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With Latest Orphan Status for Entrectinib in CRC, Ignyta Continues to Pursue Precision Rx Approach

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NEW YORK (GenomeWeb) – Entrectinib, an investigational agent that drug firm Ignyta is studying in multiple molecularly targeted subsets of colorectal cancer patients, this week received orphan drug designation from the US Food and Drug Administration.

Entrectinib is Ignyta's lead product and was licensed worldwide from Nerviano Medical Sciences. The San Diego-based biotech is currently advancing the drug, with orphan status, in patients with TrkA-positive, TrkB-positive, TrkC-positive, ROS1-positive, and ALK-positive colorectal cancer and non-small cell lung cancer.

The company, which incorporated in 2011, has also received orphan designation and rare pediatric disease designation for entrectinib in neuroblastoma, and is looking for signals in patients whose disease is characterized by the same cancer markers.

Drugs for rare diseases that impact fewer than 200,000 patients in the US qualify for orphan designation. The designation means that upon approval of the drug, the sponsor receives a seven-year period of marketing exclusivity in the US for the compound, in addition to tax credits, and is eligible for grant funding, assistance with clinical trial design, and can forgo filing fees under the Prescription Drug User Fee Act.

In NSCLC, approximately 2 percent to 7 percent of NSCLC tumors are positive for ALK fusions and 1 percent are positive for ROS1 fusions. In colorectal cancer, the rates of these markers are also exceedingly rare. For example, in a study presented at the American Society of Clinical Oncology's annual meeting in 2013, researchers reported that out of 236 metastatic colorectal cancer patients, two tested positive by fluorescence in situ hybridization for ROS1 and one patient was positive for an ALK rearrangement. 

Meanwhile, Trk was among the first oncogenes identified in the early 1980s as being involved in causing colon cancer. Trk encodes proteins that play a part in neuronal growth for babies while they are in the womb. Once the baby is born, these genes are silenced, but sometimes Trk genes can fuse with other genes located nearby, which rev up their ability to improperly signal cells to grow and cause cancer.

Recent studies suggest that NTRK fusions can drive 3 percent of lung cancers, under 2 percent of colorectal cancers, 12 percent of thyroid cancers, approximately 2 percent of glioblastomas, and 7 percent of pediatric brain tumors. In total, Ignyta estimates that up to 35,000 newly detected tumors in the US have an alteration – including translocations, splice variants, mutations, and overexpression – in TrkA, TrkB, TrkC, ROS1, or ALK.

At Ignyta, its precision medicine focus goes beyond its efforts around entrectinib and according to the company, Rx/Dx strategies are at the core of its drug development efforts. In December, Ignyta's laboratory passed the State of California's survey for CLIA certification, which enabled it to begin conducting molecular testing in the context of its drug development programs. The firm also plans to get accreditation for its lab from the College of American Pathologists later this year.

"We can now use our CLIA lab to screen patients for enrollment in clinical trials of RXDX-101 [or entrectinib] as well as any future clinical-stage product candidates," Ignyta CEO Jonathan Lim said in a statement back in December. The company also plans to perform commercial companion diagnostic testing in the lab in the event that entrectinib or another product achieves FDA approval, Lim added.

Entrectinib has shown antitumor effects in mouse xenograft models of human tumors driven by TrkA, ROS1, and ALK markers. The drug is being studied in two Phase I/II trials, STARTRK-1 and ALKA-372-001.

Ignyta presented interim data from the ALKA-372-001 trial in September at a medical conference, showing that one patient with ROS1-positive NSCLC had a complete response to entrectinib. Five patients on the drug experienced partial responses, including a neuroblastoma and an NSCLC patient with ALK alterations; two NSCLC patients with ROS1 alterations; and one colorectal cancer patient with a TrkA-positive tumor. One ALK-positive NSCLC patient and one ROS1-positive pancreatic cancer patient on the drug had prolonged stable disease. Patients in this early trial had no dose-limiting toxicities and only one patient experienced grade 3 fatigue that went away after the dose was reduced.

STARTRK-1 involves a dose-escalation cohort of up to 24 patients with Trk, ROS1, or ALK alterations. The study also includes a "basket design" expansion cohort of 100 patients with TrkA, TrkB, TrkC, ROS1, or ALK markers. All patients will receive the recommended Phase II dose of entrectinib, except the ALK subpopulation will be split into treatment-naïve and treated patients.

Ignyta's CLIA-certified lab has been set up in time for beginning enrollment for the STARTRK-1 trial in the third quarter of this year. In the Phase IIa portion of the trial, the company is planning to use an internally developed companion diagnostic to stratify patients. Ignyta CFO Jacob Chacko told GenomeWeb that the company hasn't publicly disclosed the specific diagnostic platform it plans to use for this purpose. However, he noted that Ignyta's lab has next-generation sequencing, immunohistochemistry, FISH, and PCR capabilities.

The company also hopes to start the pivotal STARTRK-2 studies for entrectinib in the second half of this year. The plan, according to Chacko, is to look at how the specific molecularly defined "baskets" are doing in the STARTRK-1 study, and then quickly move to enrich the best performing patient populations into pivotal trials. Which subpopulation moves ahead into pivotal studies and when will "depend on how quickly we enroll patients and then how quickly we see efficacy in one of the arms of the trial," Chacko noted.

There are a number of ongoing National Cancer Institute-sponsored "basket" trials exploring precision cancer drugs, such as MATCH and M-PACT. The MATCH trial is using a targeted NGS panel to identify gene fusions and direct patients to different Phase II trials for targeted therapies. In the M-PACT study, researchers are sequencing patients with refractory solid tumors for nearly 400 mutations in 20 genes and stratifying them to one of two treatment arms, in which they will receive one of four treatment regimens being investigated in the trial.

Meanwhile, Novartis in 2013 launched the so-called Signature trial series, in which patients are enrolled into mutation-specific study protocols that are tissue agnostic. Patient enrollment has been steadily growing in these trials, according to company officials. 

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