Merck KGaA Strengthens Anticancer Pipeline With Novel EGFR-Targeted Antibody Combination
This article was originally published in The Pink Sheet Daily
Executive Summary
A mixture of two antibodies that may have a novel synergistic effect against EGFR-expressing tumors has been licensed to Merck KGaA for development worldwide by Denmark's Symphogen, the recipient back in 2011 of one of the largest ever VC-backed financing rounds in Europe.
Danish biotech Symphogen AS has licensed its lead oncology product, Sym004, a mixture combining two antibodies targeting the epidermal growth factor receptor (EGFR) on tumor cells, to Merck KGAA for an upfront payment of €20 million ($25 million). Symphogen was evaluating Sym004 in two Phase I/II studies, which have shown initial signs of the drug's clinical benefit and been transferred into Merck’s control.
The deal underlines the growing interest in combination therapies for cancer, as well as Merck’s desire to build on its marketed EGFR-targeted anticancer drug Erbitux (cetuximab), which is its second largest-selling product, garnering sales of €855 million ($1.13 billion) for the Darmstadt, Germany-based pharmaceutical company in 2011 (Also see "Merck KGaA Changes Manager Incentives, But Stays Mum On Job Losses" - Pink Sheet, 8 Mar, 2012.). Merck holds marketing rights to Erbitux for Europe, Japan and some other non-U.S. markets, and, although the drug starts to lose EU patent protection in 2014, it is still gaining new indications (Also see "Can Erbitux Make Inroads In First-line Colon Cancer With Approved Companion Dx In Tow?" - Pink Sheet, 10 Jul, 2012.).
Merck receives exclusive development and commercialization rights for Sym004 worldwide, and now will fund all further development of the compound. In return, Symphogen receives the upfront and potentially could earn €225 million in clinical development and regulatory milestones, as well as €250 million in combined sales performance milestones and royalties on net worldwide sales, bringing the total potential value of the deal to €495 million.
One of the unique features of Sym004 is its potential novel mechanism of action compared with other EGFR-targeted therapies. “Sym004 strengthens our early development pipeline by adding a product that is thought to act via a proposed synergistic mechanism of action not previously studied," noted Dr. Susan Jane Herbert, head of global business development and strategy for Merck Serono SA, in a statement.
Merck is much in need of clinical-stage products that it can advance quickly following a string of late-stage product failures, which have prompted a management reorganization and the start of a cost-saving program including job losses at its R&D facilities in Switzerland, and across functions in Germany (Also see "Merck KGAA Begins Transformation Effort By Closing Geneva Site" - Pink Sheet, 25 Apr, 2012.).
Novel Mechanisms A Prerequisite For Development
The finding of a novel mode of action associated with Sym004 is a key characteristic. “This particular combination of EGFR-targeted antibodies appears to aggregate those EGFR receptors, causing them be internalized and degraded, so that they are no longer present on the surface of tumor cells,” explained Symphogen's CEO Kirsten Drejer in an interview.
Drejer noted that 12 years ago, when Symphogen was founded, it was difficult to find key opinion leaders in oncology interested in novel combination chemotherapies. Now, there is widespread interest in preventing the emergence of treatment-resistant tumors with a multivalent approach, whether by using bispecific antibodies, mixtures or some other combination approach.
Symphogen has developed a suite of technologies that identify, select and manufacture mixtures of antibodies, from two to 25, which mimic the natural diversity of immune responses. The amount of antibodies administered was similar to that administered with single monoclonal antibodies, and the cost of goods was similar, thereby removing two objections to antibody mixtures, Drejer said.
Regulatory authorities have not raised any objections to Symphogen’s antibody mixtures approach, and have not asked for each component to be studied individually, Drejer reported. Of course, it helps if you have a strong scientific rationale for your approach and compelling preclinical data, she added.
In the two clinical studies started by Symphogen, Sym004 was evaluated in patients with colorectal cancer who already had become refractory to other anti-EGFR therapies, a significant hurdle for the product to get over. Drejer said she wanted to set the bar high to make sure the data were compelling, and because animal data indicated Sym004 would be beneficial. Initial signs of clinical benefit have been seen, with further details expected when the results are published by Merck.
Sym004 was being evaluated in a Phase I/II trial in patients with advanced KRAS wild-type metastatic colorectal cancer (mCRC) who had progressed on standard chemotherapy and a marketed anti-EGFR MAb. A second study, a single-arm, open-label Phase II trial in patients with squamous cell carcinoma of the head and neck who had failed anti-EGFR based therapy, is also under way. In 88 patients treated so far in clinical studies, adverse events have included diarrhea, skin rash, mucosal inflammation and nausea.
Symphogen has attracted big pharma partners for its infectious disease projects: Genentech Inc. for two antibody mixtures, Sym008 and Sym009, and Meiji Seika Pharma Co. Ltd. for a third, Sym006 (an anti-pseudomonal product). It has two unpartnered oncology products in early preclinical development: Sym013, which contains six different antibodies, and Sym014.
The venture capital community appears already to have made up its mind about the usefulness of Symphogen’s technology. The Danish company raised €100 million ($131 million) 18 months ago from a group of investors including Novo AS and Essex Woodlands Health Ventures, in one of the largest financing rounds ever for a European biotech (Also see "Denmark's Symphogen Breaks European Private Funding Record With €100m Haul" - Pink Sheet, 6 Jan, 2011.).
The second of three tranches from that financing was received in April 2012, following the achievement of an undisclosed clinical milestone, and Drejer reckoned the company might not need the final tranche in the near future, although it was nice to know that it was there. Company CFO Martin Olin estimated Symphogen's cash runway now extends to beyond 2016.