4.1 HealthCare

Pharmaceuticals

Research areas and sites

Drug discovery in the Pharmaceuticals segment focuses on indications with high medical need in the areas of cardiology, oncology, ophthalmology, hematology and gynecology. We conduct research and development activities at several locations, the most important of which are as follows:

Research and Development Sites

Site
Country
Focus

Berlin

Germany

R&D in oncology, gynecology and non-indication-specific areas

Wuppertal

Germany

R&D in cardiology, ophthalmology and non-indication-specific areas

Mission Bay, San Francisco

U.S.A.

Research in the areas of hematology and biologicals

Berkeley

U.S.A.

Development in the areas of hematology and biologicals

Turku

Finland

Development of hormone-releasing intrauterine devices and implants for contraception

Oslo

Norway

Research on thorium conjugates for the treatment of cancer

Cooperation

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. A number of examples are listed in the table below:

Pharmaceuticals Cooperation Partners

Cooperation objective

Strategic partnership in the field of genome and drug research in cardiology aimed at using findings from human genetics to develop new cardiovascular therapies

Development of an antisense molecule for the prevention of thrombosis

Development of Xarelto™ (rivaroxaban)

Research into lung vascular disease, especially pulmonary hypertension

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

Access to BiTE™ antibodies for developing novel tumor therapies

Codevelopment of oncology products based on MEK (mitogen-activated ERK kinase) inhibitors

Strategic partnership in oncology to discover and develop active substances that specifically target tumor-specific gene mutations

Collaboration for the research and development of new immunotherapy approaches in oncology

Strategic partnership for the research and development of new therapeutic options in oncology, especially in immunotherapy

Access to antibody library with the option to in-license antibodies for the development and commercialization of novel tumor therapies

Development of antibody-drug conjugates (ADCs) for novel tumor therapies

Discovery and development of novel therapeutics relating to cancer stem cells

Codevelopment of Nexavar™ (sorafenib) for various types of cancer

Development of ODM-201 for the treatment of patients with prostate cancer

Development of diagnostic tests in personalized oncology treatment

Access to technology for antibody-drug conjugates (ADCs) for novel tumor therapies

Research and development of oncological drug candidates

Research into new approaches for the treatment of various eye diseases

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

Development of Eylea™ (aflibercept) to treat various eye diseases
Development of a PDGFR-beta antibody for ophthalmology

Development of a novel gene therapy for hemophilia A

Research collaboration to identify and validate development candidates in endometriosis

Strategic research alliance for the development of novel gynecological therapies

Codevelopment of tedizolid to treat various infections

Development of a targeted antibiotic inhalation therapy for lung infections (ciprofloxacin DPI)

Codevelopment of a targeted antibiotic inhalation therapy for lung infections (amikacin inhale)

Access to antibody library with in-licensing of antibodies

Research cooperation and establishment of a research center for joint projects

Research cooperation and establishment of a research center for joint projects

1 Bayer is not active in the area of human embryonic stem cell research.

We also operate our own science and innovation centers. We coordinate primarily our research partnerships in Asia through our science hubs in Beijing, China; Singapore; and Osaka, Japan. In Berlin, Germany, and San Francisco, California, United States, we operate the “CoLaborator™,” an incubator model for young life science companies. The objective of the global CoLaborator™ concept is to offer these companies suitable laboratory and office infrastructure in the direct vicinity of Bayer’s own research facilities. In the area of crowdsourcing, we are very successfully continuing our “Grants4Targets™” program. We supplemented “Grants4Leads™,” which concentrates on small molecules, with “PartnerYourAntibodies™,” a program that focuses on the evaluation of biological actives. Furthermore, the “Grants4Apps™ Accelerator Program” offers mentoring to start-up companies that can offer innovative solutions relevant to health care and therapy. In the area of venture capital, we are active with the “High-Tech Gründerfonds” and Versant Ventures.

Clinical trials

Clinical trials account for a major portion of the development process for medicines. They are an essential tool for determining the efficacy and compatibility of new developmental products before they can be used to treat diseases. The benefits and potential risks of new medicines must always be scientifically proven and well documented. All studies at Bayer satisfy strict international guidelines and quality standards, as well as the respective applicable national laws and standards.

Online annex: 3-4.1-1:

limited assurance

Bayer publishes information about clinical trials in line with the respective applicable national laws and according to the principles of the European (EFPIA) and North American (PhRMA) pharmaceutical associations, these principles being defined in a joint position paper.

HealthCare publishes information on its own clinical trials both in the publicly accessible register www.ClinicalTrials.gov and in its own “Trial Finder” database. In the case of approved products, summarized results of Phase II, III and IV clinical trials are accessible online through the “Trial Finder.” Upon request, scientists can receive access to anonymized data at the patient level via the portal www.clinicalstudydatarequest.com.

Further information on our globally uniform standards, the monitoring of studies and the role of the ethics committees can be found on the internet.

Activities in 2015

Group target 2015:

HealthCare – transition of more than 10 new molecular entities (NMEs) into development

In line with our targets for 2015 we transferred 12 new molecular entities from our research pipeline into preclinical development in the reporting year. We define a new molecular entity (NME) as a new chemical or biological substance that has not been in development to date. In preclinical trials these substances are examined further in various models with respect to their suitability for clinical trials and linked “first-in-man” studies. In 2015, we conducted clinical trials with several drug candidates from our research and development pipeline. We strengthened products that were already on the market through life cycle management activities to improve their application and / or expand their spectrum of indications.

We are investigating some of our development candidates with respect to their potential for the treatment of rare diseases, also known as orphan diseases. In February 2015, copanlisib received orphan drug designation from the U.S. Food and Drug Administration (FDA) for the treatment of follicular lymphoma, a histological subtype of non-Hodgkin lymphoma.

The following tables show our most important drug candidates currently in Phase II or III of clinical testing:

Research and Development Projects (Phase II)1

Indication

Cancer

Heart failure

Contraception

Heart failure

Prevention of thrombosis2

Endometriosis

Recurrent / resistant non-Hodgkin lymphoma (NHL)

Renal anemia

Wet age-related macular degeneration3

Bone metastases in breast cancer

Cancer, various studies

Cancer

Cancer

Pulmonary hypertension (IIP)

Diffuse systemic sclerosis

Cystic fibrosis

Secondary prevention of acute coronary syndrome (ACS)4

Small-cell lung cancer (SCLC)

Chronic heart failure

Symptomatic uterine fibroids

Endometriosis

1 As of January 27, 2016
2 Sponsored by Ionis Pharmaceuticals, Inc.
3 Sponsored by Regeneron Pharmaceuticals, Inc.
4 Sponsored by Janssen Research & Development, LLC
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 Food and Drug Administration (FDA), European Medicines Agency (EMA) or other regulatory approvals will not be granted for these compounds.

Research and Development Projects (Phase III)1

Indication

Pulmonary infection

Prostate cancer

Hemophilia A

Pulmonary infection

Various forms of non-Hodgkin lymphoma (NHL)

Chronic heart failure

Diabetic kidney disease

Combination treatment of castration-resistant prostate cancer

Refractory liver cancer

Pulmonary arterial hypertension (PAH) in patients who do not sufficiently respond to PDE-5i / ERA

Prevention of major adverse cardiac events (MACE)

Anticoagulation in patients with chronic heart failure2

Long-term prevention of venous thromboembolism

Prevention of venous thromboembolism in high-risk patients after discharge from hospital2

Embolic stroke of undetermined source (ESUS)

Peripheral artery disease (PAD)

Pulmonary infection

1 As of January 27, 2016
2 Sponsored by Janssen Research & Development, LLC
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 Food and Drug Administration (FDA), European Medicines Agency (EMA) or other regulatory approvals will not be granted for these compounds.

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:

Products Submitted for Approval1

Indication

E.U., U.S.A., Japan; treatment of hemophilia A

E.U., U.S.A.; contraception

Japan; treatment of prostate cancer patients with bone metastases

U.S.A.; secondary prophylaxis of acute coronary syndrome (ACS)

1 As of February 4, 2016

2 Submitted by Janssen Research & Development, LLC

In 2015, we achieved further progress in various therapeutic areas:

Cardiology

Xarelto™ (active ingredient: rivaroxaban) has been approved for more indications in the area of venous and arterial thromboembolism than any of the other non-vitamin-K-dependent oral anticoagulants. Xarelto™ is approved in more than 130 countries worldwide across all indications, its approval status varying from country to country. Xarelto™ is marketed in the United States by Janssen Pharmaceuticals, Inc., a subsidiary of Johnson & Johnson.

In May 2015, Xarelto™ was approved by the China Food and Drug Administration (CFDA) for the prevention of stroke and systemic embolism in patients with nonvalvular atrial fibrillation and for the treatment of deep vein thrombosis (DVT). The approval also includes the use of Xarelto™ to reduce the risk of recurrent DVT and pulmonary embolism following acute DVT. In September 2015, Xarelto™ was approved by the Japanese Ministry of Health, Labour and Welfare (MHLW) for the treatment and secondary prevention of pulmonary thromboembolism and deep vein thrombosis.

In addition to the already approved indications, the use of rivaroxaban is also being investigated in other cardiovascular diseases such as prevention of major adverse cardiac events, embolic stroke of undetermined source or peripheral artery disease.

Rivaroxaban was invented by Bayer and is being jointly developed with Janssen Research & Development, LLC, United States, a subsidiary of Johnson & Johnson.

Adempas™ (active ingredient: riociguat) is the first member of a new class of vasodilation agents known as soluble guanylate cyclase (sGC) modulators. Administered in tablet form, riociguat is currently being investigated as an innovative, specific approach for the treatment of various forms of pulmonary hypertension.

Adempas™ is approved in the United States and Europe for the treatment of particular forms of chronic thromboembolic pulmonary hypertension (CTEPH) and pulmonary arterial hypertension (PAH). In Japan, Bayer was granted marketing authorization for CTEPH in 2014 and for PAH in February 2015.

The trial program for riociguat also includes studies outside of the pulmonary hypertension indication. For example, riociguat is also in Phase II testing for the treatment of patients with diffuse systemic sclerosis.

Another representative of the sGC modulator class is vericiguat, currently in Phase IIb clinical testing to treat chronic heart failure.

The development and commercialization of sGC modulators is part of our strategic collaboration with Merck & Co., Inc., United States.

The active ingredient finerenone (BAY 94-8862) is a novel oral nonsteroidal mineralcorticoid receptor antagonist (MRA) that is currently in Phase III clinical development. In September 2015, two 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. were initiated to investigate the efficacy and safety of finerenone in patients with diabetic kidney disease. Another Phase III trial is being prepared in the indication chronic heart failure.

The development candidate molidustat is being investigated for the treatment of patients with anemia accompanied by chronic kidney disease and / or end-stage kidney failure.

In March 2015, we expanded our partnership with the Broad Institute at the Massachusetts Institute of Technology (MIT) and Harvard University, United States, to include collaboration on cardiovascular genomics and drug discovery.

In April 2015, furthermore, we entered into an exclusive license agreement with Ionis Pharmaceuticals, Inc., United States, pertaining to IONIS-FXIRx (BAY 2306001), an antisense drug in clinical development for the prevention of thrombosis. Under the agreement, Bayer will further develop and commercialize BAY 2306001 in areas of high medical need. Antisense drugs bind to the mRNA molecules in the cell in a targeted way and inhibit the production of proteins that may become significant in the course of a disease. The novel mechanism of inhibiting Factor XI synthesis may offer an additional treatment option for patients for whom none is currently available.

Oncology

Stivarga™ (active ingredient: regorafenib) is an oral multikinase inhibitor. It inhibits various signal pathways that are responsible for tumor growth. Stivarga™ is approved in the United States, Europe, Japan and other countries for the treatment of patients with metastatic colorectal cancer (mCRC) and gastrointestinal stromal tumors (GIST).

In March 2015, we suspended enrollment in a Phase III trial with regorafenib due to insufficient patient recruitment at that time. The trial is investigating regorafenib as an adjuvant treatment option for patients with colorectal cancer following resection of liver metastases with curative intent. The results of a further 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. with regorafenib as a second-line treatment for liver cancer are expected in 2016.

Stivarga™ was developed by Bayer. In 2011, Bayer and Onyx Pharmaceuticals, Inc., a subsidiary of Amgen Inc., United States, agreed that Onyx would receive royalties on global sales of Stivarga™ in the area of cancer treatment.

Xofigo™ (active ingredient: radium-223 dichloride) is approved in the E.U. and the United States for the treatment of adult patients with castration-resistant prostate cancer (CRPC) with symptomatic bone metastases but no known visceral metastases. In April 2015, we submitted an application to the Japanese health authority MHLW for marketing authorization for radium-223 dichloride for the treatment of prostate carcinoma with bone metastases. The active ingredient is being investigated in additional trials in prostate cancer and in Phase II trials involving breast cancer patients.

The active ingredient copanlisib is a novel, intravenous phosphatidylinositol 3-kinase (PI3K) inhibitor. In 2015, we expanded our global clinical development program. A new Phase II and two Phase III trials are designed to investigate the safety and efficacy of copanlisib in patients with recurring indolent non-Hodgkin lymphoma (NHL) and diffuse large b-cell lymphomas (DLBCL), an aggressive subtype of NHL.

Another active ingredient, BAY-1841788 (ODM-201), is being jointly developed with Orion Corporation, Espoo, Finland. This novel oral androgen receptor inhibitor is in Phase III clinical development for the treatment of patients with prostate cancer.

In July 2015, we entered into a collaboration and license agreement with Sprint Bioscience AB, Sweden, for the research, development and commercialization of oncological drug candidates. Under the agreement, we will receive the license for a research program currently undergoing preclinical development that is geared toward the inhibition of tumor cell metabolism.

Ophthalmology

Eylea™(active ingredient: aflibercept) is our joint development project with Regeneron Pharmaceuticals, Inc., United States. Aflibercept blocks the natural growth factor VEGF (vascular endothelial growth factor), thus preventing the abnormal formation of new blood vessels that tend to leak fluid. The medication is administered directly into the eye. Regeneron Pharmaceuticals, Inc., United States, holds exclusive rights to the product in the United States, while in other countries it is marketed by Bayer.

Eylea™ is approved for the treatment of wet age-related macular degeneration (AMD), visual impairment due to macular edema secondary to central retinal vein occlusion (CRVO) and diabetic macular edema (DME). In Japan, Eylea™ is additionally approved for the treatment of myopic choroidal neovascularization (mCNV).

In February 2015, the European Commission extended marketing authorization for Eylea™ to include the treatment of patients with visual impairment due to macular edema secondary to branch retinal vein occlusion (BRVO). Eylea™ therefore can be used in Europe by all patients with visual impairment due to macular edema resulting from retinal vein occlusion (RVO). In June 2015, the product was approved in this indication in Japan. In October 2015, Eylea™ was approved by the European Commission for the treatment of myopic choroidal neovascularization (mCNV).

A Phase IIa clinical study with regorafenib eye drops did not show the desired results and the project is therefore being discontinued. The study investigated the use of regorafenib for the treatment of wet age-related macular degeneration (AMD).

In June 2015, we entered into a strategic research alliance with Johns Hopkins University, United States, concerning the discovery and development of innovative drugs for the treatment of serious back-of-the-eye diseases that affect many people worldwide. The five-year collaboration will aim to develop new ophthalmic therapies for various retinal diseases.

Hematology

In June 2015, we submitted an application to the Japanese MHLW for marketing authorization for the recombinant Factor VIII compound BAY 81-8973 for the treatment of hemophilia A. The approval process has been under way in the United States and Europe since the end of 2014. In December 2015, the European Committee for Medicinal Products for Human Use (CHMP) recommended approval. BAY 81-8973 is a further development of recombinant Factor VIII (rFVIII) which has demonstrated clinical evidence of efficacy when used for prophylaxis twice or three times per week, with standard dosages.

Damoctocog alfa pegol (BAY 94-9027) is a long-acting recombinant Factor VIII that is currently in Phase III clinical development.

Gynecology

Vilaprisan (sPRM) is a novel oral progesterone receptor modulator that is currently being investigated in Phase II trials for the treatment of uterine fibroids and endometriosis. In June 2015, an additional Phase II trial began that is investigating the efficacy of vilaprisan compared with its major competitor product.

In November 2015, we filed for marketing authorization for the new intrauterine system (IUS) LCS-16 in the European Union and the United States. This low-dose, levonorgestrel-releasing product enables contraception for a period of up to five years.

Consumer Health

Research and development at Consumer Health is performed essentially at the following sites:

Research and Development Sites

Site
Country
Focus
Consumer Care

Morristown

U.S.A.

Allergy, analgesic, cough & cold and dermatological products

Memphis

U.S.A.

Suncare, footcare and dermatological products; consumer research testing center

Gaillard

France

Nutritional supplements, dermatological and gastrointestinal products

Darmstadt

Germany

Herbal medicines

Chengdu

China

Over-the-counter (OTC) products and herb-based traditional Chinese medicines (TCM)

Medical Care (Radiology)

Pittsburgh

U.S.A.

Medical devices, sterile disposables, informatics

Berlin

Germany

Contrast agents

Animal Health

Monheim

Germany

Antiparasiticides, anti-infectives and pharmaceuticals

Shawnee

U.S.A.

Antiparasiticides, anti-infectives and pharmaceuticals

Auckland

New Zealand

Dairy cattle health

São Paulo

Brazil

Antiparasiticides

In Consumer Care, research and development activities focus on the development of nonprescription (over-the-counter = OTC) medications as well as skin and foot care products, sunscreens, dietary supplements and other self-medication products. Placing the consumer at the center of everything we do, our development strategies are geared toward expanding and improving our brand portfolio. We want to achieve this through new product developments, forms, formulations, claims, pack designs and other innovations. We introduced a number of new product line extensions to various markets in 2015. They included new delivery forms and uses and innovations for existing brands such as Aspirin™, Elevit™, Berocca™, Canesten™, Bepanthen™ / Bepanthol™ and Coppertone™. We also actively pursue the reclassification of current prescription medicines as OTC products.

The goal of our research and development activities in Medical Care is steadily to improve our contrast agents and our contrast injection systems in order to build on our leadership position in the field of radiology.

In March 2015, we received approval in Japan for Gadovist™ (active ingredient: gadobutrol) injection for use with resonance imaging (MRI). Gadovist™ is the first high concentration / high relaxivity gadolinium-based contrast agent to be made available in Japan. In July 2015, Gadovist™ was approved by the European Commission for use in children under two years of age. This label extension applies to all indications that have already been approved.

In August 2015, the MRXperion injection system was approved by the FDA for the injection of contrast agents. Our system optimizes injection workflow, provides enhanced point-of-care capabilities and can be connected to our Radimetrics™ Enterprise platform.

In 2015, we also worked to expand the capabilities of our informatics product offerings by developing new software applications to improve contrast agent and radiation dosage management across CT, MRI and nuclear medicine modalities.

At Animal Health we focus our research and development activities on antiparasitics, antibiotics, medicines to treat noninfectious disorders and nonantibiotic alternatives for infectious diseases. Our central research activities are conducted as part of our Life Sciences Field of activities comprising particularly health care and agriculture; at Bayer this refers to the activities of the Pharmaceuticals, Consumer Health and Crop Science divisions and the Animal Health business unit. platform in conjunction with pharmaceutical research and in close collaboration with our researchers at CropScience. We also reinforce the business by continually identifying further product development candidates through our existing collaborations.

Since August 2015, our innovative immunostimulant Zelnate™ has been available in the United States. It was approved by the United States Department of Agriculture (USDA) to aid in the treatment of bovine respiratory disease caused by Mannheimia haemolytica bacteria. The product offers veterinarians and farmers a new approach alongside vaccines and antibiotics for mitigating this complex infectious disease that has substantial negative impact on the cattle industry.