Tasquinimod

Tasquinimod is a once-daily, oral immunomodulatory compound that reduces a tumor’s ability to grow and spread. Tasquinimod is in development for treatment of multiple myeloma, a rare form of blood cancer with a high medical need. Patents in key markets have been granted, providing protection for the use of tasquinimod in malignant blood disorders, specifically acute forms of leukemia and multiple myeloma, until 2035. Furthermore, the FDA has granted orphan drug designation for tasquinimod for the treatment of multiple myeloma, which provides for seven years of market exclusivity in the event of future registration.

Tasquinimod shows potent antitumor effects, both as monotherapy and in combination with immunomodulatory drugs and proteasome inhibitors, in experimental models of multiple myeloma. Currently, a phase 1b/2a study in relapsed or refractory multiple myeloma patients is ongoing. The study is a dose finding study and will include up to 54 patients. The primary endpoint is optimal dose and schedule of tasquinimod as single agent and in combination with a standard oral myeloma regimen of ixazomib, lenalidomide, and dexamethasone (IRd). Key secondary endpoints include preliminary antimyeloma activity with single agent tasquinimod and during therapy with tasquinimod in combination with IRd. The study was initiated in July 2020 and the principal investigator is Dr Dan Vogl, Abramson Cancer Center, Philadelphia, University of Pennsylvania.More information about the study is available at clinicaltrials.gov (NCT04405167).

Tasquinimod targets the tumor microenvironment in multiple myeloma

The immunosuppressed tumor microenvironment is essential for development of multiple myeloma in the bone marrow. Tasquinimod targets suppressive immune cells in the tumor microenvironment, specifically immunosuppressive myeloid cells, and thereby unlocks the body’s immune system to attack the cancer cells. With this novel mode of action tasquinimod has the potential, as a single therapy and in combination with other medicines, to overcome resistance and increase survival in patients that have progressed on standard therapy.

Tasquinimod targets the immunosuppressive myeloid cells in the tumor microenvironment

Clinical trials

Tasquinimod has previously been in development for the treatment of prostate cancer with completed phase 1-3 clinical trials. While the results from the phase 3 trial in prostate cancer showed that tasquinimod prolonged progression free survival compared to placebo. Tasquinimod did not extend overall survival in this patient population and development for prostate cancer was discontinued. The clinical development of tasquinimod is today focused on the blood cancer multiple myeloma.

Tasquinimod has been studied in both healthy subjects and cancer patients. Clinical effects and an overall good tolerability have been demonstrated through more than 650 person-years of exposure to tasquinimod.

Targeting the tumor microenvironment

Phase 1 and 2 studies in solid tumors

Completed

Safety and clinical effects of tasquinimod have been studied in phase 1 and 2 studies in healthy subjects and patients with various solid tumors, including prostate cancer (Bjork et al, 2009; Pili et al, 2011; Armstrong et al, 2016; Fizazi et al, 2017), hepatocellular, ovarian, renal and gastric cancer (Escudier et al, 2017).

Proof-of-Concept was demonstrated both in chemotherapy-naïve patients with minimally symptomatic metastatic castrate-resistant prostate cancer (mCRPC) and in patients who had received previous chemotherapy treatment. In the phase 2 study in chemo-naïve patients, tasquinimod treatment significantly delayed disease progression by a median of 4.3 months compared to placebo and had an acceptable safety profile (Pili et al, 2011). In the phase 2 study in mCRPC patients with stable disease after docetaxel treatment, tasquinimod maintenance therapy significantly reduced the risk of radiographic progression or death by 40% (Fizazi et al, 2017).

Phase 3 study in prostate cancer

Completed

The phase 3 study was a global, randomized, double-blind, placebo-controlled trial in 1,245 mCRPC patients who had not received chemotherapy. While the study showed that tasquinimod reduced the risk of radiographic 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) (Sternberg et al, 2016). Thus the positive effect on rPFS did not translate into an improved overall survival in phase 3 in this patient population, which might be due to delayed use of life-prolonging agents in the tasquinimod arm due to later onset of progression.

About Multiple Myeloma (MM)

Publications

Inhibition of S100A9 with tasquinimod demonstrates potent anti-tumor activity in pre-clinical models of multiple myeloma. Cindy Lin , Aubrey Leso , Matthew Rosenwasser , Marie Torngren , Helena Eriksson , Yulia Nefedova. Presented at the Virtual Edition of the 25th European Hematology Association (EHA) Annual Congress Meeting, 2020. Read the abstract here and the poster here.

A randomized, double blind, placebo controlled phase 2 study of maintenance therapy with tasquinimod in patients with metastatic castration-resistant prostate cancer responsive to or stabilized during first-line docetaxel chemotherapy. Fizazi K, Ulys A, Sengeløv L, Moe M, Ladoire S, Thiery-Vuillemin A, Flechon A, Guida A, Bellmunt J, Climent MA, Chowdhury S, Dumez H, Matouskova M, Penel N, Liutkauskiene S, Stachurski L, Sternberg CN, Baton F, Germann N, Daugaard G. Ann Oncol. 2017; 28: 2741-46

A Phase II Multicentre, Open-Label, Proof-of-Concept Study of Tasquinimod in Hepatocellular, Ovarian, Renal Cell, and Gastric Cancers. Escudier B, Faivre S, Van Cutsem E,  Germann N, Pouget J-C, Plummer R, Vergote I, Thistlethwaite F, Bjarnason GA, Jones R, Mackay H, Edeline J, Fartoux L, Hirte H, Oza A. Targ Oncol. 2017; 12: 655–61

Phase Ib Trial of Cabazitaxel and Tasquinimod in Men With Heavily Pretreated Metastatic Castration Resistant Prostate Cancer (mCRPC): The CATCH Trial. Armstrong A, Humeniuk M, Healy P, Szmulewitz R, Winters C, Kephart J, Harrison M, Martinez E, Mundy K, Halabi S, George D. The Prostate. 2017; 77: 385-95

Randomized, Double-Blind, Placebo-Controlled Phase III Study of Tasquinimod in Men With Metastatic Castration-Resistant Prostate Cancer. Sternberg C., Armstrong A., Pili R., Ng S., Huddart R., Agarwal N., Khvorostenko D., Lyulko O.,  Brize A., Vogelzang N., Delva R., Harza M, Thanos A, James N., Werbrouck P., Bögemann M., Hutson T, Milecki P., Chowdhury S., Gallardo E., Schwartsmann G., Pouget J-C., Baton F., Nederman T., Tuvesson H., Carducci M. J. Clin. Oncol. 2016; 34(22): 2636-43.

Tasquinimod modulates tumor-infiltrating myeloid cells and improves the antitumor immune response to PD-L1 blockade in bladder cancer. Nakhlé J., Pierron V., Bauchet A-L., Plas P., Thiongane A., Meyer-Losic F., Schmidlin F. Oncoimmunol 2016; 5:6, e1145333

Tasquinimod triggers an early change in the polarization of tumor associated macrophages in the tumor microenvironment. Olsson A., Nakhlé J., Sundstedt A., Plas P., Bauchet A-L., Pierron V., Bruetschy L., Deronic A., Törngren M., Liberg D., Schmidlin F., Leanderson T. J ImmunoTher Cancer. 2015; 3:53

A novel agent tasquinimod demonstrates a potent anti-tumor activity in pre-clinical models of multiple myeloma. Ramachandran I.R., Lin C., Chase T., Gabrilovich D., Nefedova Y. Blood 2014; 124: 5729.

Tasquinimod modulates suppressive myeloid cells and enhances cancer immunotherapies in murine models. Shen L, Sundstedt A, Ciesielski MJ, Miles KM, Celander M, Adelaiye R, Orillion A, Ciamporcero E, Ramakrishnan S, Ellis L, Fenstermaker RA, Abrams SI, Eriksson H, Leanderson T, Olsson A, Pili R. Cancer Immunol Res. 2014; 3(2): 1-13

Phase II Randomized, Double-Blind, Placebo-Controlled Study of Tasquinimod in Men With Minimally Symptomatic Metastatic Castrate-Resistant Prostate Cancer. Pili R, Häggman M, Stadler W.M, Gingrich J.R, Assikis V.J, Björk A, Nordle Ö, Forsberg G, Carducci M.A, Armstrong A.J. J. Clin. Oncol. 2011; 29(30): 4022-4028

Open-label, clinical phase I studies of tasquinimod in patients with castration-resistant prostate cancer. O Bratt, M Häggman, G Ahlgren, Ö Nordle, A Björk and J-E Damber. Br J Cancer. 2009; 101(8): 1233-40

Identification of ABR-215050 as lead second generation quinoline-3-carboxamide anti-angiogenic agent for the treatment of prostate cancer. Isaacs JT, Pili R, Qian DZ, Dalrymple SL, Garrison JB, Kyprianou N, Björk A, Olsson A, Leanderson T. Prostate. 2006; 66: 1768-78