Pushkal Garg, MD, Chief Medical Officer at Alnylam discusses acute hepatic porphyria (AHP) and givosiran, an investigational, subcutaneously administered RNAi therapeutic targeting aminolevulinic acid synthase 1 (ALAS1) in development for the treatment of AHP.

AHP often features chronic, debilitating symptoms punctuated by acute, potentially life-threatening exacerbations. They may inflict years of suffering and impaired quality of life. The symptoms of AHP can often resemble those of other more common conditions such as irritable bowel syndrome (IBS), fibromyalgia, and endometriosis, and consequently, patients afflicted with AHP are often misdiagnosed or remain undiagnosed for an average of 15 years.

AHP is a family of rare, genetic diseases that lead to accumulation of neurotoxic intermediates aminolevulinic acid (ALA) and porphobilinogen (PBG), which causes disease manifestations. In people with the genetic defect for AHP, 1 of the 8 enzymes in the pathway that creates heme is deficient. Certain triggers can impact the pathway and can cause an increase of aminolevulinic acid synthase 1 (ALAS1) in the liver. This increase of ALAS1 results in the buildup of neurotoxic intermediates—ALA and PBG—throughout the body. ALA and PBG are harmful to nerve cells and are thought to cause the acute attacks and chronic symptoms characteristic of AHP.

AHP affects the autonomic, peripheral, and central nervous systems.