Overview | SARM/LI | Semparatide | SPRM
Many complex diseases, such as cancer, involve cellular growth abnormalities regulated by the endocrine system. Based upon proprietary insight into the complexities of the endocrine system, Tokai is building a pipeline of therapeutics focusing initially on castration resistant prostate cancer.
Specific Androgen Receptor Modulator/Lyase Inhibitor, or SARM/LI (TOK-001)
Castration Resistant Prostate Cancer (CRPC)
Every year, over 200,000 men are diagnosed with prostate cancer. The American Cancer Society cites prostate cancer as the most frequently diagnosed cancer among men in the United States. Prostate cancer is the second leading cancer related death.
Prostate cancer cells are unique in that their growth is fueled by male “sex hormones,” called androgens, which are produced mainly in the testes. Reducing androgens by medical or surgical castration can control prostate cancer, but these therapies usually fail after several years. Prostate cancer that thrives after castration therapy is called castration resistant prostate cancer (CRPC).
The only approved treatment for CRPC is taxotere, a chemotherapy with serious side effects in some patients, limiting its use. An effective treatment for CRPC, better tolerated than taxotere, would extend patient survival and improve quality of life.
Specific Androgen Receptor Modulator/Lyase Inhibitor (SARM/LI or TOK-001)
CRPC cells become resistant to castration therapy by developing alternative mechanisms for satisfying their androgen requirement. CRPC cells:
- Synthesize their own androgens;
- Rely on low-level androgens secreted by the adrenal glands;
- Increase the number of androgen receptors they contain, becoming more androgen responsive.
Tokai’s lead compound, TOK-001, targets all three of these non-testicular androgen-dependent growth mechanisms. In nonclinical studies, TOK-001 has been shown to:
- Stop the adrenal gland and tumor cells from making androgens by inhibiting CYP17, the enzyme that produces testosterone;
- Decrease androgen growth signals by binding to and blocking the androgen receptor;
- Decrease androgen growth signals by decreasing the number of androgen receptors.
TOK-001 is the only specific androgen receptor modulator/lyase inhibitor (SARM/LI) in development today. Targeting CRPC via three separate pathways, TOK-001 has the potential to suppress cancer recurrence and reduce the emergence of resistant cancer.
Tokai intends to commence Phase I/II clinical trails with TOK-001 for CRPC in 3Q09.
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Semparatide (Parathyroid Hormone-related Peptide, or PTHrP) for Improved Engraftment in HSC Transplantation
Semparatide is a synthetic version of Parathyroid Hormone-related Peptide (PTHrP), which increases the population of bone cells called osteoblasts. These cells not only improve bone strength but, in nonclinical studies, have been shown to form niches within the bone marrow that protect and nourish hematopoietic stem cells (HSCs). Treatment with semparatide therefore could increase HSC availability for HSC transplantation. Often used to treat patients with multiple myeloma or lymphoma, an estimated 60,000 HSC transplants are done annually.
Tokai licensed semparatide from Roche Biosciences. Roche demonstrated that semparatide has an acceptable safety profile, administering the drug to 167 healthy female subjects in Phase 1 trials and 137 women with osteoporosis in Phase 2 clinical trials. Tokai intends to leverage Roche’s clinical data to develop a drug that may improve bone marrow transplantation outcomes.
The company intends to file an IND for PTHrP for this indication in 4Q09.
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Specific Progesterone Receptor Modulators, or SPRMs, for Uterine Fibroids
Uterine Fibroids
Found in as many as forty percent of women, fibroids are benign tumors of the uterus. Fibroids can cause heavy painful periods, abdominal discomfort, back aches, urinary frequency and infertility. Nearly 250,000 women undergo hysterectomies annually to alleviate the problems associated with fibroids.
Existing medical treatments can provide symptomatic improvement; however, drug-induced menopause and infertility limit their use. Surgical removal of fibroids is an option but can lead to scarring and adhesions; moreover, surgery does not guarantee that fibroids will not re-grow.
Tokai licensed specific progesterone receptor modulators from Meiji Seika Kaisha, Ltd.. These proprietary small molecules have been shown to be orally bioavailable and effective in biochemical, tissue culture and animal models of uterine fibroids.
Tokai’s SPRMs have been shown in nonclinical studies to:
- Specifically bind to the progesterone receptor;
- Inhibit the growth of uterine fibroids;
- Not interfere with the normal growth of uterine muscle cells.
The company is working with scientists and clinicians at the National Institutes of Health to develop SPRMs as the first truly effective medical therapy for fibroids.
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