ARIAD Pharmaceuticals (NASDAQ:ARIA) is hoping to receive FDA approval to commercialize in early 2017 its second orphan oncology product, brigatinib, for the treatment of certain genetic forms of non-small cell lung cancer.
At the end of 2012, the company launched Iclusig (ponatinib) to treat patients with several genetic types of chronic myeloid leukemia.
“As an orphan oncology company, we address discrete populations of patients that are genetically defined,” Tim Clackson, president of R&D and CSO, says in an interview with BioTuesdays.com.
“We go after patient populations that have high need, are well defined and potentially neglected by current medicines, either because there is no targeted therapy at the moment or the therapies are inadequate and can be improved,” he adds.
Dr. Clackson explains that Iclusig and brigatinib, both of which were developed internally by ARIAD, are pan-inhibitors, which means that in preclinical studies, they inhibited all mutated versions of their targets that cause resistance to other therapies.
He says ARIAD has developed an integrated small-discovery platform that employs innovative chemistry, computational analysis to screen drug candidates and predictive biology to predict and overcome the resistance potential of drug candidates.
Iclusig is approved for sale in North America, parts of Europe, where the company uses a direct sales force, and in Turkey, Israel, Asia, Australia and New Zealand, where distribution partners sell the drug. ARIAD generated sales of $113-million in 2015.
Last week, ARIAD agreed to sell its European sales and marketing operations to Incyte (NASDAQ:INCY) for $140-million and out-license sales of Iclusig in Europe and 22 other countries to Incyte as part of an ongoing strategic review.
Under the accord, ARIAD will be entitled to receive tiered royalties of between 32% and 50% on net sales of Iclusig in Europe and up to $135-million in potential development and regulatory milestones for Iclusig in new oncology indications.
Incyte has also agreed to fund a portion of the ongoing clinical development of Iclusig in ARIAD’s OPTIC and OPTIC-2L clinical trials through cost-sharing payments of up to $7-million in each of 2016 and 2017.
In the U.S., Iclusig is approved for the treatment of adult patients with T315I-positive chronic myeloid leukemia (chronic, accelerated or blast phases) or T315I-positive chromosome positive acute lymphoblastic leukemia (Ph+ ALL).
It is also cleared for the treatment of adult patients with chronic phase, accelerated phase, or blast phase chronic myeloid leukemia or Ph+ ALL for whom no other tyrosine kinase inhibitor (TKI) therapy is indicated.
Dr. Clackson points out that as a third-line treatment option, Iclusig has produced response rates in the range of 60%, compared with 30% for other third-line therapies.
In December, ARIAD initiated a randomized Phase 3 trial of Iclusig in second-line patients with chronic myeloid leukemia (CML) in the chronic phase (CP).
The OPTIC-2L Phase 3 trial is designed to investigate the efficacy and safety of Iclusig, administered at two starting doses, compared with nilotinib, in patients who are resistant to front-line treatment with imatinib.
The primary endpoint of the OPTIC-2L study, which is now open for patient enrollment, is major molecular response by 12 months. Approximately 600 patients are expected to be enrolled at clinical sites in Europe, Asia, Latin America and Canada.
ARIAD also is conducting an important dose-ranging Phase 2 trial of Iclusig to provide randomized clinical data on the benefit and risk of initiating treatment at lower doses of the drug in about 450 patients with chronic myeloid leukemia.
In its lung cancer program, Dr. Clackson says brigatinib is an inhibitor of anaplastic lymphoma kinase (ALK) and has the “potential to be a best-in-class, orally active TKI for this subset of lung cancer. We believe brigatinib’s competitive profile can garner significant market share.”
ARIAD plans to update data from a Phase 2 study of brigatinib at the ASCO meeting in June. “This will be an important landmark for the medicine, as we expect data from this trial to form the basis for an NDA filing of brigatinib in patients with refractory non-small cell lung cancer in the third quarter this year,” he adds.
The pivotal Phase 2 trial is designed to support accelerated approval of the drug in the U.S. as a second-line therapy. Last month, ARIAD initiated a Phase 3 randomized trial of brigatinib as a first-line treatment for patients with ALK-positive non-small cell lung cancer. The trial is designed to assess the efficacy of brigatinib in comparison to crizotinib based on evaluation of progression free survival.
“We believe the encouraging results shown in our preclinical and ongoing Phase 1/2 studies suggest brigatinib has the potential to improve outcomes for ALK-positive, non-small cell lung cancer patients, as compared to treatment with crizotinib,” Dr. Clackson points out.
ARIAD presented updated clinical data from the Phase 1/2 study of brigatinib at the European Lung Cancer Conference in Geneva last month. The data demonstrated a one-year overall survival rate of 100% in eight patients previously not treated with crizotinib and brigatinib was their first TKI, and 81% in patients with prior treatment of crizotinib.
“The safety, pharmacokinetics and efficacy results with this update provide the potential for differentiation of brigatinib in the crizotinib-resistant patient population,” Dr. Clackson contends.
ARIAD’s pipeline also includes another investigational drug, AP32788. It is a TKI designed to target specific mutations in EGFR or HER2 exon 20 present in a subset of patients with non-small cell lung cancer, for whom there are currently no targeted therapies available.
“Preclinical data suggested that efficacious levels of exposure to AP32788 may be achievable in patients with these challenging mutations – a hypothesis we will be testing in a Phase 1/2 to begin in the current quarter,” Dr. Clackson says.
“We believe AP32788 is the first TKI that has been designed and optimized to inhibit the underlying mutation present in these orphan oncology disease subsets.”