Brain cancers are among the most difficult to treat, as Tocagen’s struggles follow late-stage study failures earlier this month from AbbVie and Bristol-Myers Squibb.

The biological barrier mechanism that keeps some blood-borne substances from entering the brain and spinal fluid also impedes the entry of systemic drugs that might otherwise be effective against tumors.

No standard of care exists for recurrent disease, with chemotherapy or Avastin typically used. Treatment with Avastin induces remission in only about 20% to 25% of patients, who on average progress after only four months.

Tocagen’s approach has been to combine a viral vector, Toca 511, that selectively infects tumor cells and stimulates production of an enzyme that can convert the second drug, Toca FC, into the chemotherapeutic agent 5-fluorouracil.

The Phase 3 trial has enrolled 403 patients to receive the Tocagen combination, or physicians’ choice of Avastin or chemotherapy as a comparator. The company asserted that after 257 patient deaths it will be able to calculate whether its combination significantly extended survival compared to the alternative treatment. The trial design assumed that the comparator arm would have a survival of 9.8 months and Toca 511/FC patients would live 14.3 months.

The interim analysis announced Tuesday was based on 193 deaths. The independent committee overseeing the trial decided that it should not be stopped, signaling that the combination had not shown that it extended survival.

This was taken as a sign of failure. In a May 22 note to clients, Leerink’s Graybosch lowered the chance of success by about half from 11% before the analysis. “A great outcome is more likely to show itself early,” Graybosch wrote.

Tocagen management and more bullish analysts argue that the Food and Drug Administration will consider other positive signs of benefit other than survival, given the relative lack of treatments for high grade gliomas. Cantor Fitzgerald’s Elemer Piros argued that the durability of response in Phase 1 patients should be taken into account, for example. Avastin’s approval in brain cancer relied on single arm trials that measured response rates and durability of response.

Secondary endpoints in this trial include remission rates at 24 weeks, duration of response and percentage of patients with stable disease at 18 months.

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