5 Trends affecting gene therapy development

This feature is part of a series focused on gene therapy. To view other posts in the series, check out the spotlight page.

The premise — and often bragging point — of gene therapies is the idea that they are one-off cures. Rather than having patients take continuous doses of medicine their whole lives, gene therapy providers can just go in, insert, cut or replace the defective DNA that causes disease in the first place, and voila! Problem solved.

Theory, however, is much different than reality. Incredibly complex science, uncharted regulatory waters and battles over who thought of innovations first have impeded the drug class from breaking into most markets. UniQure's Glybera (alipogene tiparvovec) was the first gene therapy to ever get the go-ahead to market by regulators when the European Medicines Agency approved it back in 2012.

But the product's $1 million-plus price tag coupled with the small population of lipoprotein lipase deficiency patients it aimed to treat ultimately led to its demise. In April, UniQure decided not to seek reauthorization for the drug in Europe, the only market to give it the thumbs up.

Glybera's development and rollout offered other drugmakers a glimpse of the hurdles such treatments must clear if they stand any chance of helping patients and delivering return on investment. Yet with the gene therapy space still maturing, pharmas and biotechs are investigating the best routes to take for their would-be disruptive products. Here are five trends affecting those decisions:

1. Gene editing takes center stage

Compared to other drug classes, gene therapies haven’t been around for very long. A primary reason for their infancy has been a lacking understanding of DNA and the ways it can be altered. After all, it wasn’t until 2003 that researchers completed the Human Genome Project and gained access to mankind’s genetic map.

However, as is characteristic of medicine making, what was fresh just a few years ago is already becoming old news. Whereas early therapies focused on turning a gene on or off or simply (though it’s far from that simple) inserting sequences into genetic code, more modern drugs are looking to actually edit DNA, thereby providing a more precise cutting and pasting tool. The CRISPR/Cas9 gene editing system is one such tool garnering widespread attention.

Cells engineered using CRISPR/Cas9 entered into humans for the first time last year, and more clinical studies are on the horizon. Many have heralded the system as a breakthrough for disease treatment, while many others have called out the permanent damage it can do to patients if the wrong section of DNA is spliced.

Investors, meanwhile, have teetered back and forth between the two wavelengths. Editas Medicine, which only has drugs in the discovery phase, raised more than $94 million at the beginning of 2016 through an initial public offering. Priced at $16 per share, the company’s stock rose over its first few months on the market, reaching over $37 apiece at one point, before sliding way down over the last year. Stock is now trading at about $14 per share. Similar trends can be seen among other CRISPR/Cas9-centered biotechs, including Intellia Therapeutics and CRISPR Therapeutics. Those heavy initial investments, however, still evoke the industry's appetite for these potentially revolutionary treatments.

2. Patent protection

As with any area ripe for drug development, pharmaceutical companies have been eager to get in on the ground floor and stake their claim in gene therapies.

Historically, patents have been a useful weapon to that end, and the gene therapy space is seeing its fair share of intellectual property battles. Here again, the CRISPR/Cas9 system is generating a lot of buzz. The University of California is in the throes of patent litigation with Broad Institute of MIT and Harvard, and each side has the backing of different biotechs that respectively license the schools' technology.

But the problem extends beyond CRISPR. Silence Therapeutics, for instance, announced last month expansions to patents covering its chemical modification technology, which is used for the development of small interfering RNA treatments. Under current Food and Drug Administration guidelines, patents are initially given a 20-year lifespan, though companies can employ various tactics and legal maneuvers to extend that exclusivity.

"Twenty years is not an answer," Silence CEO Ali Mortazavi said in an interview. "And for patent protection in novel therapeutics it should be longer, because it's take us fourteen years to basically be able to say we have a really viable technology that says what it does on the tin, and then we have to get in the game of clinical trials and biological risk."

3. How much do we charge?

The current relationships between drugmakers, payers and insurers rest largely on the tradition that patients will need multiple trips to the doctor and potentially a lifetime of doses of a medicine in order to manage their illness. Gene therapies are poised to shift that paradigm, leaving healthcare stakeholders wondering what a new pricing system would look like.

"You imagine customers that stay with you and patients that keep taking your medicine. This year, next year, you have a constant revenue stream," Sangamo Therapeutics CEO Sandy Macrae told BioPharma Dive. "How do you balance with a payer a one-time payment that is sufficiently reflective of the costs you're going to save and the benefit you're going to give the patient against a bill that is spread over their life?"

That discussion has yet to be fully hashed out, according to Macrae.

The good news across the healthcare spectrum is there's time to iron out the details. The tricky part is that it might not be much time. Spark Therapeutics finished a rolling Biologics Licensing Application for its vision loss drug voretigene neparvovec in May. Should the FDA accept the filing, a decision on the gene therapy could come in the first half of 2018.

"Nobody fully knows what the right price for a gene therapy is, but I think we're a little bit far away from having the debate, because I just don't think the safety and technology is there to realistically have it. That's another sort of after-dinner discussion," Mortazavi said.

4. Partnerships helping drug development

Big pharmas have long turned to tiny biotechs as a means of gaining expertise in niche and complicated therapeutics areas. Amid the alarms that gene therapies may revolutionize disease management — and, in turn, threaten traditional sources of income — large drugmakers are flashing their cash and experience to bring the relatively few players in the sector to the table.

Sangamo's pipeline is evidence of this trend. The Richmond, CA-based company is partnered with Pfizer, Bioverativ and Shire on various candidates. Intellia has inked deals with Regeneron and Novartis, while Merck, Sanofi and The Medicine's Co. have partnered with Alnylam, a biotech developing RNA interference treatments.

With no gene therapies on U.S. pharmacy shelves and few available elsewhere, it's hard to imagine dealmaking slows down anytime soon. While the potential return on investment for these medicines is alluring, pharmaceutical companies are surely even more interested in carving out a spot for themselves in an expected-to-be disruptive market. That's easier done with two pairs of hands. 

5. Ethical implications

Underlying all the pricing, patent and therapeutic decisions of gene therapy development is a difficult question: is this ethical? While that question has come up in drug making before, it has become particularly integral for products aiming to alter the very blueprint of humanity.

In response, many executives, researchers and healthcare providers are pushing for more dialogue about the ethical implications of gene therapy. Whether that dialogue centers on more theorized topics like designer babies, or one that hits closer to home, such as figuring out the best ways to inform parents about the risks of administering treatment to their children, in many cases stakeholders haven't reached a firm consensus.

"When I think of editing a gene in a patient, in a child perhaps, they're going to live with that gene for the rest of their life, and we need to be absolutely sure that the benefit-risk is correct, that the disease we're addressing is sufficiently severe, the intervention we're going to make — which will last them for the rest of their days — is the right thing for that patient," Macrae said.

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