Mapping the RNA therapeutics R&D landscape in 2022

Over the last few years, the success of Covid-19 mRNA vaccines has reinvigorated not just big pharma’s interest in RNA research, but also seem to have widened the scope of RNA therapeutics and vaccines. The Pfizer-BioNTech deal was one of the most consequential ones in 2020 to show big pharma’s appetite to harness RNA research through collaborations. Researchers say this has impacted not just companies with clinical stage-products, but also individual academic labs, which will now likely result in more RNA-focused projects in the next few years.

There are less than a dozen FDA-approved RNA therapeutics, the bulk of which are antisense oligonucleotides (ASO) and small interfering RNA (siRNA) candidates for genetic disorders. A look at the planned studies in 2022, as per GlobalData, however indicate a broader landscape of RNA-focused vaccines and therapeutics that look at oncology, ophthalmology, and infectious diseases.

Given the success of the Covid-19 vaccines, a number of these planned studies deal with the authorized candidates in different settings, or newer mRNA vaccines for other infectious diseases like influenza, RSV and malaria. In 2022, several new candidates will enter the clinic for the first time, but a few oligonucleotide therapies like Ionis Pharmaceuticals' vupanorsen sodium and Novartis’s Leqvio (inclisiran) will be studied in larger Phase III studies for metabolic disorders. Vupanorsen sodium is an ASO, or a single-stranded oligonucleotide complementary to its mRNA target which inhibits its translation. Leqvio’s RNA interference approach via double-stranded siRNA, on the other hand, induces gene silencing of the target mRNA by the partial or complete base paring.

While relatively early in the research pipeline, the resurgence in RNA exploration, coupled with advances in big data analysis, which is one of the key innovations set to transform drug development in 2022, has led to a growing interest in researching noncoding RNA targets in oncology, fibrosis and neurological disorders. Individual firms are further developing unique platforms to address delivery challenges that have plagued investigational candidates in the past, creating a diverse field of candidates using approaches like tRNA and oligomer conjugated antibodies.

Here we look at the key trends expected to influence RNA and genomic research in 2022 and the near future, gleaned from a GlobalData analysis, and leading researchers in the field.

Since it does not translate into a protein, noncoding RNA was often called "junk DNA". However, greater access to sequencing data from tumor biopsies, combined with big data and improved bioinformatic approaches, is giving researchers a chance to look at long noncoding RNA which would not have been possible even five years ago, Merkel says. The development of ASOs and CRISPR-Cas9, which allows you to manipulate the mammalian genome, has given insight into the functions of noncoding RNA, says Mark Kay, RNA researcher at Stanford University.

“What’s exciting is that there is a vast universe of unexplored molecules, that could be involved in diseases,” says Sarah Diermeier, Rutherford Discovery fellow at the University of Otago in New Zealand. She points to one such example of ION582, that is being developed for Angelman’s syndrome by Ionis's, which developed Spinraza (nusinersen), the first FDA-approved treatment for spinal muscular atrophy (SMA) currently marketed by Biogen. In Angelman’s syndrome, patients carry at least one copy of paternal UBE3A that is silenced by a long noncoding RNA. The ASO ION582 is targeting this long noncoding RNA to reactivate expression of a gene that would have been otherwise silenced, Dermeier explains. A trial to study ION582 is listed on the ClinicalTrials.gov registry but has not started yet.

Diermeier’s own work is focused on noncoding RNA in oncology from which a candidate could enter the clinic in the next two years. Even if an ASO or siRNA against this noncoding RNA target is delivered systemically, it will only be active in the tumor, hopefully with less toxicity as well, she adds.

Noncoding RNA appears to play important roles in gene regulation, but since its expression levels are lower, we will need better technology to exploit it. Kay notes that one challenge which remains is that since the sequences are not conserved between the species, there aren’t enough animal models for each disease indication.

Using ASOs and siRNAs is a logical way of studying a particular disease if the target sequence is already identified, but the best way to target the said sequence may involve other modalities. Kay, whose group has worked on another class called transfer RNA (tRNA)-derived small RNA, says it could regulate ribosomal biogenesis that is important in malignant states and be used in cancer therapeutic research. Any scenario where cells are overgrown, whether in oncology or autoimmune disorders, could have potential for tRNA-related approaches, Kay says.

Another emerging area involves circular RNAs, a subclass of noncoding RNAs. The advantage with using circular RNA is they can last longer and won’t be degraded as quickly as mRNA, Kay says. Early-stage companies like Laronde and Orna Therapeutics raised significant sums this year to advance their circular RNA candidates which are currently in the discovery stage.

Other companies are using antibodies, that attach to the target receptor, which are attached to the ASO, and Kay says this approach has shown promising early results. Dyne Therapeutics filed an IND earlier this month to study DYNE-251 which consists of an antibody conjugated to oligomer that will promote the skipping of specific Duchenne muscular dystrophy exons in the nucleus.

Intellia Therapeutics, which announced its Phase I data with NTLA-2001 to treat ATTR Amyloidosis a few months ago in collaboration with Regeneron Pharmaceuticals, uses an approach that is of interest in the field—it is a CRISPR/Cas9-based candidate administered systemically to inactivate the TTR gene in liver cells. The therapy relies on a guide RNA specific to the disease-causing gene, another emerging approach, and mRNA which encodes the Cas9 enzyme to conduct the precision editing. Intellia’s approach for ATTR amyloidosis may even compete with the siRNA one because it’s dosing schedule is less frequent than the latter, Kay says.

The biggest hurdle with RNA therapeutics is still facilitating delivery beyond the first-pass effect of the liver, Merkel says. Rare genetic disorders were the logical starting point for new drug modalities, says Diermeier, and now that proof of concept is established there is more of an interest in other fields.

Among the announced studies with RNA therapeutics for 2022 that venture into relatively new indications, there is Olix Pharmaceuticals’ androgenic asymetric siRNA for male pattern baldness, Lemonex’s LEM-S401 for addressing scars and Arrowhead Pharmaceuticals’ RNAi AROC-3 for the kidney disorder IgA nephropathy. Within oncology, there is a lot of interest in resensitizing tumors for chemotherapy or immune therapy, Merkel says.

Alnylam Pharmaceuticals’ Onpattro (patisiran), an siRNA LNP formulation to treat polyneuropathy of hereditary transthyretin-mediated amyloidosis approved in 2018, paved the way for Covid-19 mRNA vaccines, because the LNP formulation is not that different, Merkel says. “Being able to produce these nanoparticles in a reproducible way and loading them with not just short RNA but also long sequences is a significant advance,” she adds. However, LNPs can stimulate the immune system vigorously, which is favorable for vaccines, but not for Huntington’s or SMA, says Matthew Wood, a neuroscience professor at University of Oxford.

Even though intranasal delivery has been explored with infectious diseases, that did not allow enough dose to be delivered to the lungs, Merkel whose own lab at Ludwig-Maximilians-Universität München studies siRNA therapies. A single RNA sequence may be inadequate to overcome any concerns about escape mutations, she says.

Earlier this year, unsuccessful trials with candidates for Huntington’s disease from the Swiss pharma giant Roche, and Cambridge, Massachusetts-based Wave Life Sciences showed that this can be challenging. While RNA therapies for young individuals with SMA have been successful, solving the delivery challenge in adults where the drug may have to reach certain difficult areas of the brain is more challenging, Wood says.

Nonetheless, Wood says Wave’s recently initiated Phase II trial with WVE-003 does look promising and should have some preliminary results in 2022. WVE-003, delivered intrathecally or into the spinal canal, is an ASO that targets the disease allele in Huntington’s disease.

Still, translating technologies from an mRNA vaccine to an mRNA therapeutic is not straightforward. Vaccines are typically active for days, a much shorter timeframe than therapeutics, says Wood, who is also developing a natural type of nanoparticle to package mRNA or ASOs which would theoretically be safer. Overall, Merkel cautions against assigning too much hype to the rapid developments in this space without understanding the significant delivery challenges that remain.

Nonetheless, Diermeier says “the idea that you can use RNA as a drug is now on the forefront of everyone’s mind.”