Teprotumumab, a monoclonal antibody inhibitor targeting the insulin-like growth factor-1 (IGF-1) receptor (IGF-1R), was approved for the treatment of thyroid eye disease (TED) in 2020. Investigators conducted a systematic literature review to ascertain the reported ocular side effects and potential uses of IGF-1R inhibitors.
Study design
Ocular-related articles published between January 2011 and August 2021 were evaluated, and 47 publications met the study criteria and were reviewed: 28 discussing thyroid eye disease, 5 cornea and ocular surface, and 13 retina and neovascularization.
Outcomes
In the eye, IGF-1 affects ocular growth and development, epithelial proliferation, retinal angiogenesis, and inflammation, and has been implicated as an autoantigen in patients with TED. It has also been found to have a significant impact on both prenatal and postnatal somatic growth; thus, IGF-1R inhibition is considered teratogenic. Additionally, IGF-1R inhibition results in growth hormone synthesis inhibition which can impair normal growth and development; therefore, it should not be used in a pediatric population. It also appears that IGF-1R inhibition may have a role in environments where pathologic neovascularization or active inflammatory damage may predominate. There may be additional therapeutic benefits to IGF-1R inhibition that should be explored.
Limitations
This major review explains why some adverse events (AEs) are expected with IGF-1R inhibition and also describes a potential therapeutic role for other ocular conditions. However, the review is limited in scope, in that it focuses only on IGF-1R inhibition as it relates to the eye and does not review the implications of IGF-1R inhibition throughout the body. It is important to note that the IGF-1R is ubiquitous throughout the body; thus, exploration into additional ocular therapeutic uses should be balanced with potential systemic AEs.
Clinical significance
Reported teprotumumab-related AEs in patients with TED include muscle spasms, fatigue, hyperglycemia, nausea, diarrhea, and hearing impairment, alopecia, dysgeusia, headache, dry skin, ulcerative colitis, and encephalopathy, and post-approval reports suggest that the incidence of these AEs may be higher than previously reported. Understanding the implications of IGF-1R inhibition on the body overall and the eye specifically is important for patient selection, screening, monitoring, and AE management. Additionally, IGF-1R inhibition may have therapeutic benefit in promoting wound healing, increasing tissue plasticity, and improving inflammation in patients with conditions such as ocular neoplasms, diabetic retinopathy, uveitis, macular degeneration, retinitis pigmentosa, and corneal neovascularization. Additional research into the benefits and AEs of IGF-1R inhibitors, as well as their cost-effectiveness, is needed to safely and effectively advance treatments for patients with ocular and orbital diseases.
Financial Disclosures: Dr. Andrea Kossler discloses financial relationships with Argenx, Axogen, Genentech, Horizon Therapeutics, Immunovant Therapeutics, Kriya Therapeutics (Consultant/Advisor); Sling Shot Therapeutics, Viridian (Independent Contractor).