Phase 2 Trial Finds Difelikefalin Could Prove Useful in Notalgia Paresthetica

Brian Kim, MD

Results of a phase 2 trial suggests difelikefalin, a medication with approval from the US Food and Drug Administration for treatment of moderate-to-severe itching associated with chronic kidney disease in adults undergoing hemodialysis, has the potential to become the first approved therapy for notalgia paresthetica.

Named the KOMFORT trial, results of the phase 2 study, which included enrolled 126 patients with notalgia paresthetica, indicate use of difelikefalin was associated with modestly greater reductions in itch intensity scores than placebo during the study period, but investigators expressed concern regarding an increased frequency of adverse events in the difelikefalin arm of the trial.

“For those who experience chronic itch of any kind, relief can sometimes seem unattainable,” said principal investigator Brian S. Kim, MD, the Sol and Clara Kest Professor of Dermatology, Vice Chair of Research, and Director of the Mark Lebwohl Center for Neuroinflammation and Sensation at Icahn Mount Sinai.² “In this Phase 2 trial, treatment with difelikefalin resulted in a reduction in the intensity of itch in patients with notalgia paresthetica.”

A chronic neuropathic pruritus, the etiology of notalgia paresthetica is not completely understood³ and, with no FDA-approved therapies specifically indicated for the condition, a potential treatment for pruritus associated with notalgia paresthetica could improve quality of life for a large swath of patients. After demonstrating efficacy in phase 2 studies of pruritus in chronic kidney disease and atopic dermatitis, the KOMFORT trial was launched to evaluate the potential of difelikefalin, a selective kappa opioid receptor agonist, for the treatment of moderate-to-severe pruritus associated with notalgia paresthetica.¹

A randomized, double-blind, placebo-controlled trial, the KOMFORT trial enrolled adult patients aged 18-80 years of age with a diagnosis of active notalgia paresthetica by a site investigator at 28 sites across North America. For inclusion, patients were required to have at least a 6-month history of chronic pruritus caused by notalgia paresthetica, with moderate-to-severe pruritus at baseline, and to be considered a candidate for systemic therapy.

Per trial protocol, patients were randomized in a 1:1 ratio after a 7-day run-in period to either oral difelikefalin at a dose of 2 mg twice daily or matching placebo for a period lasting 8 weeks. The primary outcome of interest for the study was the change from baseline to week 8 in weekly mean score on the daily Worst Itch Numeric Rating Scale (WI-NRS), which has scores ranging from 0 to 10 with higher numbers indicating worsening itch. Secondary outcomes of interest for the study included itch-related quality of life and itch-related sleep measures.

Overall, 126 patients were rolled in the trial, with 62 randomized to oral difelikefalin and 63 randomized to matching placebo. Investigators noted a single patient who had been randomized to receive difelikefalin withdrew consent before the first dose and was not included in main analyses. Among the overall study cohort, the majority of patients were White women, the mean age was approximately 60 years, and the mean duration of notalgia paresthetica was more than 8 years. The mean WI-NRS score for each group was 7.6, with most patients reporting severe itch.¹

Upon analysis, results indicated the change from baseline to week 8 for mean WI-NRS was -4.0 points in the difelikefalin group and -2.4 points in the placebo group (difference, -1.6 points [95% confidence interval [CI], -2.6 to -0.6]; P=.001). For the secondary outcomes of interest, results indicated the mean change from baseline in the Skindex-10 total score at week 8 was -20.1 points in the difelikefalin group and -18.7 points in the placebo group (difference, -1.4 points [95% CI, −6.7 to 3.9]) and the change in score on the Sleep Disturbance Subscale was −15.7 points in the difelikefalin group and −16.3 points in the placebo group (difference in change, 0.6 points [95% CI, −6.6 to 7.7]).¹

Regarding safety and discontinuation, investigators pointed out 14 patients in the difelikefalin group and 6 patients in the placebo group discontinued the trial before 8 weeks and 103 patients (48 from the difelikefalin group and 55 from the placebo group) entered the active treatment open-label extension period. In total, adverse events were reported among 56% of the difelikefalin group and 51% of the placebo group.¹

“The encouraging results achieved in this trial could reenergize the field and mark an important step toward improving symptoms of itch for patients with notalgia paresthetica,” Kim added.²

References:

1. Kim BS, Bissonnette R, Nograles K, et al. Phase 2 trial of Difelikefalin in Notalgia paresthetica. New England Journal of Medicine. 2023;388(6):511-517. doi:10.1056/nejmoa2210699
2. Mount Sinai Health System. New formulation of FDA-approved drug shows encouraging results for treating a common itch condition. Mount Sinai Health System. https://www.mountsinai.org/about/newsroom/2023/new-formulation-of-fda-approved-drug-shows-encouraging-results-for-treating-a-common-itch-condition. Published February 8, 2023. Accessed February 9, 2023.
3. Robbins BA, Rayi A, Ferrer-Bruker SJ. Statpearls - NCBI Bookshelf. Notalgia Paresthetica. https://www.ncbi.nlm.nih.gov/books/NBK430685/. Accessed February 9, 2023.