May 20, 2023 Press Release for Alnylam
Alnylam Presents 18-Month Results from the APOLLO-B Phase 3 Study of Patisiran in Patients with ATTR Amyloidosis with Cardiomyopathy
May 20, 2023
– Continued Treatment with Patisiran in Open-Label Extension Period Showed Evidence of Sustained Benefit across Measures of Functional Capacity and Health Status and Quality of Life, as well as Cardiac Stress and Injury, through 18 Months –
– Safety Profile Consistent with that Observed in 12-Month Double-Blind Period, with No New Safety Findings –
The 18-month findings indicate that the favorable effects on functional capacity and health status and quality of life, as measured by the 6-Minute Walk Test (6-MWT) and the Kansas City Cardiomyopathy Questionnaire Overall Summary (KCCQ-OS), respectively, observed during the DB period were sustained with continued patisiran treatment during the OLE period. Patients treated with patisiran through 18 months also appear to have maintained relative stability of NT-proBNP and Troponin I levels, measures of cardiac stress and injury, respectively. Patients who crossed over from placebo in the DB period to patisiran during the OLE period appear to show slowing of disease progression or relative stabilization across these same endpoints at Month 18. While the APOLLO-B study was not designed to show benefits in cardiac outcomes between patisiran and placebo, evidence of favorable, but non-statistically significant, trends were observed for composite all-cause death and hospitalization, and mortality analyses across the DB and OLE periods.
“We are pleased to share encouraging new data from our APOLLO-B OLE study, which we believe continue to support the potential for patisiran to be an important therapeutic option for patients with ATTR amyloidosis with cardiomyopathy,” said
APOLLO-B 18-Month Study Results
APOLLO-B is a Phase 3, randomized, DB, placebo-controlled multicenter global study 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. Patients were randomized 1:1 to receive 0.3 mg/kg of patisiran or placebo intravenously administered every three weeks over a 12-month DB treatment period. After 12 months, all patients were eligible to enter the OLE period of the trial to receive patisiran. An analysis performed at Month 18 indicated:
- Favorable effects on functional capacity (6-MWT) and health status and quality of life (KCCQ-OS) were sustained in patients receiving patisiran through 18 months. In patients who received placebo during the DB period, initiation of patisiran in the OLE period was associated with a slower rate of worsening (6-MWT) or relative stability (KCCQ-OS) at Month 18 compared with the DB period.
- For 6-MWT, the mean change from baseline to Month 18 was -9.2 meters in patients initially randomized to patisiran, consistent with the Month 12 assessment. For patients initially randomized to placebo, the mean change from baseline to Month 12 was -25.4 meters and to Month 18 was -31.1 meters.
- For KCCQ-OS, the mean change from baseline to Month 18 was +0.2 points in patients initially randomized to patisiran, and -4.0 points in patients initially randomized to placebo.
- Continued treatment with patisiran through 18 months was also associated with relative stability in biomarker measures of cardiac stress (NT-proBNP) and cardiac injury (Troponin I). Patients who received placebo in the DB period showed steadily rising cardiac biomarker levels up to Month 12, which then appeared to slow or stabilize after initiating patisiran in the OLE period.
- The geometric mean fold-change from baseline at Month 18 in NT-proBNP was 1.17 for patients who continued on patisiran, and 1.53 for placebo-crossover patients.
- The geometric mean fold-change from baseline at Month 18 in Troponin I was 1.09 for patients who continued on patisiran, and 1.21 for placebo-crossover patients.
- Additionally, while the APOLLO-B study was not designed to show a treatment difference in death and hospitalizations between patisiran and placebo in the DB or OLE period, and no statistically significant differences were achieved, evidence of favorable trends were observed for these composite endpoints. The analyses of outcomes included all available data from the DB and OLE periods at the time of the Month 18 data-cut.
- The point estimate of hazard ratio (HR) for the composite of all-cause mortality and frequency of all-cause hospitalization and urgent heart failure visits was 0.801 (95% CI, 0.573–1.118).
- The HR for all-cause mortality was 0.554 (95% CI, 0.281–1.094).
Patisiran demonstrated an encouraging safety profile through 18 months of treatment, consistent with the underlying disease and the known safety profile of patisiran, with no new safety concerns identified. The majority of adverse events (AEs) were mild or moderate in severity. The most common treatment-related AE was infusion-related reactions (14.1 percent).
As previously announced, the
To view the APOLLO-B 18-month results presented at Heart Failure 2023, please visit Capella.
ONPATTRO Indication and Important Safety Information
Indication
ONPATTRO is indicated for the treatment of the polyneuropathy of hereditary transthyretin-mediated amyloidosis in adults.
Important Safety Information
Infusion-Related Reactions
Infusion-related reactions (IRRs) have been observed in patients treated with ONPATTRO. In a controlled clinical study, 19% of ONPATTRO-treated patients experienced IRRs, compared to 9% of placebo-treated patients. The most common symptoms of IRRs with ONPATTRO were flushing, back pain, nausea, abdominal pain, dyspnea, and headache.
To reduce the risk of IRRs, patients should receive premedication with a corticosteroid, acetaminophen, and antihistamines (H1 and H2 blockers) at least 60 minutes prior to ONPATTRO infusion. Monitor patients during the infusion for signs and symptoms of IRRs. If an IRR occurs, consider slowing or interrupting the infusion and instituting medical management as clinically indicated. If the infusion is interrupted, consider resuming at a slower infusion rate only if symptoms have resolved. In the case of a serious or life-threatening IRR, the infusion should be discontinued and not resumed.
Reduced Serum Vitamin A Levels and Recommended Supplementation
ONPATTRO treatment leads to a decrease in serum vitamin A levels. Supplementation at the recommended daily allowance (RDA) of vitamin A is advised for patients taking ONPATTRO. Higher doses than the RDA should not be given to try to achieve normal serum vitamin A levels during treatment with ONPATTRO, as serum levels do not reflect the total vitamin A in the body.
Patients should be referred to an ophthalmologist if they develop ocular symptoms suggestive of vitamin A deficiency (e.g., night blindness).
Adverse Reactions
The most common adverse reactions that occurred in patients treated with ONPATTRO were upper respiratory tract infections (29%) and infusion-related reactions (19%).
For additional information about ONPATTRO, please see the full
About ONPATTRO® (patisiran)
ONPATTRO (patisiran) is an RNAi therapeutic that is approved in
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 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
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Alnylam Forward Looking Statements
This press release contains forward-looking statements within the meaning of Section 27A of the Securities Act of 1933 and Section 21E of the Securities Exchange Act of 1934. All statements other than historical statements of fact regarding Alnylam’s expectations, beliefs, goals, plans or prospects including, without limitation, expectations regarding Alnylam’s aspiration to become a leading biotech company and the planned achievement of its “Alnylam P5x25” strategy, the potential for
This release discusses investigational RNAi therapeutics and uses of previously approved RNAi therapeutics in development and is not intended to convey conclusions about efficacy or safety as to those investigational therapeutics or uses. Patisiran has not been approved by any regulatory agency for the treatment of ATTR amyloidosis with cardiomyopathy. No conclusions can or should be drawn regarding its safety or effectiveness in treating cardiomyopathy in this population. There is no guarantee that any investigational therapeutics or expanded uses of commercial products will successfully complete clinical development or gain health authority approval.
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