PRIVILEGED & CONFIDENTIAL — ATTORNEY-CLIENT COMMUNICATION
Lisa, Karen,
Thank you both for making time to speak with us last evening and for sharing the CLARION-3 top-line data ahead of this morning's press release. I know November 17 was not the day the team had hoped for, and I appreciate the candor and thoroughness of the briefing. I wanted to memorialize our preliminary regulatory assessment in writing so we can align on next steps.
**I. Summary of CLARION-3 Top-Line Results**
Based on last evening's call and this morning's public announcement, the following is our understanding of the top-line results from the CLARION-3 trial (N = 698; three-arm, randomized, double-blind study of velonatib hydrochloride 10 mg once daily vs. adalimumab biosimilar vs. placebo in adults with moderate-to-severe chronic plaque psoriasis):
**Co-Primary Endpoint — PASI-90 at Week 16:**
- Velonatib 10 mg: 43.9% - Adalimumab biosimilar: 39.7% - Placebo: 8.3% - Velonatib vs. adalimumab: p = 0.174 - **Endpoint not met.** The velonatib-vs.-adalimumab comparison did not achieve statistical significance.
**Co-Primary Endpoint — sPGA 0/1 at Week 16:**
- Results have not yet been publicly disclosed. Based on our discussion, we understand this endpoint was met for the velonatib-vs.-adalimumab comparison, but confirmation of the p-value is pending final data lock. We will await the locked dataset before drawing firm conclusions on this endpoint.
**Key Secondary Endpoint — PASI-75 at Week 16:**
- Velonatib 10 mg: 69.8% - Adalimumab biosimilar: 62.1% - Placebo: 10.5% - Velonatib vs. adalimumab: p = 0.012 - **Met.**
**II. Regulatory Assessment**
1. **Filing is not viable at this time.** As you will recall, FDA communicated clearly at the May 4, 2022 Type B Pre-sNDA meeting (Meeting ID: FDA-2022-M-1743) that both co-primary endpoints in the confirmatory trial were required for the agency to consider the efficacy supplement for a new indication (Section 505(b), FD&C Act) under NDA No. 215-847. Because PASI-90 at Week 16 did not achieve statistical significance for the velonatib-vs.-adalimumab comparison, the CLARION-3 data as reported do not satisfy FDA's stated evidentiary standard. We cannot in good conscience recommend proceeding with the sNDA filing on the current data package.
2. **CLARION-2 standing alone is insufficient.** CLARION-2 met both co-primary endpoints robustly — PASI-75 at Week 16 (71.5% vs. 9.1%, p < 0.001) and sPGA 0/1 at Week 16 (58.3% vs. 5.7%, p < 0.001) — and remains a strong study. However, a single pivotal trial is generally insufficient to support an efficacy supplement for a new indication absent extraordinary circumstances, such as a very large treatment effect, high consistency across subgroups, and substantial additional supportive evidence. Given that CLARION-3 was specifically designed to serve as the confirmatory trial and failed to meet one of its co-primary endpoints, it is our assessment that FDA would not accept a filing predicated on CLARION-2 alone.
3. **Possible paths forward.** We see three principal options for Penterra to consider:
**(a) Redesigned confirmatory trial.** Penterra could design and conduct a new Phase III confirmatory study with revised endpoints — for example, PASI-75 at Week 16 as the primary endpoint, with PASI-90 repositioned as a key secondary endpoint. This would require an IND amendment and, in all likelihood, a new Type B meeting with FDA to reach agreement on acceptable endpoints and trial design before initiation. This is the most straightforward path to a viable filing, though it carries obvious cost, time, and execution implications.
**(b) Request for a Type A meeting.** Penterra could request a Type A meeting with FDA to present the totality of the CLARION program data and explore whether any modified analysis, pooled data approach, or additional evidence from the existing program could address FDA's concerns. We feel obligated to note, however, that the magnitude of the miss on PASI-90 is substantial — a p-value of 0.174 is not close to the threshold of statistical significance, and the absolute difference between velonatib and adalimumab on this endpoint (4.2 percentage points) is modest. Our assessment is that the likelihood of FDA accepting modified analyses as a substitute for a positive confirmatory result is low. That said, a Type A meeting could still serve a useful purpose in clarifying the agency's expectations for any future trial.
**(c) Withdrawal or pause of the sNDA effort.** Penterra could elect to pause the psoriasis sNDA program and undertake a broader reassessment of the clinical development strategy for the moderate-to-severe chronic plaque psoriasis indication. This may be appropriate if internal portfolio prioritization or resource considerations favor redirecting investment to other indications or development programs for VELONATIB®.
4. **Labeling drafts on hold.** We recommend that all draft labeling documents be placed on hold immediately. This includes specifically the USPI Rev. 3 (dated October 15, 2022) and the Medication Guide Rev. 2 (dated October 20, 2022). No further development, revision, or review of the sNDA submission package is warranted until there is a viable clinical data package to support the filing.
**III. Immediate Next Steps**
We recommend convening a meeting of the full regulatory team — Penterra Regulatory Affairs, Calderwood & Harkness, and Callendar Baines Group — early next week to discuss the options outlined above in greater detail and begin aligning on a go-forward strategy. Sean and I are available Monday or Tuesday. Could you let us know your availability, and Karen, whether CBG can accommodate those dates as well?
**IV. Closing Thought**
I want to acknowledge directly that this is a significant setback for the psoriasis program and for everyone who has invested so much effort in bringing VELONATIB® to patients who need it. Clinical development rarely proceeds in a straight line, and the strength of the CLARION-2 data and the positive secondary endpoints in CLARION-3 suggest that velonatib has meaningful efficacy in this population. The question is one of regulatory pathway, not of science.
Please know that Calderwood & Harkness is fully committed to supporting Penterra through this reassessment process and through whatever regulatory interactions follow. We will bring the same rigor and focus to the path forward that we have brought to the program to date.
I look forward to speaking with you both early next week.
Best regards,
Joel Strauss Partner
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