Optimizing Optimata

November 15, 2005 | Twenty-five years ago Zvia Agur believed she could use mathematics to identify optimum therapy regimes for cancer. It wasn’t a popular idea then and is only modestly accepted now. But by the late ’80s, Agur had completed persuasive proof-of-concept work in which she doubled the length of survival in cancer-bearing mice by selecting optimal therapy protocols using mathematical models.

SYSTEMS SHERPA: Zvia Agur likens Optimata's cancer focus to climbing Everest first.

Getting to humans has taken a bit longer. Today, Agur’s small 20-person Israeli company, Optimata, is conducting a clinical trial at Nottingham City Hospital in Britain and Soroka Medical Center in Israel to predict breast cancer therapy outcomes for drugs such as Adriamycin, Docetaxel, Paclitaxel, Vinorelbine, and Tamoxifen. Optimata’s Virtual Patient Engine is able to capture information about individual patients (or larger populations) and let physicians simulate the use of many drugs and protocols in search of optimum outcomes.

Says Agur, Optimata’s founder and CSO: “The patient can come to the clinic. You take the baseline measurements. So the patient has a tumor with given characteristics, and we can tell the doctor our prediction as to which drug regimen will be best for this particular patient. We are personalizing medicine today.”

Unlike many systems biology companies that tackle drug discovery, Optimata is focused on preclinical, clinical trial design, and clinical work. The models include information about pathology, physiology, and drug attributes. Cancer is Optimata’s primary focus — Agur likens that choice to climbing Everest first, after which everything else will be easy — but the company also has growing expertise in hematology.

“In cancer we describe the whole disease dynamics. So when we’re talking about the growth of very miniscule tumors, they have geometric arrangements, cell cycles, diffusion of nutrients, and the drug eventually in the tumor. We create a detailed mathematical description of all that. Just to give you an idea, to translate only angiogenesis into biomathematical algorithms is a question of about 2.5 man-years work,” says Agur.

The platform seems to have broad applications. “It could be completely choice of drug; it is certainly choice of drug schedule; but not necessarily of an existing schedule. It could be also putative schedule. In reality we are in the stage in which we prefer to make predictions about the best among existing therapies,” she says.

Nothing Virtual
Drug salvage is an obvious opportunity, and Agur relates Optimata’s work with thrombopoietin (TPO). Around 2001, development of TPO was shelved after it was found to be immunogenic. Working with a Genentech collaborator, Optimata plugged the data into its Virtual Patient and produced a protocol the model said was efficacious but not immunogenic.

The drug had already been pulled. The human model was adjusted to become a virtual mouse, and the protocol it produced was validated in the lab. The model was upgraded to a rhesus monkey, and its protocol validated. Today, “The Optimata protocol is the protocol for blood donation in rhesus. It’s not used in humans, but it’s a very successful protocol,” says Agur.

Optimata has raised around $15 million, and Agur concedes she was miffed when another journal questioned how far this sum would take Optimata. “It is hard to judge our expenditures in American standards,” she bristles. The company has two ongoing collaborations with a large and a small pharma. Both projects involve the transition from preclinical to Phase I.

So 25 years ago, graduate student Agur had this idea for changing medicine. Since then, she has served as president of the Israeli Society of Theoretical and Mathematical Biology (1996-2001) and was a member of the board of directors for the European Society of Mathematical Biology (1997-2002). In 2000, she founded Optimata and a not-for-profit Institute for Medical BioMathematics. Nothing virtual about those accomplishments.