Hours after Alex Ovechkin became the first NHL player to score 800 goals with a single team, Avidity Biosciences (RNA) – Get a free report announced a first in its industry.
The pre-commercial drug developer has provided positive results in a Phase 1 clinical trial evaluating AOC-1001 in myotonic dystrophy type 1 (DM1). The drug candidate uses RNA interference (RNAi) to treat rare muscle disease at the genetic level. Importantly, this was the first time an RNAi drug candidate was successfully delivered into muscle tissue.
If achieving delivery can be replicated across the pipeline, then Avidity Biosciences could be one of the first companies to use highly effective RNAi drugs to treat a range of muscle diseases. However, the specific details of the achievement suggest that investors may not want to get too excited just yet.
Pizza chains aren’t the only ones struggling with delivery
Decades before the emergence of CRISPR gene editing, RNAi won the 2006 Nobel Prize in Physiology or Medicine for its potential to treat various diseases at the genetic level. It took another decade to get the first FDA approval, but the pace is picking up. More than a dozen drugs based on this technology are expected to hit the market over the next few years.
In fact, RNAi drugs have the least risk of development in the industry. While 7.9% of drug candidates entering a phase 1 clinical trial eventually reach the market, this number rises to 60% for RNAi drugs targeting the liver. It’s not even close.
Savvy readers will note the “liver-targeting” qualifier. Gene drugs spanning RNAi, gene therapy, and gene editing are overwhelmingly directed to the liver. This makes sense for two reasons.
- First, the liver is an important organ for health and disease. Many genetic diseases are caused by mutated genes expressed primarily in the liver.
- Second, scientists have developed very precise tools to shuttle molecules administered by intravenous infusion or subcutaneous injection (collectively referred to as “systemic delivery”) to the liver. This is largely thanks to breakthroughs spurred by the failures of the early days of RNAi development.
Delivery is one of the most important factors determining the success of genetic drugs. If a disease is caused by a mutated gene expressed in the brain, heart or lungs; then the therapeutic intervention must also end primarily in that specific tissue. At best, off-target delivery will lead to ineffective processing. At worst, it could lead to deadly side effects.
The key to efficient delivery in RNAi is a molecule called a ligand. Think of a ligand as a key – one that only fits the lock of certain receptors on the surface of certain cells. Liver-targeting RNAi is money in the bank thanks to a ligand called GalNAc, which is a sugar that mainly integrates into the asialoglycoprotein receptors that dot the surface of some liver cells. Attach GalNAc to the end of an RNAi payload and it will definitely end up in the liver.
A strong development for muscle diseases
Avidity Biosciences has taken a unique approach to administration outside of the liver. Rather than using simple compounds such as GalNAc as ligands, the company is developing monoclonal antibodies for the same function. If it develops an antibody that targets muscle cells, it should be able to direct systemically delivered RNAi payloads to muscle cells. These drug candidates are called antibody-oligonucleotide conjugates (AOC).
The company announced promising preliminary results for AOC-1001 in a Phase 1 clinical trial for the rare muscle disease DM1. The disease is caused when a protein called DMPK clumps together, causing painful muscle contractions that patients cannot voluntarily release. It also affects the whole body, including the heart and brain, and often leads to heart failure.
Patients in the mid-dose cohort achieved significant reductions in DMPK protein. Importantly, AOC-1001 resulted in improvements in other proteins that are often negatively affected by misfolded DMPK. It was too early to assess changes in myotonia, or involuntary muscle contractions, which are likely to become a key endpoint for regulators.
Despite the early promise and steep rise in share price, AOCs may not be worth the risk.
The downside of antibodies for targeting
Although the use of antibodies for ligands facilitates development work at an early stage, it makes long-term development more risky. Antibodies are large molecules, which can make them difficult to deliver into cells. They are also more active at the molecular level, which can lead to side effects unrelated to RNAi payload. Simpler molecules such as GalNAc are more difficult to develop as ligands, but have impeccable safety profiles.
Indeed, Avidity Biosciences is still working to lift a clinical hold on AOC-1001. The FDA prohibited the company from enrolling additional patients due to a single serious adverse event in an individual receiving a high dose of the investigational treatment. Investors do not have further details at this time.
Most other RNAi drug developers have moved away from antibody conjugates due to the complexity and risk involved. These include the three most advanced and oldest companies, Alnylam Pharmaceuticals (YOU UNDERSTAND) – Get a free report Arrowhead Pharmaceuticals (A HERO) – Get a free report and Dicerna Pharmaceuticals (acquired by Novo Nordisk (NGO) – Get a free report). Therefore, despite the excitement over this industry first RNAi, investors should be cautious with Avidity Biosciences until more mature data becomes available.
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