Research &
Development

Therapeutic focus

TGCT

Tenosynovial Giant Cell Tumour (TGCT) is a typically benign but sometimes aggressively growing tumour in the synovial lining of joints, tendon sheaths or bursae, primarily located in knee, hip, and ankle. TGCT is caused by excessive production of CSF-1 as a result of a chromosome abnormality. TGCT is a serious and chronically debilitating disease in which patients experience severe pain, swelling, loss of function of the affected joints and diminished quality of life. TGCT is usually found in adults aged 35-50 years old, but it may also be found in children1.

Symptoms of these tumours are often initially like those of other conditions, such as sports injuries or arthritis, so they may initially be difficult to diagnose and treat effectively. TGCT can affect nearly every aspect of a person’s daily life. Common everyday activities, such as walking or shopping, can be very tough for people with TGCT.

There are generally two types of TGCT: localised TGCT and diffuse TGCT, which is less common and more difficult to treat. Overall, TGCT is estimated to affect approximately 200,000 patients in the U.S. and 179,000 patients in the EU4 +UK, with an estimated incidence of approximately 50 per million.

Surgery is often the first-line treatment approach. Some diffuse tumours may be inoperable due to the size or location of the tumour within the joint. Surgery may damage portions of the joint lining and high recurrence rates of up to 72% for diffuse TGCT, often requiring multiple surgeries, have been reported. Excessive damage to the joint may lead to the requirement of a joint replacement or amputation.

Emactuzumab’s combination of rapid onset, response rate, meaningful functional improvement, and a defined short-course regimen positions it as a potential alternative to chronic therapy. We believe this approach directly addresses key limitations of existing treatments and represents an important advancement for patients suffering from this debilitating disease.

Ray Barlow

Chief Executive Officer

Scientific background

CSF-1R inhibition

The monoclonal antibody emactuzumab is a potent, specific inhibitor of CSF-1R and data generated to date show its potential as a therapeutic platform targeting serious macrophage-driven inflammatory, fibrotic and neovascular diseases. The CSF-1 receptor, via its binding to two regulatory cytokines, CSF-1 and IL-34, is critically involved in the regulation of macrophages and related cells in multiple biological processes across many organ systems, making it an attractive target with broad therapeutic applications.

TGCT is caused by a translocation error in chromosome 1 and chromosome 2, which results in an overproduction of a protein called colony stimulative factor 1 (CSF-1).

In healthy cells, CSF-1 helps white blood cells to grow and develop. The overproduction of CSF-1 triggers the migration of tumour-associated macrophages (TAMs) to tumour sites. TAMs suppress the T-cell mediated immune response.

Emactuzumab blocks the CSF-1R on TAMs, enhancing T-cell infiltration and anti-tumour T-cell immune response. Emactuzumab was originally discovered and developed by Roche and has been tested in several phase 1a/b studies as monotherapy and in combination with other agents, including chemotherapeutics and immunotherapies in patients with a variety of solid tumours. It was demonstrated that emactuzumab monotherapy led to a substantial tumour response (ORR of 71%)4 and improvements in functional ability of patients with good tolerability and a manageable safety profile in patients with diffuse TGCT.

Tumour Microenvironment

Clinical Trials

TANGENT

Disease:
Tenosynovial Giant Cell Tumour (TGCT)

Phase:
Phase III

Study title:
A Phase III, Multicentre, Randomised, Double-Blind Study to Assess the Safety and Efficacy of Emactuzumab vs. Placebo in Subjects with Tenosynovial Giant Cell Tumour

More info:
Clinicaltrials.gov

TANGENT is a global Phase III trial for the treatment of adult and adolescent patients with TGCT.

Most patients currently receive surgical intervention as the primary course of treatment, with high rates of post-surgery recurrence. TANGENT provides an option for TGCT patients, both adults and adolescents, that are not amenable for surgery or that have relapsed from previous treatment including systemic therapies with TKIs and/or other CSF-1R inhibitors.

Emactuzumab is the only short course treatment option in late-stage development for patients suffering with TGCT. These Phase 3 data provide compelling evidence of tumor response, a manageable safety profile, and most importantly for patients, of significant durable functional and quality of life benefits that allow patients struggling with TGCT to move forward with their lives, without continuous therapy.

Jean-Yves Blay

M.D, PhD, Principal Investigator Lyon, France

References

  1. Karami M et al. Pediatric Rhematology, 2018.
  2. Stacchiotti S, et. al. Best clinical management of Tenosynovial Giant Cell Tumour (TGCT): A consensus paper from the community of experts. Cancer Treat Rev. 2023;112:102491. doi:10.1016/j.ctrv.2022.102491.
  3. (3) Verspoor FG, Zee AA, Hannink G, van der Geest IC, Veth RP, Schreuder HW. Long-term follow-up results of primary and recurrent pigmented villonodular synovitis. Rheumatology (Oxford). 2014 Nov;53(11):2063-70. doi: 10.1093/rheumatology/keu230.
  4. Cassier et al. European Journal of Cancer, 2020. Long-term clinical activity, safety and patient-reported quality of life for emactuzumab-treated patients with diffuse-type tenosynovial giant-cell tumour (synoxtherapeutics.com).