Pipeline

Addressing unmet needs for fragile populations

Bio-Path is developing targeted therapies for acute myeloid leukemia (AML), chronic myeloid leukemia (CML) and other challenging cancers. The company has two candidates in development, prexigebersen (Liposomal Grb2), formerly BP1001, and BP1002 (Liposomal Bcl2), which block the production of proteins in cancer cells that are involved in cell growth and resistance to chemotherapy. Inhibition of these proteins may prove to be a low-toxicity approach to treating patients with AML and other cancers who would not historically be eligible for anticancer therapies because of their age or other comorbidities.

Prexigebersen (Liposomal Grb2 Antisense) for Acute Myeloid Leukemia (AML)

Acute myeloid leukemia (AML) is characterized by the rapid accumulation of immature myeloid cells in the blood, resulting in a drop of the other cell types, such as red blood cells and platelets. Incidence increases with age, with a majority of patients aged 65 or older. AML is the most common acute leukemia in adults. The National Cancer Institute estimates that approximately 20,000 new cases occur each year. Approximately 36% of all leukemias are AML. There is a critically unmet need for non-toxic therapies for older, fragile AML patients who are unfit or ineligible for high-dose chemotherapy or a stem cell transplant. Remission rates for elderly AML patients is between 5-10% and only 5% of patients over the age of 65 will survive more than 5 years after diagnosis.

Prexigebersen (Liposomal Grb2 antisense) is Bio-Path’s lead product candidate, a neutral-charge, liposome-incorporated antisense drug designed to inhibit protein synthesis of Grb2 (growth factor receptor bound protein 2). Grb2 plays an essential role in cancer cell activation via the RAS pathway. Grb2 is an adapter protein that bridges signals between activated and mutated tyrosine kinases, such as Flt3, c-Kit, and Bcr-Abl, and the Ras pathway, leading to activation of the ERK and AKT proteins. Inhibition of Grb2 by prexigebersen represents a significant advance in treating cancers with activated tyrosine kinases using a target not druggable with small molecule inhibitors. Inhibition of Grb2 has been demonstrated to halt cell proliferation and enhance cell killing by chemotherapeutic agents without added toxicity.

Bio-Path has completed a Phase 1 clinical trial on prexigebersen as a monotherapy in relapsed and refractory AML, CML, and MDS patients (cohorts 1-6) and a Phase 2 safety segment for AML in combination with the frontline treatment, low dose Ara C (LDAC) (cohorts 7 and 8). Prexigebersen demonstrates excellent safety profiles with no serious treatment-related adverse events reported, and with data suggesting potential anti-leukemic activity. In the Phase 2 combination trial safety segment, out of a total of six evaluable patients, three patients achieved complete remission, and two achieved partial remission.

Prexigebersen has received orphan drug designation from the FDA for both CML and AML, and from the European Medicines Agency for AML.

Bio-Path is currently conducting a Phase 2 program, which will include two clinical trials of prexigebersen in combination with frontline chemotherapy. The first trial will evaluate the efficacy of prexigebersen in combination with LDAC in de novo AML patients who are elderly and induction therapy ineligible. The second trial will evaluate the efficacy of prexigebersen in combination with LDAC in relapsed and refractory AML patients. More details for these studies may be found on www.clinicaltrials.gov.

Prexigebersen (Liposomal Grb2 Antisense) for Chronic Myeloid Leukemia (CML)

Chronic myeloid leukemia (CML) is characterized by expansion in the blood and bone marrow of mature myeloid cells and their precursors. The average age of diagnosis is 64 years old. Untreated or relapsed/refractory CML will progress to an accelerated phase and eventually blast crisis, at which point it becomes an acute leukemia. For the 1.5 percent of patients who go into blast crisis, few treatment options currently exist. Response rate to treatment for blast crisis CML is less than 30% and patients in blast crisis have an average survival of between 7 to 11 months. New therapies for this critical population are essential.

The dose determining segment of the Phase 2 clinical trial for prexigebersen in combination with the CML frontline therapy, dasatinib, is preparing to enroll patients for treatment. More details may be found on www.clinicaltrials.gov.

Prexigebersen (Liposomal Grb2 antisense), Bio-Path’s lead product candidate is a neutral-charge, liposome-incorporated antisense drug designed to inhibit protein synthesis of Grb2 (growth factor receptor bound protein 2) expression, which is critical in bridging tyrosine kinases to Ras activation in cancer cells. A hallmark of CML disease is the Philadelphia chromosome abnormality, a translocation that fuses part of the BCR gene with the ABL gene, resulting in a continuously activated tyrosine kinase leading to cell proliferation. Inhibition of Grb2 by prexigebersen represents a significant advance in treating cancers with activated tyrosine kinases using a target not druggable with small molecule inhibitors. Inhibition of Grb2 has been demonstrated to halt cell proliferation and enhance cell killing by chemotherapeutic agents without added toxicity.

Prexigebersen (Liposomal Grb2 Antisense) for Solid Tumors

Analyses of solid tumors with activated or mutated tyrosine kinases indicate that BP1001 has high potential for success in treatment of diseases beyond blood cancers. BP1001’s indications include triple negative breast cancer (TNBC), inflammatory breast cancer (IBC), ovarian cancer and autoimmune disease. Preclinical investigation is ongoing to assess the efficacy of BP1001 in treating solid tumors and the autoimmune disease systemic lupus erythematosus.

BP1002 (Liposomal Bcl2) for Follicular Lymphoma and other forms of Non-Hodgkin’s Lymphoma

Follicular lymphoma (FL) is the most common form of low grade or slow-growing non-Hodgkin’s lymphoma (NHL). There are 56,000 new cases of NHL per year, with approximately 30 percent of these follicular lymphoma and approximately 60% being the more aggressive diffuse large B cell lymphoma (DLBCL) type. Treatments of varying efficacy exist for FL and DLBCL; however, due to the wide variety of subtypes of this disease, a frontline approach is lacking. FL can arise anywhere in the body within the germinal centers of the lymph nodes. Between 40 to 80 percent of patients will respond to initial therapy, but virtually all will relapse. Ten percent of the relapsed patients will not respond to treatment at all (refractory).

BP1002 (Liposomal Bcl2) is a neutral-charge, liposome-incorporated antisense drug designed to inhibit protein synthesis of Bcl2, a protein involved in regulating programmed cell death. Bcl2 is overexpressed in more than 90 percent of FL and in a wide variety of solid tumors. Amplified expression of Bcl2 protein in FL is due to the defining genetic hallmark of the disease, the chromosomal translocation t(14;18), which moves the Bcl2 gene from chromosome 18 into the heavy chain immunoglobin locus on chromosome 14. Overexpression of Bcl2 stops affected cells from being killed by chemotherapy. We believe that BP1002 overcomes the failures of previous attempts at inhibiting Bcl2 by specifically interrupting the protein expression of one protein and not a family of necessary proteins and does so without inherent toxicity. With BP1002, more drug substance can reach the circulating lymphocytes so that the cancer cells can be treated with a therapeutically relevant dose. We believe BP1002 provides a new tool for cancer treatment for not just lymphomas, but also many cancers for which Bcl2 expression is preventing cell death. The introduction of a new, non-toxic, and specific Bcl2 inhibitor could be a major advance in cancer therapeutics.

Bio-Path is preparing to submit an IND for BP1002 and is planning to initiate a Phase 1 clinical trial for lymphoma in 2017.