Babies born with a severe form of a rare genetic condition known as spinal muscular atrophy almost always die before their second birthday.
A gene therapy approved Friday by the Food and Drug Administration promises to change that, offering a potential one-time fix for the genetic deficiency behind the neuromuscular disease.
Zolgensma, as the treatment is called, is only the second gene therapy for an inherited disorder to be cleared for commercial use in the U.S. Its keenly awaited approval marks another milestone for a fast-moving field, and validates the decision by Novartis last year to acquire its developer, the biotech company AveXis, for $8.7 billion.
The therapy is also notable for its price. At $2.125 million per dose, Zolgensma is the most expensive treatment ever brought to market. Novartis intends for that price to be paid in installments of $425,000 a year for five years.
Novartis justifies that unprecedented cost with Zolgensma's life-saving benefit. In the clinical trial used by the FDA to make its decision, all 15 infants treated with Zolgensma were alive and off permanent breathing assistance at two years.
Follow-up results presented last month by Novartis showed the 10 who continued with follow-up study maintained all motor function gains from treatment, such as sitting without support, and were alive at three to five years of age.
"It has the potential to be a cure if patients are treated early before they have manifestations of the disease," said Jerry Mendell, a physician at Nationwide Children's Hospital in Ohio and a lead investigator for the initial study of Zolgensma, in an interview.
Each year in the U.S., roughly 450 to 500 people are born with SMA, about 60% of whom are diagnosed a severe form of the condition known as Type 1. In affected babies, a gene called survival motor neuron 1 is defective, hindering or preventing production of a crucial protein responsible for motor neuron development.
For those with Type 1, typical motor milestones are never attained and affected infants quickly develop problems breathing and swallowing. Natural history data cited by Novartis suggests less than 10% are alive and off ventilation support at two years.
The FDA approved Zolgensma for pediatric patients under the age of two with bi-allelic mutations in the SMN1 gene. This label includes both babies newly incident with the condition, as well as those previously diagnosed who are still younger than two. Notably, that also would include patients with the less severe SMA Types 2 and 3.
Novartis estimates the current treatable patient population to be roughly 1,100 in the U.S.
Until recently, no approved treatments were available for SMA. That changed in December 2016, when Biogen won an OK from the FDA for Spinraza, which works by altering gene expression to help create a back-up version of the needed protein. It's approved to treat SMA Type 1, as well as later-onset forms.
Spinraza can help babies survive and improve motor function, but is not a cure. After an initial 4 injections, doses are taken chronically every four months. Each vial costs $125,000 at list price, a figure that the Institute for Clinical and Economic Review determined "far exceeds commonly accepted thresholds" for cost effectiveness.
Zolgensma presents patients, prescribers and payers with even greater sticker shock, but is intended as a one-time, curative therapy. While unprecedented, Novartis' price does come close to what ICER deems to be cost-effective, according to a newly released estimate.
By a measure of cost per life-years gained, ICER judges an appropriate value-based price for Zolgensma to be between $1.2 million and $2.1 million.
Due to their high costs, gene therapies like Zolgensma and Spark Therapeutics' blindness treatment Luxturna before it could force changes in how drugs are paid for and reimbursed.
"Our insurance system is not designed for one-time, very large payments," Michael Sherman, chief medical officer for the New England-based insurer Harvard Pilgrim Health Care, told attendees at a recent gene therapy conference in Washington, D.C.
A key question in valuing Zolgensma is whether benefits shown to date will endure. In principle, addressing the genetic cause of the disease should reverse the progressive muscle weakening seen with SMA.
"This is one of the longest clinical trials where we have evidence of sustained gene expression," said Mendell. "I think it's very encouraging and we have every reason to believe it will be sustained."
Beyond the longer-term data Novartis has from the first small study of Zolgensma, though, there's limited clinical proof of how long a one-time dose of Zolgensma could be effective.
Three patients in the extension arm of that initial trial did go on to receive combination therapy, but that decision was made by either physicians or parents rather than due to loss of motor function, Novartis has said.
For the SMA patients for whom Zolgensma is approved, Novartis believes Zolgensma should be the preferred treatment option over Spinraza.
"We believe Zolgensma will be a very strong option for patients who are already being treated by the currently approved therapy," said Novartis CEO Vas Narasimahn on a Friday conference call with reporters.
With Zolgensma's approval, families of infants born with SMA now have two disease-modifying treatment options when less than three years ago there were none.
Recent research presented by Roche suggest the Swiss pharma could have a third in the experimental oral drug risdiplam, which analysts view as competitive to both Zolgensma and Spinraza. Roche plans to file the drug for approval later this year.
The accelerating research in SMA is reflective of an industry-wide turn toward rare disease and the RNA- or DNA-targeting medicines that hold hope for improved treatment.
Gene therapies for hemophilia, muscular dystrophies, sickle cell disease and retinal disorders are advancing rapidly through drugmaker pipelines and could reach patients over the next several years.
Their eventual success or failure will depend on clinical results foremost, but whether drugmakers and insurers solve payment and reimbursement will matter nearly as much.
"A therapy that can cure disease in a single treatment isn't a unit of drug," wrote former FDA Commissioner Scott Gottlieb in a recent op-ed. "It's a public health solution."