On August 29, 2017 Pfizer Inc. (NYSE:PFE) and Avillion LLP reported that a supplemental New Drug Application (sNDA) for BOSULIF (bosutinib) has been accepted for filing and granted Priority Review by the U.S. Food and Drug Administration (FDA) (Press release, Pfizer, AUG 29, 2017, View Source [SID1234520332]). If approved, the sNDA would expand the approved use of BOSULIF to include patients with newly diagnosed chronic phase Philadelphia chromosome-positive (Ph+) chronic myeloid leukemia (CML). BOSULIF is currently indicated in the U.S. for the treatment of adult patients with Ph+ CML with resistance or intolerance to prior therapy. Priority Review status accelerates FDA review time from 10 months to a goal of six months from the day of acceptance of filing, and is given to drugs that may offer major advances in treatment or may provide a treatment for which no adequate therapy exists. The Prescription Drug User Fee Act (PDUFA) goal date for a decision by the FDA is in December 2017.

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In addition, the European Medicines Agency (EMA) has validated for review a Type II Variation application for use of BOSULIF in the same patient population. In Europe, BOSULIF has conditional marketing authorization for the treatment of adult patients with Ph+ CML previously treated with one or more tyrosine kinase inhibitors (TKIs) and for whom imatinib, nilotinib and dasatinib are not considered appropriate treatment options.

The submissions are based on results from BFORE (Bosutinib trial in First line chrOnic myelogenous leukemia tREatment), a multi-center, multinational, open-label Phase 3 study which showed BOSULIF 400 mg was associated with a significantly higher rate of patients achieving major molecular response (MMR) at 12 months (the primary endpoint) compared to the rate achieved in patients treated with imatinib. Results from the trial were presented at the American Society of Clinical Oncology (ASCO) (Free ASCO Whitepaper) Annual Meeting in May 2017 and at the European Hematology Association (EHA) (Free EHA Whitepaper) Meeting in June 2017. The adverse events seen in the trial were consistent with the known safety profile for BOSULIF. The proposed dosing for the newly diagnosed patients is 400 mg daily, which is different from the currently approved dosing in patients who are resistant or intolerant to prior TKI therapy (500 mg daily).

"As physicians gained experience with BOSULIF, they have come to appreciate its favorable risk-benefit profile in patients with Ph-positive CML who no longer responded to or could not tolerate prior TKI therapy," said Mace Rothenberg, MD, Chief Development Officer, Oncology, Pfizer Global Product Development. "At the 400 mg dose, we believe that the BFORE study demonstrates a similarly favorable risk-benefit in previously untreated patients with Ph-positive CML. We look forward to working with the FDA in our efforts to expand the label for BOSULIF to include this important group of patients."

"These are important milestones for the CML community and for our partnership with Pfizer, which represent the commitment of both of our companies to work collaboratively toward our ultimate goal of improving the lives of patients," said Allison Jeynes-Ellis, MD, Chief Executive Officer of Avillion.

Pfizer and Avillion entered into an exclusive collaborative development agreement in 2014 to conduct the BFORE trial. Under the terms of the agreement, Avillion provided funding and conducted the trial to generate the clinical data used to support these applications and other potential regulatory filings for marketing authorization for BOSULIF as first-line treatment for patients with chronic phase Ph+ CML. If approved for this indication, Avillion will be eligible to receive milestone payments from Pfizer. Pfizer retains all rights to commercialize BOSULIF globally.

Pfizer is advancing a broad range of therapies that leverage select pathways and mechanisms of action to address acute and chronic leukemias, myeloproliferative disorders and lymphoma.

ABOUT CHRONIC MYELOID LEUKEMIA (CML)

Chronic myeloid leukemia (CML) is a rare blood cancer, which begins in the bone marrow, but often moves into the blood.1 Researchers estimate that by 2020, more than 412,000 people worldwide will be diagnosed with leukemia (all types).2 CML accounts for 10-15% of all incident leukemia cases.1,3 In the U.S., approximately 48,000 people are living with CML.4 Around 9,000 new CML cases will be diagnosed in the U.S. in 2017.5

ABOUT BOSULIF (bosutinib)

BOSULIF (bosutinib) is an oral, once-daily, tyrosine kinase inhibitor (TKI), which inhibits the Bcr-Abl kinase that promotes CML; it is also an inhibitor of Src-family kinases. BOSULIF was approved in September 2012 in the U.S. for the treatment of adult patients with Ph+ CML with resistance or intolerance to prior therapy and offers an important treatment option for these patients. In Europe, BOSULIF was granted conditional marketing authorization in March 2013 for the treatment of adult patients with Ph+ CML previously treated with one or more TKIs and for whom imatinib, nilotinib and dasatinib are not considered appropriate treatment options. The current approved dose of BOSULIF is 500 mg orally once daily with food. For more information on BOSULIF resources available for healthcare professionals and patients, please visit www.BOSULIF.com.

IMPORTANT BOSULIF (bosutinib) SAFETY INFORMATION

Contraindication: History of hypersensitivity to BOSULIF. Reactions have included anaphylaxis. Anaphylactic shock occurred in less than 0.2% of treated patients in clinical trials.

Gastrointestinal Toxicity: Diarrhea, nausea, vomiting, and abdominal pain can occur. In the clinical trial, median time to onset for diarrhea was 2 days, median duration was 2 days, and median number of episodes per patient was 3 (range 1-268). Monitor and manage patients using standards of care, including antidiarrheals, antiemetics, and/or fluid replacement. Withhold, dose reduce, or discontinue BOSULIF as necessary.

Myelosuppression: Thrombocytopenia, anemia, and neutropenia can occur. Perform complete blood counts weekly for the first month and then monthly or as clinically indicated. Withhold, dose reduce, or discontinue BOSULIF as necessary.

Hepatic Toxicity: Twenty percent of patients experienced an increase in either ALT or AST. Liver enzyme elevation usually occurs early in treatment. The median time to onset of increased ALT and AST was 35 and 33 days, respectively, and the median duration for each was 21 days. Perform hepatic enzyme tests at least monthly for the first 3 months and as clinically indicated. In patients with transaminase elevations, monitor liver enzymes more frequently. One case consistent with drug-induced liver injury occurred in a trial of BOSULIF in combination with letrozole. Withhold, dose reduce, or discontinue BOSULIF as necessary. In patients with mild, moderate, or severe hepatic impairment, the recommended starting dose is 200 mg daily.

Renal Toxicity: An on-treatment decline in estimated glomerular filtration rate has occurred in patients treated with BOSULIF. Monitor renal function at baseline and during therapy, with particular attention to patients with preexisting renal impairment or risk factors for renal dysfunction. Consider dose adjustment in patients with baseline and treatment emergent renal impairment. The recommended starting doses for patients with severe renal impairment (CrCL <30 mL/min) or moderate renal impairment (CrCL 30-50 mL/min) are 300 mg and 400 mg daily, respectively.

Fluid Retention: Fluid retention can occur and may cause pericardial effusion, pleural effusion, pulmonary edema, and/or peripheral edema. In the clinical trial, Grade 3/4 fluid retention was reported in 26 patients (5%). Monitor and manage patients using standards of care. Interrupt, dose reduce, or discontinue BOSULIF as necessary.

Embryofetal Toxicity: BOSULIF can cause fetal harm when administered to a pregnant woman. Women of childbearing potential should be advised of potential hazard to the fetus. Advise females of reproductive potential to use effective contraceptive measures to prevent pregnancy while being treated with BOSULIF and for at least 30 days after the final dose.

Adverse Reactions: The most common adverse reactions observed in greater than or equal to 20% of patients in the Phase 1/2 safety population (N=546) were diarrhea, nausea, thrombocytopenia, rash, vomiting, abdominal pain, respiratory tract infection, anemia, pyrexia, liver test abnormalities, fatigue, cough, and headache. The most common Grade 3/4 adverse reactions and laboratory abnormalities observed in greater than 10% of patients were thrombocytopenia, neutropenia, and anemia.

CYP3A Inhibitors and Inducers: Avoid concurrent use with strong or moderate CYP3A inhibitors or inducers.

Proton Pump Inhibitors: Consider using short-acting antacids or H2 blockers instead of PPIs to avoid a reduction in BOSULIF exposure. Separate antacid or H2 blocker dosing and BOSULIF dosing by more than 2 hours.

Nursing Mothers: Given the potential for serious adverse reactions in nursing infants, a decision should be made whether to discontinue nursing or BOSULIF, taking into account the importance of the drug to the mother.

Please see full Prescribing Information at www.bosulif.com.