A rare opportunity: aTyr Pharma and orphan drugs

In the US, a rare or orphan disease is defined as a condition that affects fewer than 200,000 Americans. Europe recognises rare diseases as those that affect fewer than one per 2,000 people. While there is no standard for what defines a rare disease, it is agreed that they are often genetic, and usually life-threatening.

An estimated 6,000 to 8,000 rare diseases, including Huntington’s disease, Crohn’s disease and Duchenne muscular dystrophy, affect 25 million people in the US, and 29 million in the EU.

For many years, patients with rare diseases struggled to get access to treatments, as drug companies could rarely profit from developing drugs for such small populations.

The US Orphan Drugs Act of 1983 aimed to change this, providing pharmaceutical companies an incentive to create drugs for the treatment of rare diseases, or orphan drugs, by providing tax credits and increased IP protection.

Even unpatented drugs are protected under the act, which states that once a drug has been designated for a rare disease or condition, no other applications to treat the same condition may be approved for seven years.

The EU introduced a similar directive in 2000. The Orphan Drug Regulation allowed orphan drugs marketing exclusivity for 10 years, regardless of whether or not they have been patented.

San Diego-based aTyr Pharma develops novel drugs for the treatment of rare inflammatory and autoimmune diseases, conditions where the immune system has been disordered or is out of balance, either because of genetic reasons or environmental factors.

Although support for research into these diseases is increasing, and IP protection for their treatments has been enhanced, does aTyr face any challenges when it comes to making its work commercially viable?

“We’ve had very clear support from investors and indications of interest from partners on our approach to the treatment of rare diseases,” says John Mendlein, PhD, executive chairman and CEO of aTyr.

“There’s limited value in biological discovery, or novel targets, but there’s a great deal of value in first-in-class drugs that address an unmet medical need.”

“Some rare diseases are more exaggerated, grave examples of how the immune system went awry,” he says. “If you can treat the more aggressive examples, you may be able to treat some of the other immune-related diseases as well. We think it’s better for patients to go after the more severe cases first,” he explains.

aTyr works with physiocrines, fragments of the tRNA synthetase family of enzymes, to create treatments for rare inflammatory and autoimmune diseases.

tRNA synthetases evolved in organisms before the immune system for the purpose of tissue recovery. Their role in protein synthesis had been known for decades, and they were overlooked as “housekeeping” enzymes until Paul Schimmel of the Scripps Research Institute in California discovered they create small protein molecules, eventually named physiocrines, which are involved in immune response and tissue recovery.

aTyr is working on therapies based on physiocrines to treat immune system disorders, including inflammation and disordered immunity. The company has mapped a total of 200 physiocrines and is currently looking for their possible associations with diseases.

Mendlein explains that patients with autoimmune diseases currently only have steroids and other immunosuppressants available as treatments, though aTyr offers an alternative, which may have less of an adverse reaction on the body.

“One of the advantages of our drug is that it is a naturally occurring protein that can be used to treat the patient,” he says.

“The body has evolved these proteins to be tailor-made to promote tissue recovery, and therefore they are potentially more efficacious than the drugs out there.”

These are new pathways in the treatment of genetic diseases, Mendlein explains, which may put aTyr in a more competitive position, and can inform work for other companies.

“Currently we’re the only company that I’m aware of that’s working on these pathways,” he says.

Mendlein was involved in creating a partnership between biotech Aurora Biosciences (now part of Vertex Pharmaceuticals), and the Cystic Fibrosis Foundation, an enterprise that contributed to the development of Vertex’s Kalydeco, the first drug to treat both cystic fibrosis and its underlying cause.

As he no doubt understands the workings of a successful partnership, would he consider licensing aTyr’s patents to other companies?

“The strongest, most valuable IP comes from developing a therapy or drug, which can then be sold at some commercial value.”

It’s not part of the company strategy at the moment, he says, though it may become necessary in future. “IP becomes important because eventually you need to have a marketed product, and whether it’s by investors or potential partners of the company itself we want to be able to protect those products with composition of matter claims.

“We’ve already successfully completed two different patent campaigns to the point of issuing claims in the US for composition of matter patent on the proteins,” Mendlein says.

aTyr has 250 filed patent applications in total, with 205 pending. All of aTyr’s patents are related to physiocrines.

“100 percent of our efforts are focused on physiocrine technology and therapeutic application of that biology,” Mendlein says. He adds that part of aTyr’s strategy is to have positions on antibodies to some of the physiocrines also, which have different applications.

“I think that investments are related to the strength and breadth of your patents,” he says. Although it is a novel area of research, does aTyr ever encounter imitators in its work?

“Part of the reason we have a robust patent portfolio is that we have a unique opportunity to own an entire space of biology that really hasn’t happened since the 1990s,” he says.

“These are all brand new composition of matter patents for an entire family that wasn’t discovered until the human DNA sequencing effort.”

He says that while aTyr does not face any IP challenges that are unique to the company, protecting IP against companies with very large IP portfolios, like RNAi therapeutics company Alnylam, is costly.

“A significant amount of your budget goes towards prosecuting and defending IP,” he says.

As well as patents and the physiocrine trademark, aTyr has trade secrets in its IP portfolio that cover many different aspects of the company business model, including the databases it manages related to the activity of physiocrines. aTyr collects information on every single one of the proteins it isolates, which Mendlein is confident no other entities have in the public domain.

aTyr does not yet have any drugs on the market, though Mendlein expects it will start its first round of clinical trials next year.

“In 10 years time we’ll be selling multiple drugs at different patient populations, and we’ll have a full integrated capability going from discovery to patient care,” he says.