To win proof of concept for gene therapy in the eye previously and now in the liver, with likely read-through from results in hemophilia B with SPK-9001 to efforts in hemophilia A, are "fabulous steps for the company to have taken," Spark Therapeutics Inc. CEO Jeffrey Marrazzo told BioWorld Today.

Shares of Spark (NASDAQ:ONCE) closed Thursday at $47.17, up $5.94, or 14.4 percent.

"One of the things that gives us a good degree of confidence in where we are is that most of the prior efforts in gene therapy showed that, if you were going to see an immune response that would eliminate the efficacy of the treatment, you would see it pretty early, as soon as a couple of weeks and as far out as a couple of months," Marrazzo said. "Two of these subjects [in the latest-to-report study] are already out past what we think would be the point of significant risk to that. You never know, but we feel good about the length of time we're already out." An article in the New England Journal of Medicine in 2011 found that benefits up to five years after therapy are consistent with those gained after the first two or three months. "You really need to get through that initial period and then there's a pretty high prospect of long-term duration," he said.

Philadelphia-based Spark said its Pfizer Inc.-partnered SPK-9001 for hemophilia B, the lead investigational compound in the SPK-FIX program, proved encouraging in early phase I/II data from three patients. SPK-9001, a bioengineered adeno-associated virus (AAV) capsid that expresses a codon-optimized high-activity human factor IX variant, gained factor IX expression levels of up to 30 percent that lasted as long as 18 weeks, with patients able to discontinue factor IX prophylaxis, while showing no elevations of liver enzymes. Full data from the dosing cohort that involves four – one additional – patients will be presented next month at the European Hematology Association (EHA) 21st Congress in Copenhagen, Denmark.

Specifically, data show that the first three subjects enrolled in the study experienced AAV-mediated factor IX activity levels following one administration of SPK-9001 at the initial dose level (5 x 1011 vg/kg) studied in the trial. Factor IX activity levels in the first two subjects, without prior history of liver disease, rose consistently through the first four weeks post-administration. At the time of the EHA abstract submission, the first subject stabilized at 28 percent of normal at 18 weeks, and the second subject at 30 percent of normal at seven weeks post-administration. Factor IX activity level in the third subject, with a history of liver disease, also rose consistently and was at 16 percent of normal at three weeks post-administration.

Data from a natural history of patients with hemophilia, Spark noted, suggest that circulating factor activity levels sustained at a threshold of greater than or equal to 12 percent of normal generally are considered to be sufficient to reduce the risk of joint bleeds and the need for prophylactic clotting-factor infusions. "That's obviously the significant technological disruption that we think we can have," Marrazzo said.

Over the combined 28 weeks of observation reported in the abstract, none of the three subjects received regular infusions of factor IX concentrates to prevent bleeding events. One precautionary infusion took place due to a suspected ankle bleed in one subject two days after administration of vector. SPK-9001 has been well-tolerated and no subjects have needed, or received, immunosuppression, the company said.

Often, "you see a rise in liver function testing, and then typically a corresponding fall in the factor IX level that you get," Marrazzo said. "In the earliest trials, people didn't anticipate it and it wiped out all the efficacy that happened. It has not been, so far, harmful to the patient but it wipes away the benefit. The immune system is seeing these cells that are transduced with the vector, and they're attacking and destroying them, so they're destroying the cells that are otherwise producing the factor. We monitor those very closely. The way you would try to treat for that would be to use steroids, which is what the other groups have done," though Spark hasn't needed to, he said.

'HIGHEST LEVELS' EVER: ANALYST

The low dose with SPK-9001 is a major boon. It's 120-fold lower than the dose deployed in the hemophilia A program run by San Rafael, Calif.-based Biomarin Pharmaceutical Inc., Marrazzo said. Uniqure NV, of Amsterdam, uses a dose 40-fold higher than Spark's in its hemophilia B effort. "Those are pretty big differences, and we believe this may have an impact on the immunogenicity profile," as well as manufacturing scale-up that's necessary, he said. "The aspiration of everything that we do is to try to deliver a real significant, transformative change in the disease by getting at the underlying cause of it," and "to do that simultaneously with, ideally, a single dose. We're going to continue to follow these patients for a long period of time. In fact, all of our studies have us following patients for 15 years."

Spark's deal with Pfizer brought $20 million and includes the potential for as much as $260 million in milestone payments, as the pair strives for new therapies against hemophilia B. Under the terms, Spark will conduct phase I/II studies in SPK-FIX. Pfizer, of New York, will take over at the pivotal-study stage, also handling regulatory approvals and commercialization. Spark stands to collect double-digit royalties on global sales. The pharma giant sells factor IX Benefix, the standard-of-care therapy in hemophilia B. (See BioWorld Today, Dec. 9, 2014.)

Marrazzo said he expects the nonhuman primate data in the company's hemophilia A program to be predictive of success as they did in hemophilia B. "We'll find out pretty soon because we expect to start a clinical trial in hemophilia A in the second half of this year," he said.

ISI Evercore analyst Mark Schoenebaum offered his speculations in an investor alert. "While we don't know for sure, we believe that Spark will use a similarly low dose (at least as an initial low dose on a comparative basis) in their hemophilia A trial," he said. Though it's "always difficult to read across from preclinical to human data, if a similar relationship between preclinical and clinical data holds true for hemophilia A, Spark's preclinical data in hemophilia A suggest that 30-50 percent levels of factor VIII can be achieved at a dose roughly four to six times higher than the 5x10^11 vg/kg given in the hemophilia B trial," he wrote.

Spark's most advanced candidate, SPK-RPE65, treats rare blinding conditions caused by mutations in the RPE65 gene. In October 2015, the firm disclosed positive top-line results from the phase III pivotal trial of SPK-RPE65, finding that subjects in the intervention group achieved statistically significant improvement over control subjects in both functional vision and light sensitivity. The trial of 31 subjects with confirmed RPE65 gene mutations met its primary endpoint, the bilateral mobility test change score, as well as the first two of three secondary endpoints, specifically full-field light sensitivity threshold testing, or FST, and the first eye mobility test change score. The third secondary endpoint, visual acuity was not achieved. No drug-related serious adverse events turned up and no deleterious immune responses, in either the phase III trial or in phase I studies.

Developing the eye drug took about 10 years, Marrazzo said. Asked about the length of gene therapy trials as compared to those with biologics and other drugs, he said there's "sort of a yin-yang there. Essentially, your first trial ends up providing both information on safety and early efficacy [unlike with conventional drugs]. You can take that data and usually skip straight from there to a pivotal study design. It's shorter in that respect. [But] regulators and institutional review boards may sometimes require you to have greater gaps between the dosing of subjects to make sure you've demonstrated safety." Given the success so far, he said, Spark may be able to shave at least a little time from the usual duration.

Cowen and Co. analyst Phil Nadeau said the new data show "SPK-FIX has produced some of the highest levels of factor IX transgene expression seen in any hemophilia B gene therapy trials." He pointed out in a report that Bannockburn, Ill.-based Baxalta Inc. (subject of a takeover by Shire plc, of Dublin) developed BAX 335, which produced factor IX levels 20 percent to 25 percent of normal in one patient for a duration of 12 months at a vector dose of 1*10^12 vg/kg and above 50 percent of normal at a vector dose of 3*10^12 vg/kg. But two patients at the highest dose of BAX 335 experienced an immune response resulting in decreased factor IX expression levels and one patient had to take up regular replacement infusions. (See BioWorld Today, Jan. 12, 2016.)

Uniqure's AMT-060 produced factor IX levels 4.5 percent to 5.5 percent of normal at a vector dose of 5*10^12 gc/kg in two patients at 12-plus weeks. "Based on the data from prior hemophilia B gene therapy trials, our consultants have suggested that at least 12 weeks of follow-up is important to understand the kinetics of the transgene expression, and of the immune response to it," Nadeau wrote in his comments on Spark. "We are also encouraged that the one patient that had crossed this mark had no need for immunomodulation therapy and that the transgene expression remained high and was consistently sustained. Thus far, the safety for SPK-FIX seems competitive to that of other gene therapy programs in this space."

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