Insights into the FDA Approval of Denileukin Diftitox for R/R Cutaneous T-Cell Lymphoma Treatment

Results from the Pivotal Study 302

Myron Czuczman, MD, Citius Pharmaceuticals, Cranford, New Jersey, shares expert insight into the Pivotal Study 302 that led to the FDA approval of novel immunotherapy denileukin diftitox for the treatment of patients with relapsed/refractory (R/R) cutaneous T-cell lymphoma (CTCL), a rare and chronic cancer characterized by debilitating skin lesions and severe itching, after at least 1 prior systemic therapy.

Transcript:

Hello, my name Dr. Myron Czuczman. I am the Chief Medical Officer at Citius Pharmaceuticals, as well as our subsidiary Citius Oncology. I have the pleasure of speaking to you today with respect to the first commercial drug that we will have in our company. The name of it is Lymphir, [with the] generic name [of] denileukin diftitox-cxdl.

It is an immunotoxin, which is a unique agent that has interleukin 2 protein that has been fused with diphtheria toxin, [and has] been approved for adult patients with relapsed/ refractory stage 1 through 3, cutaneous T-cell lymphoma, and patients who have had at least 1 prior systemic therapy.

It impacts about 2,000 to 3,000 patients in the United States per year who are diagnosed with the disease. With respect to that, these patients often have skin-directed disease. However, over a period of time the patients can have a significant or large area of their skin involved with the disease. It can often cause a decrease in quality of life with severe pruritus as well as at times painful lesions that can often be infected as well. With respect to that, when they're first diagnosed, however, they get treated with skin-directed therapies, typically by dermatology. However, when the disease progresses into lymph nodes and/or organs, they're referred typically to hematologist/oncologists at which time the patient would be getting systemic therapy. I would state instead of being outside in, it is inside out.

With respect to those type of therapies, some of the agents that are currently used that are targeted therapies include brentuximab vedotin—a CD30 targeted antibody drug conjugate— romidepsin, which is a histone deacetylase inhibitor, or potentially [mogamulizumab], which is a (CC chemokine receptor 4) CCR4 antibody. With respect to those agents, unfortunately, these patients aren't cured, so there's always an advantage on the patients are always looking for additional treatment options.

With respect to our agent and the Pivotal study, we note that Lymphir has a unique mechanism of action. Unlike other agents that have different mechanisms, this actually targets the interleukin 2 receptor that is found on the malignant or cancerous T-cells, but also of interest, it targets and can actually deplete temporarily to regulatory T-cell, or Tregs. The importance there is that the mechanism not only has direct binding to (leukotriene) LT receptors where the diphtheria toxin is released once it gets inside the cell, it kills not only the cancer cells but knocking out Tregs allows the patient's own body to host immune system to be more effective in killing the tumor.

In addition to that, with respect to the Pivotal study, the interest there is [that it] was performed in the United States and Australia [and] took several years because of its orphan designation, but in the patients that were reviewed, there was an objective response rate [ORR] of 36%, which is part complete and partial responses (PR). In addition, that was done by a review committee. There was [about] an additional 14% of patients that had a durable, stable disease. They did not achieve a PR, but they did have improvement of disease, especially for these patients that were heavily pretreated with respect to having a median for prior anti-cancer therapies and some patients had over 8.

In that group of patients, with respect to side effects, there is something unique with respect to our agent called capillary leak syndrome. That's where a patient may have some [peripheral edema, hypertension, weight gain.] That's something that we must monitor and to clearly state that in our patients there were primarily grade 1 or 2 in nature, and essentially was reversible. [It was] very unlikely for patients to have to stop therapy as long as the patients are being monitored and clear guidelines will be set for physicians giving this agent for the first time. One of the most important things is that the serum albumin should be monitored in these patients, and should be at ≥3. I believe that'll be a significant important aspect to limit the degree or severity of capillary leak syndrome.

[Also] of interest [with] this agent, unlike other agents in my experience where as you give a drug with respect to its side effects and it has cumulative toxicity, from our database we see that we have no evidence of cumulative toxicity. As we continue therapy and maybe you'll see more side effects. What we were documenting [are] adverse events in the first and or second cycle. After that, the patients typically had minimal to low types of side effects with the agent and could continue [the agent]. The duration of response was about 6.5 months. Over 50% of patients had 6 months or greater, and another 20% of patients were able to go past equal or greater than 1 year of therapy. Typically, this drug will be given until patients progress or [if] they wouldn't be able to tolerate it again, [which is] unlikely.

When we looked at the waterfall plot in skin disease, over 84% of patients had some degree of improvement. Many patients [had] at least 50% or greater. The median response also is quite unique, which is a median 1.4 months [of] time to response. These patients [are] symptomatic, can have painful lesions, very severe pruritus. It's important that these types of symptomatic patients have agents that can relieve those type of symptoms quickly. With respect to our agent and its rapid median time to response, about 70% of patients by the time they finished the second cycle, therapy had a significant improvement in responses. One other thing would be that the treatment is given at 9 micrograms per kilogram per day [intravenous] over 1 hour, 5 days in a row every 3 weeks.

We believe that it appears that this edition of Lymphir, for these patients suffering from relapsed/refractory cutaneous T-cell lymphoma, will be welcomed by not only the physicians but the patients who have incurable disease and need more impactful therapies that are active. Since our [FDA] approval, we are looking forward to having this agent out there and to be utilized by our colleagues, hematologists/oncologists, with respect to treating patients.

In addition to that, because of its unique mechanism of action, we'll be looking at unique combinations with respect to other active agents, not only with respect to CTCL, but we would also be exploring another very common disease called peripheral T-cell lymphoma. We're not approved for that, but we'll be looking at how to approach, how to proceed with treatment for that group of patients as well, and as well as with the mechanism of knocking out Tregs transiently, it could have activity and other options in other types of malignancies.

Source:

Citius pharmaceuticals receives FDA approval for LYMPHIR™ (denileukin diftitox-cxdl) immunotherapy for the treatment of adults with relapsed or refractory cutaneous T-cell lymphoma. PR Newswire. Published online August 8, 2024. https://www.prnewswire.com/news-releases/citius-pharmaceuticals-receives-fda-approval-for-lymphir-denileukin-diftitox-cxdl-immunotherapy-for-the-treatment-of-adults-with-relapsed-or-refractory-cutaneous-t-cell-lymphoma-302217630.html