Key Findings

• The number of siRNA clinical trials is steadily increasing.
• GalNAc conjugates, self-delivery and lipid nanoparticles are the most common methods of siRNA delivery.
• These three modalities are used to target a limited number of therapeutic areas, primarily liver disorders.
• Inadequate delivery systems are cited as factors in siRNA clinical trial terminations.
• A small number of early stage (Phase 1 and 2) clinical trials in therapeutic areas beyond the liver and eye signals siRNA approach could have broader application
• There is wide recognition that more effective drug delivery systems are urgently required

Over the past decade, the development of cell and gene therapies — such as short interfering RNA (siRNA) for therapeutic gene silencing — has been accelerating

siRNAs are short strands of RNA, typically 21-23 nucleotides long, that are designed to degrade a target mRNA to prevent its translation into protein, subsequently halting the potential unwanted downstream actions of that particular protein [1].

There are currently two FDA-approved siRNA therapies on the market: Alnylam Pharmaceuticals’ patisiran (Onpattro, a lipid nanoparticle formulation) [2] for the treatment of the polyneuropathy of hereditary transthyretin-mediated amyloidosis in adults, and givosiran (Givlaari, a GalNAc-conjugate formulation) [3] for the treatment of adults with acute hepatic porphyria.

GalNAc conjugates: A popular delivery modality

Clinical trials of drugs utilising siRNAs have been steadily increasing in number since 2004 (Fig. 1). In 45% of these trials, the delivery modality used involves conjugating siRNA to a trimer of N-acetylgalactosamine (GalNAc), which binds to the asialoglycoprotein receptor (ASGPR) that is predominantly expressed on liver hepatocytes; hence it is used for targeting therapeutic siRNAs to the liver.

Whilst in 20% of clinical trials siRNAs are self-delivered to the target organ, lipid nanoparticles are the next most common delivery vehicle, being used in 19% of siRNA clinical trials to date (Fig. 2).

The use of GalNAc conjugates is accelerating relative to other siRNA delivery approaches

The use of GalNAc-siRNA conjugates is growing at the fastest rate as a proportion of the total number of siRNA clinical trials (Fig. 3a) and siRNA therapies (Fig. 3b; see Methods). In 2019, the number of clinical trials using GalNAc technology was 23, whilst alternative delivery systems were used in between 1 and 4 clinical trials. During the same year, there were 9 distinct GalNAc-siRNA therapeutics in the clinic.

The Liver: An advanced target for siRNA therapies

The three major modes of delivery — GalNAc conjugates, self-delivery and lipid nanoparticles — can be used to deliver siRNAs to a limited number of target organs, namely the liver and eye (Fig. 4). In particular, GalNAc conjugates and lipid nanoparticles are used primarily to target the liver (in 100% and 71% of trials, respectively), while self-delivery is most commonly used to target the eye (75% of total use).

Therapeutic focus: Liver, Eye and Cardio-metabolic disease

While these three therapeutic areas (liver, eye and cardio-metabolic disorders) have the highest numbers of siRNA clinical trials and the most mature pipelines — i.e. the highest proportions of therapies in late stages of clinical development — there is a number of early stage clinical trials (Phase 1 and Phase 2) in other therapeutic areas, such as solid cancer indications (Fig. 5).

Nine out of eighty six of the analysed siRNA clinical trials were terminated, typically in Phase 1 (78%), including three lipid nanoparticle-siRNA formulations, two GalNAc-siRNA conjugates, two dynamic polyconjugates, one polymeric nanoparticle and one self-delivered siRNA trial. For instance, Calando’s polymer-based siRNA formulation candidate for treatment of solid tumours, CALAA-01, was terminated due to an unstable delivery system, which prevented adequate buildup of drug in the tumour [4].

Expert Opinion

The need for better delivery systems for siRNA therapeutics is widely recognised by industry. We asked two scientists at leading companies working in this space to share their opinion on the largest limiting factors for siRNA therapies.

Dr Marianne Ashford Senior Principal Scientist, Advanced Drug Delivery, Pharmaceutical Sciences, R&D AstraZeneca

siRNA has the potential to enable us to target novel pathways not amenable to more traditional drug discovery approaches. To maximise the potential of this modality, successful targeted and efficient intracellular drug delivery approaches will be key.

Dr Duygu Yilmaz Senior Scientist, Molecular Technologies, Medicines Discovery Catapult

Effective drug delivery systems can greatly improve the therapeutic potential of nucleic acid based drugs broadening their application in a wide range of disease areas.

This report was compiled by Sixfold Bioscience Ltd, a drug delivery company based in London, UK. Content is subject to copyright and should not be reproduced without permission. We thank visiting Imperial College London students students, Julia Dabrowska and James Korossy, for their input.

Methods

Data was collected in April 2020 by searching the following terms in https://clinicaltrials.gov/: ‘siRNA’, ‘short interfering RNA’, ‘small interfering RNA’, ‘RNAi’ and ‘RNA interference’. All interventional studies, except the withdrawn trials, were recorded into a database. Data collection methods for figures refer to siRNA clinical trials, wherein a drug present in multiple trial phases or currently in trials for various indications, is counted multiple times, once per individual trial. Where figures refer to siRNA therapeutics, a drug present in multiple phases or multiple indications is counted once.

References

1. https://www.nature.com/articles/33 02356
2. https://investors.alnylam.com/pres s-release?id=22946
3. https://investors.alnylam.com/pres s-release?id=24281
4. https://www.ncbi.nlm.nih.gov/pubm ed/27352638