Bisphosphonates

Bisphosphonates are a class of compounds that have been developed in the past three decades for use in various diseases of bone and calcium metabolism. In addition to Paget's Disease and osteoporosis, they are also currently used as bone-specific treatments in multiple myeloma, breast and prostate cancer. Bisphosphonates, have been shown in clinical trials in multpile myeloma and breast cancer to prolong the time to the first skeletal related event (SRE) (with combination of anti-cancer therapy), decrease incidence of SRE's, decrease the need for preventive or palliative radiotherapy or bone surgery, and decrease the incidence of hypercalcemia. Bisphosphonates have a strong physicochemical attraction for the mineralized matrix of bone. These drugs, once localized in the bone, inhibit the resorption of bone by osteoclasts (the cells that break down bone) and are therefore classified as antiresorptive agents. The biological effects of bisphosphonates are attributed to the incorporation of the drug into bone, enabling direct interaction with osteoclasts and/or osteoblasts. Bisphosphonates directly inhibit osteoclast activity, directly and indirectly inhibit osteoblast-mediated recruitment of osteoclasts and activate osteoclast apoptosis through differing mechanisms. The commercial impact of the bisphosphonate family of compounds is significant. The leading osteoporosis medications Foasmax® (alendronate), Actonel® (risedronate) and Boniva® (ibandronate) account for over $5 billion in annual sales. Additionally, the bisphosphonate drug Zometa® (zoledronate) sells over $1 billion annually for indications related to the management of skeletal complications associated with various cancers.

  Problems With Currently Marketed Bisphosphonates

The oral bioavailability of any bisphosphonate is extremely limited. Generally less than 1 percent of an oral dose is absorbed from gastrointestinal tract and, moreover, intake of any food further diminishes absorption. Patients must take bisphosphonates on an empty stomach with a minimum amount of water. As a consequence, oral bisphosphonates therapies have surprisingly high non-compliance rates and are poorly tolerated by some patients.

Although i.v. bisphosphonates have had a substantial benefit on the clinical course of patients with metastatic bone disease, bone metastases still progress in the majority of patients and limitations of bisphosphonate use exist. Adjuvant bisphosphonate therapy does not conclusively impact metastatic tumor burden or overall survival rates. Additionally, such therapy may lead to increased visceral metastes and only a partial reduction in skeletal complications. These collective disadvantages raise serious pharmacoeconomic concerns.

  MBC Pharma's Solutions

Our patented technology addresses these problems. To improve the oral absorption of aminobisphosphonates, we chemically attach a vitamin molecule (see Picture 1) known to be actively absorbed in the GI tract to the bisphosphonate. Active absorption will enable lower doses and improved patient tolerance, which could be a critical improvement in bisphosphonate therapy. Known information about the metabolism of vitamin B₆ and its possible role as a transporter-enhanced delivery system of bioactive compounds allows us to suggest that this moiety may indeed serve as a delivery vehicle (see Picture 2) that helps the attached biphosphonate penetrate through the cell membrane. Once inside the cell, the bishosphonate will be released by a specific enzyme (pyridoxine/pyridoxamine phosphate oxidase). Thus, the bisphosphonate will be both absorbed and delivered inside cells using vitamin B₆ metabolic pathways. At present, preclinical model studies evaluating the therapeutic benefits vis a vis the parent compounds are underway. It is noteworthy that a single drug from this class of conjugates will have clinical applications for not only osteoporosis therapy, but cancer and nuclear medicine, as well.

A second embodiment (see Picture 3) of MBC Pharma's proprietary technology is based on exploiting the bone-seeking properties of bisphosphonates to deliver a drug of interest (anticancer, antibiotic, anti-inflammatory, etc) to the bone or surrounding tissue. At present, our initial focus is in the area of chemotherapy. Existing therapies do not adequately address cancer-associated skeletal complications and contribute to poor skeletal health for cancer patients of all stages. The related morbidity (such as bone pain and fractures) is a major contributor to a reduced quality of life for afflicted patients. The presentation of metastatic lesions on bone is a prognosticator of reduced long-term survival. To design compounds to treat metastatic bone lesions, we formulated the following criteria for the successful design of bisphosphonate conjugates:

• Both compounds (i.e., bisphosphonate and anti-cancer compound) liberated from conjugate at bone tissues should be clinically approved drugs for treatment of bone diseases and/or cancer.
• The covalent bond or bonds connecting a bisphosphonate to an anti-neoplastic drug or prodrug should be sensitive to acid hydrolysis because osteoclasts, as well as cancer cells, export protons into media.
• The rate of accumulation of an intact conjugate in bone tissues must substantially exceed the rate of any decomposition which could occur in the course of delivery.

Based on these criteria, we developed proprietary technology for the design and synthesis of novel bisphosphonate conjugates that are able to bind bone and release both drugs when bound. The design concept can be seen on  Picture 4. The first generation of our anticancer bisphosphonate conjugates are based on phosphate linkages between antineoplastic nucleotide analogs and simple bisphosphonates to create active triphosphate analogs. Our preliminary efficacy studies with these compounds in murine models of metastatic bone disease (breast cancer and multiple myeloma) have shown encouraging results and additional distribution, toxicology and efficacy studies are underway or planned for initiation shortly.