Contract analysis

I. PURPOSE This memorandum is prepared at the request of Penterra Pharmaceuticals Corp. ("PPC" or "Penterra") and is intended to provide a comprehensive analysis of Penterra's regulatory options for pursuing a supplemental New Drug Application ("sNDA") for Velonatib (NDA No. 215-847) for the chronic plaque psoriasis indication, following the top-line results of the CLARION-3 Phase III confirmatory trial announced on

II. CURRENT STATUS OF THE CLINICAL PROGRAM A. CLARION-3 Top-Line Results CLARION-3 was a Phase III, double-blind, randomized, placebo- and active-comparator-controlled confirmatory study designed to evaluate the efficacy and safety of Velonatib 10 mg administered orally once daily in adult patients with moderate-to-severe chronic plaque psoriasis. The study enrolled a total of 698 patients randomized across three tre

III. REGULATORY OPTIONS We have identified three principal regulatory options for Penterra to consider. Each option is analyzed below in terms of its description, design considerations (where applicable), timeline, cost, regulatory risk, and our recommendation. Option A: Redesigned Confirmatory Trial (CLARION-3R) Description. Under this option, Penterra would design and conduct a new Phase III confirmatory study — de

1. Maintain the Calderwood & Harkness engagement on dormant status to allow rapid reactivation of the regulatory and labeling workstreams when Penterra is ready to proceed. Dormancy terms should be agreed and documented to ensure continuity of the attorney-client relationship and preservation of work product.

2. Continue monitoring the following areas during the pause period: (i) FDA guidance documents and advisory committee proceedings relating to JAK inhibitors, including any developments affecting class-wide labeling, REMS, or study requirements; (ii) Competitor labeling changes in the psoriasis therapeutic area, including new approvals, supplemental approvals, and labeling revisions for IL-17, IL-23, and JAK inhibitor

IV. RECOMMENDED COURSE OF ACTION Based on our analysis of the three regulatory options set forth above, we recommend Option A (Redesigned Confirmatory Trial), combined with certain elements of Option C in the near term to allow orderly planning and engagement with FDA before committing to trial initiation. Specifically, we recommend the following course of action:

1. Place the sNDA effort on formal dormancy effective immediately. No further work should be performed on labeling drafts, REMS assessment preparation, submission assembly, or other sNDA-related activities until CLARION-3R data are available and analyzed. All draft work product should be preserved in its current state and filed in accordance with the document hold procedures described in Section V below. This include

2. Request a Type B meeting with FDA in Q1 2023. The meeting request should be submitted to the Division of Dermatology and Dentistry, Office of Immunology and Inflammation, CDER, and should focus on the following objectives: (a) Presentation of the CLARION-3R study design, including the proposed primary endpoint (PASI-75 at Week 16), key secondary endpoint (PASI-90 at Week 16), and the rationale for the revised endp

3. Redesign CLARION-3R with the following key parameters: • Primary endpoint: PASI-75 at Week 16 (superiority of Velonatib 10 mg vs. placebo) • Key secondary endpoint: PASI-90 at Week 16 (Velonatib 10 mg vs. placebo and vs. adalimumab biosimilar) • Target enrollment: Approximately 950 patients • Comparator arms: Adalimumab biosimilar (active comparator) and placebo • Study design: Double-blind, randomized, three-arm,

4. Submit the IND amendment for CLARION-3R upon FDA alignment on the protocol. The target submission date for the IND amendment is March 2023, contingent on the timing and outcome of the Type B meeting.

5. Initiate CLARION-3R enrollment. Projected initiation is Q3 2023, subject to the timeline considerations discussed in Section III.A above.

6. Reactivate the labeling supplement engagement upon receipt of CLARION-3R top-line data (projected: H2 2024). Upon reactivation, Calderwood & Harkness will: (a) Prepare a comprehensive regulatory-landscape update memorandum analyzing any developments in FDA guidance, class-wide JAK-inhibitor labeling, and competitor approvals that occurred during the dormancy period; (b) Update all draft labeling documents (USPI, M

V. LABELING AND WORK-PRODUCT STATUS A. Draft Documents on Hold All draft labeling documents prepared by Calderwood & Harkness in connection with the Velonatib psoriasis sNDA should be placed on formal hold effective as of November 22, 2022, the date on which the working group determined that the sNDA filing timeline would need to be revised in light of the CLARION-3 results. The key drafts currently on file are as fo

VI. ADDITIONAL CONSIDERATIONS A. Pediatric Study Deferral FDA granted a pediatric study deferral for Velonatib on July 28, 2022, in connection with the pediatric Written Request for studies in the pediatric psoriasis population. Under the terms of the deferral, the deadline for submission of the required pediatric studies is 18 months following approval of the adult psoriasis indication. The deferral remains in effec

VII. CONCLUSION The CLARION-3 outcome, while a significant setback for the Velonatib psoriasis development program, does not foreclose the psoriasis indication. The trial's failure was limited to a single co-primary endpoint — PASI-90 at Week 16 in the comparison against the adalimumab biosimilar — and must be understood in the context of a study that otherwise demonstrated clinically meaningful and statistically sig