What do Adzenys XR-ODT, Dyanavel, Vyvanse, Dexedrine, Concerta, QuiliChew and ProCentra have in common?
Answer: They’re all variations of either dextroamphetamine (Adderall) or methylphenidate (Ritalin). With few exceptions, those two compounds dominate the global pharmaceutical market for attention deficit hyperactivity (ADHD), generating billions of dollars in sales each year.
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There is value in the different formulations, to be sure. Yet there is also strong demand for a non-stimulant alternative — especially from parents struggling to treat children with the disorder.
“For the last 20 years, most of what we’ve done in ADHD is just find new ways to package and deliver the same molecules over and over again,” lamented Gregory Mattingly, a practicing ADHD physician and an associate clinical professor at Washington University School of Medicine in St. Louis, via phone.
Fortunately, a compound with a new mechanism of action may be on the way.
On Wednesday, Switzerland-based NLS Pharma announced results from its Phase 2 trial of mazindol CR (NLS-1) in 85 adults with ADHD. The drug met its primary and secondary endpoints in the double-blind, placebo-controlled study, showing both a reduction in symptoms and a gain of function.
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Safety and tolerability were similar to what was seen in the placebo arm and no participants dropped out of the six-week study.
Mattingly was heartened by the data, having served as a study investigator for NLS Pharma’s trial and many other experimental ADHD medications.
The drug began to relieve symptoms within the first week of dosing, he said. By comparison, non-stimulants often take six weeks or longer to kick in — too long for many patients. “They need to feel better quickly and they lose patience. That’s part of the condition,” Mattingly explained.
On the other hand, the effects of mazindol CR weren’t instantaneous and there was no noticeable high or peak. Both Ritalin and Adderall regularly feature in top ten lists of the most abused prescription drugs in the United States, alongside opioids and benzodiazepines such as Xanax.
“As a clinician and as a researcher, I like once-daily medicines that are as smooth as possible,” Mattingly said. “I don’t like medicines that require multiple dosing because people forget them. I don’t like medicines where people feel them kick in and wear off because they start using them for the wrong reasons.”
Longer acting forms of the stimulants have helped to decrease the likelihood of abuse, but the underlying drug still affects mood. It’s a problem for society at large and for those using the medications. Logistically, there are a lot of restrictions placed on the dispensing of the drugs (such as no refills).
Many patients also don’t like the idea that they or their child is dependent on a psychostimulant. But the need remains. The majority of children with the disorder will continue to experience symptoms into adolescence and 30-50 percent of children diagnosed will continue to have problems as adults.
While it’s new to ADHD, mazindol CR has been quietly sitting on the market for other indications. It was approved in Europe as a tool for weight loss or to modulate sleep. However, it soon became apparent that the anti-obesity effects weren’t sustained and users reported significant anxiety. Either way, the effects wore off after a few weeks.
“As a weight loss drug, it hasn’t been very popular,” Mattingly said. “The good news is, for an ADHD medication that’s exactly what you want. You don’t want one that keeps causing weight loss and people keep trying to use it for issues other than what they should be using it for, which is cognition.”
According to Mattingly, the drug raises dopamine and norepinephrine; two neurotransmitters strongly associated with ADHD. He also points to some interesting preliminary data showing mazindol’s activity on orexin (hypocretin), which helps control the sleep-wake cycle. This could be valuable for patients who might struggle to switch their brains off at night and then struggle to concentrate the next day. It also suggests there could be uses beyond ADHD, for the treatment of hypersomnia (excessive daytime sleepiness) or perhaps narcolepsy.
“This is one of the two or three compounds coming through that I think really has breakthrough status,” Mattingly said, singling it out from a pipeline of amphetamine and methylphenidate derivates. But as always, there are risks with doing something new.
Tel Aviv, Israel-based Alcobra was also developing a novel non-stimulant therapy, metadoxine. Unfortunately, the drug failed to reach its primary endpoint in a Phase 3 trial in January, causing its stocks to plummet 43 percent.
Photo: Thinglass, Getty Images
