Contract analysis

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. ("Pent

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 agenc

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 seri

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 trea

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 stren

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 even

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

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

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, an

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 cr

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 com

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 Phys

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

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

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 p

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 inconsisten

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 modifica

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 curr

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 a

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 recom

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

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