Shares of San Diego-based Tocagen Inc. (NASDAQ:TOCA) fell 77.7% to 93 cents Thursday after its two-part immunotherapy for people with recurrent brain cancer failed to surpass standard of care on overall survival (OS), the primary endpoint of the company's phase III Toca 5 trial. Secondary endpoints in the registrational study were also missed, showing no meaningful difference between study arms.

Noting his team's disappointment with the outcome, CEO Marty Duvall said answers to detailed questions about the results would have to wait for further analysis. Meanwhile, an operational review of the business is in the works.

Duvall said that despite having the data for a very short period of time, "there's no doubt when we look at the overall intent-to-treat population, it's a clear miss on the primary endpoint. But a full review of the data is, of course, in order."

It's too soon to tell how the trial's failure will affect Tocagen's exclusive licensing of the combination therapy to Beijing-based Apollobio Corp., a representative of the company told BioWorld. But net proceeds from that deal's up-front payment – $15.2 million at the end of Tocagen's second quarter – clearly helped create some cushion for the business. At the quarter's end, Tocagen had $68.3 million in cash, cash equivalents and marketable securities. A third-quarter earnings report lies ahead on Nov. 6.

Sizable study

Toca-511 (vocimagene amiretrorepvec) is a replication-competent murine leukemia virus vector that delivers the cytosine deaminase gene (CDA) to malignant cells. It's designed to be used in combination with Toca-FC, an oral tablet extended-release formulation of 5-flucytosine that gets converted by CDA to active metabolite 5-fluorouracil.

The expectation at the company is that, in addition to directly killing Toca-511-infected cancer cells, 5-FU can kill neighboring uninfected cancer cells and immune-suppressive myeloid cells, such as myeloid-derived suppressor cells and tumor-associated macrophages. As a result of that process, a cascade is triggered, resulting in "further induction and harnessing of these cells against the cancer-associated antigens to kill more cancer cells and provide durable control of the cancer," the company explains on its website.

With 403 participants at the time it completed enrollment in May 2019, Toca 5 was one of the largest randomized trials conducted in patients with recurrent high-grade glioma (HGG) to date, according to the company. The trial was designed to test Toca-511 together with Toca-FC in patients undergoing surgery for the tumors vs. standard-of-care treatment with lomustine, temozolomide or bevacizumab.

The study included two planned interim analyses, the most recent of which at least one analyst said foreshadowed Thursday's outcome.

"In our view a study failure announcement by year-end is now likely," SVB Leerink analyst Daina Graybosch said in May. (See BioWorld, May 23, 2019.)

The prediction came true with announcement of the trial's top-line outcome on Thursday. On the primary endpoint of OS, the statistical plan assumed a median OS of 9.8 months for the control arm vs. 14.3 months for the Toca-511 and Toca-FC arm. Instead, median OS in the control arm hit 12.2 months vs. just 11.1 months for the experimental combination therapy. The safety, tolerability and adverse event profile of Toca-511 and Toca-FC was as expected.

Whether the combination didn't function as expected or another factor was at play will be the object of analyses that lie ahead. But Thursday, the top-line data seemed to be taken as a bottom-line message by investors trading nearly 15 million shares of the venture, about 63 times the average volume.

Leerink's Graybosch said her team now expects that Tocagen and its collaborator, NRG Oncology, a nonprofit research group, will reconsider their plans for a phase III trial in treatment-naive glioblastoma patients that was set to start this fall.

"As we continue to interrogate the data, understand the data, we'll continue, of course, the discussions with the NRG," said CEO Duvall. "Our intent would be to incorporate learnings from Toca 5 into those plans," he said. Plans to test Toca-511 and Toca-FC in Toca 8, a trial designed to try the combination against recurrent high-grade non-muscle invasive bladder cancer, will also be under review.

"We will continue to engage with regulatory authorities, as appropriate, to determine potential paths forward," Duvall said.

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