Research and Development

We conduct research and development (R&D) worldwide in order to develop new products and services designed to improve the quality of life of patients and to satisfy the needs of our customers. Further optimizing the relevance and efficiency of our research and development activities – either on our own or in cooperation with third parties – is one of our top priorities.

Approximately 6,800 employees work for Merck researching innovations to serve long-term health and technology trends in both established and growth markets.

Merck spent around € 2.1 billion on research and development in 2017. In our research and development activities, we focus on both in-house research and external collaborations which enable us to increase the productivity of our research while simultaneously ­reducing financial outlay. The organizational set-up of our research and ­development activities reflects the structure of Merck with three ­business sectors.

Healthcare

BIOPHARMA

Oncology and Immuno-Oncology

In 2017, we achieved a number of significant milestones with ­avelumab, an anti-PD-L1 antibody that we are co-developing and co-commercializing with Pfizer. The first regulatory milestone took place in March, when the U.S. Food and Drug Administration (FDA) granted accelerated approval for avelumab under the brand name Bavencio® for the treatment of adults and pediatric patients 12 years and older with metastatic Merkel cell carcinoma (MCC), based on tumor response and duration of response. Continued approval for this indication may be contingent on verification and description of clinical benefit in confirmatory ­trials. Metastatic MCC is a rare and aggressive skin cancer that previously had no approved treatment options, making this the first indication for Bavencio® and the first FDA-approved treatment and immunotherapy for metastatic MCC. Since fewer than half of patients with metastatic MCC survive more than one year and less than 20% survive beyond five years, ­Bavencio® offers patients a much-needed treatment option that could make a meaningful difference in the treatment of this.

The FDA in 2015 granted avelumab Orphan Drug Designation for MCC, as well as Fast Track and Breakthrough Therapy Designations for the treatment of patients with metastatic MCC whose disease has progressed after at least one previous chemotherapy regimen. Breakthrough Therapy Designation is intended to expedite the development and review of treatments for serious or life-threatening ­disease where preliminary clinical evidence indicates that the drug may demonstrate substantial improvement over existing therapies for one or more endpoints.

This FDA approval was based on data from JAVELIN Merkel 200, an international, multicenter, single-arm, open-label, Phase II study with two parts. The first, part A, included 88 patients with metastatic MCC whose disease had progressed after at least one chemotherapy treatment. The objective response rate was 33%, with 11% of patients experiencing a complete response and 22% of patients experiencing a partial response. At the time of analysis, tumor responses were durable, with 93% of responses lasting at least six months (n=25) and 71% of responses lasting at least 12 months (n=13). Duration of response ranged from 2.8 to more than 24.9 months.

The second, part B, at the time of the data cut-off included 39 patients with histologically confirmed metastatic MCC who were treatment-naïve to systemic therapy in the metastatic setting. The objective response rate was 62%, with 14% of patients experiencing a complete response and 48% of patients experiencing a partial response. 67% of patients experienced a progression-free survival rate of three months.

The next regulatory milestone followed in May, when the FDA granted Bavencio® accelerated approval for the treatment of patients with locally advanced or metastatic urothelial carcinoma (UC) who have disease progression during or following platinum-containing chemotherapy, or who have disease progression within 12 months of neoadjuvant or adjuvant treatment with platinum-containing chemotherapy. This indication was also approved under the Accelerated Approval Program based on tumor response and duration of response, and continued approval for this indication may be contingent upon verification and description of clinical benefit in confirmatory trials.

Advanced urothelial carcinoma is an aggressive disease with a high rate of recurrence. Bladder cancer accounts for approximately 90% of urothelial carcinomas and is the sixth most common cancer in the United States. Despite advances in the treatment of locally advanced or metastatic disease, the prognosis for patients remains poor, with the five-year survival rate at approximately 5%, meaning more treatment options are urgently needed.

The efficacy and safety of Bavencio® in urothelial carcinoma were demonstrated in the corresponding cohorts of the JAVELIN Solid Tumor trial, a Phase I, open-label, single-arm, multicenter study of Bavencio® in the treatment of various solid tumors. These urothelial carcinoma cohorts (n=242) enrolled patients with locally advanced or metastatic urothelial carcinoma with disease progression on or after platinum-containing chemotherapy, or who had disease progression within 12 months of treatment with a platinum-containing neoadjuvant or adjuvant chemotherapy regimen. Patients with six months or more of follow-up experienced an overall response rate of 16.1%. Duration of response was not precisely estimable, with a range of response from 1.4 to 17.4 months.

In September, we gained three further regulatory approvals for Bavencio®. The first was from the regulatory authority in Switzerland (Swissmedic) for the treatment of patients with ­metastatic MCC whose disease has progressed after at least one chemotherapy treatment. In mid-September, the European ­Commission granted approval for Bavencio® as a monotherapy for the treatment of adult patients with metastatic MCC, making it the first and only approved treatment for metastatic MCC in the 28 member states of the European Union as well as Liechtenstein, Iceland and Norway. A few days later, the Japanese Ministry of Health, Labour and Welfare (MHLW) granted the first Asian approval for Bavencio®, making it the first-ever treatment indicated for curatively unresectable MCC and the first anti-PD-L1 to become available in Japan. Regulatory approval for the treatment of metastatic MCC followed in December in Canada and in January 2018 in Australia as well as in Israel. In addition, ­Bavencio® was approved in Israel at the end of January to treat patients with urothelial carcinoma.

Through our strategic alliance with Pfizer, we continue to explore the therapeutic potential of avelumab. Our clinical development ­program known as JAVELIN involves more than 30 clinical programs, including various Phase III trials and over 7,000 patients being ­evaluated across more than 15 different tumor types. In addition to MCC and UC, these cancers include breast, gastric/gastro-esophageal junction, head and neck, Hodgkin’s lymphoma, melanoma, mesothelioma, non-small cell lung, ovarian, and renal cell carcinoma (RCC).

On December 21, the FDA granted Breakthrough Therapy Designation for avelumab in combination with INLYTA® (axitinib) for ­treatment-naïve patients with advanced RCC.

In addition to the host of abstracts presented at key congresses in 2017 – including the 2017 American Society of Clinical Oncology (ASCO) Annual Meeting and the 2017 European Society for Medical Oncology (ESMO) Congress - we provided an update on our Phase III JAVELIN Gastric 300 study in November. The study is the first global trial of a checkpoint inhibitor versus an active chemotherapy comparator rather than placebo in patients with pre-treated advanced gastric cancer. The trial did not meet its pre-specified primary endpoint of superior overall survival. The data are being further ­examined in an effort to better understand the results and we will present them at a medical congress in 2018. We remain committed to our ongoing gastric clinical development program with avelumab.

As part of our commitment to developing new treatment options for patients with hard-to-treat cancers who would otherwise have a low chance of survival and to exploring all potential options, we entered into several strategic collaborations in 2017. The first of these was in March, when our collaboration with EpiThany to evaluate avelumab in combination with EP-101 STEMVAC, an investigational multi-antigen, polyepitope cancer vaccine, in a Phase II trial in women with breast cancer was announced. The second was announced in May, with Swiss/German biotech company VAXIMM AG to evaluate avelumab in combination with VAXIMM’s VXM01. VXM01 is an investigational oral T-cell immunotherapy designed to activate T-cells to attack the tumor vasculature, and, in several tumor types, attack cancer cells directly. Under the terms of the agreement, ­VAXIMM will be responsible for conducting two open-label Phase I/II trials – one in glioblastoma and one in metastatic colorectal cancer (CRC).

In June, we announced a collaboration with eFFECTOR Therapeutics to evaluate a novel immuno-oncology combination in microsatellite stable colorectal cancer. Together we plan to initiate a Phase II, open-label, randomized, non-comparative study to evaluate the safety, tolerability and efficacy of avelumab in combination with eFFECTOR’s investigational small molecule MNK1/2 inhibitor, eFT508, in microsatellite stable relapsed or refractory CRC patients.

In September, we entered into a collaboration with Phosplatin Therapeutics to evaluate avelumab in combination with PT-112, a novel small molecule inducer of apoptosis with evidence of downstream immunogenic cell death (ICD) properties, currently in Phase I development in solid tumors and hematological malignancies.

At the 53rd ASCO Annual Meeting (June 2 – 6 in Chicago), we shared results from our increasingly broad oncology portfolio, from immuno-oncology to DNA ­damage response (DDR) approaches, in a wide range of hard-to-treat cancers. Over 40 abstracts showcased the impact of our commitment to shaping cancer care today and tomorrow, including data for ­avelumab, Erbitux® (cetuximab), and pipeline updates on the anti-PD-L1/TGF-β trap M7824, the DNA-PK inhibitor M3814, the BTK inhibitor M7583, and tepotinib, an investigational small-molecule inhibitor of the c-Met receptor tyrosine kinase.

Multiple presentations on avelumab at ASCO included data in first-line metastatic Merkel cell carcinoma and previously treated metastatic urothelial carcinoma, as well as results from the Phase Ib trial of avelumab in combination with axitinib in RCC. Beyond metastatic MCC, locally advanced or metastatic UC and RCC, we also presented further avelumab abstracts in non-small cell lung cancer and metastatic castrate-resistant prostate cancer, locally advanced squamous cell carcinoma of the head and neck, and relapsed or refractory diffuse large B-cell lymphoma.

We also featured new research at ASCO on our investigational bifunctional immunotherapy anti-PD-L1/TGF-β trap (M7824), which is thought to have the potential to simultaneously block both PD-L1 and TGF-β. An oral presentation showcased dose escalation Phase I clinical data exploring the potential of M7824 in advanced solid ­tumors.

Pipeline updates at ASCO also included early clinical results for tepotinib, M7583, an oral, highly selective, covalent inhibitor of Bruton’s tyrosine kinase (BTK), and the first clinical data for M3814, an investigational DNA-dependent protein kinase (DNA-PK) inhibitor.

We are investing significant resources in the promising area of DDR. In January, we signed a licensing agreement with Boston-based Vertex Pharmaceuticals that covers the worldwide development and commercialization of four research and development programs that investigate novel approaches to the treatment of cancer. The addition of the DDR portfolio in-licensed from Vertex to our own in-house DDR platform has positioned us as one of the key players in the DDR field. Our broad DDR portfolio includes inhibitors for enzymes of major DDR pathways, such as Ataxia Telangiectasia and Rad3-related kinase (ATR), DNA-PK and Ataxia Telangiectasia Mutated kinase (ATM).

At the ESMO congress (September 8 – 12 in Madrid), we presented a total of 23 abstracts representing five therapeutic agents, which highlighted our ­company’s expanding scientific expertise. Data were presented on the role of established medicine Erbitux® (cetuximab), with quality of life (QoL) data in colorectal cancer and real-world data in both CRC and squamous cell carcinoma of the head and neck. With respect to avelumab, we presented updated efficacy and safety data in metastatic MCC and UC (12-month follow-up data in pre-treated patients with locally advanced or metastatic disease). We also presented new data and updates from our rapidly evolving pipeline, including first stand-alone data in metastatic triple negative breast cancer from potential first-in-class ATR inhibitor M6620. M6620 is currently being investigated in several ongoing Phase I trials across a variety of tumor types. Other pipeline updates included data on the potential first-in-class dual p70S6K/Atk inhibitor M2698 and tepotinib in patients with advanced hepatocellular carcinoma (HCC).

In January, we kicked off a collaboration and licensing agreement with Domain Therapeutics of Strasbourg, France, to explore the potential of adenosine inhibition in the development of novel immuno-oncology agents. Domain Therapeutics is a company focused on the discovery and development of first-in-class compounds against transmembrane targets, and in particular against G protein-coupled receptors (GPCRs). This collaboration strengthens our combination strategy in immuno-oncology and underscores our science-driven approach to discovering and developing novel compounds through both internal capabilities and external collaborations.

Also in January, we announced a three-year strategic ­collaboration with The University of Texas MD Anderson Cancer Center, the aim of which is to accelerate the development of investigational cancer therapies in four cancers – breast, colorectal, glioblastoma and ­leukemia. The collaboration will enhance the value of our future oncology/immuno-oncology pipeline, with a goal of starting multiple ­registration phase studies in novel indications in the next two to three years.

In June, we announced our entry into a new strategic ­collaboration with the biopharmaceutical company F-star of Cambridge, United Kingdom, for the development and commercialization of five ­bispecific immuno-oncology antibodies. Beyond these, we will have further rights to replace, as well as to add to these antibodies using F-star’s bispecific antibody platform. This collaboration will further strengthen our immuno-oncology pipeline and underscores our commitment to discovering and developing breakthrough cancer therapies that make a meaningful difference to patients’ lives.

On July 6, we introduced the winners of our seventh Biopharma Innovation Cup. The winning team received € 20,000 for its innovative idea around the role of natural killer cells in cancer ­immunology. The Biopharma Innovation Cup is designed to support the professional development of post-graduate students and to ­foster innovation from a promising new generation of academic talent. It showcases our strong commitment to leveraging innovation, c­uriosity and collaboration. With more than 1,400 applications from 60 countries, the Biopharma Innovation Cup in 2017 achieved a new level of popularity.

In September, we announced the recipients of the fourth annual Grant for Oncology Innovation (GOI) awards. The three winners of this program shared prize money totaling € 1 million to progress their research. A scientific steering committee of internationally renowned oncology experts selected the winning proposals from around 100 applicants worldwide based on ­relevance to patient care, innovative approach, scientific impact, feasibility and relevance for the personalization of treatment.

Neurology & Immunology

Multiple sclerosis (MS) is one of the world’s most common neurolo­gical disorders and there are still significant unmet needs for MS patients, particularly those with highly active relapsing MS (RMS). Following a positive opinion from the Committee for ­Medicinal Products for Human Use (CHMP) of the European Medicines Agency (EMA) in June, the European Commission (EC) granted marketing authorization in August for Mavenclad® 10 mg (cladribine tablets) for the treatment of highly active relapsing multiple sclerosis in the 28 countries of the European Union (EU) as well as in Norway, Liechten­stein and Iceland. Mavenclad® is the first oral short-course treatment to have shown efficacy across key measures of disease activity in patients with highly active RMS, including disability progression, annualized relapse rate and magnetic resonance imaging (MRI) activity.

On November 30, Health Canada approved Mavenclad® as mono­therapy for the treatment of adult patients with relapsing-remitting multiple sclerosis (RRMS) to reduce the frequency of clinical exacerbations and delay the progression of disability.

On December 7, Merck received approval (Updated Registration) for Mavenclad® in Australia. The Therapeutic Goods Administration (TGA) updated the registration including the indication, dosing and safety information of Mavenclad® for the treatment of RRMS in ­Australia. On January 14, the Israeli Ministry of Health approved Mavenclad® for the treatment of adult patients with highly active RMS as defined by clinical or imaging features.

The Mavenclad® marketing authorizations in Europe, Canada, Australia, and Israel are based on more than 10,000 patient-years of data with over 2,700 patients included in the clinical trial program, and up to ten years of observation in some patients. Mavenclad® is the first treatment in relapsing multiple sclerosis (RMS) to show sustained clinical efficacy for up to four years with a maximum of 20 days of oral treatment over two years. The efficacy and safety results of these studies allowed for a detailed characterization of its benefit-to-risk profile. Mavenclad® is a selective immune reconstitution therapy that simplifies treatment administration by giving patients two short annual courses of tablets in four years without the need for frequent monitoring. The most clinically relevant adverse reactions were lymphopenia and herpes zoster.

Several Mavenclad® submissions are currently under review and we plan to conduct additional filings for regulatory approval in other countries, including the United States.

Data for approved multiple sclerosis treatments Mavenclad® and Rebif® (interferon beta-1a) and investigational product evobrutinib were presented at the MSParis 2017, 7th Joint ECTRIMS-ACTRIMS Meeting (October 25-28 in Paris). A post hoc analysis in high disease activity sub-groups from the two-year CLARITY study confirmed that Mavenclad® significantly increased the proportion of patients with no evidence of disease activity (NEDA) compared with placebo (43.7% vs 9.0%). Efficacy data from the CLARITY, CLARITY Extension and ORACLE-MS trials highlighted that Mavenclad® delivers and sustains four years of disease control with a maximum of 20 days of oral treatment in the first two years. An additional safety analysis assessing malignancy and infection risk was presented along with data for Mavenclad®, which further detailed how the treatment is thought to selectively target the adaptive immune system.

Additionally, the recipients of the fifth annual Grant for Multiple ­Sclerosis Innovation (GMSI) were announced during the 7th Joint ECTRIMS-ACTRIMS Meeting. In 2017, 77 proposals from 25 countries were submitted. Three research teams from Canada, Portugal and the United States were selected to share the € 1 million grant.

We presented 11 abstracts in oral and poster sessions for clinical programs in systemic lupus erythematosus (SLE), osteoarthritis (OA), rheumatoid arthritis (RA) and fibrotic diseases, including one late-breaker, at the 2017 American College of Rheumatology/Association of Rheumatology Health Professionals (ACR/ARHP) Annual Meeting held from November 3 – 8, 2017 in San Diego. Noteworthy data included a late-breaking abstract on FORWARD, a five-year Phase II study of sprifermin in OA of the knee, providing insights into its potential disease-modifying properties. The study of 549 patients met its primary endpoint, demonstrating statistically significant, dose-dependent increases in MRI total femorotibial joint cartilage thickness from baseline in the two sprifermin groups receiving the highest doses as compared with the placebo group after the two-year treatment period. Demonstration of an increase in cartilage thickness as opposed to a delay in decreasing cartilage thickness has not been previously reported.

On September 12, we announced that a Phase IIb study of evobrutinib, a Bruton’s tyrosine kinase inhibitor (BTKi) discovered by Merck, had been initiated in rheumatoid arthritis (RA) following a Phase IIa study which met the pre-defined criteria for progressing to a dose-finding study in this disease. Evobrutinib is now in Phase IIb studies in three immunological indications: RA, MS, and SLE. Evobrutinib was discovered in our own laboratories and is an example of the innovation of our R&D activities within Healthcare.

We presented data at the American Academy of Neurology (AAN) 69th Annual Meeting (April 22 – 28 in Boston). A total of 15 abstracts on MS, including studies evaluating Rebif® (interferon beta-1a) and Mavenclad®, were presented.

On June 26, at the European Association of Neurology meeting held in Amsterdam, analyses of data from three clinical studies (CLARITY, CLARITY Extension and ORACLE-MS) were announced which suggest that Mavenclad® selectively and discontinuously reduces both B and T lymphocytes in patients with early and relapsing forms of MS. An early reduction of peripheral blood B cells was seen, with cell numbers reaching a nadir at 13 weeks after treatment, followed by a rapid reconstitution toward baseline. A moderate reduction in T cell counts was also shown, although to a lesser degree than B cells; this reduction was more pronounced in CD4+ than in CD8+ lymphocytes.

Fertility

In early 2017, the CHMP granted a positive opinion for the new ­Pergoveris® Pen, followed by a European Commission approval in May. The pen addresses an unmet medical need by providing a convenient and ready-to-use fertility combination treatment option for women with severe follicle stimulating hormone (FSH) and luteinizing hormone (LH) deficiency. The liquid version of Pergoveris® was created by evolving the original freeze-dried powder and solvent combination – which required patients to mix the product vials themselves before daily injection – towards a ready-to-use pre-filled Pen solution. The new Pergoveris® Pen is the only premixed combination of human FSH and human LH on the European market available in a pre-filled injection device for self-administration.

We further underscored our commitment to innovation in fertility in July, when we awarded € 1.25 million to external research projects, supporting the advancement of medical science through the Grant for Fertility Innovation (GFI). Launched as the first of the Merck Grants for Innovation in 2009, it is dedicated to transforming innovative translational fertility research projects into actual solutions aimed at improving fertility treatment outcomes. In 2017, the GFI Award Ceremony included the announcement of the Merck Lifetime Achievement Award in Fertility Innovation, granted to Professor Bruno Lunenfeld for his revolutionary work within the fertility field since 1954.

In November, the FDA approved a new version of Gonal-f® (­follitropin alfa injection) pre-filled pen. Known as Gonal-f® RFF ­Redi-ject™ pre-filled pen in the United States and originally approved by the FDA in 2013, the new version of the pen, based on input from people who use the pen, is easy both to learn and to use. Gonal-f® is the only gonadotropin that comes in a pre-filled, ready-to-use pen in the United States. The new Gonal-f® pen, like its predecessor, enables a fine-tuning of treatment allowing for minimum increments of 12.5 IU to titrate a wide range of doses and precisely target the dosing to patient needs. In addition, its new design features include an amendment to the dose display window for enhanced readability.

General Medicine & Endocrinology

In May, the Medicines and Healthcare Products Regulatory Agency (MHRA) in the United Kingdom authorized Glucophage® SR ­(sustained release formulation; metformin), for the reduction in the risk or delay of the onset of type 2 diabetes in adult, overweight patients with impaired glucose tolerance (IGT) and/or impaired fasting glucose (IFG), and/or increased glycated hemoglobin (HbA1c), when intensive lifestyle changes for 3 to 6 months have failed.

On September 18, we announced the recipients of the Grant for Growth Innovation (GGI) for 2017 during the 10th International Meeting of Pediatric Endocrinology in Washington, D.C. Sixty-five applications were received from 28 countries and reviewed by an independent scientific steering committee consisting of six internationally renowned endocrinologists and researchers. Research groups based in France and Denmark were each awarded a grant for innovation projects in the field of growth and growth disorders.

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BIOPHARMA PIPELINE

as of December 31, 2017

Therapeutic area
Compound Indication Status
Neurology
Cladribine tablets (lymphocyte-targeting agent) Relapsing multiple sclerosis Registration1
Evobrutinib (BTK inhibitor) Multiple sclerosis Phase II
     
Oncology
Tepotinib (c-Met kinase inhibitor) Non-small cell lung cancer Phase II
Tepotinib (c-Met kinase inhibitor) Hepatocellular cancer Phase II
M2698 (p70S6K and Akt inhibitor) Solid tumors Phase I
M3814 (DNA-PK inhibitor) Solid tumors Phase I
M9831 (VX-984, DNA-PK inhibitor) Solid tumors Phase I
M6620 (VX-970, ATR inhibitor) Solid tumors Phase I
M4344 (VX-803, ATR inhibitor) Solid tumors Phase I
M3541 (ATM inhibitor) Solid tumors Phase I
M8891 (MetAP2 inhibitor) Solid tumors Phase I
M7583 (BTK inhibitor) Hematological malignancies Phase I
     
Immuno-Oncology
Avelumab (anti-PD-L1 mAb) Non-small cell lung cancer, 1st line Phase III
Avelumab (anti-PD-L1 mAb) Non-small cell lung cancer, 2nd line Phase III
Avelumab (anti-PD-L1 mAb) Gastric cancer, 1st line maintenance Phase III
Avelumab (anti-PD-L1 mAb) Ovarian cancer platinum-resistant/-refractory Phase III
Avelumab (anti-PD-L1 mAb) Ovarian cancer, 1st line Phase III
Avelumab (anti-PD-L1 mAb) Urothelial cancer, 1st line maintenance Phase III
Avelumab (anti-PD-L1 mAb) Renal cell cancer, 1st line Phase III
Avelumab (anti-PD-L1 mAb) Locally advanced head and neck cancer Phase III
Avelumab (anti-PD-L1 mAb) Merkel cell cancer, 1st line Phase II
Avelumab (anti-PD-L1 mAb) Solid tumors Phase I
Avelumab (anti-PD-L1 mAb) Hematological malignancies Phase I
M9241 (NHS-IL12, cancer immunotherapy) Solid tumors Phase I2
M7824 (anti-PD-L1/TGF β trap) Solid tumors Phase I
M4112 (cancer immunotherapy) Solid tumors Phase I
     
Immunology
Sprifermin (fibroblast growth factor 18) Osteoarthritis Phase II
Atacicept (anti-BLyS/anti-APRIL fusion protein) Systemic lupus erythematosus Phase II
Atacicept (anti-BLyS/anti-APRIL fusion protein) IgA nephropathy Phase II
Abituzumab (anti-CD51 mAb) Systemic sclerosis with interstitial lung disease Phase II
Evobrutinib (BTK inhibitor) Rheumatoid arthritis Phase II
Evobrutinib (BTK inhibitor) Systemic lupus erythematosus Phase II
M1095 (ALX-0761, anti-IL-17A/F nanobody) Psoriasis Phase I3
M6495 (anti-ADAMTS-5 nanobody) Osteoarthritis Phase I
     
General Medicine
M5717 (PeEF2 inhibitor) Malaria Phase I
1
As announced on August 25, 2017, the European Commission has granted marketing authorization for cladribine tablets for the treatment of highly active relapsing multiple sclerosis in the 28 countries of the European Union in addition to Norway, Liechtenstein and Iceland./dd>
2
Sponsored by the National Cancer Institute (USA).
3
As announced on March 30, 2017, in an agreement with Avillion, anti-IL-17 A/F nanobody will be developed by Avillion for plaque psoriasis and commercialized by Merck.
More information on the ongoing clinical trials can be found at www.clinicaltrials.gov.
Pipeline products are under clinical investigation and have not been proven to be safe and effective.
There is no guarantee any product will be approved in the sought-after indication.
ADAMTS-5
A disintegrin and metalloproteinase with thrombospondin motifs
Akt
Protein kinase B
APRIL
A proliferation-inducing ligand
ATM
Ataxia Telangiectasia Mutated kinase
ATR
Ataxia Telangiectasia and Rad3-related kinase
BLyS
B-lymphocyte stimulator
BTK
Bruton’s tyrosine kinase
IgA
Immunoglobulin A
IL
Interleukin
mAb
Monoclonal antibody
MetAP2
Methionine aminopeptidase 2
PD-L1
Programmed cell death ligand 1
PeEF2
Plasmodium eukaryotic elongation factor 2
PK
Protein kinase
TGF β
Transforming growth factor β
Consumer Health

Our Consumer Health business develops and sells over-the-counter medicines and food supplements as well as several prescription medicines in Europe, in particular in France, Germany and the United Kingdom, and in growth markets in Latin America, the Middle East, Africa, and Southeast Asia. The focus of our research and development activities is on the continuous improvement of existing formulations as well as on the development of new products and line extensions. For example, in 2016/2017 we successfully launched the all-new brand Vivera® across several Latin American markets, containing one of the most researched and most effective probiotics in the world for the treatment of gastro-intestinal upset. We are following a consumer-centric innovation approach based on intensive market research across all our key markets. Since 2014, we have been establishing cooperation agreements with ­independent third-party research facilities to leverage their specific capabilities and expertise for the development of new products that meet the specific needs of consumers.

Allergopharma

Allergopharma, our allergy business, is one of the leading manufacturers of diagnostics and prescription drugs for allergen immunotherapy. With its own research department and in cooperation with research institutes and other partners, Allergopharma is developing a better understanding of the immunological mechanism that underlies the development of allergies and is working on the next generation of drugs for allergen immunotherapy.

Life Science

Across our three Life Science business units of Research Solutions, Process Solutions and Applied Solutions, our R&D teams are dedicated to finding innovative solutions to our customers’ toughest challenges. In the Life Science business sector, we invest significantly in R&D, with more than 1,500 employees working in various R&D functions around the world.

In 2017, we continued to focus on delivering the promise of accelerating access to health for people everywhere. We launched 15,000 products, while aiming to:

  • Improve and expand our portfolio
  • Invest in new and disruptive technologies for the long term
  • Partner with the global scientific community
  • Meet customer needs
Improve and expand our portfolio

We launched innovations across all segments of our portfolio throughout 2017. In Research Solutions, we introduced a next-generation high-sensitivity protein detection platform, SMCxPRO™ technology, which allows scientists to detect and quantify low-abundance biomarkers that traditional methods cannot measure.

In addition, we introduced the Stericup® Quick Release 500mL vacuum filtration system, a filter bottle system ideally suited for sterile filtration of cell culture media, buffers and reagents. Even routine processes like microfiltration must be reliable and consistent because quality and reproducibility are critical to the cell culture process. The improved liquid sterile filtration system offers ergonomic design updates that optimize user control and streamline the filtration process, while safeguarding results with the proven performance of Millipore® membranes.

In Process Solutions, we launched CAN MultiFlow™ screening services to more accurately predict genotoxic and mode-of-action properties of substances, ingredients and drug compounds. We were the first company to provide this service in the United States. Assessing toxicity is one of the most important steps in the development of chemicals, ingredients and drugs for use in pharmaceuticals, agriculture or consumer goods.

We took a significant step towards increasing manufacturing flexibility and enabling higher productivity with the launch of the Ex-Cell® Advanced™ HD Perfusion Medium. This first off-the-shelf, high-density cell culture medium supports perfusion processes and facilitates high productivity at low perfusion rates, increasing production yield and speed to clinic.

We also introduced Millistak+®HC Pro, the first portfolio of high-­capacity, fully synthetic depth filters for non-treated Chinese Hamster Ovary harvest clarification and downstream filtration applications. The product provides a cleaner and more consistent depth filtration process than traditional diatomaceous earth (DE) and cellulose-based filtration processes.

In Applied Solutions, we introduced a new testosterone calibrator kit for in vitro diagnostic use. The certified kit allows users to calibrate assays and verify calibrations and is the first of its kind to receive CE mark approval – indicating compliance with the European Union’s Medical Device Directive.

We also launched MC-Media Pads for convenient food and beverage testing. The product offers streamlined, convenient indicator organism testing for robust quality control of food and beverages, helping customers improve their sample-testing workflows by increasing efficiency without compromising quality.

Invest in new and disruptive technologies for the long term

CRISPR genome-editing technology is advancing treatment options for some of the toughest medical challenges faced today, including chronic illnesses and cancers for which there are limited or no treatment options. Merck has a 12-year history in the genome-editing field and was the first company to globally offer custom biomolecules for genome editing (TargeTron™ biomolecules and zinc finger nucleases), driving adoption of these techniques within the worldwide research community.

In 2017, we developed an alternative CRISPR genome-editing tool that makes CRISPR more efficient, flexible and specific, giving researchers more experimental options and faster results, which can accelerate drug development and access to new therapies. Our research on proxy-CRISPR, ‟Targeted Activation of Diverse CRISPR-­Cas Systems for Mammalian Genome Editing via Proximal CRISPR Targeting,” was published in the April 7, 2017, edition of Nature Communications.

The Australian Patent Office granted Merck patent rights relating to the use of CRISPR in a genomic-integration method for eukaryotic cells. With this CRISPR genomic-integration technology, scientists can replace a disease-associated mutation with a beneficial or functional sequence, a method important for creation of disease models and gene therapy. Additionally, scientists can use the method to insert transgenes that label endogenous proteins for visual tracking within cells.

We further strengthened our patent portfolio in August, when the European Patent Office (EPO) issued a ‟Notice of Intention to Grant” for a patent application covering our CRISPR technology used in a genomic-integration method for eukaryotic cells. The patent provides protection for our CRISPR technology, which gives scientists the ability to advance treatment options for the toughest medical challenges we face today.

In addition, the Canadian Patent Office issued a ‟Notice of Allowance” for the patent application covering CRISPR technology used in a genomic-integration method for eukaryotic cells. And, in December, we were granted a patent for CRISPR technology by the Singapore Intellectual Property Office. Patents have also been filed for the insertion CRISPR method in the United States, Brazil, China, India, Israel, Japan, and South Korea.

We recognize the potential benefits of conducting properly defined research with genome editing because of the breakthrough therapeutic potential. Therefore, we support research with genome editing under careful consideration of ethical and legal standards. The Group has established the Merck Bioethics Advisory Panel to provide guidance for research in which its businesses are involved, including research on or using genome editing.

Beyond basic gene-editing research, Merck supports development of gene- and cell-based therapeutics and manufacturing viral vectors.

In October, our Carlsbad, California-based manufacturing facility for the production of BioReliance® viral and gene therapy products completed both a U.S. Food and Drug Administration pre-license inspection and a European Medicines Agency marketing authorization application inspection. As a leading contract manufacturing organization for the production of next-generation gene therapies, the achievement underscores our commitment to bring our customers closer to commercialization of novel therapies. In December, we signed a commercial supply agreement to manufacture viral vectors for bluebird bio for use in potentially transformative gene therapies.

Partner with the global scientific community

In collaboration with Stelis Biopharma, we opened a new joint process scale-up lab in Bengaluru, India, to provide end-to-end solutions – from process development to scale-up manufacturing – for pre-clinical, clinical and commercial supply. Both companies bring technological expertise and an extensive bioprocess development and manufacturing portfolio that will help customers accelerate development of biopharmaceuticals for clinical trials and manufacturing with greater reliability and cost effectiveness.

In 2017, we also formed a strategic alliance with Baylor College of Medicine, Houston, Texas, and its vaccine product development partnership, Texas Children’s Hospital Center for Vaccine Development, to advance vaccine research and development for neglected and emerging infections. The collaboration focuses on bringing vaccines through development to efficiently deliver them to societies in need. Together, we are working to optimize the vaccine manufacturing process to increase vaccine stability and yield.

Progress continued within the scope of our participation in ­Horizon 2020, the EU Framework Program for Research and Innovation, to improve biopharmaceutical downstream processing. The ­nextBioPharmDSP, a consortium of seven organizations, is developing a more efficient, cost-effective and environmentally friendly downstream process to manufacture monoclonal antibodies and biosimilars. The biopharmaceutical industry faces pressures to reduce manufacturing costs and deliver greater efficiencies while being environmentally responsible. Through the Horizon 2020 program, ­consortium members are already delivering important advances for downstream processing.

In addition, we extended our strategic alliance with Samsung BioLogics after a memorandum of understanding (MoU) was signed in November. The alliance aims to accelerate process development and clinical material production at small biotech start-ups focusing on novel drug development for which Samsung BioLogics acts as a contract manufacturer. The new MoU is an extension of an MoU signed in 2014 that encompasses a long-term supply agreement under which we provide raw materials for biopharmaceutical manufacturing.

Meet customer needs

We expanded our BioReliance® End-to-End Biodevelopment Centers in North America, China and Europe to meet increasing customer demand for their turnkey portfolio of bioprocessing products, manufacturing capabilities and industry-leading technological expertise. The expansion includes the opening of two new process development centers, located in the United States and China, following the commercial success of our biodevelopment center in Martillac, France. The two new facilities provide a full range of process development capabilities and services, including cell line development services and both upstream and downstream process development, as well as non-GMP clinical production. The United States facility will be open to customers in 2018.

Angiex Inc., Cambridge, Massachusetts, will be the first project undertaken by the new U.S. BioReliance® End-to-End Biodevelopment Center. We formed a collaboration with Angiex Inc. to help accelerate clinical readiness of a new cancer therapy. Our goal is to support the biotechnology start-up’s ability to speed its lead oncology antibody drug candidate to clinical use by providing access to end-to-end process development tools, education programs and training.

Performance Materials

We are the undisputed market and technology leader in liquid crystals (LCs) and photoresist materials, which are primarily used in televisions and mobile communication applications. We are also one of the leading suppliers of OLED materials as well as decorative and functional effect pigments. Materials for integrated circuits round off the portfolio.

Display Materials

In 2017, we continued to work with our customers, the display manufacturers, to further develop high-performance liquid crystal technologies. The systematic introduction of new liquid crystal materials and the development of higher-performance liquid crystal mixtures led to numerous newly qualified and commercialized products in all applications, including large-screen TVs, public information displays, as well as mobile devices and automotive applications. We developed and commercialized a number of new photoresist formulations for producing the thin-film transistor backplanes that are used for both LC and OLED display manufacture. Our high-resolution photoresist technology is especially important for the more complex and demanding electronic patterning required in increasingly high-­resolution displays. Our innovative liquid crystal technology UB-FFS (ultra-brightness fringe-field switching) also saw growth in the mobile device display sector. UB-FFS is highly attractive for mobile applications. It provides the highest light efficiency as pixel sizes become increasingly smaller due to the demand for higher-­resolution smartphones and tablets. We also further developed this energy-­saving technology for larger display applications, including TVs and public information displays, where high light efficiency is particularly valuable in the highest-resolution displays, for example 8K.

Our new liquid crystal technology SA-VA (self-aligned vertical alignment) is eco-friendly and resource-conserving; it requires less energy and creates fewer waste products than conventional modes during display manufacture. We have been developing the materials and process within the scope of close technical partnerships. The technology also provides a more efficient display manufacturing process and could offer improved design features for display manufacturers. SA-VA has the potential to be used in all types of display applications, including mobile IT applications, but most importantly large-screen TVs. We expect the first products in mid-sized applications, but extending quickly to large-screen and high-end TV applications. We also made further progress with the development of new liquid crystal technologies to enable free-form LC displays. Here we aimed to enable the use of low-cost plastic substrates rather than the thin glass commonly used in LC displays to date. We are working closely with display makers in Asia to optimize the materials and process for our innovative polymer wall LC technology. This could provide robust and bendable plastic displays without the defect patterns that typically occur when an LC display is pressed or bent.

Beyond classic displays, we have more strongly positioned liquid crystals under the licrivision™ brand as an innovative material for windows in architectural and automotive applications. We are currently focusing on three variants: sun protection, glare protection, and privacy control where the windows switch to opaque. At the end of November, we opened our first production facility for switchable liquid crystal window modules in Veldhoven, the Netherlands. In addition, we presented our liquid crystal window technology for automotive sunroofs at the International Motor Show (IAA) in Frankfurt, Germany. We continued to advance the development of smart antennas, which can also be used in the automotive industry. Thanks to a thin functional layer of liquid crystals, the antenna can be electronically pointed to a satellite without the need to move the device mechanically. Together with Hella, a light and electronics expert, and other partners, we have developed a smart automotive headlight system based on an LC display. With a total of 30,000 pixels, the smart adaptive lighting can be set in a continuously variable manner and in real time to various driving situations. Hella is to bring the developed technology to series production.

To accelerate the development of free-form displays, Merck is cooperating with FlexEnable of the United Kingdom. This company is working in the field of conformable, large area, full color and video rate organic liquid crystal displays (LCDs) on polymer substrates. With a bend radius that can go below 30 millimeters, organic LCDs can meet new market requirements, for example in automotive applications, where thin, conformable and shapeable displays are needed. It will soon be possible to curve organic LCDs around complex surfaces and shapes when our innovative polymer wall LC technology is used. In order to develop new digital optical applications with liquid crystals, in May we entered into a five-year collaboration with the University of Leeds. This is one of the United Kingdom’s most renowned research institutions for liquid crystal applications and has recently built a reputation in particular for non-display applications such as switchable contact lenses.

Integrated Circuit Materials

Gas-phase deposition materials are a growth area within our semiconductor chemicals business. To meet the constantly growing challenges in chip production, increasingly more chemical elements are being used in advanced semiconductor fabrication processes; this is often enabled by atomic layer deposition technology. For the deposition of layers that often are only a few atoms thick, novel materials such as precursor chemicals are required, which can be applied at lower temperatures and/or selectively to only certain parts of a wafer. Such surface-selective processes automatically carry the target materials to the right position. This provides advantages for our customers as they can eliminate costly photolithography steps and at the same time automatically avoid overlay registration errors.

In order to better support our customers in Asia, in 2017 we opened a new research center in Taiwan, where we are conducting research in atomic layer deposition and gas phase deposition for front-end applications, as well as very thermally conductive, economically sustainable, high-performance sinter pastes for chip packaging applications. At our sites in Shizuoka, Japan, and Darmstadt, Germany, we are developing innovative dielectrics that can be used at lower application temperatures and are thus suitable for novel chip types. Our thick-film photoresist technology found new applications for the production of 3D NAND storage chips that enable higher storage capacity than conventional planar technology with the same surface area. Besides other applications, these new-generation storage chips are increasingly being used in solid-state drives (SSDs), successors of classic hard drives.

Pigments & Functional Materials

The exceptional color saturation and brilliance of Meoxal® effect ­pigments based on aluminum flakes is finding increasing use in automotive and plastic coatings. In addition, Xirallic® NXT Cougar Red, a pure, bluish red pigment with an extraordinary sparkle, was introduced for automotive coatings as the latest addition to the Xirallic® NXT series. Further pigment developments support the market trend towards achromatic coatings. In the plastics field, the extremely pure, silver-white Iriodin® 6163 WAY was added to the WAY series of weather-proof pigments for outdoor applications. For the cosmetics sector, both new sparkle effects and matte effect pigments were successfully launched as part of the Smart Effects initiative. In the fillers area, new formulations, such as an alcohol-free variant of the anti-aging active ingredient RonaCare® CP5, were added to the portfolio. Based on two-dimensional and three-dimensional skin models, we developed a technology to more efficiently assess new cosmetic actives. Particularly in efficacy testing of natural substances, we expect to already have marketable products in 2018.

In technical applications, we intensified our activities in additives for 3D laser direct structuring with a focus on 3D printing of plastics. Together with our partners, we also developed laboratory prototypes which we presented at the LASER World of Photonics 2017 in Munich, Germany and the International Motor Show (IAA) 2017 in Frankfurt, Germany. Laser additives enable computer-controlled fabrication of three-dimensional components with integrated electronic parts and laser-assisted circuit board bonding. We made good progress in high-voltage technology. Within the scope of the iShield research project, which is funded by the German Federal Ministry of Education and Research (BMBF), we are collaborating with academic and industrial partners to develop and qualify a novel material to shield generators and engines.

We further developed our range of fluorosurfactants, which strongly differentiates itself from competing products owing to its favorable ecotoxicological profile. In early 2017, Tivida® FL 3000 was added to our portfolio of nonionic surfactants. Even in very low ­concentrations, it significantly improves the flow and wetting behavior of coating systems.

Advanced Technologies

In 2017, we made significant progress with our material and technology developments for flexible displays. At major exhibitions, for example, together with strategic partners we presented prototypes demonstrating the market readiness of our materials and the related technologies. During SID Display Week in May, we additionally reported on the development of printing inks. In 2017, our printed red, green and blue layers demonstrated first-ever efficiency values comparable to those of vacuum evaporation technology. This will allow flexible or rollable screens to be manufactured in the future, such as for automotive applications or large-area displays. Printed displays achieve greater brightness and better energy efficiency. In reflective displays, our partner Clearink Displays won the prestigious Best in Show Award at SID 2017. To respond to the growing demand from the industry for our innovative material solutions, we started investing in our R&D site in Chilworth, United Kingdom, to increase our lab capacity.

In electronic packaging, we strengthened our research activities by participating in a consortium led by the Fraunhofer Institute for Reliability and Microintegration in Berlin. We are further advancing material and technology development in hybrid electronics. At the LOPEC 2017 exhibition in Munich in March, we presented the prototype of a flexible display consisting of a backplane with organic thin-film transistors as well as liquid crystals from Merck. We will continue to focus strongly on the development of these technologies.

In 2017, a number of lighthouse projects demonstrated the diversity of use of printable organic solar cells (OPV). For example, OPV modules integrated into a glass façade in São Paulo, Brazil, provide shade, innovative design and energy efficiency. We presented a novel façade concept combining OLED and OPV module design with functionality at the Biennale of Architecture and Urbanism in Seoul, Korea. The growing interest of architects in this innovative construction material was reflected in the Innovation Award for Architecture and Construction, which went to OPV at BAU 2017, the world’s leading exhibition for architecture, materials and systems. The upcoming technology trend in the LED lighting market – human centric lighting (HCL) – places the focus of light planning on people’s health and well-­being. This trend is impressively confirmed by the 2017 Nobel Prize in Physiology or Medicine, which was awarded for discoveries of molecular mechanisms controlling the circadian rhythm, which is significantly affected by light. Our product developments specifically address this up-and-coming market for HCL LED lighting. Micro-LED displays are also currently attracting great attention. From our broad portfolio for the LED industry, we have already supplied our customers with first materials for this new application.

Strategic realignment

In 2018, we want to focus even more strongly on the needs of our customers and markets. Therefore, in December 2017, we announced that we will combine our expertise in three newly created business units aligned with our target markets: Display Solutions, Semiconductor Solutions, and Surface Solutions. In the future, all activities pertaining to research, business development and external partnerships will be united in a central research and innovation unit.