Bristol-Myers Squibb: Opdivo, And Everything Else
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All sales are in millions of dollars.
In millions of dollars, except EPS
If Bristol-Myers Squibb’s past year had to be boiled down to one word, that word would most likely be Opdivo. The company’s prized immuno-oncologic earned its first U.S. approval in December and is up to a total of two each in both the United States and Europe, with several other applications pending. And a large percentage of BMS’ collaboration activity of late has involved the setting up of joint trials combining Opdivo with other companies’ oncology assets. Most importantly, Opdivo and its fellow immuno-oncologic Yervoy — now officially a blockbuster — reflect the latest signs of success for the company’s strategic turn towards biopharma.
“I am excited by our progress in immuno-oncology as we continue to advance our leadership position and transform cancer treatment,” says new CEO Giovanni Caforio, M.D. “As our immuno-oncology data continues to emerge, it is clear we have a tremendous opportunity, and we are making the right strategic investments to capitalize on the full potential of our portfolio.”
Bristol-Myers Squibb’s top-line revenue was $15.88 billion in 2014, a 3.1 percent decrease compared with the previous year. However, excluding the company’s diabetes portfolio — divested in February 2014 — total sales actually grew by 6 percent, and new and inline product sales were up 19 percent. Net income was down 21.4 percent to $2.03 billion and earnings per share for the year fell 34 cents to $1.20. In the first half of 2015, the company’s top line rose 6.5 percent to $8.2 billion, with net income down 14.3 percent to $1.09 billion and diluted EPS down 13 cents to 63 cents. Company leaders are projecting full-year EPS for 2015 at $1.02 to $1.12.
Following a board announcement of the change in January, Dr. Caforio took over as CEO of Bristol-Myers Squibb in May. At the same time, outgoing CEO Lamberto Andreotti transitioned to executive chairman of the company’s board of directors, replacing the retiring James Cornelius.
Dr. Caforio brings a broad range of experience to his role as CEO, company leaders say. Through a variety of expanding roles, he has made significant contributions to improving the company’s strategic focus and operational performance. He helped build BMS’s leadership in immuno-oncology through his roles in U.S. and Global Oncology. As chief commercial officer and chief operating officer he led the transformation of the company’s global commercial organization into one designed to be able to differentially invest in the most important opportunities. As a member of Bristol-Myers Squibb’s senior management team since 2011 and the board of directors since 2014, Dr. Caforio has been integral in shaping the company’s transformation to a diversified specialty biopharma company. A trained physician, he began his career in medical affairs at Abbott Laboratories. He joined Bristol-Myers Squibb in 2000 as VP and general manager, Italy. Dr. Caforio earned his M.D. from the University of Rome prior to joining the pharmaceutical industry.
“I am honored to have the privilege to lead this great company,” Dr. Caforio says. “Lamberto has led the successful transformation of BMS from a broad-based health care company to a diversified specialty biopharma leader with his passion for our business, our people and, most importantly, our patients. I look forward to working with our very talented team of people at BMS to build on what we’ve accomplished, to deliver on the promise of our innovative portfolio and to continue to make a real difference for our patients.”
Collaborations and acquisitions
In August 2014, BMS and Celgene Corp. established a clinical trial collaboration to evaluate the safety, tolerability, and preliminary efficacy of a combination regimen of Bristol-Myers Squibb’s investigational PD-1 immune checkpoint inhibitor Opdivo and Celgene’s nab technology-based chemotherapy Abraxane, in a Phase I study. Multiple tumor types will be explored in the study including HER-2 negative metastatic breast cancer, pancreatic cancer, and non-small cell lung cancer.
Opdivo is part of a new class of cancer treatments known as immunotherapies that are designed to harness the body’s own immune system in fighting cancer. Opdivo targets distinct regulatory components of the immune system, while Abraxane works by interfering with the ability of cancer cells to divide. By combining an immunotherapy with a standard chemotherapy, the companies will explore whether these two agents may lead to an enhanced anti-tumor response compared to either agent alone.
The study, which was expected to begin in the fourth quarter of 2014, is being conducted by Celgene. Patients with HER-2 negative breast cancer are being treated with Abraxane and Opdivo, patients with NSCLC are being treated with the combination of Abraxane, carboplatin and Opdivo, and patients with pancreatic adenocarcinoma are being treated with Abraxane, gemcitabine and Opdivo. Additional details of the collaboration were not disclosed.
In October 2014, BMS entered into an agreement giving the company the exclusive option to acquire F-star Alpha Ltd. and gain worldwide rights to its lead asset FS102. FS102 is a novel Phase I ready human epidermal growth factor receptor 2 (HER2)-targeted therapy in development for the treatment of breast and gastric cancer among a well-defined population of HER2-positive patients who do not respond or become resistant to current therapies.
FS102 is a HER2 targeted Fcab that has the potential to eliminate cancer cells through a novel mechanism of action in a biomarker-defined patient population. FS102 works differently than current HER2-targeted therapies, with the potential to overcome resistance that has developed against other HER2-targeted drugs. It binds to a unique site on HER2 and then induces programmed cell death in HER2-positive tumour cells.
In preclinical studies, FS102 has demonstrated encouraging efficacy against certain HER2-positive cancers and major regression in tumors, including those that are refractory to treatment with trastuzumab plus pertuzumab.
Also in October, BMS and The University of Texas MD Anderson Cancer Center announced a novel clinical research collaboration to evaluate multiple immunotherapies, including Opdivo, Yervoy, and three early-stage clinical immuno-oncology assets from Bristol-Myers Squibb, as potential treatment options for acute and chronic leukemia as well as other hematologic malignancies.
The agreement, company leaders say, represents an innovative approach to research by focusing numerous clinical trials using multiple agents, in mono and combination regimens, on a specific disease target, in this case select hematologic malignancies. Through this approach, Bristol-Myers Squibb and MD Anderson aim to benefit patients by expediting the delivery of new therapies.
The collaboration will launch up to 10 Phase I and II clinical trials, conducted by MD Anderson, focused on evaluating investigational immune-based approaches for acute myeloid leukemia, chronic lymphocytic leukemia, chronic myeloid leukemia, myelodysplastic syndrome, and myelofibrosis. Additional studies will be determined by the collaboration at a later date.
During that same month, BMS, Pharmacyclics Inc. and Janssen Research & Development LLC entered into a clinical trial collaboration agreement to evaluate the safety, tolerability, and preliminary efficacy of Opdivo in combination with Imbruvica, an oral Bruton’s tyrosine kinase (BTK) inhibitor co-developed and co-marketed by Pharmacyclics and Janssen. The Phase I/II study will focus on evaluating the safety and anti-tumor activity of combining Opdivo and Imbruvica as a potential treatment option for patients with non-Hodgkin lymphoma (NHL), including diffuse large B-cell lymphoma (DLBCL), follicular lymphoma (FL), and chronic lymphocytic leukemia (CLL). The study will be conducted by Janssen.
Additionally in October, BMS announced the establishment of a clinical trial collaboration to evaluate the safety, tolerability, and preliminary efficacy of combining Opdivo with three molecularly targeted oncology therapies (Zykadia, INC280, and EGF816) from Novartis. Novartis will conduct two Phase I/II studies focused on non-small cell lung cancer.
One trial will evaluate the combination of Opdivo with Zykadia, an FDA-approved treatment for patients with anaplastic lymphoma kinase-positive (ALK+) metastatic NSCLC who have progressed on or are intolerant to crizotinib. A second study will investigate Opdivo with INC280, a potent and highly selective inhibitor of c-MET receptor tyrosine kinase, and EGF816, a potent, third-generation EGFR tyrosine kinase inhibitor that is active against T790 mutations. INC280 and EGF816 are being investigated in various Phase I/II NSCLC trials.
In November 2014, BMS and Five Prime Therapeutics Inc. entered into an exclusive clinical collaboration agreement to evaluate the safety, tolerability and, preliminary efficacy of combining Opdivo with FPA008, Five Prime’s monoclonal antibody that inhibits colony stimulating factor-1 receptor (CSF1R). The Phase Ia/Ib study will evaluate the combination of Opdivo and FPA008 as a potential treatment option for patients with non-small cell lung cancer, melanoma, head and neck cancer, pancreatic cancer, colorectal cancer, and malignant glioma.
Also in November, BMS entered into an agreement providing the exclusive option to acquire Galecto Biotech AB and gain worldwide rights to its lead asset TD139, a novel inhaled inhibitor of galectin-3 in Phase I development for the treatment of idiopathic pulmonary fibrosis and other pulmonary fibrotic conditions. Total aggregate payments under the agreement have the potential to reach $444 million, which includes the option fee, an option exercise fee, and subsequent clinical and regulatory milestone payments.
Under the terms of the agreement, Bristol-Myers Squibb can exercise the option to acquire Galecto at any time following the execution of the transaction agreement but no later than 60 days following completion of the Phase Ib trial. The companies have agreed on preclinical studies and a Phase I development plan that will be executed by Galecto AB during the option period.
Galectin-3 is a protein that binds to carbohydrate structures in the body, and plays a central role in various types of fibrosis. By targeting and inhibiting the protein’s binding ability, galectin-3 inhibitors represent a promising approach to treat diseases that exhibit galectin-3 expression such as IPF, a chronic, progressive form of lung disease characterized by the scarring of lung tissue for which there are limited treatment options. TD139 is a highly potent, specific inhibitor of the galactoside-binding pocket of galectin-3 formulated for inhalation, which enables direct targeting of the fibrotic tissue in the lungs, while minimizing systemic exposure.
In January 2015, BMS and the California Institute for Biomedical Research (Calibr) entered into a worldwide research collaboration to develop novel small molecule anti-fibrotic therapies, and an exclusive license agreement that allows Bristol-Myers Squibb to develop, manufacture, and commercialize Calibr’s preclinical compounds resulting from the collaboration.
Identifying novel medicines to halt or slow the progression of fibrotic disease and improve upon the current standard of care is a key part of Bristol-Myers Squibb’s R&D strategy. Calibr, an independent, not-for-profit organization established to accelerate the translation of basic biomedical discoveries into innovative new medicines, brings to the collaboration substantial expertise in identifying and optimizing small molecules with anti-fibrotic activity through its high-throughput screening, target identification, and preclinical drug discovery infrastructure.
That same month, BMS and Lilly announced a clinical trial collaboration to evaluate the safety, tolerability, and preliminary efficacy of Opdivo in combination with Lilly’s galunisertib. The Phase I/II trial will evaluate the investigational combination of Opdivo and galunisertib as a potential treatment option for patients with advanced (metastatic and/or unresectable) glioblastoma, hepatocellular carcinoma, and non-small cell lung cancer. The study will be conducted by Lilly.
Galunisertib is a TGF beta R1 kinase inhibitor that in vitro selectively blocks TGF beta signaling. TGF beta promotes tumor growth, suppresses the immune system and increases the ability of tumors to spread in the body. This collaboration will address the hypothesis that co-inhibition of PD-1 and TGF beta negative signals may lead to enhanced anti-tumor immune responses than inhibition of either pathway alone.
Also in January, BMS and Seattle Genetics Inc. entered into a clinical trial collaboration agreement to evaluate the investigational combination of Seattle Genetics’ antibody-drug conjugate Adcetris and Opdivo in two planned Phase I/II clinical trials. The first trial will evaluate the combination of Adcetris and Opdivo as a potential treatment option for patients with relapsed or refractory Hodgkin lymphoma (HL), and the second trial will focus on patients with relapsed or refractory B-cell and T-cell non-Hodgkin lymphomas (NHL), including diffuse large B-cell lymphoma (DLBCL). Adcetris is an ADC directed to CD30, a defining marker of classical HL, which combines the targeting ability of a monoclonal antibody with the potency of a cell-killing agent. The studies are expected to begin in 2015, with Seattle Genetics conducting the HL trial and Bristol-Myers Squibb conducting the NHL trial.
In February, BMS signed a definitive agreement to acquire all of the outstanding capital stock of Flexus Biosciences, a privately held biotechnology company focused on the discovery and development of novel anti-cancer therapeutics. The transaction has a potential total consideration of $1.25 billion, including $800 million upfront and development milestones that, upon achievement, could total up to $450 million.
The acquisition gives Bristol-Myers Squibb full rights to F001287, Flexus’ lead preclinical small molecule IDO1-inhibitor targeted for IND filing in the second half of 2015. In addition, Bristol-Myers Squibb acquired Flexus’ IDO/TDO discovery program that includes its IDO-selective, IDO/TDO dual and TDO-selective compound libraries. A newly formed entity established by the current shareholders of Flexus will retain, from and after the closing, all non-IDO/TDO assets of Flexus including those related to Flexus’ Phase 1 FLT3 and CDK4/6 inhibitor, its earlier-stage small-molecule Treg cancer immunotherapy programs, and its current personnel and facilities.
Also in February, BMS and Rigel Pharmaceuticals Inc. entered into a collaboration agreement for the discovery, development, and commercialization of cancer immunotherapies based on Rigel’s extensive portfolio of small molecule TGF beta receptor kinase inhibitors. TGF beta can promote tumor growth, broadly suppress the immune system, and increase the ability of tumors to spread in the body. The collaboration will focus on developing a new class of therapeutics aimed at increasing the immune system’s activity against various cancers either as monotherapy or in combination with immune checkpoint inhibitors, including Bristol-Myers Squibb’s Opdivo and Yervoy.
Under the terms of the agreement, Bristol-Myers Squibb will obtain exclusive, worldwide rights to develop and commercialize small molecule therapeutics derived from Rigel’s TGF beta library, including, but not limited to, those approved to treat cancer. Bristol-Myers Squibb paid $30 million upfront and Rigel is eligible to receive development and regulatory milestones that could total more than $309 million for a successful compound approved in multiple indications. Rigel will also be eligible to receive tiered royalties on the net sales of any products from the collaboration.
In March, BMS signed an agreement providing an exclusive option to license and commercialize Prostvac, Bavarian Nordic’s investigational Phase III prostate-specific antigen (PSA) -targeting cancer immunotherapy in development for the treatment of asymptomatic or minimally symptomatic metastatic castration-resistant prostate cancer. The parties have also agreed to enter into a supply contract, under which Bavarian Nordic will undertake the future commercial manufacturing of Prostvac. An investigator sponsored Phase II study is currently in the planning stages to investigate the combination of Bristol-Myers Squibb’s Yervoy and Prostvac. The companies have also entered into an agreement by which they may conduct one or more exploratory combination studies of Prostvac and agents from Bristol-Myers Squibb’s immuno-oncology portfolio.
In April, BMS signed an agreement with uniQure N.V. providing exclusive access to that company’s gene therapy technology platform for multiple targets in cardiovascular diseases. The collaboration includes uniQure’s proprietary gene therapy program for congestive heart failure that is intended to restore the heart’s ability to synthesize S100A1, a calcium sensor and master regulator of heart function, and thereby improve clinical outcomes for patients with reduced ejection fraction. Beyond cardiovascular diseases, the agreement also includes the potential for target-exclusive collaboration in other disease areas. In total, the companies may collaborate on 10 targets, including S100A1.
uniQure leads discovery efforts and is responsible for manufacturing of clinical and commercial supplies using its vector technologies and industrial, proprietary insect-cell based manufacturing platform. Bristol-Myers Squibb is leading development and regulatory activities across all programs and is responsible for all research and development costs. Bristol-Myers Squibb is solely responsible for commercialization of all products from the collaboration.
In July 2015, Kyowa Hakko Kirin Co. and BMS entered into a clinical trial collaboration agreement to conduct a Phase I/II combination study with mogamulizumab, an anti-CCR4 antibody, and Opdivo. The study, which will be conducted in the United States, will focus on evaluating the safety, tolerability, and anti-tumor activity of combining mogamulizumab and Opdivo as a potential treatment option for patients with advanced or metastatic solid tumors. Prior to this agreement, Kyowa Hakko Kirin, Bristol-Myers Squibb, and Ono Pharmaceutical Co. entered into a clinical trial collaboration agreement to study the combination of mogamulizumab and Opdivo in Japan. The study will be conducted by Kyowa Hakko Kirin.
Also in July, BMS entered into a translational research collaboration with the Medical University of South Carolina (MUSC) focused on fibrotic diseases, including scleroderma, renal fibrosis, and idiopathic pulmonary fibrosis. The agreement includes studies designed to improve the mechanistic understanding of fibrosis, explore patient segmentation based on disease characteristics and/or biomarker approaches and predictors of disease progression.
Bristol-Myers Squibb and MUSC are committed to addressing the unmet need in fibrotic diseases that are characterized by the formation of excess fibrous connective tissue in an organ or tissue, by identifying novel medicines to halt or slow disease progression. Among the assets in Bristol-Myers Squibb’s fibrosis portfolio are BMS-986020, a lysophosphatidic acid 1 (LPA1) receptor antagonist in Phase II development for the treatment of idiopathic pulmonary fibrosis, and a CCR2/5 dual antagonist in Phase II development for diabetic kidney disease.
In August, BMS entered into an agreement granting an exclusive right to acquire Promedior Inc. and gain worldwide rights to its lead asset PRM-151, a recombinant form of human pentraxin-2 protein in Phase II development for the treatment of idiopathic pulmonary fibrosis (IPF) and myelofibrosis (MF). PRM-151 has been granted Fast Track designation in the United States and Orphan designation in the United States and Europe for the treatment of MF and Orphan designation in the United States and Europe for the treatment of IPF.
The clinical-stage immunotherapy company Promedior is pioneering the development of targeted therapeutics to treat fibrotic diseases. Total aggregate payments to Promedior under the agreement have the potential to reach $1.25 billion, which includes an upfront cash payment for the right to acquire Promedior, an exercise fee payable if Bristol-Myers Squibb elects to exercise its right to acquire the company, and subsequent clinical and regulatory milestone payments. PRM-151 has been shown in multiple preclinical models to regulate monocytes and macrophages at areas of tissue damage to prevent and reverse fibrosis, including IPF, acute and chronic nephropathy, liver fibrosis and age-related macular degeneration. Promedior has advanced PRM-151 into clinical trials focused on two orphan fibrotic diseases (MF and IPF).
Also in August, BMS and QIMR Berghofer Medical Research Institute signed a research collaboration and license agreement to discover novel therapeutic antibodies against an undisclosed immuno-oncology target. QIMR Berghofer Medical Research Institute is a leading translational research institute focused on cancer, infectious diseases, mental health and a range of complex disorders. Bristol-Myers Squibb will be solely responsible for clinical development and commercialization of antibodies discovered through the collaboration.
The antipsychotic Abilify remained Bristol-Myers Squibb’s top seller in 2014, but the product’s reign ended with a loss of exclusivity in April 2015. Abilify generated $2.02 billion in sales for the company in 2014, a decrease of 11.8 percent; in the first half of the new year, sales declined another 39.6 percent to $661 million.
The immunologic Orencia placed second among Bristol-Myers Squibb’s products in 2014, with sales up 14.4 percent to $1.65 billion due to higher net selling prices and growing demand for the drug’s subcutaneous formulation. The product’s sales rose another 12.5 percent in the first half of 2015 to $861 million. Orencia is indicated for adult patients with moderate-to-severe active rheumatoid arthritis and for reducing signs and symptoms in certain pediatric patients with moderately to severely active polyarticular juvenile idiopathic arthritis.
In June 2015, Bristol-Myers Squibb announced data from the Orencia Phase IIIb AVERT and AMPLE trials. These trials included early moderate-to-severe RA patients with active disease. AVERT trial data suggests potentially faster onset of clinical response and greater drug-free clinical remission with earlier use in patients taking Orencia plus methotrexate over patients taking methotrexate alone. Exploratory data of patients with high anti-citrullinated protein antibody levels at baseline in the AMPLE trial suggest better response with Orencia than with adalimumab, which is marketed as Humira.
Also enjoying a year of solid growth was the oncology product Sprycel, with sales up 16.6 percent to $1.49 billion. The company is planning to study Sprycel alone and in combination with assets in its immuno-oncology portfolio (including Opdivo) to determine whether certain patients can continue to sustain a clinical response after discontinuing therapy. Early studies are also ongoing to investigate the potential use of Sprycel in certain patients with advanced non-small cell lung cancer. In the first half of 2015, Sprycel sales rose 9.9 percent to $780 million. In August, FDA approved an update to the Sprycel product labeling including five-year efficacy and safety data in adult patients with newly diagnosed Philadelphia chromosome-positive (Ph+) chronic myeloid leukemia (CML) in chronic phase (CP) and seven-year data in CP Ph+ CML patients who are resistant or intolerant to prior therapy, including Gleevec.
Sales of the Sustiva franchise for HIV fell by 10.5 percent to $1.44 billion in 2014 due to a loss of exclusivity in Europe at the end of 2013. In the first half of 2015, sales were down another 10.7 percent to $607 million. Sales of Bristol-Myers Squibb’s other HIV blockbuster, Reyataz, dropped 12.2 percent to $1.36 billion in 2014 and another 15.4 percent to $597 million in the first half of 2015.
Baraclude, indicated for the treatment of hepatitis B, encountered generic competition for the first time in September of 2014; sales for the year fell 5.6 percent to $1.44 billion. In the first half of 2015, Baraclude sales dropped another 11.9 percent to $683 million.
The melanoma product Yervoy enjoyed an impressive year in 2014, with sales up 36.3 percent to $1.31 billion. In March, FDA accepted for filing and review the supplemental biologics license application for Yervoy for the adjuvant treatment of patients with stage 3 melanoma who are at high risk of recurrence following complete surgical resection.
The projected FDA action date is Oct. 28, 2015. The acceptance is based on clinical data from a randomized, double-blind Phase III trial, CA184-029, assessing the efficacy of Yervoy at the investigational dose of 10 mg/kg, in preventing or delaying recurrence after complete resection of high-risk stage 3 melanoma.
The drug is in late-stage development for squamous NSCLC and small cell lung cancer, and in Phase II trials for ovarian cancer and adolescent melanoma. In the first half of 2015, Yervoy sales were up another 4.9 percent to $621 million.
The cardiovascular product Eliquis took a major leap in 2014, with sales growing from $146 million to $774 million. In the course of the year the drug earned additional approvals in the United States and Europe for the treatment and reduction in the risk of recurrent venous thromboembolism, which includes deep vein thrombosis (DVT) and pulmonary embolism. Eliquis was already approved for use in patients with nonvalvular atrial fibrillation and the prophylaxis of DVT following hip and knee replacement surgeries. Eliquis continued its rapid upward trend in the first half of 2015, with sales jumping from $277 million in January-June 2014 to $792 million.
The last year has been a busy one for the immuno-oncologic Opdivo, the crown jewel of Bristol-Myers Squibb’s pipeline. Since December, Opdivo has earned two approvals in the United States and two more in Europe, and three additional applications to FDA have all earned priority review status. In addition to its new lung cancer and melanoma indications and applications, the drug also remains in Phase II development for lymphomas and colon and esophageal cancers; overall the drug is being studied across 20 tumor types in more than 50 trials. In the first half of 2015, Opdivo generated $162 million in sales for BMS, with three-quarters of that coming in the second quarter.
In December, FDA approved Opdivo injection, for intravenous use, for the treatment of patients with unresectable or metastatic melanoma and disease progression following Yervoy and, if BRAF V600 mutation positive, a BRAF inhibitor. The indication was approved under accelerated approval based on tumor response rate and durability of response. Metastatic melanoma is the deadliest form of skin cancer, and despite recent advances, there are limited treatment options available for patients who have been previously treated with approved agents.
Opdivo is the only human programmed death receptor-1 blocking antibody that has demonstrated efficacy in a Phase III, pivotal clinical trial with advanced melanoma in patients who had been previously treated and progressed with Yervoy and, if BRAF mutation positive, a BRAF inhibitor. The efficacy of Opdivo was evaluated based on a single-arm, non-comparative planned interim analysis of the first 120 patients who received Opdivo with a minimum of 6 months follow-up in the Phase III CheckMate -037 trial.
In March, FDA approved Opdivo, for intravenous use, for the treatment of patients with metastatic squamous non-small cell lung cancer with progression on or after platinum-based chemotherapy. Opdivo is the first PD-1 (programmed death receptor-1) therapy to demonstrate overall survival in previously treated metastatic squamous NSCLC. Opdivo demonstrated significantly superior overall survival versus docetaxel, with a 41 percent reduction in the risk of death, in a prespecified interim analysis of a Phase III clinical trial. The median OS was 9.2 months in the Opdivo arm and 6 months in the docetaxel arm.
In April, FDA accepted for filing and review a supplemental biologics license application for Opdivo for the treatment of previously untreated patients with unresectable or metastatic melanoma. FDA also granted priority review for this application. The new sBLA includes data from CheckMate -066, which evaluated Opdivo in treatment naïve patients with BRAF wild-type advanced melanoma as compared to dacarbazine chemotherapy.
“The CheckMate -066 trial marked the first time that a PD-1 immune checkpoint inhibitor showed a survival benefit in a randomized Phase III trial,” says Michael Giordano, senior VP, head of development, oncology, Bristol-Myers Squibb. “We look forward to continuing to work with the FDA to ensure cancer patients are provided the latest clinical advances that have the potential for improved responses and long-term survival.”
In June, the European Commission approved Opdivo for the treatment of advanced (unresectable or metastatic) melanoma in adults, regardless of BRAF status. The approval followed an accelerated assessment by the Committee for Medicinal Products for Human Use, which was announced in April. The accelerated assessment was granted because Opdivo qualified for the designation as a “medicinal product of major interest from the point of view of public health and in particular from the view point of therapeutic innovation.” Opdivo is the only PD-1 immune checkpoint inhibitor to receive an accelerated assessment in Europe, and is the first approval given by the European Commission for a PD-1 inhibitor in any cancer.
Also in June, FDA accepted for filing and review a supplemental biologics license application for Opdivo plus Yervoy regimen in patients with previously untreated advanced melanoma. FDA also granted priority review for this application, which was approved as announced by Bristol-Myers Squibb on Oct. 1, 2015.
This new sBLA includes data from CheckMate -069, the first randomized trial evaluating the Opdivo plus Yervoy regimen in patients with previously untreated advanced melanoma. In the trial, patients with BRAF wild-type mutation status treated with the regimen experienced improved objective response rate as compared to patients administered Yervoy monotherapy. The Opdivo plus Yervoy regimen achieved an objective response rate of 61 percent, including a 22 percent complete response rate, in previously untreated advanced melanoma patients. The safety profile also was consistent with previously reported studies evaluating the Opdivo plus Yervoy regimen.
In July, the European Commission approved Nivolumab BMS for the treatment of locally advanced or metastatic squamous non-small cell lung cancer after prior chemotherapy. This approval marks the first major treatment advance in SQ NSCLC in more than a decade in the European Union. Bristol-Myers Squibb submitted two separate marketing authorization applications in Europe for nivolumab, one in advanced melanoma under the trade name Opdivo and one for SQ NSCLC under the Nivolumab BMS tradename in order to accelerate availability of nivolumab for health care professionals in both indications. The company’s goal is to have these two marketing authorizations “reconciled” into a single marketing authorization under the Opdivo brand name toward the end of 2015.
Also in July, the European Medicines Agency validated Bristol-Myers Squibb’s type II variation application that seeks to extend the use of Opdivo in combination with Yervoy for treating advanced (unresectable or metastatic) melanoma in adults. The application is based on data from the Phase III CheckMate-067 study, Phase II CheckMate-069 study, and the Phase Ib CA209-004 study. Validation of an application confirms that the submission is complete and starts the EMA’s centralized review process. That same month, EMA also validated the company’s type II variation application that seeks to extend the use of Opdivo monotherapy in nonsquamous NSCLC based on data from the Phase III CheckMate-057 study.
In September 2015, FDA accepted for filing and review a supplemental biologics license application for Opdivo for the treatment of previously treated patients with non-squamous non-small cell lung cancer. This sBLA seeks to expand the current indication for Opdivo in patients with previously treated squamous NSCLC. The agency has also granted this application priority review, and Opdivo Breakthrough Therapy Designation for this indication.
The submission is based on CheckMate -057, a Phase III study that evaluated the survival of patients with NSQ NSCLC who had progressed during or after one prior platinum doublet-based chemotherapy regimen. The positive results of a separate study, Checkmate -017, formed the basis of the current lung cancer indication; study -017 evaluated the survival of patients with SQ NSCLC who had progressed during or after one prior platinum doublet-based chemotherapy regimen. In both studies Opdivo demonstrated an overall survival benefit.
In the pipeline
In January, FDA approved Evotaz (atazanavir 300 milligrams and cobicistat 150 milligrams) tablets in combination with other antiretroviral agents for the treatment of HIV-1 infection in adults. Evotaz is coformulated to be one pill, once-daily, combining the protease inhibitor atazanavir, which is marketed as Reyataz, and cobicistat, a pharmacokinetic enhancer marketed by Gilead Sciences.
Evotaz is the first protease inhibitor pharmacoenhanced by cobicistat that is supported by comparative Phase III trial data. The randomized, double-blind clinical trial evaluated the efficacy and safety of Reyataz 300 milligrams with cobicistat 150 milligrams versus Reyataz 300 milligrams with ritonavir 100 milligrams, another pharmacokinetic enhancing agent, in combination with emtricitabine/tenofovir disoproxil fumarate in treatment-naive adults. At 48 weeks, 85 percent of patients in the Evotaz arm achieved HIV-1 RNA levels of <50 copies/mL compared to 87 percent of patients in the Reyataz/ritonavir arm. Low rates of virologic failure were observed at 48 weeks, making Evotaz the only protease inhibitor pharmacoenhanced with cobicistat with virologic failure rates as low as 6 percent.
In February, BMS announced data supporting the clinical development of BMS-955176, an investigational component designed to prevent the maturation of HIV-1. The Phase IIa study findings confirmed the antiretroviral activity of BMS-955176 as an HIV-1 maturation inhibitor and support its further clinical development.
BMS-955176 is designed to inhibit one of the last steps of the HIV-1 viral lifecycle, resulting in the release of immature non-infectious HIV-1 particles to potentially provide a new approach to attacking the virus. In the proof-of-concept study, the next-generation maturation inhibitor drug candidate demonstrated antiviral activity in the presence of baseline HIV mutations not responsive to bevirimat, an earlier maturation inhibitor investigational candidate. BMS-955176 achieved maximum median declines of -1.70 log10 c/mL in HIV-1 RNA at a dose of 40 milligrams once daily, with a plateau of ~1.64 log10 c/mL observed at 40–120 milligrams once daily. The study’s primary endpoint of change in HIV-1 RNA from baseline to Day 11 of greater than -1 log10 c/mL in HIV-1 RNA was met.
In July, FDA approved Daklinza, an NS5A replication complex inhibitor. This approval marks the first time patients with chronic hepatitis C virus genotype 3 have a 12-week, once-daily, all-oral treatment option. Daklinza is indicated for use with sofosbuvir for the treatment of patients with chronic HCV genotype 3 infection. Sustained virologic response rates are reduced in HCV genotype 3-infected patients with cirrhosis receiving this regimen. The recommended dosage of Daklinza is 60 milligrams in combination with sofosbuvir for 12 weeks. Daklinza had already been approved by European regulators in August 2014.
The pivotal Phase III open-label ALLY-3 clinical trial enrolled 152 patients with chronic HCV genotype 3 infection and compensated liver disease (101 treatment-naïve patients and 51 treatment-experienced patients). The co-primary endpoints were sustained virologic response rates 12 weeks after completing therapy (SVR12) in each treatment group. In the trial the Daklinza plus sofosbuvir regimen demonstrated SVR12 in 90 percent of treatment-naïve and 86 percent of treatment-experienced chronic HCV genotype 3 patients. SVR12 rates were higher (96 percent) in genotype 3 patients without cirrhosis, regardless of treatment history. In the more difficult-to-treat patients with cirrhosis, SVR12 rates were reduced (63 percent). These SVR12 rates were achieved with 12 weeks of therapy without the use of ribavirin.
Also in July, FDA granted breakthrough therapy designation to the investigational compound BMS-663068 when used in combination with other antiretroviral agents for the treatment of HIV-1 infection in heavily treatment-experienced adult patients. BMS-663068 is an oral prodrug of the molecule BMS-626529 and first-in-class HIV-1 attachment inhibitor. The attachment inhibitor is designed to work differently than entry inhibitors, a current class of drugs that targets co-receptors’ activity or fusion after HIV attaches to the CD4+ host cell. BMS-663068 is thought to work at an earlier point in the replication process to prevent the virus’ initial interaction with immune cells entirely, and thus blocks its entry into the cell.
FDA’s designation is based on data from the Phase IIb clinical study comparing BMS-663068 to a boosted protease inhibitor, Reyataz and ritonavir, in treatment-experienced patients, with a treatment backbone across all arms of raltegravir, in addition to tenofovir disoproxil fumarate. Week 48 results from the Phase IIb trial supported the continued clinical development of the attachment inhibitor. A Phase III trial in heavily treatment-experienced patients (defined as individuals who can no longer formulate a viable three-drug treatment regimen due to accumulation of drug resistance, past intolerabilities, or antiretroviral contraindications) began in February 2015 and is ongoing.
In September, BMS and partner developer AbbVie announced that FDA had accepted for priority review the Biologics License Application (BLA) for Empliciti (elotuzumab), an investigational Signaling Lymphocyte Activation Molecule (SLAMF7)-directed immunostimulatory antibody, for the treatment of multiple myeloma as combination therapy in patients who have received one or more prior therapies. Empliciti was previously granted Breakthrough Therapy Designation by FDA; the European Medicines Agency also validated for review the Marketing Authorization Application for Empliciti, granting it accelerated assessment.
The filing acceptance is primarily supported by data from the ELOQUENT-2 trial, a Phase III, randomized, open-label study that evaluated Empliciti in combination with lenalidomide and dexamethasone versus lenalidomide and dexamethasone alone. The results of this trial were published in the New England Journal of Medicine on June 2. Additionally, the filing was supported by data from study CA204-009, a Phase II, randomized, open-label study which evaluated Empliciti with bortezomib and dexamethasone versus bortezomib and dexamethasone alone.