Alnylam Presents Positive Results from the APOLLO-B Phase 3 Study of Patisiran in Patients with ATTR Amyloidosis with Cardiomyopathy

– Study Results Validate the Hypothesis That TTR Silencing by an RNAi Therapeutic has the Potential to be an Effective Approach for Treating Cardiomyopathy of ATTR Amyloidosis –

– Patisiran met Primary Endpoint, Demonstrating Significant Clinical Benefit on Functional Capacity (6-MWT) Compared to Placebo at Month 12 –

– Patisiran Also met the First Secondary Endpoint, Demonstrating Significant Clinical Benefit on Health Status and Quality of Life, as Measured by the Kansas City Cardiomyopathy Questionnaire, Compared to Placebo at Month 12 –

– Patisiran Demonstrated Encouraging Safety and Tolerability Profile in Patients with ATTR Amyloidosis with Cardiomyopathy –

CAMBRIDGE, MA, USA I September 08, 2022 I Alnylam Pharmaceuticals, Inc. (Nasdaq: ALNY), the leading RNAi therapeutics company, today announced positive results from the APOLLO-B Phase 3 study of patisiran, an investigational RNAi therapeutic in development for the treatment of transthyretin-mediated (ATTR) amyloidosis with cardiomyopathy. The results were presented today in a late-breaker session at the 18th International Symposium on Amyloidosis (ISA). The Company previously announced positive topline results from the APOLLO-B study in August 2022.

The 12-month study achieved its primary endpoint, with patisiran demonstrating a statistically significant and clinically meaningful benefit on functional capacity, as measured by the 6-Minute Walk Test (6-MWT), compared to placebo, with a median difference of 14.7 meters (p-value 0.0162) favoring patisiran. The study also met its first secondary endpoint, 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 (KCCQ-OS) score, compared to placebo with least squares (LS) mean difference of 3.7 points (p-value 0.0397) favoring patisiran. The study also included additional secondary composite outcomes endpoints. A non-significant result (p-value 0.0574) was found on the composite endpoint of all-cause mortality, frequency of cardiovascular events, and change from baseline in 6-MWT over 12 months compared to placebo. As a result, formal statistical testing was not performed on the final two composite endpoints. Patisiran also demonstrated an encouraging safety and tolerability profile in patients with ATTR amyloidosis with cardiomyopathy.

“The results of the APOLLO-B Phase 3 study are impressive, as I believe they underscore the potential for patisiran to provide a benefit on functional capacity and quality of life in patients living with ATTR amyloidosis with cardiomyopathy. Furthermore, these results were seen after only 12 months of treatment,” said Mathew Maurer, M.D., Arnold and Arlene Goldstein Professor of Cardiology at Columbia University Irving Medical Center. “The cardiac manifestations associated with ATTR amyloidosis can have a devastating impact on patients’ lives and current treatment options are limited. With the rapidly progressive nature of the disease, there is a significant need for treatments like patisiran, which has the potential to be a new option for patients and physicians to treat the cardiomyopathy of ATTR amyloidosis.”

APOLLO-B Study Results
APOLLO-B is a Phase 3, randomized, double-blind, placebo-controlled multicenter global study designed and powered to evaluate the effects of patisiran on functional capacity and quality of life in patients with ATTR amyloidosis with cardiomyopathy. The study enrolled 360 adult patients with ATTR amyloidosis (hereditary or wild-type) with cardiomyopathy at 69 sites in 21 countries. Patients were randomized 1:1 to receive 0.3 mg/kg of patisiran or placebo intravenously administered every three weeks over a 12-month treatment period. After 12 months, all patients will receive patisiran in an open-label extension.

At 12 months, the study results presented today are as follows:

  • For 6-MWT, the median change from baseline to Month 12 was -8.15 meters for the patisiran group and -21.345 meters for the placebo group; the Hodges-Lehmann estimate of the median difference was 14.7 meters (p-value 0.0162) favoring patisiran.
  • For KCCQ-OS, the LS mean change from baseline to Month 12 was +0.300 for the patisiran group and -3.408 for the placebo group, with an LS mean difference of 3.7 points (p-value 0.0397) favoring patisiran.
  • Secondary composite outcome endpoints were tested in a hierarchical manner; however, the secondary composite outcomes endpoints did not achieve statistical significance.
    • A non-significant result (win ratio 1.27, 95% CI: 0.99, 1.61; p-value 0.0574) was found on the secondary composite endpoint of all-cause mortality, frequency of cardiovascular events, and change from baseline in 6-MWT over 12 months compared to placebo.
    • The final two composite endpoints were not powered for statistical significance given the sample size and short duration of the study — all-cause mortality and frequency of all-cause hospitalizations and urgent heart failure visits in patients not on tafamidis at baseline (Hazard Ratio (HR) 0.997, 95% CI: 0.620, 1.602; nominal p-value 0.9888), and in the overall study population (HR 0.883, 95% CI: 0.582, 1.341; nominal p-value 0.5609).
    • Efficacy analysis of all-cause mortality excluded deaths due to COVID-19 (1 patisiran patient) and treated heart transplants in the same manner as deaths (2 placebo patients), as pre-specified in the statistical analysis plan. Per this definition, there were 4 deaths (2.2%) observed in patisiran-treated patients and 10 deaths (5.6%) observed in the placebo group.
  • Patisiran achieved a rapid and sustained reduction in serum TTR levels, with a mean percent reduction from baseline in serum TTR reduction of 87% at Month 12
  • A beneficial effect on the exploratory endpoint, NT-proBNP, a measure of cardiac stress, was observed in the patisiran arm compared to placebo.
    • The adjusted geometric mean fold change from baseline at Month 12 in NT-proBNP was 1.11 for the patisiran group and 1.38 for the placebo group, indicating a 20% reduction in the patisiran arm compared to placebo (nominal p-value 1.825x10-5).

Patisiran also demonstrated an encouraging safety and tolerability profile, including no cardiac safety concerns relative to placebo, during the 12-month treatment period. The majority of adverse events (AEs) were mild or moderate in severity. Treatment emergent AEs occurring in 5% or more patients in the patisiran group and observed at least 3% more commonly than in the placebo group included infusion-related reactions (12.2% vs 9.0%), arthralgia (7.7% vs 4.5%), and muscle spasms (6.6% vs 2.2%). In the safety analysis there were 5 deaths (2.8%) observed in patisiran-treated patients and 8 deaths (4.5%) observed in the placebo group.

“We believe the totality of the APOLLO-B study results provides a compelling clinical profile of patisiran for patients and families living with ATTR amyloidosis with cardiomyopathy, a fatal, multi-system disease. It was encouraging to see the impact of patisiran on functional capacity in the study, as the change from baseline in 6-MWT for patisiran-treated patients was in the range of the approximately 5 meter decline typically seen in healthy older adults over a 12-month period.1 Furthermore, health status and quality of life in patisiran-treated patients was maintained relative to baseline, which is another important aspect of the potential benefit that patisiran treatment may provide to patients,” said Pushkal Garg, M.D., Chief Medical Officer at Alnylam. “Importantly, we believe these data validate the therapeutic hypothesis that TTR silencing by an RNAi therapeutic may be an effective approach to treating cardiomyopathy of both wild-type and hereditary ATTR amyloidosis. ATTR amyloidosis with cardiomyopathy is an increasingly recognized cause of heart failure, affecting greater than 250,000 patients around the world, and with these results, we can take another important step forward towards delivering a potential new treatment to the patients who need it, assuming favorable regulatory review.”

Alnylam plans to file a supplemental new drug application (sNDA) for patisiran as a potential treatment for ATTR amyloidosis with cardiomyopathy in the U.S. in late 2022. Additional results from the APOLLO-B study will be presented at the upcoming Heart Failure Society of America (HFSA) annual meeting being held in Washington DC, September 30 to October 3, 2022.

To view the APOLLO-B data presented at ISA, please visit, Capella.

Other Patisiran Data: 36-Month Global Open Label Extension (OLE) and Phase 4 Observational Study Results
Alnylam also presented 36-month results from the ongoing Global OLE study of patisiran in eligible patients who completed the APOLLO Phase 3 and Phase 2 OLE studies, evaluating the effect of long-term patisiran treatment on mortality and ambulatory function.

Findings demonstrate that patients who initiated treatment with patisiran earlier in the Phase 3 APOLLO and Phase 2 OLE studies experienced greater survival as compared with the APOLLO placebo patients who initiated treatment with patisiran later during the Global OLE study. Further, those same patients who initiated patisiran earlier showed stabilized or improved ambulation versus patients in the APOLLO placebo group as assessed by polyneuropathy disability (PND) score. The long-term safety profile of patisiran was consistent with prior analyses.

These results highlight the substantial impact of earlier diagnosis and treatment with patisiran in patients with hereditary transthyretin-mediated (hATTR) amyloidosis with polyneuropathy.

Additional data were also 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. These variants are historically associated with cardiomyopathy, thus further evidence that patients with these variants also experience polyneuropathy is emerging.

After 12 months of treatment with patisiran, 93.3% of patients (42/45) experienced stabilization or improvement in PND score from baseline. Treatment with patisiran also resulted in clinically meaningful improvements in QOL and autonomic symptoms after 12 months. Patisiran demonstrated an acceptable safety profile, consistent with existing data.

Conference Call Information
Management will discuss the APOLLO-B results via conference call on Thursday, September 8, 2022, at 8:00 a.m. ET. To access the call, please register online at https://register.vevent.com/register/BI6a961cac960e44388f73484c61dc79cf. Participants are requested to register a minimum of 15 minutes before the start of the call. A replay of the call will be available two hours after the call and archived on the same webpage for six months.

A live audio webcast of the call will be available on the Investors section of the Company’s website at www.alnylam.com/events. An archived webcast will be available on the Company’s website approximately two hours after the event.

About ATTR Amyloidosis
Transthyretin-mediated (ATTR) amyloidosis is a rare, rapidly progressive, debilitating disease caused by misfolded transthyretin (TTR) proteins which accumulate as amyloid fibrils in multiple tissues including the nerves, heart, and gastrointestinal (GI) tract. There are two different types of ATTR amyloidosis – Hereditary ATTR (hATTR) amyloidosis, caused by a TTR gene variant, and Wild-type ATTR (wtATTR) amyloidosis, which occurs without a TTR gene variant. hATTR amyloidosis affects approximately 50,000 people worldwide, while wtATTR amyloidosis is estimated to impact 200,000 – 300,000 people worldwide.

About ONPATTRO® (patisiran)
ONPATTRO is an RNAi therapeutic that is approved in the United States and Canada for the treatment of the polyneuropathy of hATTR amyloidosis in adults. ONPATTRO is also approved in the European Union, Switzerland and Brazil for the treatment of hATTR amyloidosis in adults with Stage 1 or Stage 2 polyneuropathy, and in Japan for the treatment of hATTR amyloidosis with polyneuropathy. ONPATTRO is an intravenously administered RNAi therapeutic targeting transthyretin (TTR). It is designed to target and silence TTR messenger RNA, thereby reducing the production of TTR protein before it is made. Reducing the pathogenic protein leads to a reduction in amyloid deposits in tissues. For more information about ONPATTRO, including full Prescribing Information, visit ONPATTRO.com.

ONPATTRO Indication and Important Safety Information

Indication
ONPATTRO is indicated for the treatment of the polyneuropathy of hereditary transthyretin-mediated amyloidosis in adults.

About LNP Technology
Alnylam has licenses to Arbutus Biopharma LNP intellectual property for use in RNAi therapeutic products using LNP technology.

About RNAi
RNAi (RNA interference) is a natural cellular process of gene silencing that represents one of the most promising and rapidly advancing frontiers in biology and drug development today. Its discovery has been heralded as “a major scientific breakthrough that happens once every decade or so,” and was recognized with the award of the 2006 Nobel Prize for Physiology or Medicine. By harnessing the natural biological process of RNAi occurring in our cells, a new class of medicines, known as RNAi therapeutics, is now a reality. Small interfering RNA (siRNA), the molecules that mediate RNAi and comprise Alnylam’s RNAi therapeutic platform, function upstream of today’s medicines by silencing messenger RNA (mRNA) – the genetic precursors – that encode for disease-causing proteins, thus preventing them from being made. This is a revolutionary approach with the potential to transform the care of patients with genetic and other diseases.

About Alnylam Pharmaceuticals
Alnylam (Nasdaq: ALNY) has led the translation of RNA interference (RNAi) into a whole new class of innovative medicines with the potential to transform the lives of people afflicted with rare and prevalent diseases with unmet need. Based on Nobel Prize-winning science, RNAi therapeutics represent a powerful, clinically validated approach yielding transformative medicines. Since its founding 20 years ago, Alnylam has led the RNAi Revolution and continues to deliver on a bold vision to turn scientific possibility into reality. Alnylam’s commercial RNAi therapeutic products are ONPATTRO® (patisiran), GIVLAARI® (givosiran), OXLUMO® (lumasiran), AMVUTTRA™ (vutrisiran) and Leqvio® (inclisiran) being developed and commercialized by Alnylam’s partner, Novartis. Alnylam has a deep pipeline of investigational medicines, including multiple product candidates that are in late-stage development. Alnylam is executing on its “Alnylam P5x25” strategy to deliver transformative medicines in both rare and common diseases benefiting patients around the world through sustainable innovation and exceptional financial performance, resulting in a leading biotech profile. Alnylam is headquartered in Cambridge, MA. For more information about our people, science and pipeline, please visit www.alnylam.com and engage with us on Twitter at @Alnylam, on LinkedIn, or on Instagram.

1 Enright P, Sherrill D, Am J Prespir Crit Care Med. 1998;158(5 Pt 1):1384-1387.

SOURCE: Alnylam Pharmaceuticals

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