Research and Development at Merck 

Nearly 4,000 employees around the world work for Merck researching innovations to serve long-term health and technology trends in established and emerging markets as well as in developing countries.

Overall, the Merck Group invested around € 394 million in research and development in the second quarter of 2014. In addition, we are focusing on a newly defined mix of in-house research and cost-saving collaborations, which enables 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 divisional structure of the Merck Group. Within the Executive Board, Stefan Oschmann is responsible for the Merck Serono and Consumer Health divisions, and Bernd Reckmann is responsible for the Performance Materials and Merck Millipore divisions.

Apart from the details reported below with regard to the second quarter of 2014, more information on the company’s research and development activities can be found in the Merck Annual Report for 2013.

Merck Serono

Immunology

The FORWARD study, a Phase II trial of sprifermin in patients with primary osteoarthritis of the knee, being conducted in collaboration with Merck’s strategic alliance partner Nordic Bioscience Clinical Development completed enrollment following the inclusion of 549 patients.

Neurology

Merck and Ono Pharmaceutical reached a mutual agreement to terminate the license agreement on ceralifimod (ONO-4641) since the project does not meet Merck’s threshold for continued investment. The drug candidate is currently in Phase II clinical development for relapsing- remitting multiple sclerosis (MS).

Opexa Therapeutics, the biotechnology company developing Tcelna®, a novel T-cell immunotherapy for MS, announced it reached targeted enrollment in its Phase IIb clinical trial in secondary progressive MS (Abili-T). Merck Serono has the option to in-license Tcelna.

Oncology

In the second quarter, several developments pertaining to oncology projects occurred. At the 2014 American Society of Clinical Oncology (ASCO) Annual Meeting new biomarker findings from a retrospective analysis of the completed Phase III CRYSTAL study were presented. This study compared Erbitux® plus FOLFIRI with FOLFIRI alone. The analysis involved a subgroup of patients with KRAS wild-type (exon 2) metastatic colorectal cancer (mCRC). A significant clinical improvement was observed in patients with RAS wild-type tumors (defined as having no mutations in exons 2, 3 or 4 of KRAS and/or in exons 2, 3 or 4 of NRAS) when Erbitux® was added to FOLFIRI compared with patients receiving FOLFIRI alone in first line mCRC. This included a 27.7% increase in response rate, a 3.0-month increase in median progression-free survival, and an 8.2-month increase in median overall survival. This analysis of the CRYSTAL study, as well as similar analyses from the OPUS study which compared Erbitux® plus FOLFOX vs. FOLFOX alone, confirm that RAS biomarker testing is essential for patient-centric care and a truly personalized approach to mCRC. These findings are in line with the updated EU label.

The Chinese Food and Drug Administration (SFDA) issued a negative opinion concerning the registration of Erbitux® in squamous cell carcinoma of the head and neck (SCCHN), since it considered that the bridging study performed in Chinese patients was inadequate to warrant approval in that country. Merck Serono is therefore considering the possibility of performing a randomized, controlled study in China in SCCHN. Erbitux® is already registered in over 90 countries in this indication.

A Phase II trial of the investigational hypoxia-activated prodrug, TH-302, in combination with pemetrexed as a potential second-line treatment for patients with non-squamous non-small cell lung cancer (NSCLC) was initiated during the quarter. The primary endpoint in this 440-patient trial is overall survival; secondary endpoints include safety and assessment of anti-tumor activity as determined by progression-free survival and objective response rate.

For abituzumab, an investigational anti-integrin monoclonal antibody designed to target certain integrins expressed on tumor and endothelial cells, two Phase II trials were recently completed. Results of a study in patients with metastatic castrate-resistant prostate cancer (PERSEUS) were presented at 2014 ASCO Meeting. No significant improvement in progression free survival was observed and development therefore will not continue in this indication. The results of the POSEIDON study, a combination of abituzumab with Erbitux® and irinotecan in KRAS wild-type mCRC, were presented at the ESMO 16th World Congress on Gastrointestinal Cancer. The primary endpoint of increased progression free survival was not met. The addition of abituzumab to Erbitux® and irinotecan resulted in a trend toward improved overall survival, and high integrin αvβ6 expression was identified as a potential predictive marker of increased response rate and prolonged overall survival in the abituzumab treatment arms. Further biomarker analyses are warranted to confirm and further validate the current findings and to inform about future clinical development of abituzumab in this disease.

The development of Sym004 in SCCHN (Phase II) was discontinued due to a strategic focus on the currently ongoing development of Sym004 in later lines of mCRC (Phase II) and metastatic NSCLC (Phase I).

BGB-290 (an inhibitor of poly [ADP-ribose] polymerase, or PARP), being developed in collaboration with BeiGene, entered Phase I testing in patients with solid tumors.

The further development of pimasertib in pancreatic cancer was discontinued as the Phase II study did not reach the primary endpoint of progression-free survival. The Phase I study of pimasertib and the PI3K/mTOR inhibitor from Sanofi (SAR245409) was completed and this combination is being investigated in an already ongoing double-blind, randomized, placebo-controlled, two-arm Phase II trial in low-grade serous ovarian cancer.

Merck Serono and Mersana Therapeutics, Inc. entered into an agreement to collaboratively develop next-generation antibody-drug conjugates (ADCs). ADCs are composed of an antibody linked to a cytotoxic drug, whereby the antibody part specifically targets and delivers the cytotoxic drug to cancer cells which could lead to higher drug levels at the tumor site. The two companies intend to leverage Mersana’s Fleximer® technology to generate ADCs for multiple targets. Both parties have agreed to test a variety of ADCs by utilizing Mersana’s platform technologies and several cytotoxic agents as conjugates.

Immuno-Oncology

For MSB0010718C, an investigational anti-PD-L1 antibody currently in development, initial data from the Phase I dose escalation study in solid tumors were presented at ASCO 2014. A dose for further efficacy evaluation has been identified and patients are now being enrolled into expansion cohorts in seven cancer types. MSB 0010718C is also being tested in a recently initiated Phase II study in patients with metastatic Merkel cell carcinoma. This is an aggressive form of skin cancer which is rare but increasing in frequency, and currently has limited treatment options. The study is a multicenter, single arm, open trial in patients who have previously been treated with one line of chemotherapy.

Merck and MorphoSys entered into a strategic immuno-oncology collaboration to discover and develop therapeutic antibodies against immune checkpoints. Under the terms of the agreement, the two companies will join forces to develop therapies that modulate the immune system’s natural ability to fight tumors. MorphoSys, a leader in fully human antibody technologies, will apply its proprietary Ylanthia® antibody phage library and technology platform to identify antibodies against the targets of interest. Merck Serono with its strong portfolio and capabilities in the field of immuno-oncology and clinical development will be fully responsible for execution of development from Phase I onwards.

Other highlights

On July 1, Merck announced its strong support for the Grant for Fertility Innovation (GFI) with grants totaling up to €2 million for the years 2014/2015. The announcement was made during the 30th annual meeting of the European Society of Human Reproduction and Embryology (ESHRE). Launched in 2009, the GFI is dedicated to transforming innovative translational fertility research projects into concrete health solutions to improve the outcomes of assisted reproductive technologies (ART). In the last five years, 640 applications to GFI were received from over 50 countries around the world. At this year’s award ceremony nine projects from eight countries were awarded a grant.

In May on the occasion of the 67th World Health Assembly, Merck proposed the creation of a global alliance to help the World Health Organization (WHO) achieve its goal of eliminating the parasitic worm disease schistosomiasis worldwide. Merck will be a founding member of this new global alliance aiming to further support WHO’s goal of eliminating schistosomiasis. Merck calls for different NTD (neglected tropical diseases) constituencies to join on focusing efforts to address remaining gaps and challenges to meet the elimination target. Merck has committed to raise its donation up to 250 million tablets by 2016 and is fostering a holistic, integrated approach to supporting WHO in reaching the ultimate elimination target.

Consumer Health

Consumer Health research and development activities focus on constantly improving tried and proven formulations consistent with the needs of consumers. At the same time, the division is further developing its established brand-name products by making them simpler to use, for example through new forms of applications, and by offering accompanying services.

Performance Materials

Merck is the undisputed market and technology leader in liquid crystals, which are primarily used in televisions and mobile communication applications. We are also one of the leading suppliers of functional and decorative effect pigments. Our high-tech materials and solutions are used by customers in the consumer electronics, lighting, coatings, printing technology, plastics applications, and cosmetics industries. Merck is also focusing on growth dynamics in emerging markets within Performance Materials. As a new part of Performance Materials, AZ brings additional fields of business to the Merck portfolio. AZ serves two main markets, the sector of IC Materials for integrated circuit manufacture, and materials for display applications (Optronics).

Liquid crystals

In the area of LC displays for mobile devices, Merck has developed a new LC switching mode that has the potential to increase display light transmittance by 20%. First products based on this new switching mode will be launched in 2014. The new technology offers many advantages. Firstly, it reduces energy consumption and increases the battery life of the mobile devices. Secondly, it improves mobile display quality and supports the trend towards higher resolutions.

The Merck LC2021 strategic initiative combines the company’s future LC activities, with a special focus on applications beyond displays. For example, liquid crystals can regulate the light and heat transmittance of windows in building facades. In order to bolster this strategic direction, as announced by Merck on June 30, 2014, Merck acquired the remaining 30% interest in Peer+, a Dutch specialist for smart windows technology as of July 1, 2014. This acquisition enables Merck to accelerate the development of LC materials for these applications and enter into collaborations with partners in the glass and facade technology sector.

OLEDs

Organic light-emitting diodes (OLEDs) are used in innovative lighting applications and display technologies. They provide brilliant colors and sharp images from any viewing angle; they have a long lifespan and are highly energy efficient. In addition, OLEDs enable round or flexible displays, making them perfect for use in the latest technical applications. One such example is the smartwatch, a wristwatch that provides additional computer functionality along with Internet access.

The Merck product line for these types of applications is called livilux®. Merck has developed a strong portfolio of worldwide patents, based on more than ten years of experience. Development partnerships with customers are a way of testing new technologies and making them market-ready. For instance, with printer manufacturer Seiko Epson the Performance Materials division has co-developed a technology that can be used to print OLED displays. While Merck contributed its expertise in OLED material and ink development to the collaboration, Seiko Epson contributed its expertise in print heads featuring micro piezo inkjet technology as well as process expertise. The jointly developed technology offers the advantage of lower costs and higher material efficiency. In contrast to evaporated OLED displays, the materials are applied at room temperature and under normal pressure in the case of printed OLED displays. In addition, this technique only deposits material in the areas where diodes are actually located.

High-quality pigments and functional materials

Besides high-quality decorative effect pigments, Merck also offers functional materials used, for example, in laser marking of plastics, in conductive coatings, and in heat reflection for greenhouses. The Meoxal® brand is the latest development in effect pigments. These pigments captivate with their excellent color saturation and exceptional performance. This is the result of their innovative layer technology and the use of aluminum flakes as the substrate. They are highly suitable for a multitude of high-performance applications, especially for automotive and plastic coatings. The third pigment in the new brand family – Meoxal® Atacama Red – was launched in the second quarter of 2014. With Xirallic® NXT, Merck is launching a new patented product generation of the well-known high-tech effect pigments. These offer customers an exceptional ”living-sparkle effect”, high styling potential and consistent quality. The first product of the new generation – Xirallic® NXT Panthera Silver – is a dark-gray, metallic effect pigment, which Merck has been offering since April.

AZ Electronic Materials

In its IC Materials business, which supplies products for integrated circuit manufacture, AZ has developed a range of products for Extreme UV Lithography (EUV) applications which has already been qualified by several customers for their processes. The increased complexity of patterning processes has opened up opportunities for novel materials. AZ’s “shrink” technology makes it possible to reduce lithographically generated structures after patterning, thus circumventing resolution limitations of existing exposure equipment in a cost-effective manner. New products are on the verge of production implementation. AZ is a leader in Directed Self Assembly (DSA), a revolutionary technology which is being pursued intensively by all advanced semiconductor manufacturers. In DSA, the information for the smallest structures is already contained in the chemical make-up of the coating material. Additionally, AZ is intensively engaged in developing thick perhydropolysilazane (PHPS) products for 3D chip technology as well as novel insulator materials.

The continuous development of flat panel display technology towards larger formats and higher operating frequencies requires the use of transistors with feature sizes that are at the limit of the resolution capability of the exposure tools. In the Optronics business, AZ has successfully transferred from its IC sector so-called tandem resin technology with a specific molecular weight distribution, thus achieving a photoresist resolution near the theoretical resolution limit. In silicon technology, new siloxane materials are in an advanced stage of qualification as planarization materials for high-resolution displays and as a thin film barrier for OLED lighting.

Merck Millipore

In the second quarter of 2014, Merck Millipore launched a € 12 million investment in its Molsheim, France facility. This investment will expand Merck Millipore’s Ready-To-Use (RTU) media manufacturing capabilities, better provide security of supplies for customers in the region, and sustain the heipha Hycon product lines. The increased manufacturing capacity will serve global market demand, and will ensure sufficient capacity to support the market growth.

The Bioscience business area launched Simplicon™ RNA Reprogramming Technology, which uses synthetic self-replicating RNA to create large numbers of human induced pluripotent stem cells (iPSCs) using a single transfection step. This efficient reprogramming of somatic cells offers a more defined and safer system for iPSC generation.

The Process Solutions business area expanded Provantage® Upstream Bioproduction services to the North American market. The expansion provides North American customers with media and feed screening, small-scale material production, and optimization of conditions for scale-up and technology transfer. Process Solutions also announced a new Formulation Lab in India, its first outside of Europe. The Lab is strategically located at Nerul, Navi Mumbai, with easy accessibility from the major pharmaceutical manufacturing centers at Ahmedabad, Goa and Hyderabad. The facilities at the lab are built to provide services and application assistance to the pharmaceutical industry for classical pharmaceutical clients working on solid dose formulations.

In the second quarter of 2014 Merck Millipore also celebrated the 40^th anniversary of the Steritest™ system, the first closed filtration device for sterility testing. Since introducing the Steritest™ system in 1974, Merck Millipore has improved standards in sterility testing, reducing the risk of false positive and false negative results, increasing reliability and streamlining workflows for microbiologists around the world. As part of the celebration of 40 years of sterility testing, Merck Millipore will be launching three new pumps in 2014.