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Almac Developing Next-Generation Sequencing Assay for TP Therapeutics' Anti-Tumor Therapy

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NEW YORK (GenomeWeb) – A recently announced collaboration between Almac Diagnostic Services and precision oncology pharma TP Therapeutics could lead to the submission of regulatory data in a few years for clearance of a drug targeting gene fusions and its companion diagnostic.

Almac is developing a next-generation sequencing assay to enroll patients for clinical trials used to develop TP Therapeutics' drug repotrectinib, an investigational tyrosine kinase inhibitor targeting ROS1, NTRK1-3, and ALK gene fusions in advanced solid tumors. The drug has already been through an early-phase clinical study for which TP published results last month in Cancer Discovery.

The NGS assay being developed in collaboration with TP Therapeutics uses the ArcherDx Anchored Multiplex PCR chemistry, and is a good example of the type of project in which Almac Diagnostic Services engages to develop companion diagnostic assays for clinical trials associated with oncology, Paul Harkin, president and managing director of Almac Dx, said in an interview. 

The project is one of a few programs that Almac has underway which uses the Archer technology for clinical trial assay development, but overall Almac tends to be technology agnostic, he noted. The diagnostics business, a division of the Almac Group, works with a range of diagnostic partners, including Illumina, Thermo Fisher Scientific, and Qiagen and employs various technologies in its CDx development initiatives with pharma and biotech firms, he said.

For example, the firm has developed a prostate cancer test using a custom Affymetrix microarray that can be used to identify prostate cancer patients at high risk of metastatic recurrence following treatment. Overall, the firm has a portfolio of molecular diagnostics using various genomic technologies, and the firm has been a diagnostic partner with Thermo Fisher Scientific, including its Affymetrix business, as well as other prominent diagnostic business entities, Harkin said.

Almac's portfolio of assays are based on NGS, qPCR, DNA and RNA gene expression, and more recently liquid biopsy, Harkin said. "Multiple different assay technologies are either in analytical validation or supporting patient enrollment in clinical trials," he said. "For fusion detection, gene expression, or mutation detection, a lot of assays are moving [toward use of NGS]."

Fusion genes are attractive as therapeutic targets and diagnostic tools due to their inherent expression in tumor tissue alone.

The authors of the recent study concluded that repotrectinib overcomes resistance due to acquired solvent-front mutations involving ROS1, NTRK1-3, and ALK, and it could represent an effective therapeutic option for patients with ROS1-, NTRK1-3-, or ALK-rearranged malignancies that developed resistance to earlier-generation tyrosine kinase inhibitors.

Repotrectinib is currently being evaluated in a Phase 1/2 open-label, multicenter, first-in-human study of the safety, tolerability, pharmacokinetics, and anti-tumor activity in patients with advanced solid tumors harboring ALK, ROS1, or NTRK1-3 rearrangements, Armin Graber, vice president of companion diagnostics and biomarkers at TP Therapeutics, said in an interview. Open-label clinical trials don't disguise the new drug or treatment.

Importantly, TP Therapeutics and Almac plan to use the data from the trial to support a potential submission for clearance to the US Food and Drug Administration, after which — if the trial is successful — clinicians would use the companion diagnostic to identify suitable patients for the drug in clinical settings, Harkin said.

Co-development of companion diagnostics and therapeutic products is critical to the advancement of targeted therapies and precision medicine, and "CDx tests are critical to identify patients most likely to benefit from a targeted treatment," Graber said. "Since repotrectinib is a rationally designed TKI with the objective to inhibit ALK, ROS1, and TRK family kinases, a CDx designed to confirm the presence of ALK, ROS1, or NTRK1-3 rearrangement is required to select patients based on their individual molecular characteristics."

Almac Diagnostic Services and his firm are suitable commercial partners because they have the joint vision to improve patient lives through precision medicine, Graber said.

TP Therapeutics evaluated various diagnostic companies, test modalities, and technologies, and it selected Almac Dx as a diagnostic partner for the co-development of the pan-cancer companion diagnostics and the next-generation TKI because the diagnostics services company provides the oncology pharma company with "deep experience in the development and regulatory approval of diagnostic assays, and their culture fits well with ours," Graber said.

He noted that TP Therapeutics pursues a long-term strategy of developing an oncology panel test for multiple tumor types and indications, and that NGS facilitates a "paradigm shift from one test for one target to a panel test for multiple targets of one or several drugs for multiple CDx indications."

Graber said that TP Therapeutics evaluated various NGS approaches to detect genomic alterations using total nucleic acids and considered various target-enrichment strategies, such PCR amplification or hybrid capture, prior to selecting the Almac assay with ArcherDx chemistry.

If the test and drug are cleared, clinicians would send patients' samples to Almac's CLIA-accredited laboratory in Durham, North Carolina for testing and to select appropriate patients for treatment.

In its external diagnostics pipeline Almac is working with a range of global biopharma clients on bespoke projects associated with research use only assays, clinical trial assays, and CDx developments. The main platforms used in this work are based on NGS and qPCR.

In its internal diagnostics pipeline, Almac also has a range of its own proprietary assays in various stages of research and development, including some that have been launched to market in conjunction with partners. Almac is developing a predictive immuno-oncology biomarker assay that it plans to take through analytical and clinical validation and then commercial launch. A second predictive assay — which is for predicting response to anti-angiogenic agents — is undergoing analytical and clinical validation, as are predictive assays for DNA damaging agents and epithelial to mesenchymal transition (EMT) targeted agents.

Almac has also developed a prognostic assay for prostate cancer, based on gene expression, that can be used to identify prostate cancer patients at high risk of metastatic recurrence following treatment, which has been through analytical and clinical validation, and it has launched a prognostic assay to detect stage II or stage III colon cancer.

Further, the firm has developed a tumor protein 53 (TP53) clinical trial assay for clients and performs research-use-only microsatellite instability testing.

Just last month, the firm launched ClaraT software for classifying biologically relevant gene expression signatures into a comprehensive, easy-to-interpret report. Biopharma and academic biomarker discovery and translational research entities receive an interactive report that enables visualization of the key discriminating biological processes within an individual tumor sample.

The software classifies relevant published gene expression signatures alongside Almac’s proprietary assays and single gene targets, and it links them to multiple key biological processes in The Hallmarks of Cancer, a seminal peer-reviewed article published in the journal Cell in 2000 and update in 2011.

In October, Almac announced the completion of an investment in its Durham, clinical diagnostic services with the opening of a 24,000 square-foot building. 

As part of Almac’s ongoing growth strategy, the expansion added a fourth building to the Durham campus and provided additional office space for more than 100 new employees over the next three years. The firm provides a range of end-to-end clinical trial supply solutions and biomarker diagnostic services for clinical trials in the facility.

The expansion of service capacity came on the back of the conclusion of a previous $5.2 million investment at the Durham facility in 2016, which included an expansion of its clinical services operations and development of its diagnostics and clinical technologies services.

In April, Almac Dx said it had analytically validated the Illumina TruSight Tumor 170 cancer mutation panel as an investigational-use-only assay for prospective testing in clinical trials, positioning it as a partner with interested pharma and biotech firms that would use the assay to support clinical trial enrichment for future cancer trials.

In February, Almac said that it selected Clinical Trial Solution, a product launched by DNAnexus, a biomedical informatics and data management company, to enable it to streamline the use of NGS data in regulated clinical trials. The DNAnexus cloud-based CTS enables the use of genomic and other -omic information in combination with trials data to reduce the time and cost of clinical development, and improve trial results and patient care, Almac said.

In March 2017, the European Organization for the Research and Treatment of Cancer (EORTC) — which has been seeking to streamline patient inclusion in clinical trials of molecularly targeted treatments, and to standardize next-generation sequencing and gene expression analysis — selected Almac to establish molecular profiles of cancer patient samples.

Last November, it acquired BioClin Laboratories, an Athlone, Ireland-based organization providing analytical services, including GMP microbiology testing and GLP bioanalysis.

Harkin said he believes that Almac's ownership by the broader Almac Group, which has 5,000 employees and has existed for 50 years, provides it with a stability that is attractive to customers when it is competing for business with other organizations, including smaller standalone companies and businesses that are part of larger companies, such as Covance, part of LabCorp, and Foundation Medicine, part of Roche.

In the context of clinical trials, demonstrating stability as a business is important, Harkin said, because CDx programs can run for five, or more, years.

 

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