FDA panel supports patisiran for ATTR amyloidosis with cardiomyopathy
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Key takeaways:
- An FDA panel voted that the benefits of patisiran outweighed the risks for patients with ATTR cardiomyopathy.
- Panelists cited modest but consistent improvements in functional status with no safety concerns.
An FDA panel voted 9-3 in favor of expanding approval of patisiran to patients with cardiomyopathy of wild-type transthyretin-mediated or hereditary transthyretin-mediated amyloidosis, noting modest benefits but no significant safety concerns.
In a meeting of the FDA’s Cardiovascular and Renal Drugs Advisory Committee (CRDAC), panel members expressed concern that observed benefits with patisiran (Onpattro, Alnylam) seen in the APOLLO-B study appeared modest at best, with small beneficial signals for improvements in 6-minute walk test and Kansas City Cardiomyopathy Questionnaire overall summary score, both markers of functional status. Additionally, researchers did not observe a benefit with patisiran in patients who were also prescribed tafamidis (Vyndamax, Pfizer), a subgroup who made up 25% of the study cohort.
Still, most panelists ultimately decided that the unmet need for transthyretin amyloidosis (ATTR) should be given extra weight.
Rare disease with ‘devastating consequences’
“We are dealing with a rare disease with few options and devastating consequences,” Ravi Thadhani, MD, MPH, executive vice president for health affairs at Emory University and executive director of Woodruff Health Sciences Center in Atlanta, said after a “yes” vote. “We heard from clinicians loud and clear that options and alternatives are critical and there is a continuous decline of cardiac function and worsening of disease in many patients that have received the current standard of care. The sponsor had to deal with what was relevant at the time, and that is that standard of care had not been established at the time [of study design] and tafamidis use was capped at the time of the study.”
Tafamidis, the first FDA-approved treatment for ATTR-CM, was approved in May 2019. Patisiran, a small interfering RNA agent, is approved to treat polyneuropathy in patients with hereditary ATTR amyloidosis but is not yet approved to treat ATTR-CM.
“This is a bunt single vs. a homerun like tafamidis,” Christopher M. O’Connor, MD, MACC, FESC, FHFA, FHFSA, professor of medicine at Duke University and president and executive director of Inova Heart and Vascular Institute, said during discussion after the vote. “I voted ‘yes’ because I believe we can develop the proper ‘swim lane’ with the agency for the use of this drug, particularly in tafamidis-naive patients.”
Panel chairperson and Healio | Cardiology Today Editorial Board Member Javed Butler, MD, MPH, MBA, FACC, FAHA, FESC, president of the Baylor Scott and White Research Institute, senior vice president for Baylor Scott and White Health and distinguished professor of medicine at the University of Mississippi, cited the lack of a robust benefit as the reason for his “no” vote.
“I certainly struggled with this vote,” Butler said. “My ‘no’ vote absolutely does not reflect that the disease state is not important or that there is not an unmet need. I voted ‘no’ largely because I was not sure whether the benefits were clinically meaningful in the context of the study design and how the study was done ... In the absence of robust benefit, analytic issues become more important.”
Transthyretin amyloidosis (ATTR) is a rare and progressively debilitating systemic disease with a median survival of 2 to 5 years.
Study data
In the APOLLO-B study, researchers randomly assigned 360 patients to IV patisiran 0.3 mg/kg every 3 weeks, capped at 30 mg for patients weighing 100 kg or more (n = 181) or placebo (n = 179). The median age of participants was 76 years; most patients were white men. Within the cohort, 80% had wild-type ATTR and 20% had hereditary ATTR. Approximately 25% of the cohort was already taking tafamidis.
The primary efficacy endpoint was change from baseline in 6-minute walk test at 12 months; the secondary endpoint was change from baseline to 12 months in the Kansas City Cardiomyopathy Questionnaire (KCCQ) overall summary score.
The study was not designed to assess outcomes, but secondary endpoints included all-cause mortality, frequency of CV events (CV hospitalizations and urgent HF visits) and change from baseline in 6-minute walk test; a composite endpoint of all-cause mortality and frequency of all-cause hospitalizations and urgent HF visits for participants not taking tafamidis at baseline as well as in the overall population. The trial was not powered for a mortality endpoint.
At 12 months, study participants entered an ongoing, open-label extension study.
In background briefing documents, FDA staff stated that APOLLO-B showed a statistically significant but small treatment effect for the primary efficacy endpoint. Patisiran-treated patients experienced an average decrease in 6-minute walk distance of 13 meters at 12 months and placebo-treated patients experienced an average decrease of 31 meters at 12 months. The change from baseline at month 12 in 6-minute walk distance for patisiran vs. placebo was 14.7 m (95% CI, 0.7-28.7; P = .04).
The key secondary endpoint also favored the patisiran group, as the least squared mean change in KCCQ overall summary score was 0.3 in the patisiran group and –3.408 in the placebo group (least squared mean difference, 3.709; standard error of mean, 1.796; P = .0397). Secondary composite endpoints were not significant.
The treatment effect observed was maintained in the open-label extension for up to 2 years, demonstrating ongoing preservation of functional capacity, according to John Vest, MD, senior vice president of clinical research for Alnylam Pharmaceuticals. Favorable effects on KCCQ scores were consistent across all KCCQ domains; 2-year data were similar, Vest said.
“Remaining stable is a very good outcome,” Best said during a Q&A session after the public comment portion of the meeting.
Debate at several points in the meeting centered around including change in KCCQ overall summary scores as a trial endpoint, when FDA has stated there is no evidence regarding what is considered a “meaningful change” in KCCQ score.
“In the APOLLO-B trial, there were neither appropriate anchor scales administered nor qualitative data collected to aid in the evaluation of the clinical meaningfulness of the treatment effects of the 6-minute walk test or the KCCQ overall summary score, from the perspective of subjects,” the FDA wrote in briefing documents. “Although the primary efficacy endpoint of 6-minute walk test and key secondary endpoint of KCCQ overall summary score were statistically significant, the effects of patisiran compared to placebo on both endpoints were small, of questionable clinical meaningfulness, and may not be detectable by patients. Moreover, the effects of patisiran compared to placebo on 6-minute walk test appeared confined to patients not on background therapy with tafamidis.”
Potential benefit with longer follow-up
“This was a binary vote but I think we are all saying much the same thing,” David Moliterno, MD, professor of internal medicine in the division of cardiovascular medicine at University of Kentucky Medical Center, said after a “yes” vote. “The study was executed very well but I have reservations about study design. A large proportion of the patients did not show benefits, so the sponsor will be obligated to do more.”
Moliterno said there could be potential benefits observed with longer follow-up, and it will be important to continue to follow the APOLLO-B cohort. However, Moliterno cautioned that patisiran should not be viewed as an alternative to a first-line treatment like tafamidis.
“Had we stopped the tafamidis studies at 1 year, we would not have seen a mortality benefit,” Moliterno said. “I would hate to see this drug get marketed as an alternative to tafamidis and see unintended consequences of patients who do not get put on tafamidis because of this drug. “
The FDA is not required to follow the recommendations of its advisory panels, but it usually does.
References:
- Alnylam briefing documents. Available at: http://www.fda.gov/media/171979/download. Accessed Sept. 13, 2023.
- FDA briefing documents. Available at: http://www.fda.gov/media/171977/download. Accessed Sept. 13, 2023.
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FDA. Cardiovascular and Renal Drugs Advisory Committee (CRDAC) Live Video. Presented Sept. 13, 2023. Accessed Sept 13, 2023.
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