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Clinical Trials

Date: 2018-07-04

Type of information: Publication of results in a medical journal

phase: 3

Announcement: publication of results in The New English Journal of Medicine

Company: Alnylam Therapeutics (USA - MA)

Product: patisiran

Action mechanism:

  • RNAi. Patisiran is an investigational RNAi therapeutic targeting transthyretin (TTR).

Disease: transthyretin-mediated amyloidosis (ATTR) - familial amyloidotic polyneuropathy (FAP)

Therapeutic area: Rare diseases - Genetic diseases

Country: Argentina, Australia, Brazil, Bulgaria, Canada, Cyprus, France, Germany, Italy, Japan, Republic of Korea, Malaysia, Mexico, Netherlands, Portugal, Spain, Sweden, Taiwan, Turkey, UK, USA

Trial details:

  • The APOLLO Phase 3 trial is a randomized, double-blind, placebo-controlled, global study designed to evaluate the efficacy and safety of patisiran in patients with FAP. The primary endpoint of the study is the difference in the change in a modified neuropathy impairment score, "mNIS+7," from baseline to 18 months between patisiran and placebo. mNIS+7 measures disease progression including muscle weakness, impaired reflexes, and changes in other sensory measures. Secondary study endpoints include: the Norfolk Quality of Life-Diabetic Neuropathy (QOL-DN) score; modified body mass index (mBMI); timed 10-meter walk; an autonomic symptom score called "COMPASS-31," amongst other endpoints. In addition, nerve regeneration by measurement of sweat gland nerve fiber density will be assessed in patients who elected to provide skin punch biopsy samples. All patients completing the APOLLO Phase 3 study are eligible to enroll in the ongoing APOLLO Phase 3 open-label extension (OLE) study (APOLLO-OLE).
  • APOLLO-OLE is an open-label, multi-center study designed to evaluate the long-term safety and tolerability of patisiran in ATTR amyloidosis patients with FAP who were previously enrolled in the APOLLO Phase 3 study. Eligible patients treated in APOLLO can enroll in the study, where they will receive patisiran at a dose of 0.3 mg/kg every three weeks for up to the earlier of two years or until the drug is commercially available in their market. The primary objective of APOLLO-OLE is to evaluate the long-term safety and efficacy of patisiran administration. The study will measure a number of clinical endpoints, including Neuropathy Impairment Score at baseline and every 12 months thereafter. A number of additional clinical endpoints will be assessed, including: quality of life; timed 10-meter walk test to evaluate mobility; modified body mass index as a measure of nutritional status; level of disability; and nerve fiber density in skin biopsies. (NCT02510261)
             

Latest news:

  • • On July 4, 2018, Alnylam Pharmaceuticals announced  that the pivotal study results from the APOLLO Phase 3 trial of patisiran were published online in The New England Journal of Medicine (NEJM) (Patisiran, an RNAi Therapeutic, for Hereditary Transthyretin Amyloidosis).
  • The study showed that patisiran improved measures of polyneuropathy, quality of life, activities of daily living, ambulation, nutritional status, and autonomic symptoms relative to placebo in patients with hereditary transthyretin-mediated (hATTR) amyloidosis. Patisiran treatment also led to favorable effects on exploratory endpoints related to cardiac structure and function in patients with cardiac involvement. Further, the frequency and severity of adverse events (AEs) were similar in patients receiving patisiran and placebo, with the exception of peripheral edema and infusion-related events which were higher in patisiran-treated patients and generally mild to moderate in severity.
  • The APOLLO study publication presents robust evidence for patisiran’s potential to treat a broad constellation of hATTR amyloidosis clinical manifestations and their disabling effects. Relative to placebo, data from APOLLO showed that treatment with patisiran resulted in significant and clinically meaningful improvements in measures of polyneuropathy and quality of life. In addition, compared to baseline and after 18 months of patisiran treatment, improvement was observed in a majority of patients in the primary endpoint, mNIS+7 score (a composite measure of neuropathy), and in the key secondary endpoint, Norfolk QOL-DN (a quality of life questionnaire). The improvement in mNIS+7 was shown to be correlated with degree of TTR knockdown. Significant effects on muscle strength, activities of daily living, ambulation, nutritional status, and autonomic symptoms were also noted in patisiran patients relative to placebo. Moreover, patisiran patients with echocardiographic evidence of cardiac amyloid involvement at study entry demonstrated favorable effects on exploratory endpoints related to cardiac structure and function when compared to placebo.
  • A lower proportion of patients randomized to patisiran than placebo discontinued treatment (7 versus 38 percent) and discontinued the study (7 versus 29 percent). The incidence and severity of AEs and the frequency of serious AEs (SAEs) and deaths were similar in patisiran- and placebo-treated patients. Compared to placebo, patisiran treatment was associated with fewer treatment discontinuations (5 versus 14 percent) due to AEs. The AEs occurring more frequently with patisiran than placebo were peripheral edema (30 versus 22 percent) and infusion-related reactions (IRRs; 19 versus 9 percent) both of which were generally mild to moderate in severity. IRRs decreased over time and led to study withdrawal in one patient (0.7 percent). No clinically-relevant changes in laboratory values related to patisiran treatment, including platelet counts and liver and kidney function tests, were observed during the study.
  • • On September 20, 2017, Sanofi Genzyme and Alnylam Pharmaceuticals announced that the APOLLO Phase 3 study of patisiran for the treatment of hereditary ATTR amyloidosis with polyneuropathy, met its primary efficacy endpoint and all secondary endpoints. The primary endpoint for the study was the change from baseline in the modified neuropathy impairment score (mNIS+7) at 18 months. The key secondary endpoint was improvement in quality of life assessed by the Norfolk Quality of Life Questionnaire-Diabetic Neuropathy (Norfolk QOL-DN).
  • The APOLLO trial enrolled 225 hATTR amyloidosis patients with polyneuropathy, representing 39 genotypes, at 44 study sites in 19 countries around the world. Patients were randomized 2:1 to patisiran or placebo, with patisiran administered intravenously at 0.3 mg/kg once every three weeks for 18 months. For both the mNIS+7 and Norfolk QOL-DN endpoint measures provided below, a lower score indicates a better clinical result.
  • At 18 months, the mean change from baseline in mNIS+7 was significantly lower in the patisiran group as compared with placebo (p less than 0.00001). The mean and median changes in mNIS+7 impairment scores for patisiran both achieved negative values, indicating an improvement overall and in the majority of patients compared with baseline. Patients in the patisiran group experienced improvement in quality of life compared to placebo, as assessed by the Norfolk Quality of Life Questionnaire-Diabetic Neuropathy (Norfolk QOL-DN) (p less than 0.00001). The mean and median changes in QOL scores for patisiran also both achieved negative values, indicating an improvement overall and in the majority of patients compared with baseline. All five other secondary endpoints also demonstrated statistically significant favorable differences in the patisiran arm compared to placebo (p less than 0.001). These were: - NIS-W, the subdomain of mNIS+7 assessing muscle strength; - Rasch-built Overall Disability Scale (R-ODS), a patient reported outcome measure of daily living and disability; 10-meter walk test, assessing gait speed; - Modified body mass index (mBMI), assessing nutritional status; and - COMPASS-31, a questionnaire to assess autonomic symptoms. The overall safety profile of patisiran was encouraging. The patisiran and placebo arms had similar frequencies of adverse events (AEs) (96.6 percent and 97.4 percent, respectively) and serious adverse events (SAEs) (36.5 percent and 40.3 percent, respectively).
  • The frequency of deaths in the study was similar in the patisiran (4.7 percent) and placebo (7.8 percent) arms. Patisiran treatment was associated with fewer discontinuations from treatment compared with placebo (7.4 percent and 37.7 percent, respectively) and discontinuations from treatment due to AEs (4.7 percent and 14.3 percent, respectively). AEs reported in greater than 10 percent of patients and seen more frequently with patisiran compared with placebo were peripheral edema (29.7 percent vs. 22.1 percent, respectively) and infusion-related reactions (18.9 percent vs. 9.1 percent, respectively), both of which were generally mild-to-moderate in severity. Based on these positive results, Alnylam expects to file its first New Drug Application in late 2017 and first Marketing Authorisation Application shortly thereafter. Sanofi Genzyme is currently preparing for regulatory filings for patisiran in Japan, Brazil and other countries, to begin in the first half of 2018. Pending regulatory approvals, Alnylam will commercialize patisiran in the U.S., Canada and Western Europe, with Sanofi Genzyme commercializing the product in the rest of the world.
  • Full results, including data from an exploratory analysis of the subgroup of patients with cardiac involvement, will be presented at the 1st European ATTR Amyloidosis Meeting for Patients and Doctors, on November 2,2017 in Paris, France.
  • * On October 10, 2016, Alnylam Pharmaceuticals announced that the Data Monitoring Committee (DMC) for the Phase 3 APOLLO study of patisiran in patients with hereditary ATTR amyloidosis with polyneuropathy (hATTR-PN) met on October 7, 2016 and recommended continuation of the trial without modification. The APOLLO DMC met at the request of the Company following the decision - announced on October 5, 2016 - to discontinue development of revusiran for the treatment of hereditary ATTR amyloidosis with cardiomyopathy (hATTR-CM). The DMC will continue to meet periodically per their remit to monitor the overall safety of patisiran in the APOLLO study through its completion. The APOLLO study has completed enrollment of 225 patients at 44 sites in 19 countries, between December 2013 and January 2016 .
  • * On February 1, 2016, Alnylam Pharmaceuticals announced that it has completed enrollment in its APOLLO Phase 3 study with patisiran for the treatment of TTR-mediated amyloidosis (ATTR amyloidosis) in patients with familial amyloidotic polyneuropathy (FAP). The study was significantly over-enrolled with a total of 225 FAP patients with Stage 1 or Stage 2 disease, compared to the original anticipated enrollment of 200. Patients were randomized 2:1 (patisiran:placebo) with patisiran administered at 0.30 mg/kg once every three weeks for 18 months. The study was designed with 90% power to conservatively detect as little as a 37.5% difference in change in mNIS+7 between treatment groups, with a two-sided alpha of 0.05. The expected placebo mNIS+7 progression rate of 24 points over 18 months was derived from an analysis of natural history data from 283 FAP patients ( Adams et al., Neurology, 2015;85:675-682).
  • The company also reiterated its previous guidance that it expects to report data from the APOLLO study in 2017, and due to the competitiveness of this timing, it is not planning to perform an interim analysis for efficacy. If APOLLO is positive, the Company expects to submit a New Drug Application (NDA) and Marketing Authorisation Application (MAA) for patisiran, based on an analysis of the full APOLLO data set, in late 2017.
  • • On July 20, 2015, Alnylam Pharmaceuticals announced that it has initiated its Phase 3 open-label extension study (APOLLO-OLE) with patisiran, an investigational RNAi therapeutic targeting transthyretin (TTR) for the treatment of TTR-mediated amyloidosis (ATTR amyloidosis) in patients with Familial Amyloidotic Polyneuropthy (FAP). All patients who complete the APOLLO Phase 3 trial with patisiran are eligible to enroll in APOLLO-OLE. The study will evaluate the long-term safety and efficacy of patisiran and will also measure effects of treatment toward a number of clinical endpoints, including the modified Neuropathy Impairment Score, or "mNIS+7," which is an evaluation of muscle weakness, sensory and autonomic function, and nerve conductance. The company is also reiterating its previous guidance that - assuming positive study results in the APOLLO Phase 3 study - it expects to be in a position to file a New Drug Application (NDA) for patisiran in the 2017 timeframe.
  • In addition to the APOLLO and APOLLO-OLE trials, Alnylam is also currently conducting a Phase 2 OLE study, where patients previously treated in a Phase 2 study are receiving open-label patisiran at a dose of 0.3 mg/kg every 3 weeks. Initial 12-month clinical data from this study were presented recently at the 67th Annual Meeting of the American Academy of Neurology (AAN) held April 18 - 25, 2015. Patisiran was found to be generally well tolerated out to 17 months of drug administration, with no drug-related serious adverse events to date. In addition, patisiran treatment achieved a sustained mean serum TTR knockdown at the 80% target level for approximately 16 months, with an up to 88% mean knockdown achieved between doses. Results of neuropathy assessments showed a mean 2.5 point decrease in mNIS+7 at 12 months in patients (N=20) who had reached the 12-month endpoint at the time of data cutoff. This decrease in neuropathy progression compares favorably to the 13 to 18 point increase in mNIS+7 at 12 months that can be estimated from the literature in untreated FAP patients with similar baseline characteristics. In aggregate, these results are consistent with the therapeutic hypothesis that TTR knockdown has the potential to halt neuropathy progression in patients with FAP. Alnylam plans to report complete 12-month data (N=27) and preliminary 18-month data from the patisiran Phase 2 OLE study in late 2015.

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