Lantern Pharma & Starlight Therapeutics Present LP-184 (STAR-001) Phase 1b Trial Design and Preclinical Data in Glioblastoma at Society for Neuro-Oncology (SNO) 2024 Highlighting Novel Synthetic Lethality
Lantern Pharma and its subsidiary Starlight Therapeutics presented new preclinical data and Phase 1b trial design for LP-184 (STAR-001) in glioblastoma at SNO 2024. The data shows LP-184 combined with spironolactone increases GBM cell sensitivity up to 6-fold through ERCC3 degradation. The drug demonstrates favorable brain penetrance and effectiveness in temozolomide-resistant GBM models. Currently in Phase 1a trials, LP-184 has shown no dose-limiting toxicities across nine patient cohorts. The planned Phase 1b trial will evaluate LP-184 as both monotherapy and in combination with spironolactone in patients with IDH wild type GBM at first progression.
Lantern Pharma e la sua controllata Starlight Therapeutics hanno presentato nuovi dati preclinici e il design della fase 1b della sperimentazione per LP-184 (STAR-001) nel trattamento del glioblastoma al SNO 2024. I dati mostrano che LP-184 combinato con lo spironolattone aumenta la sensibilità delle cellule GBM fino a 6 volte attraverso la degradazione di ERCC3. Il farmaco dimostra una favorevole capacità di penetrazione nel cervello e efficacia nei modelli di GBM resistenti al temozolomide. Attualmente nella fase 1a, LP-184 non ha mostrato tossicità limitanti delle dosi in nove gruppi di pazienti. La fase 1b pianificata valuterà LP-184 sia come monoterapia che in combinazione con lo spironolattone nei pazienti con GBM wild type IDH alla prima progressione.
Lantern Pharma y su filial Starlight Therapeutics presentaron nuevos datos preclínicos y el diseño del ensayo de fase 1b para LP-184 (STAR-001) en glioblastoma en el SNO 2024. Los datos muestran que LP-184 combinado con espironolactona aumenta la sensibilidad de las células GBM hasta 6 veces a través de la degradación de ERCC3. El fármaco demuestra una buena penetración en el cerebro y eficacia en modelos de GBM resistentes a la temozolomida. Actualmente en ensayos de fase 1a, LP-184 no ha mostrado toxicidades limitantes de dosis en nueve cohortes de pacientes. El ensayo de fase 1b planeado evaluará LP-184 tanto como monoterapia como en combinación con espironolactona en pacientes con GBM tipo salvaje IDH en la primera progresión.
란턴 파마와 그 자회사 스타라이트 테라퓨틱스는 SNO 2024에서 LP-184 (STAR-001)에 대한 새로운 전임상 데이터 및 1b 단계 시험 설계를 발표했습니다. 데이터에 따르면 LP-184는 스피로노락톤과 결합할 때 GBM 세포의 민감도를 최대 6배 증가시키며 ERCC3 분해를 통해 작용합니다. 이 약물은 뇌 침투성이 좋고 테모졸로미드 저항성 GBM 모델에서 효과를 보여줍니다. 현재 1a 단계 시험 중이며, LP-184는 아홉 개 환자 집단에서 용량 제한 독성이 나타나지 않았습니다. 계획된 1b 단계 시험은 첫 번째 진행에서 IDH 와일드 타입 GBM 환자에 대해 단독 요법 및 스피로노락톤과의 병용 요법으로 LP-184를 평가할 것입니다.
Lantern Pharma et sa filiale Starlight Therapeutics ont présenté de nouvelles données précliniques et le design de l'essai de phase 1b pour LP-184 (STAR-001) dans le glioblastome lors de SNO 2024. Les données montrent que LP-184 combiné avec spironolactone augmente la sensibilité des cellules GBM jusqu'à 6 fois par le biais de la dégradation d'ERCC3. Le médicament démontre une bonne pénétration dans le cerveau et une efficacité dans des modèles de GBM résistants à la témozolomide. Actuellement dans des essais de phase 1a, LP-184 n'a montré aucune toxicité limitante de dose auprès de neuf cohortes de patients. L'essai de phase 1b prévu évaluera LP-184 à la fois en monothérapie et en combinaison avec spironolactone chez des patients présentant un GBM de type sauvage IDH lors de la première progression.
Lantern Pharma und ihre Tochtergesellschaft Starlight Therapeutics haben auf dem SNO 2024 neue präklinische Daten und das Prüfdesign der Phase 1b für LP-184 (STAR-001) bei Glioblastom vorgestellt. Die Daten zeigen, dass LP-184 in Kombination mit Spironolacton die Sensitivität von GBM-Zellen um bis zu das 6-Fache erhöht, indem ERCC3 abgebaut wird. Das Arzneimittel zeigt eine günstige Gehirnpenetration und Wirksamkeit in temozolomidresistenten GBM-Modellen. Derzeit in Phase 1a-Studien hat LP-184 keine dosislimitierenden Toxizitäten in neun Patientengruppen gezeigt. Die geplante Phase-1b-Studie wird LP-184 sowohl als Monotherapie als auch in Kombination mit Spironolacton bei Patienten mit IDH-wildtypigem GBM in der ersten Progression untersuchen.
- No dose-limiting toxicities observed in Phase 1a trial across nine patient cohorts
- LP-184 shows superior brain penetrance ratio (0.2) compared to standard care temozolomide (0.1)
- 6-fold increase in GBM cell sensitivity when combined with spironolactone
- FDA granted both Orphan Drug and Fast Track designations
- Effective in temozolomide-resistant GBM models
- None.
Insights
The presentation of LP-184's Phase 1b trial design and preclinical data reveals significant therapeutic potential in glioblastoma treatment. The key findings demonstrate up to 6-fold increase in GBM cell sensitivity when combined with spironolactone and favorable brain penetrance with a 0.2 brain tumor/plasma concentration ratio compared to temozolomide's 0.1.
Several critical advantages stand out: LP-184's effectiveness in temozolomide-resistant cases, independence from MGMT methylation status and enhanced activity in PTGR1-overexpressing tumors (present in 80% of recurrent GBM cases). The combination with spironolactone represents an innovative synthetic lethality approach through ERCC3 degradation, potentially offering a more effective treatment strategy for this aggressive brain cancer.
The ongoing Phase 1a trial's progress without dose-limiting toxicities across nine patient cohorts is encouraging, though early-stage results should be interpreted cautiously. The FDA's Orphan Drug and Fast Track designations add regulatory support to the development pathway.
- The Phase 1b clinical trial design presented at SNO2024 combines LP-184 (STAR-001) with spironolactone to potentially enhance therapeutic response in recurrent glioblastoma (GBM) patients.
- Preclinical data, including in previously published research by Lantern Pharma, demonstrates up to 6-fold increase in GBM cell sensitivity when LP-184 is combined with spironolactone.
- LP-184 continues to advance through the existing Phase 1a clinical trial to assess safety and establish a maximum tolerated dose (MTD); no dose-limiting toxicities have been observed to date across nine patient cohorts enrolled.
- The clinical development for LP-184 in CNS cancers is planned to be advanced as STAR-001 by Starlight Therapeutics in later stage human clinical trials.
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.
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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
ABOUT STARLIGHT THERAPEUTICS
Starlight Therapeutics, a wholly owned subsidiary of Lantern Pharma, is focused exclusively on the clinical development and commercialization of promising oncology therapies for CNS and brain cancers. Starlight leverages Lantern's RADR® AI platform to advance precision medicine approaches for adult and pediatric patients with CNS cancers, many of which have limited or no treatment options. For more information, please visit – www.starlightthera.com .
ABOUT LANTERN PHARMA
Lantern Pharma (NASDAQ: LTRN) is an AI company transforming the cost, pace, and timeline of oncology drug discovery and development. Our proprietary AI and machine learning platform, RADR®, leverages billions of oncology-focused data points and a library of 200+ advanced ML algorithms to help solve billion-dollar, real-world problems in oncology drug development. For more information, please visit http://www.lanternpharma.com .
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