Tasquinimod

Tasquinimod is an orally active small molecule immunomodulator with a novel mode of action, blocking tumor supporting pathways in the bone microenvironment.

This is tasquinimod

The tumor microenvironment in the bone marrow is essential for development of blood cancers and a key driver of disease recurrency as well as resistance to treatment.

Tasquinimod targets cells in the microenvironment of the bone marrow, immunosuppressive myeloid cells, endothelial cells, and mesenchymal cells, which play a central role in the development of blood cancers. Tasquinimod affects the function of these cells, leading to reduced tumor growth, reduced fibrosis, and restored hematopoiesis.

Multiple myeloma

Multiple myeloma is an incurable blood cancer where abnormal 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 anemia, infections, destruction of bone tissue and progressive loss of renal function. Despite new treatments which have greatly improved survival of multiple myeloma patients the biological heterogeneity of the disease and the emergence of drug resistance is a major challenge, and the medical need of innovative treatment modalities remains high.

The market for treatment of multiple myeloma is substantial

The expected annual incidence of new diagnosed cases of multiple myeloma in the US alone is approximately 30,000 patients. In Europe and Japan approx. 40,000 and 7,000 new patients, respectively, are expected to be diagnosed each year (Global Data Report 2019, Multiple Myeloma – Global Drug Forecast and Market Analysis to 2027).

The global sales of drugs for the treatment of multiple myeloma is projected at USD 27.8 billion in 2027 (Global Data Report 2019, Multiple Myeloma – Global Drug Forecast and Market Analysis to 2027).

The market for drugs used in the treatment of multiple myeloma experience strong growth and is expected to continue to grow strongly due to the greater incidence in an elderly population, longer progression-free and overall survival, and thanks to more treatments and combination options are made available. The US accounts for around half of the market and the EU for approximately 40 percent of the total market sales (Global Data Report 2019, Multiple Myeloma – Global Drug Forecast and Market Analysis to 2027).

Multiple myeloma – a major market driven by novel treatment options and propulsion of drug combination strategies

Presented data are from GlobalData (March 2019) based on 2027 forecast numbers in 8 major markets (US, EU5, Japan, China).

Current treatments

Multiple myeloma patients undergo several lines of treatment. In both early and relapse treatment, the goal is to stabilize the patient’s disease and thereby achieve as long a period of effective disease control as possible. To support deeper and durable responses and overcome treatment resistance patients are as standard treated with combinations of drugs from available product classes. Currently, the market is dominated by drugs that can be divided into four different classes: immunomodulatory imides (IMiDs), proteasome inhibitors (PI), monoclonal antibodies and alkylating agents.

Disease course of multiple myeloma

Tasquinimod in multiple myeloma

Tasquinimod will be developed as a new product class with a novel mechanism of action that differs from the others and thus has the potential to overcome the problem of drug resistance. The clinical safety profile of tasquinimod is well known. Given the good tolerability and the possibility to combine with the available product classes, tasquinimod has the potential to expand over time from an initial position as the 3rd line treatment as well as to earlier lines of treatment, similar to the patient population in the ongoing clinical study. There is a significant market opportunity for a novel drug in a new product class in multiple myeloma.

Ongoing clinical development

Tasquinimod is currently being evaluated in a clinical trial in multiple myeloma. The study, which started in August 2020 and is ongoing in the US, is evaluating tasquinimod both as monotherapy and combination therapy, more information about the ongoing study can be found in the box below.

Myelofibrosis

Myelofibrosis is a rare (orphan) blood cancer belonging to a group of disorders called myeloproliferative neoplasms with an estimated annual incidence of 0.1-1.0 cases per 100 000 people in Europe. The underlying cause of myelofibrosis is unknown. Patients with myelofibrosis have an abnormal production of blood-forming cells leading to the replacement of healthy bone marrow with scar tissue (fibrosis). Due to the lack of normal blood cell production patients typically present with laboratory value abnormalities such as anemia and changes in white blood cell counts and blood cell-differentiation. Later symptoms include enlargement of the spleen, an increased risk for infections, night sweats and fever. Myelofibrosis is associated with shortened survival and causes of death include bone marrow failure and transformation into acute leukemia.

Current treatments and market

Myelofibrosis can be treated with bone marrow transplantation for eligible individuals, erythropoietin to manage anemia and JAK2 inhibitors to reduce spleen size. Today there are three drugs approved for these patients as symptom-directed therapy: Hydroxy-urea, ruxolitinib and fedratinib (the latter two are JAK2-inhibitors). At present there are no approved therapies that would reverse bone marrow fibrosis in myelofibrosis, and there are only limited treatment options available for myelofibrosis patients. The market is projected at over USD 0.8 billion by 2028 (MarketWatch 2021).

Tasquinimod in myelofibrosis

In collaboration with a research group at Erasmus MC, the Netherlands, Active Biotech will explore myelofibrosis as a new high value orphan indication for tasquinimod within blood cancers. A proof-of-concept study with tasquinimod in myelofibrosis patients is planned to start early 2023.

Previous clinical experience with tasquinimod

Tasquinimod has been in development for the treatment of prostate cancer and has completed a phase I-III clinical development program. While the results from the phase III trial in prostate cancer showed that tasquinimod prolonged progression-free survival (PFS) compared to placebo, tasquinimod did not extend overall survival (OS) in this patient population and the development for prostate cancer was discontinued. Tasquinimod was studied in both healthy volunteers and cancer patients. Clinical effects and a favorable safety profile have been demonstrated in more than 1,500 patients, equivalent to more than 650 patient-years of exposure to tasquinimod. Extensive datasets including a regulatory package of preclinical and clinical safety and full commercial scale CMC documentation has been generated.

Targeting the tumor microenvironment

Phase Ib/IIa in multiple myeloma

Ongoing

Based on preclinical data and the previous clinical experience with tasquinimod, a clinical study was initiated, and the first patient was dosed in August 2020. The study recruits relapsed refractory
multiple myeloma patients after at least one prior anti-myeloma therapy and is conducted in two parts:

  • First part (A) studying of tasquinimod as a monotherapy
  • Second part (B) studying the combination of tasquinimod and an oral standard anti-myeloma
    regimen (IRd; ixazomib, lenalidomide, dexamethasone)

Primary endpoint in both parts is safety and tolerability, and key secondary endpoint is preliminary efficacy by objective response rate.

Important milestones were reached in October 2021 and February 2022, respectively. Ten patients in part A had been treated with increasing doses of tasquinimod and the safety read-out showed that tasquinimod was generally well tolerated. The optimal dose and schedule of tasquinimod, when used as a single agent in patients with multiple myeloma has been established at 1 mg per day after a one-week run in of 0.5 mg daily. This is similar to the treatment schedule used in previous studies of tasquinimod. The patients included in this study phase were heavily pretreated and 8 of the 10 patients were triple calls refractory to Imids, proteosome inhibitors, and anti-CD-38 monoclonal antibodies. While none of the patients formally achieved a partial response, two patients with documented progressive myeloma at study entry achieved significant periods of stable disease on single-agent tasquinimod therapy.

In February 2022, the trial subsequently advanced to the previously planned combination part, in which treatment with tasquinimod is tested in patients with multiple myeloma together with the orally administered anti-myeloma agents ixazomib, lenalidomide, and dexamethasone (IRd). Once an optimal dose and schedule of tasquinimod for the IRd combination is established, an expansion cohort will be recruited to further document the biological activity of tasquinimod in myeloma patients. Key secondary endpoints will include anti-myeloma activity using the response criteria of the International Myeloma Working Group.

The study is carried out in an academic partnership with Abramson Cancer Center in Philadelphia, PA, US, with Dr. Dan Vogl as the principal investigator. More information about the study design is available at clinicaltrials.gov (NCT04405167).

Publications

Tasquinimod Targets Immunosuppressive Myeloid Cells, Increases Osteogenesis and Has Direct Anti-Myeloma Effects By Inhibiting c-Myc Expression in Vitro and In Vivo. Rong Fan, Hatice Satilmis, Niels Vandewalle, Elke De Bruyne, PhD, Eline Menu, PhD, Andrew D Chantry, PhD, MD, Holly Evans, BSc, Marie Törngren, Helena Eriksson, PhD, Karine Breckpot, PhD, Ken Maes, PhD, Karin Vanderkerken, PhD, Kim De Veirman, PhD. Presented at the 63rd ASH Annual Meeting & Exposition 2021. Read the abstract here and the poster here.

Targeting the Inflammatory Niche in MDS By Tasquinimod Restores Hematopoietic Support and Suppresses Immune-Checkpoint Expression in Vitro. Manja Wobus, PhD, Ekaterina Balaian, Uta Oelschlaege, PhD, Russell Towers, Kristin Möbus, Ivonne Habermann, Rebekka Wehner, Friedrich Stölzel, Triantafyllos Chavakis, Marie Törngren, Helena Eriksson, PhD, Uwe Platzbecker, MD, Christoph Röllig, MD, MSC, Martin Bornhäuser, MD, Katja Sockel. Presented at the 63rd ASH Annual Meeting & Exposition 2021. Read the abstract here and the poster here.

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