Positive results from the APOLLO-B phase III study of patisiran in patients with ATTR amyloidosis with cardiomyopathy

The results were presented 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 III 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 III, 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 are as follows: i. 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. ii. 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. iii. Secondary composite outcome endpoints were tested in a hierarchical manner; however, the secondary composite outcomes endpoints did not achieve statistical significance. a. 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. b. 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). c. 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.

iv. 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. v.A beneficial effect on the exploratory endpoint, NT-proBNP, a measure of cardiac stress, was observed in the patisiran arm compared to placebo. a. 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. 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.

Other Patisiran Data: 36-Month Global Open Label Extension (OLE) and Phase IV 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 III and Phase II 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 III APOLLO and Phase II 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 IV 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.