And now for something completely different.
In a sea of “me-too” drugs built around incremental scientific advances, San Diego, California-based aTyr Pharma is an island of originality. Almost to a fault.
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On Wednesday, the Scripps Research Institute spin-out announced the completion of its foundational patent estate, which now covers “all the waterfront real estate” concerning the use of so-called ‘Physiocrines,’ CEO John Mendlein explained.
Physiocrines are an important class of molecules produced by aminoacyl-tRNA synthetases (AARSs). They come from a gene family believed to date back some 3.6 billion years.
Until recently, research surrounding AARSs focused on their intracellular role in protein synthesis. But in 1999, aTyr’s scientific cofounder Paul Schimmel published work showing that one of these enzymes included an extracellular signaling region.
Over the years, Schimmel and Scripps colleague Xiang-Lei Yang added other AARSs to the list. By 2014, the researchers, the company and a team of collaborators published a paper in Science stating that extracellular signaling and alternative splicing of tRNA Synthetases occurs in all 23 genes from the AARS family.
A Deep-dive Into Specialty Pharma
A specialty drug is a class of prescription medications used to treat complex, chronic or rare medical conditions. Although this classification was originally intended to define the treatment of rare, also termed “orphan” diseases, affecting fewer than 200,000 people in the US, more recently, specialty drugs have emerged as the cornerstone of treatment for chronic and complex diseases such as cancer, autoimmune conditions, diabetes, hepatitis C, and HIV/AIDS.
“People had missed previously that this gene family has an alternate lifestyle,” Mendlein said in a phone interview. “It has a housekeeping function, which is related to protein synthesis. And then it has this other function that we believe is related to a different form of homeostasis, which is extracellular signaling activities.”
Mendlein said the company has evidence to suggest the enzymes interact with both the innate and adaptive immune system. They even talk to T-cells.
“Do you remember from Star Wars that scene ‘these aren’t the droids you’re looking for’?” Mendlein asked. “There were these Imperial stormtroopers and they were looking for R2-D2 and then Obi-Wan Kenobi said ‘these aren’t the droids you’re looking for.’ This protein basically tells T-cells, ‘this is not the tissue you want.’”
It’s the idea of self-tolerance. The immune system doesn’t so much recognize foreign tissue — it learns to recognize self-tissue. By doing so it can usually distinguish between healthy cells and those that threaten the system.
Unfortunately, this immune regulation goes haywire in myriad diseases, ranging from autoimmune conditions such as rheumatoid arthritis to muscle wasting disorders in which the immune system aggravates the underlying disease.
The company’s first therapeutic, Resolaris, is in clinical trials to treat severe myopathies (muscle-wasting diseases) that have an immune component.
Mendlein explained that as muscles break down the immune system begins to contribute to the progression of the disease.
“You have chronic damage and so the immune system resides in the muscle instead of having a transient relationship with it,” he said. “So when that happens, the immune system starts to have a counterproductive response, because now it has set up camp in the muscle, waiting for things to get damaged.”
In the absence of better therapies, patients take steroids to dampen the immune response. Yet steroids have a direct negative effect on the muscles, Mendlein said.
That, incidentally, goes a long way to explaining the industry’s outcry over Marathon Pharmaceuticals’ pricing of its recycled steroid for Duchenne muscular dystrophy at $89,000 per year. It’s a suboptimal therapy.
“Unfortunately, we don’t really know what these patients would look like if they had a properly controlled immune system that didn’t negatively affect their muscle cells.”
Data from a small clinical trial of Resolaris showed 50-78 percent of patients with two rare genetically distinct myopathies had improved muscle strength. And with its nuanced mechanism of action, Mendlein said the wider immune system isn’t suppressed, preventing a host of side effects.
By the end of the year, the company expects to have two more clinical candidates in the pipeline.
What’s not to love about aTyr?
There is some cause for concern, given the recent patent disputes surrounding CRISPR and the potential that the field will be slowed down. aTyr now has a monopoly on an entire field of research.
Mendlein said he is cognizant of the responsibility the company has — in his own colorful way.
“What we want to be able to do is to work in a way that is balanced for all the different stakeholders,” he said. “So one balance is academic research. You still want that to be able to go on. The other balance is what partnerships you can work with. But on the other hand, we’ll be a mama bear or a papa bear if somebody wants to get a bit too much into our knitting and steps into a piece of real estate that we own for the purpose of developing a therapeutic.”
Photo: Tetra Images, Getty Images
