On September 24, 2015, we hosted an online RNAi Roundtable to review the progress with ALN-AS1 in development for the treatment of acute hepatic porphyrias.
Hepatic porphyrias are a series of rare inherited disorders caused by deficiencies in certain liver enzymes involved in the biosynthesis of heme. Acute intermittent porphyria (AIP) is a type of hepatic porphyria characterized by a deficiency in the enzyme porphobilinogen deaminase (PBGD).
Patients with AIP can suffer acute, and at times recurrent attacks that are characterized by severe abdominal pain, peripheral and autonomic neuropathy, neuropsychiatric manifestations, and in very severe cases paralysis and respiratory failure.
Hormonal changes, exposure to certain drugs, or dieting in AIP patients can cause the induction of aminolevulinic acid synthase 1 (ALAS1), the rate-limiting enzyme in the heme biosynthesis pathway, leading to the overproduction of aminolevulinic acid (ALA) and porphobilinogen (PBG) that trigger the attack symptoms. Current treatment options for AIP patients suffering from an attack are not adequate in that they have a slow onset of effect and/or require multiple days of IV infusion; they include the use of heme preparations that show limited efficacy and are associated with a number of complications. Approximately 5,000 patients in the U.S. and Europe suffer acute porphyria attacks annually, and approximately 500 patients are afflicted with recurrent debilitating attacks. Currently there is no approved prophylactic treatment available to prevent recurrent attacks, which often occur monthly in women in association with menses. There exists a significant need for therapies for AIP and other hepatic porphyria patients that are more effective and safer, with more convenient administration.
ALN-AS1 for the Treatment of Hepatic Porphyrias
In September 2015, we reported positive initial results from our ongoing Phase 1 clinical trial with ALN-AS1. Study results showed that single subcutaneous doses of ALN-AS1 resulted in an up to 82% lowering of ALA and an up to 93% lowering of PBG in asymptomatic “high excreter” (ASHE) patients, who carry the genetic mutation of acute intermittent porphyria (AIP) and have elevated levels of ALA and PBG, the toxic heme intermediates that mediate porphyria attacks. Furthermore, analysis of exosomal mRNA preparations from serum and urine revealed that treatment resulted in potent, dose-dependent, and durable silencing of liver ALAS1 mRNA. Importantly, ALN-AS1 was found to be generally well tolerated with no clinically significant drug-related adverse events as of the data cutoff date of September 2, 2015. These data provide human proof-of-concept for ALN-AS1 as a potential therapy for AIP and other acute hepatic porphyrias. We are currently conducting the multi-dose Part B of the study with monthly subcutaneous dosing and plan to report data from this part of the study in 2016. In addition, we plan to initiate Part C in AIP patients suffering from recurrent attacks in early 2016.
In addition, with our collaborators from the American Porphyria Consortium and The European Porphyria Network, we are conducting the EXPLORE trial, a prospective observational study of patients with hepatic porphyrias suffering from recurrent attacks. With this study, we and clinical investigators aim to learn more about the clinical course, management, and disease burden of patients with hepatic porphyrias that suffer from recurrent attacks. Initial data from 68 patients, presented in September 2015, provided meaningful insights into the natural history and substantial disease burden of patients. In baseline evaluations, patients reported a poor quality of life. A total of 101 porphyria attacks were documented in 41/68 (60%) of patients in the study. During acute attacks, there were increases in ALAS1 liver mRNA levels as well as in urinary levels of ALA and PBG. The EXPLORE study is ongoing, and we plan to report additional data from this study in 2016.