Bristol Meyers Squibb is #9 on our Top 20 Pharma and Biopharma Companies 2023 report.

Below is a look at the company’s 2023/24 highlights, recent acquisitions, best-selling drugs, and more.

Headcount: 34,100
Revenues: $45,006 (-2%)
Earnings: $8,040 (+27%)
R&D: $9,299 (-2%)

Bristol Myers Squibb’s year was highlighted by several significant transactions, including acquisitions of Karuna Therapeutics, RayzeBio and Mirati Therapeutics, adding neuroscience and oncology assets, and a strategic collaboration with SystImmune for an antibody-drug conjugate (ADC).

Meanwhile key pipeline advances include U.S. FDA approval of Augtyro for solid tumors and the FDA acceptance of its sBLAs for Breyanzi in follicular lymphoma and mantle cell lymphoma for priority review.

Financial results for the year reflect lower sales of Revlimid due to generic erosion, partially offset by higher sales of the company’s new product portfolio and Opdivo. Of note, a subcutaneous version of Opdivo is currently under review and has potential to be the first and only subcutaneously administered PD-1 inhibitor.

New product portfolio sales increased to $3.6 billion compared to $2.0 billion in 2022, representing 77% growth, primarily driven by higher demand across the portfolio, including for Opdualag, Reblozyl, Camzyos, Breyanzi, Zeposia and Sotyktu.

Acquisitions and Alliances

Among efforts to strengthen its long-term growth profile and pipeline, BMS acquired Mirati Therapeutics, Inc., diversifying its oncology portfolio adding commercialized lung cancer medicine Krazati, and strengthening its pipeline with several promising clinical assets, including a potential first-in-class MTA-cooperative PRMT5 inhibitor in Phase 1 and a leading KRAS and KRAS-enabling program with two candidates in Phase 1.

Krazati recently received approval in combination with cetuximab for previously treated KRASG12C-mutated locally advanced or metastatic colorectal cancer, marking the drug’s second approval by the FDA.

Krazati is also approved to treat KRASG12C-mutated locally advanced or metastatic non-small cell lung cancer. potential across tumor types

BMS also agreed to acquire Karuna Therapeutics, a clinical-stage biopharmaceutical company developing medicines for psychiatric and neurological conditions. Once complete, the transaction is expected to strengthen the company’s position in neuroscience and add assets including KarXT (xanomeline-trospium), an antipsychotic with a novel mechanism of action and differentiated efficacy and safety.

Karuna’s New Drug Application for KarXT for the treatment of schizophrenia in adults was accepted for review by the FDA and given a PDUFA date of September 26, 2024. The transaction is expected to close in the first half of 2024.

In addition, the company agreed to acquire RayzeBio, Inc., a clinical-stage radiopharmaceutical therapeutics (RPT) company with an innovation-leading position in actinium-based RPTs and a pipeline of potentially first-in-class and best-in-class drug development programs targeting solid tumors. The acquisition also adds state-of-the-art radiopharmaceutical manufacturing capabilities. The transaction is also expected to close in the first half of 2024.

Meanwhile, BMS entered an exclusive license and collaboration agreement with SystImmune for its BL-B01D1 asset, a potentially first-in-class EGFRxHER3 bispecific antibody-drug conjugate (ADC) currently being evaluated in a global Phase 1 study for safety and efficacy in metastatic or unresectable non-small cell lung cancer. The collaboration further diversifies its oncology portfolio and enhances the company’s presence in the ADC space.

Efforts to Advance Cell Therapies

Manufacturing cell therapies is costly and operationally and technically complex. As cell therapies offer the potential to transform the way diseases are treated, demand is on the rise. A collaboration with Cellares aims to enable BMS to expand its manufacturing capacity for its range of cell therapies through a platform that is scalable and has the potential to improve turnaround time.

BMS and Cellares, a company dedicated to clinical and industrial-scale cell therapy manufacturing, announced a worldwide capacity reservation and supply agreement for the manufacture of CAR T cell therapies in a transaction valued at up to $380 million in upfront and milestone payments.

As part of the agreement, Cellares will optimize, automate, and tech-transfer select BMS CAR T cell therapies onto its automated and high-throughput manufacturing platform, the Cell Shuttle. Cellares will dedicate multiple Cell Shuttle and Cell Q systems with fully automated, high-throughput quality control for BMS’s exclusive use. The Cell Shuttles and Cell Qs will be deployed in Cellares’ Smart Factories in the U.S., EU, and Japan.

Also of note, the FDA approved commercial production at the company’s newest cell therapy manufacturing facility in Devens, MA. The Devens site is a critical component of BMS’ global cell therapy manufacturing footprint for long-term supply of its cell therapy portfolio. The new 244,000 sq.-ft. cell therapy manufacturing facility is the second significant expansion at the Devens site.

R&D

Bristol Myers Squibb’s R&D pipeline includes 55 compounds in development in more than 40 disease areas. In addition to Krazati, recent advances include approvals for Augtyro and cell therapy Breyanzi.

The FDA granted accelerated approval of Augtyro for the treatment of solid tumors that have a neurotrophic tyrosine receptor kinase (NTRK) gene fusion, are locally advanced or metastatic or where surgical resection is likely to result in severe morbidity and have progressed following treatment or with no alternative therapy.

In the TRIDENT-1 trial with NTRK-positive locally advanced/metastatic solid tumors collectively representing 15 different types of cancer, 58% of TKI-naïve patients, with a median follow up of 17.8 months, had a confirmed objective response rate, and of those 43% experienced partial responses and 15% had complete responses. Of the TKI-naïve responding patients, 83% were still in response at one year.

Additionally, Breyanzi, a CD19-directed chimeric antigen receptor (CAR) T cell therapy, was approved for several indications, including the treatment of relapsed or refractory mantle cell lymphoma (MCL) with two prior lines of therapy.

In the MCL cohort of the TRANSCEND NHL 001 trial, Breyanzi delivered responses in 85% of patients with a one-time infusion and demonstrated a consistent safety profile across clinical trials. Breyanzi is the only CAR T cell therapy approved by the FDA for four distinct subtypes of non-Hodgkin lymphoma, reaching a broad array of patients with B-cell malignancies.

The FDA also granted accelerated approval for Breyanzi for the treatment of relapsed or refractory follicular lymphoma (FL) with two or more prior lines of therapy. This indication is approved under accelerated approval based on response rate and duration of response, with 95.7% of patients responding to Breyanzi in the TRANSCEND FL trial.

Breyanzi was also granted accelerated approval for the treatment of relapsed or refractory chronic lymphocytic leukemia (CLL) or small lymphocytic lymphoma (SLL) who have received at least two prior lines of therapy.

Finally, BMS and partner 2seventy bio, Inc. received FDA approval of Abecma for the treatment of relapsed or refractory multiple myeloma after two or more prior lines of therapy, based on results from the KarMMa-3 trial.

Headcount: 34,300
Revenues: $46,159 (+3%)
Net Income: $6,345 (-10%)
R&D: $9,509 (-7%)

Bristol Myers Squibb (BMS) posted revenues of $46.2 billion, consistent with the prior year, driven by in-line products—Eliquis and Opdivo—and the new product portfolio driven by Opdualag, Abecma, and Reblozyl.

Revenues for in-line products were $33.3 billion compared to $31.3 billion, representing an increase of 7%. Eliquis revenues grew 10% to $11.8 billion while Opdivo revenues also increased 10% to $8.2 billion.

New product portfolio revenues grew to $2.0 billion compared to $1.1 billion, representing growth of 87% driven by the launch of Opdualag and higher demand for Abecma and Reblozyl.

During the year, BMS received approval from the U.S. FDA for Camzyos (mavacamten) for the treatment of adults with symptomatic New York Heart Association (NYHA) class II-III obstructive hypertrophic cardiomyopathy (obstructive HCM) to improve functional capacity and symptoms. Camzyos is the first and only FDA-approved allosteric and reversible inhibitor selective for cardiac myosin that targets the underlying pathophysiology of obstructive HCM. Bristol Myers has forecast the drug reaching $4 billion in sales by 2029.

Cancer collaborations

In May 2022 BMS entered an exclusive license agreement with BridgeBio to develop and commercialize BBP-398, a potentially best-in-class SHP2 inhibitor, in oncology. BridgeBio is eligible to receive up to $905 million, including an upfront payment of $90 million, and up to $815 million in additional milestone payments and royalties.

The SHP2 inhibitor deal expands an earlier agreement between BridgeBio and BMS to study BBP-398 in combination with Opdivo (nivolumab) in advanced solid tumors with KRAS mutations. BridgeBio will continue to lead its three current Phase 1 monotherapy and BBP-398 combination therapy trials with additional support from BMS; future clinical trials will be performed and funded by BMS.

In June 2022 BMS acquired Turning Point Therapeutics, a leading oncology company, for $4.1 billion. Turning Point Therapeutics is a clinical-stage precision oncology company with a pipeline of investigational medicines designed to target the most common mutations associated with oncogenesis. Turning Point Therapeutics’ lead asset, repotrectinib, is a next-generation, potential best-in-class tyrosine kinase inhibitor (TKI) targeting the ROS1 and NTRK oncogenic drivers of non-small cell lung cancer (NSCLC) and other advanced solid tumors. Repotrectinib has been granted three Breakthrough Therapy Designations from the U.S. Food and Drug Administration. In the Phase 1/2 TRIDENT-1 clinical trial, longer duration of response has been observed in the landmark analysis with repotrectinib than with existing ROS1 agents in first-line NSCLC.

BMS expects repotrectinib to be approved in the U.S. in the second half of 2023 and become a new standard of care for patients with ROS1-positive NSCLC in the first-line setting. The company also plans to continue to explore the potential of Turning Point Therapeutics’ promising pipeline of novel compounds.

BMS also entered a collaboration Century Therapeutics to develop iPSC-derived allogeneic cell therapies. The collaboration brings together Century’s industry leading iPSC-derived allogeneic cell therapy platform with Bristol Myers Squibb’s expertise in cell therapy and oncology drug development. The first two programs include a program in acute myeloid leukemia and a program in multiple myeloma, which could incorporate either the iNK or a gamma delta iT platform. Century Therapeutics received $150 million with potential for additional $3 billion in payments plus royalties on global product sales across multiple programs in hematologic malignancies and solid tumors.

In another deal with Immatics N.V., a clinical-stage biopharmaceutical company active in the discovery and development of T cell-redirecting cancer immunotherapies, BMS expanded their strategic alliance to pursue the development of multiple allogeneic off-the-shelf TCR-T and/or CAR-T programs.

Under this collaboration, Bristol Myers Squibb and Immatics will develop two programs owned by Bristol Myers Squibb and both companies have an option to develop up to four additional programs each. The programs will utilize Immatics’ proprietary gamma delta T cell-derived, allogeneic Adoptive Cell Therapy (ACT) platform, called ACTallo, and a suite of next-generation technologies developed by Bristol Myers Squibb.

Under the terms of this agreement, Immatics received an upfront payment of $60 million as well as up to $700 million per Bristol Myers Squibb program through development, regulatory and commercial milestone payments, and tiered royalty payments.

Immatics will be responsible for preclinical development of the initial two Bristol Myers Squibb-owned programs and will receive additional payment for certain activities that Immatics could perform at Bristol Myers Squibb’s request. Bristol Myers Squibb will assume responsibility for clinical development and commercialization activities of all Bristol Myers Squibb-owned programs thereafter.

In addition, Bristol Myers Squibb and Immatics will expand their 2019 collaboration agreement focused on autologous T cell receptor-based therapy (TCR-T), with the inclusion of one additional TCR target discovered by Immatics. As part of this expansion, Immatics received an upfront payment of $20 million and is eligible for milestone payments and royalties.

World-class R&D building at Alexandria Point

In March 2022, BMS executed a long-term lease for the development of the company’s newest core R&D facility, a 427,000 square foot world-class building at Alexandria Point in the heart of the University Town Center (UTC) submarket in San Diego. Alexandria Point is the company’s first leading-edge, highly sustainable amenity-rich mega campus.

This milestone lease marks the second-largest life science lease in Alexandria’s history and further enhances its long-term strategic relationship with BMS. Since 1998, Alexandria has strategically partnered with BMS, aggregating over 900,000 square feet across five of Alexandria’s cluster markets, San Diego, Greater Boston, the San Francisco Bay Area, New York City and Seattle.

When complete, Alexandria Point will provide more than 2 million square-feet of mission-critical lab and office space, as well as over 100,000 square-feet of amenities.

Headcount: 32,200
Revenues: $46,385 (+9%)
Earnings: $6,994
R&D: $11,354 (+2%)

TOP SELLING DRUGS

In 2021, Bristol Myers Squibb (BMS) reported revenues of $46 billion. This 9% increase from the previous year was driven by Eliquis and recently launched new products, Revlimid and Opdivo/Yervoy. During the year, BMS obtained more than 20 approvals for new medicines and additional indications and formulations of currently marketed medicines in major markets (the U.S., EU and Japan), including regulatory approvals of Breyanzi and Abecma in hematology malignancies, the first approvals of its cell therapy portfolio.

BMS also reported progress in its immuno-oncology portfolio with additional approvals for both Opdivo and Opdivo+Yervoy in various indications. The immunology portfolio expanded with the FDA approval of Zeposia for the treatment of adults with moderately to severely active ulcerative colitis (UC). The company also bolstered its cardiovascular franchise by adding mavacamten with the acquisition of MyoKardia in 2020. In 2021, the FDA accepted the NDA for mavacamten for patients with symptomatic obstructive hypertrophic cardiomyopathy (HCM).

R&D alliances

In 2021, BMS obtained a global exclusive license to Agenus’ proprietary AGEN1777 bispecific antibody program that blocks TIGIT and an additional target. AGEN1777 is being studied in oncology and a Phase I clinical trial was initiated in October 2021. BMS will be responsible for the development and any subsequent commercialization of AGEN1777 and its related products worldwide, including strategic decisions, regulatory responsibilities, funding and manufacturing. The transaction included an up-front payment of $200 million and Agenus is eligible to receive milestones up to $1.4 billion.

In another collaboration, BMS and Eisai entered a partnership for the co-development and co-commercialization of MORAb-202, a selective folate receptor alpha antibody-drug conjugate being investigated in endometrial, ovarian, lung and breast cancers. MORAb-202 is currently in Phase I/II clinical trials for solid tumors. The companies will jointly develop and commercialize MORAb-202 in the U.S., Canada, Europe, Russia, Japan, China and certain other countries in the Asia-Pacific region. Eisai will be responsible for the global manufacturing and supply. Profits, research and development and commercialization costs are shared in the collaboration territories. BMS will be responsible for development and commercialization outside of the collaboration territory and will pay a royalty on those sales. Eisai received a $650 million up-front collaboration fee and BMS is also obligated to pay up to $2.5 billion upon the achievement of milestones.

During the year BMS entered into a global exclusive license with Immatics for its TCR bispecific IMA401 program. IMA401 is being studied in oncology and a Clinical Trial Application has been filed with the German federal regulatory authority and began in the first half of 2022. BMS and Immatics will collaborate on development and BMS will be responsible for the commercialization of IMA401 and its related products worldwide, including strategic decisions, regulatory responsibilities, funding and manufacturing. The transaction included an upfront payment of $150 million and Immatics is eligible up to $770 million in milestones.

With Prothena, BMS exercised an option under the global neuroscience research and development collaboration for the exclusive U.S. rights to PRX005, an anti-tau antibody that specifically targets an area within the microtubule binding region for the potential treatment of Alzheimer’s disease. PRX005 is currently in a Phase I clinical trial.

Lastly, with Rockefeller University, BMS obtained a global exclusive license to develop, manufacture and commercialize Rockefeller’s novel monoclonal antibody duo treatment that neutralizes the SARS-CoV-2 virus for treatment and potentially for prevention of COVID-19. Phase I clinical trials to assess dosing for IV and subcutaneous formulations and to assess safety have been completed by Rockefeller University. In May 2021, enrollment initiated in the Phase II study within the NIH ACTIV-2 protocol at a network of sites within the U.S. Phase II enrollment was completed in August 2021 and topline data was expected in the first quarter of 2022.

Investment in cell therapy operations

In support of continued investment in its cell therapy portfolio, BMS expanded its manufacturing capabilities in 2021 through the construction of new state-of-the-art cell therapy manufacturing facilities in Devens, MA, and Leiden, Netherlands.

In April 2021, BMS said it selected Leiden as the locations to house a new cell therapy manufacturing site in Europe, leveraging the growing life sciences region near Amsterdam and convenient access to transportation for shipping patient cells.

As part of BMS’ continuing commitment to patients with aggressive hematological cancers and its growing cell therapy franchise, the company is making this significant new investment to expand global manufacturing capacity and bring treatments to patients faster. Leiden will be the company’s fifth state-of-the-art cell therapy manufacturing facility and first in Europe, in addition to major contract manufacturing partnerships globally.

The European facility will be commercially focused with capabilities for multi-product cell therapy manufacturing and the ability to scale up capacity. It will leverage innovative technologies, the latest manufacturing equipment and advanced digital systems to deliver these critical cell therapies to patients.

In addition to the new Leiden facility, construction is underway for the new cell therapy manufacturing facility in Devens to further support clinical and commercial manufacturing of cell therapies for patients with aggressive hematological cancers.

The 244,000 square foot facility adds to the company’s already established state-of-the-art cell therapy manufacturing network with cutting-edge technologies and highly trained manufacturing teams. The Devens site will be equipped to enable quick ramp up of capacity for clinical and commercial cell therapy products.

Manufacturing cell therapies is both operationally and technically complex because they are manufactured uniquely for each individual patient, using a patient’s own T cells as the starting material. Each batch of engineered T cells is made for infusion back to the original cancer patient, and it is critical for companies to develop reliable quality supply, and rapid turnaround time.

The new cell therapy facility will be located on BMS’ current 89-acre Devens campus that supports process development, clinical manufacturing and commercial manufacturing for biologics medicines, including an immuno-oncology medicine. The new cell therapy facility allows accelerated career development for current and prospective employees across biologics and cell therapies on a single campus, with employees having access to all existing campus amenities. The company plans to hire several hundred employees over the next few years to support the new operations.

The Devens campus is part of BMS’ growing presence in Massachusetts. The company also operates two R&D facilities in Cambridge, MA and will be bringing those two sites together into a new building at Cambridge Crossing in 2023—construction is currently underway on the 480,000 square-foot state-of-the-art research and early development center that will bring together more than 550 employees now based in Kendall Square and Alewife.

The new biomedical hub at Cambridge Crossing will be situated on a 43-acre development at the intersection of Cambridge, Somerville and Boston. The company’s work on cancer resistance, neuroscience and immune-related diseases—such as discovery biology, translational science and chemistry research—will be housed at the new location. Additionally, work at the new site will facilitate end-to-end drug discovery: biotherapeutics, informatics and predictive sciences, drug metabolism pharmacokinetics and other research activities.

Current plans call for the building to be completed in January 2023, and employees are expected to relocate to Cambridge Crossing. The Cambridge Crossing property is being converted into a life science hub to inspire collaboration, innovation and connection through its proximity to MIT, Harvard and Kendall Square.

Headcount: 30,000
Revenues: $42,518 (+63%)
Loss: $8,995 (n/m)
R&D: $11,143  (+81%)

TOP SELLING DRUGS

With the $74 billion acquisition of Celgene, Bristol-Myers Squibb catapulted into 2020’s #6 position. Completed in November 2019, financials for 2020 include a full year of Celgene operations, which contributed $15.7 billion of revenues or 60% of BMS’ 63% growth for the year. Eliquis, a leading oral anti-coagulant drug, also drove growth with sales up 16% to $9.2 billion. Additionally, the acquisition of MyoKardia for approximately $13.1 billion was completed in November 2020. Both acquisitions broaden BMS’ biopharmaceutical endeavors with several near-term assets in oncology, hematology, immunology and cardiovascular disease.

In 2020, BMS gained 13 approvals for new medicines and additional indications for marketed medicines in major markets (the U.S., EU and Japan), including regulatory milestones for Opdivo and Opdivo+Yervoy combinations, which BMS continues to explore along with other anti-cancer agents in numerous tumor types. In the field of hematology, BMS now has a leading presence through in-line assets Revlimid and Pomalyst.

Key regulatory approvals include Zeposia and Onureg, and liso-cel for the treatment of large B-cell lymphoma. Additionally, pipeline assets show promise in hematology malignancies through the company’s CELMoD agents, multiple modalities targeting B-Cell Maturation Antigen (BCMA), and next-gen cell therapies.

Corporate endeavors
With the acquisition of MyoKardia, BMS bolstered its cardiovascular franchise with mavacamten and a pipeline of promising candidates. Mavacamten, a potential first-in-class medicine for the treatment of obstructive hypertrophic cardiomyopathy (HCM), a chronic heart disease with high morbidity, brings significant commercial potential. Mavacamten in HCM was submitted for review by the FDA in March. BMS plans to explore mavacamten in additional indications, as well as develop MyoKardia’s two clinical-stage therapeutics danicamtiv and MYK-224.

In September, BMS also acquired Forbius, a clinical-stage protein engineering company that designs and develops biotherapeutics for the treatment of cancer and fibrotic diseases. The acquisition provides full rights to Forbius’s TGF-beta program, including the program’s lead investigational asset, AVID200, which is in Phase I development.

Additionally, for $475 million in near-term upfronts, BMS obtained a global exclusive license to Dragonfly’s interleukin-12 immunotherapy program, including its extended half-life cytokine DF6002. Dragonfly received FDA clearance in May 2020 for its investigational NDA to develop DF6002, which is currently in Phase 1/2 development in advanced solid tumors. BMS intends to advance the development of DF6002 in oncology and hematology.

BMS has also been focusing on expanding its manufacturing resources to support its growing cell therapy franchise. In March, construction began on a new, 244,000 sq.-ft., state-of-the-art cell therapy manufacturing facility in Devens, MA. This significant investment to support clinical and commercial manufacturing of cell therapies for patients with aggressive hematological cancers, will enable quick ramp up of capacity for cell therapy products.

In addition, BMS recently selected Leiden, Netherlands to house a new cell therapy manufacturing site in Europe. Leiden will be the company’s fifth facility dedicated to cell therapy and its first in Europe, in addition to major contract manufacturing partnerships globally.

R&D advances
BMS’ core therapeutic areas encompass cancer, hematology, immunology, cardiovascular and fibrotic disease, with more than 50 unique compounds in clinical development.

Most recent approvals dating back to January include the use of Opdivo in combination with Cabometyx for the first-line treatment of advanced renal cell carcinoma, the most common kind of kidney cancer. In a trial, the drug combo reduced the risk of death by 40% vs. sunitinib, and the median progression-free survival (PFS), the trial’s primary endpoint, was doubled compared to those receiving sunitinib alone: 16.6 months vs. 8.3 months, respectively.

In addition, the drug combination demonstrated a superior objective response rate with twice as many patients responding compared to sunitinib (56% vs. 27%), and 8% vs. 5% achieved a complete response.

BMS picked up two more approvals in February 2021. The FDA approved Breyanzi, a new CD19-directed chimeric antigen receptor (CAR) T cell therapy for the treatment of adult patients with relapsed or refractory large B-cell lymphoma after two or more lines of systemic therapy. Also, the European Commission approved lnrebic for the treatment of disease-related splenomegaly or symptoms in adults with myelofibrosis, who are Janus Associated Kinase inhibitor naive or have been treated with ruxolitinib.

In March of 2020 BMS expanded it immunology franchise with the FDA approval of ZEPOSIA (ozanimod) for relapsing forms of multiple sclerosis (RMS). ZEPOSIA, a once daily oral medication, is the only approved sphingosine-1-phosphate (S1P) receptor modulator that offers RMS patients an initiation with no genetic test and no label-based first-dose observation required for patients. In clinical trials, ZEPOSIA demonstrated efficacy on annualized relapse rate, a key clinical marker of disease activity, as compared to Biogen’s AVONEX. This also marked the first FDA-approval since the Celgene acquisition.

This past May, Zeposia was approved by the FDA for the treatment of moderately to severely active ulcerative colitis (UC), based on data from a Phase 3 trial that met its primary endpoint of clinical remission, as well as key secondary endpoints, including clinical response and endoscopic improvement.

Notably, BMS and bluebird bio, Inc. received approval from the FDA for Abecma as the first B-cell maturation antigen (BCMA)-directed CAR T cell immunotherapy for the treatment of relapsed or refractory multiple myeloma after four or more prior lines of therapy. Abecma is a personalized immune cell therapy approved as a one-time infusion. As an anti-BCMA CAR T cell therapy, Abecma recognizes and binds to BCMA, a protein that is nearly universally expressed on cancer cells in multiple myeloma, leading to the death of BCMA-expressing cells.

Alliances
In a recent agreement with The Rockefeller University, BMS gained a global exclusive license to develop, manufacture and commercialize Rockefeller’s novel monoclonal antibody (mAb) duo treatment that neutralizes the SARS-CoV-2 virus for therapy or prevention of COVID-19. This treatment is a combination of two mAbs directed at blocking the SARS-CoV-2 spike protein and neutralizing the virus. Preclinical data suggest that this could enable effective treatment against multiple variants of the virus using a low dose subcutaneous administration, eliminating the need for intravenous infusion. Phase 1 clinical trials for the mAb duo were initiated in mid-January with plans to move rapidly to a registrational program following results.

An ongoing research collaboration with Syngene was extended through 2030 for drug discovery, including chemistry, biology, drug metabolism and pharmacokinetics, as well as translational medicine research and development. The extension will include a 40% increase in the number of scientists and the addition of a new 50,000 sq.-ft. dedicated lab space. Syngene’s first dedicated R&D Center, the Biocon BMS R&D Center, was fully commissioned in 2009 and has become a major strategic R&D site for BMS.

BMS also extended its partnership with Evotec SE in the field of targeted protein degradation, with the goal to identify first-in-class drug candidates focusing on solid tumors. The partnership leverages Evotec’s PanOmics platform and has generated a pipeline of first-in-class targeted protein degradation projects, two of which have transitioned into lead optimization.

Lastly, a strategic collaboration with Molecular Templates aims to discover and develop multiple therapies for specific oncology targets using MTEM’s next-gen engineered toxin body (ETB) platform. ETBs represent a new class of targeted therapeutics that act through differentiated mechanisms including the ability to force receptor internalization, deliver therapeutic payloads, and directly kill targeted cells through the enzymatic inactivation of ribosomes. BMS has selected the first target and has the option to obtain an exclusive worldwide license to ETBs directed to each selected target. MTEM will receive $70 million upfront and is eligible to receive milestones of up to $1.3 billion.

Headcount: 30,000
Revenues: $26,145 (+16%)
Net Income: $3,460 (-30%)
R&D: $6,148 (-3%)

TOP SELLING DRUGS

Bristol-Myers-Squibb (BMS) rounds out this year’s Top 10. In the first quarter of 2020 revenues soared 82% to $10.8 billion, supercharged by the impact of the Celgene acquisition completed in November, and representing 71% of the growth, namely from its flagship products Revlimid, Pomalyst/Imnovid, and Abraxane. BMS also saw several significant clinical and regulatory milestones across its portfolio.

In one fell swoop, the $74 billion acquisition of Celgene created leading oncology franchises in both solid tumors and hematologic malignancies with Opdivo and Yervoy as well as Revlimid and Pomalyst; a top five immunology and inflammation franchise with Orencia and Otezla; and the number one cardiovascular franchise led by Eliquis. The combined company has nine products with more than $1 billion in annual sales and is seeing growth in the core disease areas of oncology, immunology and inflammation and cardiovascular disease.

Of the near-term launch opportunities from the Celegene acquisition, Zeposia (ozanimod) won approval in relapsing remitting multiple sclerosis (RRMS), and Reblozyl (luspatercept) for the treatment of anemia. BMS recently received a Refusal to File letter from the FDA regarding the Biologics License Application (BLA) for idecabtagene vicleucel (ide-cel; bb2121) for patients with heavily pre-treated relapsed and refractory multiple myeloma, citing further CMC detail is needed to complete the review. BMS plans to resubmit no later than the end of July 2020. Finally, the BLA for liso-cel in relapsed or refractory large B-cell lymphoma is currently under priority review, with an FDA target action date of August 17, 2020.

In line with strategic efforts to simplify and to realign its business portfolio, the company completed the divestment of its consumer health business, UPSA, to Taisho Pharmaceutical Co., for $1.6 billion, to help address changes in its business and the future requirements of its evolving pipeline. Also, in August, Celgene, in connection with its merger agreement with BMS, entered into an agreement to sell the global rights to OTEZLA to Amgen for $13.4 billion, providing additional funds for strategic efforts.

Pipeline progress
Top sellers, Opdivo plus Yervoy recently picked up three additional indication approvals by the FDA, one for the first-line treatment of adult patients with metastatic or recurrent non-small cell lung cancer (NSCLC) with no EGFR or ALK genomic tumor abnormalities, which demonstrated superior overall survival versus chemotherapy regardless of PD-L1 expression or tumor histology; and another for the first-line treatment of adult patients with metastatic non-small cell lung cancer (NSCLC) whose tumors express PD-L1. Additionally, the FDA accelerated approval of the therapy for patients with Hepatocellular Carcinoma (HCC) previously treated with Sorafenib, marking the sixth indication for the therapy.

Also, a partnership with Bayer and Ono Pharmaceutical Co. is evaluating the combination of Bayer’s kinase inhibitor Stivarga (regorafenib) and Opdivo in micro-satellite stable metastatic colorectal cancer (MSS mCRC), the most common form of mCRC. Recent results from the Phase Ib REGONIVO trial demonstrated promising antitumor activity and tolerability in patients with gastric and colorectal cancer (CRC).

The recent approval of Zeposia in the U.S. and Europe for the treatment of RRMS, marked the first approvals resulting from the Celgene acquisition. ZEPOSIA demonstrated efficacy on a key clinical marker of disease activity, annualized relapse rate, as compared to Biogen’s Avonex, which had sales of $1.7 billion in 2019, a decline of 13%. However, Zeposia offers RRMS patients a new oral option to help address the disease’s hallmark relapses and brain lesions. It’s currently the only approved sphingosine-1-phosphate (S1P) receptor modulator for RRMS.

While Zeposia enters a crowded MS market, the drug recently met primary endpoints in a Phase III trial as an induction and maintenance therapy for moderate to severe ulcerative colitis, demonstrating highly statistically significant results for clinical remission and in maintenance. The study also met key secondary endpoints of clinical response and endoscopic improvement. BMS is also investigating Zeposia for the treatment of moderately to severely active Crohn’s disease in the ongoing Phase III YELLOWSTONE clinical trial program.

Additionally, in April, the FDA approved Reblozyl, becoming the first and only erythroid maturation agent (EMA), for the treatment of anemia, failing an erythropoiesis stimulating agent. The FDA approval marks the second indication for Reblozyl and the first new treatment option in over a decade for patients with myelodysplastic syndromes (MDS) who require red blood cell (RBC) transfusions. Reblozyl works by regulating late-stage RBC maturation to relieve patients from the burden of regular RBC transfusions.

Another win for Celgene’s flagship Revlimid, which had sales of $10.8 billion in 2019, a new indication in combination with rituximab (anti-CD20 antibody) for the treatment of adults with previously treated follicular lymphoma (FL), makes it the first chemotherapy-free combination regimen approved for patients with FL by the European Commission. Clinical trials touted statistically significant improvements in progression-free survival.

Also, Celgene’s second highest selling drug, Pomalyst, gained FDA approval for patients with AIDS-related Kaposi sarcoma whose disease has become resistant to antiretroviral therapy, or in patients with Kaposi sarcoma who are HIV-negative.

As mentioned above, BMS anticipates approval of idecabtagene vicleucel after resubmission in the U.S., as well as approval from the European Medicines Agency after its Marketing Authorization Application was recently validated. The companies’ lead investigational B-cell maturation antigen (BCMA)-directed chimeric antigen receptor (CAR) T cell immunotherapy for the treatment of adult patients with multiple myeloma who have received at least three prior therapies, met the primary and secondary endpoints of overall response rate and complete response rate, respectively, in KarMMa trials.

Additionally, results from a TRANSCEND trial evaluating liso-cel in relapsed/refractory large B-cell lymphomas, met its primary and secondary end points, with overall response rate of 73%, and, of the patients who responded to liso-cel, 53% achieved a complete response. The median progression-free survival was 6.8 months, and median overall survival was an impressive 21.1 months.
With several portfolio advances and the strength of BMS’ prioritized brands, Revlimid, Opdivo, and Eliquis, we can anticipate BMS’ continued rise in the rankings in the next few years.

Headcount: 23,300
Revenues: $22,561 (+9%)
Net Income: $4,952 (NM)
R&D: $6,345  (-2%)

TOP SELLING DRUGS

Moving up in the ranks this year, Bristol-Myers Squibb is making headway in its efforts to become a premier specialty Biopharma company, overcoming losses associated with its Hep C franchise and culminating in the Opdivo era. For the past several years BMS held steady at 14, inching closer to the top 10 this year, and now with the pending $74 billion Celgene acquisition, potentially to the top five in 2020.

In 2018, double digit growth for prioritized brands Opdivo, which grew by $443 million, Eliquis, which grew by $342 million, Yervoy, which grew by $115 million, as well as Orencia, helped to offset significant declines in established brands Baraclude, Reyataz, Sustiva, and Hepatitis C franchises (for which revenues have all but disappeared), representing a total of $1.5 billion in lost revenue as compared to 2017.

Continued growth in the first quarter of 2019, with revenues up 14%, reaffirms the trajectory of the company’s priority brands. Eliquis grew by $419 million, up 28%, Opdivo grew by $290 million, up 19%, Yervoy grew by $135 million, up 54%, and Orencia and Sprycel, were up 8% and 5%, respectively.

The Mega M&A news on January third, when BMS announced plans to acquire Celgene in a transaction valued at approximately $74 billion, will result in leading franchises in oncology (in both solid tumors and hematologic malignancies) led by Opdivo and Yervoy as well as Revlimid and Pomalyst; Immunology and Inflammation (led by Orencia and Otezla) and Cardiovascular Disease with Eliquis. The acquisition also expands Phase III assets with six expected near-term product launches representing more than $15 billion in revenue potential. Furthermore, Celgene’s Revlimid, for the treatment of multiple myeloma, is one of the world’s best-selling drugs. Sales were $9.7 billion in 2018, up 18%.

Following the acquisition, Thomas Lynch Jr., BMS’ chief scientific officer will leave the company on October 1st. Rupert Vessey, a Celgene research executive will serve as president, Research & Early Development, overseeing drug discovery and the early clinical development. He will report to CEO Giovanni Caforio, and serve as a member of the leadership team. For late-stage assets, oncology expert Samit Hirawat, will service as chief medical officer, joining the company from Novartis.

Additional post-closing changes include, Nadim Ahmed from Celgene, who will manage the combined company’s hematology business. The rest of the combined company’s commercial side, including its cancer, immunology and cardiovascular businesses, will be managed by Chris Boerner, currently BMS’ chief commercial officer. David Elkins, currently the chief financial officer of Celgene, will serve as executive vice president and chief financial officer.

R&D Advances

The company continues to expand indications for its top seller Opdivo, and in April announced four-year survival results from pooled analyses of four studies in patients with previously-treated advanced non-small cell lung cancer who were treated with Opdivo.

In August of last year, the FDA approved Opdivo as the first and only immuno-oncology treatment option for patients with metastatic small cell lung cancer (SCLC) whose cancer has progressed after platinum-based chemotherapy. Approval for this indication was granted under accelerated approval based on overall response rate and duration of response.

Small cell lung cancer is one of two main types of lung cancer and accounts for about 10% to 15% of all lung cancers. It’s an aggressive disease that often goes undetected until the cancer is advanced.

Additional indications for Opdivo now include melanoma and kidney cancer. In July, it was approved by the European Commission (EC) for the adjuvant treatment of melanoma with involvement of lymph nodes or metastatic disease for both BRAF mutant and wild-type melanoma patients. With this decision, Opdivo became the first PD-1 therapy to receive a EC approval in the adjuvant setting, gaining its eighth indication across six distinct tumor types. Also, in January, the EC approved the combination of Opdivo plus Yervoy for the first-line treatment of patients with intermediate- and poor-risk advanced renal cell carcinoma.

BMS is also evaluating the Opdivo/Yervoy combo in late stage trials in castration-resistant prostate cancer and advanced or metastatic renal cell carcinoma. Also, in partnership with Infinity Pharmaceuticals, a Phase II trial is evaluating Opdivo in combination with Infinity’s IPI-549 in patients with advanced urothelial cancer.

Despite its many successes, several indications for Opdivo fell short. BMS withdrew its supplemental Biologics License Application for the Opdivo and low-dose Yervoy combo for the treatment of first-line advanced non-small cell lung cancer (NSCLC) in patients with tumor mutational burden. After discussions with the FDA, further evidence on the relationship between TMB and PD-L1 is required to fully evaluate the impact of Opdivo plus Yervoy in this indication.

Also, in May, a Phase III trial evaluating Opdivo plus radiation versus temozolomide plus radiation in patients with newly diagnosed O6-methylguanine-DNA methyltransferase (MGMT)-unmethylated glioblastoma multiforme (GBM), did not meet its primary endpoint of overall survival (OS) at final analysis. Likewise, a Phase II trial evaluating Opdivo versus Opdivo plus Yervoy in patients with recurrent or metastatic squamous cell carcinoma of the head and neck, did not meet its primary endpoints.

Sprycel, the company’s next highest-selling oncology drug, gained an additional hematology indication. In January, the FDA expanded the indication for Sprycel tablets to include the treatment of pediatric patients with newly diagnosed Philadelphia chromosome-positive (Ph+) acute lymphoblastic leukemia (ALL) in combination with chemotherapy, and shortly thereafter received the same approval by the EC.

Early Research Efforts

BMS and Tsinghua University are collaborating to discover therapeutic agents against novel targets for autoimmune diseases and cancers. The collaboration brings together their respective scientific expertise and capabilities with a focus on validating new targets and generating early drug candidates for clinical development. Tsinghua University will conduct research on projects and BMS will have an option to exclusively license therapeutic resulting agents.

The collaboration expands an existing relationship that began in 2012 focused on autoimmune target discovery, structural biology research, as well as the science of mapping the 3D protein structure of biological molecular targets.

Lastly, a clinical collaboration with Compugen is evaluating Compugen’s COM701, an investigational anti-PVRIG antibody, in combination with Opdivo in patients with advanced solid tumors, including non-small cell lung, ovarian, breast and endometrial cancer. In conjunction with this collaboration, BMS will make a $12 million equity investment in Compugen. Should Opdivo prove successful in treating ovarian and breast cancer, the sky is the limit for this breakthrough therapy.

Headcount: 25,000
Revenues: $20,776 (+7%)
Net Income: $975 (-78%)
R&D: $6,411 (+30%)

TOP SELLING DRUGS  

Although industry analysts predicted the demise of the blockbuster era, we can see with Opdivo and Eliquis, it is alive and well as these drugs continue to experience strong global growth, while capturing market share. Opdivo and Eliquis sales soared to $4.9 billion each, up 31% and 46%, respectively. This growth helped offset declines for several of its key legacy products. Heavy competition has eviscerated the Hepatitis C Franchise with sales falling 74% to $406 million for the year, and all but disappeared in 1Q18 with sales of just $3 million.

In the first quarter of 2018, revenues were up 5% to $5.2 billion, driven by Eliquis sales, up 37%, Opdivo sales, up 34% and Orencia sales, up 11%, while Sprycel and Yervoy sales declined 5% and 25%, respectively. Yervoy is expected to rebound if use with Opdivo increases. The chemotherapy-sparing combination recently won U.S. approval to treat advanced kidney cancer.

In 2017 earnings were impacted by a one-time $2.9 billion charge resulting from U.S. tax reform. Also, R&D expenses were up 30% primarily attributed to the Opdivo expansion, along with higher license and asset acquisition charges. However, R&D expenses are expected to  decline and stabilize in the next few years.

A couple of investments aim to bolster BMS’ biologics portfolio. This past August, BMS acquired IFM Therapeutics for $300 million upfront and as much as $1 billion in milestones. BMS gained full rights to IFM’s preclinical STING (stimulator of interferon genes) and NLRP3 agonist programs focused on enhancing the immune response to treat cancer. IFM’s STING program includes a lead asset against this target, while the NLRP3 agonist program includes a first-in-class pipeline candidate.

Expanding its oncology development program with an immunotherapy for a broad range of tumor indications, BMS gained an exclusive license for the development and commercialization of ONO-4578, Ono Pharmaceutical’s Phase I selective Prostaglandin E2 (PGE2) receptor 4 (EP4) antagonist. The companies will also collaborate on discovery efforts to identify additional compounds from Ono’s PGE2 receptor antagonist programs. BMS paid $40 million upfront and will be responsible for the development, manufacturing and commercialization.

To accommodate this growing biologics portfolio, BMS sold its small molecule API manufacturing facility in Swords, Ireland, to SK Biotek in order to shift its manufacturing focus in Ireland with an ongoing investment in the Cruiserath biologics facility.

Opdivo Expansion Efforts

BMS paid $1 billion upfront and made an equity investment of $850 million in Nektar Therapeutics to develop and commercialize Nektar’s lead immuno-oncology program, NKTR-214 in combination with Opdivo and Opdivo plus Yervoy, in more than 20 indications across nine tumor types, as well as potential combinations with other anti-cancer agents from either of the respective companies and/or third parties. Pivotal studies in renal cell carcinoma and melanoma are expected to be initiated in mid-2018.

NKTR-214, a CD122-biased agonist, is an investigational immuno-stimulatory therapy designed to selectively expand cancer-fighting T cells and natural killer cells directly in the tumor and increase PD-1 expression on those immune cells.

In a major advance for Opdivo + Yervoy, BMS reported an improvement in progression-free survival in patients with advanced non-small cell lung cancer (NSCLC), a common form of lung cancer, in the first-line setting. The Phase III study evaluated patients who had tumor mutation burden regardless of PD-L1 expression. BMS and several other pharma companies had previously seen mixed data evaluating first-line advanced NSCLC patients using the PD-L1 biomarker, so this is promising. Roche, AstraZeneca, and Merck are also pursuing this indication.

Importantly, the study will advance to evaluate the co-primary endpoint of overall-survival. If the Opdivo + Yervoy combo demonstrates that patients can live longer compared to chemotherapy alone, it would be a huge advantage for BMS.

Additionally, promising data from BMS’ IDO inhibitor drug in combination with Opdivo showed impressive efficacy in patients with heavily pre-treated bladder cancer and cervical cancer.

Additional late-stage efforts include a Phase III trial, in partnership with Exelixis, to evaluate Opdivo in combination with Cabometyx (cabozantinib) tablets, a small molecule inhibitor of receptor tyrosine kinases, or Opdivo and Yervoy in combination with Cabometyx versus sunitinib in advanced or metastatic renal cell carcinoma. The primary endpoint for the trial is progression-free survival.

Also, an alliance with Clovis Oncology is evaluating the combination of Opdivo and Clovis Oncology’s poly (ADP-ribose) polymerase (PARP) inhibitor Rubraca in Phase III trials in advanced ovarian cancer, and advanced triple-negative breast cancers.

Early Research efforts in collaboration with TARIS Biomedical, AbbVie, and Daiichi are underway evaluating potential new indications for Opdivo. A clinical collaboration with TARIS Biomedical is evaluating TARIS’ investigational product, TAR-200 (GemRIS), in combination with Opdivo in a Phase Ib trial in patients with muscle invasive bladder cancer.

Another clinical collaboration with AbbVie is evaluating the combination of AbbVie’s antibody drug conjugate ABBV-399 and Opdivo in a Phase 1b study in c-Met overexpressing NSCLC. This study could expand into additional solid tumors in the future.

Finally, an alliance with Daiichi Sankyo is evaluating Opdivo and Daiichi’s investigational antibody drug conjugate DS-8201 in HER2-expressing metastatic breast and bladder cancers.

Alliance Endeavors

Several collaborations aim to advance drug development efforts leveraging real-world data and technology. Real World Evidence (RWE) promises to help advance drug development and timelines and BMS is betting on this through an expanded agreement with Flatiron Health. It provides access to Flatiron’s real-world data to help accelerate BMS’ R&D efforts across a range of tumors, as well as improve its ability to generate additional evidence on the use of its cancer medicines outside of clinical trials.

BMS partnered with Illumina to leverage its next-generation sequencing (NGS) technology to develop and globally commercialize in-vitro diagnostic (IVD) assays to support its oncology portfolio. The companies plan to develop a diagnostic version of the Illumina TruSight Oncology 500 assay to measure potentially predictive genomic biomarkers. BMS’ development program includes 24 clinical-stage molecules designed to target different immune system pathways across more than 50 types of cancers, and through its translational capabilities, has identified a number of potentially predictive biomarkers.

Headcount: 25,000
Revenues: $19,427 (+17%)
Net Income: $4,457 (+185%)
R&D: $4,940 (-17%)

TOP SELLING DRUGS

Headquartered in New York City, Bristol-Myers Squibb’s (BMS) sales grew 17% to $19.4 billion in 2016 from $16.5 billion the year before. Most of the revenue comes from sales in the U.S. (55%) while Europe accounts for 22% and ROW markets including Japan contributed 23% of sales revenue.

Overall, growth was driven by strong performance in the company’s Oncology segment, the largest revenue contributor in 2016, accounting for nearly 35% of the company’s total revenue. This segment reported a rise of more than 62% in 2016 compared to 2015, mainly driven by Opdivo, with nearly $3.8 billion in sales, up a staggering 301%.  Yervoy, Sprycel, and newly launched Empliciti to treat multiple myeloma, also contributed to growth.

The Virology segment contributed 24% of BMS’s total revenue, which fell 11% to $4.7 billion in 2016, compared to $5.3 billion in 2015. With increased competition in this segment, the company reported declines for all of its products, including its Hepatitis C franchise, its hepatitis B drug Baraclude, and its HIV drugs Reyataz and Sustiva.

The Immuno-Science segment, which includes Orencia, contributed nearly 12% of the company’s total revenue in 2016, driven by a 20% increase in Orencia sales to $2.3 billion compared to 2015.

The Cardiovascular segment, represented by the drug Eliquis, contributed 17% of BMS’s total revenue in 2016. Eliquis sales soared 80% to $3.3 billion in 2016, compared to $1.9 billion in 2015, due to wide use and the strength of its prescription trends.

The Neuroscience segment, represented by the drug Abilify, reported a drop of 83% in Abilify revenue to $128 million following competition launched during the year.

Also, the Matured Products segment and all other products showed a 17% drop in revenue to $2.1 billion due to increased competition.

In 2016, BMS received 19 approvals for new medicines and additional indications and formulations of currently marketed medicines in major markets—the U.S., EU and Japan—as well as multiple regulatory milestone achievements for Opdivo. BMS also said it encountered a significant setback in first-line lung cancer with the announcement of negative results of CheckMate-026. As a result, BMS did not pursue an accelerated regulatory pathway for the Opdivo+Yervoy combination therapy in first-line lung cancer, but BMS is still pursuing a broad program in this area encompassing combinations of Opdivo+Yervoy, Opdivo and chemotherapy, and Opdivo combined with Yervoy and chemotherapy.

Acquisitions and partnerships

BMS made several acquisitions and entered licensing transactions to focus resources on growth opportunities that drive the greatest long-term value. BMS is focused on the following core therapeutic areas: oncology, including IO, immunoscience, cardiovascular and fibrotic diseases. Significant transactions from 2016 are summarized below.

In December, BMS and Nitto Denko entered into an exclusive worldwide license agreement granting BMS the right to develop and commercialize Nitto Denko’s investigational siRNA molecules targeting HSP47 in vitamin A containing formulations, which includes Nitto Denko’s lead asset ND-L02-s0201, currently in a Phase Ib study for the treatment of advanced liver fibrosis.

The agreement also grants BMS the option to receive exclusive licenses for HSP47 siRNAs in vitamin A containing formulations for the treatment of lung fibrosis and other organ fibrosis.

In July 2016, BMS acquired all of the outstanding shares of Cormorant, a private pharmaceutical company focused on the development of therapies for cancer and rare diseases. The acquisition provides BMS with full rights to Cormorant’s lead candidate HuMax-IL8, a Phase I/II monoclonal antibody that represents a potentially complementary IO mechanism of action to T-cell directed antibodies and co-stimulatory molecules.

In April 2016, BMS acquired all of the outstanding shares of Padlock, a private biotechnology company dedicated to creating new medicines to treat destructive autoimmune diseases. The acquisition provides BMS with full rights to Padlock’s PAD inhibitor discovery program focused on the development of potentially transformational treatment approaches for patients with rheumatoid arthritis. Padlock’s PAD discovery program may have additional utility in treating systemic lupus erythematosus and other autoimmune diseases.

In February 2016, BMS and Pfizer entered into a collaboration and license agreement with Portola to develop and commercialize the investigational agent andexanet alfa in Japan. Andexanet alfa is designed to reverse the anticoagulant activity of Factor Xa inhibitors, including Eliquis. BMS and Pfizer are responsible for all development and regulatory activities for andexanet alfa in Japan and for exclusively commercializing the agent in Japan. Portola retains the rights to andexanet alfa outside of Japan and will be responsible for the manufacturing supply.

In addition to the above transactions, BMS provided notice of terminations to the California Institute for Biomedical Research pertaining to a research collaboration agreement for the development of anti-fibrotic preclinical compounds and Dual Therapeutics pertaining to a research collaboration agreement for the development of anti-cancer preclinical compounds.

Headcount: 25,000
Revenues: $16,560 (+4%)
Net Income: $1,624 (-19%)
R&D: $5,920 (+31%)

TOP SELLING DRUGS  

Investing in the future of its R&D operations is a top priority for Bristol-Myers Squibb (BMS), which recorded sales of $16.56 billion in the year under review. On the R&D front BMS bolstered its organization when it unveiled plans to expand its presence within hubs of scientific excellence and innovation with the opening of a new state-of-the-art research site in Cambridge, MA, in addition to the ongoing expansion of the company’s R&D Discovery site in the San Francisco Bay Area.

The new facility in Cambridge is expected to open in 2018 while the ongoing site expansion in the San Francisco Bay Area adds 61,000 square feet of laboratory and office space at the Woodside Technology Park life science campus and is expected to be completed in 2016. Consistent with evolution of the R&D organization’s strategic focus, which was previously announced in 2013, the company also discontinued discovery research efforts in virology. BMS made a deal during the year with ViiV Healthcare to divest its pipeline of investigational HIV medicines in various stages of development, for $350 million upfront with potential development and regulatory milestone payments of as much as $518 million for clinical assets and as much as $587 million for discovery and preclinical programs.

In Cambridge, Bristol-Myers Squibb scientists will focus on the company’s ongoing discovery efforts in genetically defined diseases, molecular discovery technologies and discovery platform chemistry. The company will relocate up to 200 employees from its Wallingford, CN, and Waltham, MA, sites, and a limited number from its central New Jersey locations. As part of this transition, the Waltham site is expected to close in early 2018. The existing site in Wallingford will also close in early 2018 with up to 500 employees relocating to a new location in Connecticut.

The Woodside Technology Park life science campus in the San Francisco Bay Area serves as BMS’s Discovery hub for researching breakthrough cancer immunotherapies. The company will fully occupy two of the three buildings at the campus totaling 194,100 square feet and will provide additional capacity to conduct biologics drug discovery research. The site expansion is expected to be completed in 2016.

In other expansion news, at the tail end of 2014 BMS unveiled plans to construct a new large-scale biologics manufacturing facility in Dublin, Ireland to produce multiple therapies for the company’s biologics portfolio. Once completed, the investment will in the new facility total nearly $1 billion and will significantly increase BMS’s biologics manufacturing capacity and play a central role in its global manufacturing network.

The company’s portfolio of approved and investigational biologics covers multiple therapeutic areas including oncology, virology and immunoscience. The 30,000-square meter project will house six 15,000-liter bioreactors and a purification area as well as office and lab space. The plant will be built on the grounds of the company’s existing bulk pharmaceutical manufacturing plant and the cost is expected to be comparable to the approximately $900 million investment in the company’s biologics manufacturing facility in Devens, MA. Approximately 350 to 400 scientists, engineers, bioprocess operators, quality specialists and other professionals are expected to work at the facility when operational in 2019.

Acquisition hungry

During the year, BMS made a $1.25 billion deal with Promedior to acquire 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 U.S. and Orphan designation in the U.S. and Europe for the treatment of MF and Orphan Designation in the U.S. and Europe for the treatment of IPF. Promedior is a clinical stage immunotherapy company developing 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.

BMS also acquired Flexus Biosciences, a privately held biotechnology company focused on novel anti-cancer therapeutics, for a potential total consideration of $1.25 billion, including $800 million upfront and development milestones. BMS gains full rights to Flexus’ lead preclinical small molecule, F001287, an IDO1-inhibitor targeted for IND filing in 2H15, as well as its IDO/TDO discovery program, which 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 all non-IDO/TDO assets of Flexus including those related to Phase I FLT3 and CDK4/6 inhibitor, its earlier stage small-molecule Treg cancer immunotherapy programs, and its current personnel and facilities.

BMS bought another private biotech, Cardioxyl Pharmaceuticals, which is focused on the discovery and development of novel therapeutic agents for the treatment of cardiovascular disease. The acquisition gives BMS full rights to Cardioxyl’s lead asset CXL-1427, a novel nitroxyl (HNO) donor (prodrug) in Phase II clinical development as an intravenous treatment for acute decompensated heart failure (ADHF). The transaction includes upfront and near-term milestone payments of up to $300 million and potential additional consideration of up to $1.775 billion upon the achievement of certain development, regulatory and sales milestones.

In addition to acquisitions, BMS entered several strategic alliances during the year. Together with Bavarian Nordic it entered an agreement that provides it with an exclusive option to license and commercialize Prostvac, Bavarian Nordic’s Phase III prostate-specific antigen (PSA)-targeting cancer immunotherapy in development for asymptomatic or minimally symptomatic metastatic castration-resistant prostate cancer (mCRPC).

Other collaborations include a deal between BMS and uniQure that provides BMS with exclusive access to uniQure’s gene therapy technology platform for multiple targets in cardiovascular disease. With the Moffitt Cancer Center BMS entered into a collaboration agreement as part of its Immuno-Oncology Rare Population Malignancy (I-O RPM) program in the U.S. Also, Five Prime Therapeutics entered into an exclusive worldwide license and collaboration agreement with BMS for the development and commercialization of its  colonystimulating factor 1 receptor (CSF1R) antibody program, including FPA008 which is in Phase I development for immunology and oncology indications.

Headcount: 24,000
Revenues: $15,879 (-3%)
Net Income: $2,029 (-21%)
R&D: $4,534( +22%)

TOP SELLING DRUGS

pulmonary embolism$774N/A

For nearly a decade, through acquisitions, divestitures and organic growth, Bristol-Myers Squibb has transformed itself into a highly specialized biopharma company. Five years ago about 40% of its pipeline consisted of biologics and three to five years from now, the company expects that number will grow to about 75%.

As BMS’ biologics portfolio continues to grow, so has its capability to develop and manufacture its products. This past year the company nearly doubled the size of its manufacturing complex in Devens, MA, investing $1 billion and bringing the employee count to 750. BMS is also building a new, large-scale biologics manufacturing facility in Dublin, Ireland to produce a portfolio of approved and investigational biologics covering oncology, virology and immunoscience. This venture will create as many as 400 manufacturing jobs and once completed in 2019, will significantly expand BMS’ biologics manufacturing capacity and play a central role in its global manufacturing network. The cost is expected to match that of the Devens investment.

Charged with carrying these efforts forward, BMS named a new CEO, Giovanni Caforio, M.D. As of May 5, he replaced Lamberto Andreotti who will serve as chairman after his retirement on August 3. Dr. Caforio helped build the company’s immuno-oncology portfolio as chief commercial and chief operating officer, and was integral in shaping the company’s transformation to a specialty biopharma company.

Not unlike many of its rivals, BMS has been enduring, and continues to face generic competition for several key products with patents set to expire, specifically Abilify, Baraclude, Reyataz and Sustiva.

The company remains focused on its promising immuno-oncology assets, namely Opdivo (nivolumab). In the immuno-oncology race to market, BMS’ closest competitors are Merck, Roche and Novartis. Merck’s lung cancer drug Keytruda, is pending broader approval and has the potential to infringe upon Opdivo sales.

However, Opdivo having been approved three months ahead of schedule in March has BMS in the lead, and additional indications should keep it there. Opdivo is currently pending in melanoma and non-squamous, non-small-cell lung cancer. The company recently ended a pivotal Phase III Opdivo study in the later indication, citing positive results. The drug sold $40 million in 1Q15 and analysts estimate it could reach $3.1 billion by 2017.

BMS beats forecasts

In looking at the numbers, BMS has a decent track record delivering positive earnings, and this past year, despite patent losses and looming competition, continued to make headway. Eliquis sales grew by $628 million; Orencia was up 14%; Sprycel, up 17%; Yervoy grew 36%; and the hepatitis C franchise had combined sales of $256 million.

In addition to generic competition, 2014 results were impacted by the divested diabetes alliance in February 2014, with revenues down 82% for products that include: Bydureon, Byetta, Farxiga, Onglyza/Kombiglyze, Myalept and Symlin.

However, results in the first quarter of 2015 reflect an emerging ascent from the financial impact of losses and competition. Revenues were up 4% to $4.0 billion and earnings were up 27% to $1.2 billion. With additional indications in DVT and PE, Eliquis sales soared to $355 million, up from $106 million a year ago. Yervoy sales were up 20% to $325 million. Orencia and Sprycel grew 10% to $400 million and $375 million, respectively. Daklinza and Sunvepra had combined sales of $264 million, and Opdivo brought in $40 million.

As of April 2015, Erbitux will be one less revenue stream for BMS in the year ahead, having transferred its rights to Lilly in North America, including the U.S., Canada, and PR. The cancer drug generated revenues of $723 million in 2014 (+4%), $682 million of which were from the U.S.

Furthermore, once competition picks up for the company’s top selling drug Abilify and flagship HIV products, Sustiva and Reyataz, BMS will need to recoup these losses quickly to stay afloat.

Several collaborations are underway to further advance Opdivo efforts. One with Five Prime Therapeutics offers the greatest potential in broadly expanding indications. The companies are evaluating the combination of Opdivo and FPA008, Five Prime’s monoclonal antibody targeting CSF1R, in six cancer types: non-small cell lung cancer (NSCLC), melanoma, head and neck cancer, pancreatic cancer, colorectal cancer and malignant glioma. FPA008 is in development as a potential treatment for rheumatoid arthritis (RA) but preclinical data suggest that combining antibodies targeting PD-1 and CSF1R may lead to an enhanced anti-tumor immune response compared to either therapy alone.

BMS, Ono Pharmaceutical, and Kyowa Hakko Kirin Co. are also collaborating on a Phase I combination study with Opdivo and mogamulizumab, an anti-CCR4 antibody, as a potential treatment for advanced or metastatic solid tumors.

More recently, BMS and Lilly entered a clinical trial collaboration to evaluate Opdivo in combination with Lilly’s galunisertib (LY2157299) as a potential treatment for advanced glioblastoma, hepatocellular carcinoma, and non-small cell lung cancer.

Additionally, an alliance with Rigel Pharmaceuticals based on its portfolio of small molecule TGF beta receptor kinase inhibitors, 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 BMS’ Opdivo and Yervoy.

Beyond Opdivo’s imminent success, BMS has two new HIV drugs in late stage trials and 12 therapies in clinical trials for diseases including: lupus, rheumatoid arthritis, cancer, thrombosis, fibrosis and genetic diseases. Still holding it own amidst overall industry challenges, BMS continues to make strides.

Although BMS has had a slight downward shift in the rankings this year, it isn’t showing any signs of slacking with its cancer therapies. BMS’ Phase III trial CheckMate-067 was headline news at ASCO presenting promising outcomes with combination therapy for patients with metastatic Stage III & Stage IV melanoma.  The company is in the race to head up the immuno-oncology sector alongside Merck, and as things stand this seems to be going in its favor. There are some that question whether immunotherapy may be a victim of its own success for big pharma, as they have been shown to be effective in a short space of time, but at this moment in time I suspect this isn’t on BMS’ mind. With treatment per patient around $150,000 a go, this promises to be a whopper!

Not content with its own pipeline, BMS recently acquired Flexus Biosciences and announced a strategic partnership with Rigel Pharmaceuticals. Focusing strongly on immunotherapy BMS has four of its eight drugs in the development pipeline in this category and have now taken even more under its wings to create potential new treatments.

Not forgetting that BMS also has its alliances with Pfizer in hematology and its HIV and Hepatitis portfolio, things seem to be rosy for the foreseeable future.

—Adele Graham-King

Headcount: 24,000
Pharma Reveneus: $16,385
Total Revenues: $16,38 (5-7%)
Net Income: $2,580 (3%)
R&D Budget: $3,731 (-4%)

TOP SELLING DRUGS

As the year 2013 drew to a close, Bristol-Myers Squibb’s fourth quarter was highlighted by the sale of its diabetes business to AstraZeneca, receiving $3.3 billion in closing and milestone payments during the quarter, and remaining eligible for royalty payments through 2025. The exit from metabolics is part of the company’s continued “Biopharma” strategy to transition to a specialty care model. As a result, BMS is down approximately 4,000 employees that were devoted to diabetes, most of which have been transferred to AZ.

For the year, revenues were down 7% to $16.4 billion, as top selling drug Abilify sales continue to plummet, down 19% to $2.3 billion. BMS’ cardiovascular franchise also continues to take a beating, with Avapro/Avalide and Plavix sales down 54% and 90%, respectively. While some heavy patent losses are behind them, top sellers Baraclude and Sustiva are waiting in the wings, with Reyataz not too far behind.

In the way of a bright spot, Orencia, Sprycel, and Yervoy, all boasting double-digit growth in 2013, are likely to continue to perform well for the company, as efforts to grow Eliquis revenue opportunities are pursued to recoup some cardiovascular losses.

The company achieved some important regulatory milestones in 1Q14 for Eliquis in the U.S., daclatasvir/asunaprevir in Japan, daclatasvir in Europe, and Farxiga in the U.S. BMS and its partner, Pfizer, have additional indications pending for Eliquis, including deep vein thrombosis (DVT) and pulmonary embolism (PE) and for the risk reduction of recurrent DVT and PE.

Despite lower than expected revenues at launch and beyond, Eliquis has a better risk/benefit profile than its closest competitors (Pradaxa and warfarin) in preventing stroke. The companies anticipated a slow uptick, and they were right, but the drug is showing signs of recovery. For the year sales reached $146 million, and in 1Q14 were $106 million, up from just $22 million the previous year.

As far as acquisitions go, this year-to-date proved more conservative for BMS. In 1Q14, the company acquired iPierian, a privately held biopharma company focused on neurodegenerative diseases, for $175 million, with the potential for additional development and regulatory milestones totaling $550 million, as well as future royalties on sales. iPierian’s lead asset IPN007, a monoclonal antibody with a promising new approach to treat progressive supranuclear palsy (PSP) and other Tauopathies, is scheduled to enter Phase I trials by early 2015.

In R&D news, BMS and CytomX launched a $1.2 billion cancer collaboration under which BMS will use CytomX Therapeutics’ Probody drug discovery platform to develop new immunotherapies against multiple cancer targets. These therapies focus on selective activation within the cancer while sparing healthy tissue. This transaction ties into the company’s ultimate goals for its immuno-oncology assets.

Another, more recent immunotherapy pact with Incyte will investigate a combination regimen of nivolumab, BMS’ investigational PD-1 immune checkpoint inhibitor, and INCB24360 in multiple tumor types using an action that helps the immune system to restart and target and kill cancer cells. The company recently gained an FDA Breakthrough Therapy Designation for nivolumab for the treatment of patients with Hodgkin lymphoma (HL), based on data from a cohort of patients with HL in the company’s ongoing Phase Ib study of relapsed and refractory hematological malignancies.

Additionally, BMS and AbbVie landed a breakthrough label from the FDA for Elotuzumab in multiple myeloma, based on findings from a Phase II study that evaluated two dose levels of Elotuzumab in combination with lenalidomide and low-dose dexamethasone in previously-treated MM patients. The criterion for breakthrough designation requires preliminary clinical evidence that demonstrates substantial improvement on at least one endpoint over available therapies. The company’s recently submitted (April 2014) NDA for daclatasvir (DCV) and asunaprevir, also had received this notable designation prior to submission.
BMS will also use Five Prime Therapeutics’ target discovery platform for the development of immuno-oncology therapies directed toward targets identified in two undisclosed immune checkpoint pathways.

While the company had a rather disappointing year financially, newer commercial stage products and a late-stage cancer therapy, nivolumab, are highly encouraging as potential growth drivers. The company is relying on—and devoting major resources to—its immuno-oncology assets, along with hepatitis C projects, which also brings much competition, for long-term growth prospects. With the company’s strong drug development reputation, many industry analysts are banking on its success.

Headcount: 28,000
Pharma Revenues: $17,621 (-17%)
Total Revenues: $17,621 (-17%)
Net Income: $2,501 (-52%)
R&D Budget: $3,90 (42%)

Top Selling Drugs

Account for 82% of total pharma sales, down from 83% in 2010

Bristol-Myers Squibb tied AstraZeneca for the biggest percentage drop in revenues in 2012, with a 17% fall. Plavix sales fell $4.5 billion after its May 2012 patent expiration, and another $450 million in Avapro dollars evaporated during the year. Like AZ, it has more expirations to contend with in the next few years. Unlike AZ, BMS has some bright spots in its future.

Orencia and Sprycel raced past the $1.0 billion mark last year, and will soon be joined by Yervoy. The company also gained approval for coronary syndrome treatment Eliquis late in 2012, opening the door for BMS and development partner Pfizer to try to cut into Pradaxa’s early market lead. Long-term estimates for Eliquis still consider it a double-blockbuster (bringing in at least $1.0 billion annually for each partner), but its soft launch in 1Q13 only brought in $22 million.

Meanwhile, BMS may have a mega-ace up its sleeve, as next-gen oncology immunotherapy nivolumab posted unprecedented benefits in patients with metastatic melanoma. Some analysts are excitedly projecting Avastin-like revenues from the drug.

These great results notwithstanding, BMS’ “string of pearls” strategy got all tangled up last year. For years, the company has made small and mid-sized acquisitions and licensing deals to boost its pipeline and help it survive the post-Plavix period. A number of these moves have paid off, but R&D is a cruel mistress.

In January 2012, the company spent $2.5 billion to buy Inhibitex and its Phase II oral hepatitis C treatment (BMS-094). In August 2013, BMS discontinued development of Inhibitex’s compound after safety issues arose, writing off $1.8 billion in the process. (Please note that we referred to the Inhibitex purchase as “a relative bargain” after Gilead spent $11 billion on Pharmasset.)

Eight months later, the company’s chief scientific officer, Dr. Elliot Sigal, was replaced by Dr. Francis Cuss. Since the age difference between Dr. Sigal and Dr. Cuss is only three years (61 to 58), some analysts took this as a sign that Dr. Sigal’s early retirement was attributable to the Inhibitex failure. Dr. Cuss, a 10-year veteran of BMS, was credited with integrating several past acquisitions — Adnexus, Medarex and ZymoGenetics — into the company’s R&D organization.

Shortly before BMS went public with the problems in the BMS-094 trial, the company made its biggest splurge yet, going halfsies with AstraZeneca to buy Amylin (total effective price: $7.0 billion). We covered that move in the As We Go To Press section of last year’s report. Amylin’s commercial products, Byetta and Bydureon, contributed $137 million to BMS in 1Q13 and are expected to grow as BMS and AZ market the heck out of them. (Early assessments of the buyout need to be revised, since BMS was negotiating at a time when it knew something bad was happening with its $2.5 billion Inhibitex deal.)

The partners have built up a significant diabetes portfolio, with Amylin’s products, Onglyza/Kombiglyze, and Forxiga, a first-in-class treatment for Type 2 diabetes. The FDA rejected Forxiga (a.k.a. dapagliflozin) in January 2012 based on concerns about breast and bladder cancer, but the EMA approved it in November 2012. (Sales in 1Q13 were negligible.) In June 2013, BMS and AZ received priority review status for metreleptin, an orphan treatment for lipodystrophy that came over with the Amylin acquisition. It’s not expected to be a huge product, but after the drug washed out as an obesity treatment, it still seems poised to help a patient group.

The Amylin move helped build an entire diabetes team out of whole cloth, but we’re skeptical that BMS will make another multi-billion-dollar deal anytime soon. There was some talk in the Wall Street Journal in March 2013 that BMS was looking for a major acquisition, potentially of Biogen Idec or Shire, “according to people familiar with the company’s thinking.” That sort of talk tends to come from banks and other firms that benefit from assembling M&As, not from producing therapeutics.

BMS has taken its biggest patent hits already, and even though there’s more to come as Abilify, Sustiva and Baraclude (as a result of bad news from a patent court in December 2012) face generic competition in the next few years, the company looks poised to weather the storm. It swung for the fences on a few occasions, and if Inhibitex was a strikeout, then the 2009 purchase of Medarex (for $2.3 billion), which yielded Yervoy and potentially nivolumab, was a grand slam. The company has enough promising late-stage assets, fast-growing new products, and inter-company partnerships to keep it from being M&A fodder anytime soon.

Lowe Down
Bristol-Myers Squibb managed in the past year to set some kind of dollars-per-unit-time record for deals that didn’t work out. Others have blown more cash, but it took them longer. The disastrous foray into a hepatitis C acquisition (Inhibitex) blew up spectacularly within months, but (at least from outside) there doesn’t seem to have been much that BMS could have done about it. Like all the rest of us, they have to live and die by the clinical results, which this time came up very bad indeed. They’re still in the hunt, though, in what’s becoming one of the most competitive markets around.

But that’s just one disease area, and this is a big company (albeit lacking consumer care, animal health, and some of the other sidelines of their competitors). Oncology has been a strong point, but Plavix’s expiration was just the beginning; BMS is going to have to make up for several more patent expirations and sales-rights agreement changes in the next couple of years. While some other companies look to be cruising along placidly, at BMS they’re going to be bailing water, fixing holes in the hull, repainting the railings and running fire drills, all at the same time.

—Derek Lowe

Headcount: 27,000
Pharma Revenues: $21,244 (9%)
Total Revenues: $21,244 (9%)
Net Income: $5,260 (17%)
R&D Budget: $3,839  (8%)

Top-Selling Drugs

Account for 82% of total pharma sales, down from 83% in 2010

PROFILE
Bristol-Myers Squibb entered the post-Plavix era in May 2012, as its far-and-away top seller lost patent protection. Unlike most other branded-to-generic shifts, this one doesn’t involve a six-month exclusivity period for a single generic marketer, thanks to Apotex’ hijinks in 2006. With at least seven companies jumping into the Plavix pool, we can expect a pretty massive drop in overall revenues for BMS — think 15% or more — in 2012.

BMS has been preparing for this eventuality for years. Like the rest of its cohort, the company shrank its cost structure significantly over the years. Unlike most of its competitors, however, it actually has a number of up-and-coming drugs that may help it get through this rough patch without becoming M&A fodder.

In last year’s report, we mentioned the approval of melanoma treatment Yervoy and pending applications for Nulojix. The biggest NDA is still pending: Eliquis, the blood-thinner BMS is co-developing with Pfizer. That drug will go up against Boehringer Ingelheim’s Pradaxa, a drug that nearly reached $1 billion in revenues in its first full year. Eliquis has demonstrated superior risk-reduction beside Pradaxa (and Xarelto), and some estimates are that BMS and Pfizer may be splitting $4 billion in sales at Eliquis’ peak.

In June 2012, BMS and Pfizer received a complete response letter for Eliquis for its initial NDA for prevention of stroke and systemic embolism in patients with atrial fibrillation. Eliquis is already on the market in the EU, but posted less than $1 million in sales in 2011. The CRL doesn’t require new studies, requesting only “additional information on data management and verification from the ARISTOTLE trial,” according to a joint statement from the companies. There’s no word on what timeframe that puts Eliquis on.

BMS managed to get its diabetes treatment, Onglyza (and Kombiglyze, its metformin-combo) rolling in its second full year, posting revenues of $473 million (shared with AstraZeneca). That’s nothing to sneeze at, but it’s not Januvia. Also, BMS and AZ may have to surrender on another diabetes collaboration, after the FDA asked for more clinical data for dapagliflozin in a complete response letter in January 2012.

However, it’s been more good news than bad for BMS’ development and commercialization efforts. The company’s seen very good results with Yervoy, which reached $360 million in revenues in its partial first year. It posted revenues of $154 million in 1Q12, nearly doubling the results of 1Q11. In addition, Baraclude, Orencia and Sprycel have shown strong double-digit gains, yielding a series of blockbusters.

BMS isn’t resting on its laurels. The company spent an aggressive $2.5 billion to acquire Inhibitex and lock up a promising hepatitis C treatment currently in Phase II. The price tag reportedly rose by 30% to block an unnamed suitor. Apparently, BMS first tried to buy the clinical compound itself for $550 million in October 2011, but things escalated quickly, really getting out of hand fast. Still, it was a relative bargain, after Gilead spent $11 billion to acquire Pharmasset several months earlier.

The Inhibitex acquisition came mere days after Jeremy Levin, BMS’ senior vice president of strategy, alliances and transactions, left the company to take the top role at Teva. Mr. Levin had been responsible for implementing BMS’ “string of pearls” acquisition and licensing strategy, a role that will now be handled by chief executive officer Lamberto Andreotti and chief scientific officer Elliott Sigal. We haven’t seen any speculation that his departure prompted the company to raise its bid, but it’ll be interesting to see whether their acquisition strategy is as effective in future.

Mr. Levin did a great job of helping position BMS to survive life after Plavix and Avapro, and the company overall seems to have a good perspective on the limits of its R&D capabilities and the importance of leveraging its assets. The next two years will be tough as they rebuild, but they’ll finish that stretch a lot happier than some of their mega-competitors.

As we go to press: BMS/AZ buys Amylin

Outsourcing News

In August 2011, BMS selected ICON as a preferred provider for full-service clinical pharmacology and exploratory clinical studies. ICON already provided global support for BMS’ clinical development pipeline, per the companies' June 2010 agreement. ICON will provide a broad range of early phase services from its Clinical Pharmacology Units in San Antonio, TX, Omaha, NE, and Manchester, UK, as well as scientific services such as protocol design and development, project management, clinical monitoring, medical monitoring/pharmacovigilence, data management, biostatistics, pharmacokinetics and medical writing.

Into every outsourcing news, a little insourcing must fall. BMS sources its bulk material for Orencia from an outside provider and finishes the product in its own facilities for both formulations. In May 2012, the FDA approved BMS' biologics facility in Devens, MA to produce Orencia, so it looks like some of that bulk supply's going to be in-sourced (keeping a CMO in order to maintain supply security). Lou Schmukler, president, Global Manufacturing & Supply at BMS, commented, "The increased manufacturing capacity from the Devens site will support market demand for Orencia and positions us well for future production of additional biologic medicines."

BMS outsources bulk and final dosage form for Yervoy, another biologic. No word if that one's going to be shifting to Devens, too.

Headcount: 27,000
Pharma Revenues: $19,484 (4%)
Total Revenues: $19,484 (4%)
Net Income: $4,513 (2%)
R&D Budget: $3,566 (-2%)

Top-Selling Drugs in 2010

Account for 83% of total pharma sales, up from 80% in 2009.

PROFILE

The multi-billion-dollar question is: Will Bristol-Myers Squibb’s “bet the pharm” model pay off? It’s been a few years since the company sold off its medical imaging unit and spun out its pediatric nutrition business in order to focus on drug development. With Plavix and Avapro veering toward the patent cliff, BMS is gambling that it will be able to develop enough new drugs to survive the fall.

BMS slipped one spot in this year’s report, because its organic growth couldn’t offset Abbott’s revenue-boosting acquisition of Stiefel. In this day and age, 4% revenue growth without a major acquisition is something to be proud of. BMS repeated those results in 1Q11, with a strong showing from several of its new drugs: Baraclude (+27% to $275 million), Sprycel (+31% to $172 million) and Orencia (+18% to $199 million). The upside of being a “small” big pharma is that it takes a lot less to move the sales needle.

Last year, I wrote about BMS’ reliance on its R&D pipeline and noted, “A few Phase III failures, and we’re looking at another Top 10 company disappearing from the board,” but this past year has brought good tidings for BMS. (Well, not for the 995 staffers whom BMS laid off last year, but still . . .)

In March, melanoma treatment Yervoy received FDA approval, and oral blood thinner Eliquis received its first approval in Europe in May. Both drugs carry estimates of as much as $1.7 billion in annual sales by 2015, according to some analysts, with peak sales of Yervoy ranging between $2.0 and $4.0 billion. BMS and development partner Pfizer plan to submit Eliquis to the FDA later this year, pending the results of a Phase III trial. Yervoy recently posted some monster results at the American Society of Clinical Oncology meeting, improving survival in treatment of metastatic melanoma.

Also, in December 2010, the FDA approved type-2 diabetes treatment Kombiglyze XR, an extended release, one-a-day combo of Onglyza (co-developed with AstraZeneca) and metformin. Onglyza hasn’t had an auspicious start competing with Merck’s Januvia; the hope is that this combo, which matches up with Janumet, will spark sales. Onglyza/Kombiglyze has sales of $81 million in 1Q11 after posting a total of $158 million in 2010.

BMS is hoping to hear soon from the FDA regarding the Nulojix, a biologic to treat organ rejection in kidney transplants. That BLA received a Complete Response Letter in May 2010. BMS replied in full, and the FDA put a new PDUFA date of June 2011 for the drug, contingent on BMS resolving the GMP issues in its Manati, PR fill/finish facility. An inspection in August 2010 turned up concerns of possible contamination and glass particles in drug vials, but BMS took corrective actions and satisfied the FDA. The site will also manufacture a subcutaneous version of Orencia, which should boost that drug’s market share.

Quality issues in Puerto Rico reared their ugly head later in 2010 when BMS and partner Sanofi had to recall a total of 60 million tablets of Avapro/Avalide made in their Humacao, PR facility. The tablets had potential API solubility problems. A second recall of 64 million tablets in January 2011 involved the same issue and covered facilities in Humacao and Evansville, IN.

For all the approvals and filings BMS has had of late, it hasn’t been good news. In February 2011, BMS and development partner Lilly stopped enrollment a Phase III trial of necitumumab in advanced non-small cell lung cancer, due to safety concerns about blood clots. Necitumumab was being developed by ImClone and BMS as an Erbitux followup. When Lilly acquired ImClone, the companies restructured the co-development pact, giving BMS 55% of the profits (and losses) for the drug in the U.S. and Canada. After the blood clot issue, prospects have dimmed, although a second Phase III trial in squamous NSCLC continues.

So how is BMS positioned for the future? Possibly, the most important FDA news the company got last year was the decision to extend Plavix’s patent protection for six months to May 2012, after BMS and Sanofi conducted pediatric studies of the drug. That extra time will add up to billions in revenues, but it only forestalls BMS’ inevitable decline. The erosion of Plavix and Avapro revenues next year will leave BMS gasping. Or, as the company’s financial filings put it, “We expect a rapid, precipitous, and material decline in Plavix net sales and a reduction in net income and operating cash flow.”

If the company can manage to launch all five of its new compounds — Yervoy, Eliquis, Nulojix, dapagliflozin (diabetes treatment, co-developed with AstraZeneca, submitted in March 2011) and brivanib (hepatocellular cancer) — and continue to grow its recent products (there were some good label expansions and trial results in the past year for Sprycel, Orencia and Baraclude), it won’t be enough to offset the huge loss ahead, but it can help BMS make its transition into its next phase as a biopharma.  —GYR

OUTSOURCING NEWS

In March 2011, BMS and WuXi PharmaTech entered a strategic partnership to conduct stability studies of small-molecule new chemical entities to support global marketing applications. WuXi will build and operate a dedicated, 25,000-sq.-ft. cGMP analytical testing facility in Shanghai to store and test stability samples and perform other services for BMS. WuXi will also employ a staff for stability testing, sample management, analytical testing, pharmaceutical science, quality assurance, metrology and other services, including stability data reporting to support BMS’ global dossier submissions.

“WuXi PharmaTech is an important partner for BMS’ R&D organization,” said Mark Powell, Ph.D., senior vice president, Non-Clinical Development, BMS. “This agreement will expand the scope of our relationship with WuXi and enhance the presence of BMS in China. It is also an example of our R&D organization executing our company’s BioPharma model by using selective integration to leverage the strengths and talents of both Bristol-Myers Squibb and a valued partner.”

In April, BMS signed a comprehensive third-party logistics (3PL) deal with Exel, a subsidiary of DHL.

ACQUISITION NEWS

Target: ZymoGenetics

Price: $885 million

Announced: September, 2010

What they said: “The acquisition of ZymoGenetics brings us full ownership of a promising investigational biologic that strengthens our very diversified hepatitis C portfolio [. . .] In addition, ZymoGenetics brings proven capabilities with therapeutic proteins and revenue from a marketed specialty surgical biologic.”

—Lamberto Andreotti, chief executive officer, BMS

THE LOWE DOWN

You’d think that the BMS story would all be about impending doom as Plavix goes off-patent. Well, OK, there is some of that. But looking them over, things are nowhere near as bad as they could be. And hey, they’re psychologically prepared, at any rate: BMS already has experienced what it’s like to lose Plavix, thanks to that ridiculous Apotex episode a couple of years ago.

BMS has actually done very well this year with new drug approvals, even though some of the numbers are from things that were expected to be approved last year. But they made it through, and these days, that’s nothing to look down on. I was wondering back there in my AstraZeneca writeup if anyone was ever prepared for a big patent expiration. While these new drugs aren’t going to make up the difference (at least not yet), I have to say that BMS is better prepared than you might have thought they’d be a few years ago.

Have you noticed, too, that there don’t seem to have been as many BMS-is-going-to-merge stories floating around this year? That’s partly because there are fewer people to merge with, perhaps, but they also might not be in immediate need of doing something big, expensive, and stupid. Don’t you wish more people had held back?  —Derek Lowe

Previous Profile: Abbott Laboratories // Next Profile: Teva Pharma

Headcount: 28,402
Pharma Revenue: $18,808 (+6%)
Total Revenues: $18,808 (+6%)
Net Income: $5,602 (+17%)
R&D Budget: $3,647 (+4%)

Account for 78% of total pharma sales, up from 75% in 2008.

PROFILE

Bristol-Myers Squibb continued its “next-generation biopharma” quest last year, spinning off its remaining non-pharma unit via limited IPO and pushing a slew of new potential blockbusters through the pipeline. Will they come up with enough new products to offset the loss of their biggest sellers? Not right away, and that’s the challenge facing new chief executive officer Lamberto Andreotti.

Mr. Andreotti took over that role from James Cornelius in May 2010; the board elected to keep Mr. Cornelius in his role as chairman. Mr. Andreotti, 59, was previously president and chief operating officer, joining the company in 1998, so he’s seen some highs and lows at BMS. He has his work cut out for him, albeit not because of any mess left behind by his predecessor. BMS is simply facing the realities of being a mid-tier pharma company. It’s a tough role; your resources are constrained (relative to your big competitors), but you’re just as susceptible to The Patent Cliff as the big shots are. On top of that, you’re perennially seen as a takeover target. Some analysts believe that the company authorized a $3 billion stock buyback largely to whittle down its large cash on hand, making it a less attractive target.

The company’s strategy remains to double-down on developing new drugs, both internal and licensed, and make strategic acquisitions. In this era of diversification, genericization, and geographic breadth, BMS is relying on R&D to save the day. That hasn’t worked out too well for pharma these last few years, but it could pay off for BMS if its new slate of drugs reaches the market. It’s a big “if.” A few Phase III failures, and we’re looking at another Top 10 company disappearing from the board.

That’s because BMS’s biggest seller, Plavix, is expected to lose patent protection in the U.S. at the end of 2011. There’s already been some generic erosion for Plavix in Europe (which is more Sanofi’s worry than BMS’s), but U.S. sales have remained strong, up 13% in 2009 to $5.6 billion and 18% in 1Q10 to $1.5 billion. How is BMS going to make up the slack? They’ve already conceded that there’s no replacing Plavix. The company told investors and analysts in March of this year that income in 2013 will be between 9% and 13% lower than 2010’s projected levels, as the Plavix shortfall shakes out and Avapro sales slide. Abilify, the company’s second largest drug, is currently facing patent challenges from at least seven generic companies, but at press time is still protected until at least 2015.

In July 2009, BMS bid approximately $2.3 billion to acquire Medarex, its development partner in ipilimumab, a melanoma biotherapeutic. The tender was completed in December. Medarex’s transgenic mouse antibody technology has been used in a number of marketed biologics — Simponi, Stelara, and Ilaris — providing BMS with a royalty stream to go along Medarex’s technology and its pipeline. BMS has high hopes for ipilimumab; the company recently released Phase III data showing that it’s the first drug that improves survival in patients with metastatic melanoma. The results look great; if they can mitigate the heavy-duty immune side-effects that beset some patients, they may have a blockbuster on their hands. (It’s also being tested against prostate and lung cancers.)

After a 2008 setback in a venous thromboembolism trial, BMS’s apixaban did so well in its a new Phase III study that BMS and development partner Pfizer shut down the trial early. The trial’s independent data monitoring committee determined that apixaban bestowed a “clinically important reduction” in stroke and systemic embolism in atrial fibrillation patients. The trial involved 5,600 patients who were at risk but intolerant or unsuitable for warfarin therapy. BMS brought in Pfizer as its development partner in 2007.

That was just around the same time BMS united with AZ to develop Onglyza, a treatment for type 2 diabetes. Onglyza was approved by the FDA in July 2009. It hasn’t set the world on fire, but it’s a DPP-4 inhibitor entering the post-Avandia diabetes market, and that means there’s plenty of caution among doctors. The companies are optimistic about its prospects, despite its lack of “overnight success.” Some analysts contend that “instant blockbusters” are a thing of the past (see Multaq, Effient, etc.), and that building a large franchise will take a lot more work in the current safety and reimbursement atmosphere.

BMS and AZ are also in Phase III trials with dapagliflozin, another type 2 diabetes treatment that performed well with Metformin, the generic standard treatment, and recently filed an NDA for a combo of Onglyza and Metformin.

Belatacept and brivanib comprise the other drugs that BMS hopes to launch by 2012 to put it in position for post-Plavix success (meaning, after the 2013 drop). Unfortunately, Belatacept faced a setback in May 2010 when the FDA sent BMS a CRL, asking for 12 more months of data from ongoing Phase III trials.

Brivanib, a cancer treatment, is a bit more perplexing. As recently as March 2010, the company included it among the five new drugs it will launch by 2012. At press time, BMS was still recruiting patients for several Phase III trials for brivanib — in combination with Erbitux for colon cancer, and in a number of liver cancer scenarios — so I think a 2012 approval is a bit of a longshot.

I have a soft spot in my heart for BMS. In the 10 years I’ve been compiling this report, they’ve really adopted the most naked make-or-break strategy I can recall.

Headcount: 35,000
Pharma Revenues: $17,715 (+13%)
Total Revenues: $20,597 (+13%)
Net Income: $5,247 (+142%)
R&D Budget: $3,585 (+10%)

Account for 72% of total pharma sales, up from 68% in 2007.

PROFILE

Bristol-Myers Squibb is facing patent expirations for two of its three top-sellers, Plavix (2011 for basic U.S. exclusivity) and Avapro (2012 for same), while its deal to market #2 seller Abilify is due to expire in 2012. The loss of all three products in that timeframe would leave BMS in an inescapable hole. So what’s a next-generation biopharma to do?

Renegotiate! BMS renegotiated its co-marketing deal with Otsuka Pharmaceuticals to retain commercialization rights through April 2015. It was a critical move, because without Abilify, BMS would be doomed. Instead, the company bought itself a little time to execute its strategy this year.

The deal with Otsuka wasn’t cheap. BMS paid $400 million upfront, will take a reduced share of revenues (with Otsuka contributing 30% of commercialization costs, up from nothing), and the two companies will now collaborate on a pair of oncology drugs, Sprycel and Ixempra. On the plus side, Abilify continues to grow by leaps and bounds. In 1Q09, it posted a 30% boost to $589 million in worldwide sales.

Fortunately, raising cash a huge issue for BMS. The company has been feverishly raising funds in recent years by divesting itself of non-core businesses. Most recently, it sold off $800 million in shares in an IPO for its Mead Nutritionals business (about 17% of the unit’s total shares). BMS also accelerated its Productivity Transformation Initiative, targeting an additional $1.0 billion in savings, bringing the PTI’s total goal to $2.5 billion in cuts by 2010.

And last fall, the company was paid a billion dollars it didn’t want!

Last August, you see, BMS tried to buy out ImClone, its partner in biologic cancer treatment Erbitux. The sale process got pretty ugly, as many negotiations involving Carl Icahn tend to do (just ask Biogen Idec!). BMS opened with a bid of $60/share, raised it to $62, and folded when Lilly stepped in with a $70/share offer, for a total offer of $6.5 billion. BMS elected not to match the offer, and instead took $1.0 billion in cash for the 16.6% of ImClone that it already owned.

So what’s BMS going to do with all that cash (around $9 billion on hand)? Buy itself a string of pearls!

“String of pearls,” in this case, is the nickname BMS has given its strategy of “complementing and enhancing our internal capabilities with a suite of innovative alliances, partnerships and acquisitions.” Two years ago, I speculated that BMS executed late-stage partnerships with both AZ and Pfizer in an effort to make itself unbuyable; if one acquired them, they’d lose the rights to the other’s project. (Of course, that assumed that the two partnerships would yield marketable products. BMS/Pfizer’s apixaban failed in its first Phase III trial, so plans for a 2009 FDA submission have been scrapped. They began a Phase III program for treatment of acute coronary syndrome in 1Q09.)

Now, while several major players are involved in giant acquisitions, BMS is trying to find strategic fits with drugs in external development and smallish acquisitions, in hopes of bolstering the pipeline for another decade. Its “un-J&J-ification” has helped that process along, but it still requires diligence and patience. There’s no point in throwing good money after bad.

Since last year’s edition, BMS has entered partnerships with Exelixis (CV and cancer), Zymogenetics (hepatitis C), Nissan Chemical and Teijin Pharma (atrial fibrillation), PDL Biopharma (multiple myeloma), and the aforementioned Otsuka agreement, which does reduce BMS’ share of development and commercialization costs.

All these deals are for the mid- to long-term, but BMS is close to market with several drugs. Will they (belatedly) fill in the gaps that’ll be left by Plavix and Avapro’s generic losses? BMS and development partner AstraZeneca were hoping for an FDA ruling on diabetes treatment Onglyza by April 30, 2009, but the agency pushed off the deadline by three months. Onglyza could become a huge seller, if first-in-class Januvia is any indication.

BMS also gained full approval of Sprycel in May 2009. The drug received accelerated approval two years earlier for chronic myeloid leukemia in patients who weren’t responding to Gleevec. It’s currently in Phase III trials against, um, castrate-resistant prostate cancer (CRPC).

There are also high hopes for belatacept, a biologic to block organ rejection in transplantation, currently in Phase III. That one is an in-house, unpartnered drug for BMS, so it may become another major trading chip or it could turn into the company’s next solo blockbuster. It’ll be great if the company has some big-selling biologics to move into its $750 million bio-manufacturing facility in Devens, MA when that site goes on-line in 2011.

Except for the Otsuka pact, none of these deals required a huge upfront payment, so BMS still has billions burning a hole in its pockets (and making it an appealing target for an acquisition). In June 2009, a rumor surfaced that BMS was looking to buy a stake in troubled biopharma Elan, as prelude to a full takeout, but sources squashed that rumor pretty summarily. Just like that rumor that Sanofi was looking to buy an unnamed U.S.-based pharma company. Boy, I hope those two aren’t linked. . .

Headcount: 41,000
Pharma Revenues: $15,622 (+13%)
Total Revenues:$19,348 (+12%)
Net Income: $1,968 (+38%)
R&D Budget: $3,282 (+10%)

Account for 66% of total pharma sales, up from 58% in 2006.

PROFILE

I thought Bristol-Myers Squibb might take a tumble in the ranks this year, but the restoration of its Plavix revenues — up $1.5 billion from the mess of 2006 — kept the company in the #11 spot. BMS contends that the Apotex/Plavix mess wiped out $1.2-1.4 billion in 2006 revenues and another $250-350 million in 2007. An extra $1.2 billion in revenues would’ve put it in the #10 spot in last year’s rankings, so they should let that be a lesson to them: cheaters never prosper!

Oh, and former senior vice president Dr. Andrew Bodnar is up on charges of lying to federal authorities during their investigation of the Plavix case. Since that case stems from the previous regime at BMS, I’m glad to say that Jim Cornelius’ tenure as chief executive officer and chairman of the company has been free of federal charges! (That may sound like faint praise, but BMS really has had more than its share of legal woes this decade.)

The Hole

Now that its legal-ethical house appears to be in order, BMS has plenty of work to do in order to retain its independence. Plavix’s restored numbers helped offset an enormous loss in revenue for Pravachol (from $2.3 billion in 2005 to $443 million in 2007), and schizophrenia treatment Abilify looks like it’ll become a $2.0 billion drug in 2008. But BMS loses the rights to Plavix and Abilify in 2011 and 2012, respectively, so new products and royalty streams are the order of the day.

They have their work cut out for them. The company also had a setback with its melanoma treatment, ipilimumab. In April 2008, BMS and co-developer Medarex elected to hold off on the drug’s BLA after the FDA requested overall survival data from a Phase III trial. The two companies have also asked to change the primary endpoint of the trial to cover overall survival, rather than progression-free survival.

In better-but-still-fraught-with-risk news, BMS and AstraZeneca plan to file an NDA for diabetes treatment Onglyza soon, but analysts consider it a high-risk product and fear it may be delayed or denied. A June 2008 release of Phase III data was lukewarm enough to drive BMS’ stock to a 52-week low (not that I tend to use stock price in these analyses).

BMS also began Phase III trials of apixaban, a Plavix-replacer that it’s co-developing with Pfizer.

Big(gish) Biopharma?

So how is BMS preparing for the day (in 2011) when Apotex is legally permitted to sell a generic version of Plavix? By restructuring! Sure, just about every company on our list is restructuring, but BMS has chosen a unique angle. In this case, the company has copped to its position as a mid-cap pharma company and said, “Let’s think smaller.”

Instead of trying to bulk up to compete with the big guns, BMS is embracing its (relative) lack of size to pursue what it calls a “next generation BioPharma” model. In December 2007, the company announced its plans to cut the mature product portfolio by 60% in the next four years, close or sell off half of its manufacturing sites, fire 10% of its workforce, and out-license compounds that it doesn’t have the resources to develop.

The new strategy encompasses BMS’s previous Productivity Transformation Initiative (PTI), which was designed to trim $1.5 billion in costs and new expenditures. The PTI will ultimately cost between $0.9 and $1.1 billion. Okay, maybe that doesn’t sound too innovative, but I’m impressed by their recognition of their scale.

In his 2007 letter to shareholders, Mr. Cornelius wrote, “This hybrid approach combines the strengths of a traditional pharmaceutical company — such as its global reach and its integrated commercial and manufacturing infrastructure — with the advantages of agility, entrepreneurial thinking and flexibility that are characteristic of many successful biotechnology companies.” I’m assuming those  “traditional” strengths drove the company’s recent acquisitions of Kosan and Adnexus.

This new strategy led BMS to sell off its non-pharma assets. Avista Capital Partners bought BMS’ medical imaging unit for $525 million in January 2008 and worked with Nordic Capital to acquire BMS’ ConvaTec wound therapeutics and ostomy case portfolio for $4.1 billion in May 2008. In addition, BMS announced plans to spin off 10-20% of its Mead Johnson Nutritionals business in an IPO.

Those of you who make it to the second part of this report will see that I’ve settled on a new definition for “Biopharma.” On those terms, I’m not sure that BMS’ new model is going to lead it into the Top Biopharma ranks (maybe I should launch a Top Specialty Pharma report), but I’m just hoping it’ll involve a real attempt at rethinking the structure and purpose of a pharma company, and not simply be a cover for cutting fat.

If BMS can truly blaze a new trail for development partnering and figure out how to “build flexibility” into a company with a workforce in excess of 40,000, I’ll be awfully impressed, biopharma or not.