Merck/Endocyte Mulling Vintafolide’s Future After Failure In Ovarian Cancer

Endocyte is potentially propelled back to a Phase I company after its nearest commercial prospect flops and its collaboration with Merck is expected to disintegrate now that the drug missed PFS in ovarian cancer.

Endocyte Inc. and partner Merck & Co. Inc. have another shot with vintafolide with a lung cancer trial due to report on overall survival in the fall – but the compound took a major hit when a data safety monitoring board stopped a Phase III ovarian cancer trial due to lack of efficacy.

The drug, a conjugate of folic acid that targets folate receptors on the surface of cancer cells and is linked to the cytotoxic agent desacetylvinblastine hydrazide, was being studied in folate-positive platinum-resistant ovarian cancer patients – a small subset of the overall ovarian cancer population. The incidence of ovarian cancer in the U.S. is relatively low, with only about 22,000 cases annually (Also see "Pharma Adapts Ovarian Cancer Drugs Amid Genomics Revolution" - Pink Sheet, 1 Jul, 2012.).

Endocyte and Merck announced the decision to discontinue the Phase III PROCEED trial ahead of the Indiana biotech’s earnings call with analysts on May 2. The companies had been notified the day prior that the drug showed no improvement in progression-free survival when data were viewed during an interim analysis. No safety concerns were identified.

The news – which Endocyte CEO Ron Ellis called surprising and disappointing – could have a major impact on both companies. For Endocyte, the impact will be both short- and long-term; the company’s stock dropped more than 60% to linger just under $7 per share.

A classic example of the over-inflation of biotech stock prices, Endocyte’s stock price shot up more than 175% to surpass $30 per share in late March when the drug received a positive recommendation from the EU’s Committee on Medicinal Products for Human Use (CHMP) for conditional approval (Also see "Vedolizumab, Empagliflozin And Vintafolide Receive Positive EU Opinions After CHMP Meeting" - Pink Sheet, 21 Mar, 2014.). That decision, which was based on positive PFS data seen in Phase II and was contingent on positive Phase III data, likely will be called into question, said the company.

“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, but we have not had that discussion with them. And it’s possible they’ll want to sit down and talk with us and look at the data after we’ve had a more thorough review,” Ellis said on the call.

The company has been spending approximately $5 million to $6 million a quarter on the Phase III trial, as well as another $1 million quarterly on setting up a field force in the EU. The company said that will likely have to be undone.

Credit Suisse analyst Jason Kantor said in a same-day note that he expects the Merck deal to be dissolved and for the drug to stall in development. “We believe any additional investment in the program would be viewed negatively by investors,” he wrote.

While European regulators have been more accepting of PFS in ovarian cancer, sponsors have been more likely to wait for overall survival data for FDA. Roche’s Avastin (bevacizumab), for example, was cleared for ovarian cancer in Europe but has not yet been submitted in the U.S. AstraZeneca PLC recently launched two Phase III trials of olaparib in BRCA-positive ovarian cancer, following a reassessment of olaparib’s potential based on genomic analysis (Also see "AstraZeneca Back In The PARP Mix With Olaparib In Ovarian Cancer" - Pink Sheet, 15 Oct, 2013.). The drug had been shelved in 2011 after data showed the gain in progression-free survival were not likely to translate into an overall survival benefit.

Further Repercussions

On a longer-term basis, the potential of vintafolide and Endocyte’s entire pipeline now will be called into question. Vintafolide is the biotech’s lead drug candidate and is based on small molecule-drug conjugate technology, which delivers potent warheads of chemotherapy by targeting specific receptor sites on the surface of cancer cells, similar to antibody-drug conjugates like Roche’s Kadcyla (ado-trastuzumab emtansine). Other compounds in Endocyte’s pipeline use the same technology but carry different chemotherapies.

“I think if the drug’s having difficulty, it’s probably a warhead issue more than anything. And so a different warhead with a different mechanism … may make a difference in that. But right now, until we’ve seen more data, it’s hard to decide,” noted Ellis, who said the companies have had the data less than 24 hours.

Vintafolide also is being studied currently in a Phase IIb study in patients with folate-positive non-small cell lung cancer. Data from that trial are expected in the fall. The study has already reached a point of progression-free survival and is now evaluating patients for the overall survival endpoint. A Phase I study evaluating the drug in triple-negative breast cancer was planned, but has not yet begun enrolling. Merck has no commitments to move the drug forward at this point.

The two companies teamed up originally in April 2012 when the New Jersey-based big pharma paid $120 million upfront and agreed to another $880 million in milestone payments to develop vintafolide in six cancer indications [See Deal] (Also see "Merck Gains Phase III Drug/Companion Diagnostic In Deal With Endocyte" - Pink Sheet, 16 Apr, 2012.). The compound was meant to be a major part of Merck’s push in oncology, which has been spearheaded by its anti-PD-1 immunotherapy pembrolizumab (MK-3475).