Anti-itch agents are becoming more prominent in the atopic dermatitis (AD) therapeutic space as pruritis (itchy skin) is an integral symptom, affecting all patients regardless of age and disease severity. As a result, there are multiple new product candidates in the early and late-stage pipeline, finds GlobalData, a leading data and analytics company.

Cara Therapeutics is hoping to enter the AD space with its oral kappa-opioid receptor (KOR) agonist, difelikefalin, which is already marketed in an intravenous formulation, known as Korsuva, for the treatment of moderate to severe pruritus associated with chronic kidney disease in adults undergoing hemodialysis.

Ramla Salad, Pharma Analyst at GlobalData, comments: “Cara has launched a Phase III trial, KIND-1 (NCT05387707), to evaluate the efficacy and safety of oral difelikefalin as an adjunctive therapy to topical corticosteroids (TCS) for moderate to severe pruritus in adult subjects with AD. The company aims to leverage data from this study to support first-line positioning of its oral anti-pruritic along with standard of care TCS in adults with moderate to severe pruritus. GlobalData anticipates that difelikefalin will enter the US market in Q1 2026.”

Difelikefalin’s closest competitor is Vanda Pharma’s neurokinin-1 (NK-1)-receptor antagonist, tradipitant, which has already been investigated as a monotherapy in two Phase III trials, EPIONE (NCT03568331) & EPIONE2 (NCT04140695). Despite this, tradipitant failed to meet the primary endpoint of reduction of worst itch numeric rating scale (WI-NRS) change in EPIONE, which triggered the commencement of the identical EPIONE2 study that further assesses tradipitant’s anti-pruritic effects in the mild to moderate AD patient group.

Salad continues: “EPIONE2 was on hold due to the COVID-19 pandemic but was recently marked as completed with a substantial reduction in enrolment from 200 to 80 participants. As this trial would have been pivotal for regulatory submissions, the likelihood that Vanda Pharma will initiate regulatory submissions for tradipitant is uncertain and it may be possible that another Phase III program trialling the product in combination with TCS may be needed, similar to Cara’s Phase III KIND-1 trial for difelikefalin. Even without another Phase III trial, GlobalData anticipates that tradipitant will enter the US market in Q1 2024, two years before Cara’s difelikefalin, which will likely give it a competitive advantage.”

The final anti-pruritic agent currently in development is CBP-174, a peripherally acting histamine 3 receptor antagonist, which is being developed by Connect BioPharma. So far, the product has been investigated in a Phase I (NCT04811469) trial. The company has yet to release any safety and efficacy data, but the product utilizes a unique mechanism of action, which may garner some interest as the AD pipeline continues to grow and differentiate.

Salad concludes: “The anticipated introduction of these anti-itch drugs will be advantageous for patients as it will diversify treatment options for those who have yet to alleviate their pruritus with existing therapies. Key opinion leaders interviewed by GlobalData have noted that these agents have interesting mechanisms of action, but that pivotal data is required to form solid conclusions on their potential.”