When he first saw the results from his 23-year-old patient with a painful leg clot, Paolo Simioni assumed the test was botched and angrily told his lab technician to repeat it. But the number came back the same: A key protein in the man’s blood was almost eight times more powerful than normal.
Almost 10 years later, Simioni’s discovery in Italy has become a promising treatment under development by Spark Therapeutics Inc. Part of a new field called gene therapy, it may soon offer a new option for hemophilia B, potentially relieving thousands of patients of the need for expensive, time-consuming, and sometimes unreliable treatments.
Simioni’s young patient had a tiny change in his DNA that intensified the power of a protein called factor IX. In him, the “super factor IX” caused his blood to clot too easily. But for 26,000 people in the world with hemophilia B, lack of the protein leaves them vulnerable to extreme bleeding where minor injuries can become life-threatening.
“I immediately realized the importance of this condition in a completely different context, which was gene therapy,” said Simioni, head of the thrombosis center at the University of Padua. “This might be a real treatment for hemophilia B.”
This month, Spark and its partner, the pharmaceutical giant Pfizer Inc., released data showing that in 10 hemophilia B patients receiving the gene treatment, the average annual number of bleeds fell 96 percent, to less than one a year. Since entering the trial, nine of the patients haven’t had to get infusions of the protein — a current standard of care, according to company research presented at a medical meeting this month. Spark and Pfizer are planning to move the therapy into final-stage trials.
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The company is also developing treatments for blindness and several neurodegenerative diseases. Success in any of those areas could give the $1.5 billion-valuation company a blockbuster product and make it a highly attractive takeover target.
Spark isn’t alone in the field. UniQure NV is also working on gene therapy for hemophilia B, and BioMarin Pharmaceutical Inc. is developing a treatment for the more common hemophilia A. The current global market for hemophilia is worth more than $8 billion a year, according to Bloomberg Intelligence. Investors are watching closely — while it has swung up and down as data from its trials have been released, Spark’s stock has more than doubled since its January 2015 initial public offering.
“We are definitely making progress,” said Marshall Gordon of ClearBridge Investments, which holds about 2.2 percent of Spark’s shares, according to data compiled by Bloomberg. “I would bet you that one if not two of these therapies that are under investigation today become real therapies commercially.”
Gene Problem, Gene Solution
Other companies are developing non-gene therapy approaches, as part of a new generation of potential treatments. A Roche Holding AG drug, emicizumab, succeeded in a final-stage trial reported in December. Fitusiran, a drug from Alnylam Pharmaceuticals Inc., has also shown promising early results.
Simioni sees an elegant intellectual path in the development of Spark’s treatment — random mutations in the factor IX gene cause hemophilia B, and now a random mutation in the factor IX gene could help treat or even cure it.
“I have to find the way in nature to solve the problems that nature creates,” he said. “I always believe that nature can give you the solution.”
Luck helped, too.
Two Doors Down
For years, Kathy High, now Spark’s chief scientific officer, has toiled at the Children’s Hospital of Philadelphia. She’s seen some of the darkest days of hemophilia treatment, when her patients were being infected with HIV through donated clotting factor. Looking for another solution, she tried using a virus to insert a normal clotting gene into patients’ cells. It almost worked.
Kathy High
“The DNA would go to the nucleus and start driving production of factor IX,” High said. But patients’ immune systems responded poorly. Hordes of white blood cells attacked the altered cells, squelching the treatment.
A solution was just two doors down from her office. There, her student-turned-collaborator Valder Arruda was regularly on the phone with Simioni, with whom he’d developed a friendship in the Netherlands. As Simioni described his 23-year-old clotting patient, “my heart started to beat fast,” Arruda recalled. A more powerful protein would require less gene-bearing virus, Arruda reasoned, perhaps flying under the immune system’s radar.
Simioni and Arruda began tracing the exact genetic cause of the supercharged factor IX. A one-letter change in the cellular DNA code was responsible for the more powerful version. The finding was published in the New England Journal of Medicine, and Arruda and High began using the mutated version in their gene treatment.
So far, eight of 10 patients in the trial have had no immune response, and the two who did received steroids to combat it. Neither has suffered bleeding or needed standard infusion treatments.
Ancient Disease
If ultimately successful, Spark’s treatment will be the latest breakthrough for an ancient disease, described more than 15 centuries ago in the writings of the Jewish Talmud and known for afflicting descendants of Britain’s Queen Victoria throughout Europe.
Since those ancient days, treatment has been transformed. In the mid-20th century, clotting factor from donated blood became widely available. That’s given way to safer, synthetic versions of the protein from Shire Plc and Novo Nordisk A/S.
Yet those current treatments are expensive. One hemophilia patient covered by Express Scripts Holding Co. used $6 million worth of factor protein replacement in a single year, according to the drug benefit manager. Existing drugs can also wane in effectiveness as the body reacts against them, and often require infusions as often as every other day.
With Spark’s approach, the hope is to trick the body into essentially making a drug itself. As well as being more effective, it can be less expensive. In seven patients who had been on Spark’s therapy for a combined total of two years, cutting their drug use saved a total of $1.2 million, a Spark-funded analysis found.
Payment for the treatment could be linked to how much it can reduce the costs of other drugs, Spark Chief Executive Officer Jeff Marrazzo said in his office in Philadelphia.
“We should be able to start to envision a system that can pay for disease-modified years,” he said.
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