Q&A: Keeping it small (molecule) and focused on cancer

DDNews talks to Timothy Clackson, Ph.D., president of research and development at ARIAD, about the company's drug discovery programs and structure-based drug design to create molecules that overcome resistance to existing treatments

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Sometimes, a little tunnel vision isn’t a bad thing. ARIAD Pharmaceutical’s sole focus is cancer. Furthermore, the company concentrates its efforts on small-molecule medicines, targeting proteins and pathways involved in cancer in areas of great unmet need. Its internal drug discovery programs are built on ARIAD’s in-house expertise in cancer biology and structure-based drug design to create molecules that overcome resistance to existing treatments.
ARIAD’s discovery group is a multi-disciplinary team of scientists with expertise in medicinal chemistry, structural and computational drug design, cell biology and cancer genetics, pharmacology and drug metabolism. A major focus of the group is to identify inhibitors of protein kinases (enzymes that transfer phosphates between different proteins) that are implicated in specific cancers.
Dr. Timothy Clackson, president of research and development at ARIAD, recently spoke to DDNews to discuss the company’s goals and achievements.
DDNews: What is the “etiology” of ARIAD and when and why did you join the company?
Timothy Clackson: Our mission is to discover, develop and commercialize small-molecule medicines to treat cancer in patients with the greatest unmet medical need—those with aggressive cancers where current therapies are inadequate. We are committed to the highest standards of integrity and stewardship in service to patients, the medical community, employees and shareholders.
ARIAD has always been a “small molecule” company. But in our early days, we had a more platform-based approach and were exploring multiple therapeutic areas using a computational and structure-based drug design platform. When I joined ARIAD in 1994 as a scientific group leader in chemical biology, we added a second platform technology for controlling cell therapies with small-molecule drugs. In 2001 we focused exclusively on oncology and out-licensed other opportunities, which has allowed us to build in stages into a fully integrated commercial-stage oncology company.
DDNews: Can you describe how brigatinib works to overcome mutation-based resistance in NSCLC?
Clackson: Brigatinib is an investigational oral inhibitor of anaplastic lymphoma kinase (ALK). Genetic studies indicate that abnormal expression of ALK is a key driver in certain types of cancer, including non-small cell lung cancer (NSCLC). In fact, crizotinib is an approved medicine for patients with ALK+ NSCLC and has demonstrated impressive clinical benefit. However, drug resistance can emerge rapidly for many patients. Knowing this, the research and development team at ARIAD set out to design a more potent ALK inhibitor that could address the most important mechanisms of crizotinib resistance: activity against all crizotinib-resistant ALK mutants, and the potential for activity in patients with brain metastases, a key feature of many patients who experience failure of crizotinib.
We’re currently enrolling patients with ALK+ NSCLC who have been failed by crizotinib in the Phase 2 ALTA trial of brigatinib, which is expected to complete enrollment in the third quarter of this year and which will be the basis for our initial regulatory submissions.
We’re excited by the clinical data we’re seeing from our Phase 1/2 trial of brigatinib, particularly for patients whose NSCLC has metastasized to the brain. At the 2015 European Lung Cancer Conference (ELCC) in Geneva, we shared clinical data from the Phase 1/2 trial that showed robust anti-tumor activity of brigatinib in patients with crizotinib-resistant ALK+ NSCLC, with objective response rates ranging from 68 to 81 percent, depending on the dose, and with those responses approaching one year.
DDNews: What benefits do you foresee from having received Breakthrough Therapy designation from the FDA?
Clackson: Brigatinib received Breakthrough Therapy designation from the U.S. Food and Drug Administration in October 2014 for the treatment of patients with ALK+ metastatic NSCLC whose tumors are resistant to crizotinib. This designation is based on results from the ongoing Phase 1/2 trial that show antitumor activity of brigatinib in patients with ALK+ NSCLC, including patients with active brain metastases. A Breakthrough Therapy designation is intended to expedite the development and FDA review of drugs for serious or life-threatening conditions. We are very pleased that the FDA has granted Breakthrough Therapy designation to brigatinib, as it may expedite the review of our regulatory filing.
DDNews: What is the current status of the Phase 2 ALTA trial, and when do you expect to have additional data to report?
Clackson: We are focused on completing patient enrollment in the ALTA trial and expect to have preliminary data from this trial late in 2015, though we expect to have a more robust look at the data for the American Society of Clinical Oncology meeting in 2016. As an important side note, the first U.S. patent for brigatinib was issued last month, which provides important composition of matter protection until at least the end of 2030. We’re excited by the progress we’re making with this drug candidate.
DDNews: ARIAD has announced that the company will be partnering brigatinib. What will you be looking for as you evaluate potential partners?
Clackson: Our stated goal is to secure a broad co-development and co-commercialization partnership for brigatinib that will allow us to leverage our existing infrastructure, allow us to build on our commercial capabilities, both in the U.S. and in Europe, and allow us to accelerate the start of a randomized frontline trial of brigatinib versus the standard of care in ALK-positive lung cancer, crizotinib.
In addition, we will look to a partnering approach to bring opportunities for combination strategies with brigatinib—for example, combinations with immuno-oncology therapies.
DDNews: Over the next 12 months, what clinical milestones for brigatinib do you hope to see?
Clackson: Within the next year, we hope to begin a front-line trial of brigatinib in treatment-naive patients. Over the next 12 months we also expect to complete enrollment in the Phase 2 ALTA trial and to use that data as the basis for our regulatory submission, planned for mid-2016. It’s an exciting time for the team here at ARIAD. It was only a few short years ago that we first designed brigatinib, and now we’re closing in on submitting an NDA. It’s enormously rewarding to see patients who have been helped by advanced treatments developed internally here at ARIAD.

Dr. Timothy P. Clackson has served as president of research and development at Cambridge, Mass.-based ARIAD since June 2010 and chief scientific officer since 2003, having joined the company in 1994. Prior to joining ARIAD, Clackson was a postdoctoral fellow at Genentech Inc. from 1991 to 1994, where he studied the molecular basis for human growth hormone function. Clackson is on the board of directors of the Massachusetts Biotechnology Council, also known as MassBio. He received his bachelor’s degree in biochemistry from the University of Oxford and his doctoral degree in biology from the University of Cambridge.

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