Lixte Biotechnology Holdings Inc., a small OTC-listed company developing inhibitors of protein phosphatases to be used alone and in combination with cytotoxic agents and/or x-ray and immune checkpoint blockers for treating cancer, has filed to raise $10.7 million in a public offering of shares on Nasdaq. Proceeds from the financing would primarily support advancement of LB-100, one of a series of serine/threonine phosphatase inhibitors that are the company's primary focus.

Lixte, initially listed its shares on the OTC board in 2007, under the symbol LIXT. Its uplisting would give effect to a one-for-six reverse stock split, consolidating shares that on Sept. 4 were valued at $1.18 each. Westpark Capital Inc., placement agent for a private placement of company shares in 2007, is underwriting the offering.

Lixte, of East Setauket, N.Y., was founded and is led by oncology and pharmacology expert John Kovach. Its creation, he told BioWorld, was initially inspired by scientific literature suggesting that modulating protein phosphatases, particularly protein phosphatase 2 (PP2A), had significant impact on brain tumors. Finding very little in the way of PP2A-inhibiting compounds, he enlisted SUNY Stony Brook professor Francis Johnson’s company, Chem-Master International Inc., to synthesize the first variants of LB-100.

Serine/threonine phosphatases "have long been appreciated as potentially important targets for anticancer drugs. However, because of the multifunctionality of these enzymes, it had been widely held that pharmacologic inhibitors of [serine/threonine phosphatase] would be too toxic to allow their development as anticancer treatments, but we have shown that this is not the case," the company said.

Preclinical research at the National Institute of Neurologic Disorders and Stroke helped establish early evidence that LB-100 might be able to address a spectrum of human cancers. Combined with standard cytotoxic drugs and/or radiation, it also appeared to potentiate those treatments' effectiveness against hematologic and solid tumor cancers without increasing toxicity.

Given at very low doses in animal models of cancer, LB-100 also "markedly increased the effectiveness of a PD-1 blocker," the company said.

A phase I trial of LB-100 to evaluate its safety found it to be "associated with antitumor activity in humans at doses that are readily tolerable," the company said. Responses in the study showed tumor shrinkage lasting for 11 months in a pancreatic cancer patient and stabilization of disease for four months or more in nine other progressive solid tumors out of 20 patients who had measurable disease. Now, additional studies are underway to further evaluate the candidate in several contexts.

At the Moffitt Cancer Center and Research Institute Hospital in Tampa, Fla., a phase Ib/II study is ongoing to evaluate LB-100 in patients with low and intermediate-1 risk MDS who have failed or are intolerant of standard treatment. At the current rate of accrual, the final analysis and reporting are expected by July 2023, the company said.

Further work is underway in Spain to establish a randomized phase I/II trial of LB-100 plus doxorubicin vs. doxorubicin alone in first-line treatment of advanced soft tissue sarcoma. The investigator-initiated evaluation would be managed under an agreement with the Grupo Español de Investigación en Sarcomas, or Spanish Sarcoma Group. The company has hit a hitch with Spain's Agency for Medicine and Health Products, which wants it to manufacture a new inventory of LB-100 under current Spanish pharmaceutical manufacturing standards. With that work underway, a trial is now estimated to begin during the quarter ending Sept. 30, 2021, and to be completed by the quarter ending Sept. 30, 2024. An interim analysis expected in June 2023.

The U.S. National Cancer Institute is also testing LB-100. It has enrolled the first two patients of a planned eight-patient pharmacologic study testing the ability of LB-100 to enter the brain and penetrate recurrent brain tumors. "The potentiation of radiation might have a real impact on brain tumors," Kovach said. If the study is positive, "we expect there would be a lot of interest from many people about adding it into brain tumor regimens."

LB-100 may also be useful in the treatment of vascular and metabolic diseases. And, as evidence of the enduring investigator-led interest that has a growing body of scientific literature on the program, a preclinical study has even been started to investigate its applications in Angelman syndrome.

In addition to LB-100, the company has in its portfolio a series of histone deacetylase inhibitors in its LB-200 program, though they're at an earlier stage of development. LB-200 candidates may be useful for the treatment of chronic hereditary diseases, such as Gaucher’s disease, the company said.

As the company prospects grow and its clinical work expands, it has moved to broaden its leadership ranks to include a chief medical officer. In July, it announced the appointment of pediatric hematologist and oncologist James Miser to the role.

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