Sanofi Genzyme, the specialty care global business unit of Sanofi, and Alnylam Pharmaceuticals,  the leading RNAi therapeutics company, announced positive complete results from the APOLLO phase 3 study of patisiran, an investigational RNAi therapeutic being developed for patients with hereditary ATTR (hATTR) amyloidosis with polyneuropathy.

These clinical data were presented in an oral presentation at the 1st European ATTR Amyloidosis Meeting for Patients and Doctors being held November 2-3, 2017 in Paris, France. Based on these results, Alnylam intends to file a new drug application (NDA) in the United States for patisiran by end-2017 and a marketing authorization application (MAA) in the European Union shortly thereafter.

The full APOLLO results showed improvement with patisiran relative to placebo in the primary endpoint of modified Neuropathy Impairment Score +7 (mNIS+7) and additional secondary endpoints encompassing sensory, motor, and autonomic neuropathy symptoms, as well as in exploratory cardiac endpoints, at 18 months.  Patients exhibited improved quality of life, activities of daily living, nutritional status, motor strength, and ambulatory ability, with reduced disease symptoms and disability. Favorable effects of patisiran relative to placebo were observed across subgroups defined by demographic and baseline hATTR amyloidosis disease characteristics. In a pre-specified cardiac subpopulation, significant positive effects were observed for patisiran on certain exploratory cardiac biomarker and echocardiographic endpoints.

The most commonly reported adverse events (AEs) that occurred more frequently in patisiran-treated patients were generally mild to moderate and included peripheral edema and infusion-related reactions (IRRs). The frequency of deaths and serious adverse events (SAEs) was similar in the patisiran and placebo groups. These data support the potential of patisiran to stabilize and even improve the cardinal, multi-system disease manifestations of hATTR amyloidosis, including improvement in patients' quality of life.

 "We are very pleased for patients and families living with hATTR amyloidosis as we believe these results from APOLLO offer new hope for the treatment of this devastating disease. Indeed, patisiran holds the potential to halt or improve neurological impairment and broader disease features in patients with hATTR amyloidosis. We also view these results as a landmark achievement for the field of RNAi therapeutics, as we believe they demonstrate the transformational potential of this novel class of innovative medicines," said Akshay Vaishnaw, M.D., Ph.D., Executive Vice President of R&D at Alnylam. "Alnylam is indebted to all the patients, investigators, and study staff who took part in the APOLLO study, making this important and notable milestone possible. We're also grateful to the caregivers and family members whose support of APOLLO patients was such an important contribution. With these promising APOLLO data in hand, we intend to start filing our results with regulatory authorities in late 2017 with the goal of achieving approval in mid-2018."

Patisiran met the primary endpoint of mNIS+7 change from baseline at 18 months relative to placebo, and all secondary study endpoints. Specifically:  Patisiran treatment (N=148) resulted in a negative 6.0 point mean change (improvement) in mNIS+7 score from baseline at 18 months as compared to a 28.0 point mean increase (worsening) reported for the placebo group (N=77), resulting in a 34.0 point mean difference relative to placebo (p=9.26 x 10-24).  The results were found to be consistent across all sub-components of the mNIS+7 scale.  Improvement in mNIS+7 from patisiran treatment was also consistently observed across all defined patient subgroups, including age, sex, race, geographic region, baseline neuropathy impairment, genotype, prior TTR stabilizer use, baseline familial amyloid polyneuropathy (FAP) stage, and inclusion in the pre-specified cardiac subpopulation. Patisiran treatment resulted in a negative 6.7 point mean change (improvement) in Norfolk-Quality of Life-Diabetic Neuropathy (Norfolk QOL-DN) score from baseline at 18 months as compared to a 14.4 point mean increase (worsening) reported for the placebo group, resulting in a mean 21.1 point difference relative to placebo (p=1.10 x 10-10).

 Improvements in mNIS+7 and Norfolk QOL-DN with patisiran were also seen at nine months, the earliest time point for these measurements in the study with a mean 16.0 and a mean 15.0 point difference observed, respectively, relative to placebo. In a pre-specified binary analysis of neurological improvement, 56 percent (95 percent CI: 48.1, 64.1) of patisiran patients had an improvement in mNIS+7 (less than 0 point change compared to baseline at 18 months), while 4 percent (95 percent CI: 0.0, 8.2) of placebo patients had an improvement (p=1.82 x 10-15).
    Similarly, 51 percent (95 percent CI: 43.3, 59.4) of patisiran patients had an improvement in Norfolk QOL-DN (less than 0 point change compared to baseline at 18 months), versus 10 percent (95 percent CI: 3.6, 17.2) for placebo (p=1.95 x 10-10).

 Patisiran also demonstrated statistically significant and clinically meaningful improvements over placebo in all other secondary endpoints at 18 months, including: NIS-W (p=1.40 x 10-13), the subdomain of mNIS+7 assessing muscle strength; Rasch-built Overall Disability Scale (R-ODS) (p=4.07 x 10-16), a patient reported outcome measure of daily living and disability; timed ten-meter walk test (10-MWT) (p=1.88 x 10-12), assessing ambulatory ability and gait speed; modified body mass index (mBMI) (p=8.83 x 10-11), assessing nutritional status; and, COMPASS-31 (p=0.0008), a patient questionnaire assessing autonomic disease symptoms.

Favorable and significant changes in several exploratory cardiac measures, including N-terminal pro b-type natriuretic peptide (NT-proBNP), certain echocardiographic parameters, and 10-MWT were reported in patisiran-treated patients in the pre-specified cardiac subpopulation. Specifically:

Patisiran treatment resulted in a median decrease (improvement) of 49.9 pg/ml in NT-proBNP levels as compared to a median increase (worsening) of 320 pg/ml reported for the placebo arm at 18 months (nominal p=7.74 x 10-8, based on analysis of log-transformed values). Regarding echocardiographic measures, patisiran treatment resulted in a mean 0.93 mm reduction (improvement) in left ventricular (LV) wall thickness (nominal p=0.0173) and a mean absolute 1.37 percent improvement in longitudinal strain (nominal p=0.0154) relative to placebo.  Regarding functional measures in the cardiac subpopulation, patisiran treatment resulted in a 0.35 m/sec increase (improvement) in 10-MWT (nominal p=7.42 x 10-9) relative to placebo at 18 months.  Changes relative to baseline were also measured for troponin-I, LV mass, and LV ejection fraction but were not statistically significant.

 "Patients with hATTR amyloidosis are afflicted with an aggressive, rapidly progressing, debilitating and fatal disease, and have a profound need for effective and safe treatment options," said David Adams, M.D., Ph.D., Department of Neurology, Bicetre hospital, Greater Paris University Hospitals, AP-HP and Principal Investigator for the APOLLO trial. "The exciting APOLLO data that were released today demonstrate the potential of patisiran to alleviate the multiple neurological, cardiac, and autonomic manifestations of the disease. If approved, I believe that patisiran could have a tremendous impact for patients and physicians in the amyloidosis community. As a clinician, it has been deeply rewarding to see the potential impact patisiran may have on the lives of hATTR patients."