- Spark Therapeutics' experimental gene therapy SPK-8011 sharply lowered the number of bleeds in a dozen patients with hemophilia A, spurring the Philadelphia biotech to announce plans to push forward into Phase 3 clinical trials.
- Rather than encouraging investors, however, Tuesday's update caused shares in Spark to drop by more than 30% in value during morning trading, erasing nearly $1 billion off of the company's market capitalization.
- While the therapy boosted levels of a clotting factor in five of seven patients given the highest dose, the other two individuals experienced an immune response that caused factor activity to drop. Spark may also be suffering from a comparison to data from BioMarin Pharmaceutical, which is further along in developing a rival hemophilia A gene therapy.
Spark's updated results paint a clearer picture of SPK-8011's efficacy, improving upon data the biotech released last December at the annual meeting of the American Society of Hematology. Yet, as the stock market reaction suggests, questions remain about the treatment's safety and how its profile stacks up against BioMarin's competing therapy.
In people with hemophilia A, a defective gene leads to missing or defective Factor VIII, a protein that helps blood clot. Without sufficient Factor VIII, hemophilia patients are at constant risk of dangerous bleeds, particularly in joints and muscles. For severe patients, treatment usually involves several infusions of Factor VIII per week.
Gene therapy promises to potentially correct this deficiency through a one-time prophylactic infusion of a functional copy of the gene that encodes for the clotting protein.
Tuesday's update from Spark showed SPK-8011 nearly eliminated bleeds and infusions of Factor VIII in the 12 patients treated in a Phase 1/2 trial. Annualized rates for both events were reduced by 97%, beginning four weeks after infusion of the gene therapy vector.
Trial participants were given three doses of SPK-8011, with seven receiving the highest dose of 2x10^12 vector genomes per kilogram of body weight (vg/kg).
For five of those seven, Factor VIII activity levels post-infusion ranged between 16% and 49%, averaging 30% three months after treatment.
According to the World Federation of Hemophilia, Factor VIII levels between 5% and 40% are classified as "mild" hemophilia, while between 50% and 150% is considered normal.
Two patients in the high-dose group, however, experienced an immune response that caused their Factor VIII expression to drop below 5% and prompted a shift from preventive to on-demand treatment of their hemophilia.
One of the two didn't respond quickly to oral steroids and was admitted to a hospital to receive intravenous steroids, which led to the adverse event's resolution. Due to the patient's admission to a hospital, the case was classified as a serious adverse event.
Across the entire study, seven of the 12 patients received tapering oral steroids to address liver enzyme elevations, declining Factor VIII levels or a positive result on a test used to measure cytokine release. Treatment with steroids led to stabilization of clotting factor activity in all but the two participants.
Moving forward, however, Spark now plans to use a prophylactic course of steroids to suppress any immune responses and help keep Factor VIII levels above 12% in people treated with a high dose of SPK-8011.
The biotech is set to start a Phase 3 run-in study in the fourth quarter of this year using the 2x10^12 vg/kg dose.
In contrast to the negative stock reaction for Spark, shares in BioMarin rose by more than 5% on Tuesday, likely in response to the news from its competitor.
BioMarin's treatment, called valoctocogene roxaparvovec, has shown a similarly sharp reduction in annualized bleed and infusion rates among hemophilia A patients. On Factor VIII levels, however, a high dose of BioMarin's therapy resulted in activity at or near normal levels — suggestive of a more potent effect than SPK-8011.
Two Phase 3 studies of BioMarin's treatment are underway, with enrollment in the high dose trial expected to complete by the first quarter of 2019.