ALN-AS1
Small interfering RNA (siRNA)-induced RNA interference (RNAi) responses have great potential to treat a wide range of human diseases from cancer to a pandemic viral outbreak. Not surprisingly, significant efforts are placed to develop a variety of delivery systems and technologies. Foremost of these has been the design and synthesis of N-acetylgalactosamine (GalNAc)-siRNA conjugates for transport to the liver. The acute hepatic porphyrias (AHP) are triggered by inherited enzymatic deficiencies in the heme biosynthesis pathway. Induction of the first enzyme 5-aminolevulinic acid synthase 1 (ALAS1) can result in the accumulation of neurotoxic heme intermediates that cause clinical presentations of diseases. It has demonstrated that hepatic ALAS1 silencing using siRNA molecules, ALN-AS1 (trade name: Givosiran), in a lipid nanoparticle (LNP) effectively prevents induced attacks in a mouse model with AHPs.
Introduction to AHP
AHPs are a group of inherited metabolic disorders that present with episodic, acute neurovisceral symptoms and typically display serious abdominal pain, tachycardia, hypertension, motor weakness, and psychiatric symptoms. There're four types of AHP including acute intermittent porphyria (AIP), variegate porphyria, hereditary coproporphyria, and 5-aminolevulinic acid (ALA) dehydratase deficiency porphyria. Of these four AHPs, the most severe is AIP, an autosomal dominant illness owing to the half-normal activity of porphobilinogen deaminase (PBGD). Acute attacks are caused by several factors, such as cytochrome p450-inducing drugs, dieting, and hormonal fluctuations, all of which leading to the improved expression level of ALAS1, the first and rate-limiting enzyme in the heme biosynthetic pathway. When the activity of ALAS1 is induced, the inherited enzyme deficiency becomes limiting and increases the hepatic production of upstream neurotoxic porphyrin precursors, ALA, and porphobilinogen (PBG), which deposit in the plasma and urine during attacks.
Figure 1. Summary of the heme synthetic pathway, highlighting the enzymatic defects associated with the porphyrias. (Wang, 2018)
ALN-AS1 in Clinical Trials
As a rare disease, AIP is more popular than previously thought, found in approximately 1 in 1600 Caucasians, but with a very low clinical penetrance (~2-3%). Currently, liver transplant is the only cure for AIP, whereas transplantations manifest limitations of organ availability and risk of rejection action. There remains an urgent unmet medical need for a simple, efficient, fast-acting, and better-tolerated treatment for acute attacks and the prevention of recurrent attacks in AIP populations. ALN-AS1 is reported as an investigational RNAi therapeutic using GalNAc-siRNA conjugates targeting ALAS1. A prominent correlation in ALAS1 mRNA was observed in the liver, serum, and urine of both rodents and nonhuman primates after administrated by ALN-AS1.
Figure 2. Delivery of GalNAc-siRNA conjugates into hepatocytes. (Springer, 2018)
- Mechanism of action
The liver is the primary site of pathology in the AHPs, RNAi-based therapeutics, ALN-AS1, has been developed to target liver ALAS1, as a promising novel therapy for patients with AHPs. The siRNA molecules repress ALAS-1 production which is believed to reduce the accumulation of haem in the body. RNAi is a naturally occurring biological process by which siRNAs specifically and robustly silence targeted mRNA, effectively inhibiting the corresponding disease-causing proteins. The ability to utilize RNAi to selectively suppress disease-causing genes has been a highly attractive, clinically validated therapeutic method for the treatment of metabolic diseases. The recent advances in LNP and GalNAc-siRNA conjugate platforms have allowed for efficacious and liver-specific transport of siRNA, thereby enabling the development of RNAi therapeutics for liver-expressed disease targets.
Currently, ALN-AS1 has completed a Phase I clinical trial and recently is under both a Phase I/II open-label extension (OLE) studies and a Phase III ENVISION trial. Phase I clinical data illustrated no serious adverse event (SAE) attributed to ALN-AS1 with subcutaneous concentrations as high as 5 mg/kg monthly. Patients treated monthly compared to quarterly with 2.5 mg/kg showed an enhanced lowering of desired biomarkers, ALA and PBG. Increasing the monthly dosing to 5 mg/kg didn't exhibit a rising reduction of ALA and PBG expression levels. Monthly dosing of 2.5 mg/kg gave rise to an 83% reduction in annualized attack rate (AAR) and an 88% reduction in hemin use compared to placebo. With the current clinical experience of GalNAc-siRNA conjugate delivery, ALN-AS1 may be an efficient agent and a valuable candidate for patients with AIP.
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References
- Wang, B.; et al. (2018). Acute hepatic porphyrias: review and recent progress. Hepatol Commun. 3(2): 193-206.
- Springer, A.D.; et al. (2018). GalNAc-siRNA conjugates: leading the way for delivery of RNAi therapeutics. Nucleic Acid Ther. 28(3): 109-118.
