Taking their gloves off

AstraZeneca, Merck form collaboration to investigate novel combination anticancer regimen

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WHITEHOUSE STATION, N.J.—Hoping to strike at cancer with a one-two punch. AstraZeneca and Merck & Co. announced last month that they will jointly develop a pair of drugs that are part of a growing trend of combination cancer treatments.

The drugmakers will team up to collaborate on Merck's MK-2206 and AstraZeneca's AZD6244, both of which are still in very early development. Both compounds are designed to inhibit a protein known to be abnormally activated in human cancers.

AstraZeneca acquired exclusive worldwide rights to AZD6244 from Array Biopharma Inc. in December 2003. In preclinical studies, AstraZeneca's AZD6244 has been shown to work by blocking Mitogen-activated protein kinase 1 (MEK), a biochemical signal that promotes cancer cell growth. It has completed Phase I evaluation and it is being tested in Phase II monotherapy trials against a number of cancers.

Merck's MK-2206 affects AKT, a component of the phosphatidylinositol-3 kinase pathway, which is an important signal promoting cancer cell survival.

Preclinical evidence indicates that combined administration of these compounds could enhance their anticancer properties. 

"The notion that a single agent is going to be dramatically active in a broad population [of cancer patients] is unrealistic," says Alan Barge, vice president and head of oncology at London-based AstraZeneca. "Drug cocktails are widely used in cancer treatment, but regimens are typically developed only after the medicines are in late-stage trials or already on the market."

Barge points out that advances in cancer research have led to a new generation of drugs designed to precisely target features specific to cancer cells while minimizing the effect on healthy cells. 

"Several of these drugs provide patient benefit as monotherapy, but increasingly, the ability of cancer cells to adapt and develop resistance has become apparent," he says. "Research suggests that combination therapies that include drugs with different mechanisms of action impacting cancer cells in multiple ways may provide an improved anticancer benefit and decrease the risk of relapse."

According to Dr. Ian McConnell, a Merck spokesman, the collaboration has a lot of built-in flexibility.

"We believe this is the first deal of its type between large pharma companies in early development," McConnell says. "That is the novelty of it. The collaboration will more quickly advance a potentially promising anticancer treatment."

Usually, combinations of novel anticancer agents would only be studied in clinical trials when one component of the regimen is at a late stage of development or when one compound has received marketing approval.
McConnell notes that this agreement is pioneering in that two major pharmaceutical companies, each with one component of the combination regimen in its pipeline, are collaborating at an early stage in development, so that effective treatments may be brought to patients as rapidly as possible. The flexibility of the agreement will enable the companies to hammer out a new collaborative arrangement as the research moves through the various phases of study.

"We initially looked at a soup-to-nuts agreement and it was decided it would be too complicated," McConnell adds. "Controlling all of the parameters in one contract would be too complicated. This collaboration is going to be staged. Once the data is in for the Phase I clinical trials, we will then re-evaluate the collaboration."

McConnell notes the collaboration brings together two leading companies with a wealth of expertise in oncology.

"Through this agreement, we are well-positioned to implement a detailed and timely evaluation of the therapeutic potential of this novel combination, with the aim of bringing this potentially effective regimen to patients as rapidly as possible," he adds.

Barge points out that AstraZeneca decided to partner with Merck because it wanted to bring a more effective therapy to patients as soon as possible.

"Going with our own AKT inhibitor would have delayed this, whereas Merck already has encouraging Phase I data," he notes. "MK-2206 is the leading AKT inhibitor. It is an allosteric and therefore highly selective, which offers an opportunity to combine two highly selective inhibitors, with a strong scientific rationale in a timely fashion. Through this collaboration, we are taking an innovative approach to early-stage cancer drug cooperation based on AstraZeneca's and Merck's mutual determination to develop therapies that improve patients' lives."

AstraZeneca will launch joint early-stage trials in a small number of cancer patients later this year. A positive result would trigger a request to the U.S. Food & Drug Administration to approve a test of the combination in a larger number of cancer patients to assess efficacy. All development costs will be shared jointly. 

"There is strong scientific rationale to suggest that the potential benefit to cancer patients of this combination may far exceed the sum of the parts," says Gary Gilliland, senior vice president and franchise head of Oncology at Merck Research Laboratories. "In order to harness the true potential of the combined administration of the compounds, AstraZeneca and Merck have established a pioneering, early-stage collaboration based on our mutual determination to develop impactful therapies that improve patients' lives."

Molecular profiling of human solid tumors has shown that both the MEK and AKT pathways are frequently abnormally activated. Preclinical studies have suggested that simultaneously inhibiting both of these pathways may have synergistic effects on tumor cell growth.

McConnell points out that MEK and Akt "are two critical pathways in oncogene signaling. If we shut down one, the other comes up to compensate." The hope is that by hitting both pathways at once, "we will shut down the escape routes."

The collaboration between AstraZeneca and Merck on a combination treatment is unusual, normally occurring when each company has a drug either already on the market or in final human testing.

"This is really, really early," analyst Steve Brozak of WBB Securities told the Associated Press. "This is good news, as such partnerships can help produce the next generation of cancer drugs."

According to Brozak, the collaboration is a consequence of industry consolidation, with companies that or merging or cutting costs having already reduced spending on administration and other areas.

"Now what they're trying to do is cut their research expenses by combining programs," he said.

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