Research & Development
Alnylam Presents Updated Phase 1/2 Open-Label Extension Results for Givosiran, an Investigational RNAi Therapeutic for the Treatment of Acute Hepatic Porphyria
13 November 2018 - - US-based RNAi therapeutics company Alnylam Pharmaceuticals, Inc. (NASDAQ: ALNY), the leading, announced TODAY that the company presented updated results from the ongoing Phase 1/2 open-label extension study of givosiran, an investigational RNAi therapeutic, targeting aminolevulinic acid synthase 1 (ALAS1) for the treatment of acute hepatic porphyria.

The new data were presented at The Liver Meeting 2018 of the American Association for the Study of Liver Diseases (AASLD) being held November 9-13 in San Francisco, CA.

As of the data cut-off date of June 7, 2018, a robust treatment effect was maintained in givosiran-treated patients with continued dosing in the Phase 1/2 OLE study, with a mean time on treatment of 13.6 months and total time on treatment across the Phase 1 and OLE studies of up to 25 months.

Monthly dosing at 2.5 mg/kg led to sustained lowering of aminolevulinic acid and porphobilinogen toward normal levels, with a mean reduction from baseline of 87 and 83%, respectively, at 12 months.

In patients who received givosiran during the Phase 1 study and continued with givosiran dosing in the OLE study, mean reductions in annualised attack rate of 93% and annualised hemin use of 94% were observed, relative to pre-treatment results (measured in the Phase 1 blinded, prospective run-in period).

Similarly, patients in the placebo arm of the Phase 1 study crossing over to givosiran treatment in the OLE study experienced mean reductions in AAR of 95% and annualized hemin use of 98%.

Seven of sixteen patients (44 %) achieved an AAR of zero with a mean of 11.3 months on treatment; the average AAR during the run-in period for these seven patients was 15.2.

Serious adverse events were reported in four patients. Previously reported SAEs included: a patient with an upper extremity deep vein thrombosis, assessed as unlikely related to study drug by the investigator; and one patient who had an anaphylactic reaction after the third dose of givosiran, assessed as definitely related to study drug, which resolved with medical management.

New SAEs included: a patient with two episodes of pyrexia related to a suspected Port-a-Cath infection and chlamydia bronchitis, assessed as unlikely related to study drug; and one patient with a change in mental status due to a possible glucocorticoid toxicity from an acute bacterial sinusitis, both of which were assessed as unlikely related to study drug.

Adverse events occurring in three or more patients included abdominal pain, fatigue, injection site erythema, nausea, myalgia, diarrhea, headache, and nasopharyngitis. Six patients had injection site reactions, all mild to moderate.

No clinically significant increases in liver function tests or lipase levels were noted with continued dosing in the OLE study.

Results presented at AASLD can be viewed on the Capella section of the Alnylam website.

The Phase 1 study of givosiran (Part C) was conducted as a randomized, double-blind, placebo-controlled study in 17 patients with acute intermittent porphyria who experienced recurrent porphyria attacks.

Patients were initially followed in a 3-month run-in phase, where the number and frequency of porphyria attacks and levels of ALA and PBG were measured prospectively.

Patients who experienced at least one porphyria attack during the run-in phase were then eligible to enter the 6-month treatment phase of the study, where they were randomized to receive 2 once-quarterly doses or 4 once-monthly doses of placebo or givosiran at doses of 2.5 or 5.0 mg/kg.

During the treatment phase, the effects of placebo or givosiran on the number and frequency of porphyria attacks, as well as on the levels of ALA and PBG, were measured prospectively in a blinded manner and then compared to run-in phase results.

Additional measures included safety, tolerability, hospitalizations, use of hemin, levels of ALAS1 mRNA, and givosiran pharmacokinetics. Hemin is an FDA-approved agent used to treat porphyria attacks when they occur. Following the treatment phase, all patients were eligible to receive givosiran in an open-label extension study.

The ENVISION Phase 3 trial is a randomized, double-blind, placebo-controlled, global, multicenter study to evaluate the efficacy and safety of givosiran in patients with a documented diagnosis of an AHP.

Patients were randomised on a 1: 1 basis to receive 2.5 mg/kg of givosiran or placebo subcutaneously administered monthly, over a six-month treatment period.

The primary endpoint is the annualized rate of porphyria attacks requiring hospitalization, urgent healthcare visit or hemin administration at home over the six-month treatment period.

Key secondary and exploratory endpoints will evaluate reductions in the hallmark symptoms of AHP, such as pain, nausea, and fatigue, as well as impact on quality of life.

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

AHPs are 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 AHPs include severe, diffuse abdominal pain, weakness, nausea, and fatigue.

Symptoms of AHPs can often resemble that of other more common conditions such as irritable bowel syndrome, appendicitis, fibromyalgia, and endometriosis and consequently, patients afflicted with an AHP are often misdiagnosed or remain undiagnosed for an average of 15 years.

Currently, there are no treatments approved to prevent debilitating attacks and treat the chronic symptoms 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, to near 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 utilizes Alnylam's Enhanced Stabilization Chemistry ESC-GalNAc conjugate technology, which enables subcutaneous dosing with increased potency and durability and a wide therapeutic index.

Givosiran has been granted Breakthrough Therapy designation by the US Food and Drug Administration and PRIME designation by the European Medicines Agency. Givosiran has also been granted orphan drug designations in both the US and the EU for the treatment of AHP.

The safety and efficacy of givosiran are currently being investigated in the ENVISION Phase 3 clinical trial and ongoing Phase 1/2 OLE study and have not been evaluated by the FDA, the EMA or any other health authority.

RNAi (RNA interference) is a natural cellular process of gene silencing that represents one of the most promising and rapidly advancing frontiers in biology and drug development.

Small interfering RNA (siRNA), the molecules that mediate RNAi and comprise Alnylam's RNAi therapeutic platform, function upstream of TODAY's medicines by potently silencing messenger RNA the genetic precursors that encode for disease-causing proteins, thus preventing them from being made.

This is a revolutionary approach with the potential to transform the care of patients with genetic and other diseases.
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