Product Development

LIXTE PRODUCT PIPELINE

LIXTE Product Pipeline

PIPELINE OVERVIEW

Lixte has developed two series of pharmacologically active drugs, the LB-100 series that inhibit serine/threonine phosphatases and the LB-200 series that inhibit histone deacetylases. The current focus is on the LB-100 series of which LB-100 is the lead clinical candidate. LB-100 exerts its activity by a novel mechanism and is the first of its type to be evaluated so broadly in multiple animal models of cancer and now in human beings. Serine/threonine phosphatases are ubiquitous enzymes that regulate many cell signaling networks important to cell growth, division and death. They have long been appreciated as potentially important targets for anti-cancer drugs. However, because of the multi- functionality of these enzymes, it had been widely held that pharmacologic inhibitors of these phosphatases would be too toxic to allow their development as anti-cancer treatments. We have shown that this is not the case. In a Phase 1 trial, LB-100 was well-tolerated at doses associated with objective regression (significant tumor shrinkage) and/or the arresting of tumor progression in patients with progressive cancers.

Lead Product Candidate : LB-100

Pre-clinical studies showed that LB-100 alone inhibits a spectrum of human cancers but when combined with standard cytotoxic drugs and/or radiation, LB-100 potentiates their effectiveness against hematologic and solid tumor cancers without enhancing toxicity. In addition, given at very low doses in animal models of cancer, LB-100 markedly increased the effectiveness of a PD-1 blocker, one of the widely used new immunotherapy drugs. immunotherapy.

In the Phase 1 trial of LB-100, it was well tolerated at doses associated with antitumor activity. Responses included objective regression (tumor shrinkage) lasting for 11 months of a pancreatic cancer and cessation of growth (stabilization of disease) for 4 months or more of 9 other progressive solid tumors out of 20 patients who had measurable disease. As Phase 1 clinical trials are fundamentally designed to determine safety of a new compound in humans, we were encouraged by these results. The next step is to demonstrate in Phase 2 clinical trials the efficacy of LB-100 in one or more specific tumor types, against which the compound has well documented activity in pre-clinical models.

Current Studies

Myelodysplastic Syndrome In November 2018, we received approval from the U.S. Food and Drug Administration or “FDA” for our Investigational New Drug or “IND” Application to conduct a Phase 1b/2 clinical trial to evaluate the therapeutic benefit of LB-100 in patients with low and intermediate-1 risk Myelodysplastic Syndrome (MDS) who have failed or are intolerant of standard treatment. The study is being conducted at the Moffitt NCI-designated Comprehensive Cancer Center, Tampa, FL. Patients with MDS, although usually older, are generally well except for severe anemia requiring frequent blood transfusions. This Phase 1b/2 clinical trial utilizes LB-100 as a single agent in the treatment of patients with low and intermediate-1 risk MDS, including patients with del(5q) myelodysplastic syndrome (del5qMDS) failing first line therapy (NCTO3886662). The bone marrow cells of patients with del5qMDS are deficient in PP2A by virtue of an acquired mutation and are especially vulnerable to further inhibition of PP2A by LB-100. The clinical trial began at a single site in April 2019 and the first patient was entered into the clinical trial in July 2019. A total enrollment of 41 patients is planned. An interim analysis will be done after the first 21 patients are entered. If there are 3 or more responders but fewer than 7, an additional 20 patients will be entered. If at any point there are 7 or more responders, this will be sufficient evidence to support continued development of LB-100 for the treatment of low and intermediate-1 risk MDS. Recruitment has been slow and the Covid-19 pandemic has further reduced recruitment of patients into the protocol. At the current rate of accrual, the trial would be completed over a period of four years from its initiation, with the final analysis and reporting expected by July 2023. However, with additional funds, our objective would be to add two additional MDS centers to the Phase 2 portion of the study to accelerate patient accrual, with the goal of an earlier reporting date.

Advanced Soft Tissue Sarcoma In July, 2019, we entered into a Collaboration Agreement for an Investigator-Initiated Clinical Trial with the Spanish Sarcoma Group (Grupo Español de Investigación en Sarcomas or “GEIS”), Madrid, Spain, to carry out a clinical trial to obtain information about the efficacy and safety of LB-100 combined with doxorubicin in soft tissue sarcomas. Doxorubicin is the global standard for initial treatment of advanced soft tissue sarcomas (“ASTS”). Doxorubicin alone has been the mainstay of first line treatment of ASTS for over 40 years, with little therapeutic gain from adding cytotoxic compounds to or substituting other cytotoxic compounds for doxorubicin. In animal models, LB-100 consistently enhances the anti-tumor activity of doxorubicin without apparent increases in toxicity.

GEIS has a network of referral centers in Spain and across Europe that have an impressive track record of efficiently conducting innovative studies in ASTS. We agreed to provide GEIS with a supply of LB-100 to be utilized in the conduct of this clinical trial, as well as to provide funding for the clinical trial. The goal was to enter the first patient during the quarter ending December 31, 2020, with approximately 150 patients to be enrolled over two years. Advanced sarcoma is a very aggressive disease.

We had previously expected that this clinical trial would commence during the quarter ended June 30, 2020. However, during July 2020, a Spanish regulatory body advised us that although it had approved the scientific and ethical basis of the protocol, it required that we manufacture a new inventory of LB-100 under current Spanish pharmaceutical manufacturing standards. These regulations were adopted subsequent to the production of our existing LB-100 inventory. We are in the process of determining how soon new inventory of LB-100 meeting Spanish specifications can be produced. Accordingly, the clinical trial is now estimated to begin during the quarter ending September 30, 2021 and to be completed by the quarter ending September 30, 2024. The interim analysis expected in June 2023 could indicate either inferiority or superiority of the LB-100 plus doxorubicin arm compared to doxorubicin alone. A positive study would have the potential to change the standard therapy for this disease after four decades of failure to improve the marginal benefit of doxorubicin alone.

Recurrent Gliomas. During the fourth quarter of 2019, the National Cancer Institute, or NCI, enrolled the first two patients of a planned eight patient pharmacologic study of the ability of LB-100 to enter the brain and penetrate recurrent brain tumors in patients where surgical removal of the cancers is indicated (clinical trials registry NCT03027388). This study is being conducted and funded by the NCI under a CRADA with us; additional information will be reported by us as it is provided by the NCI.

Primary malignant brain tumors (gliomas) are very challenging to treat. Radiation combined with the chemotherapeutic drug temozolomide has been the mainstay of therapy of the most aggressive gliomas (glioblastoma multiforme or GBM) for decades, with some further benefit gained by the addition of one or more anti-cancer drugs, but without major advances in overall survival for the majority of patients. In animal models of GBM, LB-100 enhances the effectiveness of radiation, temozolomide chemotherapy treatments and immunotherapy, raising the possibility that LB-100 may improve outcomes of standard GBM treatment in the clinic. Although LB-100 has proven safe in patients at doses associated with apparent anti-tumor activity against several human cancers arising outside the brain, the ability of LB-100 to penetrate tumor tissue arising in the brain is not known. Unfortunately, many drugs potentially useful for GBM treatment do not enter the brain in amounts necessary for anti-cancer action.

The NCI study is designed to determine the extent to which LB-100 enters recurrent malignant gliomas. Patients having surgery to remove one or more tumors will receive one dose of LB-100 prior to surgery and have blood and tumor tissue analyzed to determine the amount of LB-100 present and to determine whether the cells in the tumors show the biochemical changes expected to be present if LB-100 reaches its molecular target. The goal is to obtain data in up to eight patients. As a result of the innovative design of the NCI study, data from so few patients should be sufficient to provide a sound rationale for conducting a clinical trial to determine the effectiveness of adding LB-100 to the standard treatment regimen for GBMs.

Angelman SyndromeAnother intriguing possible use of LB-100 at some future date to treat the symptoms of a rare genetic neurodevelopment disorder called Angelman Syndrome (AS) that affects about 20,000 persons in the US and 500,000 worldwide. A group of neuroscientists in China recently reported that LB-100 improved motor function and  learning in a mouse model of AS. This is a completely unanticipated finding. Whether LB-100 could possibly be of therapeutic benefit in AS is certainly unknown but Lixte has entered into an agreement with the Foundation for Angelman Syndrome Therapeutics (FAST) to collaborate in supporting preclinical studies underway at The University of California, Davis to verify the apparent benefit of LB-100 in a mouse model of AS. If LB-100 reduces AS signs in the model, FAST and Lixte have agreed to discuss further collaboration to assess the potential benefit of LB-100 in patients with AS.

Future Clinical Trials

Given the extensive preclinical data supporting the hypothesis that LB-100 will potentiate the current most effective regimens for a number of additional cancers there are additional clinical trials we would to like to pursue when funding allows:

(1) A clinical trial in patients with small cell lung cancer evaluating the effectiveness of a standard regimen, carboplatin/etoposide/atezolizumab, with and without LB-100. The malignant cells of this uniformly rapidly fatal lung cancer are genetically sensitive to PP2A inhibition (by a process termed synthetic lethality) and the effectiveness of both carboplatin and etoposide are enhanced by LB-100 in animal models of this especially aggressive type of lung cancer.

(2) A clinical trial in patients adding LB-100 to PD-1 inhibitors against one of several cancers in which PD-1 inhibitors alone have definite but modest activity. While the success of immunoblockers in cancer treatment is a major advance in cancer treatment, many patients do not have respond. Low doses of LB-100 have been shown to enhance the effectiveness of PD-1 blockade in  mouse models of several different tumor types.

(3) A clinical trial to determine if, as shown in several animal models, LB-100 enhances the effectiveness of radiation therapy without enhancing toxicity. Even a modest improvement in the efficacy of radiation therapy allowing a reduction of in the number or dose radiation treatments required for cancer therapy in general would be a major benefit to patients and to the cost of treatment.