PENTERRA PHARMACEUTICALS CORP. 480 Overlook Drive, Suite 700 Summit, NJ 07901 (NYSE: PTPH)

November 1, 2023

Dr. Carla M. Witherspoon, Pharm.D. Regulatory Review Officer Office of Prescription Drug Promotion (OPDP) Center for Drug Evaluation and Research (CDER) U.S. Food and Drug Administration 10903 New Hampshire Avenue Silver Spring, MD 20993-0002

Re: Request for Extension of Response Deadline

Inquiry Reference Number: OPDP-2023-1847 Product: Zelvara® (trepivant sodium), 75 mg and 150 mg oral tablets NDA No. 214-837

Dear Dr. Witherspoon:

Penterra Pharmaceuticals Corp. ("Penterra"), a Delaware corporation headquartered in Summit, New Jersey, respectfully requests a sixty (60)-day extension of the deadline to respond to the inquiry letter issued by the Office of Prescription Drug Promotion ("OPDP") dated October 12, 2023, bearing reference number OPDP-2023-1847 (the "Inquiry"). The Inquiry was received by Penterra via email and United States Postal Service certified mail on October 16, 2023. Under the current thirty (30)-day response period, Penterra's response is due on November 15, 2023. By this letter, Penterra respectfully requests that the response deadline be extended to January 15, 2024. I am Margaret Tan, Executive Vice President and General Counsel of Penterra, and I am writing on behalf of the company in connection with this request. As set forth below, the extension is warranted by the scope and complexity of the matters raised in the Inquiry, the volume of materials and data that must be reviewed, and the steps Penterra has already taken voluntarily and in good faith to address OPDP's concerns.

Penterra acknowledges that the Inquiry concerns three promotional materials disseminated in connection with Zelvara® (trepivant sodium), which was approved by the U.S. Food and Drug Administration on October 11, 2019, under NDA No. 214-837, for the acute treatment of migraine with or without aura in adults. The three promotional materials cited in the Inquiry are as follows: (1) a digital banner advertisement (Material ID: ZVR-2023-BNR-044), which ran on the healthcare-professional-targeted medical-education platform MedLinkPro from approximately April 15, 2023 through August 31, 2023; (2) a physician email blast (Material ID: ZVR-2023-EML-019), distributed on June 7, 2023, to approximately 42,000 neurologists and primary-care physicians via Penterra's commercial email distribution system; and (3) a sales representative detail aid (Material ID: ZVR-2023-DA-007), which was reviewed and approved by Penterra's internal Promotional Review Committee ("PRC") on March 22, 2023, and subsequently distributed to Penterra's field sales force for use in physician detailing. Penterra understands that the Inquiry raises concerns regarding potentially misleading efficacy claims, the omission or minimization of important risk information, unsubstantiated superiority claims, and misleading graphical presentations of clinical data, in potential violation of Section 502(n) of the Federal Food, Drug, and Cosmetic Act, 21 U.S.C. § 352(n), and the implementing regulations at 21 C.F.R. § 202.1(e)(5) and (e)(6). Penterra takes these concerns with the utmost seriousness and is committed to providing OPDP with a thorough, accurate, and fully responsive submission.

The extension is necessary, in the first instance, because of the substantial volume of promotional materials that Penterra must review in order to provide a comprehensive and accurate response. During the period from January 1, 2023 through October 16, 2023, Penterra's PRC reviewed and approved a total of sixty-seven (67) promotional materials related to Zelvara®, spanning a range of formats including digital advertisements, print journal advertisements, physician emails, sales representative detail aids, conference booth materials, patient brochures, and social media content. While the Inquiry specifically identifies three of these materials, Penterra believes that a responsible and complete response requires a review of the entire Zelvara® promotional portfolio approved during this period. This broader scope of review is necessary to ensure that Penterra's response fully addresses OPDP's concerns, identifies any additional materials that may contain language, claims, or presentations similar to those cited in the Inquiry, and enables Penterra to implement any corrective actions on a comprehensive basis rather than in a piecemeal fashion. In addition, Penterra must review the minutes and supporting documentation from nine (9) PRC meetings held between January and October 2023 at which Zelvara® promotional materials were discussed, reviewed, and approved. This review will include an assessment of the clinical and regulatory substantiation relied upon by the PRC in approving the cited materials, the internal deliberations regarding risk-benefit balance and fair-balance requirements, and any comments or objections raised during the review process. The scope and detail of this review cannot be adequately completed within the current thirty-day response period.

Second, the extension is necessary to allow Penterra to conduct an internal investigation into the field sales communications associated with the cited detail aid. Penterra employs approximately 680 field sales representatives nationwide who are responsible for detailing Zelvara® and other Penterra products to healthcare professionals. Because the Inquiry specifically references the sales representative detail aid bearing Material ID ZVR-2023-DA-007, Penterra has determined that it must investigate how its sales representatives communicated about Zelvara® in physician interactions where the detail aid was used or referenced. Through a preliminary review of distribution records, Penterra has identified fourteen (14) sales representatives in the Northeast region who received and distributed the detail aid at issue and whose customer-relationship management ("CRM") records, email communications, and text-message communications must be collected, preserved, and reviewed. To ensure the integrity and thoroughness of this process, Penterra has engaged Tavrenis Stern Consulting Group LLC, an e-discovery and forensic consulting firm based in Chicago, Illinois, to assist in the identification, preservation, collection, processing, and review of these electronic communications under the direction of counsel. The forensic review process involves multiple sequential phases — including the issuance of litigation hold and preservation notices, forensic imaging of mobile devices and laptop computers, collection and de-duplication of electronically stored information, keyword and conceptual search-term development, and document-by-document review — each of which requires sufficient time to be performed accurately and defensibly. Penterra anticipates that the data collection phase alone will require approximately three to four weeks to complete, and the subsequent review and analysis will require additional time beyond that.

Third, the extension is warranted because Penterra has only recently engaged outside counsel to assist in the preparation of its response. On October 30, 2023, Penterra retained Calderwood & Harkness LLP, with offices at 600 Lexington Avenue, New York, New York 10022, as outside counsel to advise Penterra on responding to the OPDP Inquiry, directing the internal investigation described above, and preparing a comprehensive written response and corrective action plan. Additionally, Penterra intends to engage specialist FDA regulatory co-counsel with particular expertise in prescription drug promotion and OPDP enforcement matters to ensure that the response fully and accurately addresses the applicable legal and regulatory framework, including the substantiation standards for promotional claims under FDA guidance and applicable case law. Outside counsel requires adequate time to review and familiarize themselves with the extensive factual record, including the sixty-seven approved promotional materials, the nine sets of PRC meeting minutes, the underlying clinical studies and data relied upon for promotional claims, and the electronic communications collected from field sales representatives. Counsel must then complete the internal investigation, analyze the legal and regulatory issues raised by the Inquiry, and prepare a thorough response and corrective action plan that meets the standards expected by OPDP. The engagement of qualified outside counsel is essential to ensuring that Penterra's response is complete, accurate, and appropriately addresses each of the concerns identified in the Inquiry, and this process cannot reasonably be completed within the remaining days before the current November 15, 2023 deadline.

As a demonstration of Penterra's good faith and its unwavering commitment to promotional compliance, the company has already voluntarily initiated the withdrawal of all three cited promotional materials from active use and distribution. Penterra expects to complete the withdrawal of all three materials no later than November 3, 2023. Specifically, the digital banner advertisement (Material ID: ZVR-2023-BNR-044) has been removed from the MedLinkPro platform; although the advertising campaign had already concluded on August 31, 2023, Penterra has formally withdrawn the material from its approved-for-use inventory to ensure that it is not re-deployed in any future campaign. The physician email blast (Material ID: ZVR-2023-EML-019) has been taken out of circulation and removed from Penterra's email marketing queue, and the underlying email template has been deactivated in the company's marketing automation system to prevent inadvertent redistribution. The sales representative detail aid (Material ID: ZVR-2023-DA-007) has been recalled from field use; all sales representatives who received the detail aid have been notified by Penterra's Commercial Operations department that the material is no longer approved for use and must be returned or destroyed, and electronic versions of the detail aid have been removed from the sales force's tablet-based content management system. These voluntary actions were taken promptly upon Penterra's receipt of the Inquiry and well in advance of any formal enforcement action, and they underscore Penterra's commitment to ensuring that all of its promotional communications for Zelvara® are accurate, balanced, non-misleading, and fully consistent with Zelvara®'s FDA-approved labeling.

In light of the foregoing, Penterra respectfully requests that the response deadline be extended by sixty (60) days, from November 15, 2023 to January 15, 2024. Penterra commits to submitting a thorough, comprehensive written response to the Inquiry no later than the proposed extended deadline of January 15, 2024. The additional time will enable Penterra to provide OPDP with a complete factual record, including the results of the internal investigation of field sales communications; a detailed, material-by-material analysis of each of the three cited promotional pieces and the specific claims and presentations identified in the Inquiry; and a robust corrective action plan designed to remediate any identified deficiencies and prevent recurrence. Penterra will continue to cooperate fully with OPDP throughout this process and will promptly notify OPDP of any material developments arising from its internal review.

The primary contact for Penterra regarding all matters related to this Inquiry is the undersigned, Margaret Tan, Executive Vice President and General Counsel, Penterra Pharmaceuticals Corp., 480 Overlook Drive, Suite 700, Summit, NJ 07901, telephone (908) 555-4100, email m.tan@penterrapharma.com. OPDP may also direct communications to Penterra's outside counsel, Leonard Cross, Esq., and Jeffrey Park, Esq., Calderwood & Harkness LLP, 600 Lexington Avenue, New York, NY 10022, telephone (212) 555-7800.

Thank you for your consideration of this request. We would welcome the opportunity to discuss this request further or to provide any additional information that OPDP may require at your convenience. Should you wish to schedule a telephone conference or meeting to address any questions regarding the matters set forth herein, please do not hesitate to contact the undersigned or Penterra's outside counsel at the contact information provided above.

Respectfully submitted,

PENTERRA PHARMACEUTICALS CORP.

By: ________

Margaret Tan Executive Vice President & General Counsel Penterra Pharmaceuticals Corp. 480 Overlook Drive, Suite 700 Summit, NJ 07901 Tel: (908) 555-4100

Email: m.tan@penterrapharma.com

cc: (via email and first-class mail)

Leonard Cross, Esq., Calderwood & Harkness LLP Jeffrey Park, Esq., Calderwood & Harkness LLP Christine Holloway, Vice President, Regulatory Affairs, Penterra Pharmaceuticals Corp. Rajeev Anand, M.D., Ph.D., Chief Medical Officer, Penterra Pharmaceuticals Corp.

PENTERRA PHARMACEUTICALS CORP. 480 Overlook Drive, Suite 700 Summit, NJ 07901 (NYSE: PTPH)
November 1, 2023
Dr. Carla M. Witherspoon, Pharm.D. Regulatory Review Officer Office of Prescription Drug Promotion (OPDP) Center for Drug Evaluation and Research (CDER) U.S. Food and Drug Administration 10903 New Hampshire Avenue Silver Spring, MD 20993-0002
Re: Request for Extension of Response Deadline
Inquiry Reference Number: OPDP-2023-1847 Product: Zelvara® (trepivant sodium), 75 mg and 150 mg oral tablets NDA No. 214-837
Dear Dr. Witherspoon:
Penterra Pharmaceuticals Corp. ("Penterra"), a Delaware corporation headquartered in Summit, New Jersey, respectfully requests a sixty (60)-day extension of the deadline to respond to the inquiry letter issued by the Office of Prescription Drug Promotion ("OPDP") dated October 12, 2023, bearing reference number OPDP-2023-1847 (the "Inquiry"). The Inquiry was received by Penterra via email and United States Postal Service certified mail on October 16, 2023. Under the current thirty (30)-day response period, Penterra's response is due on November 15, 2023. By this letter, Penterra respectfully requests that the response deadline be extended to January 15, 2024. I am Margaret Tan, Executive Vice President and General Counsel of Penterra, and I am writing on behalf of the company in connection with this request. As set forth below, the extension is warranted by the scope and complexity of the matters raised in the Inquiry, the volume of materials and data that must be reviewed, and the steps Penterra has already taken voluntarily and in good faith to address OPDP's concerns.
Penterra acknowledges that the Inquiry concerns three promotional materials disseminated in connection with Zelvara® (trepivant sodium), which was approved by the U.S. Food and Drug Administration on October 11, 2019, under NDA No. 214-837, for the acute treatment of migraine with or without aura in adults. The three promotional materials cited in the Inquiry are as follows: (1) a digital banner advertisement (Material ID: ZVR-2023-BNR-044), which ran on the healthcare-professional-targeted medical-education platform MedLinkPro from approximately April 15, 2023 through August 31, 2023; (2) a physician email blast (Material ID: ZVR-2023-EML-019), distributed on June 7, 2023, to approximately 42,000 neurologists and primary-care physicians via Penterra's commercial email distribution system; and (3) a sales representative detail aid (Material ID: ZVR-2023-DA-007), which was reviewed and approved by Penterra's internal Promotional Review Committee ("PRC") on March 22, 2023, and subsequently distributed to Penterra's field sales force for use in physician detailing. Penterra understands that the Inquiry raises concerns regarding potentially misleading efficacy claims, the omission or minimization of important risk information, unsubstantiated superiority claims, and misleading graphical presentations of clinical data, in potential violation of Section 502(n) of the Federal Food, Drug, and Cosmetic Act, 21 U.S.C. § 352(n), and the implementing regulations at 21 C.F.R. § 202.1(e)(5) and (e)(6). Penterra takes these concerns with the utmost seriousness and is committed to providing OPDP with a thorough, accurate, and fully responsive submission.
The extension is necessary, in the first instance, because of the substantial volume of promotional materials that Penterra must review in order to provide a comprehensive and accurate response. During the period from January 1, 2023 through October 16, 2023, Penterra's PRC reviewed and approved a total of sixty-seven (67) promotional materials related to Zelvara®, spanning a range of formats including digital advertisements, print journal advertisements, physician emails, sales representative detail aids, conference booth materials, patient brochures, and social media content. While the Inquiry specifically identifies three of these materials, Penterra believes that a responsible and complete response requires a review of the entire Zelvara® promotional portfolio approved during this period. This broader scope of review is necessary to ensure that Penterra's response fully addresses OPDP's concerns, identifies any additional materials that may contain language, claims, or presentations similar to those cited in the Inquiry, and enables Penterra to implement any corrective actions on a comprehensive basis rather than in a piecemeal fashion. In addition, Penterra must review the minutes and supporting documentation from nine (9) PRC meetings held between January and October 2023 at which Zelvara® promotional materials were discussed, reviewed, and approved. This review will include an assessment of the clinical and regulatory substantiation relied upon by the PRC in approving the cited materials, the internal deliberations regarding risk-benefit balance and fair-balance requirements, and any comments or objections raised during the review process. The scope and detail of this review cannot be adequately completed within the current thirty-day response period.
Second, the extension is necessary to allow Penterra to conduct an internal investigation into the field sales communications associated with the cited detail aid. Penterra employs approximately 680 field sales representatives nationwide who are responsible for detailing Zelvara® and other Penterra products to healthcare professionals. Because the Inquiry specifically references the sales representative detail aid bearing Material ID ZVR-2023-DA-007, Penterra has determined that it must investigate how its sales representatives communicated about Zelvara® in physician interactions where the detail aid was used or referenced. Through a preliminary review of distribution records, Penterra has identified fourteen (14) sales representatives in the Northeast region who received and distributed the detail aid at issue and whose customer-relationship management ("CRM") records, email communications, and text-message communications must be collected, preserved, and reviewed. To ensure the integrity and thoroughness of this process, Penterra has engaged Tavrenis Stern Consulting Group LLC, an e-discovery and forensic consulting firm based in Chicago, Illinois, to assist in the identification, preservation, collection, processing, and review of these electronic communications under the direction of counsel. The forensic review process involves multiple sequential phases — including the issuance of litigation hold and preservation notices, forensic imaging of mobile devices and laptop computers, collection and de-duplication of electronically stored information, keyword and conceptual search-term development, and document-by-document review — each of which requires sufficient time to be performed accurately and defensibly. Penterra anticipates that the data collection phase alone will require approximately three to four weeks to complete, and the subsequent review and analysis will require additional time beyond that.
Third, the extension is warranted because Penterra has only recently engaged outside counsel to assist in the preparation of its response. On October 30, 2023, Penterra retained Calderwood & Harkness LLP, with offices at 600 Lexington Avenue, New York, New York 10022, as outside counsel to advise Penterra on responding to the OPDP Inquiry, directing the internal investigation described above, and preparing a comprehensive written response and corrective action plan. Additionally, Penterra intends to engage specialist FDA regulatory co-counsel with particular expertise in prescription drug promotion and OPDP enforcement matters to ensure that the response fully and accurately addresses the applicable legal and regulatory framework, including the substantiation standards for promotional claims under FDA guidance and applicable case law. Outside counsel requires adequate time to review and familiarize themselves with the extensive factual record, including the sixty-seven approved promotional materials, the nine sets of PRC meeting minutes, the underlying clinical studies and data relied upon for promotional claims, and the electronic communications collected from field sales representatives. Counsel must then complete the internal investigation, analyze the legal and regulatory issues raised by the Inquiry, and prepare a thorough response and corrective action plan that meets the standards expected by OPDP. The engagement of qualified outside counsel is essential to ensuring that Penterra's response is complete, accurate, and appropriately addresses each of the concerns identified in the Inquiry, and this process cannot reasonably be completed within the remaining days before the current November 15, 2023 deadline.
As a demonstration of Penterra's good faith and its unwavering commitment to promotional compliance, the company has already voluntarily initiated the withdrawal of all three cited promotional materials from active use and distribution. Penterra expects to complete the withdrawal of all three materials no later than November 3, 2023. Specifically, the digital banner advertisement (Material ID: ZVR-2023-BNR-044) has been removed from the MedLinkPro platform; although the advertising campaign had already concluded on August 31, 2023, Penterra has formally withdrawn the material from its approved-for-use inventory to ensure that it is not re-deployed in any future campaign. The physician email blast (Material ID: ZVR-2023-EML-019) has been taken out of circulation and removed from Penterra's email marketing queue, and the underlying email template has been deactivated in the company's marketing automation system to prevent inadvertent redistribution. The sales representative detail aid (Material ID: ZVR-2023-DA-007) has been recalled from field use; all sales representatives who received the detail aid have been notified by Penterra's Commercial Operations department that the material is no longer approved for use and must be returned or destroyed, and electronic versions of the detail aid have been removed from the sales force's tablet-based content management system. These voluntary actions were taken promptly upon Penterra's receipt of the Inquiry and well in advance of any formal enforcement action, and they underscore Penterra's commitment to ensuring that all of its promotional communications for Zelvara® are accurate, balanced, non-misleading, and fully consistent with Zelvara®'s FDA-approved labeling.
In light of the foregoing, Penterra respectfully requests that the response deadline be extended by sixty (60) days, from November 15, 2023 to January 15, 2024. Penterra commits to submitting a thorough, comprehensive written response to the Inquiry no later than the proposed extended deadline of January 15, 2024. The additional time will enable Penterra to provide OPDP with a complete factual record, including the results of the internal investigation of field sales communications; a detailed, material-by-material analysis of each of the three cited promotional pieces and the specific claims and presentations identified in the Inquiry; and a robust corrective action plan designed to remediate any identified deficiencies and prevent recurrence. Penterra will continue to cooperate fully with OPDP throughout this process and will promptly notify OPDP of any material developments arising from its internal review.
The primary contact for Penterra regarding all matters related to this Inquiry is the undersigned, Margaret Tan, Executive Vice President and General Counsel, Penterra Pharmaceuticals Corp., 480 Overlook Drive, Suite 700, Summit, NJ 07901, telephone (908) 555-4100, email m.tan@penterrapharma.com. OPDP may also direct communications to Penterra's outside counsel, Leonard Cross, Esq., and Jeffrey Park, Esq., Calderwood & Harkness LLP, 600 Lexington Avenue, New York, NY 10022, telephone (212) 555-7800.
Thank you for your consideration of this request. We would welcome the opportunity to discuss this request further or to provide any additional information that OPDP may require at your convenience. Should you wish to schedule a telephone conference or meeting to address any questions regarding the matters set forth herein, please do not hesitate to contact the undersigned or Penterra's outside counsel at the contact information provided above.
Respectfully submitted,
PENTERRA PHARMACEUTICALS CORP.
By: ________
Margaret Tan Executive Vice President & General Counsel Penterra Pharmaceuticals Corp. 480 Overlook Drive, Suite 700 Summit, NJ 07901 Tel: (908) 555-4100
Email: m.tan@penterrapharma.com
cc: (via email and first-class mail)
Leonard Cross, Esq., Calderwood & Harkness LLP Jeffrey Park, Esq., Calderwood & Harkness LLP Christine Holloway, Vice President, Regulatory Affairs, Penterra Pharmaceuticals Corp. Rajeev Anand, M.D., Ph.D., Chief Medical Officer, Penterra Pharmaceuticals Corp.

PENTERRA PHARMACEUTICALS CORP. 480 Overlook Drive, Suite 700 Summit, NJ 07901 (NYSE: PTPH)

PENTERRA PHARMACEUTICALS CORP.

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