FDA Grants Orphan Drug Designation to ERAS-801 for Malignant Glioma

FDA

The FDA has granted an orphan drug designation (ODD) to the orally bioavailable, reversible small molecule EGFR inhibitor ERAS-801 for the treatment of patients with malignant glioma, including glioblastoma (GBM). In preclinical models, the agent demonstrated blood-brain barrier penetrance.¹

“GBM is an aggressive malignancy afflicting approximately 37,000 patients annually in the United States and Europe. Currently approved EGFR inhibitors are limited by insufficient central nervous system penetration to treat GBM and minimal activity against GBM-specific EGFR amplifications, mutations, and other molecular alterations, which contribute to high rates of relapse and a 5-year survival rate below 10%,” Jonathan E. Lim, MD, chairman, chief executive officer, and co-founder of Erasca, said in a press release.

“Receiving ODD recognizes both the importance of innovation for patients with GBM and the therapeutic potential of ERAS-801 to provide a targeted treatment option for these patients, who have a poor prognosis. This ODD follows the earlier fast track designation granted to ERAS-801 by the FDA and underscores the urgency of finding new treatments for this patient population.”

In animal models, ERAS-801 had a brain-to-plasma partition coefficient, Kp, of 3.7 and an unbound partition coefficient, Kp,uu, of 1.2, which was up to 4 times higher than approved EGFR inhibitors, suggesting that approximately 100% of the free drug in plasma is able to cross the blood-brain barrier.

Additionally, at clinically relevant exposures across 30 patient-derived GBM models, ERAS-801 demonstrated a survival benefit in 93% of EGFR-mutant and/or amplified models (n = 14) and statistically significantly higher brain penetrance and prolonged survival compared with approved EGFR TKIs, including osimertinib (Tagrisso), lapatinib (Tykerb), and erlotinib (Tarceva).

The agent is being evaluated as monotherapy in patients with recurrent GBM in the phase 1 THUNDERBBOLT-1 trial (NCT05222802).2 To be eligible for enrollment, patients must be at least 18 years of age and willing and able to give written informed consent, in addition to having received a diagnosis of IDH wild-type glioblastoma as defined by World Health Organization 2021 criteria, adequate organ function, ability to swallow oral medication, and willingness to comply with all protocol-specified visits, assessments, and procedures.

Patients will be excluded from enrollment if they received prior treatment with an EGFR inhibitor.

The dose-escalation portion will establish the maximum tolerated dose and recommended dose, which will then be used during the dose-expansion portion to further evaluate the efficacy and safety of ERAS-801 in patients with EGFR-mutant GBM.

Future sub-studies of THUNDERBBOLT-1 may evaluate ERAS-801 in combination with other agents and in broader patient types.

“The broad activity against both oncogenic and wild-type EGFR, high central nervous system penetration, and demonstrated ability to improve outcomes in over 90% of diverse EGFR-driven, patient-derived glioma models support the potential for ERAS-801 to overcome current challenges with existing therapies. We anticipate reporting initial monotherapy data for ERAS-801 from the phase 1 THUNDERBBOLT-1 trial in patients with recurrent GBM in the second half of 2023.”

References

1. Erasca granted FDA orphan drug designation for CNS-penetrant EGFR inhibitor ERAS-801 for the treatment of malignant glioma. News release. Erasca, Inc. June 22, 2023. Accessed June 23, 2023. https://investors.erasca.com/news-releases/news-release-details/erasca-granted-fda-orphan-drug-designation-cns-penetrant-egfr
2. A study to evaluate ERAS-801 in patients with recurrent glioblastoma (THUNDERBBOLT-1). ClinicalTrials.gov. Updated November 22, 2022. Accessed June 23, 2023. https://classic.clinicaltrials.gov/ct2/show/NCT05222802