Amicus Therapeutics Inc.’s results from the phase III trial called Propel with AT-GAA (cipaglucosidase alfa and miglustat) for late-onset Pompe disease (LOPD) met with split opinions, though Wall Street took a decidedly dim view and left shares (NASDAQ:FOLD) to close at $12.57, down $6.16, or 33%.

Cowen analyst Ritu Baral deemed the dual-component therapy “still approvable” in the wake of Propel, whereas SVB Leerink’s Joseph Schwartz said the outcome “calls approvability into question.”

The primary endpoint of the study was the mean change in six-minute walk test (6MWT) as compared with baseline at 52 weeks across the combined enzyme replacement therapy (ERT)-switch and ERT-naïve patient populations. AT-GAA’s efficacy on the 6MWT was 13.6 meters over standard of care Lumizyme (alglucosidase alfa) from Sanofi SA, which was not statistically significant (p=0.072). In the switch patient group of 95 subjects, the 6MWT did reach statistical significance, Schwartz noted, but with only a 16.9-meter difference (n=0.046). It was the treatment-naïve group that fell short, with a difference of 4.9 meters favoring the Lumizyme group (p=0.60). Amicus said it will proceed with its rolling BLA, already underway, based on the totality of the evidence, including good results with the key secondary endpoint of forced vital capacity (FVC) and other measures.

Propel enrolled 123 adult Pompe patients who still had the ability to walk and to breathe without mechanical ventilation and was conducted at 62 clinical sites in 24 countries on five continents. It was the largest controlled clinical study ever conducted in a lysosomal disorder. Patients were randomized 2-to-1, so that for every two patients randomized to be treated with AT-GAA, one was randomized to be treated with Lumizyme. Of the Pompe patients enrolled in PROPEL, 77% were being treated with Lumizyme immediately prior to enrollment and 23% had never been treated with any ERT (n=28). One hundred and seventeen patients completed the Propel study and all have voluntarily enrolled in the long-term extension study. They are being treated solely with AT-GAA.

Baral pointed out in her report that the FDA-mandated hierarchy in the analysis plan was first to show statistically significant superiority on 6MWT, which AT-GAA missed, and then statistical significance on FVC, which was achieved. “If AT-GAA was unable to show superiority in both 6MWT and FVC, a noninferiority test on FVC and then 6MWT was to be performed,” but since the drug beat Lumizyme on FVC overall, Amicus didn’t do the noninferiority tests. Baral called the data “mixed but encouraging.”

Schwartz, in his report, deemed the Propel results “very surprising” and “disappointing,” though he conceded that AT-GAA was “in the green” with regard to most endpoints in the experiment. “For what it's worth, the primary endpoint of 6MWT in the overall study (naïve and switch) would have been statistically superior with just two more meters of separation,” he wrote. “However, AT-GAA underperformed and the control Lumizyme arm outperformed, particularly in [ERT-]naïve patients.” Because of “the unclear regulatory path forward,” he downgraded Amicus to market perform and cut his price target from $30 to $15.

Baird’s Michael Ulz went down the middle. He found “a clear benefit on FVC in the overall population as well as broader benefits, particularly in switch patients, which we believe will likely be supportive of approval; however, missing on the primary endpoint does introduce some uncertainty.” He maintained his outperform rating but lowered his price target to $18 from $25.

CEO John Crowley during a conference call reminded investors that FVC “is the most important measure of respiratory muscle strength in Pompe patients. It’s an acceptable, approvable endpoint,” he said. Lumizyme was approved on the FVC endpoint in 2010. “We’re excited about all of the data together,” especially the findings in switch patients, who make up “the vast majority in the injectable category today,” he said.

“We're not going to comment on discussions we have with FDA,” Crowley said, with a nod to AT-GAA’s breakthrough therapy designation from the agency. “We have shared these data with the FDA. We began the rolling submission in the fourth quarter [of last year, and] our plan is to complete the submission in the second quarter. Of course, the standard for approval is noninferiority of this drug. We think we significantly exceeded that.”

Others making news recently in LOPD include Sanofi, of Paris, which at the Worldsymposium offered encouraging phase III data from the Comet trial testing ERT avalglucosidase alfa. With 102 participants, Comet’s duration per patient was designed to be up to about six years, consisting of a 14-day screening period (which may be extended up to eight weeks in prespecified situations), a 49-week blinded treatment period (except for the subgroup of pediatric patients age 3 to under 18 enrolling directly in the open-label long-term follow-up phase), a 240-week open-label treatment period, and four weeks of post-treatment observation.

Basel, Switzerland-based Roche Holding AG’s Spark Therapeutics about two weeks ago dosed the first participant in the phase I/II Resolute trial with SPK-3006, an investigational liver-directed adeno-associated viral vector (AAV) gene therapy. Around the same time, Provention Bio Inc., of Red Bank, N.J., reported results from a preclinical proof-of-concept study in a mouse model with bispecific antibody-based PRV-3279, targeting the B-cell surface proteins CD32B and CD79B. Researchers used mice transgenic for human CD32B, which received gene therapy with a AAV9 encoding for the enzyme acid-alpha-glucosidase (GAA) gene. Hitches in GAA are known to cause type II Pompe. The PRV-3279 surrogate dose-dependently reduced anti-AAV9 vector antibody levels, the study found.