Pfizer has entered into an agreement with Merck KGaA, Darmstadt, Germany, to jointly develop and commercialise MSB0010718C, an investigational anti-PD-L1 antibody currently in development by Merck KGaA as a potential treatment for multiple types of cancer. Pfizer and Merck KGaA will explore the therapeutic potential of this novel anti-PD-L1 antibody as a single agent as well as in various combinations with Pfizer’s and Merck KGaA’s broad portfolio of approved and investigational oncology therapies.
Building on the ongoing phase 1 programme that has treated more than 550 patients, both companies will collaborate on up to 20 high priority immuno-oncology clinical development programmes expected to commence in 2015. These clinical development programs include up to six trials (phase 2 or 3) that could be pivotal for potential product registrations.
“This global alliance enables Pfizer and Merck KGaA to join forces and combine complementary strengths with the goal of meeting the needs of patients with multiple types of cancer,” said Albert Bourla, group president Vaccines, Oncology and Consumer Healthcare Businesses, Pfizer. “Immuno-oncology is a top priority for Pfizer. Combining this promising anti-PD-L1 antibody with Pfizer’s extensive portfolio of small molecules and antibodies, provides an opportunity to potentially broaden the use of immunotherapy for patients with cancer and rapidly expand our oncology business. In addition, this alliance enables us to significantly accelerate the timeframe of our development programs and move into the first wave of potential immuno-oncology based treatment regimens.”
“Collaborating globally with Pfizer will allow us to benefit from the strengths and capabilities of both companies in immuno-oncology, further accelerating this promising asset in the race to address the needs of cancer patients across multiple tumor types. Up to 20 high priority immuno-oncology clinical development programs are expected to commence in 2015, including pivotal registration studies,” continued Belén Garijo, president and chief executive officer of Merck’s bio-pharmaceutical division Merck Serono and executive Board Member Elect. “On top of that, the global alliance will enable Merck to gain an early entry into the US oncology market as well as to strengthen our existing oncology business in several other important global markets.”
There are currently two clinical development programmes underway evaluating Merck KGaA’s anti-PD-L1 antibody. In a phase 1 trial, more than 550 patients have been treated with MSB0010718C across multiple types of cancers. As part of the Analyst and Investor Day hosted by Merck KGaA on September 18, 2014, interim data were presented from an ongoing phase 1 study demonstrating a complete response and partial responses in patients with non-small cell lung cancer and ovarian cancer. Additional data are expected to be presented at medical congresses in 2015. There is also an ongoing phase 2 trial evaluating this antibody in patients with metastatic Merkel cell carcinoma, a rare form of skin cancer.
“Early results for Merck KGaA’s PD-L1 in patient trials are impressive and consistent with the results seen with the class of PD-1 and PD-L1 antibodies,” said Mikael Dolsten, M.D, president of Pfizer Worldwide Research and Development (WRD) and executive vice president, Pfizer. “This promising foundation of research will form the basis of multiple registration trials.”
Separate from the PD-L1 programmes, Pfizer and Merck KGaA will also combine resources and expertise to advance Pfizer’s anti-PD-1 antibody into phase 1 trials. The parties have also agreed to co-promote Pfizer’s XALKORI in the United States and several other key markets.
Under the terms of the agreement, Merck KGaA will receive an upfront payment of $850 million and is eligible to receive regulatory and commercial milestone payments up to approximately $2 billion. Both companies will jointly fund all development and commercialisation costs and all revenues obtained from selling any anti-PD-L1 or anti-PD-1 products generated from this collaboration will be shared equally.
As a result of this transaction, Pfizer will recognise this upfront payment as a certain significant item which will impact Reported Diluted earnings per share or EPS. Pfizer is updating its previous 2014 Reported Diluted EPS guidance range from $1.50 - $1.59 to $1.40 - $1.49, while maintaining the other elements of its 2014 financial guidance.
Our updated 2014 financial guidance does not reflect the additional impact of the exchange of future profits of Xalkori which will be measured at fair value and will reduce our 2014 reported financial results as the fair value is currently being determined. Our current expectation is that it may be between $250-$400 million on a pre-tax basis as we have not concluded our analysis of this component as of this date.
Pfizer is working to advance the science in immuno-oncology and actively exploring a variety of novel agents, including checkpoint modulating antibodies, CAR-T therapies, bi-functional monoclonal antibodies and vaccine-based immunotherapy regimens. Pfizer’s 4-1BB agonist antibody is currently in phase 1, with several other immunotherapeutic agents expected to commence clinical testing in 2015, including a monoclonal antibody against receptor OX40 (CD134), a PD-1 monoclonal antibody, and a vaccine-based regimen for prostate cancer. Pfizer is exploring the full potential of combining immunotherapies with its broad oncology portfolio through the company’s own development efforts as well as in collaboration with other partners, working together to improve outcomes for patients with cancer.
Xalkori is a kinase inhibitor indicated in the US for the treatment of patients with metastatic non-small cell lung cancer (NSCLC) whose tumors are anaplastic lymphoma kinase (ALK)-positive as detected by an FDA-approved test. The US indication is not limited to any specific line of therapy. In the EU, Xalkori is indicated for the treatment of adults with previously treated ALK-positive advanced NSCLC. Xalkori has received approval in more than 75 countries1 including Australia, Canada, China, Japan, South Korea and the European Union.
Hepatotoxicity: Across three main clinical trials fatal hepatotoxicity occurred in 0.2 per cent of patients. Monitor with periodic liver testing. Temporarily suspend, dose reduce, or permanently discontinue Xalkori.
Pneumonitis: Across three main clinical trials interstitial lung disease (ILD)/pneumonitis occurred in 2 per cent of patients. Permanently discontinue in patients with ILD/pneumonitis.
QT Interval Prolongation: Across three main clinical trials QT interval prolongation occurred in 2.7 per cent of patients. Monitor with electrocardiograms and electrolytes in patients who have a history of or predisposition for QTc prolongation, or who are taking medications that prolong QT. Temporarily suspend, dose reduce, or permanently discontinue Xalkori.
Bradycardia: Xalkori can cause bradycardia. Across three main clinical trials 11 per cent of patients experienced a heart rate of less than 50 beats per minute. Monitor heart rate and blood pressure regularly. Temporarily suspend, dose reduce, or permanently discontinue Xalkori.
Embryofetal Toxicity: Xalkori can cause fetal harm when administered to a pregnant woman. Women of childbearing potential should be advised to avoid becoming pregnant while receiving Xalkori.
Adverse Reactions: Across three main clinical trials the most common adverse reactions (=25 per cent ) were vision disorders, nausea, diarrhea, vomiting, constipation, edema, elevated transaminases, and fatigue.
In a phase 3 study in patients with ALK-positive metastatic NSCLC randomised to Xalkori (n=172) or chemotherapy (n=171), serious adverse reactions were reported in 37.2 per cent of patients treated with Xalkori. The most frequent serious adverse reactions reported in patients treated with Xalkori were pneumonia (4.1 per cent ), pulmonary embolism (3.5 per cent ), dyspnea (2.3 per cent ), and ILD (2.9 per cent ). Fatal adverse reactions in Xalkori-treated patients occurred in 9 (5 per cent ) patients, consisting of: acute respiratory distress syndrome, arrhythmia, dyspnea, ILD, pneumonia, pneumonitis, pulmonary embolism, respiratory failure, and sepsis. Grade 3 or 4 events occurring at a higher incidence with Xalkori than with chemotherapy and at greater than 2 per cent , were syncope (3 per cent ), QT prolongation (3 per cent ), and pulmonary embolism (5 per cent ). Elevation of ALT of any grade occurred in 76 per cent of patients and grade 3 or 4 in 17 per cent of patients. Neutropenia of any grade occurred in 49 per cent of patients and grade 3 or 4 in 12 per cent of patients. Lymphopenia of any grade occurred in 51 per cent of patients and grade 3 or 4 in 9 per cent of patients. Renal cysts occurred in 4 per cent and neuropathy occurred in 19 per cent of patients treated with Xalkori.
Drug Interactions: Exercise caution with concomitant use of moderate CYP3A inhibitors. Avoid grapefruit or grapefruit juice which may increase plasma concentrations of crizotinib. Avoid concomitant use of strong CYP3A inducers and inhibitors. Dose reduction may be needed for co-administered drugs that are predominantly metabolised by CYP3A.
Nursing Mothers: Given the potential for serious adverse reactions in nursing infants, consider whether to discontinue nursing or discontinue Xalkori.
Hepatic Impairment: Xalkori has not been studied in patients with hepatic impairment. As crizotinib is extensively metabolised in the liver, hepatic impairment is likely to increase plasma crizotinib concentrations. Use caution in patients with hepatic impairment.
Renal Impairment: Administer Xalkori at a starting dose of 250 mg taken orally once daily in patients with severe renal impairment (CLcr<30 mL/min) not requiring dialysis. No starting dose adjustment is needed for patients with mild and moderate renal impairment.