Sept. 13, 2007 | Many companies are betting biomarkers will accelerate drug development, but the biggest frontier for their use is oncology. Now, a new wave of compounds, from companies such as Exelixis, Avalon, and SuperGen, are starting to demonstrate when and how such markers are most useful.
“We do things a bit differently,” says Exelixis’ Michael Morrissey, president of R & D. Besides using biomarkers, the company has a screening approach it claims delivers high-potency molecules earlier. “We built a large compound library that helps us find molecules with low nanomolar activity right away,” says Morrissey. “With a smaller library you get weaker potency and then spend a year to 18 months improving on that.” This screening strategy lets Exelixis focus on optimizing compound’s pharmacological and safety properties at the in vivo model stage. Animal studies confirmed Exelixis’ XL880 is a powerful, long-lasting inhibitor of both MET and VEGFR2 — receptor tyrosine kinases (RTKs) that are key cancer targets. The scientists were also tracking key biomarkers during those early tests. “We wanted to recapitulate the pharmacodynamics we saw preclinically in patients,” says Morrissey.
In a Phase I trial, a couple of patients responded well to the drug. So the researchers looked to see if the correct signaling pathway was being affected. A biopsy from one patient showed that the compound significantly inhibits MET autophosphorylation. Moreover, the biomarker data and genetic signal of MET activation in certain renal tumors is particularly striking, the responses reinforced the notion that the compound is working as expected.
Meanwhile, a powerful indicator of VEGFR2 inhibition in humans is a rise in blood pressure. “We saw a number of examples of that among the study subjects,” Morrissey says. Selecting targets that are real drivers of cancers is difficult, but Exelixis’ scientists believe they were first to validate MET’s role. XL880 is now in a Phase II trial involving patients with renal, gastric, and other cancers.
To best leverage their gene expression platform, Avalon has collected “an unprecedented amount of data from Phase I patients,” says president & CEO Ken Carter. The company has two approaches — one examines the patient’s entire genome, the other focuses on a set of about 30 genes indicative of apoptosis and DNA metabolism. These markers “get to the central mechanism of how AVN944 works,” he says.
AVN944 is Avalon’s inhibitor of Inosine Monophosphate Dehydrogenase (IMPDH) 1 and 2. IMPDH2 is necessary for many cancers to produce guanine nucleotides and grow. Avalon scientists used gene expression profiling and GTP levels to study AVN944’s effects in cancer cell lines, followed by a
Phase I trial using used gene signatures to see if they could predict response to the drug. That 30-plus gene set will probably be trimmed to about 10-12 genes for use in upcoming trials. “Based on the Phase I trial, we are confident that we can do real patient stratification as early as Phase II,” says Carter.
Combination Markers
SuperGen, meanwhile, has been studying a biomarker called Rad51 to accelerate development of its multi-targeted tyrosine kinase inhibitor, MP470. “There was initially no obvious connection between the activity of this compound and Rad51,” explains SuperGen chief scientist David Bearss. “We came across this marker while we were studying combination therapies.”
SuperGen aims to team MP470 with other treatments, such as radiation, platinum agents, and topoisomerase inhibitors, which attack cancer cells by inflicting DNA damage. Most cells use DNA repair pathways featuring Rad51 to fix such breaks. Patients with lower levels of this gene appear to be most sensitive to combination therapies that include MP470.
The company recently initiated a Phase I trial of MP470 that monitors Rad51 levels. “If that works, we’ll use the marker in Phase II,” Bearss says. Those studies should address most questions about whether the drug works, even if that means excluding some patients from receiving it. At the same time, biomarker proponents hope they can speed things up too.
“Gleevec went from first in man to approved drug in 28 months,” Carter says. “The idea is to accelerate the process by enriching patient populations.” Avalon SVP of product & pharmaceutical development David Bol says that payors will soon be forcing this issue: “If you are going to charge $100,000, you better know the drug is going to work in that patient.”
But, as Bearss points out, such studies can sometimes confuse as well as clarify. “What if you see a clinical response but no biomarker response? A lot of people are trying to wrap their heads around how to deal with that one.”
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