FDA Issues CRL for Patisiran in Treatment of ATTR Cardiomyopathy


Announced on October 9, the decision to issue a CRL is based on the FDA's belief the clinical meaningfulness of patisiran’s treatment effects for the cardiomyopathy of ATTR amyloidosis had not been established.

US FDA logo in black over a white background. | Credit: US Food and Drug Administration

Credit: US Food and Drug Administration

The US Food and Drug Administration has issued a Complete Response Letter (CRL) for patisiran in the treatment of transthyretin amyloid cardiomyopathy (ATTR-CM).1

Announced on October 09, 2023, the decision comes less than a month after the FDA’s Cardiovascular and Renal Drugs Advisory Committee (CRDAC) voted 9 to 3 in favor of the benefit-risk profile from the phase 3 APOLLO-B trial. According to a statement from Alnylam Pharmaceuticals, the CRL is based on the belief treatment effects for ATTR-CM had not been established and the company disclosed plans to no longer pursue an expanded indication for patisiran in the US, but will continue to focus on the development of vutisiran.1,2

“First and foremost, our hearts go out to patients with the cardiomyopathy of ATTR amyloidosis who are living with a rapidly progressive, debilitating and fatal disease and face significant unmet need. While we are disappointed by this decision, we are committed to supporting them and are well positioned to address their needs with continued innovation that can potentially help improve their outcomes and treatment experience,” said Yvonne Greenstreet, MBChB, Chief Executive Officer of Alnylam Pharmaceuticals. “We remain confident in the HELIOS-B Phase 3 study of vutrisiran and look forward to sharing topline results in early 2024. If successful, we believe vutrisiran will offer convenient, quarterly subcutaneous dosing with a therapeutic profile that may potentially include cardiovascular outcome benefits. Beyond vutrisiran, we are excited about the potential for ALN-TTRsc04, which may allow for greater TTR knockdown and less frequent dosing, providing patients with ATTR amyloidosis an optimized treatment regimen.”

The basis of Alnylam Pharmaceuticals’s application for patisiran, APOLLO-B was a phase 3, randomized, double-blind, placebo-controlled trial launched in 2019 and conducted at 69 sites in 21 countries with the intent of assessing the efficacy and safety of patisiran in patients with ATTR-CM. The trial enrolled 360 adult patients and randomized them in a 1:1 ratio to receive either 0.3 mg/kg patisiran or placebo intravenously every 3 weeks over a 12-month double-blind treatment period.3

At the conclusion of this 12-month period, study protocol required patients to be switched to patisiran for an open-label extension period.2 The primary endpoint of the trial was change in from 6-minute walking test score from baseline to 12 months compared to placebo therapy. A key secondary endpoint for the trial was changes in health-related quality of life, which was measured through KCCQ-OS change.3

Upon analysis, results suggested there was a median difference of 14.7 meters (P = .0162) for 6-minute walking test at 12 months favoring the patisiran group. The trial also indicated use of patisiran was associated with a statistically significant and clinically meaningful benefit on health status and quality of life (P = .0397).3

The subsequent release of 18-month results from the open-label extension period at the Annual Congress of the Heart Failure Association of the European Society of Cardiology provided evidence of a treatment response similar to that seen in the 12-month trial, with a mean change of —9.2 meters at 18 months among those randomized to patisiran at baseline. Among those randomized to placebo at baseline, the mean change from baseline to month 12 was —25.4 meters and —31.1 meters to month 18.4

Despite not being powered to show a treatment difference in clinical outcomes, results from the 18-month follow-up suggested there was a favorable, but not statistically significant, trend toward benefit for all-cause mortality (Hazard ratio [HR], 0.554 [95% CI, 0.281 to 1.094]) and a composite endpoint of all-cause mortality and frequency of all-cause hospitalization and urgent heart failure visits (HR, 0.801 [95% CI, 0.573 to 1.118]).4

Already boasting a historic approval from the FDA as the first agent approved for the treatment of polyneuropathy caused by hereditary transthyretin-mediated amyloidosis in adult patients in 2018, the journey to an official regulatory decision for patisiran in ATTR-CM from the FDA has been winding road characterized by uncertainty.5 Less than a month before the FDA’s decision, patisiran was the subject of a CRDAC meeting convened on September 13, 2023 to discuss the agent’s New Drug Application for treatment of ATTR-CM.2

Although the vote was non-binding, the FDA’s committee voted 9 to 3 in favor of the benefit-risk profile of patisiran, but some committee members expressed concerns about the trial design of APOLLO-B and the clinical meaningfulness of treatment effects.2

“I voted yes because I believe we can develop the proper swim lane with the agency for the use of this, in particularly in the tafamidis naive patients. I want to compliment the sponsors for the conduct of the trial and impress how they were able to power through COVID and get a meaningful trial and they met their primary endpoint,” said CRDAC member Christopher O’Connor, president and executive director of the Inova Heart and Vascular Institute, during the meeting.2

In an interview following the CRDAC vote, Ahmad Masri, MD, MS, director of the Hypertrophic Cardiomyopathy Center at the Oregon Health and Sciences University, explained he was surprised by the positive vote given the criticisms of trial data, but noted the CRDAC’s recognition of the significant unmet need for patients with ATTR-CM.

“When you have such a negative stance on the study and its results, and when the advisory committee, for most of the hours, echoes this negative perspective, but then the vote turns out to be inconsistent with the overall discussion, it becomes very challenging to anticipate the next steps,” explained Masri, in an interview with HCPLive Cardiology.6


  1. Alnylam announces receipt of Complete Response Letter from U.S. FDA for Supplemental New Drug Application for. Investor Relations | Alnylam Pharmaceuticals, Inc. October 9, 2023. Accessed October 9, 2023. https://investors.alnylam.com/press-release?id=27741.
  2. Campbell P. FDA committee endorses patisiran for attr cardiomyopathy. HCP Live. September 14, 2023. Accessed October 6, 2023. https://www.hcplive.com/view/fda-committee-endorses-patisiran-for-attr-cm.
  3. Campbell P. Patisiran meets primary endpoint in Apollo-B Trial. HCP Live. August 3, 2022. Accessed October 6, 2023. https://www.hcplive.com/view/patisiran-meets-primary-endpoint-in-apollo-b-trial.
  4. Campbell P. 18-month data for patisiran in attr with amyloidosis consistent with primary results. HCP Live. May 25, 2023. Accessed October 6, 2023. https://www.hcplive.com/view/18-month-data-for-patisiran-in-attr-with-amyloidosis-consistent-with-primary-results.
  5. Kunzmann K. Patisiran infusion approved as first-ever therapy for polyneuropathy caused by hattr. HCP Live. August 10, 2018. Accessed October 6, 2023. https://www.hcplive.com/view/patisiran-infusion-approved-as-firstever-therapy-for-polyneuropathy-caused-by-hattr.
  6. Campbell P. Expert perspective: FDA CRDAC vote on patisiran for attr-cm, with Ahmad Masri, MD, MS. HCP Live. September 16, 2023. Accessed October 6, 2023. https://www.hcplive.com/view/expert-perspective-fda-crdac-vote-on-patisiran-for-attr-cm-with-ahmad-masri-md-ms.
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