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Research and Development

Science is at the heart of everything we do. 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 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. 

In 2019, approximately 7,800 employees worked for our company researching innovations to serve long-term health and technology trends in both established and growth markets (2018: approximately 7,200).

Expenditure on research and development (R&D) incurred by our company amounted to € 2.3 billion in the year under review (2018: € 2.2 billion). In our R&D activities, we focus on both in-house research and external collaborations that enable us to increase the productivity of our research while simultaneously reducing financial outlay. The organizational setup of our R&D activities reflects the structure of our company with three business sectors. In Healthcare, we aspire with our research pipeline to make a positive difference for patients – always with the purpose to help create, improve, and prolong life. Our main research areas include oncology, immuno-oncology, and immunology including multiple sclerosis. In our Life Science business sector, our research activities focus in particular on technologies for laboratory and life science applications as well as the promotion of new developments. Improved test kits, chromatography methods, substrates for separating active substances, and innovations continue to be in focus in the fields of microbiology and hygiene monitoring. Research activities in our Performance Materials business sector include the development of new and improved basic materials and mixtures for LC displays, for innovative OLED applications, and for materials for the production of integrated circuits. To strengthen the Pigments business, new effect pigments for the automotive, cosmetics, and printing ink sectors are being developed.

9.67 KBEXCEL
RESEARCH AND DEVELOPMENT COSTS1
 
      Change
€ million 2019 2018 € million %
Healthcare 1,666 1,687 -21 -1.3%
Life Science 276 251 25 10.1%
Performance Materials 267 242 25 10.5%
Corporate and Other2 59 47 12 24.7%
Total 2,268 2,227 41 1.8%
1 Previous year’s figures have been adjusted, see Note (45) “Effects from new accounting standards and other presentation changes” in the Notes to the Consolidated Financial Statements.
2 R&D spending that cannot be allocated to individual business sectors.


The ratio of research spending to sales was 14.0% (2018: 15.0%). The decline is attributable to positive sales development.

Healthcare*

Biopharma

Oncology and immuno-oncology 

Oncology and immuno-oncology are core focus areas in our R&D portfolio. With an emphasis on biology-driven research, we aim to deliver transformative treatments. Translational research is embedded into the whole R&D process, with several projects addressing unmet needs in hard-to-treat cancers through innovative treatment approaches and novel combinations. In 2019, we achieved a number of significant milestones across our oncology and immuno-oncology pipeline.

We continue to develop much-needed new treatment options for patients with hard-to-treat cancers and have made key progress in this area with avelumab, an anti-PD-L1 antibody we are co-developing and co-commercializing with Pfizer Inc. To date, avelumab has received approval in more than 50 countries across the world under the brand name Bavencio®. In May, we and Pfizer announced that the U.S. Food and Drug Administration (FDA) approved Bavencio® in combination with axitinib for the first-line treatment of patients with advanced renal cell carcinoma (RCC). As well, in October, we and Pfizer reported that the European Commission (EC) authorized Bavencio® in combination with axitinib for the first-line treatment of adult patients with advanced RCC. In December, the combination was approved in Japan for the treatment of unresectable or metastatic RCC.

The United States, EC and Japanese approvals in RCC were based on interim results from the pivotal Phase III JAVELIN Renal 101 trial, which were published in the New England Journal of Medicine in February. The combination of Bavencio® and axitinib significantly extended median progression-free survival (PFS) by more than five months compared with sunitinib as a first-line treatment for patients with advanced RCC.

Through our strategic alliance with Pfizer, we continue to explore the therapeutic potential of avelumab. Our clinical development program JAVELIN currently involves at least 30 clinical programs and more than 10,000 patients evaluated across more than 15 different tumor types. In addition to RCC, these tumor types include head and neck cancer, Merkel cell carcinoma (MCC), non-small cell lung cancer (NSCLC), and urothelial cancer (UC).

In March, we and Pfizer reported the discontinuation of the ongoing Phase III JAVELIN Ovarian PARP 100 study evaluating the efficacy and safety of avelumab in combination with chemotherapy followed by maintenance therapy of avelumab in combination with talazoparib, a poly (ADP-ribose) polymerase (PARP) inhibitor, versus an active comparator in treatment-naïve patients with locally advanced or metastatic ovarian cancer. The decision was based on several emerging factors since the trial’s initiation, including the previously announced interim results from JAVELIN Ovarian 100 as well as the rapidly changing treatment landscape. The discontinuation of the trial was not based on safety results.

In November, we and Pfizer announced topline results of the Phase III JAVELIN Gastric 100 study evaluating avelumab as first-line maintenance therapy following induction chemotherapy in patients with unresectable, locally advanced or metastatic HER2-negative gastric or gastroesophageal junction cancer versus continuation of chemotherapy or best supportive care. While the study showed clinical activity for avelumab in this setting, it did not meet the primary endpoints of improved overall survival (OS) compared with the standard of care in the overall intent-to-treat population or the PD-L1–positive population.

At the 2019 American Society of Clinical Oncology (ASCO) Annual Meeting, May 31 – June 4 in Chicago, Illinois, United States, we presented new data:

  • For avelumab, we shared data from five studies across tumor types including MCC, RCC, hepatocellular carcinoma and UC. These included an oral presentation of biomarker analyses of baseline tumor samples from the Phase III JAVELIN Renal 101 trial in previously untreated patients with advanced RCC.
  • Erbitux® (cetuximab) data from a retrospective analysis of OS by subsequent therapy in patients with RAS wild-type metastatic colorectal cancer from the Phase III EPIC study were presented. The analysis evaluated the effect of post-study therapies (with cetuximab, without cetuximab, or no subsequent therapy) on OS following treatment with cetuximab plus chemotherapy or chemotherapy alone.
  • For the investigational targeted therapy tepotinib, updated results from the potentially registrational Phase II VISION study showed promising activity in advanced NSCLC patients harboring MET exon 14 skipping mutations detected by liquid biopsy or tissue biopsy.
  • Abstracts also showcased the scientific innovation and diversity of our pipeline, with results from a number of high-priority clinical development programs, including tepotinib, bintrafusp alfa and our comprehensive DNA Damage Response (DDR) portfolio.

In October, we and Pfizer shared three-year results from Part A of the pivotal Phase II JAVELIN Merkel 200 trial regarding long-term OS and durable responses in patients with previously treated metastatic MCC (mMCC) who received avelumab. In this exploratory analysis, the OS rate at three years was 32%; the median duration of response (DOR) was 40.5 months; and the objective response rate (ORR) was 33.0%, which was unchanged from the one-year analysis. These data were presented at the First International Symposium on Merkel Cell Carcinoma in Tampa, Florida, United States on October 21-22.

In September, we shared important milestones for two combination studies of tepotinib in locally advanced or metastatic NSCLC with epidermal growth factor receptor (EGFR) mutation and select MET dysregulations. These include PFS and OS data from the Phase Ib/II INSIGHT study of tepotinib plus the EGFR inhibitor gefitinib, along with an update stating that the Phase II INSIGHT 2 study of tepotinib plus the tyrosine kinase inhibitor (TKI) osimertinib is now open for enrollment. Tepotinib, discovered in-house at our company, is an investigational oral MET inhibitor that underscores our strategic focus on delivering innovative precision medicines to patients with cancer.

In September, we announced that the FDA granted Breakthrough Therapy Designation (BTD) for tepotinib in patients with metastatic NSCLC harboring MET exon 14 skipping alterations who progressed following platinum-based cancer therapy. This BTD is based on data from the ongoing VISION study (NCT02864992) showing preliminary clinical evidence that tepotinib may offer an improvement over available therapy in patients with metastatic NSCLC harboring MET exon 14 skipping alterations detected by liquid biopsy or tissue biopsy across different lines of treatment.

Also in September, the National Medical Products Administration (NMPA) of China approved Erbitux® for the first-line treatment for patients with RAS wild-type (wt) metastatic colorectal cancer (mCRC) in combination with Folfox or Folfiri, or in combination with irinotecan in patients who are refractory to irinotecan-based chemotherapy. The pivotal Phase III evidence from the TAILOR study, on which the approval was based, shows significant benefit in overall response rate, PFS and OS for patients treated with cetuximab in combination with Folfox, compared to Folfox alone, in the first-line setting for this challenging type of cancer.

At the 2019 European Society for Medical Oncology (ESMO) Congress, September 27 - October 1, in Barcelona, Spain, we presented new data representing several key therapeutic agents from our diverse oncology pipeline, including avelumab data in advanced RCC, cetuximab data in RAS wt mCRC, and our investigational oral MET inhibitor tepotinib in advanced solid tumors. In addition, a number of investigator-sponsored studies (ISS) and collaborative research studies (CRS) exploring our pipeline were also presented.

In early October, the first patient was enrolled in the bintrafusp alfa INTR@PID BTC 055 study (NCT04066491), a Phase II/III, multicenter, randomized, placebo-controlled study of gemcitabine plus cisplatin with or without bintrafusp alfa in patients with 1L biliary tract cancer (BTC). Bintrafusp alfa is our investigational bifunctional fusion protein immunotherapy and currently in clinical development. BTC is a collective term for a group of rare and aggressive gastrointestinal cancers with limited treatment options and poor patient outcomes.

In November, we reported that the Japanese Ministry of Health, Labour and Welfare (MHLW) granted orphan drug designation (ODD) for tepotinib for patients with NSCLC harboring MET gene alterations. The MHLW ODD program is designed to promote research and development of orphan drugs for diseases that affect fewer than 50,000 patients in Japan, and for which significant unmet medical need exists. An investigational drug can qualify for ODD if there is no approved alternative treatment option or if there is an expectation of high efficacy or safety compared to existing treatment options. Drugs receiving ODD qualify for several benefits intended to support development, such as guidance and subsidies for research and development activities from the MHLW, preferential tax treatment, priority consultation for clinical development, and priority review of applications.

In February, we announced a global strategic alliance with GlaxoSmithKline (GSK) to jointly develop and commercialize bintrafusp alfa, including potential registrational studies, for multiple difficult-to-treat cancers. During the year, we achieved our alliance objective of eight trials ongoing or with protocol under development. Our advanced clinical program includes three studies focused on NSCLC, two studies focused on BTC and a study focused on cervical cancer. Our lung cancer studies include a randomized, open-label controlled Phase II study of bintrafusp alfa compared with pembrolizumab as a first-line (1L) treatment in patients with PD-L1 expressing advanced NSCLC (INTR@PID LUNG 037); a Phase II study of bintrafusp alfa with concurrent chemoradiation therapy (cCRT) in unresectable Stage III NSCLC (INTR@PID LUNG 005), and a Phase Ib/II, open-label study of bintrafusp alfa in combination with chemotherapy in participants with Stage IV NSCLC regardless of PD-(L)1 expression status (INTR@PID LUNG 024). Our BTC studies include a phase II, open-label study to evaluate bintrafusp alfa monotherapy in participants with locally advanced or metastatic BTC who failed, or were intolerant to, first line platinum-based chemotherapy (INTR@PID BTC 047), and a phase II/III, multicenter, randomized, placebo-controlled study of gemcitabine plus cisplatin with or without bintrafusp alfa in patients with 1L BTC (INTR@PID BTC 055). In addition to use as a single agent, bintrafusp alfa is also being considered for use in combination with other assets from the pipelines of both companies.

In accordance with the agreement with GSK, we received an upfront payment of € 300 million and is eligible for potential development milestone payments of up to € 500 million triggered by data from the lung cancer program. Our company will also be eligible for further payments of up to € 2.9 billion upon successful achievement of future approval and commercial milestones. The total potential deal value is up to € 3.7 billion. Both companies will jointly conduct development and commercialization. In the event of regulatory approval, net sales will be realized by our company in the United States and by GSK in all other countries, whereas net profits from sales and defined expense components will be shared equally by the alliance partners.

In September, we signed a collaboration and license agreement with Y-Trap Inc. of Baltimore, Maryland, United States for the exclusive development of multiple specific antibody-ligand traps for cancer immunotherapy. The collaboration leverages Y-Trap’s proprietary platform of multifunctional antibody-ligand traps for immuno-oncology. The Y-Trap platform exploits combinatorial protein engineering to counteract key determinants of immune dysfunction in the tumor microenvironment. Y-Trap and we will collaborate to explore the pharmacology of Y-Trap multifunctional proteins and we will be responsible for all development, manufacturing and commercialization activities. Under the agreement, we will provide Y-Trap with an upfront payment in addition to milestone payments and royalties based on the achievement of specific pre-clinical, clinical development, regulatory, and commercial milestones.

Neurology & Immunology 

Multiple sclerosis (MS) is one of the world’s most common neurological disorders. Despite the emergence of a number of therapies in the last two decades, there are still significant unmet needs for MS patients. At the end of March 2019, our MS therapy Mavenclad® (cladribine tablets) was approved in the United States for the treatment of adults with relapsing-remitting multiple sclerosis (RRMS) and active secondary progressive multiple sclerosis (SPMS).

Cladribine tablets have been approved by the FDA as a treatment for RRMS and SPMS that provides two years of proven efficacy with a maximum of 20 days of oral treatment, during a two-year period. Cladribine tablets have demonstrated clinical efficacy across key measures of disease activity, such as annualized relapse rate, disability progression, and magnetic resonance imaging (MRI) activity. We continue to receive regulatory approvals for Mavenclad® around the world. Mavenclad® is now approved in more than 70 countries, including those of the European Union, Australia, Canada and Switzerland.

At the American Academy of Neurology (AAN) 2019 Annual Meeting, May 4–10 in Philadelphia, Pennsylvania, United States, we presented a total of 20 abstracts (18 posters and two platform presentations), including data on Mavenclad®, Rebif® (interferon beta-1a) and evobrutinib.

Key Mavenclad® data included a post-hoc analysis of the CLARITY Extension study to examine the durability of no evidence of disease activity-3 (NEDA-3) in RMS patients receiving cladribine tablets, plus an integrated analysis of pooled long-term safety data of cladribine tablets in patients with MS collated from the CLARITY, CLARITY Extension, ORACLE-MS studies and the PREMIERE registry. We also presented abstracts from the ORACLE-MS study describing the effect of cladribine tablets on early MS, as well as results from studies investigating the biological effects of cladribine tablets to offer further insights on the mode of action.

Key Rebif® data included the results of an investigation into the prevalence of pregnancy outcomes in IFNβ-exposed women from the European Interferon Beta (IFNβ) pregnancy registry and Nordic health study. These data add to the wealth of pregnancy outcome data that have been collected over more than 20 years for Rebif® and other beta interferons.

Key evobrutinib data included new 48-week results of the double-blind, randomized, placebo-controlled, Phase II study in patients with RMS. The new data showed that the effect on T1 gadolinium-enhancing lesions reduction seen at week 12 was maintained through 48 weeks with evobrutinib 75 mg QD and 75 mg BID. The results were simultaneously published in the New England Journal of Medicine.

In July, we shared further new pregnancy outcomes data in women with MS treated with IFNβ, including Rebif®, at the European Academy of Neurology (EAN) 2019 Congress in Oslo, Norway. Results from the largest population-based observational study in women treated with IFNβ who became pregnant showed no increased risk of major congenital anomalies compared to those unexposed. The results are based on Finnish and Swedish health registry data collected between 1996 and 2014.

At the 35th Congress of the European Committee for Treatment and Research in Multiple Sclerosis (ECTRIMS) from September 11-13, 2019 in Stockholm, Sweden, we presented 39 abstracts highlighting key data with Mavenclad®, Rebif® and evobrutinib. The data we presented at ECTRIMS include key insights from real-world follow-up of patients from our clinical trials and the post-approval setting for Mavenclad®, further validating it as an important treatment option available to patients in more than 70 countries worldwide. Among the data presented on cladribine tablets were:

  • Long-term efficacy data on our oral treatment for MS, showing that 75% of patients from the CLARITY and CLARITY Extension studies exhibited no disability progression at five years post-treatment.
  • A retrospective analysis of real-world follow-up data from an Italian MS registry showed that five years after receiving the last dose of our oral treatment, nearly two-thirds of patients (64%) had no disability progression and more than half of the patients (57%) were free of relapse.
  • Final results from the PREMIERE safety registry were presented, which allowed for a thorough characterization of the long-term safety profile of cladribine tablets and showed no new safety findings. Furthermore, post-marketing data in the first 8,419 patients treated with cladribine tablets worldwide were consistent with the safety profile seen in the clinical development program, with no increase in incidence of adverse events from original clinical program findings.

We also presented new long-term efficacy data for Rebif® showing no evidence that exposure to our injectable before and during pregnancy in women with MS affected infant birth weight for gestational age and head circumference. These data points expand on safety data presented at recent congresses that suggest exposure to IFNβ does not increase risk of spontaneous abortions or affect other pregnancy outcomes, such as ectopic pregnancies or fetal malformations.

New data on evobrutinib were also presented at ECTRIMS, further elucidating the proposed mechanism of action for this investigational MS therapy, which is the first oral, highly selective Bruton’s Tyrosine Kinase (BTK) inhibitor to demonstrate clinical proof of concept in relapsing multiple sclerosis.

In early September, we reported the initiation of two global pivotal Phase III trials (EVOLUTION RMS 1 and 2) studying the efficacy and safety of evobrutinib in adult patients with RMS.

In late September, we announced that the Committee for Medicinal Products for Human Use (CHMP) of the European Medicines Agency (EMA) issued a positive opinion to update the product label of Rebif® to include that women with RMS may continue treatment with Rebif® during pregnancy if clinically needed and while breastfeeding. Treatment with Rebif® while breastfeeding is an important option as many patients experience a relapse in their MS during the first three months following childbirth.

In October, we gave notice that results from FORWARD, a five-year, multicenter Phase II study of sprifermin, a recombinant human fibroblast growth factor-18, in patients with symptomatic radiographic knee osteoarthritis (OA) were published online in the Journal of the American Medical Association (JAMA). Published results, based on the two-year primary outcome and the three-year follow-up analysis from the trial, show statistically significant, dose-dependent increases in total femorotibial joint cartilage thickness compared to both baseline and placebo comparator.

We also announced that we are evaluating external partnership opportunities for our OA portfolio, including sprifermin, with the goal of finding the right partner to advance the development of structurally-modifying treatments to change the course of OA. By pursuing alternative paths to internally driven development, our plan is to further focus our efforts in inflammatory neurology and immunology diseases with potentially overlapping inflammatory mechanisms like MS and systemic lupus erythematosus (SLE).

Fertility 

To date, an estimated three million babies have been born with the help of our Fertility portfolio.

The Pergoveris® Pen, a convenient and ready-to-use fertility combination treatment option for women with severe follicle stimulating hormone and luteinizing hormone deficiency, was successfully launched in several countries in Europe, Asia-Pacific and Latin America in 2019. Additional launches in other countries are planned.

Fertility Lab Technologies continued to expand its footprint in Asia-Pacific, successfully launching the fertility lab devices Geri®, Gavi®, Gems®, and Gidget® in Korea and India.

In June, we announced we are working with the Leibniz Institute for Zoo and Wildlife Research (IZW), Berlin, Germany and other research partners to support efforts to save the northern white rhinoceros from extinction.

General Medicine & Endocrinology

Our new formulation of Euthyrox® (levothyroxine) for the treatment of hypothyroidism obtained further regulatory approvals in 2019, resulting in a total of 35 countries where this incremental innovation is registered, allowing for more precise dosing. New launches planned for the coming quarters include the remaining eight EU countries (Portugal and Spain, for example), China, Colombia and two countries in Asia-Pacific (Malaysia and Singapore).

Glucophage®, containing the active ingredient metformin, is now approved in 53 countries for prediabetes when lifestyle intervention is not enough to control the condition. At the 55th Annual Meeting of the European Association for the Study of Diabetes (EASD) in Barcelona, Spain in September, a first-of-its-kind Millennial Advisory Board was held with a new generation of healthcare professionals (HCPs) to discuss treatment paradigms for prediabetes. In Brazil, we successfully launched Glucophage XR 850 dedicated to the prediabetes condition.

We continued to execute our Branded Off-Patent Products (BOPPs) strategy. Toreza® (rosuvastatin) was approved in Chile in July. Toreza® is available in two strengths, 10 mg and 20 mg, offering HCPs an important choice for the treatment of dyslipidemia.

The number of patients taking Saizen® (somatropin) enrolled on Easypod® Connect continued to grow in 2019, reaching almost 21,000 at the end of Q4. Saizen® is our main endocrinology product and is indicated for the treatment of growth hormone deficiency in children and adults, while Easypod® Connect is a unique web-based platform that allows HCPs to monitor their patients’ adherence to treatment with real-time injection data collected and transmitted from their Easypod® devices.

The launch of Aluetta®, our new pen for the injection of Saizen®, complements our device portfolio and supports the growth of Saizen® by expanding our business in key geographies like Germany. Aluetta® is currently approved in 20 countries.

Other collaborations

In January, we signed a strategic collaboration agreement with Tencent, a leading provider of Internet services. The collaboration will primarily focus on increasing public disease awareness and providing more accessible healthcare services via digital platforms in China.

In March, we entered a collaboration agreement with Iktos, a French start-up company specialized in the development of artificial intelligence (AI) solutions applied to chemical research. The collaboration will comprise the use of Iktos’ generative modeling AI technology to facilitate rapid and cost-effective discovery and design of promising new compounds.

11.25 KBEXCEL
BIOPHARMA PIPELINE
As of: December 31, 2019
 
Therapeutic area
Compound
Indication Status
Neurology    
Evobrutinib (BTK inhibitor) Multiple sclerosis Phase III
     
Oncology    
Tepotinib (MET kinase inhibitor) Non-small cell lung cancer, METex14 skipping4 Registration
Tepotinib (MET kinase inhibitor) Non-small cell lung cancer Phase II
Peposertib (M3814) (DNA-PK inhibitor) Rectal cancer Phase II
M3258 (LMP7 inhibitor) Multiple myeloma Phase I
Peposertib (M3814) (DNA-PK inhibitor) Solid tumors1 Phase I
M4344 (ATR inhibitor) Solid tumors Phase I
M6620 (ATR inhibitor) Solid tumors Phase I
M8891 (MetAP2 inhibitor) Solid tumors Phase I
     
     
Immuno-Oncology    
Avelumab (anti-PD-L1 mAb) Renal cell cancer, 1st line5 Registration
Avelumab (anti-PD-L1 mAb) Non-small cell lung cancer, 1st line Phase III
Avelumab (anti-PD-L1 mAb) Urothelial cancer, 1st line maintenance Phase III
Avelumab (anti-PD-L1 mAb) Locally advanced head and neck cancer Phase III
Abituzumab (pan-αν integrin inhibiting mAb) Colorectal cancer, 1st line Phase II
Avelumab (anti-PD-L1 mAb) Merkel cell cancer, 1st line Phase II
Avelumab (anti-PD-L1 mAb) Solid tumors2 Phase II
Avelumab (anti-PD-L1 mAb) Non-small cell lung cancer2 Phase II
Avelumab (anti-PD-L1 mAb) Urothelial cancer2 Phase II
Bintrafusp alfa (TGFbeta trap / anti-PD-L1) Non-small cell lung cancer, 1st line Phase II
Bintrafusp alfa (TGFbeta trap / anti-PD-L1) Non-small cell lung cancer, 1st and 2nd line Phase II
Bintrafusp alfa (TGFbeta trap / anti-PD-L1) Locally advanced non-small cell lung cancer Phase II
Bintrafusp alfa (TGFbeta trap / anti-PD-L1) Biliary tract cancer, 1st line Phase II
Bintrafusp alfa (TGFbeta trap / anti-PD-L1) Biliary tract cancer, 2nd line Phase II
Avelumab (anti-PD-L1 mAb) Solid tumors Phase I
Bintrafusp alfa (TGFbeta trap / anti-PD-L1) Solid tumors Phase I
M9241 (NHS-IL12, cancer immunotherapy) Solid tumors1 Phase I
     
Immunology    
Atacicept (anti-BLyS / anti-APRIL fusion protein) Systemic lupus erythematosus Phase II
Atacicept (anti-BLyS / anti-APRIL fusion protein) IgA nephropathy Phase II
Evobrutinib (BTK inhibitor) Rheumatoid arthritis Phase II
Evobrutinib (BTK inhibitor) Systemic lupus erythematosus Phase II
Sprifermin (fibroblast growth factor 18) Osteoarthritis Phase II
M1095 (ALX-0761, anti-IL-17 A/F nanobody)3 Psoriasis Phase II
M5049 (TLR7/8 antagonist) Immunology Phase I
M6495 (anti-ADAMTS-5 nanobody) Osteoarthritis Phase I
     
Global Health    
M5717 (PeEF2 inhibitor) Malaria Phase I
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.
1 Includes studies in combination with avelumab.
2 Avelumab combination studies with talazoparib, axitinib, ALK inhibitors, cetuximab or chemotherapy.
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 our company.
4 In Q4 2019, tepotinib was filed in Japan for the treatment of patients with non-small cell lung cancer harboring METex14 skipping.
5 On December 20, 2019, avelumab in combination with axitinib was approved in Japan for treatment of patients with curatively unresectable or metastatic renal cell carcinoma.
ADAMTS-5: A disintegrin and metalloproteinase with thrombospondin motifs
APRIL: A proliferation-inducing ligand
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
METex14: MET exon 14
MET: MET proto-oncogene, receptor tyrosine kinase
PD-L1: Programmed cell death ligand 1
PeEF2: Plasmodium eukaryotic elongation factor 2
PK: Protein kinase
TGFbeta: Transforming growth factor beta
TLR7/8: Toll-like receptors 7 and 8

Allergopharma

Allergopharma is a leading manufacturer of diagnostics and prescription drugs for allergen immunotherapy. As scientists, we are determined to fully understand allergies so as to be optimally positioned to discover new solutions and therapeutic concepts. In close cooperation with research institutions and other experts around the world, we are constantly acquiring valuable insights into the complex immunological mechanisms responsible for allergy development. Equipped with these insights, we pursue new pathways to innovative treatments to meet the needs of allergy patients now and in the future.

Life Science*

Across our three business units of Research Solutions, Process Solutions and Applied Solutions, our R&D teams of more than 2,000 employees continue to bring a diversified and relevant portfolio of products and services to our customers around the world. In 2019, our Life Science business sector focused on delivering the promise of accelerating access to health for people everywhere with investment in collaboration with the global scientific community.

As such, we launched more than 18,500 products, including those launched through our “faucet program” for antibodies, reference materials, chemicals and nanomaterials. These included innovations from all our business units, such as ZooMAb® recombinant antibodies, Sucrose Ultrafiltrated, a Millipak® Final Fill extension and a Stericup® extension of our Milli-Q® 7000 line.

Advancing CRISPR technology globally

In early 2019, we received our first United States patent for proxy-CRISPR technology. The patent addresses a new genome-editing technique that makes CRISPR more efficient, flexible, and specific by opening the genome for modification of DNA. This technique helps scientists modify difficult-to-access regions on the genome.

In April, we were formally granted a Canadian patent for the use of paired CRISPR nickases in eukaryotic cells. Covering paired Cas9 nickase technology, the patent advances gene therapy and research as well as reducing off-target effects. It provides an important and specific solution for scientists who need accurate methods when developing treatments for difficult-to-treat diseases, improving the ability to fix diseased genes without affecting healthy ones. Similar patents were granted in Australia and Europe in late 2018.

Life Science was granted seven additional patents for genome-editing technology in August, adding CRISPR patents in Europe, Israel, South Korea and the United Kingdom. The European Patent Office allowed patents for vectors for CRISPR integration, proxy-CRISPR technology, and engineered Ribonucleic Acid (RNA)-guided endonuclease and protein-RNA complexes. The Israeli and South Korean IP Offices allowed patents for paired nickase technology, while the United Kingdom Office allowed patents for proxy-CRISPR technology.

In November, we again were granted patents covering paired Cas9 nickase CRISPR genome-editing technology, this time from the Japan Patent Office and the Intellectual Property Office of Singapore. This technology increases specificity, reducing off-target effects in gene editing through a highly flexible and efficient approach. In total, we have achieved 22 CRISPR patents across nine markets, including China and Europe.

Furthermore, we announced an agreement with the Massachusetts-based Broad Institute of MIT and Harvard to offer non-exclusive licenses to CRISPR intellectual property (IP) under our respective control for use in research and commercial product development. The offering streamlines access for scientists, contributing to our goal of allowing all entities to apply CRISPR technology with a wider range of tools.

To complete an active year advancing and licensing the IP of our CRISPR technology, in November, we executed an agreement to license our CRISPR IP to Evotec SE of Hamburg, Germany. The license accelerates research and enables testing and development of new drugs.

In addition to patent allowances, we expanded our global network of genome-editing experts by announcing a CRISPR core partnership with Zhejiang University in Hangzhou, China. The CRISPR Core Partnership Program provides researchers from leading institutions with a network of commercial and research scientists stemming from its 80-some partners.

Increasing collaboration with partnerships and agreements

Along with our CRISPR partnerships and agreements, we signed a Memorandum of Understanding (MoU) with Chinese biotech company GenScript in March of 2019. The planned alliance aims to accelerate cell and gene therapy industrialization in China by collaborating to build a global standard platform for plasmid and virus manufacturing. Today, more than 130 companies in China are developing cell and gene therapies. The confluence of demand, growth, and consequent need to scale the cell and gene therapy market is an important driver for us to deliver in this region.

We signed a non-binding MoU with Phanes Therapeutics Inc. of Shanghai, China to collaborate on the development of biologics for the treatment of solid tumors. This allows us to support Phanes in accelerating research and development as well as commercializing new therapies as their demand increases for process development solutions. Under the terms of the MoU, we plan on providing Phanes our BioReliance® End-to-End Solutions for cell line development, process development, and GMP manufacturing up to commercialization.

In April, we announced a partnership with India’s Food Safety and Standards Authority (FSSAI) on food safety skill development, handing over a fully equipped microbiological testing lab. There, food safety scientists from government labs and FSSAI-ratified private labs will be trained by the Center for Microbiological Analysis Training on the latest microbiological testing technology.

In May, we joined the TRANSVAC2 Program to participate in the collaboration to accelerate vaccine development and manufacturing under the European Union’s (EU) Horizon 2020 program. As part of our participation, we provided training sessions at our M Lab™ Collaboration Center in Molsheim, France, tapping into our internal manufacturing expertise and process knowledge in viral vaccines and vectors.

Expanding our portfolio and accessibility to benefit customers

Throughout 2019, we launched innovations across all segments of our portfolio from the Research Solutions, Process Solutions, and Applied Solutions business units. Those included Trehalose Emprove® Expert, a broadly used stabilizer in lyophilization (freeze drying) of biomolecules; recombinant Cas9 and eCas9 GFP fusion proteins, offering all the advantages of ribonucleoprotein-based (RNP) genome editing; and a new formulation of modified Tryptic Soy Broth (mTSB), an enrichment broth for the detection of Salmonella, E. coli O157 and non-O157 STEC from food and animal feed. 

In March, we launched our new, cloud-based lab water service and monitoring capability: Milli-Q® Connect. The product combines deep water purification expertise with cloud-based digital technology to allow users to monitor lab performance remotely and securely. Available on all Milli-Q® CLX 7000 clinical water purification systems, the portfolio addition delivers the value of convenience to our customers via remote diagnostics and assistance features. In September, we again advanced the Milli-Q® product portfolio with the launch of Milli-Q® IQ Element. This portfolio addition is a water purification and dispensing unit that provides our customers with ultrapure water tailored for trace elemental analysis.

Additional novel digital offerings launched in 2019 include our Supelco® SmartTitrants and Supelco® SmartStandards. These tools leverage SmartChemicals Radio Frequency Identification (RFID) tags on our titration consumables, allowing seamless transfer of relevant product data to titration instruments. The technology saves time, reduces transcription errors and ensures maximum data integrity for our customers.

In April 2019, we launched our BioContinuum™ Buffer Delivery Platform, a first-of-its kind integrated solution for streamlined buffer management. Used for continuous processing and in batch mode, this configurable platform is comprised of four components: a selection of distinct buffer concentrates, reliably delivered in Mobius® Select single-use assemblies, and an automated, highly accurate, and precise buffer dilution system with tailored system services.

We also launched Cyrene™, a sustainable dipolar aprotic solvent produced in two steps from a renewable cellulose source. The bio-derived alternative reflects our focus on green chemistry and the need for solvents to meet stricter regulation requirements for both employee safety and environmental sustainability.

Over the course of 2019, we expanded our portfolio with acquisitions in addition to our own product launches, adding to our breadth of tools and technology. With the acquisition of BSSN Software of Darmstadt, Germany, which we announced in August, we added marketing data management and integrated software that unifies data from instruments and data systems to make it available for analyzing, processing, and sharing. The middleware offering collects and converts scientific data from a broad range of more than 200 lab instrument models into a single, unified format.

In October, we acquired FloDesign Sonics of Wilbraham, Massachusetts, United States, to leverage their acoustic cell processing platform. The addition allows enhanced cell washing and concentration for manufacturing cell therapies.

We remain conscious of ensuring ease of access to our broad product portfolio. In addition to our industry-leading e-commerce website, www.sigmaaldrich.com, we launched our official flagship store on Alibaba’s 1688.com in China. We became the first life science business to do so, improving the e-commerce experience for our customers in China. The launch also allows us to leverage Alibaba’s leading technology in big data, cloud services, and artificial intelligence, as well as its digitalized operations and offline channel capabilities.

Recognized for award-winning innovation

To begin the year, Life Science won BioInformatics LLC’s 2018 Life Science Industry Award® for best use of social media. Recognized for our strategic use of social media platforms, we were selected for our engagement with scientific customers and industry peers as well as the satisfaction and loyalty of our customers. The award speaks to our dedication to our stakeholders and their experience with our company.

In April, our Pellicon® Capsule with Ultracel® Membrane, an innovation in next-generation bioprocessing, won an INTERPHEX Exhibitor Award for Best New Product. This first-of-its-kind product acts as a single-use tangential flow filtration capsule used in antibody drug conjugate (ADC) and monoclonal antibody (mAb) bioprocessing. That same month and coinciding with the launch of our new Supelco® products, Supelco® founders Dr. Walter Supina and Mr. Nicholas Pelick received the prestigious 2019 Pittcon Heritage Award for their contributions to the instrumentation and laboratory supplies community.

In November of 2019, Life Science won an R&D 100 Award for our Eshmuno® CP-FT Chromatography Resin. This first-to-market product used in biopharmaceutical manufacturing received the prestigious award to recognize its status as one of the 100 most innovative and significant technologies introduced in 2019. This tool removes aggregates, delivering capacities 10 times higher than traditional bind/elute chromatography. Part of our BioContinuum™ Polishing Platform, the significant reduction in resin and buffer volume results in a smaller manufacturing footprint as well as lower costs.

Through our Advance Biotech Grant Program, we announced 12 total grant recipients for 2019, selected based on the scientific and societal merit of their respective therapies in development, as well as process challenges and expertise gaps.

Performance Materials*

Within our Performance Materials business sector, we are the market and technology leader in most of our industries. As a science and technology company, we offer leading-edge products and solutions that in many cases set us apart from the competition. In order to bring our R&D closer to our businesses and reflect our new organizational structure after the acquisition of Intermolecular and Versum Materials, we transferred our research activities of Early Research & Business Development to our business units. We have also set up a Chief Technology Office (CTO) that bundles important technology competencies and technology scouting. As a dedicated technology organization, the CTO focuses on interacting with top-level customers and the electronics industry, managing research partnerships, shaping our technology roadmap and managing our long-term R&D portfolio.

Semiconductor Solutions

With the additions of Versum Materials and Intermolecular, we are now more capable than ever of addressing all our customers’ critical material needs through every step of the wafer manufacturing process. The outstanding capabilities and competencies of the businesses are manifold and will enable us to bring game-changing innovations for our customers into the market faster.

Despite the market experiencing a flat year in the semiconductor space, our R&D teams were busier than ever, taking advantage of the increased bandwidth our customers had for their own product development activities – which is often the case during periods of reduced manufacturing demand. In the logic/foundry space we continue to focus on 3D transistor technology and to interconnect improvements to drive performance, size, and power efficiency. In the memory segment, there is a drive to increase the number of levels in vertical and 3D NAND architectures to enable even higher memory capacities, and in DRAM (dynamic random-access memory), continuing node shrinkage drives density, speed and reliability. This translates into adoption of more new materials and higher volume requirements for our products in the future. Enhanced technological competence in combination with a strengthened supply chain resulting from the acquisition of Versum Materials and Intermolecular will contribute to this growth.

We were successful this year in broadening our portfolio of high-value products for both advanced memory and logic applications. Our pathfinding teams are developing next-generation precursors and processes for flowable CVD (chemical vapor deposition) gap fill applications, high aspect ratio etching, and area selective deposition. In the patterning space, our R&D is expanding the DSA (directed self-assembly) pipeline with several customized solutions for additional applications. We continue to see a strong pull for our high-performance dielectric (HPD) series advanced colloidal ceria slurries for oxide/shallow trench isolation (STI) applications as a result of their demonstrated industry-leading low defectivity, extremely high uniformity, broad operating window, and polishing efficiency. Our conductive paste materials adopted a solutions-focused approach to create high-value products for our customers that go beyond just materials. The unique attributes of our conductive pastes plus novel packaging fabrication techniques, developed by our engineering team, enable packaging architectures needed for the enormous 5G infrastructure deployment.

With respect to our Delivery Systems & Services (DS&S) business, we completed the manufacture and installation of ISO Bulk Specialty Gas Systems (ISO-BSGS) at two new fabs for a customer in Xi’an, China, and another project near Pyeongtaek, Korea. ISO-BSGS systems provide the safe and efficient factory-level distribution of bulk container specialty gases, such as NF3, N2O, NH3, and SiH4, and are key enablers of our Specialty Gases business.

To better support our customers in Asia, we opened a new manufacturing facility in Shanghai, China, to produce our latest specialty gas delivery equipment product line, GasSTAR®. Both the GasSTAR cabinet and BSGS enable semiconductor manufacturers in Asia to meet the rising demand for 200 and 300-mm memory and logic devices, flat panel displays, photovoltaics, LEDs, and other applications.

In 2019, we also introduced CHEMGUARD® CG350, which heats process molecules in a safe, process-stable manner and provides the reliable uptime needed for high-volume manufacturing.

Display Solutions

In our Display Solutions business unit, our liquid crystal technology UB-FFS (ultra-brightness fringe-field switching) continues its successful growth, thanks to new product qualifications and rising demand in the liquid crystal displays (LCD) sector for mobile devices, especially mobile phones and tablet PCs. The development of high-resolution 4K and 8K TV sets continues to pose a challenge, as the LCD backlight transmission and efficiency will be reduced due to higher pixel density. We are therefore actively working to expand our ultra-bright (UB) technology offering with our UBplus liquid crystal materials for the TV market. With such technologies, we increase the light transmission efficiency of applications for large-format TV sets and display panels by 10% to 15%.

Our VA (vertical alignment) liquid crystal platform including PS-VA (polymer-stabilized vertical alignment) technology remains predominant when it comes to large-format TV sets. Here, our latest materials provide additional performance benefits and improve processing efficiency in the production of TV sets. Moreover, we have successfully demonstrated our manufacturing expertise with respect to the new liquid crystal technology SA-VA (self-aligned vertical alignment). We are now focusing our attention on applications for specialized display products from the premium segment through to TV applications produced in large numbers, as this technology offers the high contrast and image quality of the PS-VA technology while also enabling improvements in display design and panel production, for example through the reduction of waste and energy consumption in the production of LCDs.

OLED technology continues to gain shares in the display market, particularly in the premium segment. Our R&D activities are covering a broad variety of OLED materials, targeting a wide range of applications from smartphones to TVs. We continue to be successfully qualified in a number of upcoming devices from leading consumer electronics players. In addition, we are supporting our customers in their ambition to establish inkjet printing as a new OLED display manufacturing process.

Surface Solutions

In our automotive pigments business, our focus on developing achromatic pigments continues. The latest example is Xirallic NXT Amur Black, a blue-black effect pigment with a silky-silvery fine texture and a wealth of Living Sparkle®. Another key topic in our development is fueled by the evolution of autonomous driving. In our pipeline, we address the special requirements that radar and lidar sensor applications demand of coating pigments.

Completing the Smart Effects initiative in our Cosmetics business, we are further driving the development of cosmetic pigments on matte effects (Allure series) and luster effects (Lights series). The newest additions will be the blue interference effect pigments Ronastar® Blue Lights and Ronastar® Dazzling Lights, a new gold pigment with a spectacular body color. In addition, we further drove the development of active ingredients of natural origin for new cosmetics solutions. We are currently in the process of preparing for the product launches in 2020.

* The contents of this chapter or section are voluntary and therefore not audited. However, our auditor has read the text critically.