AMB-051 for TGCT

Disease and Prevalence

Previously known as pigmented villonodular synovitis (PVNS), TGCT is a rare, non-malignant tumor of the synovium in musculoskeletal joints that results in significant joint damage, painful swelling, and debilitating functional impairments.  

TGCT lesions typically present in the 3rd to 5th decades of life as either localized (L-TGCT) or diffuse (D-TGCT) disease (3). L-TGCT involves mainly the digits and wrist and less frequently larger joints. D-TGCT involves mainly large joints – particularly the knee (60-75% of the cases), but also hip, ankle, shoulder and elbow, and it is locally invasive. TGCT are typically intra-articulate but D-TGCT can become extra-articular (5). Typically, only one joint is affected at a time. 

Figure 1. Diffuse TGCT tumor of the knee. Sagittal T1 MRI of the knee illustrates (✰) tenosynovial giant cell tumor extending throughout the joint. Also shown is erosion into the tibial plateau (  ) and secondary osteoarthritis (     )

Figure 2. A 23-year-old female with L-TGCT

L-TGCT is much more common compared to D-TGCT with a ratio of approximately 10:1. The combined incidence rate is estimated at roughly 4.3 in 100,000, translating into ~40,000 new cases per year in US and Europe (2-4).

Pathogenesis and AMB-051 Mechanism of Action

TGCT is caused by excessive production of CSF-1. A small proportion of the TGCT cells are neoplastic with translocation at the CSF-1 gene locus resulting in the dysregulated CSF1 levels which then acts at the CSF-1 Receptor (CSF-1R) to expand the neoplastic cells and attract immature myeloid cells and inflammatory cells, including macrophages, which then comprise the bulk of the tumor (6,7).

AMB-051 is an antibody against the CSF-1R, potently inhibiting CSF-1 action in vivo (1). As inhibition of CSF-1 action at the CSF-1R has been proven effective against TGCT in clinical studies (8,9), CSF-1R represents a clinically validated target for the treatment of TGCT.

Current Treatment & Unmet Need

Treatment is individualized based on disease progression, types of TGCT, location of the tumor mass and expected post-operative morbidity. In general, surgical resection is the first line treatment for L-TGCT. It can be effective although it often requires extended rehabilitation (Sarcoma Advisory Group) adding to the disease burden. D-TGCT is surgically problematic, difficult to remove completely and often requires a total synovectomy, or at times a joint replacement, or even amputation. Recurrence occurs in about 10% of L-TGCT patients and up to 50% of D-TGCT patients who undergo surgical resection (5, Sarcoma Advisory Group). For these patients, the prognosis is grim with severe long-term morbidity and poor quality of life.

An oral small molecule CSF-1R kinase inhibitor, pexidartinib, was approved in 2019 for the treatment of symptomatic TGCT associated with severe morbidity or functional limitations and not amenable to improvement with surgery. The approval of pexidartinib, as the first pharmacological agent, represents a breakthrough in the management of TGCT and provides validation of CSF-1R as a therapeutic target. However, pexidartinib carries a black-box warning for hepatotoxicity and notation that such severe liver problems may lead to death. In addition, it leads to substantial undesirable side effects such as edema (10). Given the non-life-threatening nature of this debilitating disease, pexidartinib’s side effect profile is problematic and limiting in terms of a broader applicability.

There remains a significant unmet need for a safe and efficacious pharmacological agent that serves not only patients with non-resectable tumor mass but also patients with resectable tumors to avoid surgical morbidity or reduce postoperative recurrence rate. AMB-051 has a therapeutic profile that would potentially meet the significant unmet need and provide unprecedented pharmacotherapy benefit in TGCT.

AMB-051 Differentiation

LifeMax’s patented novel delivery approach capitalizes on desirable AMB-051 physico-chemical and biological properties to optimize efficacy and minimize potential side effects. This Best-in-Class profile would afford an opportunity to serve a broader segment of patients including both L-TGCT and D-TGCT and provide a viable alternative to surgical intervention.

References

  1. Papadopoulos KP et al., Clin. Cancer Res. 2017; 23:5703,

  2. Ehrenstein V et al., J. Rheumatol. 2017; 44:1476,

  3. Mastboom MJL et al., Acta. Orthop. 2017; 88:688,

  4. ORPHA:66627

  5. Gouin F and Noailles T, Orthopaed. & Traumatol.: Surg. & Res. 2017; 103:S91–S97

  6. West RB et al., Proc. Natl. Acad. Sci. USA 2006; 103:690

  7. Cupp JS et al., Am. J. Surg. Pathol 2007; 31:970

  8. Cassiere PA et al., Lancet Oncology 2015; 16:949

  9. Tap WD et al., Lancet 2019; 394:478

  10. TURALIOTM (pexidartinib) prescribing information (08/2019)

Figure 1: https://www.tgcthcp.com/en/tenosynovial-giant-cell-tumor-overview

Figure 2: Krishna D, et al., J. Orthopaed. Traumatol. Rehab. 2017; 9:115

Licensed from Amgen, AMB-051 is a human monoclonal antibody against the CSF-1R (M-CSF-R, c-fms), which has been shown to be safe and well tolerated in Phase 1/2 clinical studies (1) and is in clinical development for the treatment of Tenosynovial  Giant Cell Tumors (TGCT).  

Delivered via a patented technology and with a clinically validated target, AMB-051 represents a best-in-class and well-differentiated therapeutic option with minimal side effects that would potentially address the significant unmet needs for both the localized TGCT (L-TGCT) and diffuse TGCT (D-TGCT) patients.   

LifeMax is additionally developing the same molecule for two other serious, rare, and unmet-need indications: IPF (AMB-053) and ARPKD (AMB-055). 

 

Treating Orphan Diseases With Few or No Options.

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