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Ambit Biosciences, In Third Incarnation, Gears Up for Pivotal Study of Leukemia Drug

Xconomy San Diego — 

Biotech companies run into walls all the time, and either reinvent themselves or die. If they’re fortunate, they get one shot at a turnaround. San Diego-based Ambit Biosciences is getting a third chance, and this time it has some hard data, not just a flashy concept, to offer.

Ambit got started in May 2000, just when the bubble was starting to pop on the Internet and genomics stock bubbles. Ambit’s original plan was to take some technology out of Yale University to build a database of all the proteins in the body and sell the information to drug companies.

When that business model fell out of favor just seven months later, Ambit re-started around the idea of screening ideal drug candidates against certain protein targets. Two multi-billion dollar drugs for diabetes and neurological conditions, metformin and gabapentin, were losing patent protection, and Ambit thought it could develop more effective second-generation treatments if it could discover how they really interacted with protein targets. It raised $20 million on that effort in 2001 and 2002, before it flamed out the next year.

“At the end of the second incarnation, we had nothing. It didn’t work,” says Scott Salka, Ambit’s CEO. “We had two strikes against us, we were standing at the plate, and had hardly any money. We could fold up our tent and go home, or salvage something.”

Ambit’s next chance came with an emerging class of drugs known as kinase inhibitors. They have been a hot area for prospective cancer drugs over the past decade, and block certain enzymes called kinases. Novartis’ imatinib (Gleevec) achieved breakthrough status (and multi-billion-dollar sales) as an inhibitor of a very specific kinase involved in chronic myeloid leukemia. Other pioneering kinase inhibitors, like Pfizer’s sunitinib (Sutent) appeared to work well against kidney cancer even though it blocked several variations in the family of kinases. That stirred debate about whether it was better to be more selective to certain targets, or less, in developing new compounds. That created demand among drug companies to do in-depth selectivity studies, Salka says. As a result, drug companies lined up for services from Ambit, which could screen large numbers of kinases for the best possible drug to block them.

That core skill of Ambit’s was good enough to win support from Roche, Bristol-Myers Squibb, GlaxoSmithKline, Pfizer, Johnson & Johnson, and Cephalon, and has provided some cash to keep the doors open of a fledgling biotech company for nine years. It’s also enabled Ambit to raise a total of $105 million from a list of investors that now stretches 14 deep.

But just like genomics was the hot new thing that faded in 2000, it’s hard to get investors excited about a biotech business that collects fees for services from Big Pharma. The big potential, as always, is in developing new drugs for deadly diseases.

While Ambit was screening kinases for Big Pharma customers, it was also building up a portfolio of kinase drug candidates of its own. The company’s lead asset of the moment is AC220 for acute myeloid leukemia. It’s a malignancy that strikes 13,000 people each year in the U.S., mostly elderly, who have a short life expectancy and no realistic treatment options beyond chemotherapy. With little notice, Ambit is gearing up this month to start a pivotal clinical trial of this product and is even in partnership talks. If this drug can match striking results seen in an earlier study, then Ambit could have this product on the market by the first half of 2011, Salka says.

“It’s a great story for San Diego biotech,” Salka says. “Hopefully we can deliver the goods.”

Ambit drew some attention for its drug last December at the American Society of Hematology meeting in San Francisco. That was where researchers reported that 16 of the first 54 patients with relapsed forms of acute myeloid leukemia had tumor shrinkage after taking nothing but the Ambit drug. The responses lasted a median time of 3.5 months. Side effects included nausea, vomiting, diarrhea, fever, headache, and fatigue, most of which were mild to moderate in severity, researchers said.

“The patients who enrolled in this trial had a median of three separate rounds of prior treatment, representing a heavily pre-treated population. Yet, we are seeing responses for nearly one out of three patients, which is very encouraging,” said Jorge Cortes, the deputy chair of the Department of Leukemia at MD Anderson Cancer Center in Houston and principal investigator for the study, in an Ambit statement. “The fact that we are seeing these responses for significant durations of time, and in a monotherapy trial where optimal dosing has not yet been determined is really exciting; we were not expecting to see this kind of data in what was originally designed to be a safety study.”

The results were so promising that the company met with the FDA afterwards to form a plan to run a more rigorous clinical trial that could pave the way for Ambit to bring the drug to the market, Salka said.

The company is now gearing up for that trial, which could give the company its first marketed drug in the U.S. The trial will enroll 180 patients who will get AC220, and the study will not randomly assign any patients to a comparison group, because there is no established standard of care for patients with relapsed acute myeloid leukemia. The trial will restrict enrollment to patients with a mutation of the FLT3 kinase, the specific target the drug is made to block. About one-third of patients with acute myeloid leukemia, or 4,000 new cases a year, are estimated to have this mutation, which gives them a worse prognosis than other patients, Salka says.

Ambit doesn’t have a mountain of data to build on as it heads into its pivotal trial. The small study disclosed at ASH looked at a variety of doses from 12 milligrams to 450 milligrams. The company picked a dose of 200 milligrams for the pivotal trial based on a subpopulation from the earlier trial, which showed that four of the five patients with active mutations of FLT3 and who got the 200 milligram dose had complete disappearances of their tumors, Salka says.

If Ambit can show anything close to that kind of result in the more rigorous pivotal trial, it should have a winner, Salka says. But to get that answer, it needs more money, he says. That’s likely to come from a partner.

“We have investors with deep pockets, and we’ll likely have a new partner very soon,” Salka says.

Ambit and whoever its partner may be will be up against some formidable competitors pursuing drugs for acute myeloid leukemia. At various stages of development, Novartis has PKC412, Genzyme is working on clofarabine, Cephalon has CEP-701, and Seattle Genetics is testing lintuzumab (SGN-33).

Ambit sees its drug being different in the marketplace because of its specific targeting of FLT3 kinase. If it can confirm this idea in the pivotal study about to get underway, it will be quite a turnaround for a company that’s better known for reinventing itself than for creating a new identity as an emerging cancer drug developer.

“For people who don’t keep a close eye on us, they can’t believe how quickly things have moved for us,” Salka says.

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    Please contact me,

    Dr. Ashok Srivastava, DM, Ph.D., MBA
    CMO and EVP
    Cell. 908-720-9315
    Office: 732-694-3394