Updates from Patisiran and Revusiran, in Development for the Treatment of hATTR Amyloidosis

We reported new clinical data from our ongoing Phase 2 open-label extension (OLE) studies with patisiran and revusiran, investigational RNAi therapeutics targeting transthyretin (TTR) for the treatment of hereditary TTR-mediated amyloidosis (hATTR amyloidosis). These data were presented at the XV International Symposium on Amyloidosis held July 3 – 7, 2016 in Uppsala, Sweden.

In the patisiran Phase 2 OLE study, new results for hATTR patients with polyneuropathy (hATTR-PN, also known as Familial Amyloidotic Polyneuropathy, or FAP) who reached the 24-month endpoint as of a data cutoff date of May 12, 2016 (N=24), showed a mean decrease of 6.7 points from baseline in mNIS+7 after 24 months of treatment. These data compare favorably to an estimated increase in mNIS+7 of 26 to 30 points at 24 months, based upon analyses of historical data sets in untreated hATTR-PN patients with similar baseline characteristics. In a new analysis, over 70 percent of patients showed either improvement or no change in mNIS+7 at 24 months, supporting the therapeutic hypothesis that TTR knockdown with patisiran can potentially halt or improve neuropathy progression in patients with hATTR-PN.  Further, the results of an exploratory analysis showed positive correlation between the degree of serum TTR knockdown on Day 17 after the first dose of patisiran and changes in mNIS+7.  The strongest correlations were observed at 6 and 12 months, and a trend was observed at 18 and 24 months. Over 24 months, patients with lesser degrees of initial TTR knockdown also had improvements in mNIS+7, suggesting that there may be an accrual of clinical benefit to even those patients with lesser degrees of TTR knockdown if treated over longer periods of time.

Patisiran administration was found to be generally well tolerated in hATTR-PN patients out to 25 months, with no drug-related serious adverse events (SAEs) reported through the data transfer date.  The most common drug-related or possibly drug-related adverse events (AEs) were flushing and infusion related reactions (ISRs), all of which were mild in severity and did not result in any discontinuations.  There were no clinically significant changes in liver function tests, renal function, or hematologic parameters, including platelet counts.

We also presented baseline demographics from our APOLLO Phase 3 study of patisiran in hATTR-PN patients, showing that the 225 patients enrolled represent a global patient population with a wide range of disease severity and TTR mutations.  The majority of patients enrolled also showed evidence of cardiac disease (N=122, 54 percent), which should allow for the evaluation of patisiran’s potential effects on cardiac manifestations of hATTR amyloidosis.

Initial 12-month data from the revusiran Phase 2 OLE study continued to show robust and sustained knockdown of serum TTR in hATTR patients with cardiomyopathy (hATTR-CM, also known as Familial Amyloidotic Cardiomyopathy, or FAC).  The majority of hATTR-CM patients evaluable for 6-MWD at 12 months (5/9) showed generally stable results, with a mean change of -14 ± 8 meters in those patients. On average, all evaluable patients with hATTR-CM (N=9) exhibited a mean change of -73 ± 26 meters, and those with wild-type ATTR amyloidosis (wtATTR, also known as Senile Systemic Amyloidosis, or SSA) (N=6) exhibited a mean change of -152 ± 36 meters. These results are generally in line with natural history data at 12 months.

The revusiran Phase 2 OLE study population has advanced ATTR cardiomyopathy with a mean time from diagnosis to first dose of 35 months, in a disease where median survival ranges from 26-43 months. Fourteen patients (56 percent) in the study presented with serious adverse events (SAEs).  One event, a case of lactic acidosis, was deemed possibly related to study drug.  There were a total of seven deaths, all of which were not related to study drug. The majority of AEs were mild or moderate in severity, and included injection site reactions (ISRs) in 12 patients (48 percent).  The majority of reported ISRs were found to be mild in severity, and beyond the three cases previously reported, there were no further discontinuations due to ISRs.  There were no other notable changes in liver function tests, renal function or hematologic parameters, including platelets.

We look forward to additional data from our studies with patisiran and revusiran, and we continue to be committed to improving the lives of patients with ATTR amyloidosis through advancement of patisiran, revusiran and ALN-TTRsc02. We are hopeful that these promising investigational RNAi therapeutics have the potential to halt disease progression in patients with ATTR amyloidosis and provide important treatment options for management of this disease, where there is enormous unmet need.