Northwest Biotherapeutics (NWBO) snuck a brand new risk nugget about the brain cancer vaccine DCVax into its annual report filed with the Securities and Exchange Commission on Tuesday.
It pays to read 10-Ks closely.
Northwest Bio is now acknowledging that no agreement with FDA was ever reached on the progression-free survival (PFS) primary endpoint for the DCVax phase III brain cancer study.
The new addition to the company's regulatory risk factor statement is bolded:
Our products and our ongoing development activities are subject to regulation by regulatory authorities in the countries in which we and our collaborators and distributors wish to test, manufacture or market our products. For instance, the FDA will regulate the product in the U.S. and equivalent authorities, such as the EMA will regulate in Europe. Regulatory approval by these authorities will be subject to the evaluation of data relating to the quality, efficacy and safety of the product for its proposed use, and there can be no assurance that the regulatory authorities will find our data sufficient to support product approval of DCVax-L. In addition, the endpoint against which the data is measured must be acceptable to the regulatory authorities. The primary endpoint of our Phase III trial is progression free survival. Sometimes regulators have accepted this endpoint, and sometimes not. There can be no assurance that the regulatory authorities will find this to be an approvable endpoint for Glioblastoma multiforme cancer. [Emphasis added.]Companies don't make changes to risk statements in their SEC filings willy nilly.
The DCVax study in GBM has gone through numerous design changes and patient enrollment freezes since it was started in 2005 as a small, non-randomized phase II study expected to enroll 90 patients. In addition to upsizing to 312 newly diagnosed GBM patients, Northwest Bio added a placebo arm to the study and changed its designation to "phase III" -- implying positive results could be used to support an FDA approval filing.
Northwest Bio claims FDA agreed to the changes made the DCVax study but the company does not have a Special Protocol Assessment (SPA) agreement with regulators.
The lack of an SPA is a real concern because Northwest is using a primary endpoint for the DCVAx study -- progression-free survival -- which appears to fall short of FDA's approval standards for therapies addressing newly diagnosed GBM patients.
ImmunoCellular Therapeutics (IMUC) used overall survival as the primary endpoint for a recently completed phase II study of its brain cancer vaccine ICT-107 based on feedback from the FDA.
In a recent shareholder letter, ImmunoCellular stated:
We selected OS as the primary endpoint for clear, pragmatic reasons: to follow the guidance of the FDA relative to what constitutes a registration endpoint, and to inform the design of a phase III registration study. In 2011 written correspondence with our Company regarding our phase II protocol, the FDA indicated "progression free survival (PFS) as an endpoint is acceptable for hypothesis testing, but not as a primary endpoint for a phase 3 trial to support a BLA." Based on FDA's guidance, we focused the trial on generating detailed survival data, and retained PFS as an important secondary clinical endpoint.
Celldex Therapeutics (CLDX) is also using overall survival as the primary endpoint for an ongoing phase III study of its brain cancer vaccine rindopepimut.
Northwest Bio has never explained why FDA would agree to review DCVax for approval based on progression-free survival data when two other companies also developing vaccines for newly diagnosed GBM patients said FDA wanted overall survival as the primary endpoint.Northwest Bio's newly filed 10-K doesn't include an update on patient enrollment in the phase III brain cancer study and says the long-delayed interim efficacy analysis is still pending.