Focus on Innovation

Pharmaceuticals

Pharmaceuticals focuses on indications with high medical need in the areas of cardiovascular disease, oncology, gynecology, hematology and ophthalmology. We conduct research and development at several locations, mainly in Germany, the United States, Japan, China, Finland and Norway.

Bayer worldwide; see also graphic in Chapter “Corporate Structure”

Promising new molecular entities from our research pipeline are transferred to preclinical development. We define a new molecular entity (NME) as a chemical or biological substance that is not yet approved for use in humans. In preclinical development, these substances are examined further in various models with respect to their suitability for clinical trials and the associated “first-in-humans” studies.

In 2018, we developed a new strategy for our global research and development organization that will boost our innovation potential and productivity. Aimed at producing quality rather than quantity, the strategy focuses on a deeper understanding of diseases, better characterization of product candidates and modality-independent approaches to improve the technical success rate.

Our more intensive characterization of product candidates led to a shift in our schedule in 2018. We transferred five new active ingredients to preclinical development instead of nine new active ingredients and one new indication or one new formulation project as had been originally planned. Future active ingredient candidates will come from internal research, collaborations and purely external sources. On the basis of our throughput model, we expect that five to seven active ingredients will be transferred to development each year following full implementation of the innovation model.

We conducted clinical trials with several drug candidates from our research and development pipeline in 2018. We strengthened products that were already on the market through additional development activities to further improve their application and / or expand their spectrum of indications.

Clinical trials are an essential tool for determining the efficacy and safety of new drugs before they can be used to diagnose or treat diseases. The benefits and risks of new medicinal products must always be scientifically proven and well documented. All clinical trials at Bayer satisfy strict international guidelines and quality standards, as well as the respective applicable national laws and standards.

Bayer also publishes information about clinical trials in line with the applicable national laws and according to the principles of the European (EFPIA) and U.S. (PhRMA) pharmaceutical industry associations, these principles being defined in position papers.

Information about our own clinical trials can be found in the publicly accessible register www.ClinicalTrials.gov and our own Trial Finder database. Further information on our globally uniform standards, the monitoring of studies and the role of the ethics committees can be found on the internet.

Progress in Phase II clinical projects

The following table shows our most important drug candidates currently in Phase II clinical testing projects.

Research and Development Projects (Phase II)1

Projects

 

Indication

1

As of January 31, 2019

2

Sponsored by Ionis Pharmaceuticals, Inc.

The nature of drug discovery and development is such that not all compounds can be expected to meet the predefined project goals. It is possible that any or all of the projects listed above may have to be discontinued due to scientific and / or commercial reasons and will not result in commercialized products. It is also possible that the requisite U.S. Food and Drug Administration (FDA), European Medicines Agency (EMA) or other regulatory approvals will not be granted for these compounds. Moreover, we regularly review our research and development pipeline so that we can give priority to advancing the most promising pharmaceuticals projects.

BAY 1093884 (anti-TFPI antibody)

 

Hemophilia

Fulacimstat (BAY 1142524, chymase inhibitor)

 

Chronic kidney disease

BAY 1193397 (AR alpha 2c rec ant.)

 

Peripheral artery disease (PAD)

BAY 1213790 (anti-FXIa antibody)

 

Prevention of thrombosis

BAY 1817080 (P2X3 antagonist)

 

Chronic cough

BAY 2253651 (TASK channel blocker)

 

Obstructive sleep apnea

BAY 2306001 (IONIS-FXIRx)2

 

Prevention of thrombosis

Levonorgestrel (progestin) + indomethacin (NSAID) combi IUS

 

Contraception

Rogaratinib (pan-FGFR inhibitor)

 

Urothelial cancer

Vericiguat (sGC stimulator)

 

Chronic heart failure with preserved (HFpEF) ejection fraction

Vilaprisan (S-PRM)

 

Endometriosis

Below are the most significant changes that occurred in 2018 compared with the previous year:

The Phase II study with copanlisib in patients with relapsed or refractory diffuse large B-cell lymphoma (DLBCL), an aggressive form of non-Hodgkin lymphoma (NHL), was concluded. A Phase III study in this indication is not currently planned.

The Phase I-IV studies are clinical phases in the development of a drug product. The active ingredient candidate is generally tested in healthy subjects in Phase I, and in patients in Phases II and III. The studies test the therapeutic tolerability and efficacy of active ingredients in a specific indication. Phase IV studies are conducted following the approval of a new drug product to monitor its safety and efficacy over an extended period of time. The studies are subject to strict legal requirements and documentation procedures. in which the angiopoietin2 (Ang2) antibody nesvacumab was tested in combination with aflibercept (tradename: Eylea™) in comparison with aflibercept monotherapy were concluded. The results of these studies do not justify proceeding to Phase III of clinical development.

Based on the results of a Phase II trial investigating anetumab ravtansine as a second-line monotherapy for malignant mesothelioma, which failed to meet its primary endpoint of progression-free survival, we will not pursue any further studies in this indication. Anetumab ravtansine will continue to be investigated in other indications in Phase I studies.

In September 2018, the development of the oral AKR1C3 inhibitor to treat endometriosis was discontinued ahead of schedule due to an unfavorable benefit-risk profile.

Also in September 2018, the development of neladenoson bialanate, an oral partial adenosine A1 receptor agonist, was discontinued. Phase II studies involving cardiac insufficiency patients did not reach their primary efficacy endpoints.

Bayer and Merck & Co., Inc., United States, decided in October 2018 to not pursue riociguat any further in the indication diffuse cutaneous systemic sclerosis. A Phase II study in this indication did not meet its primary endpoint.

Likewise in October 2018, following an interim analysis of available clinical data to date, Bayer decided to not further pursue the development of radium-223 dichloride in breast cancer.

In November 2018, Bayer decided to halt the combined Phase I / Phase II study of radium-223 dichloride in the indication multiple myeloma for strategic reasons.

In December 2018, Bayer decided to halt development of the chymase inhibitor fulacimstat in the indication left ventricular dysfunction after myocardial infarction after a Phase II study failed to reach the efficacy endpoints. Development of fulacimstat in the indication chronic kidney disease will continue unchanged.

Progress in Phase III clinical projects

The following table shows our most important drug candidates currently in Phase III clinical testing projects:

Research and Development Projects (Phase III)1

Projects

 

Indication

1

As of January 31, 2019

2

Sponsored by Merck & Co., Inc., U.S.A.

The nature of drug discovery and development is such that not all compounds can be expected to meet the predefined project goals. It is possible that any or all of the projects listed above may have to be discontinued due to scientific and / or commercial reasons and will not result in commercialized products. It is also possible that the requisite U.S. Food and Drug Administration (FDA), European Medicines Agency (EMA) or other regulatory approvals will not be granted for these compounds. Moreover, we regularly review our research and development pipeline so that we can give priority to advancing the most promising pharmaceuticals projects.

Copanlisib (PI3K inhibitor)

 

Various forms of non-Hodgkin lymphoma (NHL)

Darolutamide (ODM-201, AR antagonist)

 

Castration-resistant nonmetastatic prostate cancer

Darolutamide (ODM-201, AR antagonist)

 

Hormone-sensitive metastatic prostate cancer

Finerenone (MR antagonist)

 

Diabetic kidney disease

Molidustat (HIF-PH inhibitor)

 

Renal anemia

Rivaroxaban (FXa inhibitor)

 

Peripheral artery disease (PAD)

Rivaroxaban (FXa inhibitor)

 

VTE treatment in children

Vericiguat (sGC stimulator)2

 

Chronic heart failure with reduced ejection fraction (HFrEF)

Vilaprisan (S-PRM)

 

Symptomatic uterine fibroids

Below are the most significant changes that occurred in 2018 compared with the previous year:

Bayer and the U.S. study network NSABP (National Surgical Adjuvant Breast and Bowel Project) decided to discontinue ahead of schedule a Phase III clinical study investigating the active substance regorafenib as an adjuvant therapy in colon carcinoma due to an insufficient number of participants.

In March 2018, Bayer and MSD International GmbH, a Group company of Merck & Co., Inc., decided to discontinue the joint development and commercialization of Sivextro™ (active ingredient: tedizolid phosphate) to treat infections of the skin and subcutaneous tissue.

At the ESC (European Society of Cardiology) congress in Munich in August 2018, Bayer and development partner Janssen Research & Development, LLC, United States, presented the results of the clinical Phase III COMMANDER HF and MARINER trials conducted by Janssen investigating the oral Factor Xa inhibitor rivaroxaban (tradename: Xarelto™).

The COMMANDER HF trial investigated whether, when administered additionally to the standard therapy, rivaroxaban reduces the risk of cardiovascular events in coronary heart disease patients following acute worsening of heart failure. The data showed a numerical reduction in stroke and myocardial infarction events in patients treated with rivaroxaban, but this was outweighed by the high rate of death events in both study arms, many of which were not related to thrombosis, contributing to a failure to achieve the primary endpoint of the study. Work in this indication will not be continued.

The MARINER trial investigated whether rivaroxaban is superior to placebo in the prevention of symptomatic venous thromboembolism (VTE) and VTE-related death after hospital discharge for acutely medical ill patients at high risk of VTE. While the composite primary efficacy endpoint was not achieved, the evaluation showed a reduction of symptomatic VTE events. The major bleeding events rate with rivaroxaban was low and not significantly different compared with placebo.

In October 2018, the Phase III ARAMIS trial investigating the safety and efficacy of darolutamide in patients with nonmetastatic castration-resistant prostate cancer met its primary endpoint. The substance significantly extended metastasis-free survival compared to placebo, and its safety profile and tolerability were consistent with observations from previous trials. Darolutamide is a novel androgen receptor antagonist for the oral treatment of prostate cancer that is being developed jointly by Bayer and the Finnish bio-pharmaceutical company Orion Corporation. The ARASENS trial is currently being conducted in metastatic hormone-sensitive prostate cancer.

On the basis of the results of the Phase III ERA-223 trial, Bayer decided to halt work in this indication (use of radium-223 dichloride in combination with abiraterone acetate and prednisone / prednisolone). Bayer had prematurely unblinded the trial in 2017 following reports of an elevated risk of bone fractures and reduced median overall survival in patients treated with this combination. The European, Japanese and U.S. health authorities have concluded their review of the data from the ERA-223 trial and confirmed that, overall, the risk-benefit profile of Xofigo™ (radium-223 dichloride) remains positive in the approved indication, subject to the required changes to the respective labeling. The results of the ERA-223 trial were presented at the ESMO (European Society for Medical Oncology) Congress in October 2018.

In November 2018, researchers observed anomalies in animal studies involving vilaprisan. The aim of these studies was to investigate the safety of vilaprisan in long-term use. Vilaprisan is a development candidate that Bayer is developing for the treatment of symptomatic uterine fibroids and endometriosis. Although the findings are preliminary and preclinical – and were not observed in other vilaprisan studies – Bayer has decided as a precaution to not recruit any additional patients to the ongoing Phase II and Phase I-IV studies are clinical phases in the development of a drug product. The active ingredient candidate is generally tested in healthy subjects in Phase I, and in patients in Phases II and III. The studies test the therapeutic tolerability and efficacy of active ingredients in a specific indication. Phase IV studies are conducted following the approval of a new drug product to monitor its safety and efficacy over an extended period of time. The studies are subject to strict legal requirements and documentation procedures. until the findings have been thoroughly analyzed and understood. We have notified health authorities, ethics committees and trial investigators about the preliminary findings. We will coordinate any consequent modifications to our ongoing clinical development program with health authorities and ethics committees.

Filings and approvals

We regularly evaluate our research and development pipeline in order to prioritize the most promising pharmaceutical projects. Following the completion of the required studies with a number of these drug candidates, we submitted applications to one or more regulatory agencies for approvals or approval expansions. The most important drug candidates in the approval process are shown below.

In February 2018, Eylea™ (active ingredient: aflibercept solution for injection into the eye) was approved by the China Food and Drug Administration (CFDA) for the treatment of visual impairment due to diabetic macular edema.

In May 2018, Eylea™ was approved by the Chinese regulatory authorities for the treatment of visual impairment due to neovascular (wet) age-related macular degeneration.

In July 2018, Kovaltry™ (active ingredient: octocog alfa) was approved by the Chinese regulatory authorities for use in adults and children with hemophilia A for routine prophylaxis, on-demand treatment and perioperative management of bleeding. Kovaltry™ is an unmodified recombinant Factor VIII product.

In August 2018, the European Commission approved a new treatment approach for Eylea™ that enables early extension of the injection interval for patients with neovascular age-related macular degeneration already in the first year of treatment. The new regimen allows clinicians to extend patients’ individual injection intervals based on visual and / or anatomic outcomes.

Likewise in August 2018, the European Commission approved a combination of Xarelto™ (rivaroxaban) 2.5 mg twice daily plus acetylsalicylic acid (ASA) 75 to 100 mg once daily for the prevention of atherothrombotic events in adults with coronary artery disease (CAD) or symptomatic peripheral artery disease (PAD) at high risk for ischemic events. The U.S. FDA approved the combination in October 2018.

In November 2018, the European Commission approved damoctocog alfa pegol (tradename: Jivi™) for the treatment and prophylaxis of bleeding in adults and adolescents aged 12 years and older who have been previously treated for hemophilia A. Prior to that, Jivi™ had been approved by the United States in August 2018 and by Japan in September 2018.

Likewise in November 2018, larotrectinib (tradename: Vitrakvi™) was approved in the United States for the treatment of adult and pediatric patients with solid tumors that have a neurotrophic receptor tyrosine kinase (NTRK) gene fusion without a known acquired resistance mutation. The approval also applies to patients with tumors with an NTRK gene fusion that are either metastatic or where surgical resection is likely to result in severe morbidity, and for patients who have no satisfactory alternative treatments or whose cancer has progressed following treatment. The active substance larotrectinib was designed to specifically block the signaling pathway responsible for tumor growth. In August 2018, Bayer filed an application seeking approval of larotrectinib in the European Union as well.

In December 2018, our development partner Janssen Research & Development filed in the United States for approval of Xarelto™ for prevention of venous thromboembolism (VTE) in high-risk patients. The decision to file for approval was based on data from the Phase III MAGELLAN study supported by data from the MARINER study. Both studies evaluated the efficacy of Xarelto™ for the prevention of VTE in patients during hospitalization and immediately after discharge from hospital.

Collaborations

We augment our own research capacities through collaborations and strategic alliances with external industrial and academic research partners. In this way we gain access to complementary technologies and external innovation potential.

See also Chapter “Focus on Innovation” “Global open innovation network”

In June 2018, Bayer and the MD Anderson Cancer Center at the University of Texas in Houston, United States, signed a five-year collaboration agreement to accelerate the development of novel targeted treatments for cancer patients based on patient or tumor characteristics for which current drug therapies have not shown satisfactory clinical efficacy.

Also in June 2018, Bayer and the Broad Institute of the U.S. universities MIT and Harvard expanded their strategic research collaboration for the development of new therapies for patients with cardiovascular diseases such as heart failure. Researchers from the Broad Institute and Bayer are working together in a joint Precision Cardiology Laboratory at the Broad Institute in Boston. The collaboration is focused on better understanding cardiovascular diseases on a molecular level and developing new therapies for patients.

In August 2018, Bayer and Haplogen GmbH, Austria, entered into a multiyear research collaboration agreement to identify new drug candidates for the treatment of pulmonary diseases such as chronic obstructive pulmonary disease (COPD). Within the context of their collaboration, Bayer and Haplogen will jointly identify and research new potential drug candidates. Bayer will be responsible for subsequently developing and commercializing any suitable drug candidates.

In January 2019, Bayer and Kyoto University agreed on a strategic research alliance to jointly identify new drug targets for the treatment of pulmonary diseases such as idiopathic pulmonary fibrosis. The goal of the research alliance is to identify specific targets and pathways that are causing the disease and to discover new treatments to modulate these pathways and prevent further lung function decline. Bayer will have an option for the exclusive use of the collaboration results.

The following table shows examples of the main R&D collaborations.

Main Collaborations

Partner

 

Collaboration objective

Broad Institute

 

Strategic partnership to research and develop new therapeutic options in the fields of cardiovascular medicine and oncology and establishment of a joint research laboratory

Compugen Ltd.

 

Research and development of new immunotherapy approaches in oncology

German Cancer Research Center (DKFZ)

 

Strategic partnership to research and develop new therapeutic options in oncology, especially in immunotherapy, and establishment of a joint research laboratory

Evotec AG

 

Collaboration to identify development candidates for the treatment of endometriosis and kidney diseases

Haplogen GmbH

 

Research collaboration in the field of pulmonary diseases such as chronic obstructive pulmonary disease (COPD)

Ionis Pharmaceuticals, Inc.

 

Development of the antisense drug IONIS-FXIRx for thrombosis prevention and development of IONIS-FXI-LRx in the preclinical phase

Janssen Research & Development, LLC of Johnson & Johnson

 

Development and marketing of Xarelto™ (rivaroxaban) for the treatment of coagulation disorders

Kyoto University

 

Research alliance to identify new therapeutic approaches for pulmonary diseases

Loxo Oncology, Inc.

 

Development and marketing of larotrectinib (LOXO-101, tradename Vitrakvi™) for the treatment of cancer patients with a mutation of the TRK gene and LOXO-195 for the treatment of patients with cancer types that have acquired resistance to initial TRK therapies such as larotrectinib

MD Anderson Cancer Center

 

Development collaboration in oncology

Merck & Co., Inc.

 

Development and marketing collaboration in the field of soluble guanylate cyclase (sGC) modulation

Orion Corporation

 

Development and marketing of darolutamide (previously ODM-201) for the treatment of patients with prostate cancer

Peking University

 

Research collaboration and establishment of a research center for joint projects

PeptiDream Inc.

 

Active ingredient research in various therapeutic areas and target classes with the help of PeptiDream’s Peptide Discovery Platform System Technology

Tsinghua University

 

Research collaboration and establishment of a research center for joint projects

Ultragenyx Pharmaceuticals

 

Research and development of a novel gene therapy for the treatment of hemophilia A

University of Oxford

 

Strategic research partnership to develop novel gynecological therapies

Vanderbilt University Medical Center

 

Strategic research alliance to identify and develop new potential active ingredients for the treatment of kidney diseases

Wilmer Eye Institute of Johns Hopkins University

 

Research and development of innovative drug products to treat serious back-of-the-eye diseases

X-Chem, Inc.

 

Active ingredient research in various therapeutic areas and target classes

Compare to Last Year