New analyses from the APOLLO Phase III study of patisiran for the treatment of hereditary ATTR (hATTR) amyloidosis.

Alnylam Pharmaceuticals, Inc. announced that the Company presented new analyses from the APOLLO Phase III study of patisiran, an investigational RNAi therapeutic for the treatment of hereditary ATTR (hATTR) amyloidosis, in six presentations at the 2018 Peripheral Nerve Society (PNS) Annual Meeting being held July 22-25, in Baltimore, MD.

Results on Overall Health Status Endpoints : Overall health status was an exploratory endpoint assessed in APOLLO using EuroQOL-5-dimension 5-level (EQ-5D-5L), a standardized measure of health status based on five dimensions: mobility, self-care, usual activities, pain/discomfort, and anxiety/depression, and the EuroQOL visual analogue scale (EQ-VAS), a measure of a patient’s global impression of their overall health as evaluated on a scale of zero (worst possible health) to 100 (best possible health). At 18 months, a larger proportion of patients on patisiran than placebo, respectively, showed preservation (defined as no change in score) or improvement relative to baseline in each EQ-5D-5L domain: mobility, 70 versus 22 percent; self-care, 66 versus 21 percent; usual activities, 72 versus 25 percent; pain/discomfort, 73 versus 31 percent; anxiety/depression, 81 versus 45 percent. Overall health, as measured by EQ-VAS, improved by an average of 2.4 points in patients on patisiran, while declining by an average of 7.1 points in placebo patients, indicating a 9.5 point difference (nominal p value less than 0.001).

Results from an Indirect Treatment Comparison (ITC) of Tafamidis and Patisiran : We also presented results from an ITC of patisiran and tafamidis (a transthyretin tetramer stabilizer) using the standard pairwise Bucher method. The analysis was based on publicly available randomized trial efficacy data for tafamidis in hATTR amyloidosis with polyneuropathy1-2. Importantly, there are limitations to this approach, and there have been no head-to-head studies comparing the safety and effectiveness of patisiran and tafamidis. With those caveats, indirect comparisons were conducted for endpoints or components of endpoints measured in both trials: change from baseline in NIS-LL (Neuropathy Impairment Score of the Lower Limbs), NIS-LL response (less than two point increase in NIS-LL from baseline), Norfolk QoL-DN, and mBMI (modified body mass index). Safety was not compared as part of this analysis. The base case analysis indirectly compared these results in patients with Stage 1 polyneuropathy after 18 months of treatment. In the base case ITC, statistically significant differences in mean change from baseline for NIS-LL (-5.5 [95% CI -10.0, -1.0]) and Norfolk QoL-DN (-13.1 [95% CI -23.6, -2.7]) at 18 months were observed favoring patisiran treatment as compared to tafamidis, and the differences were corroborated by sensitivity analyses. Favorable trends were also seen for NIS-LL response rate and mBMI.

Relationship between Improvements in Neuropathy Impairment and Ambulatory Status : The primary endpoint in APOLLO was the change from baseline in the modified Neuropathy Impairment Score + 7 (mNIS+7) relative to placebo, with patisiran demonstrating significant improvement in neuropathy. Results were presented from an analysis conducted to interrogate whether changes in mNIS+7 were associated with ambulatory status (as measured by polyneuropathy disability [PND] score) at 18 months in patisiran-treated patients. Predictive modeling analysis demonstrated that greater reduction in mNIS+7 is consistently associated with a higher probability that a patient will have improved or stabilized ambulatory status (p value less than 0.0001). Modeling also showed that patients with an mNIS+7 change of less than zero points after 18 months of patisiran treatment were predicted to have substantially greater odds of improving or stabilizing their ambulatory status compared to patients with an mNIS+7 score of greater than or equal to zero (p value less than 0.0001). FAP (familial amyloid polyneuropathy) Stage and PND score are commonly used to indicate neuropathy severity in hATTR amyloidosis and are based largely on ambulatory ability (e.g. whether, and how many, walking aids are required). It was shown that following 18 months of treatment, a greater proportion of patisiran patients compared to placebo showed stable or improved FAP Stage (79 versus 44 percent) and PND score (73 versus 30 percent). Improvements in FAP Stage and PND score were only seen with patisiran, and worsening occurred twice as frequently with placebo compared to patisiran. The observed changes in FAP Stage and PND score were statistically significant (p=9.5 x 10-8 and p=1.3 x 10-10, respectively), and further support the clinical benefit of patisiran compared to placebo in improving or preserving ambulation. Finally, results highlighting neuropathy progression in the placebo arm of the APOLLO study were presented. Patients randomized to placebo experienced significant neuropathy progression as early as 9 months, the first assessment time point in APOLLO. At 9 and 18 months, neuropathy progression relative to baseline was observed with a least squares (LS) mean increase in mNIS+7 of 14.0 and 28.0 points, respectively. Placebo patients had substantial progression regardless of their baseline disease severity. The rapid disease progression observed across multiple endpoints underscores the need for early administration of an effective therapy for patients with hATTR amyloidosis to prevent disability and morbidity accumulation.