Because the investigational compound continues to be vetted by the FDA, analysis sheds gentle on its interactions with different widespread therapies, security and opposed occasions, and abuse potential.
Pitolisant is a first-in-class molecule with a novel mechanism of motion. The selective histamine Three receptor antagonist/inverse agonist is being developed in america by Concord Biosciences LLC for the potential remedy of extreme daytime sleepiness and/or cataplexy in grownup sufferers with narcolepsy.
Whereas the FDA evaluations the New Drug Utility, to which it granted Precedence Evaluation, analysis abstracts offered on the American Academy of Neurology (AAN) 2019 convention and SLEEP 2019 present a set of insights into the drug’s laboratory and real-world efficiency.
Use as Mono and as Mixture Remedy
Pitolisant demonstrated incremental symptom enchancment when added to widespread narcolepsy therapies within the Concord Three trial, an open-label real-world examine that came about in France and Hungary from 2011 to 2012—”much like the enhancements seen when pharmacological brokers are added on to CPAP use to deal with residual extreme sleepiness,” says Concord chief medical officer Jeffrey Dayno, MD.
A SLEEP 2019 summary revealed that Epworth Sleepiness Scale (ESS) scores decreased 4.7 factors (imply) from baseline to month 12 for sufferers on pitolisant alone; 3.2 factors when pitolisant was added on to stimulants (equivalent to modafinil); 3.6 factors in sufferers when pitolisant was added on to anticataplectics (equivalent to sodium oxybate); and Four factors when pitolisant was added on to stimulants and anticataplectics. Cataplexy episodes have been decreased in sufferers who used pitolisant as monotherapy (-71.5%) in addition to in those that used it as mixture remedy with stimulants (-100%), anticaplectics (-100%), and who used all Three drug sorts (-66%).
One other glimpse into how pitolisant interacts with widespread narcolepsy medicines comes from a compassionate use expanded entry program in america. Launched at SLEEP 2019, interim information reveals that the majority sufferers (98.1%) within the expanded entry program have beforehand tried different narcolepsy medicines, and 89% of sufferers had been on two or extra narcolepsy medicines previous to being began on remedy with pitolisant. The protection/tolerability profile of pitolisant remained in step with that seen within the medical growth program and the postmarketing setting in Europe—no new security indicators have been recognized.
Knowledge has additionally been launched from a proper drug-drug interplay pharmacokinetic (PK) evaluation, performed in two components: one was with sodium oxybate and the opposite with modafinil. “It demonstrated no clinically related PK interplay between pitolisant and sodium oxybate in addition to between pitolisant and modafinil,” Dayno says. “Primarily based on these information, no dosage changes could be required when pitolisant is dosed with these widespread therapies for narcolepsy.”
Security and Opposed Occasions
At SLEEP 2019, the highlights from an built-in evaluation of security (from Concord’s New Drug Utility work) have been offered. It discovered pitolisant to be usually protected and well-tolerated. Within the medical trials, about 3% of sufferers in each the pitolisant remedy group and placebo discontinued from the trials on account of an opposed occasion.
The commonest opposed occasion was headache, which was reported by 18% of sufferers within the pitolisant arm and 13.7% within the placebo arm. “Headache is the most typical opposed occasion, which has been constant throughout the medical trials within the growth program,” Dayno says. “One potential technique is you may decrease the dose to regulate for tolerability points.” He provides that headache and migraine are comorbid in sufferers with narcolepsy, so whereas it is without doubt one of the extra widespread unwanted effects of pitolisant, it is usually generally seen in sufferers with narcolepsy generally.
Effectiveness at One-12 months
Concord Three information offered at AAN 2019 shared outcomes from 68 sufferers who accomplished 12 months of remedy on pitolisant Total, primarily based on Epworth Sleepiness Scale (ESS) scores, 63.2% of sufferers have been responders, with 36.8% of the 68 having their ESS rating normalized at one yr. What’s extra, partial and whole cataplexy assaults have been decreased (-64% and -75%, respectively), as have been hypnagogic hallucinations (-54%) and sleep paralysis (-63%).
“Recognizing it was an open label examine, it’s vital that it checked out extreme daytime sleepiness out to 1 yr, which demonstrated reductions of about 5 factors on the Epworth Sleepiness Scale, in addition to sturdiness of impact, which was maintained out to 1 yr,” Dayno says. “The general security and tolerability profile was in step with the information from the randomized managed trials—related tolerability profile by way of the opposed occasions, no new security indicators, no proof of growth of tolerance with long-term use, and no signs associated to withdrawal in these sufferers who discontinued the examine.”
Along with the Concord Three information unveiled on the AAN and SLEEP conferences, an extended manuscript with extra information has been accepted for peer-reviewed journal publication and is predicted to publish later this yr.
Knowledge was additionally just lately launched concerning the abuse potential of pitolisant. A SLEEP 2019 summary compares pitolisant towards the Schedule IV stimulant phentermine—a typical lively comparator in abuse potential research—and towards placebo.
Pitolisant demonstrated considerably decrease drug liking and willingness to take drug once more in contrast with phentermine and a profile much like placebo. “What’s most attention-grabbing is that the general profile of pitolisant seems similar to placebo on nearly all of the scales used on this abuse potential examine. We’re not seeing a sign suggestive of serious abuse potential,” Dayno says.
Sree Roy is editor of Sleep Evaluation.