Focus on Innovation

Pharmaceu­ticals

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

Group target 2017:

transition of 10 new molecular entities (NMEs) into development

In 2017, we achieved our target for the year and were able to transfer ten new molecular entities from our research pipeline into preclinical development. 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 the associated “first-in-man” studies. In 2017, we conducted clinical trials with several drug candidates from our research and development pipeline. 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.

Pharmaceuticals publishes information on its own clinical trials both in the publicly accessible register www.ClinicalTrials.gov and in its own “Trial Finder” database.

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Transparency through publication of clinical trials

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

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 here.

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

Indication

Malignant pleural mesothelioma

Endometriosis

Heart failure

Peripheral artery disease (PAD)

Prevention of thrombosis

Prevention of thrombosis2

Relapsed / refractory diffuse large B-cell lymphoma

Solid tumors3

Chronic heart failure

Serious eye diseases4

Breast cancer with bone metastases

Multiple myeloma

Systemic sclerosis

Endometriosis

1 As of January 26, 2018
2 Sponsored by Ionis Pharmaceuticals, Inc.
3 Sponsored by Loxo Oncology, Inc.
4 Sponsored by Regeneron 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.

Below are the most significant changes that occurred in 2017 compared with the previous year:

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, which are primarily sponsored by investigators, have been taken out of the overview of the most important Phase II projects. However, these studies are continuing.

In February 2017, our partner Regeneron Pharmaceuticals, Inc., United States, decided to halt development of rinucumab, a PDGFR antibody, in combination with aflibercept (tradename: Eylea™) for the treatment of wet age-related macular degeneration, based on the results of the CAPELLA Phase II clinical trial after 28 weeks. The trial missed its clinical endpoint, which had been for a statistically significant improvement in visual acuity after 12 or 28 weeks.

In the second quarter of 2017, based on the results of the GEMINI trial conducted by Janssen Research & Development, LLC, which had tested rivaroxaban (tradename: Xarelto™) in connection with a single antiplatelet therapy (SAPT) for the secondary prophylaxis of acute coronary syndrome (ACS), the decision was made to stop pursuing the development of rivaroxaban in this indication.

Bayer reported in July 2017 that a Phase II clinical trial evaluating Bayer’s oncological development candidate anetumab ravtansine, also known as BAY 949343, as a monotherapy in previously treated patients with advanced malignant pleural mesothelioma (MPM) did not meet its primary endpoint of progression-free survival. The safety and tolerability of anetumab ravtansine corresponded with observations from previous trials. Anetumab ravtansine is currently being reviewed in other Phase I clinical trials as both a monotherapy and in combination with other drugs, including in a Phase Ib multi-indication study of six different types of advanced solid tumors and a Phase Ib combination study with patients with recurrent platinum-resistant ovarian cancer.

Bayer began a Phase II clinical trial in 2014 on the safety, tolerability and efficacy of riociguat in adult cystic fibrosis patients with the delta F508 gene mutation. The preliminary analysis of selected data from the first part of the trial indicated that there was no evidence of a positive trend in the efficacy of riociguat. A continuation of the trial was not considered meaningful at that time. In August 2017, Bayer decided to terminate the trial ahead of schedule. No concerns were raised about the safety of riociguat.

In November 2017, our partner Regeneron Pharmaceuticals, Inc., United States, published data from two Phase II studies in which the angiopoietin2 (Ang2) antibody nesvacumab had been tested in combination with aflibercept (tradename: Eylea™) against aflibercept monotherapy. One of these studies investigated patients with diabetic macular edema, while the other focused on patients with wet age-related macular degeneration. Regeneron reported that the differences in the improvement in visual acuity between the treatment groups did not justify Phase III development with the goal of obtaining marketing approval in the United States. At the same time, the efficacy of aflibercept monotherapy was confirmed for both indications. The results of the studies will be analyzed further and submitted for presentation at a future medical congress.

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

Indication

Various forms of non-Hodgkin lymphoma (NHL)

Castration-resistant nonmetastatic prostate cancer

Hormone-sensitive metastatic prostate cancer

Diabetic kidney disease

Renal anemia

Combination treatment of castration-resistant prostate cancer

Colon cancer, adjuvant therapy

Anticoagulation in patients with chronic heart failure2

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

Peripheral artery disease (PAD)

VTE treatment in children

Pneumonia

Chronic heart failure3

Symptomatic uterine fibroids

1 As of January 26, 2018
2 Sponsored by Janssen Research & Development, LLC
3 Sponsored by Merck & Co., 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.

Below are the most significant changes that occurred in 2017 compared with the previous year:

In July 2017, Bayer began the ASTEROID Phase III clinical trial program to investigate the development candidate vilaprisan in women with symptomatic uterine fibroids. Vilaprisan is a novel orally dosed, selective progesterone receptor modulator developed by Bayer for enabling long-term treatment of uterine fibroids.

In October 2017, Bayer and its development partner Janssen Research & Development, LLC, announced that the Phase III NAVIGATE ESUS trial had been terminated ahead of schedule. The trial investigated the efficacy and safety of rivaroxaban (tradename: Xarelto™) for the secondary prevention of strokes and systemic embolisms in patients who had recently suffered an embolic stroke of unknown origin. Following a planned interim analysis conducted by the independent Data Monitoring Committee (DMC), the DMC recommended that the trial be terminated early since the efficacy of rivaroxaban compared with acetylsalicylic acid (ASA) was similar in the treatment groups and offered only limited potential for clinical benefit to patients if the trial continued.

In November 2017, the results of the global Phase III clinical study program INHALE, which investigated Amikacin Inhale in intubated and mechanically ventilated patients with Gram-negative pneumonia in addition to standard treatment, were announced. Amikacin did not demonstrate any clinical superiority versus the standard treatment in combination with an aerosolized placebo. Neither the primary endpoint nor the secondary endpoints were achieved. Amikacin Inhale is the development name for a drug-device combination comprising a specially formulated Amikacin inhalation solution and a patented synchronized inhalation system with a vibrating mesh nebulizer. Bayer terminated its research into Amikacin Inhale and the associated cooperation with Nektar Therapeutics, Inc.

Following the recommendation of an independent data monitoring committee, Bayer in November 2017 unblinded ahead of schedule a Phase III trial of radium-223 dichloride in combination with abiraterone acetate and prednisone / prednisolone in patients with metastatic castration-resistant prostate cancer. The reason for this recommendation was the observance of an imbalance in terms of more fractures and deaths in the treatment arm investigating radium-223 in combination with abiraterone acetate and prednisone / prednisolone.

In December 2017, on the basis of positive Phase II data, Bayer launched a Phase III clinical study program in Japan that investigates the development candidate molidustat in patients with renal anemia. Molidustat is an inhibitor of the enzyme hypoxia-inducible factor-prolyl hydroxylase (HIF-PH) that stimulates the production of erythropoietin and the formation of red blood cells.

There is currently a study program investigating the efficacy and safety of rivaroxaban for the treatment and secondary prevention of venous thromboembolism in children. Timely and successful completion of this program would extend patent protection for Xarelto™ in Europe and the United States by a further six months.

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.

Main Products Submitted for Approval1

Indication

Europe, U.S.A., Japan: hemophilia A

Europe, U.S.A.: prevention of major adverse cardiac events (MACE), COMPASS study

U.S.A.: secondary prophylaxis of acute coronary syndrome (ACS), rivaroxaban in combination with dual antiplatelet therapy (DAPT); ATLAS trial

1 As of January 26, 2018

2 Submitted by Janssen Research & Development, LLC

In August 2017, Bayer received approval from the European Commission to modify the prescribing information for the oral Factor Xa inhibitor Xarelto™ (active ingredient: rivaroxaban) based on data from the PIONEER Phase III study. The information contains a dosage recommendation for patients with nonvalvular atrial fibrillation who undergo percutaneous coronary intervention with stent placement and require oral anticoagulation.

Also in August 2017, the European Commission approved the oral multikinase inhibitor Stivarga™ (active ingredient: regorafenib) for an additional indication. The approval relates to the treatment of adult patients with hepatocellular carcinoma (HCC) who had previously been treated with Nexavar™ (active ingredient: sorafenib). Stivarga™ is the first medicine to show a significant improvement in overall survival in second-line treatment of patients with HCC for whom there was previously no further treatment option. The product had been approved for second-line treatment of HCC in the United States in April 2017 and in Japan in June 2017.

In early September 2017, Bayer applied for marketing authorization to the European Medicines Agency (EMA) for the long-acting site-specifically PEGylated recombinant human Factor VIII (damoctocog alfa pegol) for the treatment of patients with hemophilia A. The regulatory submission is based on the data from the PROTECT VIII trial. In that trial, damoctocog alfa pegol offered patients protection from bleeds when used prophylactically once every seven days, once every five days, or twice per week. Bayer had already submitted an application for an authorization to manufacture biopharmaceutical products (Biologics License Application, BLA) for damoctocog alfa pegol to the U.S. Food and Drug Administration (FDA) in August 2017. In October 2017, Bayer submitted an application for the authorization of damoctocog alfa pegol in Japan as well.

In September 2017, the U.S. Food and Drug Administration (FDA) likewise granted Bayer approval for copanlisib, which will be sold under the tradename Aliqopa™ in the future, for the treatment of previously treated patients with relapsed follicular B-cell non-Hodgkin lymphoma. The accelerated approval was granted based on the results of the CHRONOS-1 Phase II trial including 142 patients with indolent non-Hodgkin lymphoma (iNHL) whose disease had relapsed after two previous treatments, of which 104 patients had follicular B-cell non-Hodgkin lymphoma. The approval was issued on the basis of the overall response rate and must still be confirmed in a further trial. Copanlisib is an intravenous pan-class I phosphatidylinositol-3-kinase (PI3K) inhibitor with predominant inhibitory activity against PI3K-α and PI3K-δ isoforms.

Based on data from the EINSTEIN CHOICE Phase III study, in October 2017 Bayer and its development partner Janssen Research & Development, LLC, received additional marketing approval from the U.S. Food and Drug Administration (FDA) for the oral Factor Xa inhibitor Xarelto™ (active ingredient: rivaroxaban) in the United States for a once-daily 10 mg dose of rivaroxaban for long-term prevention of recurrent venous thromboembolism. The authorization is for patients at continued risk of deep vein thrombosis and / or pulmonary embolism who have already received at least six months of standard anticoagulation therapy. The European Commission granted corresponding approval for Xarelto™ in October 2017.

In November 2017, Bayer submitted a further application for Xarelto™ to the European Medicines Agency (EMA) for a vascular dose of rivaroxaban in combination with acetylsalicylic acid (ASA) for the treatment of chronic coronary artery disease (CAD) or peripheral artery disease (PAD). This application is based on the results of the COMPASS Phase III clinical study. This demonstrated that a twice-daily dose of 2.5 mg rivaroxaban in combination with 100 mg ASA once a day reduced the combined risk of stroke, cardiovascular death and heart attack by an unprecedented 24% (relative risk reduction) in patients with CAD or PAD, compared with a once-daily dose of 100 mg ASA. In the United States, the application for marketing approval was submitted to the FDA in December 2017.

In December 2017, our cooperation partner Loxo Oncology, Inc., United States, initiated the submission of a rolling New Drug Application (NDA) for larotrectinib in the United States. The NDA relates to the treatment of unresectable or metastatic solid tumors with NTRK-fusion proteins in adults and children who require systemic therapy, where the disease has progressed following prior treatment and there is no acceptable alternative treatment. Bayer and Loxo Oncology are jointly developing larotrectinib. The active ingredient is in clinical development for cancers where the tropomyosin receptor kinase (TRK) gene becomes connected to other, unrelated genes (gene fusion). The rolling NDA submission is expected to be completed in early 2018.

Also in December 2017, Bayer obtained marketing approval in China for Stivarga™ (active ingredient: regorafenib) for the treatment of adult patients with hepatocellular carcinoma (HCC) who have previously been treated with Nexavar™ (active ingredient: sorafenib). In the Phase III RESORCE study (REgorafenib after SORafenib in patients with hepatoCEllular carcinoma), regorafenib demonstrated a significant and clinically relevant improvement in overall survival in second-line treatment of patients with HCC compared with a placebo. Regorafenib is the first product to be approved in China for second-line treatment of HCC.

In December 2017, Bayer received a Complete Response Letter from the U.S. Food and Drug Administration notifying it that its application for approval of the investigational drug product ciprofloxacin DPI (Dry Powder for Inhalation) for the treatment of adults with non-cystic fibrosis bronchiectasis (NCFB) cannot be approved in the present form. Bayer decided to discontinue development of Cipro DPI in NCFB for the time being and will evaluate possible further options for this asset.

Cooperations

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.

In August 2017, Bayer and Vanderbilt University Medical Center in Nashville, Tennessee, United States, signed a five-year strategic research alliance to fight kidney disease. Both partners will work together on identifying and developing new potential compounds for treating kidney diseases. The goal is to rapidly transfer innovative approaches from the laboratory to preclinical development.

In November 2017, Bayer and PeptiDream Inc., a publicly listed Japanese biopharmaceutical company, concluded a drug discovery cooperation agreement. Their collaboration covers various therapeutic areas such as oncology and cardiology, as well as classes of drug targets. Using PeptiDream’s Peptide Discovery Platform System technology, the partners will be working together to identify novel drug discovery candidates for target structures that are difficult to address.

Also in November 2017, Bayer signed a global exclusive cooperation agreement with the biopharmaceutical company Loxo Oncology, Inc., Stamford, Connecticut, United States, for the development and commercialization of larotrectinib (LOXO-101) and LOXO-195. Both compounds are being investigated in global studies for the treatment of patients with cancers harboring tropomyosin receptor kinase (TRK) gene fusions, which are genetic alterations across a wide range of tumors resulting in uncontrolled TRK signaling and tumor growth.

The following table shows examples of the main cooperations.

Main Cooperations in 2017

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 and in the field of oncology to identify and develop active ingredients that target tumor-specific gene alterations

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

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

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

Development of Xarelto™ (rivaroxaban)

Development and marketing of larotrectinib (LOXO-101) and LOXO-195 for the treatment of cancer patients with a mutation of the TRK gene

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

Development of antibody-drug conjugates using MorphoSys’s HuCAL technology

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

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

Development of Eylea™ (aflibercept) to treat various eye diseases

Development of a combination therapy of the angiopoietin2 (Ang2) antibody nesvacumab and aflibercept for the treatment of serious eye diseases

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

In April 2017, Bayer decided not to exercise its option for further development and marketing of biopharmaceutical Wnt pathway inhibitors vantictumab (OMP-18R5) and ipafricept (OMP-54F28) as part of the partnership between Bayer and OncoMed Pharmaceuticals, Inc., United States. The small molecule program under the companies’ collaboration continues without change.

Further examples are shown in this augmented version.

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Other Cooperations in 2017

Cooperation objective

Access to antibody library with in-licensing of antibodies

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

Development of a novel gene therapy for hemophilia A

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

Development of diagnostic tests in personalized oncology treatment

Research into lung vascular disease, especially pulmonary hypertension

Codevelopment of tedizolid to treat various infections

Codevelopment of a targeted antibiotic inhalation therapy for lung infections (Amikacin Inhale)

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

Discovery and development of novel anticancer stem cell therapeutics

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

Research cooperation and establishment of a research center for joint projects

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

Research cooperation and establishment of a research center for joint projects

Strategic research alliance for the development of novel gynecological therapies

Development of diagnostic tests in personalized oncology treatment

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

1 Terminated in December 2017

Compare to Last Year