FDA Grants Orphan Drug Designation to LP-284 for Mantle Cell Lymphoma

FDA

The FDA has granted an orphan drug designation to LP-284, a novel small-molecule, next-generation acylfulvene, for the treatment of mantle cell lymphoma (MCL), a rare and aggressive form of B-cell non-Hodgkin lymphoma (NHL), according to an announcement from Lantern Pharma.¹

“Receiving orphan drug designation is an important milestone for our latest drug candidate, LP-284, and further validates our data-driven approach to oncology drug discovery and development,” Panna Sharma, president and chief executive officer of Lantern Pharma, stated in a news release. “We recently reported positive preclinical data demonstrating LP-284’s potent antitumor activity in new MCL tumors and also against tumors that had grown resistant to the MCL standard-of-care agents ibrutinib [Imbruvica] and bortezomib [Velcade]. These findings are critically pertinent due to the high relapse rate and poor prognosis of the majority of MCL patients.”

Approximately 40% to 50% of patients with MCL harbor inactivating mutations in the gene ATM, which plays a key role in the cell’s DNA damage response system. MCL cells with mutations in ATM have increased chromosomal imbalance, copy number loss, and hypersensitivity to DNA damaging agents.

In a poster presented at the 2022 SOHO Annual Meeting, preclinical results with LP-284 demonstrated antitumor activity across non-Hodgkin lymphomas (NHL) when tested on in vitro and in vivo models, and in MCL cell lines showing greater sensitivity to the drug. LP-284 is effective in cancers with impaired DNA damage repair (DDR) pathway genes that are expressed in MCL, and it showed activity even in cells that were resistant to approved therapies for MCL.²

When tested in NHL cell lines including MCL, double-hit, double-expressor, Burkitt, and anaplastic large cell lymphomas, all 6 MCL cell lines tested had among the lowest IC50 sensitivity levels, suggesting LP-284 has greater potency in MCL. These MCL cell lines were known to be resistant to bortezomib and ibrutinib, plus venetoclax (Venclexta) and zanubrutinib (Brukinsa). The lowest IC50 sensitivity value of 88 nM was found in the MINO MCL cell line, which was resistant to bortezomib, followed by the MAVER1 MCL cell line with an IC50 sensitivity value of 193 nM, which was resistant to ibrutinib and venetoclax.

In other findings presented at SOHO, LP-284 demonstrated superior antitumor activity compared with LP-184, Lantern’s drug candidate for the treatment of malignant gliomas, atypical teratoid rhabdoid tumors, and pancreatic cancer.

LP-184 induces DNA damage by activating the oxidoreductase prostaglandin reductase 1 (PTGR1), which is expressed at low levels in many hematological cancers. In contrast, LP-284 is an enantiomer of LP-184 that retains synthetic lethality in cancers with impaired DNA damage repair pathway genes, with activity independent of PTGR1 expression.

Lantern expects to file an investigational new drug application with the FDA and launching a first-in-human phase 1 trial for LP-284 in B-cell NHLs, including MCL, by mid 2023.

References

1. FDA grants Lantern Pharma orphan drug designation for drug candidate LP-284 in mantle cell lymphoma. News release. Lantern Pharma. January 5, 2023. Accessed January 9, 2023. https://yhoo.it/3ZlwCHs
2. Zhou J, Sturtevant D, Biyani N, et al. LP-284 - A highly potent small molecule targeting mantle cell lymphoma. Presented at: 2022 SOHO Annual Meeting; September 28-October 1, 2022; Houston, TX. Poster MCL-319