Tasquinimod is a once-daily oral, investigational, small molecule immunomodulatory drug with a novel mechanism of action. It has primarily been in development for treatment of prostate cancer but the mechanism is broadly applicable as anti-tumor treatment and pre-clinical data shows therapeutic activity in models for multiple myeloma as well as in several other tumor models.

Tasquinimod mode of action

In order to grow and metastasize, tumors are dependent on successful interaction with the microenvironment at sites of growth. This includes formation and maintenance of blood vessels for nutrient and oxygen supply, suppression of the local immune defense, as well as establishment of metastatic niches for tumor localization. Preclinical studies have shown that tasquinimod's anti-tumor efficacy involves its ability to interfere with all of these tumor requirements.

Tasquinimod binds to the protein S100A9 which is expressed in the tumor microenvironment and has been implicated in the development of cancer by recruiting and activating specific immune cells, e.g. myeloid-derived suppressor cells (MDSCs). Immunosuppressive cells, such as myeloid-derived suppressor cells (MDSCs), play a key role in tumor progression due to their capability to promote immune-escape, angiogenesis, and metastasis. By targeting the S100A9 pathway tasquinimod interferes with the accumulation and activation of MDSCs in the tumor microenvironment which in turn will decrease immune suppression and angiogenesis. In addition, tasquinimod inhibits the hypoxic response in the tumor by binding to HDAC4.

Tasquinimod for treatment of multiple myeloma (MM)

With the aim to expand the patent protection for tasquinimod, a preclinical program was performed and very good results were achieved in models for multiple myeloma. A patent application to cover the use of tasquinimod in multiple myeloma until 2035 (WO 2016/042112) was submitted and recently approved by the European Patent Office. Also, Orphan Drug Designation for tasquinimod for the treatment of multiple myeloma is granted by FDA.

MM is an incurable form of blood cancer where the plasma cells in the bone marrow grow uncontrollably while other blood forming cells such as white and red blood cells and blood platelets are suppressed. This leads to bone pain and fractures, anemia, infections, and other complications. Normal plasma cells produce antibodies and play a key role in immune function. New treatments have greatly improved prognosis and survival of MM patients but the biological heterogeneity of the disease and the emergent drug resistance is a big challenge. Here we see a need for new treatment alternatives.

Immunosuppressive cells, such as MDSCs, play a key role in tumor progression in MM due to their capability to promote immune-escape, angiogenesis, and metastasis. The existing medical need and the possibility for combination treatments makes tasquinimod, with its unique mode of action, a strong candidate for development in MM. Active Biotech intends to actively seek a collaboration partner with the appropriate expertise for further development.

Current results

Tasquinimod has been extensively studied in prostate cancer. The program includes a complete regulatory pre-clinical package as well as clinical phase 1, Phase 2, Phase 3 and clinical pharmacology studies. Tasquinimod has mainly been studied as single agent therapy but in one Phase 1/2 study combination with chemotherapy was successfully used. One Phase 2 study also included other tumor types (advanced or metastatic hepatocellular, ovarian, renal cell and gastric carcinomas). Overall, the extensive clinical data confirms therapeutic efficacy as demonstrated by prolonged PFS in Phase 2 and 3, and an acceptable and manageable safety profile of tasquinimod.

Based on the positive outcome of a Phase 2 trial in approximately 200 men with metastatic castrate-resistant prostate cancer (mCRPC) a Phase 3 study, 10TASQ10, was performed under a collaboration agreement with Ipsen. 10TASQ10 was a global, randomized, double-blind, placebo-controlled trial in 1,245 patients with mCRPC who had not received chemotherapy. While the study showed that tasquinimod reduced the risk of radiographic cancer progression or death compared to placebo (rPFS, HR=0.69, CI 95%: 0.60 - 0.80) the treatment did not extend overall survival (OS, HR=1.09, CI 95%: 0.94 - 1.28). Based on lack of OS benefit in this population  the development of tasquinimod in prostate cancer was discontinued.