hydroxyureamethylacylfulvene (STAR-001)

These preclinical findings illustrate the potential of LP-184 as a pan-HRD cancer therapeutic. Taken together, our results support continued clinical evaluation of LP-184 in a large subset of HRD solid tumors.

P1, N=30, Recruiting, Lantern Pharma Inc. | Phase classification: P1a --> P1

P1a, N=30, Recruiting, Lantern Pharma Inc. | Phase classification: P1 --> P1a

Our results provide valuable biomarkers for clinical testing of LP-184 in a large subset of genetically defined characterized refractory carcinomas. High PTGR1 expression and deleterious DDR mutations are present in approximately one third of PDAC making these patients ideal candidates for clinical trials of LP-184.

These results establish LP-184 as a promising chemotherapeutic for GBM with enhanced efficacy in intrinsic or spironolactone-induced TC-NER deficient tumors.

H460 KEAP1/STK11 mutant cell line derived xenograft model was used to demonstrate the anti-tumor activity of LP-184. LP-184 displayed strong nanomolar potency in 7 day ex vivo treatment in a panel of patient derived lung cancer models carrying ATM, BRCA1 or CHEK1 mutations with IC50s in the range of 30 - 200 nM, which turned out to be 12-350 times superior to that of Olaparib across the same models. LP-184 is highly effective in selected molecular subsets of lung cancer in proof-of-concept ex vivo and in vivo studies, supporting its clinical development in small cell and non-small cell lung cancers. IND-enabling repeat dose GLP toxicology studies of LP-184 show it to be well tolerated in rats and dogs. A first-in-human dose escalation Phase 1A trial with LP-184 is expected to enroll all advanced solid tumors including lung cancers.

P1, N=35, Recruiting, Lantern Pharma Inc.

LP-184 treatment resulted in complete tumor regression (107-141% TGI) in 10/10 HR deficient triple negative breast cancer PDX models of which 7/10 were resistant Olaparib/ Niraparib and to Doxorubicin/ Cyclophosphamide. Unlike PARPi, LP-184 has striking activity in both NERD as well as HRD cancers. These strong data have prompted the development of a soon to be launched clinical trial to translate the broad preclinical anticancer activity of LP-184 in solid tumors with HR/NER pathway defects, such as pancreatic, prostate, ovarian and breast cancers.

LP-184, a small-molecule DNA-damaging agent, is known to be synthetically lethal in tumors with DNA-repair deficiencies, including tumors with ATM mutations...These MCL cell lines included cell lines resistant to ibrutinib, zanubrutinib, venetoclax, and bortezomib...Because ATM orchestrates the activities of the NER and HR pathways, MCL patients with ATM deficiencies are likely to have better responses to LP-284 treatment. Collectively, these data indicate that LP-284 is a promising preclinical DNA-damaging agent that possesses nanomolar-range anti-tumor activities in multiple and diverse MCL cell lines, with the potential to treat MCL patients who are resistant to other therapies.

> 50% of newly diagnosed GBMs fail to respond to standard of care temozolomide (TMZ) due to MGMT expression (i.e.unmethylated mgmt promoter) and essentially all GBMs ultimately develop TMZ resistance. LP-184 was also active in vitro against models of brain metastases from primary lung and breast cancers. These findings identify LP-184 as a promising new agent and support its further development for treating CNS tumors in adult and pediatric populations.

LP-184 was orders of magnitude more potent in vitro than cisplatin and pemetrexed. These correlations were then extended to TCGA analysis of 517 lung adenocarcinoma patients, out of which 35% showed elevated PTGR1, and 40% of those further displayed statistically significant co-occurrence of KEAP1 mutations. The gene correlates of LP-184 sensitivity allow additional personalization of therapeutic options for future treatment of NSCLC.

In CaP cell lines, LP184 turned out equipotent as standard chemotherapeutic Docetaxel, 100-2000 times more potent than another alkylating agent Cisplatin, and 100-9000 times more potent than PARP inhibitor, Olaparib. Advancement of LP184, potentially exploiting recurrent and actionable DDRG mutations, is anticipated to be translated into future clinical trials for mCRPC, a lethal CaP that is responsible for ~33,000 deaths/year in the US alone. Given that only a subset of patients responds to any single drug in this advanced CaP stage, LP184 stands out as a unique agent that may complement or synergize with drugs currently used in treatment of mCRPC and improve the outcomes for men with lethal CaP.

The top 279 cell line records with a predicted IC50 below 100nM represented solid tumors with NSCLC, renal, CNS and head & neck cancers as the most sensitive. In conclusion our results demonstrate that the development of LP-184 guided by tumor gene expression patterns modeled using a combination of algorithms and signatures provides a valuable component to the armamentarium of drugs in diverse solid tumors.

Overall, LP184 is a novel alkylating agent with nanomolar potency in solid tumor cell lines, especially NSCLC, and can serve as a molecularly guided therapy option in multiple tumors. The correlated genes KDM4A/ HPGD that impart high sensitivity at low expression levels, suggest potential synergistic combinations of their respective inhibitors in development PKF118-310/ ML147 with LP184. Research Funding: Lantern Pharma