February 20, 2013 10:14 pm

Active Biotech/Ipsen’s prostate cancer drug mechanism clouds opinion of improving overall survival

This article is provided to FT.com readers by BioPharm Insight—a news service focused on providing insight into the most price sensitive issues in the global pharmaceutical market. www.biopharminsight.com

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Active Biotech (STO:ACTI) and Ipsen’s (EPA:IPN) tasquinimod has experts uncertain on whether it can delay time to death in prostate cancer patients, experts told BioPharm Insight. Although tasquinimod demonstrated the ability to delay disease worsening, they were ambiguous on whether tasquinimod’s ability to limit the formation of new blood vessels, or angiogenesis, can stop tumour growth and progression.

In prostate cancer, several antiangiogenic drugs have failed to translate benefits in delaying disease worsening, or progression-free survival (PFS), into a delay in time to death, or overall survival (OS), the experts noted. Thus far, tasquinimod’s demonstration of therapeutic benefits in clinical trials, or efficacy results, could be driven by a number of other proposed drug mechanisms.

Tasquinimod is in a Phase III trial - the final clinical stage - for the treatment of metastatic castrate-resistant prostate cancer (mCRPC). The primary endpoint is PFS, and the secondary endpoint is OS. PFS is the time after treatment that a patient lives without the cancer getting worse, where as OS is the length of time from the start of treatment for which those patients are still alive.

Trial enrolment completed in December 2012.

Mechanism of action

Tasquinimod showed statistically significant results in Phase II, where the median PFS was 7.6 months among patients treated with tasquinimod compared to 3.3 months for those given placebo, said lead investigator Dr Michael Carducci, professor, oncology and urology, Johns Hopkins Medical Institutions, Baltimore, Maryland.

The PFS seen with tasquinimod so far does look better than past antiangiogenic drugs that failed in CRPC, such as Pfizer’s (NYSE:PFE) Sutent (sunitinib) or AstraZeneca’s (LON:AZN) zibotentan, said investigator Dr Roberto Pili, Roswell Park Cancer Institute, Buffalo, New York.

Active Biotech has been working on elucidating tasquinimod’s mechanism of action (MOA), and the results have not been straightforward, Carducci said. The drug has shown some beneficial effects on the immune system inhibiting S100A9 but also may work by increasing thrombospondin-1 (TSP-1), which may have additional antiangiogenic abilities, he explained. There are several other targets that the drug appears to hit, for example inhibition of HIF-1a, which leads to some confusion about what is driving the antitumour effect, Carducci said.

Antiangiogenesis may not be tasquinimod’s main MOA, but rather the drug’s efficacy could be down to its effects on myeloid-derived suppressor cells (MDSC), Pili added, pointing to data from his recent publication (Curr Oncol Rep. 2013 Jan 20).

Tasquinimod binds to S100A9, which has been shown to be involved in the spread of cancer from one part of the body to another and to be critical for the function of tumour-associated MDSCs, which suppress immunity and stimulate angiogenesis as well as stromal growth, Tomas Leanderson, CEO of Active Biotech, said.

Additionally, investigator Dr Andrew Armstrong, associate professor, medicine and surgery, Duke Cancer Institute Divisions of Medical Oncology and Urology, Duke University, Durham, North Carolina, noted, tasquinimod appears to be inflammatory because it increases fibrinogen, a marker of inflammation.

Although tasquinimod has multiple potential MOAs, one of the major ones is through inhibition of angiogenesis, countered Dr Evan Yu, associate professor, Department of Medicine at the University of Washington. Yet, he noted, success has not been seen with other antiangiogenic agents in prostate cancer. “Thus, I think we have to hope that the other proposed mechanisms of tasquinimod action have potent effect,” he said.

Phase II data

The PFS seen so far with tasquinimod is in the order of other drugs that have later gone on to show OS, like Johnson and Johnson’s (NYSE:JNJ) Zytiga (abiraterone) and Medivation’s (NASDAQ:MDVN) Xtandi (enzalutamide), both approved for CRPC, Armstrong said. The PFS was more than doubled with tasquinimod and the hazard ratio was 0.57, which is similar to what Zytiga has shown, Leanderson added.

Active Biotech published Phase II data showing a trend towards OS in the intention-to-treat (ITT) population, Leanderson said. ITT is a statistical analysis that includes patients based on the assigned treatment regime, rather than only including those who actually completed the treatment assignment.

Yet, Leanderson and Pili pointed out, placebo patients were allowed to cross over into the treatment group, meaning most patients eventually received tasquinimod and that the study was unbalanced in disfavour of the tasquinimod arm.

Although there was no OS difference in the Phase II trial, it was not powered for the analysis, said Pili.

Pili believed Active Biotech conducted a strong study, and the sponsor was courageous in its use of trial endpoints measuring clinical progression with radiographic measures rather than just prostate specific antigen levels, as radiographic measures is currently not the gold standard but could be in the future. Armstrong said, however, he is uncertain about using radiographic PFS as the primary endpoint, because some drugs have shown a PFS benefit that does not translate to OS, for example, Roche’s (VTX:ROG) Avastin (bevacizumab), while other drugs like Dendreon’s (NASDAQ:DNDN) Provenge (sipuleucel-T) showed it can delay OS without impacting PFS, he explained.

Phase III trial

The Phase III trial may have a primary endpoint for radiographic PFS, but it is powered for detecting an OS signal, Carducci said. The European Medicines Agency only required the endpoint to be radiographic PFS, whereas the US Food and Drug Administration (FDA) requires OS at the moment, he noted. However, the FDA has said it will accept radiographic change depending on what the PFS signal looks like and that can only be interpreted in the context of what the OS data looks like.

Given that delaying chemotherapy use is medically relevant and that all OS data in this early patient segment will be heavily corrupted by all downstream treatments, Active Biotech thinks that this design still is very viable, Leanderson added.

When asked whether the proposed MOA of the drug could bring extra scrutiny of the PFS data from regulatory bodies, Armstrong said: “If I was the FDA I would want to see the OS data.” Currently, PFS is not the gold standard, and the fact that with some drugs PFS does not translate to OS will have to be addressed, he added.

The Phase III trial is being run in the period of time that Zytiga has become available, Carducci said. The company and investigators have worked hard to keep patients on the trial and the drug for as long as possible before exploring new drug therapies, he noted.

Ensuring patients stay on the trial long enough to show a clear signal will be a hurdle for Phase III, Armstrong said. However, he added, it is possible the FDA could approve the drug if it shows a strong PFS signal with the caveat that patients do not cross over from the control arm into the active treatment arm because this would prevent a further OS analysis.

Active Biotech has a market cap of SEK 5.3bn (USD 842.9m).

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