Applied Therapeutics Inc. (ATI) CEO Shoshana Shendelman said positive top-line findings with aldose reductase inhibitor AT-007 in galactosemia were “the data we needed, and we’re going to move as quickly as we can to get in and speak to the FDA about this, not only to firm up our NDA filing but also to get into the pediatric study.”

New York-based ATI has had “ongoing conversations” with regulators about the pediatric experiment, but results from the pivotal portion of the phase II, double-blind, placebo-controlled experiment in adults called Action-Galactosemia put the firm “in a really great place in terms of design” for the next effort, Shendelman said.

Action-Galactosemia probed the safety and pharmacokinetics (PK) of AT-007 in healthy volunteers, as well as safety, PK and biomarker effects over 28 days of once-daily oral treatment. The key biomarker outcome of the study was reduction in galactitol, an aberrant toxic metabolite of galactose that’s formed by aldose reductase, and AT-007 turned up a statistically significant and robust drop vs. placebo. ATI’s biomarker-based development program is based on the recently released draft industry guidance on drug development for low prevalence, slowly progressing rare metabolic diseases. Shares (NASDAQ:APLT) closed at $35.18, up $9.02, or 34.5%.

Shoshana Shendelman, CEO, Applied Therapeutics

Enrolled patients had a mean age of 30 across a broad range of galactose-1-phosphate uridyl transferase (GALT) mutations associated with classic galactosemia. All patients had <1% GALT enzyme activity, and baseline plasma galactitol levels were 2,000-3,000 ng/mL (vs. undetectable in healthy volunteers). Patients turned up highly symptomatic, most of them with learning and cognitive deficiencies that required caregiver support. Three had a history of chronic seizures. ATI pointed out that baseline EKGs have revealed “significant cardiac dysfunction that has not been previously appreciated within galactosemia patients,” Cowen analyst Marc Frahm noted in a report.

Treatment with AT-007 led to dose-dependent reductions in plasma galactitol compared to baseline. At the low dose (5 mg/kg), patients gained a 10% to 20% reduction in galactitol vs. baseline, whereas at the high dose (20 mg/kg), they chalked up 45% to 54% knockdowns. At both doses the outcomes were statistically significant (p<0.01 at 20 mg/kg) vs. placebo-treated subjects, who ended up with no substantial changes from baseline.

Galactosemia, for which no cure or approved therapy exists, is a rare metabolic disease that affects how the body processes the simple sugar galactose. High levels of galactose circulating in the blood and tissues of galactosemia patients allows aldose reductase to convert galactose to galactitol, which causes problems ranging from central nervous system (CNS) dysfunction to cataracts. Although galactose is found in foods, it’s also produced in the body, so dietary restrictions do not prevent harm caused by the disease.

The U.S. galactosemia population is estimated about 2,800 patients, based on newborn screening data identifying 2,500 infants through 2014 and the estimated birth rate of 80 patients per year. Classic galactosemia is caused by mutations in either GALK (type 2 galactosemia) or GALT (type 1).

Cowen’s Frahm, modeling peak sales of AT-007, noted in an October report anticipating the pivotal data that the consequences of galactosemia also include severe osmotic stress, hemolysis, kidney damage, liver failure and ultimately death. “If the disease is identified quickly, lactose can be removed from the diet and the child can avoid these severe acute complications,” he said. But “neurological complications, including lowered IQ, speech difficulties, tremor and seizures still develop during the chronic phase of disease despite adherence to a lactose-free diet,” an outcome apparently driven by the de novo synthesis of galactose within the body and low-level dietary exposure to lactose/galactose, resulting in chronic exposure to galactitol, which is detectable in urine, blood and the CNS.

‘Extremely tight’ data: CEO

ATI gained orphan designation last May, coincidentally the same month that the International Journal of General Medicine published a paper, titled “Screening for galactosemia: is there a place for it?” The short answer is yes. “Despite the difficulties, challenges and complexities, galactosemia screening is advised,” the authors concluded. “Galactosemia screening by testing galactose or galactose-1-phosphate and GALT detects classic galactosemia and other forms, as whenever GALT is normal in the presence of high galactose, then subsequent testing for [galactokinase and galactose epimerase] follows. The future promises advances in technology and screening tests. Globally, many societies are collaborating to provide support worldwide for emerging neonatal screening programs,” the paper pointed out.

Analyst Frahm said newborn testing is “nearly universal.” He described ATI’s latest findings as “on the high end of investor expectations. We view today's update as a significant milestone” for the company, given that the high dose of AT-007 turned up about 50% reductions in plasma galactitol with a benign safety profile that included no treatment-related adverse events. He pointed to rat studies of AT-007 that indicated near complete resolution of galactosemia symptoms at exposures that led to the 50% galactitol knockdown. “The available data would therefore suggest that AT-007 at 20 mg/kg is likely to drive a significant impact on long-term complications of classic galactosemia,” he wrote, adding that company backers were looking for a 30% to 50% reduction. ATI will present full data from the trial at the Society for Inherited Metabolic Disorders annual meeting in Austin, Texas, this spring.

“Aside from variable potential responses to the drug, no one had ever really looked at variability over several days in these patients, how much do levels change,” CEO Shendelman said during a conference call with investors. “We learned quite a bit, and it’s actually very encouraging that patient levels of galactitol are very stable and consistent at baseline.” On the matter of response variability, she characterized the results as “extremely tight.”