SUMMARY: The FDA on August 7, 2024 approved LYMPHIR® (Denileukin diftitox-cxdl), a novel immunotherapy for the treatment of relaped/refractory Cutaneous T-Cell Lymphoma (CTCL) after at least one prior systemic therapy.
Primary Cutaneous T Cell Lymphoma is a type of Non Hodgkin Lymphoma and includes a spectrum of diseases that primarily involve the skin, but may ultimately involve lymph nodes, blood and visceral organs such as spleen, liver and lungs. CTCL initially presents as red, scaly, itchy patches on the skin and is often misdiagnosed as eczema. Approximately 3,000 new cases are reported in the United States every year, with an estimated 30,000 – 40,000 individuals living with the disease. The incidence is higher in blacks than Caucasians or Asians. It is more common in men, and is typically first diagnosed in patients between the ages of 50 and 60 years of age. Mycosis Fungoides/Sezary Syndrome is the most common type of CTCL. There is currently no curative therapy for advanced CTCL other than Allogeneic Stem Cell Transplantation. Patients often receive several skin-directed therapies as well as systemic therapies to achieve effective disease control, but the disease eventually becomes refractory. There is therefore an unmet clinical need for novel therapies.
Denileukin diftitox is a recombinant fusion protein composed of Interleukin-2 (IL-2) receptor binding domain and diphtheria toxin fragments. It selectively targets IL-2 receptor-expressing cells, causing diphtheria toxin fragments that have entered cells to inhibit protein synthesis, leading to apoptosis. Its unique mechanism of action targets both malignant T-cells and immunosuppressive regulatory T-cells (Tregs). Transiently eliminating Tregs has the potential of unleashing potent immune responses by the immune system of the patient against their tumors. This agent was approved and marketed as ONTAK® in the US from 1999-2014 for the treatment of relapsed/refractory CTCL. However, the product was withdrawn from the market in 2014 because of manufacturing issues related to its bacterial expression. Manufacturing improvements to decrease the presence of misfolded and aggregated proteins resulted in a new and more purified bioactive formulation LYMPHIR®, that has 1.5-2 times greater specific bioactivity in non-clinical assays compared with ONTAK®. It is considered a new drug by the FDA, requiring a new registrational clinical trial.
The efficacy and safety of LYMPHIR® was assessed in a multicenter, open-label, Phase III Pivotal Study 302 of CTCL patients, who had previously received at least one systemic treatment. This analysis included 69 patients (N=69) with Stage I-III CTCL who had CD25 expression on at least 20% of biopsied malignant cells per immunohistochemistry and had received a median four prior therapies. The median age was 64 years, 65% were men, 73% were White and 19% were African American, 66 patients had Mycosis fungoides and 3 had Sezary syndrome. Approximately 30% had Stage I disease, 48% had Stage II disease and 22% had Stage III disease. Patients received LYMPHIR® 9 mcg/kg/day for 5 days, every 21 days for up to 8 cycles. The Primary efficacy outcome measure was Objective Response Rate (ORR), as assessed by an Independent Review Committee (IRC).
The Objective Response Rate was 36.2%, with 8.7% achieving a Complete Response. The median time to response was 1.41 months, with 70% of responders seeing results after 1-2 cycles of treatment. Duration of response was at least 6 months for 52% of the patients and 84% (54/64) of skin evaluable patients had a decrease in skin tumor burden, and 12.5% (8/64) saw complete clearing of skin disease. Pruritis was evaluated as an exploratory endpoint with 31.7% of patients demonstrating clinically significant pruritus improvement. Importantly, no cumulative toxicity was observed in patients receiving LYMPHIR®.
The safety profile of LYMPHIR® was consistent with the known safety profile for Denileukin diftitox. Across three studies of 119 CTCL patients receiving 9 μg dose of Denileukin diftitox, the most common (20% or more) adverse reactions including laboratory abnormalities were, infusion reactions, increased transaminases, decreased albumin, nausea, edema, anemia, fatigue, musculoskeletal pain, rash, chills, constipation, pyrexia, blurred vision and Capillary Leak Syndrome (CLS). Infusion reactions, CLS, and visual impairment were mostly Grade 1/2 and effectively managed.
In conclusion, LYMPHIR® represents a significant advancement in treating Cutaneous T-Cell Lymphoma, especially for patients who have not responded well to previous treatments. As the first systemic option in years targeting the IL-2 receptor on malignant T-cells and Tregs, LYMPHIR® provides new hope for managing the long-term challenges of CTCL, such as severe skin symptoms and secondary infections. This development moves us closer to addressing the needs of CTCL patients who struggle with ongoing disease despite prior therapies.
https://www.accessdata.fda.gov/drugsatfda_docs/label/2024/761312s000lbl.pdf
