siRNA Therapies: The Need For Better Delivery Systems
We compiled a comprehensive dataset on clinical trials involving siRNA therapeutic candidates to investigate where the greatest research activity has focused and where the field needs to improve to ensure siRNA can reach broader patient populations.
Despite a clear increase in clinical activity and maturing pipelines, particularly in therapeutic indications such as liver and eye disorders, one of the key remaining challenges for unlocking the clinical and commercial potential of siRNA therapeutics is their safe and effective delivery to target organs and cells.
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
Figure 1 The number of siRNA clinical trials by phase initiated in the given period between 2004-2020.
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 .
There are currently two FDA-approved siRNA therapies on the market: Alnylam Pharmaceuticals’ patisiran (Onpattro, a lipid nanoparticle formulation)  for the treatment of the polyneuropathy of hereditary transthyretin-mediated amyloidosis in adults, and givosiran (Givlaari, a GalNAc-conjugate formulation)  for the treatment of adults with acute hepatic porphyria.
GalNAc conjugates: A popular delivery modality
Figure 2 siRNA therapeutic delivery systems used in clinical trials, for the period 2004-2020. * NP denotes nanoparticle
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.
Figure 3 Number of candidate siRNA clinical trials (A) and therapies (B) by delivery system active each given year, in the period 2004-2020. * NP denotes nanoparticle. ** “Other” include Polymeric NPs, Dynamic Polyconjugates, Cholesterol conjugates and transfected cells.
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).
Figure 4 Target organs of the three major delivery systems for siRNA therapeutics, by percentage of clinical trials in the period 2004-2020.
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 .
Figure 5 siRNA clinical trials by therapeutic area and phase, in the period 2004-2020.
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.
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.
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, Julia Dabrowska and James Korossy, for their input.