An investigational topical drug that targets a nerve sensitization pathway showed good efficacy against chronic itch in patients with pruritic psoriasis.

CT327 works by inhibiting the kinase pathway of TrkA, a receptor that controls uptake of nerve growth factor, Dr. Gil Yosipovitch said at the annual meeting of the American Academy of Dermatology.

In a placebo-controlled trial of 160 patients with pruritic psoriasis, CT327 reduced itch by a mean of 60%, said Dr. Yosipovitch, chair of dermatology at the Temple University, Philadelphia.

"Sixty percent is not 90%," he said. "But when we consider that most of the antipruritic drugs have about a 15% efficacy in comparison to a vehicle, this is an effect we should consider. It’s well tolerated, and there were no application site reactions. I see potential in this drug."

CT327, developed by Creabilis, is a selective kinase inhibitor that targets TrkA, the receptor for nerve growth factor (NGF). NGF, which is overexpressed in atopic dermatitis and psoriatic skin, sensitizes neural networks that transmit the itch sensation to the brain, Dr. Yosipovitch said.

Patients with pruritic psoriasis who took the investigational topical drug CT327 had chronic itch reduced by a mean of 60 percent.

The phase IIb study comprised 160 adults with mild to moderate psoriasis, with at least a 10% body surface area involvement. Their mean score on the modified Psoriasis Area and Severity Index (mPASI) was about 9. Most (97%) had pruritus; 69% reported this as at least moderate, with a score of 40 on a 100-point visual analog scale (VAS). A third of the group reported severe pruritus, with a VAS of more than 70. They were randomized to four groups: an emollient placebo or CT327 in concentrations of 0.05%, 0.1%, or 0.5%.

The primary endpoint was reduction on a validated 100-point pruritus visual analog scale. The secondary endpoint was change on the mPASI.

By the end of 8 weeks, most patients (108) had experienced a significant reduction on the pruritus VAS. Reductions were about 35 points for the 0.1% group and 38 points for the 0.05% and 0.5% groups. These changes represented about a 60% decrease overall, Dr. Yosipovitch said.

Changes began early and continued along a steep trajectory, reaching a significant difference from baseline by week 2. However, he pointed out, by that point, the placebo group was similarly improved. This was probably because of the benefit of the daily emollient vehicle, he noted.

The curves began to separate shortly thereafter. By week 4, all of the treatment groups had experienced about a 30-point reduction on the VAS, while the placebo group had actually increased its score slightly. The active groups continued to improve over the next 4 weeks, while the placebo group plateaued at about a 20-point decrease from baseline.

The study concluded with 4 weeks of non–treatment follow-up. During that time, the placebo group stayed at about a 20-point decline and the active groups rebounded to about that level, "suggesting that there really is something going on here biologically," Dr. Yosipovitch said.

Patients using CT327 also experienced significant – although not overwhelming – benefit on the mPASI score. About 45% responded at the 50% level, compared with 23% of those using the emollient placebo. The active groups had similar improvements, with reductions on the mPASI of between 3 and 4 points. Those in the placebo group experienced about a 1-point improvement.

Dr. Yosipovitch said he was "not too impressed" with the mPASI changes. However, he noted, "Breaking the itch-scratch cycle at its source may have broader effects on other symptoms of psoriasis."

Based on the study results, Creabilis has decided to move forward into phase III testing with the 0.05% concentration. "Preparations are already underway," Dr. Yosipovitch said in an interview. "We also have a second phase IIb study ongoing that is investigating CT327 in patients with atopic dermatitis, which will be used to help finalize our phase III programs. This study should be completed in the middle of this year."

The NGF/TrkA pathway is implicated in other disorders as well, Dr. Yosipovitch said. CT327 might be investigated in some of these.

"These include disorders [in which] pruritus is important, such as pruritus with cutaneous T cell lymphoma, where NGF/TrkA has been shown to play a role. The pathway has also been shown to play an important role in chronic neuropathic and inflammatory pain. Molecules targeting NGF have already shown clinical efficacy."

Creabilis is investigating a related molecule, CT340, an inhibitor of both TrkA and MAP2K kinase, for treating those chronic pain conditions.

Creabilis funded the study. Dr. Yosipovitch is on the company’s scientific advisory board.

msullivan@frontlinemedcom.com

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Psoriatic pruritus improves with TrkA-blocking drug