Envision-LukeMcClure

The phase 3 trial of Givocerin, an RNAi therapeutic, for acute intermittent porphyria (AIP) showed promising results. Treatment with Givocerin led to a 74% reduction in the mean annualized rate of porphyria attacks. Patients treated with Givocerin also had significantly lower levels of ALA and PBG, which are neurotoxic heme intermediates. Givocerin was well-tolerated, with injection site reactions, nausea, and fatigue being the most common side effects. Overall, Givocerin showed potential in reducing the frequency of attacks and improving quality of life in AIP patients. Luke McClure. Envision, the phase 3 trial of RNAi therapeutic. Givasarin for acute intermittent porphyria, as reported by Manisha Balwani, MD, and other authors in the New England Journal of Medicine. Givlari, or Givasarin, is indicated for the treatment of acute hepatic porphyria, or AHP, in adults and adolescents 12 years and older. In patients with AHP, induction of hepatic delta-aminolevulinic acid synthase 1, or ALAS-1, results in the accumulation of neurotoxic heme intermediates, including delta-aminolevulinic acid, or ALA, and porphybilinogen, or PBG. The accumulation of ALA, and possibly PBG, causes injury to the nervous system and other organs, resulting in potentially life-threatening acute attacks and chronic disease manifestations. Attacks that occur in AHP are characterized by severe diffuse abdominal pain, muscle weakness, hypertension, tachycardia, nausea, vomiting, and constipation, as well as changes in mental status. Attacks typically warrant urgent medical attention and sometimes prolonged hospitalization and rehabilitation. AHP has been associated with long-term coexisting illnesses that have been attributed to long-term elevated levels of ALA and PBG. Givocerin is a subcutaneously administered RNA interference, or RNAi therapeutic, that targets hepatic ALAS-1 mRNA, thereby preventing the accumulation of ALA and PBG. Givocerin was studied and envisioned. The six-month randomized double-blind placebo-controlled phase 3 trial in 94 adults with AHP with a 30 month open label extension for Givocerin. The primary endpoint is the annualized rate of composite porphyria attacks, or AAR. Secondary endpoints included urinary ALA and PBG levels, annualized days of human use, composite AAR of porphyria attacks in patients with AHP, daily worst pain, nausea, and fatigue, and change from baseline and physical component summary of the short form 12 health survey. Treatment with Givocerin 2.5 milligrams per kilogram led to a 74% reduction in the mean AAR compared with placebo in patients with AIP. Each of the composite endpoint components demonstrated a greater reduction in the Givocerin group compared with placebo, most notably in attacks requiring urgent care. 50% of patients with AHP treated with Givocerin had zero attacks compared with 17% for placebo. ALA and PBG levels were significantly lower in patients with AIP treated with Givocerin compared to baseline. Monthly treatment with Givocerin 2.5 milligrams per kilogram led to reductions that were sustained throughout the intervention period. Treatment with Givocerin resulted in a 77% reduction in mean annualized days of human use versus placebo. Reduction in human use may be beneficial as human may be associated with a range of side effects from acute fever or phlebitis to chronic iron overload or venous obliteration. Daily worst pain was significantly lower with Givocerin over time compared with placebo in patients with AIP. Givocerin treated patients with AIP reported decreased analgesic use compared with placebo. In a 12-item short-form health survey or SF-12, AIP patients treated with Givocerin reported improvement in quality of life measurements compared with placebo. A consistent effect favoring Givocerin compared with placebo was demonstrated with the largest effects in the domains of bodily pain, social functioning, and role limitations due to physical problems. In the Givocerin group, adverse events reported at least 5% more frequently were injection site reactions, nausea, chronic kidney disease, decreased EGFR, rash, increased ALT, and fatigue. Serious adverse events were 21% versus 9% for placebo. Hepatic and renal adverse effects were mostly transient and reversible. Here are some key takeaways from Envision. Treatment with Givocerin led to a significant reduction of 74% in the mean AAR in patients with AIP. Givocerin demonstrated a 77% reduction in annualized days of human use in patients with AIP. ALA and PBG levels were significantly lower in patients with AIP treated with Givocerin compared with placebo.