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Merrimack Opts to Go It Alone in Push Towards Drug Discovery, Bets on its Network Biology

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Usually, the path from proteomics startup to drug discovery company involves setting up deals to test lead compounds for big pharma. But Merrimack Pharmaceuticals has elected to skip the service stage, and to develop its own lead compounds before knocking on pharma’s door. With a compound currently in clinical trials in the UK and two recent Phase I SBIR grants under its belt, Merrimack is betting that it can make this strategy work.

“We decided that with the speed with which we’ve been able to [identify leads], it’s probably more useful to us to do it for ourselves,” Vincent Simmon, chief operating officer for Merrimack, told ProteoMonitor. ”That is, we’ll create more value making our own potential products and developing them to some level ... and then partner up with large pharmaceutical companies that are looking for products,” he said. ”The value driver three years ago was platforms and tools, and today, it’s products.”

The Cambridge, Mass.-based company, founded in 2000 and currently employing 26 people, is conducting clinical trials in the UK on alpha-fetoprotein — a compound it inherited from Atlantic Biopharmaceuticals in 2001 (see PM 11-11-02) — for the treatment of rheumatoid arthritis. It is also in the process of validating a potential drug candidate for breast cancer that it identified using a platform it calls Network Biology. The platform involves using computational analysis to develop a model for the interactions of various elements in a pathway implicated in cancer and other diseases in order to identify weak points that could be exploited for potential therapeutics.

With Network Biology, Merrimack tests the interactions using a type of protein array consisting of a 384-well plate, with each well containing spots of four to six antibodies to various proteins involved in a particular pathway. Simmon said that theoretically, up to 100 different antibodies could be spotted on each array, although the company has not yet made it work with so many. The antibodies are then treated with elements of cell culture that have been treated in a specific way over a specific period of time. Each well is treated with extract from a different variation on this treatment, so that interactions are measured over space, time, and type of treatment. Quantitative binding information is obtained through sandwich assays. The ultimate goal of all this multiplexing is to identify where and when in the pathway the interactions are most sensitive to perturbation — which could indicate where a drug would be most effective.

“What we’ve done with the microarray technology is to be able to generate a lot of data that other people don’t have yet about elements of the pathway, all of which are in concurrent time,” Simmon said. “We can [then] use our computational model to do a sensitivity analysis that allows us to find out what elements of the pathway can be altered to potentially modify disease outcome.” Potential antibody therapeutics are selected and refined based on these studies.

Merrimack has so far tested this system on the ErbB pathway, an epidermal growth factor receptor-mediated pathway implicated in a variety of cancers and targeted by the breast cancer drug Herceptin. The company is currently conducting validation studies on one antibody so far that it says will likely give broader coverage for cancer treatment than Herceptin can. According to Simmon, only about 8 to 10 percent of breast cancer patients respond to Herceptin — partly, he thinks, due to the complexity of the ErbB pathway. The antibody that Merrimack is testing has activity that is “substantially better” than this, Simmon said. He hopes that a final form of the antibody will be manufactured for clinical use within 12 to 18 months, at which point a pharma deal might be more desirable.

With the help of an SBIR Phase I grant awarded in January, the company is now also looking at the BCL2 pathway, which is also implicated in cancer. Simmon said that Merrimack is “getting ready to launch into” several other pathways as well, and that it is expanding its focus to work with array content other than antibodies. “We are, under this grant, us[ing] protein microarrays where what we spot on the plate isn’t an antibody, it’s a protein with a known function. Then the interaction is at a different level,” Simmon said. The company will be looking at protein-protein, protein-peptide, and protein-small molecule interactions, all as possibilities for intervention sites.

From Yeast to Content

Merrimack is still focused on antibody arrays, however, and like most array companies, it is experiencing a content problem, according to Rahbar Rahimpour, senior business development associate for Merrimack. “Many of the available antibodies that are used in microarray platforms are limited in [terms of] cost and quality,” he said. A second SBIR, awarded to Merrimack by the NCI last week, seeks to address this problem. The grant, which amounts to “more than $100,000” and which will last six months from the beginning of March, will support the high-throughput production of reagents with antibody-like features, using the company’s yeast display technology, Rahimpour said. “This approach allows us to introduce sequences of antibodies that we select based either on the model we’ve developed or experimentally identify sequences of antibodies that are of value to us, then we can introduce these sequences into the yeast and allow it to produce mass amounts of the antibody,” he said — “mass amounts,” in this case, referring to nanograms or micrograms.

Of course, SBIR grants are not usually major sources of funding for companies, and Merrimack is still funded almost entirely by investors. But despite their small financial value, the grants could have the effect of validating the company’s efforts, Rahimpour said. “A testament to the Network Biology approach is the two peer-reviewed grants that we were awarded,” Rahimpour said.

Time will tell whether a company that does not have “any large collaborations that generate a lot of revenue,” according to Simmon, can survive on investor money and SBIR testaments, until it comes time to market a product to big pharma. In the meantime, Merrimack is expanding with confidence: Simmon said that the company will nearly double its workforce in 2004.

— KAM

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