The Merck Serono pipeline in 2013 Audited

Merck Serono’s core R&D fields include oncology, immuno-oncology, immunology and neurology. The development pipeline continues to be weighted towards oncology, however 2013 also saw important scientific and business development advances in other areas. Merck Serono has an open collaborative model in R&D and in reflection of this a number of collaborations were entered into during 2013, some of which are highlighted below.

In December 2013 the European Commission approved an amendment to the Erbitux® (cetuximab) product information, updating the indication for Erbitux® to the treatment of patients with RAS wild-type metastatic colorectal cancer (mCRC). The European Commission approval is based on the totality of data emerging on the role of mCRC RAS tumor status in the benefit–risk profile of anti-EGFR monoclonal antibodies. The approval primarily refers to new biomarker data from the OPUS (OxaliPlatin and cetUximab in first-line treatment of mCRC) study. OPUS is a randomized, controlled, Phase II trial, involving 337 mCRC patients, 179 with KRAS wild-type (exon 2) tumors, demonstrating the efficacy of Erbitux® plus FOLFOX-4 (oxaliplatin-based therapy) versus FOLFOX-4 alone. Results of a RAS tumor status analysis were presented at the Gastrointestinal Cancers Symposium (American Society of Clinical Oncology – GI meeting) in January 2014, in San Francisco. Recent analyses of multiple studies evaluating monoclonal anti-epidermal growth factor receptor (EGFR) antibodies, such as Erbitux®, examined KRAS wild-type tumor status (exon 2) for additional RAS mutations (defined as mutations in exons 3 or 4 of KRAS and/or exons 2, 3 or 4 of NRAS). The results from these studies suggest that patients with RAS wild-type tumors may benefit from treatment with Erbitux®, while patients with RAS mutant tumors may not. The Summary of Product Characteristics of Erbitux® has therefore now been updated as part of the European Commission approval.

Initial results of the independently run FIRE-3 study, a randomized, controlled, head-to-head Phase III trial comparing Erbitux® and bevacizumab on top of standard chemotherapy (FOLFIRI) in patients with KRAS wildtype metastatic colorectal cancer (mCRC), were presented at the American Society of Clinical Oncology (ASCO) meeting in 2013 by the German cooperative investigator group AIO. The study did not achieve the primary endpoint as the objective response rate (ORR) was not significantly different for the two treatment arms: 62% for Erbitux® combination versus 58% for bevacizumab combination. However, investigators reported the median overall survival based on a 57% event rate was 28.7 months for the Erbitux® plus FOLFIRI group versus 25.0 months for the bevacizumab plus FOLFIRI group. The toxicity profiles in the two groups were manageable and as expected from previous studies.

Also at the 2013 ASCO meeting, data were presented from two proof-of-concept Phase II trials, evaluating the safety and efficacy of Sym004, an early-stage development opportunity inlicensed from Symphogen, a private Danish biopharmaceutical company developing recombinant antibody mixtures. Sym004 is a mixture of two chimeric monoclonal antibodies (mAbs) against different parts of the Epidermal Growth Factor Receptor (EGFR). Both mAbs bind EGFR with high affinity but have only limited preclinical activity individually. Synergistic inhibition has however been demonstrated by the Sym004 mixture both in vitro and in vivo. Results from a Phase II study in metastatic colorectal cancer showed clinical activity in anti‐EGFR treatment‐refractory KRAS wild-type mCRC patients, warranting further development. No unexpected adverse events were observed. In a Phase II study in squamous cell cancer of the head and neck (SCCHN), Sym004 demonstrated clinical activity in heavily pretreated patients with advanced SCCHN previously progressing on, or after therapy with already available anti‐EGFR mAbs. No unexpected toxicities were reported.

Turning to TH-302, an investigational hypoxia-targeted drug, the global Phase III MAESTRO study was launched in late 2013, to assess its efficacy and safety in combination with gemcitabine, in patients with previously untreated, locally advanced unresectable or metastatic pancreatic adenocarcinoma. This followed a positive Phase II study in this indication which was reported at the American Association for Cancer Research (AACR) meeting in 2012. MAESTRO is a randomized, placebo-controlled, international, multi-center, double-blind Phase III trial of TH-302 plus gemcitabine compared with placebo plus gemcitabine and is targeted to enroll 660 patients. The primary efficacy endpoint is overall survival and secondary endpoints include progression-free survival (PFS), overall response rate and disease control rate, as well as assessments of safety and tolerability, pharmacokinetics and biomarkers. The study is being conducted under a Special Protocol Assessment (SPA) with the U.S. Food and Drug Administration (FDA). An SPA is a review conducted by FDA on a clinical trial that will form the primary basis of an efficacy claim in a marketing application. MAESTRO is the second Phase III study of TH-302 since there is already an ongoing study in soft tissue sarcoma patients assessing the efficacy and safety of TH-302 in combination with doxorubicin. This trial is targeted to enroll 620 patients in order to investigate the effect in overall survival for patients being treated with the combination. This trial is being conducted by Threshold Inc. also under an SPA with the U.S. FDA.

In the first quarter of 2013 Merck announced that its Phase III CENTRIC study of the investigational integrin inhibitor cilengitide given in combination with standard chemoradiotherapy for patients with newly diagnosed glioblastoma (brain tumors) and methylated MGMT gene promoter status, did not reach its primary endpoint of significantly increasing overall survival. The trial was conducted in partnership with the European Organisation for Research and Treatment of Cancer (EORTC), and its results were presented at the ASCO meeting in June 2013. In view of the results of this study, Merck decided to discontinue the overall development program for cilengitide.

Tecemotide, a MUC1 antigen-specific cancer immunotherapy (formerly referred to as Stimuvax and L-BLP25) is being investigated in patients with inoperable locally advanced non-small-cell lung cancer (NSCLC). In September, Merck announced its decision to proceed with a new Phase III study: START2 which is planned to include around 1,000 patients. This was based on the results of the Phase III START study, which were also presented at the ASCO 2013 annual meeting, as well as on consultation with certain regulatory authorities. While the primary endpoint of the START study was not met, a post-hoc analysis of a large predefined subgroup of patients from the study (consisting of 853 patients), who had received initial concurrent chemoradiotherapy (CRT) followed by tecemotide, demonstrated longer overall survival compared to those who had received concurrent CRT plus placebo (30.8 months, versus 20.6 months; p=0.016). START2 is a randomized, double-blind, placebo-controlled multicenter Phase III trial designed to assess the efficacy, safety and tolerability of tecemotide in patients with unresectable, locally advanced NSCLC who showed response or stable disease after at least two cycles of platinum-based concurrent CRT. Concurrent CRT is the current standard of care for these patients. The primary endpoint of START2 is overall survival. Merck received scientific advice from the European Medicines Agency (EMA) on the program, and reached an agreement with the U.S. FDA on an SPA for this study.

Also during the ASCO 2013 meeting in June 2013 data were presented from two pimasertib trials. Results from a Phase I trial in combination with Sanofi’s dual PI3K/mTOR inhibitor (SAR245409) in advanced solid tumors showed that continuous daily dosing of pimasertib and SAR245409 is tolerated and has shown signs of activity. In addition, results from the ongoing study of pimasertib in combination with gemcitabine in patients with pancreatic cancer showed activity at a dose of 60 mg twice per day, and this is now being investigated further in this indication. In the fourth quarter of 2013 an additional Phase I trial was initiated of pimasertib in combination with Sanofi’s hDM2 inhibitor (SAR405838) in patients with solid tumors.

In June Merck Serono announced its commitment to the field of cancer immunotherapy by creating a fully dedicated immuno-oncology translational innovation platform (or TIP) integrating research, early development and biomarker strategies. In addition to the division’s existing oncology platform, this new immuno-oncology platform is focusing on developing therapies that leverage the immune system’s natural ability to fight tumors, and work in combination with existing and future therapies in the following areas:

Therapeutic cancer vaccines: targeting tumor antigens to elicit a tumor-specific immune response

Cancer stem cells: targeting cancer stem cells to prevent or reduce tumor formation and inhibit metastases

Immunotolerance: eliminating or circumventing inhibitory mechanisms in the immune system that prevent cancer cells from being recognized and attacked by the body

To ensure a broad immuno-oncology research and early development platform, an in-house team of researchers and clinicians has been assembled to build a portfolio of investigational immunotherapies, while collaborating with leading academic, research and industry organizations to complement internal capabilities. The current immuno-oncology portfolio comprises a robust pipeline of preclinical molecules as well as several therapeutic candidates in early clinical development (Phase I) in solid tumors, including:

• Anti-PD-L1, a monoclonal antibody targeting PD-L1 (programmed cell death ligand) expressed by various tumors
• NHS-IL12, a cancer immunotherapy targeting IL-12 to the necrotic regions of tumors, sponsored by the U.S. National Cancer Institute (NCI)
• NHS-IL2, targeting IL-2 to the necrotic regions of tumors

Merck’s approach is to develop immunotherapies that can be combined with other therapeutic modalities, bearing in mind that attacking multiple cancer targets simultaneously increases the possibility of therapeutic success.

Several collaborations between Merck and other organizations were announced in the field of oncology throughout 2013. These included:

• A collaboration to run innovative projects in oncology under the roof of an innovation center operated by BioMed X GmbH on the campus of the University of Heidelberg. The objective is to seed and boost early stage research projects in the field of oncology. This new research lab will establish a new way of fostering innovation, a concept that has been co-developed by Merck Serono and BioMed X. It will allow Merck Serono to run research projects with interdisciplinary project teams of young talented scientists recruited worldwide and coached by a supervisor from the division, in the vibrant environment of an open-innovation lab facility.
• Selvita, a biotechnology company based in Krakow, Poland, in the field of joint discovery and lead optimization for small-molecule-based drugs targeting proteins involved in cancer cell metabolism. The partners plan to target key metabolic pathways involved in sustaining growth and the proliferation of cancer cells with the aim of delivering potential first-in-class candidate drugs for multiple oncology indications.
• BeiGene Co., Ltd., a biotech research and development company based in China. In 2013, Merck entered into two agreements with this company to co-develop, and commercialize two molecules for the treatment of cancer: BeiGene-283, a second-generation BRAF inhibitor that is currently in preclinical development. BRAF is a protein that is a downstream component of the MAPK (mitogen-activated protein kinase) signaling pathway, which is thought to promote cancer cell growth, and that is dysregulated in a number of human cancers. BeiGene-290, a potent poly (ADP-ribose) polymerase (PARP) inhibitor which is currently in preclinical development. PARP inhibitors target an enzyme family which is involved in a number of cellular processes, including DNA repair and programmed cell death.
• Spanish National Cancer Research Centre (CNIO) in the area of cancer drug development. The agreement builds upon CNIO’s research discoveries to encourage the development and commercialization of new compounds. As part of the agreement Merck has been granted exclusive rights to develop and commercialize CNIO’s new inhibitors of the ataxia telangiectasia and Rad3-related (ATR) kinase. This enzyme has an important role in the response to DNA damage and in facilitating cell survival. Due to the fact that tumor cells accumulate more DNA damage than healthy cells, blocking ATR kinase activity with selective inhibitors is a strategy worth investigating further for specific tumor types.

The division is moving ahead with the development of a portfolio of biosimilar compounds applicable to various disease areas including oncology and rheumatology.

Turning to the multiple sclerosis (MS) field, ONO-4641 (ceralifimod), a sphingosine-1-phosphate receptor modulator, showed positive results in the Phase II DreaMS study in patients with relapsing MS, and these were presented at the American Academy of Neurology (AAN) annual meeting in 2012. In 2013 further studies, both non-clinical and clinical, were performed and provided more information on efficacy, safety and the potential for differentiation of this agent, including 12-month results from an ongoing blind DreaMS extension study presented at the 29th annual meeting of the European Committee for Treatment and Research in Multiple Sclerosis (ECTRIMS) in October. Merck Serono is in discussions with certain regulatory authorities concerning potential Phase III study designs. The final decision about the future of the Phase III program will be made in the second quarter of 2014.

One project in the MS field advanced into Phase II in the fourth quarter of 2013, namely plovamer acetate, a second-generation peptide copolymer immunomodulator. This study is targeted to include 550 patients with relapsing-remitting multiple sclerosis (RRMS) in over 120 centers internationally. In addition an immunetolerizing agent known as ATX-MS-1467, which is intended to reduce an inappropriate immune response against certain components of the patient’s own nervous tissue, completed Phase I testing and is being prepared for a proof of principle Phase IIa study in patients with RRMS. This is scheduled to start in the first half of 2014.

Early in 2013 Merck announced that it had been granted an option by Opexa Therapeutics, Inc. for the development and commercialization of Tcelna™ (imilecleucel-T), as a potential first-in-class therapy for patients suffering from MS. Tcelna™ is being developed by Opexa and currently is in a Phase IIb clinical trial in patients with secondary progressive MS (SPMS). It is being developed as a personalized therapy specifically tailored to each patient’s individual disease profile and has been evaluated in Phase I and II clinical studies in MS. Tcelna™ has received Fast Track Designation from the U.S. FDA as a potential treatment for SPMS.

In the fourth quarter of 2013 Merck Serono signed a memorandum of understanding with the Israel biotech company Kadimastem, which develops human pluripotent stem cell-related products. The aim is to utilize the screening platform of Kadimastem to characterize new compounds which could act as remyelinating agents in MS; as well as to possibly extend the collaboration into related fields like amyotrophic lateral sclerosis (a form of motor neuron disease).

In the field of Immunology, Merck decided to focus the development of its investigational drug sprifermin (recombinant human FGF-18) on the osteoarthritis (OA) indication and to embark on a new multinational Phase IIb study known as FORWARD in patients with OA of the knee. This is being performed as part of a strategic alliance on sprifermin that Merck entered into in early 2013 with Nordic Bioscience Clinical Development A/S of Denmark. Sprifermin is a protein thought to stimulate cells known as chondrocytes to synthesize cartilage matrix and to renew themselves. The alliance draws on the joint expertise and resources of Merck and Nordic Bioscience which will provide clinical development services to Merck on a shared-risk basis. Merck retains full responsibility for the development and commercialization of sprifermin. The FORWARD study further evaluates sprifermin for inhibition of the progression of structural damage, reduction of pain and improvement of physical function in patients with OA of the knee. This study was initiated in the third quarter of 2013 and is planned to include over 500 patients.

Merck is currently investigating atacicept (anti-Blys/anti-APRIL fusion protein) for the treatment of systemic lupus erythematosus (SLE). Clinical and biomarker results from the APRIL SLE Phase II study of atacicept were presented at the Annual Meeting of the European League Against Rheumatism (EULAR) in June 2013. APRIL SLE was a double-blind, placebo-controlled study assessing the therapeutic value of atacicept in SLE. While no statistically significant difference was observed in the number of patients experiencing a disease flare between atacicept 75 mg and placebo during the 52 week treatment period (primary endpoint), post hoc analyses suggested that treatment with the 150-mg dose of atacicept was associated with a reduced number of patients experiencing SLE flares versus placebo (36.6% versus 54.1%). Based on the totality of data from the APRIL SLE study Merck decided to proceed to a new Phase II study: ADDRESS II. This is a double-blind, placebo-controlled study to further assess the efficacy and safety of atacicept at two doses (75 mg and 150 mg given subcutaneously once per week) in reducing SLE disease activity in patients receiving standard-of-care therapy. The primary endpoint of the study will investigate the effect of atacicept in reducing disease activity.

In early 2013 Merck and the Feinstein Institute for Medical Research, the research division of the North Shore-Long Island Jewish Health System in New York, announced that they will collaborate to develop antibodies as potential treatments of SLE. This collaboration allows Merck Serono to further strengthen its research in SLE with the intention of developing new treatments for this disease.

In March, Merck Serono announced the creation of Calypso Biotech in Geneva, Switzerland, a spin-off company resulting from its Entrepreneur Partnership Program (EPP) which was launched in April 2012. Formed around an R&D portfolio in the field of inflammatory bowel diseases, Calypso will target selected niche indications with high unmet medical needs.

Merck Serono has a strong legacy in fertility and continues to pioneer innovative science that advances its goal of improving pregnancy outcomes and “take home baby rates”. Gonal-f® (recombinant follitropin alfa for injection) is prescribed to supplement or replace naturally occurring follicle-stimulating hormone (FSH), an essential hormone widely used to treat infertility. In the fourth quarter Merck Serono announced that the U.S. FDA granted approval for Gonal-f® RFF Redi-ject™ (follitropin alfa injection), a disposable pre-filled injection device intended for the subcutaneous injection of a liquid formulation of Gonal-f® RFF (Revised Formulation Female). This pen is part of a global product franchise of ready-to-use pens with demonstrated dose accuracy designed for patient self-administration of Merck’s fertility hormones (gonadotropins). Merck Serono is continuously innovating to improve its injection devices in order to meet the needs of patients and health care professionals alike.

Fertility research continues to be an important focus of R&D innovation. In December 2013 Merck Serono announced the creation of TocopheRx, a Boston-based spin-off company resulting from its EPP, and is seed financed by MS Ventures. TocopheRx, the eighth spin-off in the EPP will focus on an oral follicle-stimulating hormone (FSH) agonist for treatment of infertility, a promising early asset that could help couples seeking solutions for fertility problems. An oral FSH agonist would have obvious advantages to the patient since injections of this hormone would be avoided. TocopheRx will advance Merck Serono’s preclinical program towards clinical testing, bringing forward an innovative Merck Serono investigational asset through externalization in a capital-efficient manner. This project demonstrates Merck’s continued commitment to developing the next-generation of infertility treatments and required technologies to improve the success rate of in vitro fertilization procedures as well as patient convenience.

Merck announced its strong support for the Grant for Fertility Innovation (GFI) award with grants totaling up to € 4 million for the years 2013/2014. The announcement was made during the 29th 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, more than 600 applications were received from over 50 countries around the world, and 26 projects from 16 countries were awarded grants totaling € 6 million. Merck Serono has recently launched similar Grants for Innovation in the fields of multiple sclerosis, oncology and growth disorders. The first four awards of the Grant for Multiple Sclerosis Innovation (GMSI) were presented on the occasion of the 29th annual meeting of ECTRIMS in Copenhagen in October 2013.

Merck Serono entered into several collaborations relevant across all of its core R&D fields of Oncology, Immuno-oncology, Immunology and Neurology, as follows:

• Merck and Ablynx announced in the third quarter of 2013 that they have further expanded their relationship through a research alliance that could lead to several co-discovery and co-development collaborations. Merck Serono will fund a dedicated discovery group at Ablynx to develop Nanobodies® against a number of targets of interest to Merck Serono.
• Merck and Open Monoclonal Technology, Inc., a leader in the genetic engineering of animals for the development of human therapeutic antibodies, announced the expansion of the collaboration agreement they entered into in 2012. Merck Serono will now have unlimited access to the OmniRat™ technology platform.
• Merck Serono announced a five-year strategic partnership broadening its collaboration with the Lead Discovery Center GmbH (LDC), Dortmund, Germany, a renowned translational research organization. The new agreement integrates the expertise and resources of both organizations to expedite the discovery and development of therapeutic candidates in diseases with high unmet medical needs in areas of interest to Merck Serono. The first project under the new agreement is in immunology and emerged from an ongoing collaboration of LDC with the Max-Planck researcher and Nobel Laureate Professor Robert Huber.

Merck Serono’s Israel Bioincubator continued to develop in 2013. The Bioincubator is financed by the € 10 million Merck Serono Ventures Israel Bioincubator and is focused on preseed and seed opportunities originating in Israel. In addition to housing Neviah Genomics, the following two companies joined in late 2013: Metabomed, which focuses on research in the field of cancer metabolism and computational biology; and ChanBio, which focuses on the discovery of antibodies selective for ion channels, considered to be potential therapeutic targets for the treatment of MS.

In the field of growth disorders, an updated version of the easypod® system for use in European markets was presented in September 2013 on the occasion of the 9th Joint Meeting of Paediatric Endocrinology organized by the European Society for Paediatric Endocrinology (ESPE). The easypod® system is an electronic, fully automated recombinant human growth hormone injection device that provides accurate data on treatment adherence. The new easypod® system provides information to help physicians address the issues of poor patient compliance and low adherence rates that are often associated with growth hormone (GH) therapy.