Date: 2015-09-15
Type of information: Results
phase:
Announcement: results
Company: Alnylam Pharmaceuticals (USA - MA) the American Porphyria Consortium (USA) The European Porphyria Network
Product:
Action mechanism:
Disease: hepatic porphyrias, acute intermittent porphyria (AIP), variegate porphyria, and hereditary coproporphyria, suffering from recurrent attacks
Therapeutic area: Genetic diseases - Metabolic diseases - Rare diseases
Country: Bulgaria, Finland, France, Germany, Italy, The Netherlands, Poland, Spain, Switzerland, UK, USA
Trial
details: Porphyrias are a family of rare metabolic disorders with autosomal dominant inheritance predominately caused by a genetic mutation in one of the eight enzymes responsible for heme biosynthesis. Acute hepatic porphyrias constitute a subset where the enzyme deficiency occurs within the liver, and includes acute intermittent porphyria (AIP), hereditary coproporphyria, and variegate porphyria. Exposure of acute hepatic porphyria patients to certain drugs, dieting, or hormonal changes can trigger strong induction of aminolevulinic acid synthase 1 (ALAS1), another enzyme in the heme biosynthesis pathway, which can lead to accumulation of heme intermediates that precipitate disease symptoms. Patients with one of the acute hepatic porphyrias can suffer from a range of symptoms that, depending on the specific type, can include acute and/or recurrent life-threatening attacks with severe abdominal pain, peripheral and autonomic neuropathy, neuropsychiatric manifestations, cutaneous lesions and possibly death if untreated or if there are delays in treatment. EXPLORE study’s primary objective is to characterize the natural history, clinical management, and disease burden of patients with hepatic porphyrias. The study’s secondary objectives are to further characterize a number of disease features of hepatic porphyrias, including: (i) signs and symptoms of porphyria during acute attacks; (ii) levels of plasma and urinary aminolevulinic acid (ALA) and porphobilinogen (PBG), the toxic intermediates of the heme biosynthesis pathway that cause the symptoms and disease pathology of the acute hepatic porphyrias; (iii) expression levels of aminolevulinic acid synthase-1 (ALAS-1) during acute attacks; and (iv) medical and family history of hepatic porphyria patients. (NCT02240784)
Latest
news: * On September 15, 2015, Alnylam Pharmaceuticals presented initial results (from data in the database as of August 14, 2015 ) from the EXPLORE study, a multinational, prospective observational study of patients with hepatic porphyrias suffering from recurrent attacks. This study aims to provide enhanced understanding of the natural history of hepatic porphyrias in patients with recurrent attacks, as well as to obtain information about the burden of disease, current management and unmet need. Initial data presented at ICPP were from 68 patients, who had a mean of 10.6 ± 11.0 attacks for the 12 months prior to study entry. In baseline questionnaires, the most common symptoms associated with past porphyria attacks were abdominal and back pain, tiredness, nausea, weakness, and change in urine color. Also, it was found that approximately 50% of patients experience chronic porphyria symptoms even when not having an acute attack. In their baseline evaluation, the patients reported a diminished quality of life, with an EQ-5D Index of 0.74, even while not in the midst of an acute attack. After enrollment in the study, a total of 101 porphyria attacks were documented, with 41/68 (60%) patients reporting at least one attack; the mean duration of attacks was 7.9 days. The majority of attacks were treated in the hospital setting with hematin and/or pain management. At baseline, liver ALAS1 mRNA was elevated by over 4-fold compared to healthy subjects, and this was found to significantly increase further during an acute attack (p less than 0.0001, repeated measures model). Similarly, in a group of patients (n=16) with paired samples from both asymptomatic and attack periods, urinary ALA and PBG levels increased above asymptomatic levels by 6.3- and 2.5-fold, respectively, during the acute attack period. These data suggest that elevated levels of ALAS1 mRNA, ALA, and PBG are associated with acute attacks in patients with acute hepatic porphyria, and that they may be useful biomarkers for disease activity. The EXPLORE study is ongoing, and the company plans to report additional data from this study in 2016. * On October 1, 2014, Alnylam Pharmaceuticals and collaborators from the American Porphyria Consortium and The European Porphyria Network have initiated the EXPLORE trial, a prospective observational study of patients with hepatic porphyrias, including Acute Intermittent Porphyria (AIP), Variegate Porphyria, and Hereditary Coproporphyria, suffering from recurrent attacks.With this study, Alnylam 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. Data obtained from EXPLORE are expected to further the understanding of hepatic porphyrias and to assist the design of clinical trials with ALN-AS1. Alnylam is currently advancing ALN-AS1, a subcutaneously administered investigational RNAi therapeutic targeting aminolevulinic acid synthase 1 (ALAS-1) for the treatment of hepatic porphyrias, and expects to file an IND or IND equivalent in late 2014 or early 2015. In pre-clinical studies and as published in the Proceedings of the National Academy of Sciences, silencing of ALAS-1 with either prophylaxis or acute treatment dosing regimens resulted in complete inhibition of ALA and PBG production in rodent models of AIP. ALN-AS1 utilizes the company’s proprietary Enhanced Stabilization Chemistry (ESC)-GalNAc-conjugate delivery platform enabling subcutaneous dosing with increased potency and durability, and a wide therapeutic index.
