Ahmad Masri, MD, MS, provides his perspective on the APOLLO-B data and reacts to the FDA CRDAC 9 to 3 vote in favor of the benefit-risk profile for patisiran in ATTR-CM.
The future of patisiran could be in question ahead of the agent’s October 8, 2023 Prescription Drug User Fee Act Target Action (PDUFA) date.
Despite escaping the meeting with a 9 to 3 vote in favor of the benefit-risk profile of patisiran, members of the US Food and Drug Administration’s Cardiovascular and Renal Drugs Advisory Committee (CRDAC) expressed concern over whether the APOLLO-B trial, which examined change 6-minute walk test and Kansas City Cardiomyopathy Questionnaire (KCCQ) overall summary score, demonstrated a clinically meaningful benefit in patients with transthyretin amyloid cardiomyopathy (ATTR-CM).
“My no vote does not reflect that the disease’s data is not important or that there is not an unmet need or that there is not a potential with the therapy,“ explained Javed Butler, MD, chair of the FDA’s CRDAC and president of the Baylor Scott and White Research Institute. “The reason I voted no was 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. We do realize in certain circumstances once trial does lead to approval of the therapy.”
APOLLO-B was a phase 3, randomized, double-blind, placebo-controlled trial launched in 2019. 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 randomized 360 adult patients to 0.3 mg/kg patisiran or placebo intravenously every 3 weeks over a 12-month double-blind treatment period. Results of the trial provided evidence of a median difference of 14.7 meters (P = .0162) for 6-minute walking test at 12 months favoring the patisiran group, with use of patisiran was associated with a statistically significant and clinically meaningful benefit on health status and quality of life (P = .0397).
With an interest in further exploring the perspective of experts in cardiomyopathy and amyloidosis on patisiran as well as the recent CRDAC vote, HCPLive Cardiology sat down with Ahmad Masri, MD, MS, assistant professor of medicine in the Division of Cardiovascular Medicine and director of the Hypertrophic Cardiomyopathy Center at Oregon Health and Science University.
HCPLive Cardiology: Before discussing the vote, what was your reaction to the APOLLO-B trial and the results as an expert in cardiomyopathy and amyloidosis?
Masri: So, I believe there are two things to consider. One is what the actual study shows based on how it was designed, and the other is the overall sentiment in the field regarding silencers and their role. I think most of us have had positive experiences with using silencers, which is something that essentially everyone agrees on. Now, setting that aside, and considering the fact that we do have an unmet need in this field, we want to do what is best for our patients.
Now, once you move past that and consider the study itself, the question at hand was not whether patisiran improves mortality, heart failure hospitalization, or any of the usual outcomes we use to assess trials of transthyretin cardiac amyloidosis. The trial was relatively small in comparison. It assessed the 6-minute walk test at 12 months, as well as secondary endpoints such as the KCCQ overall summary score. When you think about it in this way, the trial was not designed to allow us to gain insight into anything beyond that.
There were some biomarkers and secondary endpoints, but the trial concluded at 12 months, and afterward, there was an open-label extension phase, which meant that you couldn't learn more about the drug's performance beyond the 12-month mark. This differs, for example, from the recent ATTRibute-CM acoramidis trial, which had two parts. Part A lasted for 12 months, and then Part B followed later on. This is relevant because the FDA, as well as the advisors on the committee, had to review the data at the 12-month mark and decide whether there was enough evidence to suggest a clinically meaningful difference.
HCPLive Cardiology: How relevant are the endpoints of APOLLO-B among this patient population?
Masri: I believe these factors are relevant, but their relevance varies in magnitude. There are a couple of aspects to delve into here. Firstly, what does the change in the six-minute walk test at one year actually mean in terms of how patients feel? We don't have a definitive answer to that question. This aspect has never been prospectively studied in transthyretin amyloidosis. We attempt to draw insights from other disease areas, trying to glean what seems reasonable. Moreover, it's worth noting that the study was originally powered for a much larger change in the six-minute walk test at 12 months, and this was a significant focal point in the discussions during the FDA Advisory Committee meeting.
Therefore, it's not solely the change itself that matters; it's also the magnitude of that change. Secondly, what is required to achieve this change? Are patients simply taking a daily oral pill, requiring no additional monitoring or experiencing no side effects? Or, in this case, we're dealing with an infusion that is typically administered in infusion centers, rather than at home. This is because most of these patients are mobile and able to visit the infusion center. The process involves providing three medications for pre-medication before the infusion, establishing an intravenous line, and then administering the drug. While patisiran is undoubtedly a safe drug, I believe the process of receiving the medication every three weeks is not a trivial one.
If we view the six-minute walk test as a binary assessment, it might lead us to question whether even a small improvement of one or two meters in the distance covered during the test constitutes a positive result. This is where the concept of what is clinically meaningful becomes crucial. If you attended the advisory committee meeting, you probably heard this discussed repeatedly. It's not merely a matter of labeling the result as positive or negative; it's about determining what is considered clinically meaningful in the context of the drug that will be administered to these patients.
HCPLive Cardiology: What was your reaction to the FDA CRDAC’s vote?
Masri: Well, it was a surprising result. After listening in for most of the meeting, the reason for my surprise is that most of the meeting leaned towards a negative assessment of the trial. If you paid attention to both the advisors and the FDA, they expressed fairly negative views on various aspects of the trial, from its design to how the endpoints were evaluated, including intricate details that many people are not accustomed to. According to the FDA's perspective, these factors made it nearly impossible to draw conclusions about the magnitude of the benefits.
A recurring theme that emerged was the importance of adhering to FDA guidance when assessing quality of life, particularly the use of anchor-based methods rather than solely relying on distribution-based methods. This requirement was clearly not met, and post hoc analyses were conducted in different ways to align with the FDA's expectations. The direction of the discussion seemed to be leaning towards the notion that the majority would likely have said there isn't enough evidence from this trial to support the idea that the drug results in a clinically meaningful change at 12 months. However, when the vote took place, there were 9 "yes" votes and 3 "no" votes.
What I found interesting were the comments made after the vote. These comments were still not overly enthusiastic "yeses" and continued to echo and summarize the day's discussions. The recurring sentiment was, "We want to provide more options for patients. We believe that, based on the mechanism of action and the drug's performance, it's a reasonable option for patients. However, the trial left us with a great deal of uncertainty regarding the drug's efficacy."
There were also discussions about possibly considering a narrow indication for the drug or identifying specific patient groups for whom this drug would be most suitable, rather than it being a one-size-fits-all solution for everyone with ATTR-CM. These are complex matters to address, as it now falls upon the FDA, the sponsor, and the advisors to determine how to formulate an actionable plan if the decision ultimately leans towards approving the drug.
HCPLive Cardiology: Based on the data and the vote, would you expect an indication in ATTR-CM for patisiran on October 8, 2023?
Masri: I don't know the answer. Once again, I would not have expected the outcome of the advisory committee to be as it was, and now it's really hard to predict how this will move forward. It was very clear to anyone who tuned in that the FDA held a highly negative view on most aspects of the study, as well as its results. So, it's a dilemma.
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.
Regarding the drug, it's important to remember, although it was surprising that this didn't come up in the discussions, that we have a second-generation silencer, vutrisiran, currently undergoing a trial with over 600 patients. This trial includes key outcomes such as mortality and hospitalization due to cardiovascular disease (CVD), with results expected next year in 2024. We don't have much information about the trial itself or when we can expect the actual results, but it's worth noting that it focuses on the same population—those with ATTR-CM. This omission from the discussion is also quite interesting.
So, even though we inform patients that this study doesn't clearly demonstrate a clinically meaningful difference at 12 months, it doesn't mean we're abandoning the idea of silencers altogether. There are two large trials currently underway that, hopefully, will lead to the approval of silencers for this indication. We hope to address this unmet need because we do have patients who experience disease progression on tafamidis, and some continue to have symptoms, even with tafamidis treatment.
Editor's note: This transcript has been edited for clarity using artificial intelligence.