Citing what it called poor study design and execution coupled with a lack of follow-up data, the FDA’s Oncologic Drugs Advisory Committee voted 13-2 against recommending approval of Steba Biotech SA’s NDA for Tookad (padeliporfin dipotassium) for injection in men with localized early stage prostate cancer.

The advisory committee also expressed concern that the study’s low-risk patients did not properly fit the therapy’s requested low-risk and intermediate-risk indications. The long-term trade-offs of approval were a subject of much discussion, as some said approving Tookad could cause more harm than good.

“We don’t have robust information about the consequences of the procedure and about the longer-term side effects,” said Heidi Klepin, an advisory committee member and professor of hematology and oncology at Wake Forest University Health Sciences, echoing similar concerns of other committee members.

The FDA is not bound by the advisory committee’s recommendation and will make the final determination.

The NDA is seeking approval for localized prostate cancer patients with stage T1-T2 and prostate-specific antigen ≤10 ng/mL that is either Gleason Grade Group 1 (based on transrectal ultrasound-guided biopsy) or unilateral Gleason grade group 2 (based on multiparametric magnetic resonance imaging-targeted biopsy with <50% of cores positive).

The NDA was based on data from Steba’s pivotal phase III trial of Tookad, PCM-301. The study of the vascular-targeted photodynamic therapy was an open-label, randomized controlled study in patients diagnosed with low-risk prostate cancer on transrectal ultrasound guided biopsy. Subjects were randomized to either active surveillance or Tookad and remained in the study for about 24 months after randomization.

The 24-month follow-up was another bone of contention with advisory committee members.

“Two years of follow-up is not sufficient,” said Susan Halabi, a professor of biostatistics and bioinformatics at the Duke University Medical Center.

The treatment sites were European based: Belgium, Finland, France, Germany, Italy, the Netherlands, Sweden, Switzerland and the U.K. That geography caused consternation as some advisory committee members said too many Caucasians were evaluated in the study and not enough African-Americans were included.

“I’m not sure the results were applicable to U.S. patients,” Halabi added.

The primary outcome measures were the rate of absence of definite cancer using patients on active surveillance as a comparison and the difference in the rate of treatment failure associated with observed progression of disease from low-risk prostate cancer to moderate or higher-risk prostate cancer over 24 months of follow-up.

Advisory committee member Christian Hinrichs, who is also an investigator and research scholar at the NIH’s National Cancer Institute, said the “study began with problematic endpoints and didn’t recover.”

Philip Hoffman, the advisory committee’s chairperson and a hematology/oncology professor of medicine at the University of Chicago, was in the minority, voting to approve the NDA but said he was “torn and on the fence” for most of the meeting.

“Despite its flaws, it was well articulated in analysis and endpoints,” he said. “I thought there was more positive than negative. The study did meet its endpoints. It represents a potentially important option for men with prostate cancer.”

In the written summary of its position, the FDA noted that while PCM-301 met its efficacy standpoints, the clinical relevance of the efficacy endpoint remained unclear. The FDA also said acute toxicity was worse with Tookad and that erectile function at the end of month 24 “appears worse” with Tookad. It also mentioned missing data, false negative and sampling issues making accurate assessment of the results difficult.

Another clinical trial of Tookad, PCM-306, is being planned by Steba, a phase III evaluation of Tookad’s efficacy vs. active surveillance for intermediate-risk localized prostate cancer. The primary endpoint requires follow-up through 30 months, but all subjects will be followed for 72 months regardless of initiation of other local or systemic prostate cancer treatments, which will allow assessments of recurrence rates and morbidity after conversion to radical therapy, long-term safety and tolerability, as well as oncologic outcomes. Its estimated primary completion date is 2030.

Luxembourg-based Steba was founded in 1996 by the brothers Gabriel and Raphael Harari, who previously founded and operated a European drug company, Negma Laboratories, which held 172 patents. The Hararis continued developing oncology technology with Steba Biotech. In the past 20 years, the family has invested half a billion dollars in R&D on vascular targeted focal photodynamic therapy.