Givosiran

Unassigned

New Medicines

Acute hepatic porphyrias (AHP)

Information

New molecular entity
Alnylam Pharmaceuticals
Alnylam Pharmaceuticals

Development and Regulatory status

Pre-registration (Filed)
Pre-registration (Filed)
Pre-registration (Filed)
Yes
Yes

Jul 19: Marketing Authorization Application (MAA) has been submitted to the European Medicines Agency (EMA) for givosiran in treating acute hepatic porphyria [17].


Jun 19:NDA submitted to the U.S. Food and Drug Administration (FDA) for givosiran for treatment of acute hepatic porphyria (AHP). Alnylam intends to file an MAA in mid-2019 [16].


Jul 19: Marketing Authorization Application (MAA) has been submitted to the European Medicines Agency (EMA) for givosiran in treating acute hepatic porphyria [17].

May 18: Alnylam announce that they intend to submit a NDA to the FDA at or around year-end 2018 based on possible interim analysis of the ENVISION study, and a MAA to the EMA in 2019 based on the full dataset from ENVISION [10].


Feb 18: recruitment extended to EU including UK [9].


Nov 17: PIII ENVISION trial (NCT03338816) initiated in the US [7].


May 17: Sanofi-Genzyme has elected not to opt-in to commercialisation of givosiran. Alnylam will therefore develop and commercialise the drug globally themselves [4].


May 17: Granted breakthough therapy designation in US [5].


Mar 17: Has orphan drug status in EU & US [3].


Mar 17: Alnylam will work with the EMA to move the drug into phase 3 by end 2017 [1].


Mar 17: European Medicines Agency (EMA) grants access to its Priority Medicines (PRIME) scheme for givosiran (ALN-AS1) for treatment of acute hepatic porphyrias [1].


Category

RNAi therapeutic targeting aminolevulinic acid synthase 1 (ALAS1)
AHPs constitute a subset where the enzyme deficiency occurs within the liver, and includes acute intermittent porphyria (AIP), hereditary coproporphyria (HCP), and variegate porphyria (VP). Exposure of AHP patients to certain drugs, dieting, or hormonal changes can trigger strong induction of aminolevulinic acid synthase 1 (ALAS1), another enzyme in the heme biosynthesis pathway, which can lead to accumulation of neurotoxic heme intermediates [1]. Prevalence 1/75,000 [2].
Acute hepatic porphyrias (AHP)
Peri-tumoural and peri-lymphatic

Trial or other data

Apr 19: Alnylam announce further positive data from PIII ENVISION trial at conference. Givosiran demonstrated a 74% mean and 90% median reduction in the primary endpoint of annualized rate of composite attacks vs placebo over 6 months (n=93). The company plan to file a MAA mid-2019 [14].


Mar 19: The PIII ENVISION trial (NCT03338816) of givosiran in acute hepatic porphyria met its primary endpoint by reducing annualised rate of composite porphyria attacks (requiring hospitalisation, urgent healthcare visit or hemin administration) versus placebo. The actual rate reduction was not presented in the press release. Five of the nine secondary endpoints were also met. The safety profile of givosiran was worse than expected, with serious adverse events affecting 21% of givosiran arm vs. 9% of placebo arm. Overall adverse event rates were high in the placebo arm (80%) and the givosiran arm (90%); baseline liver disease was though a potential cause for some of the safety events [12, 13].


Sep 18: Positive results from interim analysis of data from the PIII ENVISION trial reported. Givosiran treatment was associated with a statistically significant reduction in urinary ALA levels vs placebo (p<0.001). Topline full study results of the primary endpoint, the annualised attack rate after 6 months of treatment, are expected in early 2019 [11].


Apr 18: Positive results from PI/II open-label extension (OLE) study of givosiran for treatment of acute hepatic porphyrias (AHPs). Monthly givosiran dosed at 2.5 mg/kg led to mean reductions in annualised attack rate (AAR) of 83% and annualised hemin use of 88 vs. placebo. Pts (N=12) who received givosiran during the PI study and continued in the OLE had mean reductions of annualized attack rates by 93% and annualised hemin use of 94%. Placebo pts in the PI trial who “crossed over” to givosiran in the OLE study saw mean reductions of >90% in AAR and annualised hemin use. There were some safety concerns during the trial with one pt discontinuing following an anaphylactic reaction. [8]


Nov 17: ENVISION PIII trial (NCT03338816) initiated. The double-blind placebo-controlled randomised trial will enrol patients aged 12 and above with acute intermittent porphyria (estimated n=74) in the US. Primary outcome will be the annualised rate of porphyria attacks and estimated primary completion date March 2019 [7].


Jun 17: Alnylam announces results from a PI study (n=12). Givosiran achieved a 73% reduction (PDF) in annualized attack rate vs. placebo, with a 73% reduction in annualized hemin doses. Clinicians have suggested a 30% reduction in attacks would be clinically meaningful. Importantly, the reduction in attacks appeared to be dose-dependent and matched reductions in ALA/PBG levels, suggesting these could be used as biomarkers for the drug´s activity in future studies. There was one death among patients in the treatment group (due to hemorrhagic pancreatitis) as well as three other serious adverse events that the investigators concluded were not linked to the study drug. Data from an eight-patient open-label extension study found a further reduction in attacks and suggested control could be better with longer-term dosing [6].


Mar 17: Promising results from the Phase 1 study of givosiran formed the basis of the application for PRIME. The ongoing Phase 1 trial is being conducted as a randomized, double-blind, placebo-controlled study. Specifically, data were recently reported in patients with AIP experiencing recurrent attacks. As presented at the 2016 American Society of Hematology (ASH) meeting, givosiran demonstrated initial evidence for clinical activity in AIP patients with meaningful reductions in the number and frequency of porphyria attacks. In the first two dose cohorts, givosiran was found to be generally well tolerated with no drug-related serious adverse events. In the third dose cohort, which remains blinded, one death due to acute pancreatitis, considered unlikely related to givosiran or placebo, was reported after the data transfer date [1].


May 15: Alnylam initiates a phase I trial to assess the safety and tolerability of givosiran in patients with hepatic porphyria in the US, the UK and Sweden (ALN-AS1-001; NCT02452372). The trial is designed to be conducted in three parts, of which part A (single-dose) and B (multi-dose) are randomised, single-blind, dose-escalation phases, in patients with acute intermittent porphyria who are asymptomatic "high excreters" (ASHE). Part A of the trial enrolled 20 patients, five in four cohorts who received givosiran at the dosage of 0.035 mg/kg to 2.5 mg/kg. Part B of the trial enrolled eight patients, two in each of the four cohorts, who received two-monthly subcutaneous doses of 0.35 mg/kg or 1.0 mg/kg. The open-label, multiple-dose part C of the trial was initiated to assess the safety, tolerability, pharmacodynamics and clinical activity of givosiran in eight patients with recurrent attacks. In Oct 16, Alnylam initiated an extension phase I/II trial to determine the long-term safety, tolerability and pharmacokinetics of givosiran in patients with acute intermittent porphyria who have completed part C of ALN-AS1-001 study (ALN-AS1-002; NCT02949830). The open-label, single-group trial is recruiting 17 patients, by invitation only, in the US, the UK and Sweden [2].


Evidence based evaluations