Hours after Alex Ovechkin became the first NHL player to score 800 goals with one team, Avidity Biosciences (RNA) announced an industry first of its own.
The precommercial drug developer delivered positive results in a phase 1 clinical trial evaluating AOC-1001 in myotonic dystrophy type 1 (DM1). The drug candidate utilizes RNA interference (RNAi) to treat the rare muscular disease at the genetic level. Importantly, it was the first time an RNAi drug candidate had been successfully delivered to muscle tissue.
If the delivery achievement 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 investors may not want to get too excited just yet.
Pizza Chains Aren't the Only Ones Struggling with Delivery
Decades before CRISPR gene editing emerged onto the scene, RNAi won the 2006 Nobel Prize in Physiology or Medicine for the potential to treat various diseases at the genetic level. It took another decade to score the first FDA approval, but the pace is accelerating. Over one dozen drug products based on the technology should reach market in the next several years.
In fact, RNAi medicines have the least development risk in the industry. Whereas 7.9% of drug candidates entering a phase 1 clinical trial eventually reach market, that number is a whopping 60% for RNAi drugs targeting the liver. It's not even close.
Astute readers will note the "targeting the liver" qualifier. Genetic medicines spanning RNAi, gene therapy, and gene editing are overwhelmingly directed at the liver. It makes sense for two reasons.
- First, the liver is an important organ for health and disease. Many genetic diseases are caused by mutated genes primarily expressed in the liver.
- Second, scientists have developed very accurate tools for shuttling molecules administered through intravenous infusion or subcutaneous injection (collectively referred to as "systemic administration") into the liver. That's thanks in large part to the breakthroughs spurred by failures in the early days of RNAi development.
Delivery is one of the most important factors determining success in genetic medicines. If a disease is caused by a mutated gene expressed in the brain, heart, or lungs; then the therapeutic intervention also needs to primarily end up in that specific tissue. At best, off-target delivery will lead to ineffective treatment. At worst, it could lead to deadly side effects.
The key to effective delivery in RNAi is a molecule called a ligand. Think of a ligand like a key – and one that only fits the lock to certain receptors on the surface of certain cells. RNAi targeting the liver is money in the bank thanks to a ligand called GalNAc, which is a sugar that primarily fits into asialoglycoprotein receptors dotting the surface of certain liver cells. Attach GalNAc to the end of an RNAi payload and it'll definitely end up in the liver.
A Strong Development for Muscle Diseases
Avidity Biosciences has taken a unique approach to delivery outside the liver. Rather than use simple compounds such as GalNAc as ligands, the company develops monoclonal antibodies for the same function. If it develops an antibody that targets muscle cells, then it should be able to direct systemically administered RNAi payloads to muscle cells. These drug candidates are called antibody oligonucleotide conjugates (AOCs).
The company announced promising preliminary results for AOC-1001 in a phase 1 clinical trial for the rare muscular disease DM1. The disease is caused when a protein called DMPK bunches up onto itself, which leads to painful muscle contractions that cannot be voluntarily released by patients. It also affects the entire body, including the heart and brain, and often results in heart failure.
Patients in the mid-dose cohort achieved meaningful reductions in DMPK protein. Importantly, AOC-1001 led to improvements in other proteins that are often negatively impacted by misfolded DMPK. It was too early to gauge changes in myotonia, or involuntary muscle contractions, which is likely to become a key endpoint for regulators.
Despite the early promise and large increase in the share price, AOCs may not be worth the risk.
The Downside of Antibodies for Targeting
Although using antibodies for ligands makes early-stage development work easier, it makes long-term development riskier. Antibodies are large molecules, which can make them difficult to deliver into cells. They're also more active at the molecular level, which can lead to side effects unrelated to the RNAi payload. Simpler molecules such as GalNAc are more difficult to develop as ligands, but have squeaky clean safety profiles.
Indeed, Avidity Biosciences is still working to remove a clinical hold on AOC-1001. The FDA forbade the company from enrolling additional patients due to a single serious adverse event in an individual receiving a high dose of the experimental treatment. Investors don't have more details at this time.
Most other RNAi drug developers have sworn off antibody conjugates because of the complexity and risks involved. These notably include the three most advanced and longest-tenured companies, Alnylam Pharmaceuticals (ALNY) , Arrowhead Pharmaceuticals (ARWR) , and Dicerna Pharmaceuticals (acquired by Novo Nordisk (NVO)). Therefore, despite the excitement around this industry first for RNAi, investors should be cautious with Avidity Biosciences until more mature data are available.
