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PROCEED no further: Endocyte and Merck halt ovarian study on futility

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By Jennifer Boggs
Managing Editor

Endocyte Inc.'s vintafolide-induced roller coaster ride continued Friday. A month after shares jumped a whopping 92 percent on a positive opinion from European regulators on conditional approval of the drug and its companion imaging agents in ovarian cancer, shares of the West Lafayette, Ind.-based company took a 62 percent tumble on news that the phase III ovarian cancer trial was halted for futility, likely putting the kibosh on that expected EU launch.

Endocyte and partner Merck & Co. Inc. were notified Thursday that the data safety monitoring board (DSMB) for the PROCEED trial recommended that the trial be stopped after a pre-specified interim futility analysis showed that vintafolide failed to demonstrate efficacy on the progression-free survival primary endpoint. The companies informed regulatory agencies late Thursday night, though they have not had yet had any discussions, Ron Ellis, Endocyte's president and CEO, told investors on the firm's earnings call Friday morning.

"But I think it's safe to assume that this would really put in question whether the EMA approval would come through or not, since it's a conditional approval and has to be confirmed in a phase III study," Ellis said, though he cautioned it was still "too early to really call that."

The EMA's Committee for Medicinal Products for Human Use issued positive opinions in late March for conditional marketing authorization of vintafolide, to be branded Vynfinit, and imaging agents etarfolatide (branded Folcepri) and intravenous folic acid (branded Neocepri) for patients with folate receptor-positive platinum-resistant ovarian cancer in combination with pegylated liposomal doxorubicin. That decision was based on data from the 149-patient phase II PRECEDENT study showing that vintafolide plus pegylated liposomal doxorubicin (PLD) resulted in median progression-free survival (PFS) of five months vs. 2.7 months in the PLD-only group (p = 0.031.) in the intent-to-treat population, which involved patients with folate receptor-positive tumors. (See BioWorld Today, March, 24, 2014.)

Vintafolide, which comprises folic acid linked to cancer agent vinca alkaloid desacetylvinblastine hydrazide, is the most advanced small-molecule drug conjugate (SMDC) from Endocyte's platform and was partnered with Whitehouse Station, N.J.-based Merck in a potential $1 billion deal in 2012, which included a $120 million up-front payment. (See BioWorld Today, April 17, 2012.)

It will be up to Merck whether to move forward in other indications, though Ellis expects the ongoing study in non-small-cell lung cancer (NSCLC) to continue. Early results from that study, dubbed TARGET, showed that vintafolide plus docetaxel reduced the risk of disease worsening or death by 25 percent vs. docetaxel alone (p = 0.10).

Final PFS data and an update on overall survival from TARGET are anticipated in the second half of this year – Ellis said a European Society of Medical Oncology presentation in September is likely. A phase III decision will be next.

As far as whether the big pharma will move into other indications such as triple-negative breast cancer, "I don't know what Merck will do," Ellis said. "I don't think Merck knows, either." The immediate steps will be to analyze and review the PROCEED data.

"It's always hard to guess on what happened," Ellis said. Previous data showed that the folate component of the drug was able to hit the target tumors successfully, so "if the drug is having difficulties, it's probably a warhead issue more than anything. So a different warhead, a different mechanism and more potent may make a difference." Still, he added, it's too early to tell.

Ellis did, however, disclose that data from the treatment arm in PROCEED mirrored phase II results. Data from the control arm, on the other hand, proved significantly better than historical data, "but we don't know why."

The DSMB raised no safety concerns. Merck and Endocyte have suspended screening and enrollment for PROCEED.

SOLID CASH, GROWING PIPELINE

The latest news sent shares of Endocyte (NASDAQ:ECYT) falling $10.76 to close at $6.62, a new 52-week low; the firm's stock has proved fairly volatile since its early 2011 public debut.

Though it took the then-usual haircut on its initial public offering price, selling 12.5 million shares at $6 apiece, Endocyte's stock made a splash on debut, jumping 29 percent on the first day of trading and gaining as much as 60 percent over the next several months, until early data from the phase II ovarian cancer trial was less-than-compelling, dropping the stock 65 percent. (See BioWorld Today, Feb. 7, 2011.)

In 2012, the deal with Merck sent shares soaring 100 percent, and after the conditional EMA approval earlier this year, the stock hit a new 52-week high of $33.70. Shortly after that latest jump, Endocyte priced a public offering yielding net proceeds of $101.8 million. That added to the cash, equivalents and investments totaling $131.5 million as of March 31.

The company also expects to recognize about $46 million in deferred revenue from Merck in the second quarter, said Chief Financial Officer Mike Sherman.

Merck is shouldering most of the costs for the vintafolide program – Endocyte had been putting in about $5 million to $6 million per quarter for PROCEED – so Endocyte will focus resources on its earlier SMDC pipeline programs. The latest financing will help "move the programs forward more aggressively," Sherman said.

The company has initiated phase I development of EC1456, an injectable SMDC comprising folate vitamin B9 linked to tubulysin B hydrazide as the cytotoxic agent, to be co-developed with etarfolatide as its companion diagnostic. The first cohort is wrapping up, and Endocyte said it expects to start treatment in the second cohort in late May or early June.

According to Cortellis Clinical Trials Intelligence, that phase I study is enrolling patients with advanced solid tumors.

An investigational new drug application has been cleared for EC1169, a prostate-specific membrane antigen-targeted SMDC also consisting of tubulysin B hydrazide, and patient screening has begun.

More SMDC candidates are following, including a folate-targeting drug with an alternative warhead and a DNA alkylating agent, Sherman said. "We'll be judicious in bringing those agents forward as we generate additional data."

Endocyte posted a net loss of $3.1 million, or 9 cents per share, for the first quarter.