Abstract
Sixteen people with Parkinson's disease showed signs of improvement following a phase 2 trial on AAV2-GAD—one of them an oral surgeon from Michigan who in March, publicly credited the therapy with restoring his ability to move, enabling him to resume playing jazz music and traveling.
Also, at the annual meeting of the American Society of Hematology (ASH) in December 2010, Amit Nathwani, M.D., Ph.D., of the University College in London presented results by his team of researchers after they injected adults with hemophilia B with an adenovirus-associated virus serotype 8 (AAV8) vector containing a self-complementary gene encoding a codon-optimized human FIX gene under control of a liver-specific promoter.
One patient receiving a lower-dose of AAV8 vector had not required factor supplements for 9 months; while one higher-dose patient had not required factor supplements for 68 days. At each dosage, one additional patient achieved no therapeutic response, possibly because of low-titer neutralizing antibodies. The results were promising enough for Molecular Therapy to call the gene therapy a “potential holy grail.” At $30,000 for the intermediate dose, the AAV8 vector could provide substantial cost savings to patients and insurance companies or governments, subject to the additional costs of a clinical trial and economies of scale.
Research and outcomes like these give hope not only to patients, but to doctors who have spent years developing gene therapies for diseases that have not responded as well to traditional therapy. The promise shown by the results also create hope that gene therapy can finally emerge as a vibrant segment, after years in which biopharma companies, physicians, insurers, and government regulators have struggled to develop a sustainable business model.
“Right now, I think we're at the start of a renaissance for gene therapy,” said Vit Vasista, chief financial officer of REGENX BioSciences (Washington, DC). “We are looking at treatments and even potential cures for diseases where there remains serious unmet need. It will be a period of healthy disruption with unique challenges that require real solutions.”
Key among those challenges, Vasista said, is how to develop a business model robust enough to balance the profitability of gene therapy developers with affordability of treatments for patients? That business model, he said, needs to address the fact that some diseases can be reversed via gene therapies through only a single application, while other diseases require multiple applications, as with traditional biopharma drugs.
“You have to have a solution that economically makes sense, from the standpoint of, obviously, people paying for it, but then also enticing a company to want to enter that field. You have to balance those two things,” Vasista said.
“When you think about the one-and-done solution, that's something where the paradigm shift has to occur, where you have to get all relevant parties involved in the solution—the care providers, the regulators, the payers, and certainly the patients,” he added. “There will have to be some coordination of resources and ideas among public and private interests so that you can properly evaluate the costs and benefits across the entire healthcare system. These new treatments can change the landscape of how many diseases are treated and managed. Every part of the system will have to adjust to this.”
REGENX develops therapeutics and research tools based on delivering genes through a new generation of recombinant adeno-associated viral (rAAV) vectors. The company's NAV™ technology promises faster onset and higher levels of gene expression and longer-lasting gene expression compared with the previous generation of rAAV.
Weill Medical College of Cornell University is sponsoring a Phase 1 clinical trial led by Ronald G. Crystal, M.D., testing the safety of AAVrh.10 encoding the CLN2 gene, injected directly into the brain of 16 patients with Batten Disease.
In April, REGENX announced it had secured an exclusive license from ARIAD Pharmaceuticals (Cambridge, MA) for its ARGENT™ gene expression regulation technology, designed to provide control of gene expression and the potential for greater safety and efficacy in some disease populations. For REGENX, the deal could expand the market applications for NAV™ in therapeutic areas where precise calibration of pharmacologic control of gene expression is needed.
Gene therapy developers will need to identify several diseases for which they can spread the costs of their treatments in order to make them more affordable to patients, said Amber Salzman, Ph.D., president of the Stop ALD Foundation (Houston, TX). The foundation funds R&D into therapeutic technologies targeting the orphan disease adrenoleukodystrophy (ALD), the disease highlighted by the 1992 movie “Lorenzo's Oil.”
“If you're only curing one rare disease, and what you do doesn't apply to other diseases, it's really difficult to cover your costs, much less make money on it,” said Dr. Salzman, who is also president and CEO of Cardiokine (Philadelphia PA), biopharma company specializing in cardiovascular therapeutics. “However, current costs for treatment are often very high, so a one-time gene therapy cure can charge a premium.”
Depending on the treatment involved and the disease being treated, gene therapy costs can easily run up into six figures. High as that cost range is, it is comparable to the cost of current treatments. For example, some diseases are treated by an allogenic transplant which can also start in the low- to mid-six figure range, and rise from there to as much as $1 million—plus the added cost of hospitalization. The alternate gene therapy approach could reduce the hospital stay to 15 days versus 100 days, thus being overall more cost effective.
“If you use gene therapy, right now the cost of the vector for the gene therapy is high, but I do think that will go down over time, and that platform technology can be further leveraged,” Dr. Salzman said.
“The reality is that you are still going to have to charge a fair amount in today's world for it to make sense for these companies to keep going with it,” Dr. Salzman added.
Patricia M. Danzon, Ph.D., Celia Moh Professor and Professor of Health Care Management at The Wharton School at the University of Pennsylvania, says, “The reality is, we have to do rationing of healthcare. Hopefully, as part of the debate over reining in the federal budget, we will get into a more sensible discussion of how we should ration, because we can't pay for every possible treatment, no matter how small the health benefit.”
Instead, Dr. Danzon said the U.S. should consider a model of setting reimbursement levers for drugs similar to those used in Canada, the U.K., and some European nations. The basic idea, she said, is that the payer determines how much to pay for a new drug or technology based on an analysis of the medicine's incremental health benefit relative to cost. If the incremental cost per unit of incremental health gain is too high, officials may deny reimbursement, or negotiate a lower price. Such a system—not included within the Patient Protection and Affordable Care Act enacted last year by President Obama—would reward innovation, and thus foster creation of newer and less expensive therapies.
Could such a system help push gene therapies onto the market?
“If the gene therapy was giving a multi-year benefit and only required one treatment, then there is definitely great potential for it being very cost-effective. But it does all depend on what the risks are, and just how effective it is,” Dr. Danzon said.
In a study released last year, Dr. Danzon and Erin Taylor, a third-year doctoral student at Wharton, concluded that current U.S. insurance reimbursement and cost-sharing arrangements for cancer drugs created incentives for manufacturers to set relatively high prices, and for plans to shift more costs to patients.
“These trends of high pricing and cost shifting are rational responses if plans are unable—because of regulation, litigation, or other factors—to use alternative strategies rather than patient cost sharing to constrain prices paid for costly services,” Dr. Danzon and Taylor concluded.
Makers of vaccines, Dr. Danzon noted, have been able to sustain themselves treating large populations with just one or a handful of applications that offer a long duration of treatment. Because they offer preventive care, vaccines have the advantage of being able to spread their costs among entire populations, or at least larger populations than the much more targeted gene therapies. That basic difference is unlikely to force biopharma companies to change their business models to accommodate gene therapy.
“There are certain types of drugs, including many orphan drugs, that are low volume and relatively high priced. And companies have adapted to handling those, and indeed now orphan drugs are a relatively attractive disease class for companies to invest in. So I don't see a radical change in the [biopharma] business model being required to accommodate gene therapy here,” Dr. Danzon said.
One gene therapy company specializing in orphan diseases recently attracted a sizeable venture capital investment. Bluebird Bio (Cambridge, MA; formerly Genetix Pharmaceuticals) closed in April on a $30 million series C round, a year after closing on $35 million in B-round financing. Bluebird Bio has gene therapies in clinical development for childhood cerebral ALD (CCALD), and beta-thalassemia and sickle cell anemia. The company's gene therapy platform uses stem cells harvested from the bone marrow of a patient, into which a healthy version of the disease-causing gene is inserted. The cells are grown in culture, then returned to the patient.
“Gene therapy went through its ups and downs, but it's definitely on the upswing when you look at it in terms of valuations for private gene therapy companies, and the amount of money they're raising, plus a renewed interest from some big pharma companies in supporting gene therapy trials…” Vasista said, “…they realize that now is gene therapy's golden moment, and it's going to start moving forward.”