Alnylam unveils positive initial clinical results for ALN-AS1

The Phase 1 study is being performed in asymptomatic "high excreter" (ASHE) patients, who carry the genetic mutation of acute intermittent porphyria (AIP) and have elevated levels of aminolevulinic acid (ALA) and porphobilinogen (PBG), the toxic heme intermediates that mediate porphyria attacks.

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, providing human proof-of-concept for this investigational RNAi therapeutic as a potential therapy for AIP and other acute hepatic porphyrias. In addition, through analysis of exosomal mRNA preparations from serum and urine, it was demonstrated that ALN-AS1 treatment resulted in potent, dose-dependent, and durable silencing of ALAS1 mRNA in liver.

Further, ALN-AS1 was found to be generally well tolerated with no clinically significant drug-related adverse events to date. The company has now transitioned to Part B of the Phase 1 study, in which subjects are receiving monthly subcutaneous dosing, and the company expects to initiate Part C in AIP patients suffering from recurrent attacks in early 2016.

In addition, Alnylam presented initial data from the EXPLORE trial, a multinational, prospective observational study of patients with hepatic porphyrias suffering from recurrent attacks.

"The acute hepatic porphyrias are caused by mutations in heme synthesis enzymes that result in build up of ALA and PBG, the toxic intermediates that mediate porphyria attacks. Accordingly, we’re very encouraged by these initial Phase 1 data, showing up to 82% lowering of ALA and up to 93% lowering of PBG in ASHE patients with AIP. We are also impressed by the durability of effect on these disease biomarkers following a single subcutaneous injection, which we believe to be supportive of a monthly or potentially once quarterly dosing regimen, and we’ve now transitioned to the multi-dose cohorts in the Phase 1 study to explore this potential. Importantly, ALN-AS1 has been generally well tolerated, with no clinically significant drug-related adverse events reported to date. We very much look forward to the continued advancement of ALN-AS1, which we believe has the potential to be a transformative therapy for patients with acute hepatic porphyrias, a group of ultra-rare orphan diseases with enormous unmet medical need," said Akshay Vaishnaw, M.D., Ph.D., Executive Vice President of R&D and Chief Medical Officer at Alnylam.

"It’s also notable that this is now our fifth GalNAc-siRNA conjugate program to demonstrate robust clinical activity and excellent translation from non-human primate to human studies, providing further support that we’ve achieved what we believe to be a reproducible and modular platform for innovative medicines. Accordingly, our R&D efforts continue to create what we believe to be a significant opportunity for patient impact and value creation."

"Patients with AIP and other hepatic porphryias often present with acute, and at times recurrent attacks that are characterized by severe abdominal pain, neuropathy, neuropsychiatric manifestations, and, in very severe cases, cardiovascular instability, paralysis and respiratory failure. Novel therapies are clearly needed for porphyria patients who suffer from recurrent attacks, as these patients experience enormous suffering and a very poor quality of life," said Eliane Sardh, M.D., Ph.D., Senior Physician at the Porphyria Centre Sweden and the Centre for Inherited Metabolic Diseases and Department of Endocrinology, Metabolism and Diabetes at Karolinska University Hospital in Stockholm, Sweden.

"I am encouraged with these initial Phase 1 data with ALN-AS1, which I believe support the potential for an RNAi therapeutic to reduce disease burden in patients with AIP and other acute hepatic porphyrias. If proven to be safe and effective in more advanced studies, I believe a subcutaneously administered drug with an infrequent dosing regimen would be a very welcome therapeutic option for these patients and their caregivers."

ALN-AS1 is a subcutaneously administered, investigational RNAi therapeutic that employs Alnylam’s ESC-GalNAc delivery technology. The Phase 1 trial is being conducted in three parts. Parts A and B are randomized (3:1, drug:placebo), single-blind, single-dose (Part A) and multi-dose (Part B), dose-escalation studies, designed to enroll up to a total of 40 ASHE subjects.

Per protocol, ASHE subjects in the study have a defined mutation in the porphobilinogen deaminase (PBGD) gene and elevated urinary levels of ALA and PBG, but do not have a recent history of porphyria attacks or disease activity.

The primary objective of Parts A and B is to evaluate safety and tolerability of single and multiple subcutaneous doses of ALN-AS1. Secondary objectives include evaluation of clinical activity for ALN-AS1 as measured by reduction in plasma and urinary levels of ALA and PBG.

Exploratory objectives include the impact of ALN-AS1 on liver ALAS1 mRNA as measured from circulatory or excreted exosomal mRNA preparations in serum or urine, respectively. Part C will be a multi-dose study in up to eight AIP patients who experience recurrent porphyria attacks, and will assess safety, tolerability, pharmacodynamics (i.e., lowering of serum and urine ALA and PBG, as well as liver ALAS1 mRNA) and clinical activity of multiple doses of ALN-AS1. In addition, this part of the study will include an exploratory evaluation of the effects of ALN-AS1 on the number and severity of attacks and other disease symptoms, use of hematin and pain medications, number and duration of hospitalizations, and quality of life.

Initial Phase 1 study results were presented in an oral presentation at the 2015 International Congress of Porphyrins and Porphyrias (ICPP) held September 14 – 16 in Dusseldorf, Germany. All results are based on data in the database as of September 2, 2015. A total of 16 ASHE patients were enrolled in four single ascending dose (SAD) cohorts (N=4 per group), with subjects receiving 0.035, 0.1, 0.35, or 1.0 mg/kg doses of ALN-AS1. In all dose cohorts, the volume of injection was less than 1.0 mL.

The 0.035 mg/kg cohort was added to explore a lower dose after initial results were obtained from the 0.1 and 0.35 mg/kg cohorts. The multi-dose Part B of the study has now been initiated with monthly subcutaneous doses of 0.35 mg/kg.

Alnylam expects to report initial data from this part of the study in 2016.