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Porphyria

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.

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ALN-AS1 for the Treatment of Hepatic Porphyrias

We are developing ALN-AS1, an investigational RNAi therapeutic targeting aminolevulinic acid synthase 1 (ALAS1) for the treatment of hepatic porphyrias, including AIP. Inhibition of ALAS-1 is believed to reduce the accumulation of the toxic heme intermediates ALA and PBG, which cause the clinical manifestations of AIP. We believe that a subcutaneously administered RNAi therapeutic targeting ALAS-1 has the potential to be used as a prophylactic approach to prevent attacks, and also as a therapy for acute attacks. ALN-AS1 utilizes our proprietary Enhanced Stabilization Chemistry (ESC)-GalNAc-conjugate delivery platform enabling subcutaneous dosing with increased potency and durability, and a wide therapeutic index.

Please read the latest press releases and data presentations for ALN-AS1 here.

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Initial Evidence of Clinical Activity Shown with Givosiran (ALN-AS1) in Acute Intermittent Porphyria Patients with Recurrent Attacks

Initial Evidence of Clinical Activity Shown with Givosiran (ALN-AS1) in Acute Intermittent Porphyria Patients with Recurrent Attacks

We reported positive initial results from Cohorts 1 and 2 in Part C of our Phase 1 study with givosiran (gi-VOH-si-ran), the International Nonproprietary Name for ALN-AS1, an investigational RNAi therapeutic targeting aminolevulinic acid synthase 1 (ALAS1) for the treatment of acute hepatic porphyrias.  These results were presented at the 58th Annual Meeting of the American Society of Hematology (ASH), held December 3 – 6, 2016 in San Diego, California.



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Interim Results from EXPLORE Natural History Study for Acute Hepatic Porphyrias

Interim Results from EXPLORE Natural History Study for Acute Hepatic Porphyrias

We reported interim results from our ongoing EXPLORE study, a multinational, prospective, observational study aimed at characterizing the natural history and clinical management of patients with acute hepatic porphyrias (AHP) who experience recurrent attacks or receive prophylactic treatment to prevent attacks.  Results from 112 patients, of which 104 have acute intermittent porphyria (AIP), showed a mean of 9.5 acute attacks reported in the prior year with severe neuropathic pain as the cardinal feature in 100% of attacks, along with other symptoms including nausea or vomiting (>80%), fatigue (77%), and weakness (79%).  Approximately 64% of patients reported experiencing porphyria symptoms between attacks, with about 46% experiencing symptoms daily.  Patients also reported a diminished quality of life and significant healthcare utilization, with a mean of 4.6 overnight hospitalizations per year (range 0-70) and a mean hospital stay duration of 6.6 days (range 1-60).  Of the attacks reported on study, approximately 76% of them required treatment with heme or at a healthcare facility.


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Positive Interim Results from Ongoing Phase 1 Study with ALN-AS1, in Development for the Treatment of Acute Hepatic Porphyrias

Positive Interim Results from Ongoing Phase 1 Study with ALN-AS1, in Development for the Treatment of Acute Hepatic Porphyrias

We presented interim results from our ongoing Phase 1 clinical trial with ALN-AS1, an investigational RNAi therapeutic targeting aminolevulinic acid synthase 1 (ALAS1) for the treatment of acute hepatic porphyrias (AHP), at the 2016 Society for the Study of Inborn Errors of Metabolism (SSIEM) Annual Symposium, held from September 6 – 9, 2016 in Rome, Italy.



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