Alnylam Pharmaceuticals has reported compelling efficacy data for its RNAi therapeutic vutrisiran in treating cardiomyopathy associated with transthyretin-mediated amyloidosis (ATTR), potentially establishing a new treatment paradigm for this progressive and fatal disease.
The company's shares initially surged 36% following the announcement of top-line results from the pivotal HELIOS-B study, which demonstrated that vutrisiran reduced the risk of all-cause mortality and recurrent cardiovascular events by 28% compared to placebo after 36 months of treatment in the overall study population.
Efficacy Increases in Monotherapy Setting
Notably, the drug's efficacy was even more pronounced in patients not receiving Pfizer's tafamidis (marketed as Vyndamax) at baseline, showing a 33% reduction in the primary endpoint and approximately 35% reduction in all-cause mortality in this subgroup. This monotherapy cohort represented approximately two-thirds of the study population.
Extended follow-up data presented at the European Society of Cardiology (ESC) conference revealed that vutrisiran's benefits increased over time, with a 36% reduction in deaths and recurrent cardiovascular events at month 42 for the overall cohort.
Professor Marianna Fontana of University College London and the Royal Free Hospital, who presented the data at ESC, emphasized the significance of the findings: "Vutrisiran was highly effective and well tolerated in this contemporary population representative of patients that we see in our clinics, with consistent benefits regardless of background tafamidis therapy. This trial is also important as it is the first to show the benefit of gene silencers in any type of cardiomyopathy."
Comprehensive Clinical Benefits
The drug also demonstrated statistically significant improvements across multiple secondary endpoints, including the 6-minute walk test (6-MWT), Kansas City Cardiomyopathy Questionnaire (KCCQ), and New York Heart Association (NYHA) Class, indicating meaningful functional and quality-of-life benefits for patients.
"These results suggest that vutrisiran has the potential to become a new standard of care treatment for ATTR-CM, a progressive and ultimately fatal disease with limited treatment options," said Pushkal Garg, Alnylam's Chief Medical Officer.
Market Potential and Competitive Landscape
Vutrisiran is already approved under the brand name Amvuttra for treating polyneuropathy caused by ATTR, generating $558 million in sales last year from this indication alone. The drug is administered as a subcutaneous injection once every three months, compared to the daily oral administration required for Pfizer's tafamidis.
Alnylam CEO Yvonne Greenstreet described vutrisiran as a "transformative medicine" with the potential to drive the company's "next era of substantial growth." The company plans to use a priority review voucher to expedite FDA review of its upcoming marketing application, potentially securing approval for the cardiomyopathy indication by early 2025.
The ATTR therapy market represents a significant commercial opportunity. Pfizer's tafamidis products (Vyndamax and Vyndaqel) grew 39% last year to more than $3.3 billion in global sales. Analysts at Goldman Sachs have suggested vutrisiran could achieve peak sales exceeding $5 billion if approved for cardiomyopathy.
Competitive Challenges Ahead
Despite the positive data, Alnylam faces competition in the ATTR cardiomyopathy space. BridgeBio's acoramidis demonstrated a 42% reduction in all-cause mortality and recurrent cardiovascular events in its phase 3 ATTRibute-CM trial and could receive FDA approval as soon as November 2024.
Additionally, AstraZeneca and Ionis are developing eplontersen (Wainua), which is administered by self-injection every three months and is already approved for ATTR polyneuropathy. Results from the CARDIO-TTRansform study in ATTR cardiomyopathy are expected next year.
Another consideration is the patent expiration for Pfizer's tafamidis, with basic patents due to expire in the US later this year and in Europe by 2026. While Pfizer has filed lawsuits to extend patent protection, the eventual availability of generic tafamidis could impact the competitive landscape.
Combination Potential
Importantly, HELIOS-B data showed a 22% reduction in the primary endpoint for patients receiving vutrisiran alongside tafamidis, suggesting potential benefit from combination therapy. This finding could be strategically important for vutrisiran's positioning, allowing it to be used both as monotherapy and as an add-on to tafamidis, particularly once generic versions become available.
For ATTR cardiomyopathy patients, who currently have limited treatment options for a condition that significantly impacts quality of life and survival, these developments represent promising advances in addressing a serious unmet medical need.
