Developers Resubmit BLA for Denileukin Diftitox in Relapsed/Refractory CTCL

Resubmission of the BLA followed receipt of a complete response letter (CRL) from the FDA for denileukin diftitox in July 2023.

A biologics license application (BLA) for denileukin diftitox (Lymphir) as a treatment for patients with relapsed/refractory cutaneous T-cell lymphoma (CTCL) following 1 or more prior lines of systemic therapy has been resubmitted to the FDA, according to a press release from Citius Pharmaceuticals.¹

Resubmission of the BLA followed receipt of a complete response letter (CRL) from the FDA for denileukin diftitox in July 2023.² Although the regulatory agency highlighted no concerns with safety or efficacy findings included in the original BLA submission, developers were requested to implement enhanced product testing and additional manufacturing controls.

“We appreciate the FDA's expeditious review of our application. We intend to provide additional data and remain fully engaged with the FDA as we continue to work toward approval. We remain confident in the potential of [denileukin diftitox] to become an important addition to the treatment landscape for patients with relapsed or refractory CTCL and make a meaningful difference in their lives,” Leonard Mazur, cofounder, chief executive officer, and chairman of the Board of Directors of Citius Pharmaceuticals, said in a press release at the time the FDA sent the CRL.²

Developers believe they have fulfilled all requests related to manufacturing and product testing described in the CRL. Following the FDA’s acceptance of the resubmitted BLA, the regulatory agency is anticipated to issue a Prescription Drug User Fee Act date for denileukin diftitox within 30 days.

Developers submitted the original BLA for denileukin diftitox in relapsed/refractory CTCL to the FDA in September 2022.³ The FDA subsequently accepted the BLA for denileukin diftitox in December 2022.⁴

Supporting data for the BLA came from a multi-center, single-arm phase 3 study (NCT01871727).⁵ Among 69 evaluable patients in the independent review committee (IRC) primary efficacy analysis set, denileukin diftitox produced an objective response rate (ORR) of 36.2% (95% CI, 25.0%-48.7%) and a median duration of response (DOR) of 6.5 months (range, 3.0+ to 23.5+). Additionally, the median time to response (TTR) in this cohort was 1.41 months, and the clinical benefit rate (CBR) was 49.3% (95% CI, 37.0%-61.6%).

Among 71 evaluable patients included in the investigator efficacy analysis set, data highlighted an ORR of 42.3% (95% CI, 30.6%-54.6%) and a median DOR of 5.7 months (range, 0.7+ to 26.1+). Investigators also reported a median TTR of 1.41 months and a CBR of 53.5% (95% CI, 41.3%-65.5%).

Safety data in the phase 3 trial were comparable with previous reports, and investigators highlighted no new safety signals. The most common adverse effects (AEs) included nausea, fatigue, alanine aminotransferase increases, chills, and peripheral oedema.

“We are encouraged by the results of the study, which we believe are clinically meaningful, and are hopeful that [denileukin diftitox] will be an important treatment option for patients with persistent or recurrent CTCL,” Myron Holubiak, co-founder and executive vice chairman at Citius, said in a press release on these findings.⁵ “We believe the full body of data from this and prior studies will support a successful reintroduction of denileukin diftitox to the market.”

In the phase 3 study, 91 patients with stage I to IV persistent or recurrent CTCL received denileukin diftitox at 9 μg/kg per day via intravenous infusion over 60 minutes for 5 consecutive days every 21 days.

The trial’s primary end points included dose-limiting toxicities and the maximum tolerated dose during the lead-in portion and ORR in the main portion. Secondary end points included DOR, TTR, AEs, and total body clearance.

Patients 18 years and older with a histopathological diagnosis of CTCL and 1 or more prior lines of therapy were able to enroll on the trial. Other eligibility criteria included having adequate bone marrow reserves and hepatic function, a life expectancy of at least 12 months, and an ECOG performance status of 0 or 1.

References

1. Citius Pharmaceuticals resubmits the biologics license application of LYMPHIR™ (denileukin diftitox) for the treatment of adults with relapsed or refractory cutaneous T-cell lymphoma. News release. Citius Pharmaceuticals, Inc. February 13, 2024. Accessed February 15, 2024. http://tinyurl.com/4hkmmamr
2. Citius Pharmaceuticals, Inc. receives a complete response letter from the U.S. Food and Drug Administration (FDA) for LYMPHIR™ (denileukin diftitox) for the treatment of patients with relapsed or refractory cutaneous T-cell lymphoma. News release. Citius Pharmaceuticals, Inc. July 29, 2023. Accessed February 15, 2024. http://tinyurl.com/2aub7w7b
3. Citius Pharmaceuticals, Inc. submits biologics license application to the U.S. Food and Drug Administration for denileukin diftitox for the treatment of patients with persistent or recurrent cutaneous T-cell lymphoma. News release. Citius Pharmaceuticals, Inc. September 28, 2022. Accessed February 15, 2024. https://bit.ly/3fy8C1d
4. Citius Pharmaceuticals, Inc. announces U.S. Food and Drug Administration acceptance of biologics license application of denileukin diftitox for the treatment of patients with persistent or recurrent cutaneous T-cell lymphoma. News release. Citius Pharmaceuticals, Inc. December 1, 2022. Accessed February 15, 2024. bit.ly/3Upq3jd
5. Citius Pharmaceuticals reports topline data from the pivotal phase 3 study of cancer immunotherapy I/ONTAK (E7777) for the treatment of persistent or recurrent cutaneous t-cell lymphoma (CTCL) in support of BLA submission. News release. Citius Pharmaceuticals, Inc. April 6, 2022. Accessed February 15, 2024. https://prn.to/3CaaHrV