Focus on value and time to market: Clinical development pipeline set to fuel sustainable growth
London/UK and Darmstadt/Germany, 26 October 2000 - Merck KGaA´s clinical development pipeline is going to deliver innovative medicines into therapeutic areas where new or better treatments are needed. Twenty-five different projects at various stages of clinical develop-ment will each make their own decisive contributions to the growth and the expansion of the entire Merck Group in the coming few years.
- Laedership in Oncolog: Starting from 2003, Merck intends to launch every year alt least one new therapeutic option for the treatment of cancer.
- Ledership in Diabetes: The most comprehensive portfolio of oral antidiabetics (Glucophage, Glufovance, Glucophage XR and Starlix) gives Merck a leading position in type 2 diabetes, secured by future projects.
- Pipeline review process completed: Resources targered towards project with earlier potential launch or greater commercial value.
"The high expenditures for R&D we´ve invested in Pharmaceuticals over the recent years have been money well-spent. We have gained exciting results, and now it´s time to bring innovative, high potential drugs to the marketplace", Prof. Dr. Bernhard Scheuble, Chairman and CEO of Merck KGaA, told journalists and financial analysts at a business briefing in London.
Over the last years, Merck KGaA has expanded its R&D spendings to a far greater extent than has generally been the case for the industry as a whole. Most recently, Merck invested more than EUR 514 million in R&D in 1999; roughly two thirds of this amount was spent for Pharmaceutical R&D efforts in the area of in-nov-ative ethical products.
Intelligent alliances and licence agreements
One key element of Merck´s R&D strategy is the establishment of intelligent research alliances and license agreements with partners the whole world over, said Scheuble. Merck was quick to recognize the opportunities that this concept offers in allowing the company to successfully keep pace with the major companies in the international race and to continue to play a professional role in the global R&D league. Since 1994, Merck has concluded more than 25 major R&D and license agreements with cutting-edge international pharmaceutical and biotech companies.
"Acquisitions like Lexigen Pharmaceuticals (based in Lexington near Boston, MA) or intelligent research alliances such as the agreements with ImClone Systems (New York) are essential components of our success and have made a substantial contribution to our clinical R&D pipeline being as impressively fitted out as it is today", said Scheuble.
Focus on commercial value and time to market
Over recent months Merck has subjected the entire clinical R&D pipeline to a critical review, with the result that a series of refocussing measures have been taken. "Our aim here was to direct the available resources specifically towards projects with the potential of earlier product launch or greater commercial value for Merck", Scheuble said. "This target has now been achieved, and several projects have been defined which will enjoy fast track funding and development".
Particularly in the highly innovative field of Oncology, Merck is pursuing ambitious targets. From the year 2003 on, the company intends to launch one new therapeutic option per year in the fight against cancer - a new drug or an additional indication - into the market-place. In this regard, there are two specific R&D projects, the monoclonal anti-body Cetuximab (C225) and the immunocytokine KS-IL2, that are considered highly impor-tant and thus enjoy preferential funding and development. "We are committed to re-inforce our position as one of the worldwide leaders in Oncology on our four thera-peutic platforms and to expand this position even further", said Scheuble.
Focus on innovative strategies in Oncology - Biotherapeutic cancer treatment is expected to be more selective, more effective, with fewer side effects - Priority projects identified
Merck is committed to improve cancer treatment through the development of innovative therapeutic approaches. The Merck Oncology vision is to bring doctors and patients better cancer therapies by translating significant advances in medical research into new treatments. Merck's products target key factors that distinguish tumor cells from normal cells to focus treatment firmly on the tumor cells. This approach holds the promise of providing patients with more effective therapy accompanied by fewer side-effects. Four different strategies are currently under development:
Monoclonal antibodies (to block cancer growth)
Immunocytokines (to provide local stimulation of the immune system)
Angiogenesis inhibitors (to starve tumors)
Cancer vaccines (to immunize against tumors)
Monoclonal antibodies - blocking tumor growth -
Merck is developing monoclonal antibodies to target cancer cells and block tumor growth. Antibodies are proteins produced by the immune system in response to antigens (foreign substances or organisms). The human body contains millions of different antibodies, each specifically designed to bind to a different antigen. Substantial quantities of a particular antibody, known as a monoclonal antibody, can be obtained from specialized cells grown using standard laboratory techniques. Monoclonal antibodies have been used to investigate the molecular basis of cancer and have led to improvements in both the treatment and diagnosis of cancer.
Cetuximab (Phase III / Estimated Market Introduction: 2002)
In clinical terms, the most advanced of the Merck monoclonal antibody therapies is Cetuximab (also known as C225) which is being developed in collaboration with ImClone Systems Inc. in the US for the treatment of cancers of the head and neck, colon, rectum and pancreas. Cetuximab is a monoclonal antibody that specifically binds with high affinity to a cell-surface receptor called the epidermal growth factor receptor (EGFR). Activation of this receptor by binding of growth factors has been shown to contribute to the growth and spread of many different types of solid tumors. It also appears to protect cancer cells from the toxic actions of chemotherapy and radiotherapy, making these treatments less effective. Cetuximab blocks EGFR-mediated tumor-cell survival and growth by binding to EGFRs, blocking growth-factor binding and inhibiting EGFR activation.
Cetuximab is currently in clinical trials for the treatment of the cancers mentioned above, and as of June 2000, it has been used to treat more than 500 patients. Cetuximab is generally well tolerated and shows promising signs of providing effective treatment, especially when combined with chemotherapy or radiotherapy. Exciting results have also been achieved with patients for whom standard therapies were ineffective, and major international studies with Cetuximab are currently underway.
Bispecific Antibody H447
The bispecific antibody H 447 was tested in a phase II study in head and neck cancer patients. As Merck is re-focusing its resources towards project with earlier product launch or greater commercial value, Merck's funding of H447 has been put on hold.
Cancer vaccines - immunizing against cancer
Mitumomab (Phase III / Estimated Market Introduction: 2004)
Merck, together with ImClone Systems Inc., is also developing antibodies such as Mitumomab (also known as BEC 2) that act as vaccines against cancer cells. These antibodies mimic molecules present on tumor cells and stimulate the immune system to attack cancerous cells. The aim of immunotherapy with the BEC 2 vaccine is to induce an anti-tumor response in patients to a molecule called ganglioside GD3, which is found on the surface of several types of cancer cells, including lung and skin cancers. The BEC 2 vaccine was created by injecting a mouse with GD3 to produce an anti-GD3 antibody and then injecting a second mouse with the anti-GD3 antibody to generate an 'anti-idiotypic' antibody. The resulting BEC 2 antibody is similar to the original GD3 antigen, but because it is a protein, it induces a stronger immune response.
BEC2 is currently in advanced stages of clinical development. Safety data collected from a total of approximately 180 patients with small cell lung cancer and malignant skin cancer indicated that BEC2 was safe and generally well tolerated. A study of patients with small cell lung cancer conducted at the Memorial Sloan-Kettering Cancer Center in New York, USA, showed promising preliminary signs that BEC2 immunotherapy improved patient survival. A major study with BEC2 in patients with small cell lung cancer is presently underway in the US, Europe, Australia and New Zealand.
p21 RAS peptide (Phase II)
As part of an ongoing re-evaluation of its portfolio, Merck KGaA will return all rights for development of p21 RAS peptide vaccine to Norsk Hydro, the original licensor of the product. This agreement is based, in part, on a significant change to the planned launch in advanced pancreatic cancer, scheduled originally for 2003.
The collaboration between the two companies was highly successful with development of a shared expertise in the areas of production, regulatory issues and cancer vaccine development specific to peptides. Results from the phase 2 study conducted by Merck confirmed earlier studies demonstrating the immunological activity and the outstanding safety of the compound, however they also identified the need for further investigation into optimization of the vaccine regimen prior to moving into phase III. Additional results available from of a number of similar studies in the cancer vaccine field suggest the potential of the product in early (post surgical resection) settings of disease. However, due to the longer duration of such studies, launch was not possible in the original timeframe. A number of investigator-driven studies addressing these issues are scheduled.
Given the longer development timelines required to investigate either of these options, Merck prefers to focus its resources on other projects in oncology with potential for earlier launch.
Immunocytokines - local stimulation of the immune system
KS-IL2 / 14.18-IL2 (Phase I-II / Estimated Market Introduction: 2005)
The Merck Oncology portfolio also contains antibodies modified to stimulate the immune system locally, which in turn leads to the targeted destruction of cancer cells. The huKS-IL2 and hu14.18-IL2 immunocytokines, developed at Lexigen Pharmaceuticals, Merck KGaA´s U.S. Oncology Research Center based in Lexington, MA, are currently in early stages of clinical development. Immunocytokines are fusion proteins - two different proteins fused together. They are composed of an antibody portion which directs the fusion protein to the tumor cell and a molecule, such as interleukin-2 (IL2), that stimulates an immune response.
Preliminary findings show that this immune response may kill tumor cells and may lead to the development of immunological memory that provides protection from tumor cells for some time after treatment stops. Merck is developing immunocytokines to treat a variety of cancer types by targeting a number of different molecules found on the surface of tumor cells. Studies have shown that these fusion proteins elicit anti-tumor responses in several model systems, and early results from clinical trials have been encouraging. Merck has decided to further develop the KS-IL2 immunocytokine project with high priority.
Angiogenesis inhibitors - starving tumors
Cilengitide (Phase II / Estimated Market Introduction: 2004)
Merck's fourth anti-cancer strategy is to starve tumors using the angiogenesis inhibitor Cilengitide. Tumor-mediated angiogenesis is the development and growth of new vessels that link a tumor with existing blood vessels. Angiogenesis plays a significant role in the growth and spread of tumors by supplying nutrients and the means to reach multiple sites in the body. It is an ideal target for cancer therapy because angiogenesis is required for the continued growth and survival of all types of solid tumors.
The angiogenesis inhibitor Cilengitide is the product of a collaboration between Merck, the Munich Technical University and the Scripps Research Institute. It blocks angiogenesis by specifically inhibiting the function of the avb3 and avb5 integrins, receptor molecules required for the formation of new vessels. Studies with several different model systems have shown that Cilengitide is a potent and selective angiogenesis inhibitor with anti-tumor activity. Phase I/II clinical trials with Cilengitide are currently underway, and preliminary results indicate that it is well tolerated and safe in patients with advanced solid tumors.
Focus on Type-2 Diabetes - Extending the Glucophage family - New products successfully launched in the US
Merck KGaA´s metabolism franchise is currently the company´s largest therapeutic area, primarily due to the success of the Glucophage (metformin), one of the leading oral antidabetics world-wide. Glucophage, by far Merck KGaA´s best-selling product, has enjoyed remarkable sales growth following its success in the US since its launch by Merck KGaA´s US licensee, Bristol-Myers Squibb. World-wide sales of Glucophage accounted for EUR 1,393 Mio. in 1999 (+53 percent against 1998) and EUR 1,633 Mio in the first nine months 2000 (+61 percent against the same period 1999). The product represents roughly 15 percent of Merck KGaA´s total Ethicals drug sales.
As Glucophage lost its marketing exclusivity in the US by end of September 2000, Merck successfully introduced a comprehensive life cycle management program for the product during the last years. As a first result of this program, Glucovance, a combination product which contains metformin and glyburide, was approved by the FDA in August 2000 and introduced to the US market by Bristol-Myers Squibb later the same month. By the end of September, Glucovance already had attained a 2.1 percent share of new prescriptions in the market - one of the most successful product launches in the US ever.
Glucovance is intended for initial drug therapy, along with diet and exercise, for patients with Type 2 diabetes; as well as for second-line therapy in Type 2 diabetics whose blood glucose levels are inadequately controlled by either metformin or a sulphonylurea alone. By combining metformin and glyburide in a single pill, Glucovance offers significant compliance advantages for diabetics who require treatment with both drugs. Clinical trials in the USA and Europe demonstrate the efficacy of Glucovance with high levels of glycemic control combined with excellent tolerability. In Europe, Glucovance was submitted in April 2000 to the French Agency in the context of a mutual recognition procedure.
The second product resulting from the life cycle management program is Glucophage XR, a once-daily formulation that offers compliance advantages compared with the conventional formulation which requires twice or three times daily dosing. Glucophage XR is targeted at patients who require metformin monotherapy or who take metformin in combination with other oral anti-diabetic agents. In clinical trials with more than 1,200 patients, Glucophage XR was shown to be comparable to Glucophage in lowering patients' blood sugar levels. Glucophage XR was approved by the FDA mid-October 2000 and will be introduced to the US market shortly. In Europe, Glucophage XR was filed for approval in April 2000.
Earlier this month, the Swiss regulatory authorities approved Starlix® (nateglinide) for the treatment of Type 2 diabetes. Based on a co-promotion/co-marketing agreement between Merck KGaA and Novartis AG that includes Europe and certain African, Southeast Asian and Latin American countries, both companies will introduce Starlix in Switzerland by the end of this year. Starlix was approved as monotherapy as well as in combination with Glucophage for treating patients whose hyperglycemia cannot be controlled with diet and physical exercise alone.
The approval was based on clinical data from more than 4,000 patients world-wide and is the first for Starlix in Europe. Taken conveniently at any time up to 30 minutes before eating, Starlix helps to control mealtime glucose levels by restoring the early phase of insulin secretion that is lost in type 2 diabetes. The new drug thus addresses the problem of glucose "spikes" - dangerous sharp increases in mealtime blood glucose levels - which research has shown to be an important risk factor for cardiovascular mortality in patients with type 2 diabetes. Licensed by Novartis from Ajinomoto Co. Inc., Japan, Starlix was submitted for marketing approval to the FDA and the European Medicines Evaluation Agency (EMEA) in December 1999.
Together with Starlix, the Glucophage family represents one of the strongest anti-diabetic franchises in Europe. To secure this position, Merck is committed to expand its diabetes franchise by three new anti-diabetes projects:
CRE 16336 (Phase I / Estimated Market Introduction 2005)
As part of a research agreement with Ono Pharmaceuticals Co., Ltd., Japan, Merck develops the insulin sensitiser CRE 16336 as a potential therapy for Type 2 diabetes. Insulin sensitisers act to reduce raised blood glucose levels by improving insulin´s activity in the target tissues, an effect which is usually impaired in Type 2 diabetics. Phase I clinical trials started in 1998.
CRE 16257 (Phase I / Estimated Market Introduction 2005)
Currently in phase I of clinical development, CRE 16257 is a beta-cell sensitiser for the treatment of Type 2 diabetes and insulin resistance. Like CRE 16336, this compound is being developed in collaboration with Ono Pharmaceuticals. Compared with currently marketed oral anti-diabetic agents, Beta-cell sensitisers have a different mode of action. They lower blood glucose levels by making the beta-cells more sensitive to the effects of circulating glucose. This has the effect of indirectly stimulating these cells to secrete insulin.
IDD 676 (Phase I / Estimated Market Introduction 2007)
Currently in phase I of clinical development, IDD 676 is an Aldose Reductase Inhibitor, intended for the treatment of Diabetic Neuropathies. IDD 676 shows strong specifity on Aldose Reductase and good bioavailability. Market launch is planned for 2007.
Focus on acute and chronic cardiac diseases with high medical need - Expanding the Bisoprolol franchise
In the therapeutic area cardiovascular, Merck KGaA´s research and development is focused on innovative approaches for the treatment and the prevention of acute and chronic cardiac diseases with high medical need, such as heart failure, thrombosis / restenosis and cardioprotection. The roll out of the life cycle management projects for Bisoprolol, the low-dose combination with the diuretic Hydrochlorothiazide and the indication heart failure, is ongoing. These activities will stabilize and further grow our Bisoprolol franchise over the next years.
Inhibitors of the sodium-proton exchanger, so-called NHE inhibitors, represent a key area for Merck KGaA with a platform of several projects ongoing. These projects employ different chemical entities and target the indications acute myocardial infarction (AMI), cardiac surgery, non-cardiac surgery as well as chronic cardiac diseases.
NHE-inhibitors and oral GPIIb/IIIa antagonists, specifically Eniporide and Gantofiban, belong to a long-standing and fruitful R&D co-operation of Merck KGaA and Yamanouchi Pharmaceuticals. Both companies agreed to discontinue the development of one of the NHE-inhibitor projects namely Eniporide for the indication AMI, as the European multinational phase-II trial (ESCAMI) did not show a beneficial effect in patients with AMI. Likewise, both partners decided to terminate the development of Gantofiban for acute coronary syndromes since phase II results did not support a superior risk-benefit profile compared to other oral substances of this therapeutic class. The R&D co-operation between Merck KGaA and Yamanouchi still continues in several preclinical projects.
Merck KGaA has a PDE V inhibitor in phase I trials showing a superior profile compared to the available drugs in the indication male erectile dysfunction. This project is considered for partnering.
Central Nervous System
Strategic review completed - Projects repositioned towards indications with high medical need
A strategic review of the CNS pipeline has been completed recently. The three projects were partially repositioned towards indications with higher medical need.
EMD 68843 (Phase II / Estimated Market Introduction 2005)
EMD 68843, a Dual Serotonergic Antidepressant is in clinical phase II development. The compound has demonstrated antidepressant activity in the first clinical trials completed. EMD 68843 is targeted to improve the side effect profile, especially sexual related side effects, in comparison to SSRI, the standard treatment of depression today. The compound is expected to be launched in 2005.
Sarizotan (Phase II / Estimated Market Introduction 2005)
Sarizotan (EMD 128 130), a compound with a 5 HT1A full agonist profile, has demonstrated significant improvement of L-Dopa induced dyskinesias in parkinsonian monkey models. The development has therefore been moved from schizophrenia to dyskinesia in Parkinson´s Disease where Sarizotan is now in early Phase II trials. The compound is planned to be on the market in 2005. Today there is no registered treatment available for this disorder.
Asimadoline (Phase II / Estimated Market Introduction 2007)
Asimadoline (EMD 61 753) is a peripherally active kappa - opioid receptor agonist previously developed in pain. The compound has shown a good safety profile, but produced inconsistent efficacy data in clinical studies of musculo-skeletal pain. However, recent pre-clinically investigations have demonstrated significant activity in various models of pain associated with gastro-intestinal disorders such as Irritable Bowel Syndrome. First Phase II studies are scheduled to start early next year in this indication. Launch in IBS is scheduled for 2007.
Focus on Hormone Replacement Therapy and Contraception - Steady stream of new products
Merck KGaA´s development pipeline in Women´s Health was extended significantly following the acquisition of Monaco-based Theramex in 1999. Merck is presently focussing on two indications: Hormone Replacement Therapy (HRT) and Contraception.
Within HRT, Merck is currently developing transdermal and oral pharmaceutical forms (patches, gel and tablets). This large range of products will give the physicians alternatives for the individualised therapy of women in their period of hormonal transition where the choice of treatment is essential to improve compliance. Among the six HRT projects, three of them will reach the market before end 2002. One is currently in phase III and the two others are under the registration process.
In contraception, Merck is currently developing two complementary projects. One is containing a brand new progestin (phase II starting next year - launch scheduled in 2008) with favourable pharmacological properties. The other is the first contraceptive with a new treatment pattern using natural Estradiol (phase II ongoing - launch scheduled in 2007). All these projects are currently covered by world-wide patents, either applied for or delivered.