EXOME

all the information, none of the junk | biotech • healthcare • life sciences

Gene Therapy Advances, But Hemophilia Is No Easy Target

Xconomy National — 

Mark Skinner, the former longtime president of the World Federation of Hemophilia, has had the blood disease on his mind his entire life.

He doesn’t have a choice.

Skinner, 57, was born with a severe form of hemophilia A, meaning he has a tiny fraction of the necessary cellular machinery to clot blood. His disease dictates what he can or can’t do every day. He’s had multiple orthopedic surgeries and years of joint damage. Over the course of his life he’s seen hemophilia go from a disease with very few treatments to a manageable condition, but one that, as he says, chronically “tethers” him to the healthcare system.

One would think Skinner would jump at the chance, then, to try gene therapy, which offers the potential for a one-time long-lasting treatment—if not an outright cure.

BioMarin Pharmaceutical (NASDAQ: BMRN) and Spark Therapeutics (NASDAQ: ONCE) are both developing gene therapies for severe hemophilia A patients just like Skinner. BioMarin’s treatment, featured last week in the New England Journal of Medicine, is headed for late-stage clinical trials.

If the product, known as Valoctocogene roxaparvovec, or val-rox, gains approval, Skinner and others like him might no longer have to inject themselves with drugs every other day to prevent dangerous bleeds—drugs that leave him with a $1 million bill every year. Maybe Skinner, who ran the WFH from 2004 to 2012 and still leads its U.S.-based affiliate, could wake up in the morning and never think about hemophilia again.

Yet Skinner says he won’t sign up, at least not yet. He is open to gene therapy, but concerned the treatment might not work for him, or might taper off down the road. “I don’t know when to say yes,” he says. “And a big part of that is predictability and certainty.”

Even drug-industry proponents acknowledge that the new technology doesn’t have a clear timeline. “At some point in the near future, hemophilia will be cured by gene therapy,” says Glenn Pierce, a former senior executive of Biogen’s hemophilia business, who worked on such gene therapies at Avigen over a decade ago. “The question is when that will happen.”

Skinner’s hesitancy provides a cautionary tale amidst the excitement gene therapy is generating. Experimental therapies for hemophilia A and the less common hemophilia B have shown, in some cases, a stunning ability to help people with severe hemophilia produce enough clotting protein to prevent dangerous and damaging bleeds.

The results for a small handful of patients extend beyond a year. No major safety problems have emerged so far.

Crucial questions remain unanswered, however: How will people respond to treatment? Will patients still need supplemental clotting factor on top of the gene therapy? Will treatment effects wear off—especially with children—and if so, will anyone be eligible for a second dose?

“In the real world there are an awful lot of patients that the gene therapy may not be a candidate for,” Skinner says.

All these questions are opening a window for non-gene therapies, some of which are updates to old standards. Their emergence could change the dynamics of the market, give insurance companies more reasons to restrict access to certain drugs, and force gene therapy developers to recalculate their asking prices if their products reach the market.

A number of companies are either working on better clotting factors, or have already brought them to market. New hemophilia drugs that don’t rely on gene modification—and don’t promise long-lasting effects—might still come with six-figure annual price tags. Now that value is an industry watchword, companies are eyeing current annual costs as a comparison. The cost to a severe adult patient who receives regular treatment several times a week and doesn’t suffer any bleeding episodes is “quite easily” $250,000 to $400,000 worth of factor each year, says Kimberly Haugstad, president and CEO of the nonprofit Hemophilia Federation of America. The bills run higher for those who have inhibitors—immune responses that require the use of additional, expensive drugs.

Roche’s Genentech division is pricing its antibody drug emicizumab (Hemlibra) accordingly. The FDA approved emicizumab in November for the 20 percent of hemophilia A patients with inhibitors. It could soon be approved for the entire hemophilia A population.

Emicizumab is taken once a week via a subcutaneous injection, not an intravenous injection or infusion like other hemophilia treatments. And it recently showed it might work with only one dose a month.

Roche’s price: $482,000 for the first year and $448,000 each year afterwards—a discount to the list price of Shire’s FEIBA, the type of drug that emicizumab aims to replace. Because it’s a discount, Genentech spokeswoman Elizabeth Walmsley says the price was set “with the intent to reduce payer barriers to patient access.”

That strategy is unusual in a market that, despite more and more competition, has seen its drug prices increase year after year, says Haugstad. Out-of-pocket costs are climbing as well, and patients are concerned that payers may start implementing restrictive formularies, she says.

Yet another drug making its way through the pipeline could also become part of a complicated pricing puzzle. An RNA interference treatment from Alnylam Pharmaceuticals (NASDSAQ: ALNY), fitusiran, for both hemophilia A and B patients—subcutaneous, taken monthly, and cheaper to produce than biologic drugs—is in late-stage testing, though recent safety concerns have delayed the drug’s progress.

Former Biogen executive Pierce, who is a boardmember or advisor for a few hemophilia foundations and biotechs, says the eventual pricing of emicizumab for the full hemophilia A population could be a bellwether for the entire sector. For example, if it prices at a discount to clotting factor therapy, it could create a ripple effect of lower prices. “It seems like that would be a reasonable thing to do,” Pierce says. Factor VIII and Factor IX can be made “very, very inexpensively. The profit margin is huge.”

The first gene therapy ever approved had a $1 million price tag. How high could a hemophilia gene therapy go?

It’s complicated. Right now, the costs of standard factor replacement therapy are well known to insurers. Eliminating them long-term would definitely save money. In a “dream” scenario, Haugstad says, a gene therapy returns a patient’s clotting factor levels approaching 50 percent of normal, at which point the patient should no longer need other drugs or emergency room visits.

Unfortunately, clotting factor levels don’t tell the whole story and couldn’t be used solely to predict someone’s future health—or set a fair price for a gene therapy. As Haugstad notes, a therapy could raise two severe patients to a 15 percent factor level and each could have different outcomes. One patient may never have a spontaneous bleed again, while the other does and still requires more than $100,000 worth of factor each year. Because not all gene therapy recipients will have the same results, the financials will be hard to map out, Haugstad says.

BioMarin could be the first to confront these issues, given that val-rox should begin the first of two pivotal trials this year—the first hemophilia gene therapy to get this far. Jeff Ajer, BioMarin’s executive vice president and chief commercial officer, says payers have been encouraged by the effect val-rox has had on factor VIII expression, bleeds per year, and replacement therapy usage. But they’re also skeptical because of the uncertainties. “They’ve seen products not pan out before,” Ajer says.

The longest-term data BioMarin has at this point, unveiled at the American Society of Hematology’s annual meeting this week, was proof that val-rox’s effects held up for 1.5 years in a handful of patients. BioMarin will continue following these patients, and they’ll be a critical part of its case to payers should val-rox eventually get to market. Will the effects prove to last five years? 10? For life?

There’s one more consideration that often gets lost in the discussion about technology and policy and pricing: The personal decision. Would a parent decide to put a young child on treatment, not knowing whether it will work in the long term? What about others in the patient community who, Haugstad says, believe their disease is part of who they are? “I think that’s crazy, but it’s real,” she says. “Change is hard and it’s different and it’s new.”