Policy & Regulation
Alnylam Pharmaceutical, Ironwood Pharmaceuticals Enter US GI Disease Education and Promotional Agreement for Alnylam's Givosiran in Acute Hepatic Porphyria
14 August 2019 - - US-based RNAi therapeutics company Alnylam Pharmaceuticals, Inc. (NASDAQ: ALNY) and US-based GI healthcare company Ironwood Pharmaceuticals, Inc. (NASDAQ: IRWD) have inked a US GI disease education and promotional agreement for Alnylam's givosiran, an investigational RNAi therapeutic targeting aminolevulinic acid synthase 1 (ALAS1) for the potential treatment of AHP, the companies said.

Givosiran has received Priority Review designation and Breakthrough Therapy Designation from the US FDA, as well as Orphan Drug Designation in the US.

The Prescription Drug User Fee Act (PDUFA) date for givosiran is set for February 4, 2020.

Under the terms of the agreement, Ironwood will provide AHP disease education to gastroenterologists and other healthcare practitioners that Ironwood currently calls on for Linzess (linaclotide).

If approved by the US FDA, Ironwood clinical sales specialists will then begin givosiran promotional efforts, augmenting Alnylam's broader commercialization activities.

The non-exclusive agreement covers an approximately three-year term. Ironwood will collaborate with Alnylam on AHP disease education designed to help ensure AHP patients are accurately diagnosed and to support access to treatment with givosiran once prescribed (assuming approval).

Ironwood will receive fixed payments and royalties in the mid-teens % on net sales generated from prescriptions or referrals from certain physicians related to Ironwood's promotional efforts.

Alnylam will maintain responsibility for all other aspects of givosiran, and retains all global development and commercialisation rights.

Acute hepatic porphyria refers to a family of rare, genetic diseases characterized by potentially life-threatening attacks and for some patients chronic debilitating symptoms that negatively impact daily functioning and quality of life.

AHP is comprised of four subtypes, each resulting from a genetic defect leading to deficiency in one of the enzymes of the heme biosynthesis pathway in the liver: acute intermittent porphyria, hereditary coproporphyria, variegate porphyria, and ALAD-deficiency porphyria.

These defects cause the accumulation of neurotoxic heme intermediates aminolevulinic acid and porphobilinogen, with ALA believed to be the primary neurotoxic intermediate responsible for causing both attacks and ongoing symptoms between attacks.

Common symptoms of AHP include severe, diffuse abdominal pain, weakness, nausea, and fatigue.

The nonspecific nature of AHP signs and symptoms can often lead to misdiagnoses of other more common conditions such as irritable bowel syndrome, appendicitis, fibromyalgia, and endometriosis, and consequently, patients afflicted by AHP often remain without a proper diagnosis for up to 15 years.

In addition, long-term complications of AHP and its treatment can include chronic neuropathic pain, hypertension, chronic kidney disease and liver disease, including iron overload, fibrosis, cirrhosis and hepatocellular carcinoma.

Currently, there are no treatments approved to prevent debilitating attacks or to treat the chronic manifestations of the disease.

Givosiran is an investigational, subcutaneously administered RNAi therapeutic targeting aminolevulinic acid synthase 1 (ALAS1) in development for the treatment of acute hepatic porphyria.

Monthly administration of givosiran has the potential to significantly lower induced liver ALAS1 levels in a sustained manner and thereby decrease neurotoxic heme intermediates, aminolevulinic acid and porphobilinogen, towards normal levels.

By reducing accumulation of these intermediates, givosiran has the potential to prevent or reduce the occurrence of severe and life-threatening attacks, control chronic symptoms, and decrease the burden of the disease.

Givosiran utilises Alnylam's Enhanced Stabilization Chemistry ESC-GalNAc conjugate technology, which enables subcutaneous dosing with increased potency and durability and a wide therapeutic index.

The safety and efficacy of givosiran were evaluated in the ENVISION Phase 3 trial with positive results; these results have not been evaluated by the FDA, the EMA or any other health authority.