27 June 2019 - - US-based RNAi therapeutics company Alnylam Pharmaceuticals, Inc. (NASDAQ: ALNY) has detailed new advances in its RNAi therapeutics platform, including preclinical results demonstrating oral delivery of GalNAc-conjugated small interfering RNAs (siRNAs) the molecules that mediate RNAi directed to a liver target, the company said.
Oral delivery could broaden the clinical and commercial opportunities for RNAi therapeutics, which are currently administered with intravenous or subcutaneous dose administration.
The results were presented at the 3rd International Conference on the Long and the Short of Non-Coding RNAs being held June 18-23 in Crete, Greece. The company also reported on further progress on central nervous system and ocular delivery of novel siRNA conjugates.
Preclinical studies were performed to investigate the potential for oral administration of investigational RNAi therapeutics. Robust and durable messenger RNA silencing was observed in mice for a GalNAc-conjugated siRNA targeting Factor 12 with a proprietary formulation containing a permeation enhancer and delivered via oral gavage.
The knockdown effect was sustained for over 40 days with a durability profile on par with that achieved via subcutaneous administration.
Knockdown was dose-dependent and required the presence of the GalNAc conjugate and the formulation containing a permeation enhancer.
Approximately 90% knockdown was observed upon administration of three oral doses at 3 mg/kg.
Additional data on CNS delivery of RNAi therapeutics were also presented. In rat studies, a head to head comparison of silencing activity of an siRNA and a previously reported antisense oligonucleotide targeting human superoxide dismutase 1 (hSOD1) was performed in a transgenic model expressing hSOD1.
A single intrathecal injection of a hSOD1-targeted siRNA resulted in greater silencing activity as compared to its ASO counterpart across all key anatomical regions of the brain and spinal cord.
Specifically, when dosed at 0.9 mg and measured at Day 7, the hSOD1-targeted siRNA achieved superior silencing across all regions of the spine and brain, with mean silencing from 85-88% and 64-75%, respectively. In contrast, the corresponding ASO targeting hSOD1 achieved a markedly reduced level of silencing of 68-72% in the spine and 25-43% in the brain.
In additional studies at a lower dose of 0.45 mg and with measurements at Day 28, the siRNA targeting hSOD1 achieved mean silencing between 67-87% in the spine while markedly reduced levels of silencing of 28-44 % were observed for the ASO targeting hSOD1.
Finally, results on ocular delivery of RNAi therapeutics were also presented. Intravitreal administration of a conjugated siRNA targeting mouse transthyretin demonstrated a dose-dependent and sustained knockdown of TTR, with maximal (greater than 95%) suppression achieved at doses as low as 15 micrograms per eye and lasting up to Day 135 post a single injection.
Similarly, a single low intravitreal dose of a siRNA conjugate targeting human TTR resulted in virtually complete knockdown of TTR protein in the NHP eye, with effects lasting for at least three months.
To view the results presented by Alnylam at the 3rd International Conference on the Long and the Short of Non-Coding RNAs, visit www.alnylam.com/capella.
RNAi (RNA interference) is a natural cellular process of gene silencing that represents one of the most promising and rapidly advancing frontiers in biology and drug development TODAY.
Its discovery has been heralded as "a major scientific breakthrough that happens once every decade or so," and was recognized with the award of the 2006 Nobel Prize for Physiology or Medicine.
By harnessing the natural biological process of RNAi occurring in our cells, a new class of medicines, known as RNAi therapeutics, is now a reality.
Small interfering RNA (siRNA), the molecules that mediate RNAi and comprise Alnylam's RNAi therapeutic platform, function upstream of TODAY's medicines by potently silencing messenger RNA the genetic precursors that encode for disease-causing proteins, thus preventing them from being made.
This is a revolutionary approach with the potential to transform the care of patients with genetic and other diseases.
Alnylam (NASDAQ: ALNY) is advancing the translation of RNA interference into a new class of innovative medicines with the potential to transform the lives of people afflicted with rare genetic, cardio-metabolic, hepatic infectious, and central nervous system/ocular diseases.
Based on Nobel Prizewinning science, RNAi therapeutics represent a powerful, clinically validated approach for the treatment of diseases with high unmet need.
Onpattro (patisiran) is the first-ever RNAi therapeutic approved by the US FDA for the treatment of the polyneuropathy of hereditary transthyretin-mediated (hATTR) amyloidosis in adults and by the EMA for the treatment of hATTR amyloidosis in adults with stage 1 or stage 2 polyneuropathy.
Alnylam has a deep pipeline of investigational medicines, including five product candidates in Phase 3 studies and one in registration.
Looking forward, Alnylam will continue to execute on its "Alnylam 2020" strategy of building a multi-product, commercial-stage biopharmaceutical company with a sustainable pipeline of RNAi-based medicines to address the needs of patients who have limited or inadequate treatment options.
Headquartered in Cambridge, MA, Alnylam employs over 1,200 people worldwide.