NLS Pharma Group’s lead compound, NLS-1 (mazindol), more than halved a common measure of attention deficit hyperactivity disorder (ADHD) symptoms in 55 percent of treated adults vs. 15.8 percent of placebo-treated subjects in a randomized phase II trial. A broader group of participants treated in the trial, 70 percent, also saw some improvements after taking the drug.
The privately held company is now seeking an end-of-phase II meeting with the FDA to discuss the trial’s results and the potential design of a phase III study. If successful, the Stans, Switzerland-based company could potentially offer ADHD patients more prescription flexibility while largely avoiding the risks of misuse and diversion associated with amphetamine stimulants commonly used in the U.S.
The study, called NLS-1001, enrolled 85 adults with ADHD, randomizing them almost 1-to-1 to either six weeks of treatment with mazindol or a placebo. The primary endpoint was defined as change from baseline in a widely used ADHD rating scale, ADHD-RS-DSM-5, in the intent-to-treat population at week six. Each participant had a minimum baseline score of 28 on the scale. Secondary endpoints were responder analysis and the Clinical Global Impressions Scale weekly rating up to six weeks. NLS-1 met both endpoints with an effect size of 1.09. At six weeks, 70 percent of NLS-1-treated participants had a reduction of greater than or equal to 30 percent in ADHD-RS-DSM-5 score vs. 21.1 percent on placebo (p<0.001).
Prevalent adverse events in the study included constipation, nausea, fatigue and increased heart rate. But there were no serious adverse events or discontinuations due to treatment-emergent adverse events with NLS-1.
Despite the positive efficacy outcomes, NLS co-founder and CEO Alex Zwyer told BioWorld Today that efficacy is only half of the story. “Right now, efficacy is not the real issue in ADHD treatment, because you do have stimulants and they’re a very effective treatment, working for many people very well.” The problem, he said, is on the safety side. Common side effects from stimulants frequently used to treat the condition can include anxiety, irritability, decreased appetite and problems sleeping.
NLS-1, a controlled-release formulation of mazindol, a schedule IV substance in the U.S., is thought to perhaps have a role in regulating the orexins system in the hypothalamus. An immediate-release formulation manufactured by Novartis AG was previously approved in Europe, Japan and the U.S. for the short-term treatment of obesity, but it was discontinued in 1999 for reasons unrelated to its efficacy and safety, according to the FDA.
Mazindol’s potential to quell ADHD symptoms was first observed in an open-label pilot study that assessed its efficacy, safety and pharmacokinetics in children ages 9 to 12 with severe ADHD but who were low responders or nonresponsive to methylphenidate. That trial, called MAZDAH, was run at the French Assistance Publique Hôpitaux de Paris, from which NLS later acquired the patent for mazindol. For the 21 of 24 children who were evaluable, lead investigator Eric Konofal, a co-founder of NLS, found the mean change in score in ADHD RS-IV after one week of mazindol treatment was −24.1 (p<0.0001), greater than a 90 percent improvement from baseline.
Formerly known as Neurolifesciences SAS, NLS has roots going back to 2013, but it was founded in its current incarnation in June 2015. To date, it has secured $8.5 million in series A funding, which arrived at the end of August 2015, and series B financing earlier this year. As part of the series B round, the company added new investors and advisors, including former Novartis CEO Thomas Ebeling; Claus Christiansen, co-founder and chairman of the Nordic Bioscience Group; and Hervé Girsault, formerly global head of mergers and acquisitions, business development and strategy at Novartis Consumer Health. Though he declined to share the dollar value of the series B round, Zwyer said it could carry the company all the way to a potential IPO or other phase III-enabling financing.
In addition to developing mazindol in ADHD, a project it is pursuing exclusively in the U.S., NLS is also working to advance mazindol as a potential treatment for narcolepsy, a condition for which mazindol has U.S. and EU orphan drug status.