Notalgia paresthetica: may κ-opioid receptor agonists be a long-awaited effective therapy?

Until present, there are no treatment possibilities for notalgia paresthetica, a common sensory neuropathy of the back characterised by chronic pruritus. In a phase 2 trial, difelikefalin led to a rapid decrease in pruritus with first effects seen as early as day 1.

Difelikefalin activates κ-opioid receptors on peripheral sensory neurons and suppresses itch, predominantly by a neuromodulation effect. In an intravenous preparation, it is already approved for the treatment of moderate-to-severe pruritus in adults with chronic kidney disease undergoing haemodialysis. In the phase 2 KOMFORT trial (NCT04706975), the κ-opioid receptor agonist difelikefalin in an oral preparation was evaluated for the treatment of moderate-to-severe pruritus in patients with a confirmed diagnosis of notalgia paresthetica, a common sensory neuropathy of the back characterised by chronic pruritus. After a run-in period, participants were treated with difelikefalin (2 mg, twice daily) or placebo for 8 weeks. The primary study endpoint was the change from baseline in the weekly mean change of daily ≥4-point improvement (reduction) in their worst itch numerical rating scale (WI-NRS) at 8 weeks. The double-blind study phase was followed by an ongoing 4-week active extension. Prof. Mark Lebwohl (Icahn School of Medicine at Mount Sinai, NY, USA) presented the 8-week results [1].

At this time, the change from baseline in WI-NRS score was -4.0 for participants treated with difelikefalin versus -2.4 when treated with placebo (P=0.001). “A significant difference was seen as early as day 1,” Prof. Lebwohl commented. Difelikefalin was also superior regarding a couple of secondary study endpoints: 41% of participants treated with difelikefalin achieved a ≥4-point improvement in WI-NRS score at week 8 compared with 18% in the placebo group (P=0.007). In addition, 23% of participants treated with difelikefalin experienced a complete response at week 8 compared with 5% for placebo (P=0.008).

The most commonly reported treatment-emergent adverse events with difelikefalin were dizziness and nausea. All adverse events were mild-to-moderate in severity (see Table). “Dizziness was common on day 1 and 2 but disappeared quickly,” Prof. Lebwohl pointed out.

Table: Most commonly reported treatment-emergent adverse events in the KOMFORT trial [1]



TEAEs, treatment-emergent adverse events.

*Safety analyses were conducted in the safety population, which was defined as all randomised patients who received at least 1 dose of study drug.

The study underscores that difelikefalin has the potential to fill an urgent unmet need and warrants further clinical development in notalgia paresthetica, Prof. Lebwohl concluded.

1. Kim BS, et al. A phase 2 study of oral difelikefalin for moderate-to-severe pruritus in subjects with notalgia paresthetica (KOMFORT). D1T01.3I, EADV Congress 2022, Milan, Italy, 7–10 September.

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Posted on 5 November 2022