Jun 19, 2018
An experimental gene therapy appeared to dramatically increase the production of a muscle-making protein in three young boys with Duchenne muscular dystrophy, a deadly and irreversible disease, according to results being presented by the drugmaker Sarepta Therapeutics at an investor event this morning.
“We think this has huge implications for the treatment of this disease,” says Jerry R. Mendell, the principal investigator in the Center for Gene Therapy at the Research Institute of Nationwide Children’s Hospital, who is leading the study for Sarepta.
Outside experts who reviewed the data for Forbes say it is promising, though the data have not been peer-reviewed for a conference or publication. “Being in this field doing clinical research for many years, I learned to be cautious,” says Ron Crystal, chairman of genetic medicine at Weill Cornell Medicine. “But I think it’s encouraging.”
The data are a positive not only for Sarepta, but for two other companies that are racing to develop gene therapies for Duchenne: Solid Biosciences, a startup founded by an investors whose child has Duchenne, and the drug giant Pfizer.
During an interview last night, Douglas Ingram, Sarepta’s chief executive, briefly allowed himself to think very big about the four boys, all younger than six, who have been given the treatment so far. (Data are available on three of them.) “We don't want to oversell ourselves,” he says. “Dr. Mendell, he’s tired of watching kids die of this horrific disease that’s been killing kids forever. But it may be a possibility that there are four boys walking around today who have a very different future.”
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One thing’s for certain: the data live up to the heady expectations of Sarepta’s investors. Shares in the company have run up 80% so far this day, giving the Cambridge, Massachusetts-based company a market capitalization of $6.9 billion. Investors are likely to be focused on a measure of whether a test called the western blot shows that the gene therapy has sufficiently raised levels of dystrophin, the protein that is dysfunctional or missing in Duchenne patients, and without which the body cannot build and maintain muscle.
Sarepta’s marketed drug, Exondys 51, was approved based on data that it increased levels of dystrophin in patients with a particular type of mutation in the dystrophin gene by much less than 1%, measured with western blot. A May analyst note from Nomura Instinet, an investment bank, predicted the gene therapy would lead to dystrophin levels of 5% to 10% of normal.
The actual western blot number: 38.2% of normal, using Sarepta’s western blot method, and 53.7% based on a method developed at Nationwide Children’s that corrects for readings in fat and scar tissue. In other words, quadruple the best case.
But gene therapy experts pointed to other data points as more interesting than the ones that Wall Street has fixated on. For instance, boys (for genetic reasons, they’re all boys) with Duchenne have high levels of creatinine kinase, an enzyme involved in the destruction of muscle. In the study, the three boys who have been followed for at least two months saw levels of creatinine kinase drop 87% from about 30,000 units per liter.
Then there are the videos. In one shown to me via a webcast, a boy initially climbed stairs one at a time, slowly. Some time after treatment, he bounded up them. Mendell, the lead investigator, asserted that improvements like that don’t happen.
Outside researchers were more cautious. Xiao Xiao, a professor at professor at the University of California’s Eshelman School of Pharmacy and co-inventor of the Pfizer gene therapy, worried that other issues like changes in steroid treatment could lead to changes in creatinine kinase, for instance. He was nonetheless excited by the results. “I think gene therapy now is coming back after all these years of technology improvement,” he said. He would receive royalties if the Pfizer treatment reaches the market.
The excitement is so palpable, and information about the treatments is filtering out via social media. Last month, Adam Feuerstein at Stat News wrote that a teen in the Solid Biosciences study was reporting improvements on Facebook. A dramatic video from a patient in the Pfizer study has also made its way onto the social media site; the patient’s parents have talked about their son’s involvement in the Pfizer trial in fundraising efforts for CureDuchenne, a charity, but a Facebook message from their fundraising entity said they would not comment further.
“There’s multiple options that appear to be coming down the clinical path, so it’s great for the community as a whole,” says Jude Samulski, another UNC professor and cofounder with Xiao of the Duchenne startup Pfizer bought.
The big question is whether these gene therapies will be different from each other. All of them solve the same problem in a similar manner. They all use a virus called the adeno-associated vector (AAV) to insert a gene to produce dystrophin into patients’ cells. But this is even harder than it sounds. The gene for dystrophin is the largest in the human genetic code, and is far too big to fit in the AAV. So scientists created a shortened version based on patients who had less severe forms of muscular dystrophy.
One question will be whether the shortened form is as effective as normal dystrophin, or close. Another difference will be in how much virus each effort is using to try and increase the amount of dystrophin produced. Even if multiple treatments work, some patients may already have immunity to some AAV vectors, meaning that every treatment may not be a match for every treatment.
Crystal, the Cornell doctor, says that measures of enzymes and protein levels won’t be enough to determine if a gene therapy is ready for use in patients. There will need to be data showing that it really makes patients better.
Ingram, Sarepta’s CEO, says he’s well aware of that. Sarepta is already planning to start another study of 24 boys. Twelve will receive the gene therapy, and another 12 will receive a placebo. At the end of a year, the 12 patients who received placebo will get the gene therapy, too. The hope is that patients’ function will improve enough that regulators will approve the drug. Ingram says Sarepta will meet with the FDA within four months—he hopes it will be sooner—to discuss what it needs for approval, but that it is moving forward with this study regardless.
“We have a lot of thinking to do,” Ingram says. “We have a lot of talking to do. We need to sit down with the FDA and get their view on this.”