RNAi based therapeutics (Givosiran) for treatment of Acute Hepatic Porphyria

RNAi based therapeutics for treatment of Acute Hepatic Porphyria

RNAi based therapeutics of acute hepatic porphyria is recent example of how biochemical understanding of the metabolic pathways pave a path for drug discovery. Porphyria is a group of rare disease caused by a deficiency of the enzymes in the heme synthetic pathway. The heme synthetic pathway consist of nine steps catalyze by different enzymes. Please refer to pathway for detail below.

What is the therapeutic target enzyme of heme synthesis?

Among these nine enzymes, the repression of delta-amino levulinic acid synthase 1 (ALAS1)  is a lead candidate for the therapeutic development for following reason:
a) ALS 1 is a rate-limiting enzyme for the synthesis of heme and the presence of high heme repress the ALS1 synthesis thereby inhibiting the overall pathway.
b) ALS1 catalyzes the synthesis of ALA, an intermediate substrate for the downstream enzymes in the pathway. ALA and PBG have a neurotoxic effect and lead to neuronal damage. Therefore reduction of these intermediates, in theory, reduces the toxic effect.
c) Hematin a heme product has proven to mitigate the toxic effect of toxic metabolites by repressing ALS1. Therefore, direct inhibition of ALS1 should mitigate symptoms of any porphyria.

How does RNAi based therapeutics work?

Anylam Therapeutics developed an RNAi based therapeutic candidate (Givosiran) to selectively repress ALAS1 and reduce the disease symtoms. This ALAS1 siRNA is conjugated with GALNAc that selectively binds to the liver receptor and internalized into the liver tissue. In the liver tissue, it binds to the ALAS1 mRNA, thereby reducing the expression of the ALAS1.
Mechanism of action of RNAi based therapeutics for suppression of ALAS1

What are the clinical outcomes from clinical study ENVISION?

Anylam submitted the new drug application and market authorization application to FDA to FDA and EMA respectively. Both regulatory agencies granted the fast track review and the decision is expected in 2020. The filing was based on the efficacy and safety data from phase 3 ENVISION which is a randomized, double-blind, placebo-control trial with 94 subjects enrolled in the study. The study result showed significant reduction of primary endpoint composite annualized attacks (74%) in the treatment group compared to the placebo. The composite annualized attacks defined as the attack that require hospitalization, urgent healthcare visit or hemin administration of relief of symptoms. 

Snapshot of Efficacy Date: Positive outcome of RNAi based therapy for Acute Hepatic Porphyria
The biochemical endpoints included the estimation of aminolevulinic acid and porphobilinogen in the plasma. The sustained 90% reduction of ALA and PBG in the treatment group was observed a surrogate biomarker for RNAi induced repression of ALAS1 protein. Overall the study shows the significant improvement in the subjects with acute intermittent porphyria.

As with RNAi class drug, mild liver toxicity was observed in the subset of the subjects. The estimated glomerular filtration rate is stable in the study enrolled subject. In porphyrias, liver disease and chronic kidney disease may also exist before the treatment, and treatment has not shown to greatly aggravate these chronic diseases.


Based on these clinical data available for public, this drug is expected to obtain approval and would be available for the treatment for acute hepatic porphyria. While successful clinical studies are pivotal for showing clinically safety and efficacy in humans, other factors including CMC, drug manufacturers have a significant impact on the approval process. I am hopeful that this drug will make into the market, would greatly impact the much need Acute Hepatic Porphyria populations.