Loxo sets clock ticking on filing for first-in-class cancer drug

Loxo Oncology CEO Dr. Josh Bilenker

Loxo Oncology reckons it could be just a year or so away from being able to file for approval of its lead drug, just months after reporting phase 1 data.

The Stamford, Connecticut-based biotech says it is well on the way to completing enrollment in its phase 2 NAVIGATE trial of larotrectinib (LOXO-101), which it bills as a possible registration trial, and if all goes well could submit the data to the FDA in late 2017 or early 2018, and in Europe around the end of 2018.

Moreover, new data from its 59-patient phase 1 study—reported at the European Society for Medical Oncology (ESMO) Asia Congress in Singapore—give the company further cause for optimism. Just seven patients have been studied long enough to give an indication of efficacy, but six of these have met the criteria for a response to therapy, and in three the response has been sustained for more than 18 months.

Array Biopharma-partnered larotrectinib is a selective inhibitor of tropomyosin receptor kinase (TRK), a neuron-stimulating factor that is active in fetal development but has its expression switched off later in life. In some cases, the TRK gene can fuse with other genes and reactivate, causing various forms of cancer.

Loxo's development program for the drug is agnostic to any particular tumor type, focusing instead on recruiting patients whose cancer cells express the TRK gene. That means that if approved the drug could be prescribed across multiple solid tumor types on the strength of genetic testing for neurotrophic TRK (NTRK) fusion proteins.

Driven by declining costs and improving accuracy, genetic testing of multiple cancer genes is increasingly being used by oncologists to triage patients and direct them to targeted cancer therapies.

Loxo says its trial of larotrectinib is already 85% enrolled—with more than 10 different tumor types covered—and should be fully recruited in early 2017. If the results come out as hoped it should be able to file for approval in "unresectable or metastatic solid tumors with NTRK-fusion proteins in adult and pediatric patients who require systemic therapy and who have either progressed following prior treatment or who have no acceptable alternative treatments."

NTRK mutations are typically only seen in a small percentage of patients with any particular cancer, but taken together that could add up. The company told investors on a conference call today that there could be between 1,500 and 5,000 eligible late-stage cancer patients in the U.S. alone each year, with a similar number in Europe.

"Based on current enrollment and written regulatory correspondence, we are able to … begin planning for a potential commercial launch" of larotrectinib," said Loxo's chief executive, Dr. Josh Bilenker.
The company also has two follow-up candidates—LOXO-292 and LOXO-195—which target other cancer-causing genes resulting from fusions with kinase genes.   

It said today that LOXO-292, a RET inhibitor, is due to start clinical trials in early 2017, while next-generation TRK inhibitor LOXO-195—designed specifically for use when resistance develops to larotrectinib—will enter the clinic midyear.

Most targeted cancer drugs stimulate resistance which eventually causes cancers to progress, but Loxo reckons it is the first cancer drug maker to simultaneously develop a targeted therapy and its second-generation rescue therapy.

Also working on TRK inhibitors is Ignyta, whose entrectinib candidate—which also targets ROS1 and ALK—is in midstage testing.