Tomorrow's Medicine

First Million-Dollar Syringe Could Be a Sight for Sore Eyes

Brace yourself for astronomically priced injections. One on track for U.S. approval looks to treat a rare form of retinal disease.

Thomas Morrow, MD

Do a Google search on “$1,000 pill” and you will get nearly 500,000 results, with most of them being about new hepatitis C antivirals. And it’s a safe bet that almost everyone in health care has seen or read something about the $1,000 pill.

Now search on “$1 million injection” and you will find a number of articles about injections (of cash or capital) into companies or government programs, not humans.

But in the next year, somebody at some health plan in this country will likely receive a bill for $1 million for a single injection (or depending on which drug is approved first, a single patient visit for numerous injections). In fact, bills for this level of care are already being received in Europe.

The European Commission in November 2012 granted its first marketing authorization of a gene-based therapy called alipogene tiparvovec (Glybera), and the treatment has now been commercialized in parts of Europe. The pricing for alipogene tiparvovec came to light in November 2014 when uniQure, an Amsterdam-based company, and its marketing partner, Chiesi, based in Italy, filed a document in Germany that put the price at about $1.4 million per treatment. Although alipogene tiparvovec isn’t on the American market, it’s probably just a matter of time before uniQure seeks FDA approval. The company operates a 55,000-square-foot facility in a suburb of Boston.

Glybera was designed to treat familial lipoprotein lipase deficiency (LPLD), also called type 1 hyperlipidemia, a disorder that affects a very small number of people—about one or two individuals out of every million. Lipoprotein lipase is an important enzyme in the metabolic cascade involved in the generation and regulation of triglycerides. People with the deficiency suffer recurrent abdominal pain, acute and potentially life threatening episodes of pancreatitis, hepatosplenomegaly (enlarged liver and spleen) and cutaneous xanthomata (fatty deposits in the skin).

Glybera uses an adeno-associated viral vector, a small nonenveloped virus that carries a genetic snippet designed to correct the lipase deficiency. Adeno-associated viral vectors are used in gene therapy because they don’t provoke a strong immune response and can transfer their therapeutic genetic cargo into many different types of cells. Glybera is injected into multiple sites in the muscles of the leg because legs are accessible and a site of lipoprotein lipase expression.

Fixing retinal dystrophy

On this side of the ocean, a therapy to correct an inherited eye disorder might be the first gene therapy to get FDA approval and hit the market. The therapy, which is being called SPK-RPE65 for the time being, is a treatment for inherited retinal dystrophies caused by defects in the RPE65 gene. Retinitis pigmentosa is the most common form of inherited retinal dystrophy, and Leber congenital amaurosis, the most severe. Patients with Leber congenital amaurosis often have severe vision loss and abnormal eye movements (nystagmus) starting when they are infants or very young children.

Spark Therapeutics, a Philadelphia company, is now conducting the trials of SPK-RPE65, but other groups are also investigating treatments that fix RPE65-related retinal dystrophies at the genetic level. Yet this is very much a niche area of medicine. Spark estimates that only about 3,500 people in the United States and five major European markets could benefit from its gene therapy treatment, a group that includes people with the subtypes of retinitis pigmentosa (RP type 20) and Leber congenital amaurosis (LCA type 2) that can be traced back to RPE65 mutations.

On the other hand, Spark is testing the same basic gene therapy technology in other trials with other diseases as the target. SPK-RPE65 is its leading product. If it pans out and is shown to be effective in clinical trials that may bode well for its other gene therapy products and for gene therapy in general.

The RPE65 gene is expressed in the retinal pigment epithelium—thus the RPE of RPE65. The retinal pigment epithelium nourishes the retina’s photoreceptor cells—the rods and cones—and provisions important steps in the metabolic cycle that make vision possible. RPE65 is especially important for rods, so people lose most if not all of their night vision if the gene is mutated in a way that adversely affects its expression.

Like uniQure’s Glybera, Spark’s SPK-RPE65 uses an adeno-associate viral vector to ferry the therapeutic genetic material to the target tissue. One reason that gene therapy for this obscure eye disease has come so far along is researchers had a good animal model to work with. The Briard breed of dog suffers from a RPE65-related condition that is very much like human Leber congenital amaurosis.

Positive results in those dogs led to human trials, and results from those trials have been encouraging. An initial report in Lancet in 2009 said all 12 patients in a phase 1 trial that involved treating just one eye with SPK-RPE65 experienced improvement in subjective and objective measures of vision. A 2012 article in Science Translational Medicine described successful efforts to treat the second eye of three people who were in the initial study.

Spark Therapeutics appears to have some momentum going that would win it the distinction of having the first-ever gene therapy product on the American market. It finished recruiting 28 patients for the pivotal phase 3 trial of SPK-RPE65 two years ago and received FDA breakthrough therapy status for the treatment last year. The company says on its website that it will report data from the phase 3 study in the later half of this year with an expectation of filing a biologic licensing application with the FDA in 2016.

But there’s also reason to keep a finger on the pause button. Earlier this year, a British group reported results for gene therapy for Leber congenital amaurosis in the New England Journal of Medicine (NEJM) that showed the benefits to people’s vision to be modest and, more troubling, the improvements in vision wore off. Spark Therapeutics says there are important differences between its product and what the British researchers used, but the NEJM report does sow doubt. And gene therapy as a field suffered a significant setback earlier this year when Mydicar, a gene therapy product for heart failure, did not meet primary and secondary endpoints in a phase 2b study.

Some may remember when gene therapy seemed poised to take off in the ’90s. A patient death effectively shut the field down and it’s only recently gotten into recovery mode.

Managed care implications

Restoring vision, albeit limited in existing published studies, will garner a lot of attention, especially since the studies show improvement in children. If SPK-RPE emerges from its phase 3 trial with positive results and gains FDA approval, managed care companies will be hard pressed to deny coverage for a therapy for a disease that causes blindness in later decades. How it will be priced isn’t known. But the million-dollar syringe may soon make the thousand-dollar pill seem quaint, and again prove that Tomorrow’s Medicine will always be newsworthy—and sometimes very expensive!

Thomas Morrow, MD, is the chief medical officer of Next IT. He has been the founding medical director of five HMOs and a disease management company, a medical director at Genentech, and president of the National Association of Managed Care Physicians. You can contact him at


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