FDA Issues Complete Response Letter to Alnylam for Patisiran in ATTR Amyloidosis Cardiomyopathy

Yvonne Greenstreet, MBChB

According to an announcement, the FDA has issued a complete response letter (CRL) to Alnylam Pharmaceuticals for patisiran (Onpattro), an RNAi therapeutic, for the treatment of patients with cardiomyopathy of transthyretin-mediated (ATTR) amyloidosis. Patisiran, an intravenously administered therapy, has already been approved as a treatment for polyneuropathy of hereditary ATTR amyloidosis in adults.¹

In its release, the FDA noted that the clinical meaningfulness of patisiran’s treatment effects for the cardiomyopathy of ATTR amyloidosis was not confirmed. Thus in its present form, the company’s supplemental new drug application (sNDA) for the therapy could not be approved. No issues with clinical safety, study conduct, drug quality or manufacturing were indicated in the CRL. As a result, the company plans to no longer pursue an expanded indication for patisiran in the United States.

“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,” Yvonne Greenstreet, MBChB, chief executive officer at Alnylam Pharmaceuticals, said in a statement.¹

The supporting data for the new drug application (NDA) submission was made based on APOLLO-B, a randomized, double-blind, placebo-controlled, multicenter, phase 3 study (NCT03997383) that highlighted the favorable effects of patisiran on both functional capacity and quality of life. The 12-month study met its primary end points, with patisiran demonstrating a statistically significant and clinically meaningful benefit on functional capacity, as measured by the 6-minute walk test (6-MWT), compared with placebo, with a median difference of 14.7 meters (P = .0162) favoring patisiran.

The agent also met its first secondary end point as well, demonstrating a statistically significant and clinically meaningful benefit on health status and quality of life, as measured by the Kansas City Cardiomyopathy Questionnaire Overall Summary score, with a least square mean difference of 3.7 points (P = .0397) favoring patisiran over placebo. On other secondary composite outcomes end points, investigators observed a nonsignificant result (P = .0574) for all-cause mortality, frequency of cardiovascular events, and change from baseline in 6-MWT.

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In the study, patisiran achieved a rapid and sustained reduction in serum TTR levels, with a mean percent reduction from baseline of 87% observed at month 12. A beneficial effect on the exploratory end point, NT-proBNP, a measure of cardiac stress, was also observed with patisiran. Treated patients demonstrated a 1.11 adjusted geometric mean fold change in NT-proBNP while those on placebo had changes of 1.38, otherwise a 20% reduction difference (nominal P = 1.825 x 10-5).

In terms of safety, no cardiac concerns relative to placebo were observed in the 12-month study. The most common treatment emergent adverse events (AEs) included infusion-related reactions (12.2%), arthralgia (7.7%), and muscle spasms (6.6%). Throughout the study, there were 5 deaths (2.8%) observed in patisiran-treated patients and 8 (4.5%) observed in the placebo group.

At the 18th International Symposium on Amyloidosis, held September 4-8, 2023, in Heidelberg, Germany, Alnylam presented additional 36-month data from the ongoing global open-label extension (OLE) that featured patients who completed the phase 3 APOLLO study and phase 2 OLE studies. Findings showed that patients who initiated patisiran treatment earlier experienced greater survival in comparison to those on originally started on placebo and switched to active treatment later. Additionally, those same patients who initiated treatment earlier showed stabilized or improved ambulation vs patients in the APOLLO placebo group as assessed by polyneuropathy disability score.

Additional data were presented from a phase 4 observational study to evaluate the effectiveness of patisiran on ambulatory status in patients with hATTR amyloidosis with polyneuropathy with a V122I or T60A variant. After 12 months of treatment with patisiran, 93.3% (42 of 45) of patients experienced stabilization or improvement in polyneuropathy disability score from baseline. In addition to maintaining its safety profile, the therapy resulted in clinically meaningful improvements in quality of life and autonomic symptoms after 12 months.

Patisiran is designed to target and silence TTR messenger RNA, thereby reducing the production of TTR protein before its made. In a statement, the company noted that it intends to maintain the availability of patisiran for patients with the cardiomyopathy of ATTR amyloidosis who are enrolled in the OLE period of APOLLO-B and the patisiran U.S. expanded access protocol.

In September 2023, the FDA’s Cardiovascular and Renal Drugs Advisory Committee met to discuss the sNDA for patisiran. In the meeting, the committee voted 9:3 that the benefits of patisiran outweighed its risks for the treatment patients living with cardiomyopathy of ATTR amyloidosis.

Alnylam noted that it remains dedicated to the ATTR amyloidosis community and will continue to assess vutrisiran, an investigational RNAi therapeutic subcutaneously administered once every 3 months, in the HELIOS-B phase 3 study (NCT04153149). In addition, the company noted that it will resume the investigation of ALN-TTRsc04, which uses the company’s IKARIA technology that has the potential for higher than 90% TTR reduction with once annual dosing, in a phase 1 trial (NCT05661916).

“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," Greenstreet said in a statement.¹

REFERENCES
1. Alnylam Announces Receipt of Complete Response Letter from U.S. FDA for Supplemental New Drug Application for Patisiran for the Treatment of the Cardiomyopathy of ATTR Amyloidosis. News Release. Alnylam Pharmaceuticals. Published October 9, 2023. Accessed October 9, 2023. https://investors.alnylam.com/press-release?id=27741
2. Alnylam presents positive results from the APOLLO-B phase 3 study of patisiran in patients with ATTR amyloidosis with cardiomyopathy. News release. Alnylam Pharmaceuticals. September 8, 2023. Accessed October 5, 2023. https://investors.alnylam.com/press-release?id=26936