Pharmacyclics, a biopharmaceutical company focused on developing and commercializing innovative small-molecule drugs, announced that the US Food and Drug Administration (US FDA) has granted Imbruvica (ibrutinib) regular (full) approval for the treatment of patients with chronic lymphocytic leukaemia (CLL) who have received at least one prior therapy, and for the treatment of CLL patients with deletion of the short arm of chromosome 17 (del 17p CLL), including treatment naive and previously treated del 17p CLL patients.

This is the first full FDA approval for Imbruvica, and was granted within six months after the accelerated approval for patients with previously treated CLL in February 2014.  Imbruvica had received the Breakthrough Therapy Designation for patients with del 17p CLL in April 2013. Imbruvica is being jointly developed and commercialised by Pharmacyclics, Inc. and Janssen Biotech, Inc.

This full approval is based on data from the Phase III RESONATE study (PCYC-1112-CA), a randomiSed, multi-centre, international head-to-head comparison of single-agent, orally-administered Imbruvica versus the intravenous, monoclonal antibody ofatumumab targeting the CD 20 antigen. This study enrolled 373 patients with CLL and 18 patients with small lymphocytic lymphoma (SLL), who received at least one prior therapy. The median number of prior treatments was 2 (range, 1 to 13 treatments). At baseline, the median age of these patients was 67 years, 58per cent of whom had at least one tumor  >  5 cm, and 32per cent of whom had the del 17p mutation. Patients receiving Imbruvica demonstrated a statistically significant improvement in progression-free survival (PFS), overall survival (OS) and overall response rate (ORR) as compared to patients treated with ofatumumab. The median PFS and OS has not been reached on the Imbruvica arm. There was a 78per cent statistically significant reduction in the risk of progression or death as assessed by an independent review committee (IRC) according to the modified IWCLL criteria (HR 0.22, 95per cent CI, 0.15 to 0.32). In addition, the analysis of overall survival demonstrated a 57per cent statistically significant reduction in the risk of death for patients in the Imbruvica arm (HR 0.43; 95 CI, 0.24 to 0.79). This was observed despite a total of 57 patients who were initially randomized to ofatumumab crossing over to receive Imbruvica prior to the analysis. For previously treated del 17p CLL patients, there was a 75per cent reduction in the risk of progression or death as assessed by an IRC (HR 0.25, 95per cent CI, 0.14 to 0.45).

"Imbruvica demonstrated substantial evidence of its superiority over ofatumumab and significant benefit for previously treated CLL patients, while maintaining a favorable safety profile. This FDA approval for Imbruvica is a major step toward chemo-free treatment in CLL," said John Byrd, M.D.,* Director, Division of Hematology, The Ohio State University Comprehensive Cancer Center - Arthur G. James Cancer Hospital & Richard J. Solove Research Institute and lead investigator for RESONATE. "Patients with deletion 17p CLL are at particularly high risk for poor outcomes. Today's approval of Imbruvica provides these patients with the only FDA-approved treatment, regardless of whether their disease is treatment naïve or previously treated. I continue to be awed by the duration of my patients' responses to Imbruvica and am grateful Imbruvica now is available to a broader group of CLL patients."

CLL is a slow-growing blood cancer of the white blood cells. CLL is the most common adult leukemia in the Western world and predominately a disease of the elderly with a median age at diagnosis of 72 years.

"We are delighted Imbruvica has received full approval by demonstrating its ability to improve progression-free survival and, importantly, overall survival as compared to an approved standard of care, and that Imbruvica is now available to all patients with del 17p CLL," said Danelle James, M.D., vice president, Clinical Development, Pharmacyclics. "Our goal is to provide patients with clinically meaningful treatments. Thanks to the physicians and patients who helped us complete this trial in near record time, today, we have delivered on that goal by bringing Imbruvica to an even broader group of patients."

Within CLL, the most commonly occurring adverse reactions ( > 20per cent) were thrombocytopenia, neutropenia, diarrhoea, anaemia, upper respiratory tract infection, musculoskeletal pain, bruising, rash, fatigue, nausea, and pyrexia. Approximately 5 per cent of patients with CLL receiving Imbruvica discontinued treatment due to adverse events. These included infections (2 per cent), subdural hematoma (2 per cent) and diarrhea (1 per cent). Adverse events leading to dose reduction occurred in approximately 6per cent of patients. The Warnings and Precautions include: haemorrhage, infections, cytopenias, atrial fibrillation, secondary primary malignancies, embryo-fetal toxicities.

This approval for Imbruvica triggers $60 million in milestone payments to Pharmacyclics under its collaboration agreement with Janssen Biotech, Inc.
Imbruvica is a first-in-class, oral, once-daily therapy that inhibits a protein called Bruton's tyrosine kinase (BTK). BTK is a key signaling molecule in the B-cell receptor signaling 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.

Imbruvica was one 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.

The overall clinical development programme in CLL currently includes seven phase III trials and covers all lines of therapy and various combinations of treatments. Janssen and Pharmacyclics entered a collaboration and license agreement in December 2011 to jointly develop Imbruvica.

Pharmacyclics is a biopharmaceutical company focused on developing and commercializing innovative small-molecule drugs for the treatment of cancer and immune mediated diseases.