Contract analysis

I. INTRODUCTION AND PURPOSE OF LETTER Penterra Pharmaceuticals Corp. ("Penterra" or the "Company"), a corporation organized and existing under the laws of the State of Delaware and publicly traded on the New York Stock Exchange under the ticker symbol PTPH, respectfully submits this response to the inquiry letter issued by the Office of Prescription Drug Promotion ("OPDP") of the Center for Drug Evaluation and Resear

II. BACKGROUND — ZELVARA® (TREPIVANT SODIUM) Zelvara® (trepivant sodium) was approved by the FDA on October 11, 2019, under NDA No. 214-837, for the acute treatment of migraine with or without aura in adults. Zelvara® is available in two dosage strengths: 75 mg and 150 mg oral tablets. The product is Penterra's flagship pharmaceutical product and represents a significant treatment option for the millions of adults in

III. SUMMARY OF OPDP CONCERNS The Inquiry identified three specific promotional materials that OPDP determined raised concerns under applicable provisions of the Federal Food, Drug, and Cosmetic Act ("FDCA") and implementing regulations. All three materials were created as part of the "Clarity Campaign," a coordinated promotional initiative for Zelvara® that was designed and executed by Ridgeline Health Analytics LLC

III.A. Digital Banner Ad (Material ID: ZVR-2023-BNR-044) The first promotional material identified in the Inquiry is a digital banner advertisement bearing Material ID ZVR-2023-BNR-044 (the "Banner Ad"). The Banner Ad was displayed on MedLinkPro, a healthcare-professional-targeted medical-education platform, during the period from April 15, 2023, through August 31, 2023. OPDP identified two specific concerns with the

III.B. Physician Email Blast (Material ID: ZVR-2023-EML-019) The second promotional material identified in the Inquiry is a physician email blast bearing Material ID ZVR-2023-EML-019 (the "Email Blast"). The Email Blast was sent on June 7, 2023, to a distribution list comprising approximately 42,000 neurologists and primary-care physicians across the United States. Concern — Misleading Graphical Presentation. OPDP de

III.C. Sales Representative Detail Aid (Material ID: ZVR-2023-DA-007) The third promotional material identified in the Inquiry is a sales representative detail aid bearing Material ID ZVR-2023-DA-007 (the "Detail Aid"). The Detail Aid was approved by Penterra's Promotional Review Committee ("PRC") on March 22, 2023, and subsequently distributed to field sales representatives for use in physician office visits and oth

IV. PENTERRA'S RESPONSE TO EACH OPDP CONCERN Penterra has carefully reviewed each of the three concerns identified in the Inquiry and has conducted a thorough internal investigation, the scope of which is described further in Section V below. In this Section IV, Penterra provides its substantive response to each concern. Penterra approaches this response with a commitment to transparency and accountability, and where

IV.A. Response Regarding Digital Banner Ad ZVR-2023-BNR-044

IV.A.1. "Fastest Onset in Its Class" Claim Penterra acknowledges OPDP's concern that the claim "Fastest Onset in Its Class," as it appeared in the Banner Ad, constituted an unsubstantiated comparative superiority claim. Having conducted a thorough review of the evidentiary basis for this claim, Penterra provides the following response. The "Fastest Onset in Its Class" claim was based on the results of an indirect tre

IV.A.2. Omission of Hepatotoxicity Risk Penterra further acknowledges OPDP's concern that the Banner Ad failed to include risk information regarding hepatotoxicity, specifically the finding that ALT elevations exceeding 3× ULN were observed in 1.8% of clinical-trial subjects in the Zelvara® development program. This risk is clearly identified in the approved PI for Zelvara® and constitutes material safety information

IV.B. Response Regarding Physician Email Blast ZVR-2023-EML-019 Penterra acknowledges OPDP's concern that the bar chart included in the Email Blast constituted a misleading graphical presentation of the SUMMIT-3 trial data. Having conducted a detailed internal review of the circumstances surrounding the creation, review, and approval of the Email Blast, Penterra provides the following response. The bar chart in the E

IV.C. Response Regarding Sales Representative Detail Aid ZVR-2023-DA-007 Penterra acknowledges OPDP's concern that the Detail Aid cited the Harmon et al. poster presentation (American Headache Society Annual Meeting, 2022) as "real-world evidence" without providing adequate disclosure of material facts regarding the cited study. Having reviewed the Detail Aid and the circumstances surrounding its creation and approva

V. INTERNAL INVESTIGATION — SCOPE AND ADDITIONAL FINDINGS

V.A. Scope of Internal Review Promptly upon receipt of the Inquiry on October 16, 2023, Penterra, acting through outside counsel at Calderwood & Harkness LLP and Whitfield Bauer & Associates LLP and with the forensic e-discovery assistance of Tavrenis Stern Consulting Group LLC ("Tavrenis Stern"), initiated a comprehensive internal investigation into the promotional practices and materials at issue. The scope of this

V.B. Findings Beyond the Three Cited Materials The review of the sixty-four (64) Zelvara® promotional materials approved by the PRC during the January through October 2023 period that were not the subject of the Inquiry did not identify additional material compliance deficiencies. Penterra is satisfied, based on the thoroughness of this review, that the compliance issues identified by OPDP were limited to the three C

V.C. Root-Cause Analysis As part of the internal investigation, Penterra and its outside counsel conducted a root-cause analysis to identify the systemic and procedural factors that contributed to the promotional compliance failures identified by OPDP and discovered through the internal review. The root-cause analysis yielded the following principal findings: Agency Oversight Deficiency. The Clarity Campaign material

VI. CORRECTIVE ACTION PLAN In response to the concerns raised by OPDP in the Inquiry and the additional deficiencies identified through its internal investigation, Penterra has implemented or will implement the following seven corrective actions. These measures are designed to address both the specific promotional compliance failures at issue and the systemic root causes identified through the Company's investigation

VI.A. Corrective Action 1 — Immediate Withdrawal of Cited Materials All three promotional materials identified by OPDP in the Inquiry were voluntarily withdrawn from distribution on November 3, 2023, less than three weeks after Penterra received the Inquiry. The specific withdrawal actions were as follows: (a) Digital Banner Ad (ZVR-2023-BNR-044). Penterra directed MedLinkPro to immediately remove the Banner Ad from

VI.B. Corrective Action 2 — Corrective "Dear Healthcare Provider" Letter Penterra issued a corrective "Dear Healthcare Provider" letter, dated December 11, 2023, to the approximately 42,000 neurologists and primary-care physicians who received the June 7, 2023 Email Blast (ZVR-2023-EML-019). The corrective letter was distributed by email and, where email delivery could not be confirmed, by first-class mail. The corre

VI.C. Corrective Action 3 — Revised PRC Standard Operating Procedures In direct response to the governance deficiency identified in the root-cause analysis — specifically, the ability of the PRC to approve promotional materials over the objection of Medical Affairs by simple majority vote — Penterra has revised its PRC Standard Operating Procedures ("SOPs"). The revised SOPs were approved by Penterra's executive lead

VI.D. Corrective Action 4 — Mandatory Sales Force Retraining Penterra is conducting mandatory compliance retraining for all of its approximately 680 field sales representatives company-wide. This retraining program is designed to address both the off-label verbal claims identified in the internal investigation (wherein three Northeast-region sales representatives suggested that Zelvara® was effective for cluster head

VI.E. Corrective Action 5 — Termination of Ridgeline Health Analytics Engagement As described in Section V.C above, the root-cause analysis identified Ridgeline Health Analytics LLC's SOW as a contributing factor to the promotional compliance failures at issue. Specifically, the SOW did not require Ridgeline to subject draft promotional claims and data presentations to independent medical-legal review prior to their

VI.F. Corrective Action 6 — Engagement of New Promotional Agency Penterra has engaged Calloway & March Communications LLC ("Calloway & March") as the successor promotional agency for the Zelvara® brand, effective March 18, 2024. The engagement of Calloway & March was conducted following a competitive selection process that evaluated multiple candidate agencies on criteria including FDA regulatory expertise, promotion

VI.G. Corrective Action 7 — Enhanced Monitoring of Sales Representative Interactions To address the off-label promotion identified in the internal investigation and to strengthen Penterra's ongoing monitoring of field sales activity, Penterra will implement a quarterly audit program under which the Medical Affairs function reviews a random ten percent (10%) sample of sales representative interactions — including CRM

VII. PENTERRA'S COMMITMENT TO COMPLIANCE Penterra Pharmaceuticals Corp. is firmly committed to full compliance with all applicable FDA promotional regulations, including Section 502(n) of the FDCA, 21 U.S.C. § 352(n); the implementing regulations set forth in 21 C.F.R. Part 202; and applicable OPDP guidance documents. The Company recognizes that the integrity of prescription drug promotion is essential to protecting

VIII. CONCLUSION For the reasons set forth above, Penterra Pharmaceuticals Corp. respectfully requests that OPDP accept this response and the accompanying corrective action plan as a satisfactory and comprehensive resolution of the matters raised in OPDP Inquiry OPDP-2023-1847. Penterra has acknowledged each of the three specific concerns identified in the Inquiry, has conceded the deficiencies in its promotional mat