Bristol-Myers Squibb 2017: Opdivo Steps Up

 

After years of hope and hype, Bristol-Myers Squibb’s centerpiece immuno-oncologic is delivering the dollars.

 

 

Bristol-Myers Squibb Co.

345 Park Avenue
New York, NY 10154
Phone: 212-546-4000
Website: bms.com

 

Best-Selling Products

Product	2016 Sales	2015 Sales
Opdivo	$3,774	$942
Eliquis	$3,343	$1,860
Orencia	$2,265	$1,885
Sprycel	$1,824	$1,620
Hep C Franchise	$1,578	$1,603
Baraclude	$1,192	$1,312
Sustiva Franchise	$1,065	$1,252
Yervoy	$1,053	$1,126
Reyataz franchise	$912	$1,139

All sales are in millions of dollars.

Financial Performance

	2016	2015
Revenue	$19,427	$16,560
Net income	$4,507	$1,631
Diluted EPS	$2.65	$0.93
R&D expense	$4,940	$5,920

	1H 2017	1H 2016
Revenue	$10,073	$9,262
Net income	$2,448	$2,394
Diluted EPS	$1.50	$1.41
R&D expense	$2,947	$2,402

All figures are in millions of dollars, except EPS.

 

 

Bristol-Myers Squibb’s big bet on Opdivo is paying off for the company in a big way. Sales of the immuno-oncologic were up by more than four times in 2016, bringing nearly $4 billion into the company’s coffers and making the 2009 acquisition of Opdivo developer Medarex for $2.1 billion look very smart. And the Opdivo story is still only beginning; clinical research on the drug is continuing across a bewilderingly long list of potential indications – it’s already approved for a dozen – and BMS has been partnering furiously with other companies to find oncology agents that might play well with its prize possession.

But Opdivo is not the only grower in the BMS stable. Not far behind is the cardiovascular drug Eliquis, which nearly doubled its sales in 2016.

The two products together are tracking to produce in the range of $9 billion in combined sales in 2017 – not bad for a company that has not seen numbers like that since the peak days of Plavix.

“As I look ahead, I am excited by the tremendous opportunities we have to advance the science and continue making a difference in the lives of our patients and their families,” says Bristol-Myers Squibb CEO Giovanni Caforio, M.D. “It is through this important work that we will deliver long-term value for our shareholders. Building on our progress in 2016, we are well positioned to navigate the increasing complexity and competitiveness of our industry, including the very important conversations about pricing and access.”

BMS’ total revenue in 2016 was $19.43 billion, an improvement of 17.3 percent. A healthy chunk of that growth fell straight to the bottom line, with net income increasing from $1.63 billion in 2015 to $4.51 billion and earnings per share rising from $0.93 to $2.65. In the first half of 2017, the top line rose another 8.8 percent to $10.07 billion and net income grew 2.3 percent to $2.45 billion, with EPS improving by 9 cents to $1.50. BMS executives are projecting full-year 2017 EPS for the company at between $2.66 and $2.76.

 

Opdivo

2016 was the year of Opdivo’s great sales leap. After generating $942 million in sales in 2015, BMS’ keystone immuno-oncologic rolled up an impressive $3.77 billion in sales for the company in 2016, jumping to the top of its sales charts; adding in another $920 million in sales by partner marketer Ono Pharmaceutical, Opdivo was the world’s No. 5-selling oncology drug for the year. And the numbers are still rising; in the first half of 2017, BMS’ sales of Opdivo were up another 50.4 percent to $2.32 billion.

Opdivo is continuing to hit new development milestones, too. In January, BMS announced the results of ONO-4538-12, demonstrating Opdivo significantly reduced the risk of death by 37 percent in patients with previously treated advanced gastric cancer refractory to or intolerant of standard therapy, a condition without current standard-of-care treatments. ONO-4538-12 is a Phase III, randomized, double-blind, placebo-controlled clinical trial evaluating Opdivo’s efficacy and safety in such patients. The primary endpoint of the study is overall survival. Median OS was 5.32 months for patients treated with Opdivo, compared to 4.14 months for those treated with placebo. In addition, the 12-month OS in the Opdivo group was 26.6 percent versus 10.9 percent in the placebo group. Patients treated with Opdivo also experienced an objective response rate of 11.2 percent compared to 0 percent with placebo and a median duration of response of 9.53 months, which were secondary endpoints.

In February, FDA approved Opdivo injection for intravenous use for treating patients with locally advanced or metastatic urothelial carcinoma (mUC) who have disease progression during or following platinum-containing chemotherapy or have disease progression within 12 months of neoadjuvant or adjuvant treatment with platinum-containing chemotherapy. This indication was approved under accelerated approval based on tumor response rate and duration of response. The same indication was approved in the EU in June.

In July, BMS and Exelixis Inc. announced the initiation of the Phase III CheckMate 9ER trial to evaluate Opdivo in combination with Cabometyx tablets, or Opdivo and Yervoy in combination with Cabometyx versus sunitinib in patients with previously untreated, advanced or metastatic renal cell carcinoma. The primary endpoint for the trial is progression-free survival. CheckMate 9ER is an open-label, randomized, multi-national Phase III trial that aims to enroll approximately 1,014 patients with previously untreated advanced or metastatic RCC. Patients will be randomized 1:1:1 to one of three arms: Cabometyx and Opdivo; Cabometyx, Opdivo, and Yervoy; or sunitinib. The primary efficacy analysis will compare the doublet combination versus sunitinib and the triplet combination versus sunitinib in intermediate/poor risk patients with RCC.

In April, the European Commission approved Opdivo as monotherapy for the treatment of squamous cell cancer of the head and neck in adults progressing on or after platinum-based therapy. Opdivo is the first immuno-oncology treatment that demonstrated in a Phase III trial a significant improvement in overall survival for these patients.

The approval was based on results from CheckMate-141, a global Phase III, open-label, randomized trial, which evaluated Opdivo versus investigator’s choice of therapy in patients aged 18 years and above with recurrent or metastatic, platinum-refractory SCCHN who had tumor progression during or within six months of receiving platinum-based therapy administered in the adjuvant, neoadjuvant, primary, or metastatic setting. Investigator’s choice of therapy included methotrexate, docetaxel, or cetuximab. The primary endpoint was OS. The trial’s secondary endpoints included progression-free survival and objective response rate.

In the interim analysis of the pivotal trial, Opdivo demonstrated statistically significant improvement in OS with a 30 percent reduction in the risk of death, and a median OS of 7.5 months for Opdivo compared with 5.1 months for the investigator’s choice arm. There were no statistically significant differences between the two arms for PFS or ORR.

Also in April, BMS announced that CheckMate-143, a randomized Phase III clinical trial evaluating the efficacy and safety of Opdivo in patients with first recurrence of glioblastoma multiforme, did not meet its primary endpoint of improved overall survival over bevacizumab monotherapy. CheckMate-143 was the first randomized clinical trial in GBM with a PD-1 checkpoint inhibitor. BMS has two first-line GBM clinical trials, CheckMate-498 and CheckMate-548, evaluating the combination of Opdivo with radiation therapy with or without temozolomide in O6-methylguanine-DNA methyltransferase-unmethylated and methylated patients. These trials are moving forward as planned.

Also in April, BMS announced the first overall survival data from the Phase III CheckMate-067 clinical trial of Opdivo and Yervoy in patients with previously untreated advanced melanoma. With a minimum follow-up of 28 months, the median OS had not yet been reached in either of the two Opdivo treatment groups and was 20 months for the Yervoy monotherapy group. Opdivo in combination with Yervoy and as a monotherapy reduced the risk of death 45 percent and 37 percent, respectively, compared with Yervoy alone. The two-year OS rates were 64 percent for the Opdivo plus Yervoy combination, 59 percent for Opdivo alone and 45 percent for Yervoy alone.

The proportion of patients experiencing complete responses compared to a previous 18 month follow-up analysis increased in the combination group to 17.2 percent from 12.1 percent, in the Opdivo alone group to 14.9 percent from 9.8 percent, and in the Yervoy alone group to 4.4 percent from 2.2 percent. Progression-free survival and objective response rates from updated analyses were both consistent with previous reports. The risk of disease progression was significantly reduced for both the combination and Opdivo monotherapy groups, 58 percent and 46 percent, respectively, compared to Yervoy alone. The ORR for the two Opdivo groups, in combination and alone, and the Yervoy alone group was respectively 58.9 percent, 44.65 percent, and 19.0 percent.

In May, FDA accepted a supplemental biologics license application seeking to extend the use of Opdivo to patients with hepatocellular carcinoma after prior sorafenib therapy. FDA granted the application priority review and previously granted Opdivo orphan-drug designation for the treatment of HCC. The submission was based on data from the Phase I/II CheckMate-040 study investigating Opdivo in advanced HCC patients with and without hepatitis B virus or hepatitis C virus infections.

In June, BMS announced extended follow-up data in which Opdivo demonstrated responses in adult patients with relapsed or progressed classical Hodgkin lymphoma after autologous stem cell transplant, irrespective of brentuximab vedotin therapy history. Results from the Phase II CheckMate-205 study reflect the longest follow-up data of a programmed death 1 inhibitor in patients with cHL.

The ongoing multi-cohort CheckMate-205 study evaluated objective response rates, the primary endpoint, as well as duration of response rates for each cohort, all of which were assessed by the Independent Radiology Review Committee. In the BV-naïve group, with a median follow-up of 19 months, patients had an ORR of 65 percent, with a complete response in 29 percent of patients. The median DOR was 20 months and the median progression-free survival was 18.3 months. In the group that had BV therapy after ASCT, with a median follow-up of 23 months, the ORR was 68 percent, with CR in 13 percent of patients. The median DOR was 16 months and the median PFS was 14.7 months. In the BV-before-, -after-, or before-and-after-ASCT group, with a median follow-up of 16 months, the ORR was 73 percent, with CR in 12 percent of patients. The median DOR was 15 months and the median PFS was 11.9 months.

Also in June, BMS announced interim data from CheckMate-142, a Phase II, multi-cohort trial evaluating Opdivo monotherapy or in combination with Yervoy for the treatment of patients with DNA mismatch repair deficient (dMMR) or microsatellite instability-high (MSI-H) metastatic colorectal cancer. These results from the Opdivo and Yervoy combination cohort of the trial included 84 patients who received their first dose at least 6 months prior to analysis. The primary endpoint of investigator-assessed objective response rate was 54.8 percent. Responses were sustained up to 15.9 months and 85 percent of responses were ongoing; median duration of response was not yet reached. The nine-month overall survival rate was 87.6 percent and median OS had not been reached at the time of analysis.

Also in June, BMS and the French Cooperative Thoracic Intergroup (IFCT) announced results from the IFCT-1501 MAPS-2 trial evaluating the safety and efficacy of Opdivo or Opdivo combined with Yervoy for previously treated unresectable malignant pleural mesothelioma patients. The study was sponsored by the IFCT. Bristol-Myers Squibb supplied Opdivo and Yervoy, and a research grant to the IFCT.

The 12-week disease control rate, the primary endpoint of the study, was 44.4 percent with nivolumab, and 50 percent with Opdivo plus Yervoy, as assessed by an independent panel of radiologists. The objective response rate was 18.5 percent with Opdivo, and 25.9 percent with Opdivo plus Yervoy. The median overall survival was 10.4 months with Opdivo and not reached for the combined-treatment group. The progression-free survival was 4.0 months for monotherapy and 5.6 months for the combined-treatment group. The numbers of all Grade and Grade 3-4 toxicities were 86.9 percent and 18 percent in the combined-treatment group versus 77.8 percent and 9.5 percent with Opdivo alone.

In July, BMS announced that a Phase III study evaluating Opdivo 3 mg/kg versus Yervoy 10 mg/kg in patients with stage IIIb/c or stage IV melanoma who are at high risk of recurrence following complete surgical resection met its primary endpoint at a planned interim analysis, demonstrating superior recurrence-free survival in patients receiving Opdivo compared to Yervoy.

CheckMate-238 is an ongoing Phase III, randomized double-blind study of Opdivo versus Yervoy in patients who have undergone complete resection of Stage IIIb/c or Stage IV melanoma. The trial randomized 906 patients to receive either Opdivo 3 mg/kg intravenously every two weeks or Yervoy 10 mg/kg IV every 3 weeks for four doses and then every 12 weeks until documented disease progression or unacceptable toxicity, up to a maximum treatment duration of one year. The primary endpoint is RFS defined as the time between randomization and the date of first recurrence or death.

In August, FDA approved Opdivo injection for intravenous use for the treatment of adult and pediatric (12 years and older) patients with microsatellite instability-high or mismatch repair deficient metastatic colorectal cancer (mCRC) that has progressed following treatment with a fluoropyrimidine, oxaliplatin, and irinotecan. Marketing clearance for this indication was granted under accelerated approval based on overall response rate and duration of response. Continued approval for this indication may be contingent upon verification and description of clinical benefit in confirmatory trials. The recommended dose is 240 milligrams administered as an intravenous infusion over 60 minutes every two weeks until disease progression or unacceptable toxicity.

In the CheckMate -142 trial, among patients (53/74) who received prior treatment with a fluoropyrimidine, oxaliplatin, and irinotecan, 28 percent responded to treatment with Opdivo. The percentage of patients with a complete response was 1.9 percent (1/53), and the percentage of patients with a partial response was 26 percent (14/53). Among these responders, the median duration of response was not reached (range: 2.8+-22.1+ months). Among all enrolled patients, 32 percent responded to treatment with Opdivo; 2.7 percent experienced a complete response, and 30 percent experienced a partial response.

During September, the FDA placed a partial clinical hold on CA209602 (CheckMate-602), CA209039 (CheckMate-039), and CA204142, three clinical trials investigating Opdivo-based combinations in patients with relapsed or refractory multiple myeloma. This partial clinical hold was related to risks identified in trials studying another anti–PD-1 agent, pembrolizumab, in patients with multiple myeloma. FDA determined data currently available from non-Opdivo studies indicate the risks of PD-1/PD-L1 treatment plus pomalidomide or lenalidomide and possibly PD-1/PD-L1 treatments alone or with other combinations outweigh potential benefit for patients with multiple myeloma. As part of the terms of the partial clinical hold, patients currently enrolled in CheckMate-602, CheckMate-039, and CA204142 who are experiencing clinical benefit can continue treatment.

Additionally during September, Bristol-Myers Squibb announced three-year overall survival data from CheckMate-017 and CheckMate-057, two pivotal Phase III randomized studies evaluating Opdivo versus docetaxel in patients with previously treated metastatic non-small cell lung cancer. In CheckMate-017, a trial in previously treated squamous NSCLC, 16 percent of patients treated with Opdivo were alive at three years versus 6 percent of those treated with docetaxel. In CheckMate -057, a trial in previously treated non-squamous NSCLC, 18 percent of patients treated with Opdivo were alive at three years versus 9 percent of those treated with docetaxel. Similar to prior reports, an OS benefit was observed across histologies, and three-year survivors included patients whose tumors expressed PD-L1 and those that did not.

Additionally during September, BMS announced that a Phase III study evaluating Opdivo plus Yervoy in patients with previously untreated advanced or metastatic renal cell carcinoma met its co-primary endpoint, demonstrating superior overall survival compared to sunitinib in intermediate- and poor-risk patients. The combination also met a secondary endpoint of improved OS versus sunitinib in all randomized patients. Based on a planned interim analysis, an independent Data Monitoring Committee recommended that the trial be stopped early.
The combination of Opdivo plus Yervoy achieved an ORR of 41.6 percent versus 26.5 percent for sunitinib in poor- and intermediate-risk patients, a co-primary endpoint. Median duration of response was not reached for the combination and was 18.2 months for sunitinib. PFS in the intermediate- and poor-risk patients, a co-primary endpoint, improved 18 percent for those receiving the combination, but did not reach the pre-defined statistical significance threshold of 0.009 compared to sunitinib. The median PFS for the combination group was 11.6 months versus 8.4 months for the sunitinib group.

 

Other Product Performance

Overshadowed by Opdivo but still impressive in its own right, the cardiovascular drug Eliquis had a leap of its own in 2016, with sales rising from $1.86 billion to $3.34 billion and total new-to-brand oral anti-coagulant prescriptions in the United States surpassing those for long-time standard-of-care warfarin. In the first half of 2017, Eliquis sales rose another 50.7 percent to $2.28 billion.

In August, BMS and partner marketer Pfizer Inc. announced results from an analysis of real-world data pooled from four large U.S. insurance claims databases. Among non-valvular atrial fibrillation patients, Eliquis was associated with a lower risk of stroke/SE and lower rates of major bleeding compared to warfarin for the overall population as well as for each of the selected high-risk patient sub-populations.
In this real-world analysis, patients with NVAF receiving either Eliquis or other oral anticoagulants were identified through the U.S. Optum, MarketScan, PharMetrics, and Humana databases. The data was pooled after propensity score matching was completed within each database. Select high-risk subgroups were stratified by age, CHA2DS2-VASc or HAS-BLED score, congestive heart failure, coronary artery disease (CAD), and peripheral artery disease (PAD). The CHA2DS2-VASc score is a method for estimating stroke risk in patients with non-valvular atrial fibrillation, and the HAS-BLED score helps to estimate risk of major bleeding in patients with NVAF. In the subgroup analysis, based upon these variables, Eliquis was associated with lower risk of stroke/SE and lower rates of major bleeding compared to warfarin after adjustment for confounding factors.

The autoimmune drug Orencia enjoyed a solid year of growth in 2016, with sales up 20.2 percent to $2.27 billion. In the first half of 2017, Orencia sales rose another 11 percent to $1.19 billion.

In July, FDA approved Orencia for the treatment of adults with active psoriatic arthritis, a chronic inflammatory disease that can affect both the skin and musculoskeletal system. This approval marks the third autoimmune disease indication for Orencia. The approval was based on results from two randomized, double-blind, placebo-controlled trials in which Orencia improved (or reduced) disease activity in both TNF-naive and exposed patients with high disease activity, high tender and swollen joints, and a disease duration of more than seven years. The drug remains in Phase III trials for lupus nephritis and Sjogren’s syndrome.

Sprycel, indicated for first line and refractory chronic myelogenous leukemia, generated $1.82 billion in sales for BMS in 2016, an improvement of 12.6 percent. In the first half of 2017, sales of Sprycel rose another 12.9 percent to $969 million.

In July, FDA accepted BMS’ supplemental new drug application to include an indication for Sprycel to treat children with Philadelphia chromosome-positive chronic phase chronic myeloid leukemia, as well as a powder for oral suspension formulation of Sprycel. The application is under priority review with an action date of Nov. 9, 2017. The sNDA includes data from CA180-226, an ongoing Phase II, open-label, non-randomized trial studying Sprycel in pediatric patients with CP-CML that are resistant to or intolerant of imatinib and in pediatric patients newly diagnosed with CP-CML.

In the CA180-226 trial, at minimum two-year follow-up, patients with CP-CML resistant to or intolerant of imatinib who received Sprycel demonstrated a cumulative major cytogenetic response rate of 55.2 percent three months into treatment, exceeding the defined threshold of clinical interest (>30 percent) for the primary endpoint of the cohort and increasing over time to greater than 90 percent at 24 months. Newly diagnosed patients with CP-CML, who received Sprycel orally or as powder for oral suspension once daily, achieved a cumulative complete cytogenetic response rate, the primary endpoint in the cohort, of 64 percent as early as six months into treatment, exceeding the defined threshold of clinical interest (>55 percent) and increasing over time to 94 percent at 24 months.

 

Acquisitions & Collaborations

In January, BMS and GeneCentric Diagnostics Inc. announced a biomarker research collaboration to explore whether the application of GeneCentric’s Cancer Subtype Platform might be able to identify translational biomarkers for Opdivo, which may help inform future clinical trials. Additionally, GeneCentric announced it has secured equity funding from Bristol-Myers Squibb that will support the clinical development of GeneCentric’s CSP and build-out of GeneCentric’s new laboratory in Research Triangle Park.

CSP, GeneCentric’s proprietary core technology, identifies biologic subtypes of cancer through an integrated analysis of tumor genomics. Cancer subtypes can support rational clinical trial design, as biomarkers to identify patient cohorts optimally suited for certain therapeutic compounds, and as companion diagnostics.

Also in January, BMS announced a new clinical research collaboration with Janssen Biotech Inc. to evaluate the combination of Opdivo and Janssen’s CD38-directed cytolytic antibody Darzalex in Phase Ib/II clinical studies in multiple myeloma and solid tumors including non-small cell lung cancer, pancreatic cancer, colorectal cancer, triple negative breast cancer, and head and neck cancer. In 2016 an existing Bristol-Myers Squibb Phase I study was expanded to include the combination of Opdivo and Darzalex in multiple myeloma; this study is ongoing. Additional studies will start in 2017. This agreement builds off Bristol-Myers Squibb and Janssen’s previous clinical research collaboration announced in July 2016 to evaluate Opdivo and Janssen’s Live Attenuated Double–Deleted (LADD) Listerial monocytogenes cancer immunotherapy, expressing mesothelin and EGFRvIII (JNJ-64041757), in patients with non-small cell lung cancer.

BMS and Exelixis during February entered into their clinical development collaboration to evaluate Cabometyx, Exelixis’ small molecule inhibitor of receptor tyrosine kinases, with Opdivo, either alone or in combination with Yervoy. The clinical development program, which is being co-funded by the companies, is expected to include a Phase III pivotal trial in first-line renal cell carcinoma, with additional trials planned in bladder cancer, hepatocellular carcinoma, and potentially other tumor types.

The clinical development collaboration builds upon previously published preclinical and clinical data that provide a scientific rationale for combining Cabometyx with immunotherapies, including Phase I data of Cabometyx in combination with Opdivo in patients with previously treated genitourinary tumors. Cabometyx and Opdivo have both received approval in the United States and European Union for specific uses in previously treated renal cell carcinoma, and both compounds are the subject of ongoing, global Phase III pivotal trials in hepatocellular carcinoma.

In March, BMS and CytomX Therapeutics Inc., a biopharmaceutical company developing investigational Probody therapeutics for the treatment of cancer, announced an expansion of their 2014 strategic collaboration to discover novel therapies that will include up to eight additional targets using CytomX’s proprietary Probody platform. Probody therapeutics are designed to take advantage of unique conditions in the tumor microenvironment to enhance the tumor-targeting features of an antibody and reduce drug activity in healthy tissues. By remaining inactive until they are activated by proteases in the tumor microenvironment, Probody therapeutics bind selectively to cells within tumor tissue with reduced binding to healthy tissue, potentially improving or creating a therapeutic window. Probody therapeutics may also have application in other diseases where proteases are dysregulated in affected tissues.

As part of the original collaboration signed in May 2014 to discover, develop and commercialize Probody therapeutics, Bristol-Myers Squibb selected four oncology targets, including CTLA-4. In the collaboration to date, Bristol-Myers Squibb has progressed the CTLA-4 Probody therapeutic to investigational new drug-enabling studies and the three other programs are in the lead discovery and optimization phase.
Under the terms of the agreement, CytomX grants Bristol-Myers Squibb exclusive worldwide rights to develop and commercialize Probody therapeutics for up to six additional oncology targets and two non-oncology targets. Bristol-Myers Squibb will make an upfront payment of $200 million to CytomX and, in addition, will provide research funding over the course of the research term. CytomX will also be eligible to receive up to $448 million in future development, regulatory and sales milestone payments for each collaboration target, as well as tiered royalties from the mid-single digits to low-double digits on net sales of each product commercialized by Bristol-Myers Squibb.

Also during March, BMS announced its equity investment and plans for a research collaboration with Grail Inc., a life sciences company whose mission is to detect cancer early when it potentially can be cured. By combining the power of high intensity cancer DNA sequencing, computer science, and large clinical studies into a diagnostic platform, Grail aims to develop highly sensitive blood tests that detect cancer in its early stages to enable earlier intervention with targeted therapies.

As an investor, Bristol-Myers Squibb will gain early access to Grail’s comprehensive clinical trial databases that may serve as a resource for understanding tumor genomics. BMS and Grail have agreed to principal terms of a research collaboration that would enable Bristol-Myers Squibb to examine its clinical data using Grail’s analytic tools to inform research and development decisions, guide strategies to advance point of care companion diagnostics, and potentially improve selection, care and management of patients through more targeted treatments.
During April, BMS and Apexigen Inc., a clinical-stage biopharmaceutical company focused on discovering and developing antibody-based therapeutics for the treatment of cancer with an emphasis on new immuno-oncology agents, announced a clinical trial collaboration to evaluate Opdivo in combination with APX005M in patients with advanced solid tumors. APX005M is designed to activate CD40, a key immune co-stimulatory receptor essential to regulating the activation of both innate and adaptive immune responses against cancer.

The proposed collaboration will evaluate the safety, tolerability and preliminary efficacy of APX005M in combination with Opdivo in second-line metastatic NSCLC patients who have failed prior chemotherapy, and in metastatic melanoma patients who have failed prior I-O therapy. Preclinical data suggest that APX005M mimics the endogenous immune activation process through activation of CD40. A receptor on the surface of antigen presenting cells of the immune system, CD40 plays a fundamental role in the activation of innate and adaptive immune system mechanisms. Opdivo is designed to overcome PD-1 pathway related immune suppression. The companies will explore the potential of combining these two agents with the goal of effectively activating antigen presenting cells (APC) in the tumor microenvironment, thus driving a more productive and sustained immune response against the tumor.

 

In The (Rest Of The) Pipeline

Also in April, BMS entered into two separate agreements to license BMS-986168, an anti-eTau compound in development for progressive supranuclear palsy, to Biogen, and BMS-986089, an anti-myostatin adnectin in development for Duchenne muscular dystrophy, to Roche. Under the agreement to license BMS-986168, Biogen will pay to Bristol-Myers Squibb an upfront payment of $300 million with potential milestone payments of up to $410 million. Biogen also will assume all remaining obligations to the former stockholders of iPierian Inc. related to Bristol-Myers Squibb’s acquisition of the company in 2014. Under the agreement to license BMS-986089, Roche will pay to Bristol-Myers Squibb an upfront payment of $170 million with potential milestone payments of up to $205 million. Bristol-Myers Squibb will receive tiered double-digit royalties if either asset is approved and commercialized.

Also in April, BMS and Incyte Corp. agreed to advance their clinical development program evaluating the combination of epacadostat, Incyte’s investigational oral selective IDO1 enzyme inhibitor, with Opdivo into Phase III registrational studies in first-line non-small cell lung cancer across the spectrum of PD-L1 expression and first-line head and neck cancer. Additionally, the companies are expanding the ECHO-204 Phase I/II study, established under a collaboration between the companies in 2014, to include anti-PD-1/PD-L1 relapsed/refractory melanoma cohorts. The expanded clinical development program, including the Phase III registrational studies, will be co-funded by the two companies.
Epacadostat is a first-in-class, highly potent and selective oral inhibitor of the IDO1 enzyme that is designed to reverse tumor-associated immune suppression and restore effective anti-tumor immune responses. In single-arm studies, the combination of epacadostat and immune checkpoint inhibitors has shown proof-of-concept in patients with unresectable or metastatic melanoma.

Also in April, BMS and Nordic Bioscience, a Danish company specializing in biomarker technologies, announced a collaboration agreement to develop biomarker technology to potentially aid in the diagnosis and monitoring of fibrotic diseases including non-alcoholic steatohepatitis (NASH). Nordic Bioscience has more than 25 years’ experience in biomarker development and clinical trials with extensive expertise in rheumatology and fibrosis. A biomarker is a molecule that may be used to diagnose a disease, or predict disease progression and indicate response to therapy.

Nordic Bioscience invented C-terminal telopeptide (CTX), a biomarker that non-invasively identifies osteoporosis patients with a high rate of bone loss and can be used to assess response to osteoporosis therapy. Under the terms of the agreement, Bristol-Myers Squibb and Nordic Bioscience will collaborate in the development of translational biomarkers and diagnostics for the evaluation of NASH in pre-clinical models of fibrotic diseases and in clinical settings.

Also in April, BMS and Transgene announced a new clinical research collaboration to evaluate the safety, tolerability and efficacy of Transgene’s investigational therapeutic vaccine TG4010 in combination with Opdivo + standard chemotherapy (CT) as a first-line treatment for advanced non-squamous non-small cell lung cancer in patients whose tumors have low or undetectable levels of PD-L1. The Phase II clinical trial will explore the potential of combining Transgene’s TG4010, an investigational therapeutic vaccine designed to generate an immune response against MUC1 expressing tumors such as NSCLC, in conjunction with Opdivo, designed to alleviate immune suppression. Both therapies will be combined with standard chemotherapy in first line NSCLC patients. The Phase II trial will evaluate objective tumor responses, and disease control in patients provided the regimen of TG4010 + Opdivo + CT, whose tumors express low and undetectable levels of PD-L1. This multi-center single-arm trial is expected to deliver first results in 2018. Under the terms of the agreement, Transgene will be the sponsor of the trial. Bristol-Myers Squibb will provide Opdivo for use in the study.

In May, BMS and Advaxis Inc. announced a clinical development collaboration to evaluate ADXS-DUAL, an investigational immunotherapy targeting HPV-associated cancers, and Opdivo, as a potential combination treatment option for women with metastatic cervical cancer.

Expected to start by the end of 2017, the study will evaluate this combination regimen in women with persistent, recurrent or metastatic (squamous or non-squamous cell) carcinoma of the cervix who have failed at least one prior line of systemic chemotherapy. Under the terms of the agreement, each party will bear their own internal costs and provide its immunotherapy agents. Advaxis will sponsor the study and pay third-party costs.

Advaxis developed ADXS-DUAL by building on the learnings from the clinical development of axalimogene filolisbac and has incorporated additional HPV target antigens into its Listeria monocytogenes (Lm) bacterial vector.

Also in May, BMS entered into a clinical research collaboration to investigate the safety, tolerability, and efficacy of Array BioPharma’s investigational MEK inhibitor binimetinib in combination with Opdivo and Opdivo + Yervoy as a potential treatment for metastatic colorectal cancer in patients with microsatellite stable tumors.

The Phase I/II study is expected to establish recommended dose regimens for further study and explore the preliminary anti-tumor activity of combining binimetinib with Opdivo, as well as binimetinib in combination with the Opdivo + Yervoy regimen. Results from this first study, which was anticipated to begin in the second half of 2017, will be used to determine optimal approaches to further clinical development of these combinations. Under the terms of the agreement, Array and Bristol-Myers Squibb will jointly support the study with Array acting as the sponsor.

Additionally during May, BMS and Calithera Biosciences Inc., a clinical-stage biotechnology company focused on discovering and developing novel small molecule drugs directed against tumor metabolism and tumor immunology targets for the treatment of cancer, announced an expansion of their existing collaboration to evaluate Opdivo in combination with Calithera’s CB-839 in patients with non-small cell lung cancer and melanoma. CB-839 is an investigational orally administered glutaminase inhibitor currently in Phase I/II clinical studies.

Preclinical data suggest that CB-839, which is designed to target a pathway to starve tumor cells of the key nutrient glutamine, may enhance the effects of checkpoint inhibitors and may also reverse tumor resistance to checkpoint inhibitors by altering the immune-suppressive microenvironment and promoting an anti-tumor immune response.

In June, BMS entered into a clinical research collaboration with Novartis to investigate the safety, tolerability, and efficacy of Opdivo and Opdivo + Yervoy regimen in combination with Mekinist as a potential treatment option for metastatic colorectal cancer in patients with microsatellite stable tumors where the tumors are proficient in mismatch repair (MSS mCRC pMMR). The Phase I/II study is expected to establish recommended dose regimens and explore the preliminary anti-tumor activity of combining Mekinist with Opdivo, as well as Mekinist in combination with the Opdivo + Yervoy regimen. Results will be used to determine optimal approaches to further potential clinical development of these combinations.

Also in June, BMS and Seattle Genetics Inc. entered into a collaboration agreement to evaluate the combination of Opdivo and Seattle Genetics’ antibody-drug conjugate Adcetris in a pivotal Phase III clinical trial. The trial will evaluate the combination of Adcetris and Opdivo versus Adcetris alone as a potential treatment option for patients with relapsed/refractory or transplant-ineligible advanced classical Hodgkin lymphoma. Adcetris is an ADC directed to CD30, a defining marker of classical HL, which combines the targeting ability of a monoclonal antibody with the potency of a cell-killing agent.

The planned Phase III study will be a randomized, open-label global clinical trial in classical HL patients with relapsed/refractory disease who are ineligible for autologous stem cell transplant (ASCT) or after failure of ASCT. Participants will be randomized to receive treatment with either Adcetris in combination with Opdivo or Adcetris alone. The pivotal study is expected to begin in mid-2017.

In July, BMS and Clovis Oncology Inc. announced a clinical collaboration agreement to evaluate the combination of Opdivo and Clovis Oncology’s poly (ADP-ribose) polymerase (PARP) inhibitor Rubraca in pivotal Phase III clinical trials in advanced ovarian cancer and advanced triple-negative breast cancers. The companies will initiate a first-line maintenance treatment study to evaluate Rubraca + Opdivo, Rubraca, Opdivo, and placebo in newly diagnosed patients with stage III/IV high-grade ovarian, fallopian tube, or primary peritoneal cancer who have completed platinum-based chemotherapy. They will also initiate a first-line maintenance treatment study to evaluate Rubraca + Opdivo, Rubraca, Opdivo, and chemotherapy in patients with stage IV or recurrent locally advanced inoperable TNBC associated with a homologous recombination deficiency.

In August, BMS and Daiichi Sankyo announced a collaborative clinical trial to evaluate the combination of Opdivo and Daiichi Sankyo’s investigational antibody drug conjugate DS-8201 in HER2-expressing metastatic breast and urothelial (bladder) cancers. The Phase Ib multicenter, open-label study will include two parts. The dose escalation part will determine a possible recommended dose of DS-8201 in combination with Opdivo in patients with HER2-expressing breast cancer who are refractory to standard therapies or for which no standard therapy is available. The dose expansion part of the study will evaluate the efficacy, safety, and tolerability of combining Opdivo with DS-8201 at the established dose level in patients with HER2-expressing advanced/metastatic breast cancer as well as HER2-expressing urothelial (bladder) cancer in patients previously treated with chemotherapy. The study is expected to begin enrollment in first quarter of 2018 in the United States and Europe. Under the terms of the agreement, Daiichi Sankyo will be the sponsor conducting the trial. FDA has granted Fast Track designation to DS-8201 for the treatment of HER2-positive unresectable and/or metastatic breast cancer in patients who have progressed after prior treatment with HER2-targeted therapies including ado-trastuzumab emtansine (T-DM1).

Also in August, BMS and IFM Therapeutics announced that the companies had signed a definitive agreement under which Bristol-Myers Squibb would acquire all of the outstanding capital stock of IFM Therapeutics, a venture-backed biotech company focused on developing therapies that modulate novel targets in the innate immune system to treat cancer, autoimmunity and inflammatory disorders. The acquisition will give Bristol-Myers Squibb full rights to IFM’s preclinical STING (stimulator of interferon genes) and NLRP3 agonist programs focused on enhancing the innate immune response for treating cancer. IFM’s STING agonist program includes a lead asset that BMS executives say will accelerate the company’s efforts against this target, while the NLRP3 agonist program includes a potential first-in-class pipeline candidate.

Under the terms of the agreement, Bristol-Myers Squibb will pay $300 million upon closing of the transaction. IFM stockholders also will be entitled to additional contingent payments of up to $1.01 billion for each of the first products from the two programs upon the achievement of certain development, regulatory and sales milestones. Also, IFM is eligible for additional contingent milestone payments for further products resulting from these programs. The deal duly closed in September.

In April, BMS announced data from a Phase II study of BMS-986036, an investigational pegylated analogue of human fibroblast growth factor 21 (FGF21), a key regulator of metabolism, in patients with biopsy-confirmed nonalcoholic steatohepatitis (NASH) (F1-F3). The study achieved its primary endpoint of significant reduction in liver fat versus placebo. Statistically significant improvements were also seen in prespecified exploratory endpoints including biomarkers of fibrosis, metabolic parameters, and markers of liver injury.

In June, BMS presented four-year follow-up data from the Phase III ELOQUENT-2 study in which Empliciti plus lenalidomide/dexamethasone continued to demonstrate efficacy in patients with relapsed/refractory multiple myeloma, compared to patients treated with lenalidomide/dexamethasone alone. The data also showed a safety profile consistent with prior findings. The results offer the longest follow-up efficacy and safety data of an immuno-oncology agent. Empliciti was approved by FDA in November 2015.

ELd therapy maintained a reduction in the risk of disease progression or death of 29 percent. At four-years, ELd therapy continued to demonstrate a clinically meaningful and sustained relative improvement of 50 percent in progression-free survival rate, 21 percent, compared to Ld therapy, 14 percent. PFS benefits seen in patients receiving ELd therapy were consistent across certain patient subsets and sustained through two-year, three-year, and four-year follow-up. Patients with high risk showed relative risk reduction of 36 percent and more than doubling of median PFS with ELd in comparison to Ld.