FDA Grants ODD to PBI-200 in NTRK Fusion–Positive Solid Tumors


Orphan drug designation has been granted by the FDA to PBI-200 for the treatment of patients with NTRK fusion–positive solid tumors, including primary and metastatic brain tumors.

The FDA has granted an orphan drug designation to PBI-200 for the treatment of patients with NTRK fusion–positive solid tumors, including primary and metastatic brain tumors, according to Pyramid Biosciences, Inc.1

PBI-200 is an oral, highly potent, selective, next-generation inhibitor currently in clinical development for patients who harbor abnormalities involving the tropomyosin receptor kinases (TRK). The inhibitor is designed to overcome a wide range of on-target resistance mutations which have been seen with previous first-generation TRK inhibitors.

A global, multicenter, open-label, phase 1/2 trial (NCT04901806) is currently evaluating PBI-200 in this patient population.

“Oncogenic NTRK gene fusions are found in a broad range of cancers. Orphan designation for drugs in development such as PBI-200 are important to ensure continued innovation to address unmet needs for these patients, including primary and metastatic brain tumors,” said Brian Lestini, MD, PhD, chief executive officer of Pyramid Biosciences, in the press release.

In preclinical studies, which included intracranial xenograft models, PBI-200 was comparable and even seen to be superior to other TRK inhibitors as it delivered higher efficacy and a manageable safety profile.2

Results from a subcutaneous xenograft model of MK-12 colorectal cancer showed PBI-200 to induce tumor stasis when administered at intraperitoneal doses of 15 mg/kg or 30 mg/kg. When given at a dose of 15-mg/kg, the agent resulted in 93% tumor growth inhibition vs 100% when given at a dose of 30-mg/kg. PBI-200 also showed superior brain penetration when administered intraperitoneally or orally compared with prior TRK inhibitors within the mouse model.

In the phase 1/2 PBI-200-101 trial, PBI-200 is being further evaluated in patients with NTRK fusion–positive advanced or metastatic tumors, including primary and metastatic central nervous system tumors.

The design of the trial will consist of a dose-escalation phase and a multicohort expansion at the recommended phase 2 dose (RP2D).

To be enrolled in phase 1 of the trial, patients must have a NTRK-gene amplified, locally advanced or metastatic solid tumor, and EWSR1 WT1–positive desmoplastic small round cell tumors (DSRCTs).3 Those with NTRK fusion–positive solid tumors, not including primary brain tumors, must have received prior treatment with a TRK inhibitor, unless the patient did not have access to treatment with a TRK inhibitor. Patients with NTRK-amplified solid tumors, primary brain tumors, or EWSR1 WT1–positive DSRCTs could have received previous treatment with a TRK inhibitor, although it is not required.

Additionally, patients with either primary brain tumors or brain metastasis must have completed brain radiation 12 weeks prior to the trial’s baseline brain MRI, which will be performed 4 weeks before the first dose of PBI-200.

In the phase 1 portion of the trial, the primary end points include examining the number of patients with adverse events and establishing the RP2D of the investigative agent. Secondary end points consist of area under the plasma drug concentration time curve after 1 dose and 28 doses, overall response rate (ORR), duration of response, and progression-free survival. Then in phase 2 of the trial, the primary end point in each cohort will be ORR.

“We are extremely pleased that the orphan designation was granted, and we look forward to continued enrollment in our global phase 1/2 clinical trial of PBI-200,” said Jordan Leef, chief operating officer and co-founder of Pyramid Biosciences co-founder, in the press release.

  1. Pyramid Biosciences receives orphan drug designation for PBI-200 from FDA. News release. Pyramid Biosciences. July 6, 2022. Accessed July 12, 2022. https://bwnews.pr/3O3OMX7
  2. Regina A, Elagoz A, Albert V, et al. PBI-200: A novel, brain penetrant, next generation pan-TRK kinase inhibitor. Cancer Res. 2019;79(suppl 13):2198. doi:10.1158/1538-7445.AM2019-2198
  3. Study of PBI-200 in subjects with NTRK-fusion-positive solid tumors. ClinicalTrials.gov. Updated July 7, 2022. Accessed July 12, 2022. https://clinicaltrials.gov/ct2/show/NCT04901806
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