How Best to Describe Precision Medicine Beyond Oncology? ‘It’s Complicated.’

As a notable example, he pointed to the December 2017 Food and Drug Administration approval of Spark Therapeutics’ gene therapy Luxturna (voretigene neparvovec-rzyl), for biallelic RPE65 mutation-associated retinal dystrophy. The potential of Spark’s precision gene therapy pipeline is such that Swiss drugmaker Roche announced plans to acquire Philadelphia-based Spark for $4.8 billion in February.

Gene therapies for other retinal diseases are in the works as well, Straatsma noted. Spark, for example, has a gene therapy in Phase I/II development for choroideremia, as well as one in discovery-stage development for Stargardt disease – both diseases are inherited eye disorders. Another company, Nightstar Therapeutics, has gene therapies for choroideremia and X-linked retinitis pigmentosa. Biogen spent about $800 million to complete the acquisitionof Nightstar in June. 

While cancers and inherited eye diseases couldn’t be more different from each other, there is one shared commonality that makes them particularly amenable to precision medicine: the prominent role specific mutations play in both diseases. That is key to understanding where precision medicine bears the lowest-hanging fruit and where a tall ladder may be required.

“Most likely, in monogenic diseases, the precision medicine approach is poised to work remarkably well,” said Dr. Tudor Oprea, professor of medicine at the University of New Mexico, in a phone interview. Monogenic means diseases driven by a single defective gene. “There are clear therapeutic approaches that are currently available, and I would dare say that’s as close to precision medicine as you’re going to get.”

One example Oprea cited was the SMN1 gene in spinal muscular atrophy. Last month, the FDA approved Novartis’ Zolgensma (onasemnogene abeparvovec-xioi), a gene therapy that delivers a functional copy of the SMN1 gene.

But what about diseases in which there is more than just a genetic mutation at play? In those cases, it’s not so simple.

“When it comes to complex, multifactorial diseases where things like diet, microbiome and environment play a role, precision medicine has a long way to go,” he said.

Part of Oprea’s work has focused on the “dark genome,” a term referring to understudied proteins. In this month’s issue of the journal Mammalian Genome, he published a paper on it and its implications for precision medicine, an abstract of which points to several dark genes: LRRC10, which has a role in dilated cardiomyopathy; HSF2BP, in coronary artery disease; and ELFN1, in attention-deficit hyperactivity disorder. But the ability to drug these mutations in the context of precision medicine is on the far horizon, Oprea said.

Pulmonology is another good example of where precision medicine is not very straightforward. On the one hand, Chupp noted, there are diseases like cystic fibrosis, which has specific mutations and is treatable with drugs like Vertex Pharmaceuticals’ Kalydeco (ivacaftor). But in general lung diseases are complex, inflammatory diseases caused by multiple genetic and environmental abnormalities. “So having real precision is difficult to do,” Chupp said.

But that doesn’t mean there aren’t efforts underway – for example in asthma, pulmonary fibrosis and pulmonary vascular disease. Precision medicine’s foray into emphysema is lagging, however, according to Chupp. The reason for emphysema being a laggard is that it’s a smoking-related disease where there’s a lot of structural damage. This makes it hard to find specific therapies other than the traditional inhalers that prevent disease progression, and emphysema remains difficult to subtype from an immunological standpoint.

Chupp and another colleague published a paper in this month’s issue of the Journal of Allergy and Clinical Immunology that looked at different phenotypes and endotypes of adult asthma. These included early-onset allergic asthma; early-onset allergic moderate-to-severe remodeled asthma; late-onset nonallergic eosinophilic asthma; and late-onset nonallergic noneosinophilic asthma. But more needs to be done in lung diseases, he said, pointing to two things that need to happen.

“One is, we need to go back and mine existing data sets that exist that have been generated by publicly funded studies through the National Institutes of Health and other countries in Europe, where they have large cohorts of patients there’s a huge amount of clinical and genetic data,” he said. “The second thing is that large, population-based studies need to be conducted that are even larger than what we’ve done and that are more collaborative on a population scale than they’ve been in the past.”

Chupp compared the current state of this research to what the NIH’s National Cancer Institute has done. If a patient has prostate cancer, for example, he can find a clinical trial right there.

“We don’t have that in chronic lung diseases,” he said. “It will take a seismic shift in how we operate beyond cancer, but I think there needs to be a national clinical trial or disease institute.”

Another challenge is scalability, said Catherine Brownstein, a researcher at Harvard University’s Boston Children’s Hospital, who specializes in rare and orphan diseases, including in psychiatric diseases. Even when genetic testing is done, the results are not always properly taken into account.

“The sheer number of times we’ve seen a medication being given to a family that causes an adverse event, and the testing had been done, but it was buried so they couldn’t act on the testing – it’s really frustrating,” Brownstein said in a phone interview.

Whereas precision medicine’s progress in non-oncology realm has certain challenges specific to those diseases, there is one common challenge: reimbursement.

“The key challenge in any health system for actual implementation in the clinic is reimbursement,” said Aurelie Deleforge, a consultant with New York-based Bionest Partners, in a phone interview. “Payers historically didn’t have diagnostics on their radar because the ones they used were very cheap – for example $30 for an immunohistochemistry test. But now it’s something in the range of $1,000 for NGS.”

Bionest Managing Director Rachel Laing echoed Deleforge’s remarks. “There will be more questions of how to deal with things like companion diagnostics, pricing and how to ensure access,” she said in the same interview.

Another challenge in the advancement of precision medicine is sheer human knowledge.

“When it comes to things like [central nervous system] and other therapeutic areas, there’s still a lot we don’t know behind disease progression and what is driving the disease,” said Rachel Laing, a consultant with consultancy Bionest Partners, in a phone interview.”

The final challenge may be money. In oncology,investment has followed science. As an indication, oncology accounts for the vast majority of investment and exits in healthcare, Silicon Valley Bank Managing Director Jon Norris wrote in an email. In diagnostics and related tools – the area most relevant to precision medicine – oncology also remains prevalent. Three of the four initial public offerings of diagnostics and tools companies in the last nine months were of companies for which oncology was an area of focus: Guardant Health, Personalis and Adaptive Biotechnologies.

“Money talks,” Norris wrote. “The markets are large and most of the time the course of therapy and reimbursement concerns are settled. This makes it a fertile area for venture investment.”

Photo: Donald Miralle, Getty Images