Alnylam Pharma (ALNY) Announces Positive Interim Data from ALN-AS1 Phase 1 as AHP Treatment

September 7, 2016 8:16 AM EDT

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Alnylam Pharmaceuticals, Inc. (Nasdaq: ALNY) announced interim data from its ongoing Phase 1 study with ALN-AS1, an investigational RNAi therapeutic targeting aminolevulinic acid synthase 1 (ALAS1) for the treatment of acute hepatic porphyrias. These results were presented today during an oral presentation at the 2016 Society for the Study of Inborn Errors of Metabolism (SSIEM) Annual Symposium, being held from September 6 – 9, 2016 in Rome, Italy. The new data were from Parts A and B of the ongoing Phase 1 study, which were conducted in asymptomatic “high excreter” (ASHE) subjects. ASHE subjects have a mutation in the porphobilinogen deaminase (PBGD) gene as found in acute intermittent porphyria (AIP) and have elevated levels of upstream toxic heme intermediates aminolevulinic acid (ALA) and porphobilinogen (PBG) that mediate porphyria attacks. Results demonstrated that single and once-monthly, subcutaneous administration of ALN-AS1 achieved rapid, dose-dependent, and durable lowering of ALA and PBG. Further, ALN-AS1 was found to be generally well tolerated. Alnylam is currently conducting Part C of the Phase 1 study in symptomatic AIP patients with recurrent porphyria attacks. Consistent with previous guidance, the Company plans to present initial porphyria biomarker data from Part C in late 2016, with potential clinical efficacy data on the frequency and severity of recurrent attacks expected in 2017.

“The acute hepatic porphyrias are a group of ultra-rare orphan diseases with enormous unmet medical need, where novel therapies are clearly warranted. Accordingly, we’re very encouraged by these interim Phase 1 data in ASHE subjects, showing robust lowering of the toxic heme synthesis intermediates that mediate porphyria attacks,” said Akshay Vaishnaw, M.D., Ph.D., Executive Vice President of Research and Chief Medical Officer at Alnylam. “We also continue to be 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 low volume dosing regimen. Importantly, ALN-AS1 has been generally well tolerated through the data transfer date. We very much look forward to the continued advancement of this novel compound, including initial data in symptomatic AIP patients with recurring porphyria attacks expected later this year.”

New results include all available data as of the data transfer date of June 28, 2016. In Part A (N=20), subjects were enrolled in five single ascending dose (SAD) cohorts (N=4 per group, randomized 3:1, drug:placebo), receiving ALN-AS1 at doses from 0.035 to 2.5 mg/kg. In Part B (N=8), subjects were enrolled in two multiple ascending dose (MAD) cohorts (N=4 per group, randomized 3:1, drug:placebo), receiving two monthly subcutaneous doses of ALN-AS1 at 0.35 or 1.0 mg/kg. In both Parts A and B, ALN-AS1 administration resulted in rapid, dose-dependent, and durable silencing of liver ALAS1 mRNA. In addition, ALN-AS1 resulted in rapid and dose-dependent lowering of ALA and PBG of up to 95%. Reductions in ALA and PBG were highly durable, with effects lasting for over ten months after a single dose.

As of the data transfer date, ALN-AS1 continued to be generally well tolerated in ASHE subjects following single and multiple doses. There were three serious adverse events (SAEs) that were all deemed to be unlikely related to study drug. A total of 78 adverse events (AEs) were reported in both the SAD and MAD cohorts, of which 62 were determined to be not related or unlikely related to ALN-AS1 administration. With the exception of one AE, not related to study drug, that was severe, all other AEs were mild or moderate in severity, and most commonly included abdominal pain, diarrhea, hypoesthesia, nasopharyngitis, pruritis, and rash. Two mild and transient injection site reactions (ISRs) were reported. There were no clinically significant changes in vital signs, electrocardiograms, clinical laboratory parameters, or physical examination.

To view the ALN-AS1 clinical data described in this press release, please visit

Alnylam also announced today that the United States Food and Drug Administration (FDA) has granted Orphan Drug Designation to ALN-AS1 for the treatment of acute hepatic porphyrias. The FDA Office of Orphan Products Development (OOPD) mission is to advance the evaluation and development of products that demonstrate promise for the diagnosis and/or treatment of rare diseases or conditions. The Orphan Drug Act provides incentives for sponsors to develop products for rare diseases. In July 2016, the European Medicines Agency (EMA) granted Orphan Drug Designation to ALN-AS1 for the treatment of acute hepatic porphyrias.

ALN-AS1 RNAi Roundtable Webinar InformationAlnylam will review these new clinical data and discuss acute hepatic porphyrias and plans for the further development of ALN-AS1 in an RNAi Roundtable webinar next Tuesday, September 13, 2016 at 11:30 a.m. ET. Speakers include:

  • John Maraganore, Ph.D., Chief Executive Officer
  • William Querbes, Ph.D., Associate Director, Research
  • Guest Speaker: Herbert Bonkovsky, M.D., Professor of Gastroenterology at Wake Forest Baptist Medical Center and Scientific Advisory Board Member of the American Porphyria Foundation
  • Guest Speaker: Ariel Lager, living with Acute Intermittent Porphyria

To register for the webinar, please visit A replay of the webinar and downloadable PDF of the presentation will be available on that website shortly after the Roundtable.

About the ALN-AS1 Phase 1 StudyThe ALN-AS1 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 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 is a randomized (3:1, drug:placebo), double-blind, multi-dose study in up to 12 AIP patients who experience recurrent porphyria attacks, to 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 includes 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.

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