AbbVie, a global biopharmaceutical company, has submitted a supplemental New Drug Application (sNDA) to the US Food and Drug Administration (FDA) based on the randomized, multi-center, open-label phase III RESONATETM-2 (PCYC-1115) trial assessing the use of Imbruvica (ibrutinib) versus chlorambucil in treatment-naive chronic lymphocytic leukaemia (CLL) patients aged 65 years or older.
AbbVie announced top-line findings from the trial in June 2015 showing that Imbruvica improved progression-free survival (PFS; primary endpoint) and multiple secondary endpoints including overall survival (OS) and overall response rate (ORR) in treatment-naive patients with CLL. Imbruvica is jointly developed and commercialised by Pharmacyclics LLC, a subsidiary of AbbVie and Janssen Biotech, Inc.
"This submission highlights the expanded potential and strong value of Imbruvica as a treatment for CLL," said Erik von Borcke, president of Pharmacyclics. "We are pleased treatment-naive patients may soon have an alternative to traditional cytotoxic chemotherapy."
Imbruvica is currently approved for the treatment of patients with CLL who have received at least one prior therapy and CLL patients (including treatment-naive) who have del 17p, a genetic aberration that occurs when part of chromosome 17, the location of the tumour suppressor gene p53, has been lost or deleted.
The data have been submitted for publication in a peer-reviewed journal and presentation at an upcoming medical conference.
The RESONATE-2 trial is a Pharmacyclics-sponsored study and its protocol and specific performance goals were established in a special protocol assessment (SPA) with the FDA. A SPA is an agreement with the FDA that a phase III clinical trial design, its clinical endpoints and statistical analyses are acceptable to the Agency to support a submission and potential approval. The trial enrolled 269 treatment-naive patients with CLL or small lymphocytic lymphoma (SLL) aged 65 years or older in the US, EU and other regions. Patients were randomized to receive either ibrutinib 420 mg orally, once daily until progression or unacceptable toxicity, or chlorambucil on days 1 and 15 of each 28-day cycle for up to 12 cycles. The starting dose for chlorambucil in Cycle 1 was 0.5 mg/kg and was increased based on tolerability in Cycle 2 by increments of 0.1 mg/kg to a maximum of 0.8 mg/kg. The primary endpoint of the study was PFS as assessed by an Independent Review Committee according to the International Workshop on Chronic Lymphocytic Leukemia (iWCLL) 2008 criteria, with modification for treatment-related lymphocytosis. Key secondary endpoints included ORR, OS and safety.
The prevalence of CLL/SLL is approximately 115,000 patients in the United States, with approximately 16,000 newly diagnosed patients every year. As this orphan disease frequently progresses following treatment with existing first-line therapies, patients are faced with fewer treatment options and often are prescribed multiple lines of therapy as they relapse or become resistant to current standard of care treatments.
In CLL/SLL, the genetic aberration del 17p occurs when part of chromosome 17, the location of the tumour suppressor gene p53, has been lost or deleted. CLL/SLL patients with del 17p have poor treatment outcomes. Del 17p is reported in approximately 7 per cent of treatment-naive CLL/SLL cases, and approximately 20 per cent to 40 per cent of relapsed/refractory patients harbour the mutation.
Imbruvica is currently approved for the treatment of patients with chronic lymphocytic leukaemia (CLL) who have received at least one prior therapy, all CLL patients who have del 17p and patients with Waldenstrom's macroglobulinemia. Imbruvica is also approved for the treatment of patients with mantle cell lymphoma (MCL) who have received at least one prior therapy. Accelerated approval was granted for the MCL indication based on overall response rate. Continued approval for this indication may be contingent upon verification of clinical benefit in confirmatory trials.
Imbruvica is a first-in-class, oral, once-daily therapy that inhibits a protein called Bruton's tyrosine kinase (BTK). Imbruvica was one of the first medicines to receive US FDA approval via the new Breakthrough Therapy designation pathway, and is the only product to have received three Breakthrough Therapy designations.
BTK is a key signalling molecule in the B-cell receptor signalling complex that plays an important role in the survival and spread of malignant B cells. Imbruvica blocks signals that tell malignant B cells to multiply and spread uncontrollably.