Healthcare*

With our Healthcare research pipeline, we aspire to make a positive difference for patients – always with the purpose to help create, improve, and prolong lives. Our main research focus areas include oncology, neurology, and immunology.

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. As a company we have more than 20 years of experience in MS research, and we remain committed to finding solutions for patients’ significant unmet medical needs in this area.

New data for both our marketed MS treatments Mavenclad^® (cladribine tablets) and Rebif^® (interferon beta-1a), and our investigational treatments evobrutinib and enpatoran, have been presented across key congresses in 2021, including the Americas Committee for Treatment and Research in Multiple Sclerosis (ACTRIMS) Forum 2021 in February and the 2021 American Academy of Neurology (AAN) Annual Meeting in April. Generating data around our MS treatments and the risk of respiratory viral infections has remained important in 2021, helping to support clinicians as they make treatment decisions for their patients living with MS during the Covid-19 pandemic. At ACTRIMS, we presented new data from the MAGNIFY-MS study, indicating that Mavenclad-treated relapsing multiple sclerosis (RMS) patients mount a protective antibody response to common vaccines. The MAGNIFY-MS retrospective analysis demonstrated that patients develop protective antibody levels for at least six months following seasonal influenza and varicella zoster vaccines, irrespective of vaccine timing relative to Mavenclad-dosing.

At AAN, we announced a new analysis from the MAGNIFY-MS sub-study showing a specific immune repopulation pattern in patients with RMS treated with Mavenclad^®, which may contribute to their ability to fight infections and develop protective antibodies from vaccines. In addition, an independent study conducted by Anat Achiron, MD, PhD, FAAN, and colleagues, The Multiple Sclerosis Center at Sheba Medical Centre and Sackler School of Medicine Tel Aviv University, Israel, was published in the “Therapeutic Advances in Neurological Disorders” journal in April and also presented at the AAN congress, showing that patients on Mavenclad-treatment were able to generate Covid-19 antibodies following the mRNA vaccine from Pfizer/BioNTech. Humoral response to the Covid-19 vaccine was independent of lymphocyte count.

Also presented at AAN were data from a Phase II placebo-controlled randomized trial showing that evobrutinib significantly reduced blood neurofilament light chain (NfL) levels, a key biomarker of neuronal damage and inflammation, in patients with MS. Elevated blood NfL levels have been shown to be associated with damage to neurons and may predict future brain atrophy and disease progression.

Enpatoran, a highly specific potential first-in-class immune modulator blocking the activation of Toll-like receptor (TLR)7 and TLR8, was the focus of two presentations at major lupus and infectious disease congresses, including ID WEEK 2021 in September and LUPUS & CORA 2021 in October. Enpatoran is being developed as a potential new oral therapy for systemic lupus erythematosus (SLE) and cutaneous lupus erythematosus (CLE), and aims to overcome limitations of available lupus therapies by providing selective inhibition of lupus-relevant disease drivers, which may increase efficacy while preserving immunity against infections. Initiation of Phase II studies in SLE and CLE is expected in the first half of 2022.

We presented a total of 39 abstracts at the 37th Congress of the European Committee for Treatment and Research in Multiple Sclerosis (ECTRIMS) in October. Among the presentations were late-breaking real-world data on Mavenclad^®, showing a sustained benefit on long-term mobility and disability status. New data also highlighted improvement in measures of physical and mental health after one year of Mavenclad^®-treatment, plus new independent data that continued to show Mavenclad^®-treated patients receiving an mRNA Covid-19 vaccine mount a similar antibody response similar to that of the general population.

New evobrutinib data were also presented at ECTRIMS, showing that evobrutinib was effective at reducing the volume of slowly expanding lesions (SEL), an imaging biomarker of chronic active inflammation and axonal loss within the central nervous system (CNS), making it the first Bruton´s tyrosine kinase (BTK) inhibitor to show a significant effect on this biomarker. Additionally, new safety data from the first and only integrated safety analysis of a BTK inhibitor that included MS patients were also presented, showing that evobrutinib was generally well tolerated. This came shortly after the announcement of evobrutinib being the first BTK inhibitor to complete Phase III trial enrollment.

We have continued to deliver on the strategic evolution of our immunology pipeline this year, allowing us to focus our efforts on priority assets and areas of expertise to deliver the greatest impact for patients. In May, we announced the completion of an out-licensing agreement with MoonLake Immunotherapeutics AG, Switzerland, for sonelokimab (M1095). Sonelokimab is an investigational anti-IL-17 A/F Nanobody^®, which neutralizes both IL-17A and IL-17F, in patients with moderate to severe chronic plaque-type psoriasis. In January 2022 we out-licensed sprifermin, a recombinant form of human fibroblast growth factor 18, to HighLine Bio Inc, a company newly established by TrialSprak. Sprifermin is being investigated in osteoarthritis, and TrialSpark/HighLine Bio will assume full responsibility for the research, development and commercialization of the asset.

In December we announced a strategically focused expansion of our neuroinflammatory pipeline with the acquisition of the rights to develop cladribine for the treatment of generalized myasthenia gravis (gMG) and neuromyelitis optica spectrum disorder (NMOSD).

Oncology

Oncology is a core focus area 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 2021, we achieved several milestones across our 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 Bavencio^® (avelumab), an anti-PD-L1 antibody we are co-developing and co-commercializing with Pfizer Inc., United States. On January 25, the European Commission approved Bavencio^® as monotherapy for the first-line maintenance treatment of adult patients with locally advanced or metastatic urothelial carcinoma (UC) who are progression-free following platinum-based chemotherapy. Bavencio^® was first approved in the United States as a first-line maintenance treatment for advanced UC by the U.S. Food and Drug Administration (FDA) in June 2020 and is now approved for this indication in 50 countries. It is also approved as a monotherapy for the treatment of metastatic Merkel cell carcinoma in 55 countries and for the treatment of advanced renal cell carcinoma in combination with axitinib in 50 countries.

Other highlights from our development pipeline included the advancement of several potential first-in-class/best-in-class compounds. The development program for tepotinib, our oral MET inhibitor designed to inhibit the oncogenic MET receptor signaling caused by MET (gene) alterations, has continued to achieve multiple milestones in 2021. Discovered in-house at our company, tepotinib underscores our strategic focus on delivering innovative precision medicines to patients with cancer. In February 2021, the FDA granted accelerated approval to tepotinib under the brand name Tepmetko^®, making it the first and only once-daily oral MET inhibitor approved for patients with metastatic non-small cell lung cancer (NSCLC) with METex14 skipping alterations. Continued approval for this indication may be contingent upon verification and description of clinical benefit in confirmatory trials. In December 2021, Tepmetko became the first and only oral MET inhibitor to receive the Committee for Medicinal Products for Human Use (CHMP) positive opinion in Europe for adult patients with advanced NSCLC harboring alterations leading to METex14 skipping. Tepotinib is now available in a number of countries, and under review by other regulatory authorities globally.

On April 12, we announced initiation of a Phase II trial with registrational intent for berzosertib, the leading asset in the Company’s DNA damage response (DDR) inhibitor development program. The berzosertib clinical development program is one of the most advanced Ataxia telangiectasia and rad3-related (ATR) inhibitor development programs industry-wide. The global study will further assess berzosertib in combination with topotecan for the treatment of relapsed, platinum-resistant SCLC (DDRiver SCLC 250) and plans to include approximately 80 participants at about 41 study sites across Asia, Europe, and North America. As part of its new DDRiver™ Clinical Trials program, the Company is investigating DDR inhibitor targeting pathways across more than ten trials in various tumor types. Results from a Phase II proof-of-concept study conducted by the US National Cancer Institute (NCI) (NCT02487095) were also published in the April 12, 2021 edition of Cancer Cell showing that berzosertib in combination with the chemotherapy topotecan resulted in an objective response rate (ORR) of 36% among patients with relapsed small cell lung cancer (SCLC), including durable responses among a majority of responding patients with platinum-resistant disease. Berzosertib, formerly known as VX-970, was licensed from Vertex Pharmaceuticals in 2017.

At the 2021 American Society of Clinical Oncology (ASCO) Annual Virtual Meeting held June 4 – 8, we had a significant presence with 40 abstracts including seven oral presentations and seven poster discussions at the Virtual Scientific Program. Potential first-in-class/best-in-class early- and late-stage pipeline compounds, and investigational uses of our approved medicines were featured at the meeting.

For Bavencio^®, data provided further evidence of continued patient benefit across three approved indications and included:

• New analyses from the Phase III JAVELIN Bladder 100 study demonstrating consistent survival benefit of Bavencio^® as first-line maintenance treatment across key subgroups further reinforcing the role of Bavencio^® for patients with advanced UC that have not progressed on 1L platinum-containing chemotherapy (abstracts: #4520; #4525; #4527).
• In advanced renal cell carcinoma (aRCC), data confirmed the efficacy benefits of the combination of Bavencio^® plux axitinib across International Metastatic RCC Data Consortium (IMDC) risk groups including in the favorable risk group from the extended follow-up of the Phase III JAVELIN Renal 101 study (abstracts: #4514; #4574)
• More than five years of follow-up in Part A of the Phase II JAVELIN Merkel 200 study in metastatic Merkel cell carcinoma (mMCC) (#9517) showed meaningful long-term overall survival in previously treated patients with metastatic MCC (mMCC) who were treated with Bavencio^®, supporting its role as a standard of care for these patients.

For tepotinib, new data from the Phase II VISION study was presented including:

• An oral presentation on METex14 NSCLC biomarker response detected in liquid biopsy (#9012); this investigation provides evidence that liquid biopsy may provide a reliable means for monitoring.
• METex14 skipping NSCLC with brain metastases (abstract #9084) where data demonstrated efficacy in patients with METex14 skipping NSCLC with brain metastases consistent with the overall treatment population, brain metastases are reported in 20% to 40% of patients with METex14 skipping NSCLC and are associated with poor prognosis.
• NSCLC with MET amplification (METamp) (abstract #9021) in VISION Cohort B, the first study of a MET inhibitor in people with NSCLC with METamp prospectively detected by liquid biopsy, showed the potential of tepotinib to target METamp-driven disease. MET amplification is a genetic alteration occurring in approximately 1% to 5% of patients with NSCLC and has no approved targeted therapies.

For our first biology-driven leader, Erbitux^® (cetuximab), a number of Investigator Sponsored Studies (ISS) continue to demonstrate its steady role across the continuum of care in mCRC, and as a backbone of treatment in squamous cell carcinoma of the head and neck. We licensed the right to market Erbitux^®, a registered trademark of ImClone LLC, outside the United States and Canada from ImClone LLC, a wholly owned subsidiary of Eli Lilly and Company, in 1998.

At the IASLC 2021 World Conference on Lung Cancer (WCLC) and the European Society of Medical Oncology (ESMO) Annual Virtual Meetings in September 2021, we presented 27 abstracts on research from Company-sponsored, investigator-sponsored, and collaborative studies — including two oral and two mini-oral presentations.

For Bavencio^®, real-world evidence was presented supporting the continued need for first-line treatments for advanced urothelial carcinoma (abstracts: #701P; #706P; #707P). Data from an investigator-sponsored study of avelumab in combination with neoadjuvant chemotherapy to treat muscle-invasive bladder cancer was also presented for the first time (presentation #659MO).

Data for tepotinib at the WCLC (abstracts: #P45.03; #P51.01) and ESMO (abstracts: #1254P; #1255P; #1366TIP) included the VISION trial — the largest study of patients with METex14 skipping NSCLC prospectively enrolled based on liquid and/or tissue biopsy (n=275) and, a trial-in-progress update from the ongoing INSIGHT 2 study in EGFR-mutant NSCLC with MET amplification.

Erbitux^® (cetuximab) data at ESMO continue to demonstrate, in a number of studies, its significant role as the backbone of treatment in mCRC (abstract #415P; presentation #387MO).

For our investigational ATR inhibitor berzosertib (M6620), a first-time look at the ongoing Phase II study of berzosertib in patients with relapsed platinum-resistant small cell lung cancer (SCLC) was presented (abstract #1666TIP).

On September 30, we announced a mutual decision to end the global strategic alliance with GlaxoSmithKline plc, United Kingdom, (GSK) to develop bintrafusp alfa, the investigational bifunctional fusion protein designed to simultaneously block TGF-β and PD-L1. This decision was based on the clinical trial data generated to date, including three randomized clinical trials that did not demonstrate a benefit to patients.

In January, we made the decision to discontinue the INTR@PID Lung 037 clinical trial in the first-line treatment of patients with stage IV NSCLC that have high expression of PD-L1, based on the recommendation of the Independent Data Monitoring Committee, as the study was unlikely to meet the co-primary endpoint, specifically progression-free survival.

Top-line data announced in March from the Phase II INTR@PID BTC 047 study evaluating bintrafusp alfa as a monotherapy in the second-line treatment of patients with locally advanced or metastatic biliary tract cancer (BTC) who have failed or are intolerant of first-line platinum-based chemotherapy showed single-agent activity, though the study did not meet the predefined threshold that would have enabled regulatory filing for BTC in the second-line setting.

In August, based on a review of data conducted by the Independent Data Monitoring Committee, we decided to discontinue the Phase II INTR@PID BTC 055 study evaluating bintrafusp alfa with gemcitabine plus cisplatin in the first-line treatment of patients with locally advanced or metastatic biliary tract cancer (BTC), as the study was unlikely to achieve the primary objective of overall survival.

Based on these findings, several remaining studies in the program were discontinued, including those in non-small cell lung cancer, triple negative breast cancer, biliary tract cancer, and bladder cancer.

To augment the in-house innovations in our oncology portfolio with potential new solutions for patients with cancer, we announced in March 2021 that we entered into a worldwide in-licensing agreement with Debiopharm, Switzerland, for the worldwide development and commercialization of xevinapant (Debio 1143). Xevinapant, a potent oral antagonist of Inhibitor of Apoptosis Proteins (IAP), is the only medicine in its class in late-stage clinical development and has the potential to be first in class. Xevinapant is currently being investigated in the Phase III TrilynX study for previously untreated high-risk locally advanced squamous cell carcinoma of the head and neck (LA SCCHN), in combination with platinum-based chemotherapy and standard fractionation intensity-modulated radiotherapy.

Fertility

In a step forward for women with severe follicle-stimulating hormone (FSH) and luteinizing hormone (LH) deficiency and their treating physicians, in October 2021 the Committee for Medicinal Products for Human Use (CHMP) recommended an update to the Summary of Product Characteristics (SmPC) for Pergoveris^®. Current scientific and clinical knowledge regarding the nature and attributes of FSH LH and LH deficiency show that severe FSH and LH deficiency cannot be defined using specific cut-off levels of FSH and LH clinical indicators. The SmPC update ensures better clarity for healthcare professionals (HCPs) on when to dispense Pergoveris^®.

The 2021 meeting of the European Society of Human Reproduction and Embryology (ESHRE) that was taking place in June, saw three abstracts presented, including one oral presentation that highlighted comparative real-world effectiveness data of assisted reproduction technology collected in the National Health database in France, for women stimulated by different gonadotropins, including Gonal-f^®, which showed positive clinical outcomes like cumulative live birth rate. Additionally, seven high-priority fertility manuscripts have been published in top-quartile journals so far.

A meta-analysis published in April 2021¹ suggested positive outcomes for the reference product Gonal-f^® compared to treatment with biosimilar preparations of follitropin alfa regarding probability of live birth, as well as clinical and ongoing pregnancy. In addition, safety data showed for biosimilars and reference product a similar risk of ovarian hyperstimulation syndrome (OHSS), ectopic pregnancy, and multiple pregnancy¹. The evidence base for Gonal-f^® was further strengthened by a real-world study published in June 2021², which showed that treatment with Gonal-f^® resulted in higher rates of cumulative live birth, cumulative ongoing, and cumulative clinical pregnancy versus highly purified human menotropin (HP-hMG).

We continue to support efforts to save the northern white rhinoceros from extinction. We are a partner of the BioRescue Project of the Leibniz Institute for Zoo and Wildlife Research (Leibniz-IZW) in the Forschungsverbund Berlin e.V., donating technology and financial support, as well as sharing expertise and experience in fertility to their work.

¹ Chua, SJ, et al. Reprod Biol Endocrinol. 2021;19(1):1-13.

² Bühler et al. Reproductive Biology and Endocrinology 2021.

Cardiovascular Metabolism & Endocrinology (CM&E)

The new formulation of Euthyrox^® (levothyroxine) for the treatment of hypothyroidism obtained further regulatory approvals in 2021, resulting in a total of 80 countries where this incremental innovation is registered, allowing for more precise dosing.

Glucophage^®, containing the active ingredient metformin, is the drug of choice for first-line treatment of type 2 diabetes available in more than 100 countries. It is also approved in 89 countries for prediabetes when lifestyle intervention is not enough to control the condition. With the successful submission and launch of Glucophage^® XR 850, a new dose strength has been developed for the Glucophage^® family specifically dedicated to prediabetes.

Concor^® AM, our fixed dose combination drug of bisoprolol with amlodipine to treat hypertension, is now registered in 65 countries. In Q3 2021, we saw the launch in China where bisoprolol/amlodipine is the only long-acting single-pill combination (SPC) of a β-blocker combined with a calcium channel blocker. This is expected to fill the gap in B+C long-acting SPC treatment for patients in the country.

In 2021, the number of new patients using the Easypod^® electromechanical injection device for treatment with Saizen^® (somatropin) continued to grow, bringing the total number of patients enrolled on Easypod^® Connect to around 25,000. 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.

We continued the rollout of Aluetta®, our new pen for the injection of Saizen^®, which complements our device portfolio and supports the growth of Saizen®, taking the total number of countries where it is currently available to 28.

Building for the future

On July 6, we celebrated the topping out of the Biotech Development Center currently under construction in Corsier-sur-Vevey, Switzerland. This investment of € 250 million, previously announced in January 2020, will help to sustainably secure capacity and high agility to deliver clinical trial material, contribute to accelerated development timelines of new biological entities, and address the increasing manufacturing complexity of the next generations of biotech compounds in a cost-effective way.

On July 19, we announced plans to invest € 200 million at our global headquarters in Darmstadt by building a new Translational Science Center for the Healthcare business sector. As of 2025, the new Translational Science Center will offer room for more than 500 scientists, who will conduct research in a wide variety of fields ranging from the identification of disease biomarkers to the development of targeted therapies. This € 200 million investment will give rise to an integrated, flexible-use laboratory building covering more than 30,000 m², that includes a lecture hall, in vitro laboratories including a cell bank, as well as a modern and flexible knowledge environment.

The Biotech Development Center and the Translational Science Center add to recent investments aiming to strengthen our capacities in the research, development, and manufacturing of medicines, notably at our R&D facility of Billerica, Massachusetts, United States, as well as at our biotech manufacturing site in Aubonne, Switzerland.

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