A new secondary endpoint in the ongoing phase III trial with its gene therapy, SPK-RPE65, “does not represent a change in the trial design or the data collected, simply the way the data from the study are designated for analysis,” Spark Therapeutics Inc. CEO Jeff Marrazzo assured investors Thursday morning. And the primary endpoint of improved functional vision from baseline after one year has not been changed, as some worried it might.

Philadelphia-based Spark is developing the compound for inherited retinal dystrophies (IRDs) caused by mutations in the RPE65 gene. The treatment could become “the first approved gene therapy for a genetic disease in the U.S. and, equally as important, one of the first potential pharmacologic treatments for any IRD anywhere in the world,” Marrazzo said during a conference call. The prospect “demands that we engage in real-time dialogue with FDA,” he said. “You can expect that we will continue to do so.”

After talking with regulators and before locking the database, the firm designated pupillary light reflex (PLR) as an exploratory rather than a secondary endpoint. “After careful consideration of the data that we have collected in our earlier trials, we determined PLR, while [it’s] an attractive measurement, was not reliable as a quantitative endpoint given the limitations of the equipment available at the time of the trial.”

The secondary endpoint that replaces PLR is mobility test change score for an assigned first eye, a score that compares the mobility test performance between baseline and year one for the first eye injected by the surgeons for the intervention group and for the control group. “An extensive amount of data were collected throughout the trial, including, for example, mobility testing at multiple time points, and under three eye-patching conditions: left, right and both eyes unpatched,” Marrazzo said.

Spark “had planned all along to analyze and present the mobility test change scores for each eye to both FDA and European Medicines Agency as part of our submissions,” Marrazzo said, and the new secondary endpoint “will provide additional sensitivity data regarding the effectiveness of SPK-RPE65 – in this case, on the function of a single eye.” Specifically, the primary endpoint measures the bilateral mobility test change score with both eyes unpatched, and the secondary endpoints in the statistical analysis plan, to be tested hierarchically in this order, are: full-field light sensitivity threshold testing, the first-eye mobility test change score and visual acuity.

Statistical groups were added, too. The intent-to-treat (ITT) population (n = 31), which serves as the main efficacy analysis segment, will now include two patients who were randomized to the trial but never received treatment. Spark is also including a modified ITT (mITT) population (n = 29) that excludes the two untreated patients in the ITT arm. The per-protocol group (n = 28) excludes one more patient who had a mobility score at baseline that could not be improved.

J.P. Morgan analyst Cory Kasimov cited Spark’s belief that “the inclusion of the additional patients in the ITT population will strengthen the overall dataset and further estimates that there’s plenty of power to attain success.”

‘MODULARITY’ READ-THROUGHS?

On the conference call, Kasimov wanted to know “what kind of feedback you have from regulators if you were to hit on the per-protocol analysis but not on the mITT, or ITT? In other words, what happens if those patients added back do, in fact, skew the results?”

Marrazzo said it’s “a bit premature for us to hypothesize the different permutations that we could contemplate. I do believe that based on the discussions that we have had with regulators, that the totality of the data in this trial is going to be important regardless” of the results in each group.

The RPE65 gene is expressed in the retinal pigment epithelium layer of the retina, and encodes a protein that helps convert the light entering the eye into electrical signals that are transmitted to the brain. Glitches in the gene cause visual impairment that leads to blindness, and they are linked to subtypes of Leber’s congenital amaurosis (LCA type 2) and retinitis pigmentosa (RP type 20). Spark estimates about 3,500 people in the U.S. and five major European markets bear those forms of IRDs.

SPK-RPE65 deploys a neutralized virus as the vector to transport a functional RPE65 gene into the affected tissue in the eye, where it lets patients produce the missing, healthy protein. The drug won breakthrough designation from the FDA in November 2014, when Spark touted clinical findings that, following a single injection in one eye, pediatric patients in the trials no longer depended on visual aids to carry out classroom activities and were able to walk and play more like normally sighted children.

LCA type 2 is a “hot area of investigation, led largely by academia,” noted Piper Jaffray analyst Joshua Schimmer in a 150-page July report on gene therapy research for the condition. He concluded that Spark’s trial is “likely to validate the merits of gene therapy for retina conditions and meet its primary endpoint of improving mobility in dimmer light,” though in his view “it is unclear if visual acuity will be improved and unlikely that the progressive, degenerative component of LCA type 2 will be slowed.”

After the “disappointing” European launch of Glybera (alipogene tiparvovec) for lipoprotein lipase deficiency by Amsterdam-based Uniqure NV in March – more than two years after its approval there – “commercial focus for investors in gene therapy companies may soon shift” to Spark, wrote Schimmer. “Pricing remains a key unknown for gauging what we believe will be the first U.S. gene therapy launch,” he added. “Is it plausible that a one-time injection could cost $300,000 per eye or more? Given the rare nature of the disease and important impact on quality of life, such a price may be feasible and would bode well for gene therapy overall,” though the payment system “would need to adapt to accommodate that type of pricing.” Glybera comes at a cost of €$1.1 million (US$1.2 million). The FDA has told Uniqure that another trial is required in order to consider approval of the product.

Spark’s fate with SPK-RPE65 is “about more than just one product,” Schimmer wrote. “Given the modularity of gene therapy, success with one program may pave the way for successes in others. Should the trial fail, a new path forward for the platform in the retina may require novel vector and promoter constructs.”

Interest is strong in ophthalmic gene therapy, with players in his coverage universe that include Avalanche Biotechnologies Inc., of Menlo Park, Calif., partnered with Tarrytown, N.Y.-based Regeneron Pharmaceuticals Inc. on AVA-101, targeting vascular endothelial growth factor for wet age-related macular degeneration, and Cambridge, Mass-based Biogen Inc., partnered with Applied Genetic Technologies Corp., of Gainesville, Fla., on two main development programs: a clinical candidate for X-linked retinoschisis and X-linked retinitis pigmentosa. (See BioWorld Today, May 6, 2014, and July 6, 2015.)