The Merck Serono pipeline has a strong focus on oncology. Currently, 16 projects are in various phases of clinical development.
In late 2012, approval was obtained in Japan from the Ministry of Health, Labor and Welfare for the use of Erbitux® in adult patients with head and neck cancer. The division also announced the decision to voluntarily withdraw the marketing authorization application to the European Medicines Agency (EMA) of a label extension for Erbitux® in combination with standard first-line platinum-based chemotherapy in patients with advanced or metastatic non-small cell lung cancer (NSCLC) with high epidermal growth factor receptor (EGFR) expression. The decision to withdraw the application was based on feedback from the EMA, indicating that further clinical data would be required. Merck Serono reported a negative outcome of the EXPAND trial, which assessed Erbitux® as a first-line treatment for patients with advanced gastric cancer, and the PETACC-8 trial, assessing Erbitux® for the adjuvant treatment of stage III colon cancer. Merck will not pursue further development of Erbitux® in the lung, gastric or adjuvant colon indications. These results do not alter the current utility of Erbitux® in patients with KRAS wild-type mCRC and in patients with locally advanced or recurrent and/or metastatic SCCHN in those markets where Erbitux® is currently registered in these indications.
The division continued to strengthen its early- and mid-stage pipeline via strategic transactions. Two oncology projects were in-licensed during 2012. A global agreement to license and co-develop TH-302, an investigational small molecule hypoxia-targeted drug, was followed by an exclusive worldwide license agreement for Sym004, potentially complementing and building upon Merck’s existing Erbitux® franchise.
At the time of in-licensing, TH-302, a molecule designed to be activated under severe tumor hypoxic conditions was already being investigated in a Phase III in patients with soft tissue sarcoma (STS). Following the positive outcome in a Phase IIb trial in patients with advanced pancreatic cancer (PaCa), presented at the Association for Cancer Research meeting in April 2012, the decision was made later in the year to proceed to Phase III. For both indications (STS and PaCa), an agreement was reached with the FDA regarding a Special Protocol Assessment (SPA). The STS indication has also been assigned orphan drug status in the United States as well as in the EU. In addition, the use of TH-302 in other solid tumors and hematological malignancies is being evaluated in several Phase I trials.
Sym004 is an investigational product comprised of two antibodies that are designed to block ligand binding, receptor activation and downstream signaling as well as to elicit removal of EGFR from the cancer cell surface by inducing their internalization and degradation. Sym004 is currently being evaluated in a Phase I/II trial in patients with advanced KRAS wild-type mCRC. In addition, a single-arm, open-label Phase II trial is underway in patients with SCCHN who have failed anti-EGFR-based therapy.
Pimasertib, Merck Serono’s MEK inhibitor, is an investigational small molecule inhibitor of MEK1/2, which is part of the MAPK signaling pathway. This pathway is up-regulated in various types of cancer. Pimasertib moved to Phase II in PaCa as well as in N-Ras mutated cutaneous melanoma. Around 25% of melanoma patients have N-Ras mutated tumors and have currently limited effective treatment options.
L-BLP25 (formerly known as Stimuvax) is an investigational MUC1 antigen-specific cancer immunotherapy designed to stimulate the body’s immune system to identify and target cells expressing MUC1. MUC1 is expressed in many cancers, such as NSCLC. L-BLP25 was being investigated in the Phase III START trial and is currently being investigated in the Phase III INSPIRE trial, both for the treatment of unresectable stage III NSCLC. In late 2012, the START trial reported a negative outcome missing the primary endpoint of extending overall survival. Notable treatment effects were observed, however, in certain subgroups. Based on further analysis still to be done, Merck Serono will decide on the future of the L-BLP25 development program in 2013. The ongoing clinical program of L-BLP25, including INSPIRE, will continue pending discussion with relevant regulatory agencies.
Concerning cilengitide, Merck Serono’s investigational integrin inhibitor, the outcome of the pivotal, randomized Phase III CENTRIC trial is expected in the first half of 2013. The study follows a biomarker-guided approach focusing on newly diagnosed glioblastoma patients with methylated MGMT (methylguanine-DNA methyltransferase) gene promotor status since it is thought they might be more likely to benefit from combination treatment with temozolomide, radiotherapy and cilengitide. To ensure the availability of a qualified diagnostic, Merck Serono expanded its collaboration with MDxHealth, a diagnostic company, to support the development and regulatory activities for the MGMT test. During 2012, the development of cilengitide in SCCHN was stopped following negative Phase II results. The Phase II study combining cilengitide with Erbitux® and chemotherapy for the treatment of NSCLC continues. Since Erbitux® is not registered for NSCLC, the results of this study can serve only for further hypothesis generation.
In the field of MS, FDA approval of the Rebif® Rebidose injector for patients with relapsing forms of MS was received early 2013. The device was evaluated in a 12-week Phase IIIb multicenter, open-label, single-arm study for the self-administration of Rebif® with respect to ease of use, patient satisfaction and acceptability, and functional reliability.
Turning to ONO-4641, a sphingosine-1-phosphate receptor modulator, a positive outcome from the Phase II DreaMS study in patients with relapsing MS was presented at the American Academy of Neurology meeting in May 2012. Currently, further studies, both non-clinical and clinical, are being performed which will provide more information on efficacy, safety and the potential for differentiation of this agent to allow Merck Serono to make an informed decision about whether to advance this project to Phase III in 2013. An immune tolerizing agent (ATX-MS-1467) is close to delivering Phase I trial results.
After careful evaluation of the available Phase I data, the division decided to end the development of long-acting interferons in the area of MS.
In the area of immunology, Merck Serono is currently analyzing data from the double-blind, placebo-controlled Phase II study (APRIL SLE) assessing the therapeutic value of atacicept in systemic lupus erythematosus (SLE). The trial initially investigated two doses of atacicept in patients who were stable following steroid taper, and measured the effect of the drug on new disease flares. The study recruited more than 450 patients. The complete clinical and biomarker data from this study are expected to be presented at a scientific conference in the first half of 2013.
Development of sprifermin (fibroblast growth factor 18), a recombinant protein, is ongoing in the treatment of knee cartilage injury in the context of a Phase II study. Two Phase I studies were completed in patients with osteoarthritis of the knee joint.
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