On November 26, 2024 Lantern Pharma Inc. (NASDAQ: LTRN), an artificial intelligence company transforming oncology drug development, and its wholly-owned subsidiary Starlight Therapeutics, focused exclusively on CNS and brain cancers, reported the presentation of new preclinical data and Phase 1b trial design for LP-184 (to be developed as STAR-001 for CNS indications) in glioblastoma at the Society for Neuro-Oncology (SNO) 2024 Annual Meeting in Houston, Texas (Press release, Lantern Pharma, NOV 26, 2024, View Source [SID1234648673]).

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The poster presentation highlighted LP-184’s unique mechanism of action, brain penetrance properties, and potential enhanced therapeutic effect when combined with spironolactone in glioblastoma multiforme (GBM). LP-184 is currently under investigation in a Phase 1a dose-escalation safety study (NCT05933265) in adult patients with advanced solid tumors including GBM.

"The data and trial design presented at SNO2024 further validate and progress LP-184’s potential as a promising new treatment option for glioblastoma patients," said Panna Sharma, President and CEO of Lantern Pharma. "Through our subsidiary Starlight Therapeutics, we are positioned to advance LP-184 as STAR-001 specifically for brain cancers and CNS indications, where treatment options are limited and often ineffective. The combination with spironolactone represents an innovative approach, which has been developed with the aid of our AI platform RADR, to potentially enhance therapeutic response in this devastating disease."

The key highlights from the poster presented by Dr. Schreck from Johns Hopkins Medicine and Dr. Kulkarni from Lantern Pharma at SNO2024 include:

LP-184 shows favorable brain penetrance with a brain tumor/plasma concentration ratio of 0.2 compared to 0.1 for the existing standard of care, temzolomide.
Preclinical studies show spironolactone increases GBM cell sensitivity to LP-184 up to 6-fold through ERCC3 degradation – which induces NERD (nucleotide excision repair deficiency) making the cancer cells both more sensitive to LP-184/STAR-001 and largely unable to repair themselves after exposure to the drug-candidate.
Multiple time point and dose level experiments show that GBM cells treated with spironolactone showed significant depletion of ERCC3 – including at 25μM of spironolactone which showed up-to 95% depletion of ERCC3 by 24h.
LP-184 is effective in temozolomide-resistant GBM models and is agnostic to MGMT methylation status.
PTGR1 expression analysis from GTEX normal brain and TCGA GBM highlights that PTGR1 levels are higher in brain tumor tissue (median 5.15) as compared to normal brain tissue (median 3.95).
ERCC3-dependent TC-NER activity was identified as a determinant of LP-184 synthetic lethality predicting that LP-184’s therapeutic potential will be enhanced in patients with intrinsic or spironolactone-induced NER deficient tumors.
Phase 1b trial being considered will evaluate LP-184 as both monotherapy and in combination with spironolactone using Simon’s 2-stage optimal design in patients with IDH wild type GBM at first progression.
Following determination of the Maximum Tolerated Dose and/or Recommended Phase 2 Dose from the ongoing Phase 1a study, Starlight Therapeutics plans to initiate a Phase 1b trial evaluating LP-184/STAR-001 in two cohorts of recurrent GBM patients: one arm which anticipates administration of STAR-001 as monotherapy and the other arm which anticipates administration of STAR-001 in combination with spironolactone (200 mg daily).

The trial, as currently anticipated and designed, will assess safety, pharmacokinetics, and objective response using RANO 2.0 criteria. Additionally, the study will evaluate biomarkers including PTGR1 expression, ERCC3 levels, and DNA damage markers to help identify patients most likely to respond to treatment. Lantern has previously reported on achieving significant development milestones in the creation of a molecular diagnostic using quantitative PCR to assess PTGR1 levels from clinical patient samples.

LP-184 (to be developed as STAR-001 for CNS indications) is a fully synthetic small molecule that belongs to the acylfulvene class of alkylating agents. It induces DNA double-strand breaks and has shown promise across a range of solid tumors, including in preclinical GBM models. LP-184 is activated by PTGR1, which is over-expressed in approximately 80% of recurrent GBM tumors. The FDA has granted LP-184 both Orphan Drug and Fast Track designations for the treatment of malignant gliomas / glioblastoma.