefinite treatment, such as chronic plaque psoriasis, this factor may weigh in favor of risk mitigation measures, particularly where the safety concerns include risks (such as malignancy and cardiovascular events) that are associated with prolonged exposure.

5. Seriousness of any known or potential adverse events that may be related to the drug. This factor addresses the severity and clinical significance of the drug's adverse event profile. FDA considers both the nature and magnitude of known adverse events, as well as potential risks suggested by the pharmacological class, preclinical data, or signals from post-marketing surveillance. The presence of a boxed Warning is a strong indicator that this factor weighs in favor of heightened risk management.

6. Whether the drug is a new molecular entity. FDA may apply greater scrutiny to new molecular entities, which have a more limited safety database and post-marketing track record. For supplemental applications involving drugs that have been on the market for several years, this factor may cut against the imposition of a REMS, as the drug's safety profile is better characterized through accumulated clinical experience.

These statutory factors provide the analytical framework for the assessment in Section III below. It is important to note that the statute does not prescribe a mechanical formula for weighing these factors; rather, FDA exercises scientific and regulatory judgment in determining whether the totality of the evidence supports the conclusion that a REMS is necessary.

C. Potential REMS Elements Under 21 U.S.C. § 355-1(e)–(f)

If FDA determines that a REMS is necessary, the statute authorizes a range of REMS elements of varying restrictiveness. These elements are organized in a tiered structure, with the least restrictive measures listed first:

Medication Guide. Under 21 U.S.C. § 355-1(e)(2), a REMS may include the requirement that a Medication Guide, meeting the requirements of 21 C.F.R. Part 208, be provided with each dispensing of the drug. A Medication Guide is a patient-directed document written in lay language that communicates important safety information, including serious risks, contraindications, and instructions for safe use. A Medication Guide is the least restrictive REMS element and is often required even in the absence of a formal REMS. Notably, velonatib is already subject to a Medication Guide requirement under its approved RA labeling, and the Medication Guide will be updated to reflect the psoriasis indication and any associated labeling changes. Draft Medication Guide Rev. 2 is dated October 20, 2022, and is currently under internal review within Penterra Regulatory Affairs.

Patient Package Insert. Under 21 U.S.C. § 355-1(e)(1), a REMS may include a Patient Package Insert — a printed document that accompanies the drug product and provides patient-directed information about the drug. This element is functionally similar to a Medication Guide but is distributed differently and may contain additional information.

Communication Plan. Under 21 U.S.C. § 355-1(e)(3), a REMS may include a communication plan directed to healthcare providers. A Communication Plan may encompass range outreach tools, including "Dear Healthcare Provider" ("DHCP") letters, training materials, prescriber fact sheets, and continuing medical education programs. The purpose of a Communication Plan is to ensure that prescribers are informed about the drug's serious risks and the appropriate conditions for its use. A Communication Plan is more restrictive than a Medication Guide alone but significantly less burdensome than Elements to Assure Safe Use.

Elements to Assure Safe Use ("ETASU"). Under 21 U.S.C. § 355-1(f), FDA may require ETASU — the most restrictive category of REMS elements — if the agency determines that the Medication Guide, Patient Package Insert, and Communication Plan alone are insufficient to mitigate the drug's risks. ETASU may include, but are not limited to:

• Prescriber certification or specialized training requirements, such that only prescribers who have completed training and enrolled in a certification program may prescribe the drug;

• Pharmacy certification requirements, restricting dispensing to pharmacies that have enrolled in the REMS program and agreed to comply with specified conditions;

• Dispensing restrictions or restricted distribution systems, which may limit the drug's availability to specific channels (e.g., specialty pharmacies) or require verification of certain conditions before dispensing;

• Patient registries, requiring the enrollment and monitoring of patients receiving the drug in a centralized database;

• Monitoring requirements, such as mandatory laboratory testing or clinical assessments before, during, or after treatment.

ETASU represent the most burdensome form of REMS and can significantly impair patient access, increase administrative costs for prescribers and pharmacies, and create competitive disadvantages for the drug product. For these reasons, ETASU are generally reserved for drugs with uniquely severe safety profiles, such as thalidomide (Thalomid REMS), isotretinoin (iPLEDGE), and certain opioid analgesics. The imposition of ETASU on velonatib would be commercially and operationally significant for Penterra and, as analyzed below, is unlikely given the current safety profile and regulatory precedent.

Implementation System. Under 21 U.S.C. § 355-1(g), if FDA requires ETASU, it must also require the applicant to develop and maintain an Implementation System — an operational infrastructure to administer and monitor compliance with the ETASU requirements. An Implementation System is required only when ETASU are imposed and is therefore relevant to our analysis only to the extent that ETASU are considered a realistic possibility.

Timetable for Assessments. Under 21 U.S.C. § 355-1(d), a REMS must include a timetable for submission of assessments of the REMS to FDA. The statute requires assessments at 18 months, 3 years, and 7 years after the REMS is initially approved, and periodically thereafter as FDA deems appropriate. These assessment requirements apply regardless of which REMS elements are included.

D. Regulatory Requirements for sNDA Submissions

The regulatory requirements applicable to the content of sNDA submissions are set forth in 21 C.F.R. § 314.50(d)(5)(viii), which provides that an NDA or supplement must include information pertinent to the evaluation of the need for a REMS. Specifically, the regulation contemplates that the applicant will include a REMS assessment section if the applicant believes that a REMS may be necessary, or if FDA has indicated that such an assessment is required.

In this case, there is no ambiguity regarding the applicability of this requirement. FDA's Division of Dermatology and Dentistry explicitly indicated at the May 4, 2022 Type B Pre-sNDA meeting that Penterra should include a REMS assessment in the psoriasis sNDA submission. The official meeting minutes reflect this direction, and Penterra's response to the meeting minutes (transmitted June 10, 2022) acknowledged the Company's intent to comply with this guidance. Accordingly, the inclusion of a REMS assessment section in the sNDA is not discretionary; it is a regulatory expectation that must be met to avoid a Refuse to File action or a delay in the review cycle.

III. ANALYSIS — APPLICATION OF STATUTORY FACTORS TO VELONATIB PSORIASIS sNDA

A. Current REMS Status — No REMS for RA Indication

As a threshold matter, it is important to note that velonatib is not currently subject to a REMS for its approved RA indication. When NDA 215-847 was approved on June 14, 2019, FDA determined that the existing labeling — including the boxed Warning for serious infections and malignancies, and the required Medication Guide — was sufficient to ensure that the benefits of velonatib outweighed its risks for the RA population. This determination reflected FDA's assessment that, for a population of adults with moderate-to-severe RA who had failed at least one DMARD, the substantial therapeutic benefit of velonatib justified the known safety risks, and that existing labeling tools were adequate to communicate those risks to healthcare providers and patients.

No REMS has been subsequently required for velonatib in the period since original approval. This is noteworthy because, in September 2021, FDA issued a class-wide labeling update for JAK inhibitors that expanded the boxed Warning to include MACE and thrombosis (deep vein thrombosis ("DVT") and pulmonary embolism ("PE")), based in significant part on the results of the ORAL Surveillance trial for tofacitinib. Despite this expansion of the boxed Warning — which reflected FDA's view that the known risks of the JAK inhibitor class were more serious than previously understood — FDA did not impose a class-wide REMS on any marketed JAK inhibitor, including velonatib. This regulatory decision is significant because it demonstrates FDA's judgment, as recently as 2021, that enhanced labeling (rather than a formal REMS) is the appropriate risk mitigation tool for JAK-class safety concerns in the currently approved indications.

However, the absence of a current REMS is not dispositive of the question whether FDA will require a REMS for the psoriasis indication. The benefit-risk calculus for psoriasis may differ materially from the RA context, and the approval of a new indication represents a distinct regulatory decision point at which FDA has the authority to impose new risk mitigation requirements. The analysis below examines each statutory factor in light of the proposed psoriasis indication.

B. Factor-by-Factor Analysis

1. Size of the Population Likely to Use the Drug. The addition of a psoriasis indication would significantly broaden the potential patient population exposed to velonatib beyond the current RA indication. Under the approved RA indication, velonatib is indicated for a defined subset of adult RA patients — specifically, those who have had an inadequate response or intolerance to one or more DMARDs. This gated access criterion limits the RA population on velonatib to patients who have progressed through initial DMARD therapy and been found to be refractory or intolerant.

The proposed psoriasis indication, by contrast, would encompass adults with moderate-to-severe chronic plaque psoriasis who are "candidates for systemic therapy or phototherapy." This language includes patients at an earlier stage of their treatment journey — those who have not necessarily failed prior systemic therapies but who are deemed appropriate candidates for systemic treatment based on the extent or severity of their disease. The eligible psoriasis population is substantially larger than the gated RA population. Based on epidemiological data reviewed by CBG, the estimated U.S. prevalence of moderate-to-severe plaque psoriasis in adults eligible for systemic therapy is approximately 3 to 4 million individuals. By comparison, the population of RA patients currently treated with JAK inhibitors is considerably smaller.

The commercial significance of this expanded population is already reflected in Penterra's internal projections and market data. Velonatib's FY 2022 U.S. net sales for the RA indication alone were approximately $1.47 billion, representing 67.4% of Penterra's total FY 2022 revenue of $2.18 billion. A psoriasis indication, if approved, could substantially increase the number of patients exposed to velonatib and the corresponding prescribing volume. While commercial success is not itself a regulatory consideration, the anticipated expansion in patient exposure is directly relevant to FDA's assessment of population-level risk. A larger exposed population increases the absolute number of patients who may experience serious adverse events, even if the per-patient incidence rate remains unchanged. This dynamic is well understood by FDA and historically has been a factor weighing in favor of enhanced risk management.

This factor weighs in favor of heightened FDA scrutiny and potentially supports the imposition of a REMS.

2. Seriousness of the Disease or Condition. Moderate-to-severe chronic plaque psoriasis is recognized by FDA as a serious condition, and it meets the regulatory definition of a "serious condition" for purposes of expedited review programs and benefit-risk assessment. Psoriasis is associated with significant morbidity, including widespread skin involvement, pruritus, pain, and disfigurement, as well as established comorbidities such as psoriatic arthritis, cardiovascular disease, metabolic syndrome, and depression. The burden of disease on patients' quality of life is substantial and well-documented in the medical literature.

However, psoriasis is generally a non-life-threatening condition. Unlike RA — which, if inadequately treated, can result in progressive and irreversible joint destruction, disability, and increased mortality — psoriasis primarily affects quality of life rather than life expectancy. This distinction is clinically and regulatorily significant. FDA has consistently applied a more conservative benefit-risk calculus to drugs indicated for non-life-threatening conditions, reflecting the principle that patients and providers should not be expected to tolerate the same level of serious drug-related risk when the condition being treated is burdensome but not immediately dangerous.

This principle was explicitly articulated in the September 2021 class-wide JAK-inhibitor labeling update, which included a new limitation of use recommending that JAK inhibitors be used in certain populations only after failure of one or more TNF blockers, and which acknowledged that the benefit-risk balance for JAK inhibitors may differ depending on the severity and nature of the condition being treated. While the 2021 labeling update did not specifically address psoriasis (as no JAK inhibitor was approved for psoriasis at that time), the underlying reasoning is directly applicable here.

This factor weighs in favor of a more conservative regulatory approach and potentially supports the imposition of a REMS, or at minimum, the inclusion of robust risk communication tools in the labeling.

3. Expected Benefit of the Drug. The clinical evidence supporting the efficacy of velonatib for moderate-to-severe chronic plaque psoriasis is strong and clinically meaningful. The pivotal CLARION-2 study (Phase III, N=742, completed April 2022) demonstrated that velonatib 10 mg once daily achieved a PASI-75 response at Week 16 of 71.5%, compared to 9.1% for placebo (p < 0.001). The co-primary endpoint of static Physician's Global Assessment ("sPGA") score of 0 or 1 (clear or almost clear) at Week 16 was achieved by 58.3% of velonatib-treated patients, compared to 5.7% for placebo (p < 0.001). These results represent a substantial treatment effect with high statistical confidence.

These findings are consistent with the earlier Phase II CLARION-1 study (N=287, completed September 2020), which showed a PASI-75 response at Week 12 of 68.2% for the 10 mg dose versus 12.4% for placebo (p < 0.001). The consistency of efficacy results across two independent studies strengthens the clinical evidence supporting the proposed indication.

The confirmatory Phase III CLARION-3 study (N=698) is ongoing, with top-line data expected in Q4 2022. The results of CLARION-3 will be critical to the overall benefit assessment and will be incorporated into the integrated efficacy and safety analyses for the sNDA. While we anticipate that CLARION-3 will confirm the efficacy results observed in CLARION-1 and CLARION-2, the final results are not yet available, and the benefit component of the benefit-risk assessment cannot be fully characterized until those data are in hand.

An important contextual consideration is the availability of alternative therapies for moderate-to-severe plaque psoriasis. The biologic therapies currently approved for psoriasis — including IL-17 inhibitors (secukinumab, ixekizumab, brodalumab), IL-23 inhibitors (guselkumab, tildrakizumab, risankizumab), and TNF inhibitors — have demonstrated strong efficacy in clinical trials and are widely used in clinical practice. Several of these agents have safety profiles that may be perceived as more favorable than the JAK-class safety profile, particularly with respect to cardiovascular events and malignancy. The existence of effective alternatives with potentially more favorable risk profiles may cause FDA to view the incremental benefit of velonatib in psoriasis more critically, particularly for patients who have not yet tried biologic therapy.

This factor is mixed. The efficacy of velonatib is substantial and clinically meaningful, which weighs against the need for a REMS. However, the availability of effective alternative therapies with different risk profiles tempers the weight of this factor.

4. Expected or Actual Duration of Treatment. Chronic plaque psoriasis is a lifelong condition that typically requires ongoing treatment to maintain disease control. Patients who achieve clinical response on velonatib would be expected to continue therapy indefinitely, as discontinuation of treatment in psoriasis generally leads to disease relapse. The proposed velonatib psoriasis labeling does not contemplate a fixed duration of treatment, and clinical practice for systemic psoriasis therapies generally involves continuous or long-term maintenance therapy.

The chronic nature of psoriasis therapy raises meaningful safety concerns because cumulative drug exposure increases the opportunity for rare but serious adverse events — particularly those with long latency periods, such as malignancy and cardiovascular events — to manifest. FDA is aware of this concern and, at the Type B Pre-sNDA meeting, specifically requested that Penterra submit 12-month safety data from both Phase III studies. This request is consistent with FDA's general expectation that sponsors of drugs intended for chronic use provide an adequate safety database reflecting long-term exposure.

This factor weighs in favor of enhanced risk mitigation, as it increases the potential for cumulative exposure-related adverse events in the psoriasis population.

5. Seriousness of Known or Potential Adverse Events. This factor is the most significant in the REMS assessment for velonatib and warrants detailed analysis.

Velonatib carries a boxed Warning — the most prominent warning in pharmaceutical labeling — for four categories of serious adverse events:

• Serious infections, including tuberculosis, invasive fungal infections, viral and bacterial opportunistic infections, and other serious infections that may lead to hospitalization or death. Patients treated with velonatib are at increased risk for developing serious infections that may lead to hospitalization or death, and most patients who developed these infections were taking concomitant immunosuppressants.

• Malignancies, including lymphoma. An increased incidence of malignancies, including lymphoma, has been observed in patients treated with JAK inhibitors. Velonatib-treated patients had a higher rate of malignancies compared to placebo-treated patients in clinical trials.

• Major adverse cardiovascular events (MACE), including myocardial infarction, stroke, and cardiovascular death. A higher rate of MACE was observed with JAK inhibitors compared to TNF blockers in a large post-marketing safety study (the tofacitinib ORAL Surveillance trial), and this risk has been included in class-wide labeling since September 2021.

• Thrombosis, including deep vein thrombosis (DVT) and pulmonary embolism (PE). An increased incidence of thrombotic events was observed in patients treated with JAK inhibitors compared to TNF blockers.

These are JAK-class-wide safety concerns that have been codified in FDA's September 2021 class-wide labeling update. The severity of these adverse events is undeniable: serious infections, malignancies, MACE, and thrombosis are all potentially fatal. The boxed Warning reflects FDA's determination that these risks are among the most clinically significant drug-related risks in the pharmaceutical marketplace.

In addition to the boxed Warning risks, FDA flagged hepatotoxicity monitoring as an additional concern specific to the psoriasis labeling at the Type B Pre-sNDA meeting. FDA's review of the CLARION-2 safety data identified a signal for hepatic transaminase elevations in velonatib-treated psoriasis patients that, while not meeting the threshold for a boxed Warning, warranted enhanced monitoring language in Section 5.5 (Warnings and Precautions — Hepatotoxicity) of the United States Prescribing Information ("USPI"). The proposed enhancement to Section 5.5 is being drafted in Revision 3 of the USPI and will include recommendations for baseline and periodic liver function testing during velonatib therapy for psoriasis.

The psoriasis population is generally younger and less immunocompromised at baseline than the RA population, which introduces a nuanced consideration that cuts in both directions:

• On one hand, the lower baseline cardiovascular and infection risk in the psoriasis population may reduce the absolute incidence of serious adverse events attributable to velonatib. If the absolute event rates are lower in psoriasis patients than in RA patients, the population-level safety experience may be more favorable than the RA data would suggest.

• On the other hand, the broader population exposure — including patients who are earlier in their treatment course and who have not failed other therapies — raises the concern that velonatib may be prescribed to patients whose disease could be managed with therapies carrying fewer serious risks. Exposing lower-risk patients to JAK-class risks is precisely the scenario that prompted FDA's September 2021 limitation-of-use language for JAK inhibitors in RA and ulcerative colitis.

This factor weighs significantly in favor of enhanced risk mitigation and is the strongest basis on which FDA could justify requiring a REMS.

6. New Molecular Entity Status. Velonatib is not a new molecular entity ("NME") for purposes of the sNDA. It was originally approved in June 2019 and has been marketed in the United States for over three years. During this period, FDA and Penterra have accumulated substantial post-marketing safety data from the RA population, including data from spontaneous adverse event reports, periodic safety update reports, and post-marketing surveillance activities. The accumulated safety experience provides a more robust characterization of velonatib's risk profile than would be available for a newly approved NME.

This factor weighs against the imposition of a REMS, as the drug's safety profile is well characterized through clinical and post-marketing experience. However, the weight of this factor should not be overstated. Although velonatib is not an NME, the proposed psoriasis indication represents the drug's entry into a new therapeutic area (dermatology) and a new patient population (psoriasis patients who may differ from RA patients in baseline risk characteristics and treatment expectations). FDA may apply heightened scrutiny analogous to that typically applied to NMEs when a known drug enters a substantially different patient population, particularly when the benefit-risk calculus for the new population differs materially from that of the approved population.

C. Competitive Landscape Analysis

An analysis of the competitive landscape for JAK inhibitors and psoriasis therapies provides useful context for assessing the likelihood that FDA will require a REMS for velonatib in psoriasis.

As of the date of this memorandum, no currently approved oral JAK inhibitor carries a REMS for any indication, including RA, psoriatic arthritis, ulcerative colitis, or atopic dermatitis. Tofacitinib (Xeljanz), baricitinib (Olumiant), and upadacitinib (Rinvoq) are all marketed without a REMS, relying instead on enhanced labeling (including the boxed Warning and Medication Guides) as the primary risk mitigation tools. Deucravacitinib (Sotyktu), a TYK2 inhibitor approved for plaque psoriasis in September 2022, was also approved without a REMS, although deucravacitinib's selectivity for TYK2 (rather than JAK-1/JAK-2/JAK-3) results in a different safety profile and the boxed Warning requirements applicable to JAK-1 inhibitors do not apply.

Biologic therapies approved for psoriasis — including IL-17 inhibitors (secukinumab, ixekizumab, brodalumab), IL-23 inhibitors (guselkumab, tildrakizumab, risankizumab), and TNF inhibitors — generally do not require a REMS. Some carry Medication Guides, but none are subject to ETASU or formal Communication Plans under a REMS framework. Brodalumab (Siliq) is a notable exception: it is subject to a REMS with ETASU, but this is due to a specific suicidality risk signal that is not relevant to the JAK-class safety profile.

The absence of REMS precedent for oral JAK inhibitors across all approved indications is somewhat favorable to Penterra's position. However, this precedent must be considered in light of the following countervailing factors: (i) no JAK-1 inhibitor is currently approved for psoriasis, so the regulatory precedent for JAK inhibitors in dermatology is limited; (ii) the September 2021 class-wide labeling update reflects a trend of heightened FDA scrutiny of the JAK class that may not have been fully played out in the REMS context; and (iii) if FDA were to impose a REMS on velonatib for psoriasis, it could set a precedent that would affect other JAK inhibitors seeking dermatology indications, and FDA may be aware of the broader implications of such a decision.

D. Overall Likelihood Assessment

Based on the foregoing analysis, we assess the likelihood of various REMS outcomes as follows:

It is more likely than not that FDA will require some form of REMS for the psoriasis indication. The combination of a significantly expanded patient population, the non-life-threatening nature of psoriasis (leading to a more conservative benefit-risk calculus), the chronic duration of treatment, and the serious adverse events reflected in the boxed Warning collectively create a regulatory environment in which FDA is likely to conclude that existing labeling alone is insufficient and that a formal REMS is warranted.

However, the REMS elements are likely to be limited in scope. Our assessment of the likelihood of specific REMS elements is as follows:

Highly likely: Medication Guide. A Medication Guide is already required and approved for the RA indication and will be updated for the psoriasis indication. It is virtually certain that a Medication Guide will be included in any REMS for velonatib, whether as a standalone element or as part of a broader strategy. The draft Medication Guide Rev. 2, dated October 20, 2022, is currently under internal review and will reflect the psoriasis indication and any associated labeling updates.

Moderately likely: Communication Plan. Given the expansion of velonatib into a new therapeutic area and patient population, FDA may determine that a Communication Plan directed to healthcare providers is appropriate. Such a plan would likely include a "Dear Healthcare Provider" letter issued at the time of psoriasis indication approval, highlighting JAK-class risks in the psoriasis population, as well as prescriber training and educational materials. A Communication Plan is a proportionate response to the concerns identified in the factor-by-factor analysis and would not impose undue burdens on patient access or Penterra's commercial operations.

Unlikely: Elements to Assure Safe Use (ETASU). We assess it as unlikely that FDA will require ETASU for velonatib in psoriasis. The oral route of administration, the established safety profile from over three years of post-marketing RA experience, and the absence of ETASU for any currently marketed JAK inhibitor make ETASU a disproportionate response to the identified risks. ETASU are typically reserved for drugs with uniquely severe safety profiles (e.g., thalidomide, isotretinoin, certain opioids) or specific safety risks that cannot be adequately managed through labeling and healthcare provider communication alone (e.g., the suicidality risk associated with brodalumab). The JAK-class safety risks, while serious, are well-characterized and can be communicated through labeling and provider education. Additionally, the imposition of ETASU would create a significant competitive disadvantage for velonatib relative to biologic psoriasis therapies that are not subject to ETASU, and FDA is generally aware of the access implications of ETASU requirements.

Very unlikely: Implementation System. An Implementation System is required only when ETASU are imposed. Because ETASU are assessed as unlikely, an Implementation System is correspondingly very unlikely.

IV. RECOMMENDATIONS FOR THE sNDA SUBMISSION

Based on the analysis set forth above, we recommend the following approach for addressing REMS in the velonatib psoriasis sNDA.

A. Include a REMS Assessment Section

In accordance with 21 C.F.R. § 314.50(d)(5)(viii) and FDA's explicit direction at the Type B Pre-sNDA meeting, the sNDA must include a REMS assessment section. The omission of such a section would be inconsistent with FDA's stated expectations and could result in a Refuse to File letter or a request for additional information that would delay the review cycle. We therefore recommend that the REMS assessment section be treated as a required component of the sNDA submission package.

The REMS assessment should be prepared once the CLARION-3 safety data are available. As noted above, top-line data from CLARION-3 are expected in Q4 2022. The integrated safety data — combining the CLARION-2 twelve-month safety data, the CLARION-3 safety data, and relevant post-marketing safety experience from the RA indication — will form the evidentiary foundation of the REMS assessment. CBG will coordinate the preparation of integrated safety data tables, pooled analyses, and supporting clinical narratives for inclusion in the REMS assessment section.

B. Primary Position — Existing Labeling Sufficient

The primary position advanced in the REMS assessment should be that the existing and proposed risk mitigation tools are sufficient to ensure that the benefits of velonatib outweigh its risks in the psoriasis population, and that a formal REMS is not necessary. This position should be supported by a comprehensive presentation of the following risk mitigation tools:

1. boxed Warning. The boxed Warning for serious infections, malignancies, MACE, and thrombosis, consistent with JAK class labeling, provides the highest-level safety communication to healthcare providers. The boxed Warning language was updated in September 2021 to reflect the expanded risk information from the ORAL Surveillance trial and other post-marketing data, and it now comprehensively addresses the most serious risks associated with velonatib therapy.

2. Enhanced hepatotoxicity monitoring language. Section 5.5 of the USPI will be revised to include enhanced language regarding hepatotoxicity monitoring, consistent with FDA's guidance at the Type B Pre-sNDA meeting. The proposed language, which is being drafted in USPI Rev. 3, will recommend baseline and periodic liver function testing during velonatib therapy for psoriasis and will include guidance on dose modification or discontinuation in the event of clinically significant hepatic transaminase elevations.

3. Updated Medication Guide. The Medication Guide will be updated to reflect the psoriasis indication and associated risks, including hepatotoxicity monitoring recommendations. The Medication Guide is a patient-directed document that ensures patients are informed about the serious risks of velonatib therapy and can engage in shared decision-making with their healthcare providers. Draft Medication Guide Rev. 2 is currently under internal review.

4. Existing prescribing information. The USPI includes detailed information on adverse reactions, drug interactions, use in specific populations, and clinical pharmacology that collectively provide healthcare providers with the information necessary to make informed prescribing decisions and monitor patients for known risks.

The REMS assessment should support this primary position with the following evidentiary and analytical arguments:

• Integrated safety data. The integrated safety data from the CLARION clinical program should demonstrate that the adverse event profile of velonatib in the psoriasis population is consistent with the known safety profile reflected in the approved RA labeling. If the safety data show no new or unexpected safety signals, this will support the argument that existing labeling tools — which were deemed sufficient for the RA population — are equally adequate for the psoriasis population.

• Lower baseline risk in the psoriasis population. The REMS assessment should present data and analysis demonstrating that the psoriasis population has a lower baseline risk for cardiovascular events, serious infections, and other adverse events compared to the RA population. If the absolute incidence rates of serious adverse events in the psoriasis trials are lower than the rates observed in the RA trials, this would support the position that the risk profile in the psoriasis population does not warrant additional risk mitigation beyond enhanced labeling.

• Absence of REMS requirements for other JAK inhibitors. The REMS assessment should note that no currently marketed JAK inhibitor is subject to a REMS for any indication, and that FDA's consistent regulatory approach has been to rely on enhanced labeling as the primary risk mitigation tool for JAK-class safety concerns. The imposition of a REMS for velonatib in psoriasis would represent a departure from this established precedent and should be supported by specific safety data justifying the departure.

C. Alternative Position — Proposed REMS with Medication Guide and Communication Plan

If FDA determines that existing labeling is insufficient to ensure that the benefits of velonatib outweigh its risks in the psoriasis population, the sNDA should include a proposed alternative REMS consisting of two elements:

1. Medication Guide. The Medication Guide, already in place for the RA indication and updated for psoriasis (draft Rev. 2, dated October 20, 2022), would serve as the patient-directed component of the REMS. The Medication Guide would be required to be provided with each dispensing of velonatib and would communicate the serious risks of therapy, including the boxed Warning risks and the hepatotoxicity monitoring recommendations, in patient-accessible language.

2. Communication Plan directed to healthcare providers. The Communication Plan would include the following components:

• A "Dear Healthcare Provider" letter issued at the time of psoriasis indication approval, highlighting the JAK-class risks in the psoriasis population, the importance of appropriate patient selection, the availability of alternative therapies, and the recommended monitoring during velonatib therapy for psoriasis.

• Healthcare provider training materials and a prescriber fact sheet summarizing the key safety information, recommended monitoring parameters, and patient counseling points specific to the psoriasis indication.

• A periodic assessment schedule, with assessments proposed at 18 months, 3 years, and 7 years post-approval, consistent with the statutory timetable set forth in 21 U.S.C. § 355-1(d). Each assessment would evaluate the effectiveness of the REMS in communicating safety information and the continued appropriateness of the REMS elements.

The REMS assessment should emphasize, in connection with this alternative position, that ETASU are not warranted and would impose disproportionate burdens on patient access. The arguments against ETASU should be articulated clearly and supported by the following points: (i) the oral route of administration makes restricted distribution impractical and inconsistent with the drug's formulation and prescribing paradigm; (ii) the safety risks associated with velonatib are not unique to this drug but are class-wide concerns shared by all marketed JAK inhibitors, none of which are subject to ETASU; (iii) ETASU would create a significant competitive disadvantage for velonatib relative to biologic psoriasis therapies and other JAK inhibitors approved for other indications, potentially driving patients to therapies that may not be optimal for their clinical circumstances; and (iv) the purposes of risk mitigation — ensuring that healthcare providers and patients are informed about serious risks and that appropriate monitoring is conducted — can be fully achieved through a Medication Guide and Communication Plan without the access barriers created by ETASU.

D. Coordination with Penterra Teams

The preparation of the REMS assessment section will require coordination among multiple internal and external teams. We recommend the following coordination structure:

• Calderwood & Harkness LLP (Joel Strauss, Sean Morrissey): Legal framework analysis, regulatory strategy, drafting of the REMS assessment narrative, and review of the final REMS assessment section for legal sufficiency and consistency with the overall sNDA regulatory strategy.

• Penterra Regulatory Affairs (Dr. Karen Hessler, SVP, Regulatory Affairs): Submission assembly, FDA communications, coordination of the sNDA package, and review of the REMS assessment section for regulatory compliance and consistency with the USPI and Medication Guide drafts.

• Penterra Medical Affairs (Dr. Tomás Becerra): Clinical safety data interpretation, review of the integrated safety data analyses prepared by CBG, and input on the clinical characterization of the psoriasis patient population and baseline risk factors.

• Penterra Quality & CMC (Janet Ling): Review of any distribution-related considerations, including assessment of whether the current supply chain and distribution infrastructure would be affected by REMS requirements. Although ETASU (including restricted distribution) are not anticipated, Quality & CMC should be prepared to assess feasibility in the event that FDA raises distribution-related questions during the review.

• Callendar Baines Group LLC (Dr. Priya Sundaram, Managing Director; Dr. Neil Oxborough, Principal Consultant): Preparation of integrated safety data tables and pooled analyses, drafting of the clinical safety data summary for inclusion in the REMS assessment section, and strategic advice on the presentation of safety data to FDA.

Additionally, we note that patent counsel (Whitfield & Grange LLP; Dr. Eleanor Cassidy, Brian Takata) need not be directly involved in the REMS assessment specifically, as REMS-related issues do not typically implicate patent strategy. However, patent counsel should be kept informed of any labeling changes associated with the psoriasis sNDA — including changes to the boxed Warning, Warnings and Precautions, or Medication Guide — that could potentially affect the scope of patent claims or create issues related to the patent information listed in the Orange Book. We recommend that Dr. Hessler's team provide patent counsel with copies of all draft labeling revisions as they are circulated for internal review.

E. Timeline for REMS Assessment Drafting

The REMS assessment section cannot be finalized until the CLARION-3 safety data are available, as the integrated safety analysis will form the evidentiary foundation of the REMS assessment. The following timeline is proposed, contingent on the receipt of CLARION-3 top-line data in Q4 2022:

• CLARION-3 top-line data readout: Expected Q4 2022 (specific date to be confirmed by Penterra Clinical Operations).

• Integrated safety data summary: CBG to prepare integrated safety data tables, pooled analyses, and clinical safety narrative within four (4) weeks of the CLARION-3 data lock date. This deliverable will include pooled incidence rates for boxed Warning events, hepatotoxicity data, and comparison of adverse event rates between the psoriasis and RA clinical programs.

• REMS assessment section draft: Calderwood & Harkness to prepare the initial draft of the REMS assessment section for the sNDA within six (6) weeks of the CLARION-3 data lock date. This draft will incorporate the integrated safety data summary from CBG, the legal framework analysis from this memorandum, and the primary and alternative positions described above.

• Internal review cycle: The draft REMS assessment section will be circulated for review by Penterra Regulatory Affairs (Dr. Hessler), Medical Affairs (Dr. Becerra), and CBG (Dr. Sundaram, Dr. Oxborough). We anticipate one to two rounds of review and revision, to be completed within approximately three (3) weeks of circulation of the initial draft.

• Final REMS assessment section: Target completion date for the final REMS assessment section is approximately ten (10) weeks post-CLARION-3 data lock, to be included in the sNDA package for the targeted Q1 2023 filing.

• PDUFA goal date: If the sNDA is accepted for filing, the Prescription Drug User Fee Act ("PDUFA") goal date for a standard review would be approximately ten (10) months from the filing date, projecting a PDUFA date in approximately Q4 2023. If FDA grants priority review (which is not anticipated for this supplement), the review period would be six (6) months.

We emphasize that the timeline set forth above is dependent on the timely availability of CLARION-3 data and the completion of the integrated safety analyses by CBG. Any delay in the CLARION-3 readout or the data integration process would have a corresponding impact on the REMS assessment drafting timeline and potentially on the overall sNDA filing date. We recommend that Dr. Hessler's team establish a standing coordination meeting (biweekly or as needed) with CBG, Calderwood & Harkness, and the relevant Penterra functional areas to monitor progress against the timeline and address any issues as they arise.

V. CONCLUSION

Based on the foregoing analysis, we reach the following conclusions and recommendations:

First, FDA will require a REMS assessment to be included in the velonatib psoriasis sNDA, consistent with the Division's explicit direction at the May 4, 2022 Type B Pre-sNDA meeting and the applicable regulatory requirements. The inclusion of a REMS assessment section is a mandatory component of the sNDA submission.

Second, with respect to the substantive question of whether FDA will impose a formal REMS, we assess that the most probable outcome is one of two scenarios: (a) FDA will conclude that the existing and proposed labeling tools — including the boxed Warning, the enhanced hepatotoxicity monitoring language in Section 5.5 of the USPI, and the updated Medication Guide — are sufficient to ensure that the benefits of velonatib outweigh its risks in the psoriasis population, and no formal REMS will be required; or (b) FDA will require a limited REMS consisting of a Medication Guide and a Communication Plan directed to healthcare providers. These two outcomes collectively represent the most likely range of regulatory results.

Third, the imposition of ETASU — including restricted distribution, prescriber certification, patient registries, or mandatory monitoring beyond standard clinical practice — is unlikely given the established safety profile of velonatib, the absence of ETASU for any currently marketed JAK inhibitor, and the disproportionate burden that ETASU would impose on patient access. However, ETASU cannot be entirely ruled out, particularly if the CLARION-3 safety data reveal unexpected or adverse safety signals that materially alter the benefit-risk assessment. The completion and analysis of the CLARION-3 safety data is therefore a critical milestone for the REMS strategy.

Fourth, Calderwood & Harkness stands ready to draft the REMS assessment section upon receipt of the CLARION-3 top-line data, in coordination with CBG and the relevant Penterra functional teams. We recommend that Penterra Regulatory Affairs begin the process of compiling the integrated safety database at the earliest practicable date and coordinate with CBG to ensure that the safety data integration can proceed promptly after the CLARION-3 top-line readout. Early preparation of the data infrastructure will help ensure that the REMS assessment drafting timeline remains on track for the targeted Q1 2023 sNDA filing.

We look forward to discussing this memorandum and its recommendations with you at your convenience.

Please do not hesitate to contact us with any questions.

This memorandum is a privileged and confidential attorney-client communication and attorney work product. It is intended solely for the use of the addressees identified above and should not be disclosed to any third party without the prior written consent of Calderwood & Harkness LLP.

TO:

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

FROM:

Sean Morrissey, Associate, Calderwood & Harkness LLP

DATE:	September 22, 2022
RE:	REMS Assessment for Velonatib sNDA — Psoriasis Indication (NDA No. 215-847)
Matter No.:	1018-00005

CALDERWOOD & HARKNESS LLP Attorneys at Law
PRIVILEGED & CONFIDENTIAL — ATTORNEY-CLIENT COMMUNICATION ATTORNEY WORK PRODUCT
MEMORANDUM
I. INTRODUCTION
This memorandum analyzes whether the U.S. Food and Drug Administration ("FDA") is likely to require a Risk Evaluation and Mitigation Strategy ("REMS") in connection with the supplemental New Drug Application ("sNDA") for velonatib (velonatib hydrochloride) for the treatment of moderate-to-severe chronic plaque psoriasis in adults, and recommends a strategy for how Penterra Pharmaceuticals Corp. ("Penterra" or the "Company") should address REMS considerations in the sNDA submission. This analysis is informed by the regulatory record to date, the applicable statutory and regulatory framework, and the specific guidance FDA provided at the Type B Pre-sNDA meeting held on May 4, 2022.
Background. At the Type B Pre-sNDA meeting (Meeting ID: FDA-2022-M-1743), FDA's Division of Dermatology and Dentistry, within the Office of Immunology and Inflammation, Center for Drug Evaluation and Research ("CDER"), indicated that a REMS assessment would be required in connection with the sNDA for the psoriasis indication. The Division's feedback was communicated in the official meeting minutes provided to Penterra on May 27, 2022, and the specific language used was that FDA "anticipates that the sNDA submission will include a thorough assessment of the need for a REMS for the proposed psoriasis indication, taking into account the expanded patient population and the known class-wide safety concerns associated with JAK inhibitors." This direction was not unexpected, given the evolving regulatory landscape for Janus kinase ("JAK") inhibitors, but it requires careful strategic analysis to determine the appropriate scope of the REMS assessment and the substantive position Penterra should advance in the submission.
Drug Background. Velonatib (velonatib hydrochloride) is a selective JAK-1 inhibitor formulated as oral tablets in 5 mg and 10 mg strengths. Velonatib was originally approved under NDA No. 215-847 on June 14, 2019, for the treatment of moderate-to-severe rheumatoid arthritis ("RA") in adults who have had an inadequate response or intolerance to one or more disease-modifying antirheumatic drugs ("DMARDs"). Velonatib is currently marketed in the United States under the trade name Velonara. At the time of original approval, and in the period since, FDA has not required a REMS for velonatib for the RA indication. The approved labeling includes a boxed Warning addressing serious infections and malignancies, a required Medication Guide, and detailed prescribing information addressing the known safety profile of the drug.
Proposed New Indication. The proposed sNDA seeks to add an indication for the treatment of moderate-to-severe chronic plaque psoriasis in adults who are candidates for systemic therapy or phototherapy. The proposed dosing regimen for the psoriasis indication is 10 mg once daily. The sNDA is being submitted as an Efficacy Supplement — Type 10 (new indication) under Section 505(b) of the Federal Food, Drug, and Cosmetic Act ("FD&C Act"), 21 U.S.C. § 355(b), and the applicable regulations at 21 C.F.R. § 314.70(b).
Current REMS Status. As noted above, velonatib is not currently subject to a REMS for the RA indication. FDA determined at the time of original NDA approval that the existing labeling, including the boxed Warning and the Medication Guide, was sufficient to ensure that the benefits of velonatib outweighed its risks in the approved RA population. No REMS has been subsequently imposed, notwithstanding the September 2021 class-wide JAK-inhibitor labeling update that expanded the boxed Warning to include major adverse cardiovascular events ("MACE") and thrombosis.
Coordination with Callendar Baines Group. This memorandum has been prepared in coordination with Callendar Baines Group LLC ("CBG"), a regulatory and clinical strategy consultancy retained by Penterra to assist with the sNDA submission. CBG's Managing Director, Dr. Priya Sundaram, and Principal Consultant, Dr. Neil Oxborough, are providing strategic support on the integrated safety data presentation and clinical narrative for the REMS assessment section of the sNDA. CBG's work product has informed certain of the clinical and epidemiological analyses discussed herein, and CBG will be primarily responsible for the preparation of integrated safety data tables and analyses to be included in the REMS assessment section of the submission.
II. LEGAL FRAMEWORK
A. Statutory Authority — Section 505-1 of the FD&C Act
The principal statutory authority governing REMS is Section 505-1 of the FD&C Act, codified at 21 U.S.C. § 355-1. This provision was added by the FDA Amendments Act of 2007 ("FDAAA"), Pub. L. No. 110-85, § 901, 121 Stat. 823, 926-43 (2007), and has been subsequently amended. Section 505-1 grants FDA the authority to require a REMS if the agency determines that such a strategy is "necessary to ensure that the benefits of the drug outweigh the risks of the drug." 21 U.S.C. § 355-1(a)(1).
The statute contemplates the imposition of REMS requirements at several junctures. For new applications and supplements, FDA may require a REMS at the time of approval. 21 U.S.C. § 355-1(a)(1). This authority extends to supplemental applications, including sNDAs of the type Penterra intends to submit. With respect to sNDAs specifically, the statute provides that FDA may require a REMS or modifications to an existing REMS "if new safety information becomes available." 21 U.S.C. § 355-1(a)(2). The concept of "new safety information" is defined broadly in the statute and encompasses, among other things, information derived from clinical trials, post-marketing surveillance, active surveillance systems, epidemiological studies, and analyses of adverse event reports. 21 U.S.C. § 355-1(b)(3).
In the context of the velonatib psoriasis sNDA, the relevant statutory pathway is Section 355-1(a)(1), because the REMS assessment would be conducted in connection with the initial approval of the drug for a new indication. However, to the extent that safety data from the CLARION clinical program or post-marketing experience with velonatib in RA constitute "new safety information," Section 355-1(a)(2) may also be implicated. The practical effect of either statutory pathway is the same: FDA will evaluate whether a REMS is necessary to ensure that the benefits of velonatib outweigh its risks in the proposed psoriasis population.
B. Factors FDA Considers Under 21 U.S.C. § 355-1(a)(1)
The statute enumerates six factors that FDA must consider in determining whether a REMS is necessary. These factors are set forth in 21 U.S.C. § 355-1(a)(1) and apply to both new applications and supplements:
1. Estimated size of the population likely to use the drug. FDA considers the number of patients who are expected to be prescribed and use the drug if the application or supplement is approved. A larger anticipated patient population generally increases FDA's concern about population-level exposure to safety risks and may weigh in favor of requiring a REMS, particularly where the safety profile includes rare but serious adverse events whose absolute incidence would increase with broader use.
2. Seriousness of the disease or condition that is to be treated. The statute directs FDA to consider the gravity of the disease or condition for which the drug is indicated. Drugs indicated for serious, life-threatening conditions may receive a more favorable benefit-risk calculus — that is, FDA may be willing to tolerate a higher level of risk for a drug that treats a life-threatening disease than for one that treats a less serious condition. This factor is particularly significant in the velonatib psoriasis context, as discussed in Section III.B.2 below.
3. Expected benefit of the drug. FDA evaluates the magnitude and clinical significance of the therapeutic benefit demonstrated by the drug. A drug that provides substantial efficacy — particularly where unmet medical need exists — may be viewed more favorably in the benefit-risk calculus, potentially reducing the perceived need for a REMS. Conversely, marginal efficacy in the context of serious safety risks may strengthen the case for risk mitigation.
4. Expected or actual duration of treatment. The duration of anticipated drug exposure is relevant because chronic, long-term use increases cumulative exposure to drug-related risks. For conditions requiring indefinite treatment, such as chronic plaque psoriasis, this factor may weigh in favor of risk mitigation measures, particularly where the safety concerns include risks (such as malignancy and cardiovascular events) that are associated with prolonged exposure.
5. Seriousness of any known or potential adverse events that may be related to the drug. This factor addresses the severity and clinical significance of the drug's adverse event profile. FDA considers both the nature and magnitude of known adverse events, as well as potential risks suggested by the pharmacological class, preclinical data, or signals from post-marketing surveillance. The presence of a boxed Warning is a strong indicator that this factor weighs in favor of heightened risk management.
6. Whether the drug is a new molecular entity. FDA may apply greater scrutiny to new molecular entities, which have a more limited safety database and post-marketing track record. For supplemental applications involving drugs that have been on the market for several years, this factor may cut against the imposition of a REMS, as the drug's safety profile is better characterized through accumulated clinical experience.
These statutory factors provide the analytical framework for the assessment in Section III below. It is important to note that the statute does not prescribe a mechanical formula for weighing these factors; rather, FDA exercises scientific and regulatory judgment in determining whether the totality of the evidence supports the conclusion that a REMS is necessary.
C. Potential REMS Elements Under 21 U.S.C. § 355-1(e)–(f)
If FDA determines that a REMS is necessary, the statute authorizes a range of REMS elements of varying restrictiveness. These elements are organized in a tiered structure, with the least restrictive measures listed first:
Medication Guide. Under 21 U.S.C. § 355-1(e)(2), a REMS may include the requirement that a Medication Guide, meeting the requirements of 21 C.F.R. Part 208, be provided with each dispensing of the drug. A Medication Guide is a patient-directed document written in lay language that communicates important safety information, including serious risks, contraindications, and instructions for safe use. A Medication Guide is the least restrictive REMS element and is often required even in the absence of a formal REMS. Notably, velonatib is already subject to a Medication Guide requirement under its approved RA labeling, and the Medication Guide will be updated to reflect the psoriasis indication and any associated labeling changes. Draft Medication Guide Rev. 2 is dated October 20, 2022, and is currently under internal review within Penterra Regulatory Affairs.
Patient Package Insert. Under 21 U.S.C. § 355-1(e)(1), a REMS may include a Patient Package Insert — a printed document that accompanies the drug product and provides patient-directed information about the drug. This element is functionally similar to a Medication Guide but is distributed differently and may contain additional information.
Communication Plan. Under 21 U.S.C. § 355-1(e)(3), a REMS may include a communication plan directed to healthcare providers. A Communication Plan may encompass range outreach tools, including "Dear Healthcare Provider" ("DHCP") letters, training materials, prescriber fact sheets, and continuing medical education programs. The purpose of a Communication Plan is to ensure that prescribers are informed about the drug's serious risks and the appropriate conditions for its use. A Communication Plan is more restrictive than a Medication Guide alone but significantly less burdensome than Elements to Assure Safe Use.
Elements to Assure Safe Use ("ETASU"). Under 21 U.S.C. § 355-1(f), FDA may require ETASU — the most restrictive category of REMS elements — if the agency determines that the Medication Guide, Patient Package Insert, and Communication Plan alone are insufficient to mitigate the drug's risks. ETASU may include, but are not limited to:
• Prescriber certification or specialized training requirements, such that only prescribers who have completed training and enrolled in a certification program may prescribe the drug;
• Pharmacy certification requirements, restricting dispensing to pharmacies that have enrolled in the REMS program and agreed to comply with specified conditions;
• Dispensing restrictions or restricted distribution systems, which may limit the drug's availability to specific channels (e.g., specialty pharmacies) or require verification of certain conditions before dispensing;
• Patient registries, requiring the enrollment and monitoring of patients receiving the drug in a centralized database;
• Monitoring requirements, such as mandatory laboratory testing or clinical assessments before, during, or after treatment.
ETASU represent the most burdensome form of REMS and can significantly impair patient access, increase administrative costs for prescribers and pharmacies, and create competitive disadvantages for the drug product. For these reasons, ETASU are generally reserved for drugs with uniquely severe safety profiles, such as thalidomide (Thalomid REMS), isotretinoin (iPLEDGE), and certain opioid analgesics. The imposition of ETASU on velonatib would be commercially and operationally significant for Penterra and, as analyzed below, is unlikely given the current safety profile and regulatory precedent.
Implementation System. Under 21 U.S.C. § 355-1(g), if FDA requires ETASU, it must also require the applicant to develop and maintain an Implementation System — an operational infrastructure to administer and monitor compliance with the ETASU requirements. An Implementation System is required only when ETASU are imposed and is therefore relevant to our analysis only to the extent that ETASU are considered a realistic possibility.
Timetable for Assessments. Under 21 U.S.C. § 355-1(d), a REMS must include a timetable for submission of assessments of the REMS to FDA. The statute requires assessments at 18 months, 3 years, and 7 years after the REMS is initially approved, and periodically thereafter as FDA deems appropriate. These assessment requirements apply regardless of which REMS elements are included.
D. Regulatory Requirements for sNDA Submissions
The regulatory requirements applicable to the content of sNDA submissions are set forth in 21 C.F.R. § 314.50(d)(5)(viii), which provides that an NDA or supplement must include information pertinent to the evaluation of the need for a REMS. Specifically, the regulation contemplates that the applicant will include a REMS assessment section if the applicant believes that a REMS may be necessary, or if FDA has indicated that such an assessment is required.
In this case, there is no ambiguity regarding the applicability of this requirement. FDA's Division of Dermatology and Dentistry explicitly indicated at the May 4, 2022 Type B Pre-sNDA meeting that Penterra should include a REMS assessment in the psoriasis sNDA submission. The official meeting minutes reflect this direction, and Penterra's response to the meeting minutes (transmitted June 10, 2022) acknowledged the Company's intent to comply with this guidance. Accordingly, the inclusion of a REMS assessment section in the sNDA is not discretionary; it is a regulatory expectation that must be met to avoid a Refuse to File action or a delay in the review cycle.
III. ANALYSIS — APPLICATION OF STATUTORY FACTORS TO VELONATIB PSORIASIS sNDA
A. Current REMS Status — No REMS for RA Indication
As a threshold matter, it is important to note that velonatib is not currently subject to a REMS for its approved RA indication. When NDA 215-847 was approved on June 14, 2019, FDA determined that the existing labeling — including the boxed Warning for serious infections and malignancies, and the required Medication Guide — was sufficient to ensure that the benefits of velonatib outweighed its risks for the RA population. This determination reflected FDA's assessment that, for a population of adults with moderate-to-severe RA who had failed at least one DMARD, the substantial therapeutic benefit of velonatib justified the known safety risks, and that existing labeling tools were adequate to communicate those risks to healthcare providers and patients.
No REMS has been subsequently required for velonatib in the period since original approval. This is noteworthy because, in September 2021, FDA issued a class-wide labeling update for JAK inhibitors that expanded the boxed Warning to include MACE and thrombosis (deep vein thrombosis ("DVT") and pulmonary embolism ("PE")), based in significant part on the results of the ORAL Surveillance trial for tofacitinib. Despite this expansion of the boxed Warning — which reflected FDA's view that the known risks of the JAK inhibitor class were more serious than previously understood — FDA did not impose a class-wide REMS on any marketed JAK inhibitor, including velonatib. This regulatory decision is significant because it demonstrates FDA's judgment, as recently as 2021, that enhanced labeling (rather than a formal REMS) is the appropriate risk mitigation tool for JAK-class safety concerns in the currently approved indications.
However, the absence of a current REMS is not dispositive of the question whether FDA will require a REMS for the psoriasis indication. The benefit-risk calculus for psoriasis may differ materially from the RA context, and the approval of a new indication represents a distinct regulatory decision point at which FDA has the authority to impose new risk mitigation requirements. The analysis below examines each statutory factor in light of the proposed psoriasis indication.
B. Factor-by-Factor Analysis
1. Size of the Population Likely to Use the Drug. The addition of a psoriasis indication would significantly broaden the potential patient population exposed to velonatib beyond the current RA indication. Under the approved RA indication, velonatib is indicated for a defined subset of adult RA patients — specifically, those who have had an inadequate response or intolerance to one or more DMARDs. This gated access criterion limits the RA population on velonatib to patients who have progressed through initial DMARD therapy and been found to be refractory or intolerant.
The proposed psoriasis indication, by contrast, would encompass adults with moderate-to-severe chronic plaque psoriasis who are "candidates for systemic therapy or phototherapy." This language includes patients at an earlier stage of their treatment journey — those who have not necessarily failed prior systemic therapies but who are deemed appropriate candidates for systemic treatment based on the extent or severity of their disease. The eligible psoriasis population is substantially larger than the gated RA population. Based on epidemiological data reviewed by CBG, the estimated U.S. prevalence of moderate-to-severe plaque psoriasis in adults eligible for systemic therapy is approximately 3 to 4 million individuals. By comparison, the population of RA patients currently treated with JAK inhibitors is considerably smaller.
The commercial significance of this expanded population is already reflected in Penterra's internal projections and market data. Velonatib's FY 2022 U.S. net sales for the RA indication alone were approximately $1.47 billion, representing 67.4% of Penterra's total FY 2022 revenue of $2.18 billion. A psoriasis indication, if approved, could substantially increase the number of patients exposed to velonatib and the corresponding prescribing volume. While commercial success is not itself a regulatory consideration, the anticipated expansion in patient exposure is directly relevant to FDA's assessment of population-level risk. A larger exposed population increases the absolute number of patients who may experience serious adverse events, even if the per-patient incidence rate remains unchanged. This dynamic is well understood by FDA and historically has been a factor weighing in favor of enhanced risk management.
This factor weighs in favor of heightened FDA scrutiny and potentially supports the imposition of a REMS.
2. Seriousness of the Disease or Condition. Moderate-to-severe chronic plaque psoriasis is recognized by FDA as a serious condition, and it meets the regulatory definition of a "serious condition" for purposes of expedited review programs and benefit-risk assessment. Psoriasis is associated with significant morbidity, including widespread skin involvement, pruritus, pain, and disfigurement, as well as established comorbidities such as psoriatic arthritis, cardiovascular disease, metabolic syndrome, and depression. The burden of disease on patients' quality of life is substantial and well-documented in the medical literature.
However, psoriasis is generally a non-life-threatening condition. Unlike RA — which, if inadequately treated, can result in progressive and irreversible joint destruction, disability, and increased mortality — psoriasis primarily affects quality of life rather than life expectancy. This distinction is clinically and regulatorily significant. FDA has consistently applied a more conservative benefit-risk calculus to drugs indicated for non-life-threatening conditions, reflecting the principle that patients and providers should not be expected to tolerate the same level of serious drug-related risk when the condition being treated is burdensome but not immediately dangerous.
This principle was explicitly articulated in the September 2021 class-wide JAK-inhibitor labeling update, which included a new limitation of use recommending that JAK inhibitors be used in certain populations only after failure of one or more TNF blockers, and which acknowledged that the benefit-risk balance for JAK inhibitors may differ depending on the severity and nature of the condition being treated. While the 2021 labeling update did not specifically address psoriasis (as no JAK inhibitor was approved for psoriasis at that time), the underlying reasoning is directly applicable here.
This factor weighs in favor of a more conservative regulatory approach and potentially supports the imposition of a REMS, or at minimum, the inclusion of robust risk communication tools in the labeling.
3. Expected Benefit of the Drug. The clinical evidence supporting the efficacy of velonatib for moderate-to-severe chronic plaque psoriasis is strong and clinically meaningful. The pivotal CLARION-2 study (Phase III, N=742, completed April 2022) demonstrated that velonatib 10 mg once daily achieved a PASI-75 response at Week 16 of 71.5%, compared to 9.1% for placebo (p < 0.001). The co-primary endpoint of static Physician's Global Assessment ("sPGA") score of 0 or 1 (clear or almost clear) at Week 16 was achieved by 58.3% of velonatib-treated patients, compared to 5.7% for placebo (p < 0.001). These results represent a substantial treatment effect with high statistical confidence.
These findings are consistent with the earlier Phase II CLARION-1 study (N=287, completed September 2020), which showed a PASI-75 response at Week 12 of 68.2% for the 10 mg dose versus 12.4% for placebo (p < 0.001). The consistency of efficacy results across two independent studies strengthens the clinical evidence supporting the proposed indication.
The confirmatory Phase III CLARION-3 study (N=698) is ongoing, with top-line data expected in Q4 2022. The results of CLARION-3 will be critical to the overall benefit assessment and will be incorporated into the integrated efficacy and safety analyses for the sNDA. While we anticipate that CLARION-3 will confirm the efficacy results observed in CLARION-1 and CLARION-2, the final results are not yet available, and the benefit component of the benefit-risk assessment cannot be fully characterized until those data are in hand.
An important contextual consideration is the availability of alternative therapies for moderate-to-severe plaque psoriasis. The biologic therapies currently approved for psoriasis — including IL-17 inhibitors (secukinumab, ixekizumab, brodalumab), IL-23 inhibitors (guselkumab, tildrakizumab, risankizumab), and TNF inhibitors — have demonstrated strong efficacy in clinical trials and are widely used in clinical practice. Several of these agents have safety profiles that may be perceived as more favorable than the JAK-class safety profile, particularly with respect to cardiovascular events and malignancy. The existence of effective alternatives with potentially more favorable risk profiles may cause FDA to view the incremental benefit of velonatib in psoriasis more critically, particularly for patients who have not yet tried biologic therapy.
This factor is mixed. The efficacy of velonatib is substantial and clinically meaningful, which weighs against the need for a REMS. However, the availability of effective alternative therapies with different risk profiles tempers the weight of this factor.
4. Expected or Actual Duration of Treatment. Chronic plaque psoriasis is a lifelong condition that typically requires ongoing treatment to maintain disease control. Patients who achieve clinical response on velonatib would be expected to continue therapy indefinitely, as discontinuation of treatment in psoriasis generally leads to disease relapse. The proposed velonatib psoriasis labeling does not contemplate a fixed duration of treatment, and clinical practice for systemic psoriasis therapies generally involves continuous or long-term maintenance therapy.
The chronic nature of psoriasis therapy raises meaningful safety concerns because cumulative drug exposure increases the opportunity for rare but serious adverse events — particularly those with long latency periods, such as malignancy and cardiovascular events — to manifest. FDA is aware of this concern and, at the Type B Pre-sNDA meeting, specifically requested that Penterra submit 12-month safety data from both Phase III studies. This request is consistent with FDA's general expectation that sponsors of drugs intended for chronic use provide an adequate safety database reflecting long-term exposure.
This factor weighs in favor of enhanced risk mitigation, as it increases the potential for cumulative exposure-related adverse events in the psoriasis population.
5. Seriousness of Known or Potential Adverse Events. This factor is the most significant in the REMS assessment for velonatib and warrants detailed analysis.
Velonatib carries a boxed Warning — the most prominent warning in pharmaceutical labeling — for four categories of serious adverse events:
• Serious infections, including tuberculosis, invasive fungal infections, viral and bacterial opportunistic infections, and other serious infections that may lead to hospitalization or death. Patients treated with velonatib are at increased risk for developing serious infections that may lead to hospitalization or death, and most patients who developed these infections were taking concomitant immunosuppressants.
• Malignancies, including lymphoma. An increased incidence of malignancies, including lymphoma, has been observed in patients treated with JAK inhibitors. Velonatib-treated patients had a higher rate of malignancies compared to placebo-treated patients in clinical trials.
• Major adverse cardiovascular events (MACE), including myocardial infarction, stroke, and cardiovascular death. A higher rate of MACE was observed with JAK inhibitors compared to TNF blockers in a large post-marketing safety study (the tofacitinib ORAL Surveillance trial), and this risk has been included in class-wide labeling since September 2021.
• Thrombosis, including deep vein thrombosis (DVT) and pulmonary embolism (PE). An increased incidence of thrombotic events was observed in patients treated with JAK inhibitors compared to TNF blockers.
These are JAK-class-wide safety concerns that have been codified in FDA's September 2021 class-wide labeling update. The severity of these adverse events is undeniable: serious infections, malignancies, MACE, and thrombosis are all potentially fatal. The boxed Warning reflects FDA's determination that these risks are among the most clinically significant drug-related risks in the pharmaceutical marketplace.
In addition to the boxed Warning risks, FDA flagged hepatotoxicity monitoring as an additional concern specific to the psoriasis labeling at the Type B Pre-sNDA meeting. FDA's review of the CLARION-2 safety data identified a signal for hepatic transaminase elevations in velonatib-treated psoriasis patients that, while not meeting the threshold for a boxed Warning, warranted enhanced monitoring language in Section 5.5 (Warnings and Precautions — Hepatotoxicity) of the United States Prescribing Information ("USPI"). The proposed enhancement to Section 5.5 is being drafted in Revision 3 of the USPI and will include recommendations for baseline and periodic liver function testing during velonatib therapy for psoriasis.
The psoriasis population is generally younger and less immunocompromised at baseline than the RA population, which introduces a nuanced consideration that cuts in both directions:
• On one hand, the lower baseline cardiovascular and infection risk in the psoriasis population may reduce the absolute incidence of serious adverse events attributable to velonatib. If the absolute event rates are lower in psoriasis patients than in RA patients, the population-level safety experience may be more favorable than the RA data would suggest.
• On the other hand, the broader population exposure — including patients who are earlier in their treatment course and who have not failed other therapies — raises the concern that velonatib may be prescribed to patients whose disease could be managed with therapies carrying fewer serious risks. Exposing lower-risk patients to JAK-class risks is precisely the scenario that prompted FDA's September 2021 limitation-of-use language for JAK inhibitors in RA and ulcerative colitis.
This factor weighs significantly in favor of enhanced risk mitigation and is the strongest basis on which FDA could justify requiring a REMS.
6. New Molecular Entity Status. Velonatib is not a new molecular entity ("NME") for purposes of the sNDA. It was originally approved in June 2019 and has been marketed in the United States for over three years. During this period, FDA and Penterra have accumulated substantial post-marketing safety data from the RA population, including data from spontaneous adverse event reports, periodic safety update reports, and post-marketing surveillance activities. The accumulated safety experience provides a more robust characterization of velonatib's risk profile than would be available for a newly approved NME.
This factor weighs against the imposition of a REMS, as the drug's safety profile is well characterized through clinical and post-marketing experience. However, the weight of this factor should not be overstated. Although velonatib is not an NME, the proposed psoriasis indication represents the drug's entry into a new therapeutic area (dermatology) and a new patient population (psoriasis patients who may differ from RA patients in baseline risk characteristics and treatment expectations). FDA may apply heightened scrutiny analogous to that typically applied to NMEs when a known drug enters a substantially different patient population, particularly when the benefit-risk calculus for the new population differs materially from that of the approved population.
C. Competitive Landscape Analysis
An analysis of the competitive landscape for JAK inhibitors and psoriasis therapies provides useful context for assessing the likelihood that FDA will require a REMS for velonatib in psoriasis.
As of the date of this memorandum, no currently approved oral JAK inhibitor carries a REMS for any indication, including RA, psoriatic arthritis, ulcerative colitis, or atopic dermatitis. Tofacitinib (Xeljanz), baricitinib (Olumiant), and upadacitinib (Rinvoq) are all marketed without a REMS, relying instead on enhanced labeling (including the boxed Warning and Medication Guides) as the primary risk mitigation tools. Deucravacitinib (Sotyktu), a TYK2 inhibitor approved for plaque psoriasis in September 2022, was also approved without a REMS, although deucravacitinib's selectivity for TYK2 (rather than JAK-1/JAK-2/JAK-3) results in a different safety profile and the boxed Warning requirements applicable to JAK-1 inhibitors do not apply.
Biologic therapies approved for psoriasis — including IL-17 inhibitors (secukinumab, ixekizumab, brodalumab), IL-23 inhibitors (guselkumab, tildrakizumab, risankizumab), and TNF inhibitors — generally do not require a REMS. Some carry Medication Guides, but none are subject to ETASU or formal Communication Plans under a REMS framework. Brodalumab (Siliq) is a notable exception: it is subject to a REMS with ETASU, but this is due to a specific suicidality risk signal that is not relevant to the JAK-class safety profile.
The absence of REMS precedent for oral JAK inhibitors across all approved indications is somewhat favorable to Penterra's position. However, this precedent must be considered in light of the following countervailing factors: (i) no JAK-1 inhibitor is currently approved for psoriasis, so the regulatory precedent for JAK inhibitors in dermatology is limited; (ii) the September 2021 class-wide labeling update reflects a trend of heightened FDA scrutiny of the JAK class that may not have been fully played out in the REMS context; and (iii) if FDA were to impose a REMS on velonatib for psoriasis, it could set a precedent that would affect other JAK inhibitors seeking dermatology indications, and FDA may be aware of the broader implications of such a decision.
D. Overall Likelihood Assessment
Based on the foregoing analysis, we assess the likelihood of various REMS outcomes as follows:
It is more likely than not that FDA will require some form of REMS for the psoriasis indication. The combination of a significantly expanded patient population, the non-life-threatening nature of psoriasis (leading to a more conservative benefit-risk calculus), the chronic duration of treatment, and the serious adverse events reflected in the boxed Warning collectively create a regulatory environment in which FDA is likely to conclude that existing labeling alone is insufficient and that a formal REMS is warranted.
However, the REMS elements are likely to be limited in scope. Our assessment of the likelihood of specific REMS elements is as follows:
Highly likely: Medication Guide. A Medication Guide is already required and approved for the RA indication and will be updated for the psoriasis indication. It is virtually certain that a Medication Guide will be included in any REMS for velonatib, whether as a standalone element or as part of a broader strategy. The draft Medication Guide Rev. 2, dated October 20, 2022, is currently under internal review and will reflect the psoriasis indication and any associated labeling updates.
Moderately likely: Communication Plan. Given the expansion of velonatib into a new therapeutic area and patient population, FDA may determine that a Communication Plan directed to healthcare providers is appropriate. Such a plan would likely include a "Dear Healthcare Provider" letter issued at the time of psoriasis indication approval, highlighting JAK-class risks in the psoriasis population, as well as prescriber training and educational materials. A Communication Plan is a proportionate response to the concerns identified in the factor-by-factor analysis and would not impose undue burdens on patient access or Penterra's commercial operations.
Unlikely: Elements to Assure Safe Use (ETASU). We assess it as unlikely that FDA will require ETASU for velonatib in psoriasis. The oral route of administration, the established safety profile from over three years of post-marketing RA experience, and the absence of ETASU for any currently marketed JAK inhibitor make ETASU a disproportionate response to the identified risks. ETASU are typically reserved for drugs with uniquely severe safety profiles (e.g., thalidomide, isotretinoin, certain opioids) or specific safety risks that cannot be adequately managed through labeling and healthcare provider communication alone (e.g., the suicidality risk associated with brodalumab). The JAK-class safety risks, while serious, are well-characterized and can be communicated through labeling and provider education. Additionally, the imposition of ETASU would create a significant competitive disadvantage for velonatib relative to biologic psoriasis therapies that are not subject to ETASU, and FDA is generally aware of the access implications of ETASU requirements.
Very unlikely: Implementation System. An Implementation System is required only when ETASU are imposed. Because ETASU are assessed as unlikely, an Implementation System is correspondingly very unlikely.
IV. RECOMMENDATIONS FOR THE sNDA SUBMISSION
Based on the analysis set forth above, we recommend the following approach for addressing REMS in the velonatib psoriasis sNDA.
A. Include a REMS Assessment Section
In accordance with 21 C.F.R. § 314.50(d)(5)(viii) and FDA's explicit direction at the Type B Pre-sNDA meeting, the sNDA must include a REMS assessment section. The omission of such a section would be inconsistent with FDA's stated expectations and could result in a Refuse to File letter or a request for additional information that would delay the review cycle. We therefore recommend that the REMS assessment section be treated as a required component of the sNDA submission package.
The REMS assessment should be prepared once the CLARION-3 safety data are available. As noted above, top-line data from CLARION-3 are expected in Q4 2022. The integrated safety data — combining the CLARION-2 twelve-month safety data, the CLARION-3 safety data, and relevant post-marketing safety experience from the RA indication — will form the evidentiary foundation of the REMS assessment. CBG will coordinate the preparation of integrated safety data tables, pooled analyses, and supporting clinical narratives for inclusion in the REMS assessment section.
B. Primary Position — Existing Labeling Sufficient
The primary position advanced in the REMS assessment should be that the existing and proposed risk mitigation tools are sufficient to ensure that the benefits of velonatib outweigh its risks in the psoriasis population, and that a formal REMS is not necessary. This position should be supported by a comprehensive presentation of the following risk mitigation tools:
1. boxed Warning. The boxed Warning for serious infections, malignancies, MACE, and thrombosis, consistent with JAK class labeling, provides the highest-level safety communication to healthcare providers. The boxed Warning language was updated in September 2021 to reflect the expanded risk information from the ORAL Surveillance trial and other post-marketing data, and it now comprehensively addresses the most serious risks associated with velonatib therapy.
2. Enhanced hepatotoxicity monitoring language. Section 5.5 of the USPI will be revised to include enhanced language regarding hepatotoxicity monitoring, consistent with FDA's guidance at the Type B Pre-sNDA meeting. The proposed language, which is being drafted in USPI Rev. 3, will recommend baseline and periodic liver function testing during velonatib therapy for psoriasis and will include guidance on dose modification or discontinuation in the event of clinically significant hepatic transaminase elevations.
3. Updated Medication Guide. The Medication Guide will be updated to reflect the psoriasis indication and associated risks, including hepatotoxicity monitoring recommendations. The Medication Guide is a patient-directed document that ensures patients are informed about the serious risks of velonatib therapy and can engage in shared decision-making with their healthcare providers. Draft Medication Guide Rev. 2 is currently under internal review.
4. Existing prescribing information. The USPI includes detailed information on adverse reactions, drug interactions, use in specific populations, and clinical pharmacology that collectively provide healthcare providers with the information necessary to make informed prescribing decisions and monitor patients for known risks.
The REMS assessment should support this primary position with the following evidentiary and analytical arguments:
• Integrated safety data. The integrated safety data from the CLARION clinical program should demonstrate that the adverse event profile of velonatib in the psoriasis population is consistent with the known safety profile reflected in the approved RA labeling. If the safety data show no new or unexpected safety signals, this will support the argument that existing labeling tools — which were deemed sufficient for the RA population — are equally adequate for the psoriasis population.
• Lower baseline risk in the psoriasis population. The REMS assessment should present data and analysis demonstrating that the psoriasis population has a lower baseline risk for cardiovascular events, serious infections, and other adverse events compared to the RA population. If the absolute incidence rates of serious adverse events in the psoriasis trials are lower than the rates observed in the RA trials, this would support the position that the risk profile in the psoriasis population does not warrant additional risk mitigation beyond enhanced labeling.
• Absence of REMS requirements for other JAK inhibitors. The REMS assessment should note that no currently marketed JAK inhibitor is subject to a REMS for any indication, and that FDA's consistent regulatory approach has been to rely on enhanced labeling as the primary risk mitigation tool for JAK-class safety concerns. The imposition of a REMS for velonatib in psoriasis would represent a departure from this established precedent and should be supported by specific safety data justifying the departure.
C. Alternative Position — Proposed REMS with Medication Guide and Communication Plan
If FDA determines that existing labeling is insufficient to ensure that the benefits of velonatib outweigh its risks in the psoriasis population, the sNDA should include a proposed alternative REMS consisting of two elements:
1. Medication Guide. The Medication Guide, already in place for the RA indication and updated for psoriasis (draft Rev. 2, dated October 20, 2022), would serve as the patient-directed component of the REMS. The Medication Guide would be required to be provided with each dispensing of velonatib and would communicate the serious risks of therapy, including the boxed Warning risks and the hepatotoxicity monitoring recommendations, in patient-accessible language.
2. Communication Plan directed to healthcare providers. The Communication Plan would include the following components:
• A "Dear Healthcare Provider" letter issued at the time of psoriasis indication approval, highlighting the JAK-class risks in the psoriasis population, the importance of appropriate patient selection, the availability of alternative therapies, and the recommended monitoring during velonatib therapy for psoriasis.
• Healthcare provider training materials and a prescriber fact sheet summarizing the key safety information, recommended monitoring parameters, and patient counseling points specific to the psoriasis indication.
• A periodic assessment schedule, with assessments proposed at 18 months, 3 years, and 7 years post-approval, consistent with the statutory timetable set forth in 21 U.S.C. § 355-1(d). Each assessment would evaluate the effectiveness of the REMS in communicating safety information and the continued appropriateness of the REMS elements.
The REMS assessment should emphasize, in connection with this alternative position, that ETASU are not warranted and would impose disproportionate burdens on patient access. The arguments against ETASU should be articulated clearly and supported by the following points: (i) the oral route of administration makes restricted distribution impractical and inconsistent with the drug's formulation and prescribing paradigm; (ii) the safety risks associated with velonatib are not unique to this drug but are class-wide concerns shared by all marketed JAK inhibitors, none of which are subject to ETASU; (iii) ETASU would create a significant competitive disadvantage for velonatib relative to biologic psoriasis therapies and other JAK inhibitors approved for other indications, potentially driving patients to therapies that may not be optimal for their clinical circumstances; and (iv) the purposes of risk mitigation — ensuring that healthcare providers and patients are informed about serious risks and that appropriate monitoring is conducted — can be fully achieved through a Medication Guide and Communication Plan without the access barriers created by ETASU.
D. Coordination with Penterra Teams
The preparation of the REMS assessment section will require coordination among multiple internal and external teams. We recommend the following coordination structure:
• Calderwood & Harkness LLP (Joel Strauss, Sean Morrissey): Legal framework analysis, regulatory strategy, drafting of the REMS assessment narrative, and review of the final REMS assessment section for legal sufficiency and consistency with the overall sNDA regulatory strategy.
• Penterra Regulatory Affairs (Dr. Karen Hessler, SVP, Regulatory Affairs): Submission assembly, FDA communications, coordination of the sNDA package, and review of the REMS assessment section for regulatory compliance and consistency with the USPI and Medication Guide drafts.
• Penterra Medical Affairs (Dr. Tomás Becerra): Clinical safety data interpretation, review of the integrated safety data analyses prepared by CBG, and input on the clinical characterization of the psoriasis patient population and baseline risk factors.
• Penterra Quality & CMC (Janet Ling): Review of any distribution-related considerations, including assessment of whether the current supply chain and distribution infrastructure would be affected by REMS requirements. Although ETASU (including restricted distribution) are not anticipated, Quality & CMC should be prepared to assess feasibility in the event that FDA raises distribution-related questions during the review.
• Callendar Baines Group LLC (Dr. Priya Sundaram, Managing Director; Dr. Neil Oxborough, Principal Consultant): Preparation of integrated safety data tables and pooled analyses, drafting of the clinical safety data summary for inclusion in the REMS assessment section, and strategic advice on the presentation of safety data to FDA.
Additionally, we note that patent counsel (Whitfield & Grange LLP; Dr. Eleanor Cassidy, Brian Takata) need not be directly involved in the REMS assessment specifically, as REMS-related issues do not typically implicate patent strategy. However, patent counsel should be kept informed of any labeling changes associated with the psoriasis sNDA — including changes to the boxed Warning, Warnings and Precautions, or Medication Guide — that could potentially affect the scope of patent claims or create issues related to the patent information listed in the Orange Book. We recommend that Dr. Hessler's team provide patent counsel with copies of all draft labeling revisions as they are circulated for internal review.
E. Timeline for REMS Assessment Drafting
The REMS assessment section cannot be finalized until the CLARION-3 safety data are available, as the integrated safety analysis will form the evidentiary foundation of the REMS assessment. The following timeline is proposed, contingent on the receipt of CLARION-3 top-line data in Q4 2022:
• CLARION-3 top-line data readout: Expected Q4 2022 (specific date to be confirmed by Penterra Clinical Operations).
• Integrated safety data summary: CBG to prepare integrated safety data tables, pooled analyses, and clinical safety narrative within four (4) weeks of the CLARION-3 data lock date. This deliverable will include pooled incidence rates for boxed Warning events, hepatotoxicity data, and comparison of adverse event rates between the psoriasis and RA clinical programs.
• REMS assessment section draft: Calderwood & Harkness to prepare the initial draft of the REMS assessment section for the sNDA within six (6) weeks of the CLARION-3 data lock date. This draft will incorporate the integrated safety data summary from CBG, the legal framework analysis from this memorandum, and the primary and alternative positions described above.
• Internal review cycle: The draft REMS assessment section will be circulated for review by Penterra Regulatory Affairs (Dr. Hessler), Medical Affairs (Dr. Becerra), and CBG (Dr. Sundaram, Dr. Oxborough). We anticipate one to two rounds of review and revision, to be completed within approximately three (3) weeks of circulation of the initial draft.
• Final REMS assessment section: Target completion date for the final REMS assessment section is approximately ten (10) weeks post-CLARION-3 data lock, to be included in the sNDA package for the targeted Q1 2023 filing.
• PDUFA goal date: If the sNDA is accepted for filing, the Prescription Drug User Fee Act ("PDUFA") goal date for a standard review would be approximately ten (10) months from the filing date, projecting a PDUFA date in approximately Q4 2023. If FDA grants priority review (which is not anticipated for this supplement), the review period would be six (6) months.
We emphasize that the timeline set forth above is dependent on the timely availability of CLARION-3 data and the completion of the integrated safety analyses by CBG. Any delay in the CLARION-3 readout or the data integration process would have a corresponding impact on the REMS assessment drafting timeline and potentially on the overall sNDA filing date. We recommend that Dr. Hessler's team establish a standing coordination meeting (biweekly or as needed) with CBG, Calderwood & Harkness, and the relevant Penterra functional areas to monitor progress against the timeline and address any issues as they arise.
V. CONCLUSION
Based on the foregoing analysis, we reach the following conclusions and recommendations:
First, FDA will require a REMS assessment to be included in the velonatib psoriasis sNDA, consistent with the Division's explicit direction at the May 4, 2022 Type B Pre-sNDA meeting and the applicable regulatory requirements. The inclusion of a REMS assessment section is a mandatory component of the sNDA submission.
Second, with respect to the substantive question of whether FDA will impose a formal REMS, we assess that the most probable outcome is one of two scenarios: (a) FDA will conclude that the existing and proposed labeling tools — including the boxed Warning, the enhanced hepatotoxicity monitoring language in Section 5.5 of the USPI, and the updated Medication Guide — are sufficient to ensure that the benefits of velonatib outweigh its risks in the psoriasis population, and no formal REMS will be required; or (b) FDA will require a limited REMS consisting of a Medication Guide and a Communication Plan directed to healthcare providers. These two outcomes collectively represent the most likely range of regulatory results.
Third, the imposition of ETASU — including restricted distribution, prescriber certification, patient registries, or mandatory monitoring beyond standard clinical practice — is unlikely given the established safety profile of velonatib, the absence of ETASU for any currently marketed JAK inhibitor, and the disproportionate burden that ETASU would impose on patient access. However, ETASU cannot be entirely ruled out, particularly if the CLARION-3 safety data reveal unexpected or adverse safety signals that materially alter the benefit-risk assessment. The completion and analysis of the CLARION-3 safety data is therefore a critical milestone for the REMS strategy.
Fourth, Calderwood & Harkness stands ready to draft the REMS assessment section upon receipt of the CLARION-3 top-line data, in coordination with CBG and the relevant Penterra functional teams. We recommend that Penterra Regulatory Affairs begin the process of compiling the integrated safety database at the earliest practicable date and coordinate with CBG to ensure that the safety data integration can proceed promptly after the CLARION-3 top-line readout. Early preparation of the data infrastructure will help ensure that the REMS assessment drafting timeline remains on track for the targeted Q1 2023 sNDA filing.
We look forward to discussing this memorandum and its recommendations with you at your convenience.
Please do not hesitate to contact us with any questions.
This memorandum is a privileged and confidential attorney-client communication and attorney work product. It is intended solely for the use of the addressees identified above and should not be disclosed to any third party without the prior written consent of Calderwood & Harkness LLP.
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: | September 22, 2022
RE: | REMS Assessment for Velonatib sNDA — Psoriasis Indication (NDA No. 215-847)
Matter No.: | 1018-00005

CALDERWOOD & HARKNESS LLP Attorneys at Law

MEMORANDUM

I. INTRODUCTION

II. LEGAL FRAMEWORK

V. CONCLUSION

Record

Parties

Dates

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