Regulatory Decision Summary for Ledaga

The efficacy and safety of Ledaga (chlormethine gel) were evaluated in a phase II, multi-centre, randomized, non-inferiority, blinded study of 242 previously treated stage I and IIA mycosis fungoides-type cutaneous T-cell lymphoma (MF) patients. Patients were required to have central and local pathology confirmation of the diagnosis of mycosis fungoides to be eligible for the study. All patients also needed to have at least one prior skin-directed therapy. Demographic parameters (gender, age, and race) and baseline disease characteristics (stage of disease, duration of disease, prior therapies) were balanced between treatment arms. Patients were randomized to receive either Ledaga (Chlormethine gel, 0.02%) or a 0.02% Chlormethine ointment compounded in Aquaphor (AP). The primary endpoint of the pivotal trial, Composite Assessment of Index Lesion Severity (CAILS) met the acceptance criteria for non-inferiority. CAILS’s response rate ratio was 1.24 (95% confidence interval [CI] 0.98 to 1.58) in favor of Ledaga. The CAILS response rate was 60% in Ledaga arm and 48% in control arm. The secondary endpoint, Severity Weighted Assessment Tool (SWAT) supported the primary endpoint. SWAT’s response rate ratio was 1.07 (95% CI 0.82 to 1.39). The SWAT response rate was 50% in the Ledaga arm, and 46% in the control arm. Duration of CAILS response and duration of SWAT response were similar between treatment arms. Overall, the efficacy data from this trial demonstrated that Ledaga was non-inferior to the compounded topical Chlormethine formulation.

The safety of Ledaga was evaluated in 255 patients with early stage MF. The duration of treatment was similar between treatment arms with a median of approximately 52 weeks. Fifty-five percent of patients required interruption of treatment or reduction of dose frequency during the clinical trial. The most common adverse event was dermatitis which is a known adverse event with topical chlormethine. 73% of Ledaga-treated patients and 69% AP-treated patients experienced dermatitis, or a complication from dermatitis. Grade 3-4 dermatitis was reported in 29% of patients in Ledaga arm and 19% in control arm. Treatment discontinuations due to AEs (22% in Ledaga arm, 18% in control arm) were due to skin-related AEs. Most cases of dermatitis resolved, however 9% in Ledaga arm and 13% in control arm had residual dermatitis at the end of the clinical trial. Eleven of 255 (4%) patients developed non-melanoma skin cancer (nMSC) during the course of the clinical trial or during long-term follow-up. Risk factors associated with development of nMSC include age ≥ 65 years and prior history of nMSC, but not duration of MF or treatment type (Ledaga vs. control formulation). Monitoring for nMSC and new skin lesions was added to the product monograph. The safety information and relevant risk management recommendations are adequately described in the final product monograph.

The final indication was the following:

The topical treatment of stage IA and IB mycosis fungoides-type cutaneous T-cell lymphoma in adult patients who have received prior skin-directed therapy.

This indication was based on the fact that only 4 patients had been enrolled in the pivotal clinical trial with IIA mycosis fungoides-type cutaneous T-cell lymphoma, which was considered insufficient to characterize the efficacy and safety of Ledaga in this patient population with extensive skin involvement. In addition, the pivotal clinical trial included only patients that had received prior skin-directed therapy, leading to uncertainties related to the efficacy and safety of Ledaga that were treatment-naïve. The final indication is also consistent with the indication granted to Chlormethine gel product Valchlor in the United States.

Chlormethine’s non-clinical toxicology profile was gathered from published literature in support of the market authorization for Ledaga. Considering the known mode of action and main toxicities existing in the literature and the fact that topically applied chlormethine leads to no detectable systemic exposure, the sponsor’s approach was found acceptable.

A Risk Management Plan (RMP) was reviewed by the Marketed Health Products Directorate and considered acceptable.

Taking into account the overall evidence, the data support that Ledaga Efficacy/Harm/Uncertainty profile is positive for the recommended indication and used under the approved conditions of use.