Approval last week by the FDA of Novartis AG's radioactive drug, Lutathera (lutetium [177Lu] oxodotreotide), provides "a signal that there's a real opportunity for this kind of therapy, and it goes beyond neuroendocrine and prostate cancers," Endocyte Inc. CEO Mike Sherman told BioWorld.

Basel, Switzerland-based Novartis won clearance for the compound to treat gastroenteropancreatic neuroendocrine tumors. Endocyte, of West Lafayette, Ind., will soon enter phase III trials with the radioligand 177Lu-PSMA-617, which targets the prostate-specific membrane antigen (PSMA). Delivering the short-range beta-emitting radioactive isotope lutetium, or 177Lu (also part of Lutathera) selectively to tumor cells, Endocyte's candidate bypasses non-PSMA-expressing healthy cells. PSMA turns up in about 80 percent of patients with metastatic castration-resistant prostate cancer (mCRPC), the targeted indication. (See BioWorld, Jan. 29, 2018.)

"In many ways, Lutathera is applying the same concept" as 177Lu-PSMA-617, though Novartis is "using a slightly different version of lutetium" and pursuing a much smaller patient population, Sherman said.

The Swiss pharma giant gained Lutathera through its buyout of Saint-Genis-Pouilly, France-based Advanced Accelerator Applications SA, disclosed in October, through a deal that valued the latter at $3.9 billion. Such a caliber of interest likely heralds more developments with similar drugs using other isotopes such as actinium, which Sherman called "really interesting. We have about half a dozen other targets," going after cancer indications that could include ovarian, lung, breast and colorectal.

For now, though, Endocyte is busy with mCRPC, fatal for about 100,000 patients per year in the seven major markets. "The good news is that three or four drugs have been approved in the last five years," Sherman said, but they've been given the go-ahead "in a setting that doesn't exist anymore." Such therapies as Zytiga (abiraterone acetate, Janssen Biotech Inc.) and Xtandi (enzalutamide, Astellas Pharma Inc. and Pfizer Inc.) are being used in front-line metastatic prostate cancer "quite effectively," he said, and some data support using them even earlier in the disease's progression. But that has "left a void," he said. "Once you've had one of these novel anti-androgens, and maybe you've had a taxane," there's nothing left to try.

"These patients are still looking for and fit to have therapy, and there's no drug that has ever demonstrated a survival benefit in those patients that have seen those courses of therapy," he said. "That's the patient population that we'll focus our registration on, subject to discussion with regulators."

Talks with the FDA are expected to happen this quarter. If all goes well, a phase III study will begin in the first half of this year. First data could be available around the end of 2020, "based on the enthusiasm we're seeing from sites and patients," Sherman said. "It's safe to say that overall survival is the gold standard here, especially in late-stage patients," who live only about seven to 11 months, but the global trial's endpoints are yet to be nailed down.

As for size, "a nice reference would be the Xofigo trial," he said, a reference to the test with Leverkusen, Germany-based Bayer AG's radium Ra 223 dichloride. "I think they ultimately achieved their endpoints in fewer than a thousand patients," he said. "[Ours] should be smaller than that, ultimately. It depends on the benefit derived. We plan to put in early stop opportunities" so that the study can be quit early if efficacy merits.

Xofigo was approved in May 2013 for prostate cancer with bone metastases. Its example may provide clues to 177Lu-PSMA-617's dollar value in the marketplace: The Bayer therapy generates about $400 million per year, an amount growing about 30 percent annually. Endocyte's therapy, since it's not limited to bone metastases, could turn out to be worth a billion dollars.

"It's a really fascinating story, how these drugs have been developed," Sherman said. Michael Hofman, of Melbourne, Australia's Peter MacCallum Cancer Center, was active in the clinical work with Lutathera and became one of "many physicians in the space thinking [about] what's the next application for this approach," he said. PSMA came quickly to mind. "Nearly all of the work that's been done to date has been led by physicians," Sherman said. "There hasn't been a traditional drug sponsor for this."

'North of 20' publications so far

Last fall, Endocyte acquired the rights to 177Lu-PSMA-617 from ABX GmbH, of Radeberg, Germany, a chemical company. Under the terms, Endocyte was given worldwide rights to develop and commercialize the drug in exchange for an up-front payment of $12 million. Endocyte also issued 2 million shares of Endocyte common stock to ABX and issued warrants for the purchase of up to 4 million more shares of Endocyte common stock. ABX also stands to collect regulatory and commercial milestone payments of up to $160 million, and tiered royalties beginning in the midteens.

"Apart from providing the drug, [ABX was] not driving the clinical development," Sherman said. Instead, doctors with an interest have been pushing trials along. Two phase II studies are underway, and data from both likely will help make Endocyte's case. The company acquired the IND for the compound from Radiomedix Inc., of Houston, which is evaluating two separate doses of 177Lu-PSMA-617 in its phase II experiment. "We're not necessarily dependent on that trial" but will benefit from its findings, he said.

The other phase II effort is the result of a three-way agreement by Endocyte with the University of Sydney and ANZUP, the Australian and New Zealand urogenital and prostate cancer trials group. His company provides "modest financial support" along with the drug, Sherman said. It's another instance where "we don't have to fund all that work, yet we can benefit from the data."

Other helpful results are coming from compassionate-use deployment of the drug in hundreds of patients in Germany and other European countries. Findings have already yielded "north of 20 publications on this drug by physicians," he said.

Shares of Endocyte (NASDAQ:ECYT) closed Monday at $3.51, down 6 cents.