Healthcare*

With our Healthcare research, we aspire to make a positive difference for patients – always with the purpose to help create, improve, and prolong lives.

In November 2022, we announced that we aim to launch one new product or indication every 1.5 years on average, bolstered by external innovation. Our companywide focused leadership approach to pipeline enrichment builds on our established expertise in the underlying biology of our core therapeutic areas of oncology, neurology and immunology as well as technological capabilities. By building on our existing strengths and maximizing synergies within our in-house discovered pipeline and with external assets, we will secure sustainable R&D productivity that leads to innovative medicines for patients in need.

Oncology

Oncology is a core focus area in our R&D portfolio, as 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 2022, we achieved several milestones across our oncology pipeline.

We continue to deliver on our commitment to bring new standards of care for multiple tumor types to as many patients as possible worldwide, with new regulatory approvals of our marketed therapies in additional countries around the world in 2022.

Bavencio^® (avelumab), an anti-PD-L1 antibody we are co-developing and co-commercializing with Pfizer Inc., United States, is now approved as a first-line maintenance treatment for locally advanced or metastatic urothelial carcinoma (UC) in adult patients whose disease has not progressed following platinum-based chemotherapy in 63 countries. Bavencio^® was first approved for this indication in the United States by the U.S. Food and Drug Administration (FDA) in June 2020. It is also approved as a monotherapy for the treatment of metastatic Merkel cell carcinoma in 63 countries and for the treatment of advanced renal cell carcinoma in combination with axitinib in 60 countries.

In February 2022, the European Commission approved Tepmetko^® (tepotinib), our in-house-developed oral MET inhibitor, as monotherapy for the treatment of adult patients with advanced non-small cell lung cancer (NSCLC) harboring alterations leading to mesenchymal-epithelial transition factor gene exon 14 (METex14) skipping, who require systemic therapy following prior treatment with immunotherapy and/or platinum-based chemotherapy. Tepotinib is now available in several countries globally.

As part of our efforts to bring our medicines to as many patients as possible who may benefit from them, we are assessing these medicines in new settings as well, while also progressing promising molecules from our pipeline. In 2022, we initiated the Phase II JAVELIN Bladder Medley study in 2022. This randomized umbrella study is evaluating whether optimization of first-line maintenance treatment by adding a novel therapy to avelumab could improve outcomes for patients with advanced urothelial carcinoma whose disease did not progress with first-line platinum-containing chemotherapy. JAVELIN Bladder Medley is assessing avelumab monotherapy versus the combination of avelumab with the company’s investigational anti-TIGIT antibody M6223; avelumab in combination with Nektar Therapeutics’ interleukin-15 (IL-15) receptor agonist, NKTR-255; or avelumab in combination with Gilead Sciences’ Trodelvy^® (sacituzumab govitecan-hziy).

With the Phase III development program for the potentially first-in-class IAP (Inhibitor of Apoptosis Protein) inhibitor xevinapant, we are building on our long-standing leadership in the treatment of squamous cell carcinoma of the head and neck (SCCHN). We opened the second Phase III clinical trial, XRay Vision (NCT05386550), a randomized, double-blind, placebo-controlled study to evaluate the efficacy and safety of xevinapant versus placebo in combination with adjuvant, post-operative radiotherapy in patients with resected locally advanced (LA) SCCHN who are at high risk for relapse and are ineligible for cisplatin, in 2022. Recruitment continues to progress in the international, randomized, double-blind, placebo-controlled, Phase III TrilynX study (NCT04459715) to evaluate the efficacy and safety of xevinapant versus placebo when added to definitive chemoradiotherapy in patients with unresected LA SCCHN.

In 2022, we also have made progress on our ambition to deliver the next generation of innovative medicines for cancer, with two compounds from our pipeline advancing into clinical trials, with Phase I studies underway for our anti-CEACAM5 antibody-drug conjugate (ADC), M9140, and our A2aR_A2bR antagonist, M1069, in advanced solid tumors. M9140, which is the first ADC to enter clinical development that is based on our proprietary technology, showed a convincing preclinical profile with high antitumor potency in multiple models and a suitable safety profile.

We shared new data analyses for our marketed and investigational oncology medicines throughout the year at major congresses.

At the 2022 American Society of Clinical Oncology (ASCO) annual Genitourinary Cancers Symposium, February 17-19, we presented results of an exploratory analysis from the Phase III JAVELIN Bladder 100 trial with 19 additional months of follow-up data from the initial primary analysis. This analysis reinforced the original results and showed that Bavencio^® plus best supportive care (BSC) in the first-line maintenance setting prolonged median overall survival by 8.8 months versus BSC alone for patients with locally advanced or metastatic UC whose tumors had not progressed on a platinum-based chemotherapy.

In June, 30 abstracts featuring key data from our broad oncology clinical portfolio were presented at the ASCO Annual Meeting. Highlights included:

New analyses of long-term data from the Phase III JAVELIN Bladder 100 study of Bavencio^® as first-line maintenance treatment in advanced UC, including data from subgroups defined by best response to first-line chemotherapy and in patients who did or did not receive second-line treatment after Bavencio^® maintenance.

Data for the oral MET inhibitor Tepmetko^®, including two poster presentations from the VISION trial reporting efficacy, safety and quality-of-life results of Tepmetko^® in Asian patients with METex14 skipping NSCLC, and updated efficacy and safety results of Tepmetko^® and exploratory biomarker analyses in patients with NSCLC with high-level MET amplification enrolled into Cohort B of the VISION trial based on liquid biopsy.

Abstracts from key investigator-sponsored studies exploring Erbitux^® (cetuximab)-based combinations, including the Phase III FIRE-4 study of early switch-maintenance from Erbitux^®/FOLFIRI to bevacizumab/5-FU and rechallenge in later lines for patients with RAS wild-type metastatic colorectal cancer (mCRC), and the Phase II AVETUXIRI study evaluating Bavencio^® combined with Erbitux^® and irinotecan for refractory microsatellite stable mCRC.

At the European Society of Medical Oncology (ESMO) Annual Meeting, held September 9-13, we shared 29 abstracts, including five late-breaking oral presentations and two additional mini-oral presentations, demonstrating the potential to make a transformative impact for patients with cancer.

For xevinapant, a late-breaking presentation of five-year results from the 96-patient Phase II study showed that adding xevinapant to chemoradiotherapy (CRT) markedly improved long-term efficacy outcomes in patients with unresected LA SCCHN, more than halving the risk of death over five years compared with placebo. This is the first randomized trial in decades to show significant improvement in overall survival in patients with LA SCCHN, reinforcing the transformative potential of xevinapant over standard of care in the curative setting.

• Initial results from the Phase II INSIGHT 2 trial of Tepmetko^® plus osimertinib in the treatment of patients with EGFR-mutant NSCLC with MET amplification after progression on first-line treatment with osimertinib showed encouraging signs of clinical activity with this targeted, oral, chemotherapy-sparing regimen
• Data from DDRiver Solid Tumors 301, the first-in-human Phase I study of M1774, our potentially best-in-class potent and selective inhibitor of ataxia telangiectasia and Rad3-related (ATR), were featured in a mini-oral presentation. This research, which showed a favorable safety profile and pharmacologically relevant exposure in patients with advanced solid tumors, exemplify our commitment to advancing understanding of DNA damage response (DDR) inhibition mechanisms.
• For Bavencio^®, translational data characterizing genomic biomarkers in peripheral blood from patients enrolled in the Phase III JAVELIN Bladder 100 trial were shared as a late-breaker]. Additional presentations included exploratory analyses from JAVELIN Bladder 100 that examined clinical outcomes in long-term responders with advanced UC treated with Bavencio^® first-line maintenance for ≥12 months.
• Additional data for Tepmetko^® included results from cohorts A and C in the Phase II VISION trial, which demonstrated robust and durable efficacy in treatment-naïve and previously treated patients with metastatic NSCLC with METex 14-skipping. In previously treated patients, efficacy was observed regardless of prior therapies including immunotherapy and/or platinum-based chemotherapy.

On June 3, we announced that, following an interim analysis of the ongoing global Phase II DDRiver SCLC 250 trial of berzosertib in combination with topotecan in patients with relapsed, platinum-resistant small cell lung cancer (SCLC), the decision has been made to discontinue the study due to low probability of meeting the pre-defined objective of this trial. The safety profile for berzosertib plus topotecan was consistent with that observed in other clinical trials to date. The ongoing development of our ATR inhibitor M1774 will build on learnings from the exploration of berzosertib, which has been studied in approximately 1,000 patients to date in multiple combinations, including with chemotherapy, radiotherapy, immunotherapy and PARP inhibitors across company- and investigator-sponsored studies.

To further support our focused research and development efforts in the area of DDR inhibition, in September 2022 we entered a collaboration agreement with licensing option with Nerviano Medical Sciences S.r.l. for the next-generation highly selective and brain-penetrant PARP1 (poly (ADP-ribose) polymerase) inhibitor NMS-293. NMS-293 has strong potential in combination with a wide variety of DNA-damaging agents, including systemic or targeted chemotherapy (ADCs) or with DDR inhibitors, in numerous tumor types. NMS-293 is in early clinical development for the treatment of patients with BRCA-mutated tumors as monotherapy and in combination with temozolomide in recurrent glioblastoma. The option to license this molecule provides us with the optionality to develop a next-generation PARP inhibitor in combination with our early pipeline of DDR inhibitors and DNA-damaging ADCs.

Neurology & Immunology

Multiple sclerosis (MS) is one of the world’s most common neurological diseases. Despite the emergence of a number of therapies in the last two decades, there are still significant unmet needs for people living with MS. As a company we have more than 20 years of experience in MS research, and we remain committed to finding solutions for significant unmet medical needs for those living with the disease.

New data for our investigational treatment evobrutinib, along with Mavenclad^® (cladribine tablets) have been presented across key congresses in 2022, including the European Committee for Treatment and Research in Multiple Sclerosis (ECTRIMS) Congress in October, the American Academy of Neurology (AAN) Annual Meeting in April and the Americas Committee for Treatment and Research in Multiple Sclerosis (ACTRIMS) Forum in February.

We presented a total of 39 abstracts at ECTRIMS including data that demonstrated long-term disease stability, showing annualized relapse rates (ARR) remained low and Expanded Disability Status Scale (EDSS) scores were stable for people living with RMS treated with evobrutinib in the longest-running and most extensive analysis of any BTK inhibitor in development for RMS. As well, we presented phase IV study highlights improvement in measures of Quality of Life in people living with RMS after two years of treatment with Mavenclad^®.

At AAN, we presented new Phase II data which showed evobrutinib had sustained low annualized relapse rates (ARRs) and had no new safety signals at 2.5 years. As well, updated safety data continue to demonstrate people living with MS that were treated with Mavenclad^® (cladribine tablets) for their MS who had confirmed or suspected Covid-19 experienced mild to moderate disease symptoms and no increased risk of serious outcomes.

At ACTRIMS, we presented new Mavenclad^® data that showed favorable efficacy outcomes as compared to other oral DMTs, with a lower occurrence of further relapses or disability progression. Additional clinical trial data show people living with MS treated with Mavenclad^® early after a first clinical demyelinating event had a lower occurrence of further relapses or disability progression as compared to placebo.

Fertility

At the 2022 European Society of Human Reproduction and Embryology (ESHRE) in July, we announced a clinical study for a new innovative smart fertility patient hormone monitoring solution. This is a non-invasive device that allows hormone monitoring from the comfort of a patient’s home while enabling clinicians to monitor hormone levels remotely as well as to support their clinical decisions. Through this device, we hope to improve both the patient experience and the efficiency of clinic workflows by increasing convenience and flexibility. The first patient enrolled in August.

Cardiovascular Metabolism & Endocrinology

The new formulation of Euthyrox^® (levothyroxine) for the treatment of hypothyroidism obtained further regulatory approvals in 2022, resulting in a total of 91 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 69 countries prediabetes when lifestyle intervention is not enough to control the condition. With a successful label extension of Glucophage^® and Glucophage^® XR in Europe during this year, our metformin products are the first ones that are authorized to be used, in the approved indications, during the pregnancy and around conception. The label update on the mechanism of action, also achieved for EU this year, gives credit to the still growing understanding and opportunities for metformin in the diabetes continuum.

Concor^®/Concor Cor^®, containing bisoprolol, is a beta-blocker for treating hypertension and cardiovascular diseases such as coronary heart diseases and chronic heart failure. In addition to Concor^®/Concor Cor^®, the Concor^® family offers fixed-dose combinations such as Concor Plus^®/Lodoz^® (bisoprolol with hydrochlorothiazide) and Concor AM^® (bisoprolol with amlodipine). In 2022, Concor^® AM, our fixed-dose combination drug to treat hypertension, has been registered in 68 countries.

Ensuring the supply of our medicines to our patients

We are striving to ensure the supply of our high-quality medicines to patients around the world regardless of circumstances, while always observing the highest standards of health and safety for our people and partners.

Since the start of the Covid-19 pandemic, we have been continuously making every effort to proactively handle the situation and minimize the impact of the pandemic and also of any challenges from the external context on the supply of our medicines locally and globally. To this end, we are using three main levers: the thorough implementation of our business continuity plans across our network and their further development, the active management of our stocks, and the assessment of alternative transportation routes to reach our customers and patients.

In the context of the war in Ukraine, we have taken a number of measures to continue to supply to the best of our ability patients who rely on our medicines in the countries impacted, while ensuring the strictest compliance with international sanctions. These measures include constantly monitoring and updating our demand plans, building safety stocks locally, accelerating the shipment of goods from our European sites to the countries impacted and defining back-up air shipment routes in addition to truck transportation to ensure the highest flexibility at all times.

Building for the future

As part of our commitment to accelerate the discovery and availability of future medicines for patients in need, we marked the cornerstone laying for our Translational Science Center in July, and for our Launch and Technology Center in September, at our Darmstadt campus. They are both expected to be fully operational by the end of 2025 and are part of the € 1.5 billion investment package that we announced in March.

The Translational Science Center, which represents an investment of € 200 million, will be a 30,000 square meter, fully integrated, multi-use building including laboratories, a lecture hall, and office space allowing scientists from different disciplines to explore new avenues of research in fields ranging from identifying disease biomarkers to developing targeted therapies.

The Launch and Technology Center, which represents an investment of € 160 million, will offer 13,900 m² of space. It combines a highly technological environment with human-centered design, bridging research and commercial manufacturing, and ensuring that our next generation of pharmaceuticals are available for clinical trials, global launches and commercial supply on time, and in the right quality and quantity.

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