Most drug developers toil away for years and never earn approval for an experimental treatment. Alnylam Pharmaceuticals (ALNY) isn't one of them.
The genetic medicine pioneer recently earned its fifth drug approval since 2018. While the company struggled to tame its technology platform early on, it now enjoys the highest probability of success of any drug developer on the planet. The average drug candidate entering a phase 1 clinical trial has an 8% chance of earning approval. For Alnylam, it's over 60%.
The latest approval is for Amvuttra (vutrisiran). The product will launch in July as a treatment for hereditary transthyretin (hATTR) amyloidosis, a rare genetic disease characterized by scarring in multiple organs. Amvuttra represents a more convenient treatment than the current standard of care Onpattro, which is also owned by Alnylam. It also shakes up the commercial landscape for drug developers including Ionis Pharmaceuticals (IONS) and Crispr pioneer Intellia Therapeutics (NTLA).
A New Standard of Care
As a rare genetic disease, it makes sense to treat hATTR amyloidosis at the genetic level. That's exactly what Onpattro, Amvuttra, and several other experimental treatments in the industry pipeline aim to do.
The disease is caused by mutations in the transthyretin (TTR) gene that change the shape of the TTR protein. These misfolded proteins clump together in molecular logjams, building up on the surfaces of the heart, kidneys, and other organs. Nerdy scientists refer to these build ups as amyloid plaques or fibrosis, but the important takeaway is these misfolded proteins make organs work less efficiently.
Alnylam Pharmaceuticals is a pioneer in RNA interference (RNAi), which can be used to destroy molecular instructions for creating proteins. This is known as gene silencing. Both Onpattro and Amvuttra are based on RNAi tools that reduce the body's ability to produce mutated TTR proteins. Clinical studies and long-term follow-ups show hATTR can be effectively treated – and even reversed in many patients – by silencing the TTR gene. The precision of genetic medicines means both treatments are relatively safe, too.
Why develop two drugs for the same disease? Onpattro is based on first-generation tools, whereas Amvuttra is based on second-generation tools. The difference is obvious when investors consider patient convenience.
- Onpattro is administered once every three weeks through an intravenous (IV) infusion.
- Amvuttra is administered once every three months through a subcutaneous injection.
The ability to provide subcutaneous administration significantly increases patient convenience and expands the geographic availability of treatments. That's especially true considering developing countries don't always have the medical infrastructure needed to provide infusions.
Alnylam Pharmaceuticals is currently exploring the possibility of dosing patients with Amvuttra once every six months after an initial ramping phase. Once data are in hand, the company could request updated labeling from the U.S. Food and Drug Administration (FDA). The drug developer is also developing a third-generation RNAi drug candidate for hATTR amyloidosis that may only require a subcutaneous shot once a year.
The one-two punch gives the company a dominant position in the commercial landscape. Onpattro generated $475 million in full-year 2021 revenue, while analysts expect Amvuttra to reach $1.8 billion in annual sales by 2026.
Of course, creating multi-billion-dollar markets also invites competition.
Can Amvuttra Be Dislodged?
Ionis Pharmaceuticals and AstraZeneca (AZN) are developing a competing genetic medicine, eplontersen, administered via subcutaneous injection to treat hATTR. The drug candidate met multiple primary and secondary endpoints in an ongoing phase 3 clinical trial, although the companies didn't provide hard numbers. That makes it impossible to compare to Amvuttra.
Similar to Alnylam Pharmaceuticals, Ionis Pharmaceuticals earned approval for a prior-generation treatment branded as Tegsedi. However, it generated less than $55 million in full-year 2021 sales as Onpattro continued to steal market share. The arrival of Amvuttra is likely to further erode Tegsedi's commercial position.
Things get a little more interesting when investors consider Intellia Therapeutics. The Crispr pioneer is developing NTLA-2001 as a treatment for hATTR amyloidosis. The gene-silencing drug candidate has impressed in an ongoing phase 1 clinical trial. Although the Crispr gene editing therapy must be administered with an IV infusion, patients may only need to receive a single treatment.
It doesn't get more convenient than a one-and-done treatment. However, the decision may not be so simple for patients and doctors. Individuals with hATTR amyloidosis see their doctor multiple times per year, which means receiving a subcutaneous shot once every three or six months isn't necessarily inconvenient. At some point, a treatment is convenient enough. Additionally, there are questions over the precision of first-generation Crispr gene editing and whether the approach increases long-term cancer risks.
Making matters more complicated, any of the drug candidates in the industry pipeline or drug products already approved could still emerge as the long-term winner. The initial focus on hATTR amyloidosis is dwarfed by the commercial opportunity for non-hereditary forms of ATTR diseases, which means individuals randomly acquired the mutations after birth. Every drug developer plans to evaluate the potential of their pipeline assets to treat more common ATTR disease. In fact, multiple studies are already underway.
What should investors do? The most concise advice is this: Focus on outcomes, not technologies. The FDA won't be handing out style points for CRISPR gene editing or other therapeutic modalities. All that will matter is efficacy and safety. Thanks to Amvuttra, that bar has been set pretty high for everyone that follows.
