Despite the early and in some cases stunning results produced by gene therapy treatments in handfuls of hemophilia patients, significant questions remain about their durability, safety, and how broadly they’ll be used if they are ultimately shown to work. The first human data produced by Dimension Therapeutics, one of several companies developing hemophilia gene therapies, are the latest example.
DTX101 boosted the levels of the blood-clotting protein Factor IX in six patients. Those on the higher of two tested doses haven’t needed other drugs since getting treatment. But five of the six patients—and all three on the higher of the two tested doses—also saw a rise in liver enzyme levels, indicating an immune reaction to the gene therapy. While none of the five patients have had any safety problems, the liver enzyme spikes have caused a delay for Dimension. The company won’t test an even higher dose of DTX101 in patients until it gets feedback from the FDA.
Gene therapy offers the potential of a long-lasting, if not permanent treatment for hemophilia patients, who—depending on how severe their disease is—may need frequent infusions of preventative drugs to stave off dangerous bleeds. A group of experimental gene therapies have been creeping their way forward in clinical trials, accumulating data in dribs and drabs. Spark Therapeutics (NASDAQ: ONCE) and UniQure (NASDAQ: QURE) are the furthest along in hemophilia B, while BioMarin Pharmaceutical (NASDAQ: BMRN) leads the way in the more common hemophilia A.
Each experimental therapy has shown promise helping patients produce “meaningful” levels of the clotting proteins Factor IX and Factor VIII, respectively—more than 5 percent of the levels found in normal patients, which many view as the minimum bar for success—over the course of a year or more. And Spark and BioMarin have seen much higher numbers than that, in some cases. But there are caveats: Those results have come in small sample sizes, and they have varied patient to patient. Data today from Dimension show the three patients on a low dose of DTX101 had roughly 3 to 4 percent of normal Factor IX levels a year after treatment. The results are earlier for those on a higher dose: 5 and 8 percent, respectively, for two patients 12 weeks post-treatment; 7 percent for a third patient 7 weeks after DTX101.
Additionally, so far, liver enzyme increases have been seen in clinical tests for each of the hemophilia gene therapies. Such increases could indicate that patients’ immune systems were attacking their liver cells, which are the ones that take up the therapeutic gene and churn out the new clotting protein. They’re typically treated with a short course of immunosuppressive steroids and haven’t caused bad side effects so far. But in some cases they’ve stifled a response to gene therapy, which is important because it means that certain gene therapies may not work—or at least won’t work as well as they could—for some patients who develop neutralizing antibodies. It also means that patients who develop those antibodies won’t be eligible for a second dose if the gene therapy wears off. This phenomenon reduces the potential market for the firms developing hemophilia gene therapies. Such immune responses were the impetus behind a deal Spark cut last year with Selecta Biosciences (NASDAQ: SELB), for example.
“We continue to explore the therapeutic window for DTX101 as our data mature and in light of the [liver enzyme] rises that appear to be associated with a decline in [Factor IX] activity,” CEO Annalisa Jenkins said in a statement.