With last Friday's approval of Strimvelis (GSK2696273, Glaxosmithkline plc) for treatment of patients with severe combined immunodeficiency due to adenosine deaminase deficiency (ADA-SCID) by the European Commission, the number of approved gene therapies has doubled to two in Europe.

Like Glybera (alipogene tiparvovec, Uniqure BV), which was approved for the treatment of lipase deficiency (LPL) by the European Commission in 2012, Strimvelis treats an ultra-orphan disorder. ADA-SCID has an incidence of one in 200,000 to one in 1 million, while LPL's incidence is one in 1 million to 2 million.

Outside of its clinical trials, Glybera has been used to treat a single patient since its approval in 2012. (See BioWorld Today, March 5, 2015.)

Those sorts of patient numbers make the therapies the ultimate in precision medicine. They also lead to the opposite of efficiencies of scale for the companies producing them.

Paul Firuta, chief commercial officer at Uniqure, told BioWorld Today that "it's a challenging market," not just because it's a small market, but because it's a small market with large expenses. There is an extensive amount of cost that continues after development" to keep the treatment available.

The bill for treating Glybera's sole patient came to $ 1.1 million, payable up front.

Firuta said that doesn't mean that there could not be "multiple payment models" depending on both the country, and the specific gene therapy.

Sarah Spencer, head of U.S. external communications for Glaxosmithkline, told BioWorld Today that "pricing discussions are still ongoing with . . . the Italian Medicines Agency, so we can't confirm the exact price yet. However, we can reiterate it will be significantly less than $1 million."

In a policy forum published in the May 27, 2016, issue of Science, Stuart Orkin, chair of pediatric oncology at the Dana-Farber Cancer Institute, and Philip Reilly, venture partner at Third Rock Ventures, offered suggestions for how to make gene therapies viable for companies and affordable for patients and health care systems.

No gene therapies have been approved in the U.S. yet, but Orkin told BioWorld Today that "we expect a steady stream" of approvals, beginning within the next three years. For now, he added, "we're trying to stimulate discussion ahead of time."

Whether gene therapy is overall cheaper or more expensive than the ongoing treatment, he said, "is going to depend on the disease."

But the current costs of treating diseases like Gaucher disease and hemophilia A can run in the hundreds of thousands of dollars annually, and several million over a patient's lifetime.

Glaxosmithkline's Spencer put the 10-year cost of enzyme replacement alone to treat an ADA-SCID patient at $3.5 million to $5 million, while "Strimvelis is a one-off lifesaving treatment for patients with ADA-SCID for whom no suitable matched related bone marrow donor is available. We will price Strimvelis to enable access and reduce long-term health care costs."

Orkin said he believes that, overall, the costs favor gene therapy "in the majority of instances."

There are examples of the payers' accepting high up-front costs for better outcomes. Orkin pointed to the Department of Veterans Affairs' willingness to pay the extremely high prices for hepatitis C drugs Sovaldi (sofosbuvir, Gilead Sciences Inc.) and Harvoni (ledipasvir and sofosbuvir, Gilead Sciences Inc.) that result in cures.

Still, in a health care system where it can be difficult to get up-front approval for a drug that significantly reduces the chance of an ICU stay within a week – to say nothing of the challenges of funding any number of preventive public health measures – favorable overall economics are no guarantee of business success.

Orkin and Reilly suggested several possibilities for valuing, pricing and paying for gene therapies, including a requirement for the company to re-treat on its own dime if a gene therapy stops working or an annual payment that continues for as long as therapy is efficacious, similar to amortization schemes that California is discussing for stem cell therapies.

Orkin said that "in a way, [Glybera] is not the optimal case" for figuring out the economics of gene therapy treatment. "It's not even clear that it's efficacious, and it's a very rare disorder," he said.

Deya Corzo, Uniqure's senior vice president and therapeutic area head of liver and metabolism, unsurprisingly disagreed with Orkin's assessment of Glybera's efficacy.

LPL, she told BioWorld Today, is "a very rare disorder in which well-controlled studies cannot be run. . . . That does not translate into dubious efficacy."

In the clinical trials for Glybera, the patient group of 27 equated to 10 percent of the total estimated European population of LPL sufferers, which is estimated to be around 30.

The choice of LPL as first indication was not primarily a business decision. Instead, "it has to do with the origins of Uniqure," which was formerly Amsterdam Molecular Therapeutics BV (AMT) until it restructured itself into Uniqure in 2012.

AMT was co-founded by lipids expert John Kastelein, and the choice of LPL as an indication was based on the fact that it was a monogenic disorder with a known gene at its root, and on the existence of good animal models – an "ideal proof of concept," Corzo said.

The exact incidence of LPL was unknown when Kastelein began his studies, though "it was known that it was rare."