PERTH, Australia – Patients with relapsed or refractory acute myeloid leukemia (r/r AML) who have received three or more lines of therapy are often too sick to get much-needed bone marrow transplants and often run out of options. Melbourne-based Race Oncology Ltd. hopes to change those outcomes with a new take on an old drug that slipped through the cracks in the 1980s.

Race was founded in 2016 with the mission to rescue bisantrene, which was approved for AML in France in 1988 but was never commercialized. The chemotherapy drug was developed in the 1980s by Lederle Pharmaceuticals and was tested in more than 40 clinical trials that showed activity in AML as well as breast and ovarian cancers.

Lederle was later acquired by Wyeth, and the drug got lost when Pfizer Inc. acquired Wyeth, Race Oncology Chief Operating Officer Daniel Tillett told BioWorld.

Positive results from a small investigator-initiated phase II study in patients with r/r AML who had received three lines of prior therapy showed a clinical response in 40% of patients who received bisantrene. The study was an open-label, single-agent trial.

Conducted at Israel’s Chaim Sheba Medical Centre, the study involved 10 patients, including seven patients who had relapsed following allogeneic stem cell transplants. Three patients had an antecedent myeloid disorder while four patients had extramedullary disease (located outside of the bone marrow).

Of the 10 patients, one achieved a complete remission (CR) and three patients achieved partial remission (PR) after a single course of bisantrene treatment, with one patient bridged to allogeneic stem cell transplantation.

The phase II trial was a “proof of relevancy trial,” Tillett said. “We knew that [bisantrene] worked, but we didn’t know if it would still work in today’s patients who are more heavily treated than patients in the past.”

Although the trial was small, “we know it still works, which is incredibly valuable because it means all the historical data is still relevant. We know the drug is safe, and the drug has been used in about 2,000 patients.”

Poor outcomes despite targeted drugs

Although meaningful gains have been achieved in recent years with newer targeted drugs, clinical outcomes remain dismal for patients with r/r AML.

Daniel Tillett, chief operating officer, Race Oncology

Anthracyclines are an essential component of induction chemotherapy for AML patients; however, due to cardiotoxicity concerns, they are not broadly prescribed in relapsed or refractory AML settings. Bisantrene, which is an anthracene with anthracycline-like activity, was shown in earlier studies to be an effective salvage therapy in r/r AML with little or no discernible cardiotoxicity.

Bisantrene had marked activity in patients with extramedullary AML. In fact, all four patients who had a clinically significant response to bisantrene had extramedullary disease.

In AML, bone marrow transplants are always the goal, Tillett said, noting that if “you just knock down the cancer, you won’t get all of it. The only way to get a cure for the patient is a bone marrow transplant.”

There is a big difference in outcomes for patients who have measurable residual disease (MRD) as they have a much lower survival rate. The idea is to use bisantrene, which doesn’t have cross resistance to anthracyclines, to go after the last traces that survive the anthracycline treatments before patients get bone marrow treatment to reduce their chances of relapse.

About one-fourth of patients that go into CR still have residual cancer.

“It’s also much better to treat patients early in their disease, and bisantrene could transform cure rates by changing MRD status.

“In the earlier bisantrene trials, they were able to get half the patients to a complete response, but they weren’t able to get them bone marrow transplants,” Tillett added. “A couple of the patients they were able to match and get bone marrow treatments are still alive to this day.

“These days, it’s a lot more viable to give transplants; we’re much better at getting partial matches between patients. It’s much easier to find a donor than it was in the 1980s,” Tillett said.

In addition, cardiotoxicity was seen in the anthracycline class, but it wasn’t seen with bisantrene, and the recent study showed lower kidney toxicity and no liver toxicity.

Competitive space

Although there are numerous competitors in the AML space, the traditional chemotherapeutic broad agents have lost their appeal, Tillett said, and “nobody is developing new chemotherapeutic agents, because it’s all about combination therapy and targeted therapy.”

“The trial has removed a lot of the risk for the company, and it also removed concerns of some of the investors,” Tillett said, noting that the FDA has granted bisantrene orphan drug designation and rare pediatric disease designation.

Race announced a AU$3 million (US$2.1 million) private placement in July of 5 million shares priced at AU60 cents per share, a 1.96% discount to the 15-day value weighted average price. The placement was made to three sophisticated biotech investors: Kidder Williams’ David Williams; EFM Asset Management’s Jeff Emmanuel; and a follow-on investment by Merchant Opportunities Fund.

Race is pursuing a five-path clinical development strategy that involves parallel U.S. and Australian clinical trials in late-stage AML, pediatric AML, early stage residual stage and breast and ovarian cancer.

The focus for now is on the three AML pathways, and the breast cancer treatment will be for second-line therapy, while ovarian cancer will be in third-line treatment.

“One of the big things is that Herceptin [trastuzumab, Roche Holding AG] has a cardiotoxic load, so you can’t combine it with anthracyclines, so you have to do it sequentially. We know it works better if you combine drugs, but you just can’t because of the cardiotoxicity, so this could be a good alternative to balance out the side-effect risk,” Tillett said.

Trials will begin later this year in the U.S. and Australia. A phase I/II bisantrene adult r/r AML trial is planned in Israel, and a pediatric phase I/II AML trial is planned in the U.S. A phase II MRD trial will also be run in the U.S., Israel or Australia in transplant-eligible patients.

A breast cancer phase I/II proof-of-concept trial is also planned, and the strategy is to displace current anthracyclines used in breast cancer treatment, which would open up a much larger market than AML.

One of the advantages of Race’s five-pathway strategy is that if it gets blocked on one of the pathways in the U.S. due to COVID-19, it can continue trials in Australia.

“By having different parallel paths that aren’t dependent on each other, we can work around these things that happen along the way,” Tillett said.

“The idea is to get proof of principal in all these cancer types to add value to the drug as an acquisition.”

With a market cap of AU$108 million, Race’s shares on the Australian Securities Exchange (ASX:RAC) were trading at AU87 cents at close of trading on Aug. 5.

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