FDA Grants Orphan Drug Designation to PBI-200 for NTRK Fusion–Positive Solid 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.¹

PBI-200, which is an oral, highly potent and selective inhibitor of TRK kinase, was designed by Pyramid Biosciences to overcome a wide range of on-target resistance mutations that have been observed with first-generation TRK inhibitors.

“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,” Brian Lestini, MD, PhD, chief executive officer of Pyramid Biosciences, stated in a press release.

Preclinical studies in intracranial xenograft models showed that PBI-200 delivered higher efficacy and a manageable safety profile when compared with other TRK inhibitors. In a subcutaneous xenograft model of MK-12 colorectal cancer, results showed that PBI-200 induced tumor stasis when given at intraperitoneal doses of 15 mg/kg or 30 mg/kg.² At the 15-mg/kg dose, the agent resulted in 93% tumor growth inhibition compared with 100% when given at the 30-mg/kg dose. In the mouse model, PBI-200 was also found to have superior brain penetration when administered intraperitoneally or orally compared with prior TRK inhibitors.

PBI-200 will undergo further evaluation in the phase 1/2 PBI-200-101 trial (NCT04901806) in patients with NTRK fusion–positive advanced or metastatic tumors, including primary and metastatic central nervous system tumors. The trial is comprised of a dose-escalation phase and multicohort expansion at the recommended phase 2 dose (RP2D).

In phase 1 of the trial, patients will be required to have EWSR1 WT1–positive desmoplastic small round cell tumors (DSRCTs).³ Those with NTRK fusion–positive solid tumors other than primary brain tumors are required to 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 may have received prior treatment with a TRK inhibitor, although it is not required.

Key exclusion criteria include having received treatment with cytotoxic chemotherapy, a biologic agent, an investigational agent, or radiation therapy within 3 weeks of the first dose of PBI-200; or having received treatment with small molecule kinase inhibitors or hormonal agents within 14 days and 5 half-lives prior to the first dose of PBI-200.

Notably, 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.

The primary end points of the phase 1 portion of the trial include examining adverse effects and establishing the RP2D of the investigative agent. Secondary end points include 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.

In phase 2 of the trial, ORR will serve as the primary end point in each cohort examined.

“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,” Jordan Leef, chief operating officer and co-founder of Pyramid Biosciences co-founder, added in a press release.

References

1. Pyramid Biosciences receives orphan drug designation for PBI-200 from FDA. News release. Pyramid Biosciences. July 6, 2022. Accessed July 7, 2022. https://bwnews.pr/3NRX0lk
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 7, 2022. https://clinicaltrials.gov/ct2/show/NCT04901806