1018-00002 · Penterra Pharmaceuticals Corp · Corrective Materials

corrective-dhcp-letter.docx DOCUMENT M&A / Corporate

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PENTERRA PHARMACEUTICALS CORP.

[Company Logo]

480 Overlook Drive, Suite 700 Summit, NJ 07901

December 11, 2023

Dear Healthcare Provider:

This letter is being sent to approximately 42,000 neurologists and primary-care physicians who received a promotional email communication dated June 7, 2023 (Material ID: ZVR-2023-EML-019) regarding Zelvara® (trepivant sodium) tablets, 75 mg and 150 mg. The purpose of this letter is to correct misleading promotional claims and data presentations contained in that communication, as described in detail below.

1. Purpose of This Letter

Penterra Pharmaceuticals Corp. ("Penterra") is writing to correct and clarify certain promotional claims and data presentations contained in a physician-targeted email blast distributed on June 7, 2023 (Material ID: ZVR-2023-EML-019) concerning Zelvara® (trepivant sodium) tablets, 75 mg and 150 mg.

This corrective communication is being issued in connection with an inquiry from the U.S. Food and Drug Administration ("FDA"), Office of Prescription Drug Promotion ("OPDP"), reference number OPDP-2023-1847. Following an internal review prompted by this inquiry, Penterra has determined that the June 7, 2023 email contained the following deficiencies:

(a) a misleading graphical presentation of efficacy data that visually exaggerated the magnitude of the treatment effect observed in the Phase III SUMMIT-3 pivotal clinical trial;

(b) a reference to an unsubstantiated comparative superiority claim that does not accurately reflect the approved labeling for Zelvara® (trepivant sodium); and

In light of these findings, Penterra voluntarily withdrew the email material (ZVR-2023-EML-019) and two additional related promotional materials—a digital banner advertisement (ZVR-2023-BNR-044) and a sales representative detail aid (ZVR-2023-DA-007)—as of November 3, 2023. All three materials have been permanently retired and are no longer in use or distribution.

The purpose of this letter is to provide corrected information and to ensure that healthcare providers have accurate, complete, and balanced data regarding Zelvara® so that informed prescribing decisions can be made. Healthcare providers should rely on the FDA-approved prescribing information for Zelvara® for the most complete and authoritative description of the drug's efficacy, safety, and approved indications.

2. Correction of Misleading Efficacy Data Presentation

2.1 The Truncated Y-Axis Bar Chart

The June 7, 2023 email (Material ID: ZVR-2023-EML-019) included a bar chart depicting 2-hour pain-freedom rates from the Phase III SUMMIT-3 pivotal clinical trial (NDA #214-837; N = 1,842 randomized patients). This bar chart was the central visual element of the email and was intended to illustrate the primary efficacy endpoint from the trial.

However, the bar chart utilized a truncated y-axis that did not begin at zero. Specifically, the y-axis in the original chart began at approximately 10%, rather than at 0%, and extended only to approximately 30%. This truncation had the effect of visually exaggerating the magnitude of the efficacy differential between Zelvara® and placebo, creating a misleading impression for the reader regarding the size of the observed treatment effect.

The actual data from the SUMMIT-3 trial, as reported in the FDA-approved prescribing information for Zelvara®, are as follows:

• Zelvara® 150 mg: 2-hour pain-freedom rate of 23.7%

• Placebo: 2-hour pain-freedom rate of 14.2%

• Absolute difference: 9.5 percentage points

• Statistical significance: p < 0.001

While the difference between Zelvara® 150 mg and placebo on this endpoint is statistically significant (p < 0.001) and is clinically meaningful in the context of the approved indication, the truncated y-axis presentation created a visual impression that the treatment effect was substantially larger than the actual absolute difference of 9.5 percentage points. In the original chart, the Zelvara® bar appeared to be approximately three to four times the height of the placebo bar, whereas the true ratio of 23.7% to 14.2% is approximately 1.67:1.

Furthermore, the original chart included a third bar depicting a 2-hour pain-freedom rate attributed to a competitor product (lasmiditan), drawn from a separate clinical trial with a different study population and design. The use of the truncated y-axis in conjunction with this cross-trial comparison further exaggerated the apparent differential between Zelvara® and the competitor product and suggested a comparative efficacy advantage that has not been established through any head-to-head clinical trial. Cross-trial comparisons of this nature are inherently limited and should be interpreted with caution, as differences in patient populations, trial designs, endpoints, and statistical methodologies may confound any apparent differences in outcomes.

2.2 Corrected Graphical Presentation

Penterra provides below a corrected bar chart with a full-scale y-axis beginning at 0% and extending to 50%, accurately depicting the SUMMIT-3 2-hour pain-freedom data for the co-primary endpoint:

Corrected Figure 1: 2-Hour Pain-Freedom Rates — SUMMIT-3 Trial (NDA #214-837)

Y-axis: 0% to 50%, in 10-percentage-point increments. Bars are accurately proportioned to reflect the actual percentages. No cross-trial comparisons are included.

The corrected presentation reflects the data exactly as reported in the FDA-approved prescribing information for Zelvara® (NDA #214-837), which was approved on October 11, 2019. The cross-trial comparison to lasmiditan has been removed entirely from the corrected presentation, as no head-to-head data exist to support such a comparison.

Healthcare providers should refer to the full prescribing information for Zelvara® for complete efficacy data from the SUMMIT-3 trial, including secondary endpoints, subgroup analyses, and the results for both the 75 mg and 150 mg dose strengths.

3. Retraction of Unsubstantiated Comparative Claim

The June 7, 2023 email (Material ID: ZVR-2023-EML-019) and an associated digital banner advertisement (Material ID: ZVR-2023-BNR-044), which ran on the healthcare-provider-targeted medical-education platform MedLinkPro from April 15 through August 31, 2023, included the following promotional claim:

"Fastest Onset in Its Class"

This comparative superiority claim regarding the onset of action of Zelvara® relative to other agents approved for the acute treatment of migraine was not supported by adequate substantiation and is hereby retracted.

The claim was based on an indirect treatment comparison ("ITC") meta-analysis commissioned by Penterra and conducted by Keswick Bioanalytics Inc. (Keswick Report No. KB-2022-0491, dated September 14, 2022). This ITC analysis was not published in a peer-reviewed journal. Moreover, the Keswick Bioanalytics report itself contained acknowledged methodological limitations, including heterogeneity in the trial populations and endpoint definitions across the included studies, the absence of a formal assessment of transitivity, and sensitivity analyses that yielded inconsistent results for several comparators.

No head-to-head clinical trials have been conducted comparing the onset of action of Zelvara® to any other agent in its therapeutic class. In the absence of such direct comparative evidence, and given the acknowledged limitations of the ITC meta-analysis, the "Fastest Onset in Its Class" claim cannot be substantiated and should not have been included in any promotional communication.

Penterra hereby retracts the "Fastest Onset in Its Class" claim in its entirety. Healthcare providers should not rely on this claim when making prescribing decisions. Zelvara® (trepivant sodium) is approved for the acute treatment of migraine with or without aura in adults. The FDA-approved prescribing information for Zelvara® does not include any comparative superiority claims regarding onset of action, and no such claims have been reviewed or approved by the FDA.

4. Correction Regarding Cited Real-World Evidence

A sales representative detail aid (Material ID: ZVR-2023-DA-007), which was approved by Penterra's Promotional Review Committee on March 22, 2023, and subsequently distributed to Penterra's field sales force for use in healthcare provider detailing visits, cited the following study as "real-world evidence" supporting the efficacy of Zelvara®:

Harmon JT, Vasquez-Ortega R, Chen W, et al. "Acute Treatment Outcomes with Trepivant Sodium in a Community Neurology Setting: A Retrospective Chart Review." Poster presentation at the American Headache Society (AHS) Annual Scientific Meeting, June 2022; Poster No. AHS-2022-P147.

The citation of this study in the detail aid did not adequately disclose two material facts:

(a) The Harmon et al. study was funded by Penterra Pharmaceuticals Corp. This funding source was noted in the poster's disclosures section but was not disclosed in the detail aid itself, creating the potential impression that the study was independently conducted.

(b) The Harmon et al. study was a retrospective chart review that lacked a control arm. The detail aid presented the data alongside controlled trial results in a manner that could be interpreted as equating the strength of evidence from this uncontrolled observational study with that of the randomized, placebo-controlled SUMMIT-3 pivotal trial.

The Harmon et al. data have not been published in a peer-reviewed journal as of the date of this letter and should not be considered as establishing or supplementing the efficacy profile of Zelvara® beyond what is reflected in the FDA-approved prescribing information, which is based on the results of the controlled SUMMIT-3 trial. Retrospective chart reviews without a control arm are subject to inherent biases, including selection bias and confounding, and cannot establish causal relationships between drug exposure and clinical outcomes.

The detail aid (ZVR-2023-DA-007) has been withdrawn from use as of November 3, 2023, and all copies have been recalled from the field sales organization.

5. Important Risk Information — Zelvara® (trepivant sodium)

The June 7, 2023 email (Material ID: ZVR-2023-EML-019) and the digital banner advertisement (Material ID: ZVR-2023-BNR-044) omitted or minimized important risk information from the approved prescribing information for Zelvara® (trepivant sodium) tablets, 75 mg and 150 mg. To ensure that healthcare providers have access to balanced information, the following important safety information is provided.

5.1 Hepatotoxicity. Zelvara® has been associated with hepatic enzyme elevations. In the controlled clinical trial program, alanine aminotransferase (ALT) elevations greater than 3 times the upper limit of normal (>3× ULN) were observed in 1.8% of patients treated with Zelvara® compared to 0.3% of patients receiving placebo. Cases of clinically significant hepatic injury, including one case meeting Hy's Law criteria, were reported during the clinical development program, although a causal relationship with Zelvara® was not definitively established.

Liver function tests (including ALT, AST, and total bilirubin) should be obtained at baseline and monitored periodically thereafter, or as clinically indicated. Zelvara® should be discontinued if a patient develops signs or symptoms of hepatic injury, including unexplained nausea, vomiting, right upper quadrant pain, fatigue, anorexia, jaundice, dark urine, or if ALT or AST elevations exceed 5× ULN, or if ALT or AST elevations exceed 3× ULN with concurrent elevation of total bilirubin exceeding 2× ULN.

5.2 Cardiovascular Events

Zelvara® may cause serious cardiovascular events, including myocardial infarction (MI) and stroke. In the clinical trial program, cardiovascular thrombotic events occurred in patients treated with Zelvara®, including patients with cardiovascular risk factors. The incidence of major adverse cardiovascular events (MACE) in the Zelvara® clinical program was low; however, the clinical trials were not designed to assess long-term cardiovascular safety, and patients with significant cardiovascular disease or uncontrolled cardiovascular risk factors were generally excluded from the pivotal trials.

Zelvara® should not be administered to patients with a history of coronary artery disease, prior myocardial infarction, cerebrovascular disease, peripheral vascular disease, or other significant cardiovascular disease without an appropriate cardiovascular evaluation to determine that the patient can safely receive the drug. Zelvara® should also not be administered to patients with uncontrolled hypertension.

5.3 Medication-Overuse Headache

Overuse of acute migraine drugs, including Zelvara®, may lead to exacerbation of headache, a condition known as medication-overuse headache (MOH). Medication-overuse headache may present as migraine-like daily headaches or as a marked increase in frequency of migraine attacks. Detoxification of patients, including withdrawal of the overused drugs, and treatment of withdrawal symptoms (which often includes a transient worsening of headache) may be necessary.

Patients should be counseled regarding the risk of medication-overuse headache and the importance of limiting use of Zelvara® and other acute migraine therapies to no more than 10 days per month on a regular basis, or as otherwise directed by their healthcare provider.

5.4 Serotonin Syndrome

Serotonin syndrome may occur when Zelvara® is co-administered with other serotonergic drugs, including selective serotonin reuptake inhibitors (SSRIs), serotonin-norepinephrine reuptake inhibitors (SNRIs), tricyclic antidepressants (TCAs), triptans, MAO inhibitors, and other drugs that affect the serotonergic neurotransmitter system. Serotonin syndrome symptoms may include mental status changes (e.g., agitation, hallucinations, delirium, coma), autonomic instability (e.g., tachycardia, labile blood pressure, diaphoresis, dizziness, flushing, hyperthermia), neuromuscular symptoms (e.g., tremor, rigidity, myoclonus, hyperreflexia, incoordination), seizures, and/or gastrointestinal symptoms (e.g., nausea, vomiting, diarrhea).

Patients should be monitored for signs and symptoms of serotonin syndrome, particularly during treatment initiation, dose increases, and when Zelvara® is co-administered with other serotonergic agents. If serotonin syndrome is suspected, Zelvara® and any concomitant serotonergic agents should be discontinued immediately and supportive symptomatic treatment should be initiated.

5.5 Reference to Full Prescribing Information

The information provided above does not constitute a comprehensive summary of all risk information for Zelvara®. Healthcare providers should consult the full prescribing information for Zelvara® (trepivant sodium) tablets, 75 mg and 150 mg, for a complete listing of warnings, precautions, adverse reactions, drug interactions, contraindications, use in specific populations, and dosing information.

• NDA #214-837

• FDA Approval Date: October 11, 2019

• Approved Indication: Acute treatment of migraine with or without aura in adults

• boxed Warning: None

The full prescribing information is available at www.zelvara-hcp.com or by contacting Penterra's Medical Information Department (see Section 8 below).

6. Penterra's Corrective Actions

In response to the OPDP inquiry (reference number OPDP-2023-1847) and the findings of its own internal review, Penterra has taken the following voluntary corrective actions:

1. Immediate withdrawal of all three cited promotional materials. The following materials were permanently withdrawn from distribution and retired as of November 3, 2023:

• ZVR-2023-EML-019 (physician-targeted email blast, dated June 7, 2023)

• ZVR-2023-BNR-044 (digital banner advertisement, displayed on MedLinkPro from April 15 through August 31, 2023)

• ZVR-2023-DA-007 (sales representative detail aid, approved March 22, 2023)

2. Distribution of this corrective Dear Healthcare Provider letter. This letter is being sent to all approximately 42,000 neurologists and primary-care physicians who were recipients of the original June 7, 2023 email (ZVR-2023-EML-019). The letter is being sent via both U.S. mail and electronic mail to ensure maximum reach.

3. Implementation of revised Promotional Review Committee ("PRC") standard operating procedures. Effective January 2, 2024, Penterra's PRC standard operating procedures will require unanimous Medical Affairs sign-off for all promotional materials that contain efficacy claims, graphical data presentations, cross-trial comparisons, or citations to non-peer-reviewed data. Additionally, all bar charts and other graphical depictions of clinical data will be subject to enhanced review, including mandatory use of full-scale axes beginning at zero unless a scientific justification is documented and approved by the Chief Medical Officer.

4. Mandatory compliance retraining for all field sales representatives. All approximately 680 field sales representatives across Penterra's U.S. commercial organization will complete a mandatory retraining program covering FDA promotional regulations, fair balance requirements, appropriate presentation of clinical data, and the proper use and limitations of approved promotional materials. This retraining must be completed by all representatives no later than February 28, 2024, and documentation of completion will be maintained in Penterra's compliance records.

Penterra is committed to ensuring that all promotional communications regarding Zelvara® and its other marketed products are accurate, balanced, non-misleading, and fully consistent with FDA-approved labeling. Penterra takes its obligations under the Federal Food, Drug, and Cosmetic Act and applicable FDA regulations seriously and will continue to work cooperatively with OPDP to ensure compliance.

7. Reporting Adverse Events

Healthcare providers are encouraged to report any suspected adverse events or side effects associated with the use of Zelvara® (trepivant sodium). Adverse events may be reported through either of the following channels:

• Penterra Drug Safety Department: 1-888-737-8477 (1-888-PENTERRA), available Monday through Friday, 8:00 AM to 8:00 PM Eastern Time, or by email at drugsafety@penterrapharma.com. After-hours reports may be left via voicemail and will be returned within one business day.

• FDA MedWatch Program: 1-800-FDA-1088, or online at www.fda.gov/medwatch. The MedWatch Voluntary Reporting Form (FDA Form 3500) is available for download at the MedWatch website.

Prompt reporting of adverse events is essential to ensuring the ongoing safety monitoring of Zelvara® and all approved pharmaceutical products.

8. Contact Information

For medical or scientific inquiries regarding Zelvara® (trepivant sodium), including requests for the full prescribing information, clinical trial data, or medical information letters, healthcare providers may contact:

Penterra Pharmaceuticals Corp. — Medical Information Department Telephone: 1-877-463-7388 (1-877-INFO-PTV)

Email: medinfo@penterrapharma.com

Hours: Monday through Friday, 8:00 AM to 6:00 PM Eastern Time

Please reference OPDP-2023-1847 in any correspondence related to this corrective communication.

Sincerely,

PENTERRA PHARMACEUTICALS CORP.

By: ________

Rajeev Anand, M.D., Ph.D. Chief Medical Officer Penterra Pharmaceuticals Corp. 480 Overlook Drive, Suite 700 Summit, NJ 07901

Penterra Pharmaceuticals Corp. is a Delaware corporation. NYSE: PTPH.

NDA #214-837. Zelvara® (trepivant sodium) tablets, 75 mg and 150 mg. Approved October 11, 2019.

Material ID: ZVR-2023-DHCP-052. Date of Preparation: December 11, 2023.

Zelvara® 150 mg (n = 921)	Placebo (n = 921)
2-Hour Pain-Freedom Rate	23.7%	14.2%
Absolute Difference	9.5 percentage points (p < 0.001)	—

PENTERRA PHARMACEUTICALS CORP.
[Company Logo]
480 Overlook Drive, Suite 700 Summit, NJ 07901
December 11, 2023
Dear Healthcare Provider:
This letter is being sent to approximately 42,000 neurologists and primary-care physicians who received a promotional email communication dated June 7, 2023 (Material ID: ZVR-2023-EML-019) regarding Zelvara® (trepivant sodium) tablets, 75 mg and 150 mg. The purpose of this letter is to correct misleading promotional claims and data presentations contained in that communication, as described in detail below.
1. Purpose of This Letter
Penterra Pharmaceuticals Corp. ("Penterra") is writing to correct and clarify certain promotional claims and data presentations contained in a physician-targeted email blast distributed on June 7, 2023 (Material ID: ZVR-2023-EML-019) concerning Zelvara® (trepivant sodium) tablets, 75 mg and 150 mg.
This corrective communication is being issued in connection with an inquiry from the U.S. Food and Drug Administration ("FDA"), Office of Prescription Drug Promotion ("OPDP"), reference number OPDP-2023-1847. Following an internal review prompted by this inquiry, Penterra has determined that the June 7, 2023 email contained the following deficiencies:
(a) a misleading graphical presentation of efficacy data that visually exaggerated the magnitude of the treatment effect observed in the Phase III SUMMIT-3 pivotal clinical trial;
(b) a reference to an unsubstantiated comparative superiority claim that does not accurately reflect the approved labeling for Zelvara® (trepivant sodium); and
(c) omission or minimization of important risk information from the FDA-approved prescribing information.
In light of these findings, Penterra voluntarily withdrew the email material (ZVR-2023-EML-019) and two additional related promotional materials—a digital banner advertisement (ZVR-2023-BNR-044) and a sales representative detail aid (ZVR-2023-DA-007)—as of November 3, 2023. All three materials have been permanently retired and are no longer in use or distribution.
The purpose of this letter is to provide corrected information and to ensure that healthcare providers have accurate, complete, and balanced data regarding Zelvara® so that informed prescribing decisions can be made. Healthcare providers should rely on the FDA-approved prescribing information for Zelvara® for the most complete and authoritative description of the drug's efficacy, safety, and approved indications.
2. Correction of Misleading Efficacy Data Presentation
2.1 The Truncated Y-Axis Bar Chart
The June 7, 2023 email (Material ID: ZVR-2023-EML-019) included a bar chart depicting 2-hour pain-freedom rates from the Phase III SUMMIT-3 pivotal clinical trial (NDA #214-837; N = 1,842 randomized patients). This bar chart was the central visual element of the email and was intended to illustrate the primary efficacy endpoint from the trial.
However, the bar chart utilized a truncated y-axis that did not begin at zero. Specifically, the y-axis in the original chart began at approximately 10%, rather than at 0%, and extended only to approximately 30%. This truncation had the effect of visually exaggerating the magnitude of the efficacy differential between Zelvara® and placebo, creating a misleading impression for the reader regarding the size of the observed treatment effect.
The actual data from the SUMMIT-3 trial, as reported in the FDA-approved prescribing information for Zelvara®, are as follows:
• Zelvara® 150 mg: 2-hour pain-freedom rate of 23.7%
• Placebo: 2-hour pain-freedom rate of 14.2%
• Absolute difference: 9.5 percentage points
• Statistical significance: p < 0.001
While the difference between Zelvara® 150 mg and placebo on this endpoint is statistically significant (p < 0.001) and is clinically meaningful in the context of the approved indication, the truncated y-axis presentation created a visual impression that the treatment effect was substantially larger than the actual absolute difference of 9.5 percentage points. In the original chart, the Zelvara® bar appeared to be approximately three to four times the height of the placebo bar, whereas the true ratio of 23.7% to 14.2% is approximately 1.67:1.
Furthermore, the original chart included a third bar depicting a 2-hour pain-freedom rate attributed to a competitor product (lasmiditan), drawn from a separate clinical trial with a different study population and design. The use of the truncated y-axis in conjunction with this cross-trial comparison further exaggerated the apparent differential between Zelvara® and the competitor product and suggested a comparative efficacy advantage that has not been established through any head-to-head clinical trial. Cross-trial comparisons of this nature are inherently limited and should be interpreted with caution, as differences in patient populations, trial designs, endpoints, and statistical methodologies may confound any apparent differences in outcomes.
2.2 Corrected Graphical Presentation
Penterra provides below a corrected bar chart with a full-scale y-axis beginning at 0% and extending to 50%, accurately depicting the SUMMIT-3 2-hour pain-freedom data for the co-primary endpoint:
Corrected Figure 1: 2-Hour Pain-Freedom Rates — SUMMIT-3 Trial (NDA #214-837)
Y-axis: 0% to 50%, in 10-percentage-point increments. Bars are accurately proportioned to reflect the actual percentages. No cross-trial comparisons are included.
The corrected presentation reflects the data exactly as reported in the FDA-approved prescribing information for Zelvara® (NDA #214-837), which was approved on October 11, 2019. The cross-trial comparison to lasmiditan has been removed entirely from the corrected presentation, as no head-to-head data exist to support such a comparison.
Healthcare providers should refer to the full prescribing information for Zelvara® for complete efficacy data from the SUMMIT-3 trial, including secondary endpoints, subgroup analyses, and the results for both the 75 mg and 150 mg dose strengths.
3. Retraction of Unsubstantiated Comparative Claim
The June 7, 2023 email (Material ID: ZVR-2023-EML-019) and an associated digital banner advertisement (Material ID: ZVR-2023-BNR-044), which ran on the healthcare-provider-targeted medical-education platform MedLinkPro from April 15 through August 31, 2023, included the following promotional claim:
"Fastest Onset in Its Class"
This comparative superiority claim regarding the onset of action of Zelvara® relative to other agents approved for the acute treatment of migraine was not supported by adequate substantiation and is hereby retracted.
The claim was based on an indirect treatment comparison ("ITC") meta-analysis commissioned by Penterra and conducted by Keswick Bioanalytics Inc. (Keswick Report No. KB-2022-0491, dated September 14, 2022). This ITC analysis was not published in a peer-reviewed journal. Moreover, the Keswick Bioanalytics report itself contained acknowledged methodological limitations, including heterogeneity in the trial populations and endpoint definitions across the included studies, the absence of a formal assessment of transitivity, and sensitivity analyses that yielded inconsistent results for several comparators.
No head-to-head clinical trials have been conducted comparing the onset of action of Zelvara® to any other agent in its therapeutic class. In the absence of such direct comparative evidence, and given the acknowledged limitations of the ITC meta-analysis, the "Fastest Onset in Its Class" claim cannot be substantiated and should not have been included in any promotional communication.
Penterra hereby retracts the "Fastest Onset in Its Class" claim in its entirety. Healthcare providers should not rely on this claim when making prescribing decisions. Zelvara® (trepivant sodium) is approved for the acute treatment of migraine with or without aura in adults. The FDA-approved prescribing information for Zelvara® does not include any comparative superiority claims regarding onset of action, and no such claims have been reviewed or approved by the FDA.
4. Correction Regarding Cited Real-World Evidence
A sales representative detail aid (Material ID: ZVR-2023-DA-007), which was approved by Penterra's Promotional Review Committee on March 22, 2023, and subsequently distributed to Penterra's field sales force for use in healthcare provider detailing visits, cited the following study as "real-world evidence" supporting the efficacy of Zelvara®:
Harmon JT, Vasquez-Ortega R, Chen W, et al. "Acute Treatment Outcomes with Trepivant Sodium in a Community Neurology Setting: A Retrospective Chart Review." Poster presentation at the American Headache Society (AHS) Annual Scientific Meeting, June 2022; Poster No. AHS-2022-P147.
The citation of this study in the detail aid did not adequately disclose two material facts:
(a) The Harmon et al. study was funded by Penterra Pharmaceuticals Corp. This funding source was noted in the poster's disclosures section but was not disclosed in the detail aid itself, creating the potential impression that the study was independently conducted.
(b) The Harmon et al. study was a retrospective chart review that lacked a control arm. The detail aid presented the data alongside controlled trial results in a manner that could be interpreted as equating the strength of evidence from this uncontrolled observational study with that of the randomized, placebo-controlled SUMMIT-3 pivotal trial.
The Harmon et al. data have not been published in a peer-reviewed journal as of the date of this letter and should not be considered as establishing or supplementing the efficacy profile of Zelvara® beyond what is reflected in the FDA-approved prescribing information, which is based on the results of the controlled SUMMIT-3 trial. Retrospective chart reviews without a control arm are subject to inherent biases, including selection bias and confounding, and cannot establish causal relationships between drug exposure and clinical outcomes.
The detail aid (ZVR-2023-DA-007) has been withdrawn from use as of November 3, 2023, and all copies have been recalled from the field sales organization.
5. Important Risk Information — Zelvara® (trepivant sodium)
The June 7, 2023 email (Material ID: ZVR-2023-EML-019) and the digital banner advertisement (Material ID: ZVR-2023-BNR-044) omitted or minimized important risk information from the approved prescribing information for Zelvara® (trepivant sodium) tablets, 75 mg and 150 mg. To ensure that healthcare providers have access to balanced information, the following important safety information is provided.
5.1 Hepatotoxicity. Zelvara® has been associated with hepatic enzyme elevations. In the controlled clinical trial program, alanine aminotransferase (ALT) elevations greater than 3 times the upper limit of normal (>3× ULN) were observed in 1.8% of patients treated with Zelvara® compared to 0.3% of patients receiving placebo. Cases of clinically significant hepatic injury, including one case meeting Hy's Law criteria, were reported during the clinical development program, although a causal relationship with Zelvara® was not definitively established.
Liver function tests (including ALT, AST, and total bilirubin) should be obtained at baseline and monitored periodically thereafter, or as clinically indicated. Zelvara® should be discontinued if a patient develops signs or symptoms of hepatic injury, including unexplained nausea, vomiting, right upper quadrant pain, fatigue, anorexia, jaundice, dark urine, or if ALT or AST elevations exceed 5× ULN, or if ALT or AST elevations exceed 3× ULN with concurrent elevation of total bilirubin exceeding 2× ULN.
5.2 Cardiovascular Events
Zelvara® may cause serious cardiovascular events, including myocardial infarction (MI) and stroke. In the clinical trial program, cardiovascular thrombotic events occurred in patients treated with Zelvara®, including patients with cardiovascular risk factors. The incidence of major adverse cardiovascular events (MACE) in the Zelvara® clinical program was low; however, the clinical trials were not designed to assess long-term cardiovascular safety, and patients with significant cardiovascular disease or uncontrolled cardiovascular risk factors were generally excluded from the pivotal trials.
Zelvara® should not be administered to patients with a history of coronary artery disease, prior myocardial infarction, cerebrovascular disease, peripheral vascular disease, or other significant cardiovascular disease without an appropriate cardiovascular evaluation to determine that the patient can safely receive the drug. Zelvara® should also not be administered to patients with uncontrolled hypertension.
5.3 Medication-Overuse Headache
Overuse of acute migraine drugs, including Zelvara®, may lead to exacerbation of headache, a condition known as medication-overuse headache (MOH). Medication-overuse headache may present as migraine-like daily headaches or as a marked increase in frequency of migraine attacks. Detoxification of patients, including withdrawal of the overused drugs, and treatment of withdrawal symptoms (which often includes a transient worsening of headache) may be necessary.
Patients should be counseled regarding the risk of medication-overuse headache and the importance of limiting use of Zelvara® and other acute migraine therapies to no more than 10 days per month on a regular basis, or as otherwise directed by their healthcare provider.
5.4 Serotonin Syndrome
Serotonin syndrome may occur when Zelvara® is co-administered with other serotonergic drugs, including selective serotonin reuptake inhibitors (SSRIs), serotonin-norepinephrine reuptake inhibitors (SNRIs), tricyclic antidepressants (TCAs), triptans, MAO inhibitors, and other drugs that affect the serotonergic neurotransmitter system. Serotonin syndrome symptoms may include mental status changes (e.g., agitation, hallucinations, delirium, coma), autonomic instability (e.g., tachycardia, labile blood pressure, diaphoresis, dizziness, flushing, hyperthermia), neuromuscular symptoms (e.g., tremor, rigidity, myoclonus, hyperreflexia, incoordination), seizures, and/or gastrointestinal symptoms (e.g., nausea, vomiting, diarrhea).
Patients should be monitored for signs and symptoms of serotonin syndrome, particularly during treatment initiation, dose increases, and when Zelvara® is co-administered with other serotonergic agents. If serotonin syndrome is suspected, Zelvara® and any concomitant serotonergic agents should be discontinued immediately and supportive symptomatic treatment should be initiated.
5.5 Reference to Full Prescribing Information
The information provided above does not constitute a comprehensive summary of all risk information for Zelvara®. Healthcare providers should consult the full prescribing information for Zelvara® (trepivant sodium) tablets, 75 mg and 150 mg, for a complete listing of warnings, precautions, adverse reactions, drug interactions, contraindications, use in specific populations, and dosing information.
• NDA #214-837
• FDA Approval Date: October 11, 2019
• Approved Indication: Acute treatment of migraine with or without aura in adults
• boxed Warning: None
The full prescribing information is available at www.zelvara-hcp.com or by contacting Penterra's Medical Information Department (see Section 8 below).
6. Penterra's Corrective Actions
In response to the OPDP inquiry (reference number OPDP-2023-1847) and the findings of its own internal review, Penterra has taken the following voluntary corrective actions:
1. Immediate withdrawal of all three cited promotional materials. The following materials were permanently withdrawn from distribution and retired as of November 3, 2023:
• ZVR-2023-EML-019 (physician-targeted email blast, dated June 7, 2023)
• ZVR-2023-BNR-044 (digital banner advertisement, displayed on MedLinkPro from April 15 through August 31, 2023)
• ZVR-2023-DA-007 (sales representative detail aid, approved March 22, 2023)
2. Distribution of this corrective Dear Healthcare Provider letter. This letter is being sent to all approximately 42,000 neurologists and primary-care physicians who were recipients of the original June 7, 2023 email (ZVR-2023-EML-019). The letter is being sent via both U.S. mail and electronic mail to ensure maximum reach.
3. Implementation of revised Promotional Review Committee ("PRC") standard operating procedures. Effective January 2, 2024, Penterra's PRC standard operating procedures will require unanimous Medical Affairs sign-off for all promotional materials that contain efficacy claims, graphical data presentations, cross-trial comparisons, or citations to non-peer-reviewed data. Additionally, all bar charts and other graphical depictions of clinical data will be subject to enhanced review, including mandatory use of full-scale axes beginning at zero unless a scientific justification is documented and approved by the Chief Medical Officer.
4. Mandatory compliance retraining for all field sales representatives. All approximately 680 field sales representatives across Penterra's U.S. commercial organization will complete a mandatory retraining program covering FDA promotional regulations, fair balance requirements, appropriate presentation of clinical data, and the proper use and limitations of approved promotional materials. This retraining must be completed by all representatives no later than February 28, 2024, and documentation of completion will be maintained in Penterra's compliance records.
Penterra is committed to ensuring that all promotional communications regarding Zelvara® and its other marketed products are accurate, balanced, non-misleading, and fully consistent with FDA-approved labeling. Penterra takes its obligations under the Federal Food, Drug, and Cosmetic Act and applicable FDA regulations seriously and will continue to work cooperatively with OPDP to ensure compliance.
7. Reporting Adverse Events
Healthcare providers are encouraged to report any suspected adverse events or side effects associated with the use of Zelvara® (trepivant sodium). Adverse events may be reported through either of the following channels:
• Penterra Drug Safety Department: 1-888-737-8477 (1-888-PENTERRA), available Monday through Friday, 8:00 AM to 8:00 PM Eastern Time, or by email at drugsafety@penterrapharma.com. After-hours reports may be left via voicemail and will be returned within one business day.
• FDA MedWatch Program: 1-800-FDA-1088, or online at www.fda.gov/medwatch. The MedWatch Voluntary Reporting Form (FDA Form 3500) is available for download at the MedWatch website.
Prompt reporting of adverse events is essential to ensuring the ongoing safety monitoring of Zelvara® and all approved pharmaceutical products.
8. Contact Information
For medical or scientific inquiries regarding Zelvara® (trepivant sodium), including requests for the full prescribing information, clinical trial data, or medical information letters, healthcare providers may contact:
Penterra Pharmaceuticals Corp. — Medical Information Department Telephone: 1-877-463-7388 (1-877-INFO-PTV)
Email: medinfo@penterrapharma.com
Hours: Monday through Friday, 8:00 AM to 6:00 PM Eastern Time
Please reference OPDP-2023-1847 in any correspondence related to this corrective communication.
Sincerely,
PENTERRA PHARMACEUTICALS CORP.
By: ________
Rajeev Anand, M.D., Ph.D. Chief Medical Officer Penterra Pharmaceuticals Corp. 480 Overlook Drive, Suite 700 Summit, NJ 07901
Zelvara® is a registered trademark of Penterra Pharmaceuticals Corp. All rights reserved.
Penterra Pharmaceuticals Corp. is a Delaware corporation. NYSE: PTPH.
NDA #214-837. Zelvara® (trepivant sodium) tablets, 75 mg and 150 mg. Approved October 11, 2019.
Material ID: ZVR-2023-DHCP-052. Date of Preparation: December 11, 2023.
© 2023 Penterra Pharmaceuticals Corp. All rights reserved.
Zelvara® 150 mg (n = 921) | Placebo (n = 921)
2-Hour Pain-Freedom Rate | 23.7% | 14.2%
Absolute Difference | 9.5 percentage points (p < 0.001) | —

PENTERRA PHARMACEUTICALS CORP.

PENTERRA PHARMACEUTICALS CORP.

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