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The ATTRibute-CM Phase III trial, which formed the basis for the FDA’s approval, enrolled 632 subjects with symptomatic ATTR-CM. Credit: Theerani lerdsri/Shutterstock. The US Food and Drug Administration (FDA) has approved BridgeBio Pharma ’s Attruby (acoramidis), an oral transthyretin (TTR) stabiliser, to treat adults with transthyretin amyloid cardiomyopathy (ATTR-CM). The approval aims to decrease cardiovascular deaths and related hospitalisations. Attruby is the first approved product with a label that specifies near-complete TTR stabilisation. The approval triggers a $500m payment to BridgeBio under a royalty funding agreement. The ATTRibute-CM Phase III trial, which formed the basis for the FDA’s approval, enrolled 632 subjects with symptomatic ATTR-CM. Participants were randomised in a 2:1 ratio to receive either Attruby or a placebo for 30 months. The primary endpoint of the ATTRibute-CM trial included a composite of all-cause mortality, cardiovascular-related hospitalisations, levels of N-terminal prohormone of brain natriuretic peptide and the six-minute walk test. The trial met its primary endpoint with a win ratio of 1.8. Attruby’s positive impact was further evidenced by its statistically significant treatment effect observed in the six-minute walk test and the Kansas City Cardiomyopathy Questionnaire. The treatment also halved the increase in NT-proBNP levels compared to the placebo group. In recognition of the trial participants’ contribution in the US, the company is set to provide these patients with Attruby free for life as a gesture of gratitude. BridgeBio Pharma CEO and founder Neil Kumar stated: “With the landmark approval of Attruby, we gain the ability to serve patients with ATTR-CM. I’m grateful to each trial participant, their families and the physicians, scientists and our team at BridgeBio who made this possible. “Our journey is not over as we look to pursue approvals globally, next in Europe, Japan and Brazil, and to continue exploring the full potential of this treatment. I am thrilled to extend our mission of putting patients first with this third FDA approval in less than 10 years.” The company has also submitted a marketing authorisation application (MAA) to the European Medicines Agency, expecting a decision by 2025. Bayer has secured exclusive rights from the company to commercialise acoramidis to treat ATTR-CM in Europe. The outcomes from the Phase III ATTRibute-CM trial were published by the company in January 2024.

The FDA on Friday approved BridgeBio Pharma's Attruby (acoramidis) to reduce cardiovascular death and cardiovascular-related hospitalisation in patients with transthyretin amyloid cardiomyopathy (ATTR-CM), setting up a showdown with Pfizer's tafamidis, which has the same mechanism of action, but a more limited label. The clearance for Attruby, an oral TTR stabiliser, specifies that the drug provides near-complete stabilisation of TTR, which is not present in the tafamidis indication. The list price will be $18,759 for a 28-day supply.Tafamidis — marketed as Vyndamax and Vyndaqel — became the first drug approved by the FDA for ATTR-CM when it was greenlit in 2019. Since then, drugmakers have been racing to nab their own piece of the potentially lucrative heart disease pie. Last year, Pfizer's products brought in a total of $3.3 billion in global sales. Now, Attruby is set to reach patients faster than the other major horse in the race, Alnylam's RNAi therapeutic vutrisiran. A series of physician polls conducted by FirstWord this year has shown that, if approved, cardiologists view vutrisiran as an important new treatment option, but whether that therapy, or Attruby, can topple tafamidis and become the new standard of care will be dependent on different interpretations of available clinical data. For related analysis, see Physician Views Results: Cardiologists have much to ponder with ATTR-CM treatment options set to expand; Physician Views Poll Results: Amvuttra another compelling treatment option for ATTR-CM, say majority of cardiologists; and Physician Views Results: Cardiologist feedback suggests Alnylam well placed to take on Pfizer in ATTR-CM field.However, given Attruby's market lead on vutrisiran and the strength of its pivotal data, some Wall Street analysts have suggested that Alnylam could have a more challenging time commercialising its RNAi therapeutic — and that the TTR stabiliser poses more of a significant threat to Pfizer's stronghold.Mortality reduction, fastAttruby's approval was based on data from the ATTRibute-CM Phase III trial, which enrolled 632 patients with symptomatic ATTR-CM to receive either Attruby or placebo for 30 months.BridgeBio's drug met the study's primary goal by achieving statistically significant improvements over placebo on each of the four components of a composite endpoint: all-cause mortality (ACM), cardiovascular-related hospitalisations (CVH), NT-proBNP and 6-minute walk distance. Specifically, patients who received Attruby saw a 25% reduction in ACM and a 50% reduction in CVH at 30 months, with 81% of patients alive at that time point. And notably,  Attruby achieved a three-month time to separation of outcomes curve.By comparison, tafamidis demonstrated a 30% reduction in all cause mortality and 32% reduction in cardiovascular hospitalisations at 30 months in the ATTR-ACT study, with 70% of patients receiving Pfizer's therapy remaining alive at this cut-off. The drug had an 18-month time to separation on ACM and a nine-month time to separation on CVH.Global plansBridgeBio CEO Neil Kumar said the company plans to file for approval of Attruby in Japan and Brazil next. A submission in the EU — where Bayer holds exclusive commercialisation rights — is already under review, with a decision expected next year. Meanwhile, BridgeBio said it will receive a $500-million payment under a royalty funding agreement.

Encouraging early clinical data from Alnylam Pharmaceuticals and Intellia Therapeutics presented at the American Heart Association’s (AHA) scientific sessions over the weekend hinted at significant progress in developing novel treatments for transthyretin amyloidosis (ATTR).While Alnylam’s next-generation siRNA therapeutic, nucresiran, demonstrated rapid and durable reduction of serum transthyretin (TTR) in healthy participants, a one-time administration of Intellia’s Regeneron-partnered CRISPR-based gene editing therapy, nexiguran ziclumeran (nex-z), showed disease stabilisation or improvement, alongside TTR lowering in a cohort of ATTR amyloidosis with cardiomyopathy (ATTR-CM).Robust siRNA-induced TTR knockdownIn one ongoing Phase I study, 48 healthy participants were randomised to receive a single ascending dose of nucresiran in the range of 5 mg to 900 mg, or placebo. Results showed that a ≥300-mg nucresiran dose achieved rapid and consistent knockdown of serum TTR, with mean reductions >90% by day 15, peaking >96% by day 29, and sustained through day 180. For the 300-mg dose, TTR reductions remained >70% at day 360. Moreover, nucresiran demonstrated low inter-patient variability in TTR reductions at all doses by day 29. Safety remained favourable across all doses, with no injection site reactions or liver-related signals identified. “Nucresiran utilises our IKARIA platform, which has now demonstrated the potential to achieve durability supportive of biannual or annual dosing, representing a potential new paradigm in the treatment of ATTR amyloidosis,” remarked Pushkal Garg, chief medical officer of Alnylam.Garg noted that the company will unveil Phase III development plans for the drug early next year. Subject to successful late-stage testing and approval, nucresiran would become the third addition to Alnylam’s siRNA portfolio for ATTR, which includes Onpattro (patisiran) and Amvuttra (vutrisiran), approved by the FDA in 2018 and 2022, respectively.CRISPR therapy alters ATTR-CM progressionMeanwhile, Intellia’s Phase I study is investigating nex-z in two cohorts: a 36-participant ATTR-CM arm and a 33-participant ATTR with polyneuropathy (ATTRv-PN) arm. Results for the ATTR-CM arm at the August 21 data-off showed that a single dose of nex-z led to a 90% reduction in serum TTR by month 12, which was sustained in 11 participants reaching the 24-month follow-up. Notably, the treatment also demonstrated disease-modifying effects, with 81%, 94% and 77% of participants achieving significant improvements on cardiac markers such as NT-proBNP, high sensitivity Troponin T and 6-minute walk test, respectively. On the safety front, nex-z was well tolerated, with no instances of treatment-related discontinuation.“The stability or improvement…in multiple markers of cardiac disease progression is remarkable, especially considering the high proportion of patients with cardiomyopathy who had advanced heart failure,” explained John Leonard, chief executive of Intellia. The company also noted positive and consistent trends, reflecting a disease-modifying effect in the ATTRv-PN cohort. Intellia is currently recruiting for the Phase III MAGNITUDE study of nex-z for ATTR-CM and is set to commence the MAGNITUDE-2 study for ATTRv-PN. The latest findings for nex-z could spell good news for the biotech, whose stock tumbled over 20% last month after investor concerns persisted despite positive mid-stage results of another CRISPR-based therapy, NTLA-2002, for hereditary angioedema.