Early data on potential anti-cancer compound now in human trials was falsified, company admits

A pharmaceutical company has admitted that one of its former researchers falsified early data on a compound that’s designed to fight cancer, now in human trials.

The data, published as an abstract in August 2015 in the journal Cancer Research, reported a therapeutic benefit of acalabrutinib in a mouse model of pancreatic cancer. The compound, developed by the company Acerta Pharma, has also been the subject of additional trials published in the New England Journal of Medicine and Blood in 2015. The 2015 NEJM study, which had several authors in common with the Cancer Research abstract, showed the agent had “promising safety and efficacy profiles in patients” with relapsed chronic lymphocytic leukemia.

But an investigation into the data underlying the 2015 abstract shows some were falsified, prompting the journal to retract the abstract.

Ed Tucker, senior vice president of Medical Safety, Quality and Compliance at Acerta Pharma, told us that in August 2016 the company identified an issue with the data in the Cancer Research abstract and started an investigation:

Our investigation was initiated following a communication from an external research collaborator to one of our Acerta scientists in August 2016 regarding the pre-clinical data set in question.

Tucker explained:

Through an internal review, we determined that the pre-clinical data cited as support for a statement within the abstract was falsified.

According to Tucker, the investigation concluded that the falsification “was limited to pre-clinical laboratory research that had no impact on the integrity of acalabrutinib data in any clinical trials, and no risk to patient health.”

The investigational compound targets the protein Bruton tyrosine kinase (Btk). Studies have shown that inhibiting Btk can provoke tumor-fighting immune responses; the FDA approved the first Btk inhibitor, ibrutinib, in August 2013.

Tucker told us that the company identified one employee who was responsible for the falsification; according to Tucker, the employee responsible has left the company:

We interviewed the former employee as part of our investigation.  We investigated work conducted by others and did not find similar findings.

Tucker declined to name the individual.

He explained that Acerta informed the FDA of the investigation in early October 2016, and issued a final report in January 2017:

The FDA, on receipt of the investigation reports, have not requested Acerta to undertake further actions.

FDA declined to comment on the company’s investigation. In August 2017, the FDA gave priority review for the company’s new drug application for acalabrutinib to treat mantle cell lymphoma.

The path from bench to bedside

Driven by the commercial potential of acalabrutinib (which is being tested in a number of tumor types, including solid tumors and blood cancer), in February 2016, the pharmaceutical giant AstraZeneca invested billions in the company for 55% ownership, according to Acerta’s website.

Tucker told us that “extensive data” in over 40 pre-clinical studies, along with data on the Btk inhibitors in oncology more generally, “provide a consistent, robust scientific rationale for all acalabrutinib clinical trials:”

Therefore, this single pre-clinical study was contributory but not pivotal to the decision to proceed with our clinical development program for ACP-196.

Here’s the retraction notice for “ACP-196, An Orally Bioavailable Covalent Selective Inhibitor of Btk, Modulates the Innate Tumor Microenvironment, Exhibits Antitumor Efficacy and Enhances Gemcitabine Activity in Pancreatic Cancer:”

The above-referenced Abstract, which was published in the August 2015 Cancer Research supplement (1), is being retracted at the request of Acerta Pharma. The Abstract was included in a retrospective review conducted by the sponsor as part of an assessment of research activities. The sponsor worked with several of the authors and the collaborating academic research institute to establish the source of data that contributed to the information in the Abstract. The review demonstrated that no source of the data could be identified to support the statements in the second paragraph of the Abstract. As the source of these data cannot be located, it was determined that these data were not reliable and Acerta Pharma requests retraction of the Abstract.

The authors have agreed to this Retraction.

The paper has been cited two times, according to Clarivate Analytics’ Web of Science.

Here’s the abstract:

In an orthotopic mouse model of pancreatic cancer, KPC derived pancreatic cancer cells (KrasG12D; Trp53R172H; Pdx1-Cre) were injected into the pancreases. Vehicle, single agent ACP-196 (15 mg/kg/BID, gavage), single agent gemcitabine (50 mg/kg, IV) and combination ACP-196 with gemcitabine were evaluated for efficacy. By 4 weeks of treatment, mice in the vehicle group showed signs of health deterioration and all mice were euthanized, tumors were collected and measured. Relative to the vehicle treatment, ACP-196 monotherapy resulted in a >2-fold reduction in tumor growth compared with less than a 2-fold reduction with gemcitabine alone. The combination of ACP-196 and gemcitabine resulted in a further reduction in tumor growth when compared to each single agent. Interestingly, analysis of tumor tissues showed that single agent ACP-196 inhibited immunosuppressive populations of TAMs and MDSCs. Surprisingly, Treg populations were also reduced with a robust expansion of CD8+ T cells in the tumors. None of these effects were observed with gemcitabine alone. Although Btk is not expressed in T cells, this finding maybe the result of inhibiting the MDSC and TAM populations within the tumor microenvironment, a mechanism of action which is currently under investigation. Taken together, these data identify Btk as a novel target for modulating tumor immune escape and suggest that pharmacologic targeting of suppressive myeloid cells by ACP-196 induces therapeutic benefit. ACP-196 is currently being evaluated in clinical trials including frontline and salvage pancreatic cancer.

We asked Tucker what parts of the abstract are affected by the falsification. He explained:

As part of the investigation, the figures presented in this abstract were reviewed against source data.  Several could not be source verified and others appeared to contain data that differed from the source available.  As a result of these findings, Acerta decided to retract this abstract.

Tucker told us that Acerta Pharma filed three Investigational New Drug applications with the FDA for acalabrutinib in December 2014. Currently, according to ClinicalTrials.gov, Acerta Pharma has 25 clinical trials underway to test the compound in patients with various cancers, one of which is a phase II trial in patients with advanced pancreatic cancer that began in April 2015. Eight of the studies are still recruiting patients. On March 9, 2016, Acerta terminated a second phase II trial (ACE-ST-004) in patients with pancreatic cancer who had not received prior treatment.

Trials can be terminated for many different reasons; when we asked what prompted the company to end this one, Tucker told us:

It was decided that there was greater unmet medical need and more potential benefit for patients in other parts of the acalabrutinib development program, so we terminated ACE-ST-004.

On its website, the company claims that “as of September 2016, acalabrutinib has been administered to over 1800 participants in clinical studies, including subjects with hematologic malignancies and solid tumors.”

The NEJM study reported the results of a Phase 1-2 clinical trial. Among 61 patients, at least half of whom were followed for more than one year, 95% showed at least some response to the compound. Eight of the 61 patients discontinued treatment (including one patient who died of pneumonia during the study).

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