FDA Accepts Ibrutinib Application for GVHD

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The FDA has accepted a supplemental new drug application for ibrutinib as a treatment for patients with chronic graft-versus-host-disease after failure of 1 or more lines of systemic therapy.

The FDA has accepted a supplemental new drug application (sNDA) for ibrutinib (Imbruvica) as a treatment for patients with chronic graft-versus-host-disease (cGVHD) after failure of 1 or more lines of systemic therapy, according to Janssen and AbbVie, the codevelopers of the BTK inhibitor.

The sNDA is based on data from the single-arm phase Ib/II PCYC-1129 trial, which were first presented during the 2016 ASH Annual Meeting. In the study, ibrutinib induced an overall response rate of 67% and showed clinically meaningful and durable responses in patients who failed at least 1 prior treatment for cGVHD. Twenty-one percent of responders had a complete response and 45% had a partial response. Additionally, most responders were able to reduce steroid doses to an acceptable minimal level.

The FDA granted a breakthrough therapy designation to ibrutinib as a potential treatment for cGVHD after failure of 1 or more lines of systemic therapy in June 2016. Under its standard review process, the FDA will issue its final decision on the ibrutinib sBLA within 12 months from the time of submission.

“Patients with chronic-graft-versus-host-disease are traditionally prescribed corticosteroids, which often do not produce an adequate response and may cause serious health complications for some patients,” Lori Styles, MD, senior medical director and GVHD program clinical lead at Pharmacyclics, an AbbVie company, said in a statement. “This regulatory filing is meaningful as it signifies the first potential indication for ibrutinib outside of hematological malignancies in a disease that severely impacts the patient's quality of life.”

In the PCYC-1129 trial, researchers evaluated 42 previously treated patients with cGVHD who continued on steroid-based regimens. Eligible patients had failed 3 or fewer prior therapies for cGVHD and had either more than 25% body surface area involving an erythematous rash or an NIH mouth score greater than 4.

Patients received once-daily oral ibrutinib (420 mg) in combination with ongoing therapies, including corticosteroids and other immunosuppressants, until progression/worsening of cGVHD, recurrence of underlying malignancy, or unacceptable toxicity. The primary endpoint was cGVHD response based on the 2005 NIH consensus response criteria.

Seventy-one percent of patients had a sustained cGVHD response of at least 5 months. Furthermore, cGVHD response was observed across multiple organs: 56% (20/25) of patients with 2 or more involved organs at baseline responded in at least 2 organs, and 42% of patients with 3 or more involved organs at baseline responded in at least 3 organs.

The most common adverse events (AEs) were fatigue (57%), diarrhea (36%), muscle spasms (29%), nausea (26%), and bruising (24%). Twenty-two (52%) patients experienced serious AEs, including pneumonia (6 patients ), septic shock (2 patients), and pyrexia (2 patients).

Based on these data, researchers initiated a phase III study to evaluate ibrutinib with corticosteroid versus placebo with corticosteroid as a first-line therapy for patients with new onset moderate or severe cGVHD. That trial is currently ongoing.

“Patients with chronic graft-versus-host-disease face an unpredictable, debilitating and sometimes life-threatening disease journey, which is further complicated by lack of FDA-approved medicines,” Sen Zhuang, MD, PhD, vice president of clinical development, hematology for Janssen Research & Development, said in a statement. "We continue to study the mechanism of action of Imbruvica, and are committed to exploring its potential to transform treatment paradigms and patient outcomes beyond its current indications in blood cancers.”

Ibrutinib was first approved in 2013 as a treatment for patients with mantle cell lymphoma, and has since gained further indications for chronic lymphocytic leukemia and Waldenström's macroglobulinemia.

Miklos D, Cutler CS, Arora M, et al. Multicenter open-label phase 2 study of ibrutinib in chronic graft versus host disease (cGVHD) after failure of corticosteroids. Presented at: 2016 ASH Annual Meeting; December 3-6, 2016; San Diego, California. Abstract LBA3.