In this day and age, when watching TV or paging through a magazine, you will likely see at least one advertisement for biologic therapy. Biologics, also referred to as biopharmaceuticals, are complex target-mediated medical therapies that are developed from living organisms like humans, animals, or microorganisms, instead of chemicals synthesized in a lab.
Examples of this include tissues, blood products, proteins, steroids, antibodies, T-cells, and stem cells, among others. They target cytokines and specific proteins, and cellular receptors involved in inflammation and other disease processes.1-2
The history of biologics
Insulin is considered the first biologic therapy, initially discovered in 1921 in Canada. This protein was first manufactured from cow pancreas cells but was genetically engineered as human insulin in 1978 and finally achieved FDA approval as Humulin (human recombinant insulin) in 1982.3
The first humanized monoclonal antibody was daclizumab in 1997, which marks the beginning of modern biopharmaceuticals.4
Over the past 25 years since the commercialization of daclizumab, many of these newly developed therapies are highly specific targeted treatments for autoimmune disorders, certain cancers, and genetic conditions.
Biosimilars
Biosimilars are complex target-mediated medical therapies that are developed from living organisms, which sounds a lot like a biologic! An FDA-approved biosimilar has a nearly identical molecular structure and bioactivity to a comparable FDA-approved biologic, known as the reference product. In order for a biosimilar to be FDA-approved, it must show no clinically meaningful differences in pharmacokinetics, pharmacodynamics, immunogenicity, safety, or efficacy when compared to the reference product.5
Lucentis (ranibizumab, Genentech) is a biologic in eyecare that has two FDA approved biosimilars: Byooviz (ranibizumab-nuna, Biogen) and Cimerli (ranibizumab-eqrn, Coherus).
Biosimilars are not equivalent to generic medications. Generic drugs have a chemical structure that is identical to the brand name drug. Biosimilars are highly similar to the reference product but can have minor differences in the clinically inactive components, such as post-translational modifications. Biosimilars may provide patients with more treatment options and at a lower cost (around 30% less) than biologics, due to the decreased time and money required in development and manufacturing.6
Biologics for ocular indications
As optometrists, our scope of practice is limited to the prescription and use of topical ophthalmic biologic treatments. However, we often co-manage patients who require the administration of intravitreal or systemic biologics, and this section will review these therapies in detail.
Humira
Humira (adalimumab, AbbVie) was initially approved by the FDA in 2002 and is considered the first FDA-approved fully human monoclonal antibody.
Dosing
In eyecare, it is indicated for the treatment of non-infectious intermediate, posterior, and panuveitis. It is administered as a subcutaneous injection with an initial induction dose of 80mg (0.8mL), followed by 40mg (0.4mL) 1 week later, then 40mg (0.4mL) every 2 weeks thereafter.
Mechanism of action
Humira is a recombinant human IgG1 monoclonal antibody that binds to and blocks tumor necrosis factor alpha (TNFα) from interacting with its receptors. TNFα is a cytokine that is involved in inflammatory and immune responses and is more active in people with pathological inflammation. Humira should be avoided in patients with an active infection.
Rheumatology should be consulted for the prescription and management of these patients. Rheumatologists routinely prescribe and manage patients on Humira for rheumatoid arthritis, juvenile idiopathic arthritis, psoriatic arthritis, ankylosing spondylitis, Crohn’s/ulcerative colitis, plaque psoriasis, and hidradenitis suppurativa.
Contraindications and risks
Patients who receive treatment with Humira are at higher risk for tuberculosis (active infection and reactivation of latent infection), fungal/bacterial/viral infections, and lymphoma. They are also at risk for hepatitis B reactivation, central nervous system/peripheral nervous system demyelinating diseases, pancytopenia, congestive heart failure, and the development of other autoimmune conditions.7
Tepezza
Tepezza (teprotumumab-trbw, Horizon Therapeutics) was FDA-approved in 2020 and is the first and only FDA-approved treatment specifically for thyroid eye disease.
Dosing
Tepezza is administered via an intravenous infusion with an initial induction dose of 10mg/kg, then seven additional infusions of 20mg/kg every 3 weeks, for a total of eight infusions.
Mechanism of action
Tepezza is a recombinant human immunoglobulin G1 (IgG1) monoclonal antibody that specifically binds to and blocks the insulin-like growth factor-1 receptor (IGF-1R). The IGF-1R is over-expressed on orbital fibroblasts in thyroid eye disease.
Activation of IGF-1R is responsible for the pathological inflammation and edema of extraocular muscles and fat tissue behind the eye, causing proptosis, diplopia, and compressive optic neuropathy.
Contraindications and risks
While Tepezza does not have any serious contraindications, treatment with Tepezza may worsen symptoms of inflammatory bowel disease and cause hyperglycemia, hearing impairment, dysgeusia, alopecia, and menstrual disorders.8
Actemra
Actemra (tocilizumab, Genentech) gained initial FDA approval in 2010 and has an ophthalmological indication for giant cell arteritis.
Dosing
It can be administered as an intravenous infusion with a dosage of 6mg/kg every 4 weeks, or as a subcutaneous injection of 162mg (0.9mL) administered weekly.
It is recommended that, regardless of the route of administration, patients on Actemra are also treated with oral glucocorticoids on a tapered dose schedule, but once the glucocorticoids are discontinued, patients can maintain treatment with Actemra alone.
Mechanism of action
Actemra is a recombinant humanized IgG1-kappa monoclonal antibody that binds to and blocks interleukin-6 (IL-6) receptors. A humanized monoclonal antibody refers to a biologic product in which part of its DNA sequence comes from a mouse, whereas in a fully human monoclonal antibody, where none of its DNA sequence comes from a mouse. IL-6 is a pro-inflammatory cytokine and is involved in the activation of T-cells.
Contraindications and risks
Actemra does not have any known contraindications other than known hypersensitivity. Patients who undergo treatment for giant cell arteritis with Actemra are at higher risk for tuberculosis (active infection and reactivation of latent infection) and fungal/bacterial/viral infections. There is also a risk of hepatotoxicity, GI perforation, neutropenia, thrombocytopenia, and lipid abnormalities.9
Acthar Gel
Acthar Gel (repository corticotropin injection, Mallinckrodt) was FDA-approved in 1952 for multiple indications, including severe, acute, and chronic ocular inflammation, keratitis, uveitis, optic neuritis, and chorioretinitis.
Acthar gel is a mixture of adrenocorticotropic hormone (ACTH) and other proteins sourced naturally from the pituitary glands of pigs.
Dosing
Acthar Gel is given as an intramuscular or subcutaneous injection at a dose of 40 to 80 units (0.5 to 1.0mL) every 1 to 3 days, and then when clinically appropriate, tapered down over 2 weeks.
Mechanism of action
Acthar works by activating melanocortin receptors on the adrenal gland cortex to secrete cortisol, corticosterone and aldosterone—all to reduce inflammation.
Contraindications and risks
Acthar Gel is contraindicated in patients with active infections (especially fungal or herpetic), scleroderma, osteoporosis, peptic ulcers, congestive heart failure, uncontrolled hypertension, primary adrenocortical insufficiency, or adrenocortical hyperfunction.
Additionally, patients who receive Acthar Gel as a treatment may be at higher risk for infection and reactivation of latent infections, adrenal insufficiency, Cushing's syndrome, GI ulcers/bleeding, worsening hypertension, insomnia, irritability, reduced bone density, cataracts, and glaucoma.10
Avastin
Avastin (bevacizumab, Genentech) was FDA-approved in 2004 for advanced colorectal cancer but has gained several more indications including lung, kidney, brain (glioblastoma), cervical and ovarian cancer.
Avastin does not have FDA-approval for any ophthalmic indications, however it is often used off-label for:
- Choroidal neovascularization secondary to exudative age-related macular degeneration and myopic degeneration
- Diabetic macular edema and macular edema associated with retinal vein occlusion
Dosing
Avastin is given as an intravitreal injection, with a typical dose of 1.25mg (0.05mL) every 4 to 6 weeks, depending on clinical response.11
Mechanism of action
Avastin is a recombinant humanized monoclonal IgG1 antibody that binds to vascular endothelial growth factor (VEGF) to prevent its action on endothelial cells. This inhibition reduces microvascular growth in the eye by blocking endothelial cell proliferation and new blood vessel formation.
Contraindications and risks
Contraindications to treatment with Avastin include ocular and periocular infections. Risks include increased intraocular pressure, retinal detachment, thromboembolic events (stroke, heart attack), vasculitis, and endophthalmitis.12
Lucentis
Lucentis (ranibizumab, Genentech) was FDA-approved in 2006 for the treatment of exudative age-related macular degeneration, diabetic retinopathy, diabetic macular edema, myopic choroidal neovascularization, and macular edema after a retinal vein occlusion.
Dosing
Lucentis is administered as an intravitreal injection typically every 4 weeks, and with a positive clinical response, is then administered in a treat-and-extend protocol.
This method is used to attempt to increase the amount of time between injections. This is not always possible and many patients require injections every 4 weeks.
The dosage is 0.30mg (0.05mL) for diabetic retinopathy and diabetic macular edema, and slightly higher at 0.50mg (0.05 mL) for macular edema after retinal vein occlusion, choroidal neovascularization secondary to age-related macular degeneration, and degenerative myopia.
Mechanism of action
Lucentis is a recombinant humanized monoclonal IgG1 antibody fragment that binds VEGF to prevent its action on endothelial cells. Lucentis is a smaller molecule than Avastin, and has a higher binding affinity to VEGF when compared to Avastin, however, it has a nearly equivalent effect on VEGF.
Contraindications and risks
Similar to Avastin, contraindications to Lucentis injection are ocular and periocular infections, and the risks are the same.13
Biosimilar treatments for Lucentis
Byooviz
Overview
Byooviz (ranibizumab-nuna, Biogen) was FDA approved in 2021 as a biosimilar to Lucentis. It is the first FDA-approved biosimilar in eyecare. Like Lucentis, Byooviz is a recombinant humanized monoclonal IgG1 antibody fragment that binds VEGF to prevent its action on endothelial cells. It has the same indications, contraindications, and risks as Lucentis.14
Cimerli
Overview
Cimerli (ranibizumab-eqrn, Coherus) was FDA-approved in 2022 as the first interchangeable biosimilar to Lucentis. Just like Byooviz, it must meet the FDA requirements for a biosimilar and prove no clinically meaningful differences to its reference product in safety and efficacy.
Interchangeable biosimilar status
It’s important to note that an interchangeable biosimilar has to undergo further studies to prove that patients can switch back and forth from the reference product to the biosimilar and have no evidence of reduced efficacy or increased risks compared to sole treatment with the reference product. The FDA may require more than one interchangeable study to prove that patients have identical clinical results with the biosimilar compared to the reference product.15
Susvimo
Susvimo (ranibizumab ocular implant, Roche) is a novel delivery system approved in 2021 that uses an ocular implant to deliver treatment.
Dosing
Susvimo is an ocular implant that houses 2mg of ranibizumab for continuous release and is refilled every 6 months. It is clinically equivalent to monthly intravitreal injections of 0.5mg ranibizumab.
The implant is placed in the superior temporal quadrant of the globe through a pars plana incision.
Contraindications and risks
This method of treatment has a 3-fold increased risk of endophthalmitis when compared to traditional intravitreal injection of ranibizumab, and this should be considered for each patient.16
Eylea
Eylea (aflibercept, Regeneron) was FDA-approved in 2011 to treat exudative age-related macular degeneration, diabetic retinopathy, diabetic macular edema, and macular edema after retinal vein occlusion.
Dosing
Eylea is an intravitreal injection of 2.0mg (0.05mL) every 4 weeks for three to five doses, and then can be dosed every 4 to 8 weeks, depending on clinical response.
Mechanism of action
Eylea is a fully human recombinant fusion protein that acts as a decoy receptor for VEGF and placental growth factor (P1GF) and therefore inhibits actual VEGF receptor binding.
It has a 100-times stronger binding affinity to VEGF when compared to Avastin and Lucentis, and also inhibits VEGF for a longer duration.
Contraindications and risks
Contraindications and risks are the same as Avastin and Lucentis.17
Beovu
Beovu (brolucizumab-dbll, Novartis) was approved in 2019 as the first FDA-approved single-chain antibody fragment, which is the smallest functional unit of an antibody. It is indicated for exudative age-related macular degeneration and diabetic macular edema.
Dosing
It is administered as an intravitreal injection of 6.0mg (0.05mL) every 4 to 6 weeks for three doses, and then the schedule is reduced to one injection every 8 to 12 weeks. Therefore, after the first three doses, it is likely that patients need only four injections per year.
Mechanism of action
Beovu is a recombinant humanized monoclonal single-chain antibody fragment that binds VEGF to block its action, thus suppressing endothelial cell proliferation, new blood vessel formation, and vascular permeability.
Contraindications and risks
It has the same contraindications and risks as Avastin, Lucentis, and Eylea.18
Beovu is under scrutiny for a relatively significant number of patients affected by vaso-occlusive retinal vasculitis after injection when compared to other intravitreal anti-VEGF treatments, so its use is limited at this time.19
Vabysmo
Vabysmo (faricimab-svoa, Genentech) was approved in 2022 as the first bispecific antibody to treat exudative age-related macular degeneration and diabetic macular edema.
Dosing
It is an intravitreal injection of 6.0mg (0.05mL) administered every 4 weeks for four to six doses, then given every 4 to 8 weeks, depending on clinical response.
Mechanism of action
Vabysmo is a humanized recombinant bispecific IgG1 antibody that targets and inhibits VEGF and angiopoietin-2 (Ang-2) simultaneously. While VEGF inhibition blocks endothelial cell proliferation, neovascularization, and vascular permeability, Ang-2 inhibition helps to promote vascular stability and desensitize blood vessels to VEGF in a separate pathway.
The goal is to have longer lasting effects due to the synergistic effect of blocking both VEGF and Ang-2, thus requiring less injections for patients.
Contraindications and risks
Vabysmo has the same contraindications and risks as the previously discussed intravitreal treatments.20
Oxervate
Oxervate (cenegermin-bkbj, Dompe) was approved in 2018 as the first FDA-approved treatment for neurotrophic keratitis that specifically targets corneal nerve degeneration.
Dosing
Cenegermin 0.002% is a topical eye drop dosed six times per day for 8 weeks. There are no contraindications to treatment, and risks include eye pain, corneal deposits, and ocular hyperemia.
Mechanism of action
Oxervate is a recombinant human nerve growth factor (NGF) protein that is identical in structure to endogenous NGF. This protein is responsible for corneal innervation, tear secretion, and corneal epithelial cell proliferation and differentiation.
Contraindications and risks
Adverse events include eye pain, which is a good sign as it indicates the growth of functional corneal nerves.
The majority of patients who are prescribed Oxervate have complete corneal healing at the conclusion of treatment, but some may need to repeat the treatment protocol.21
Treatments using amniotic membranes
Prokera
Prokera (Biotissue) is the only FDA-cleared cryopreserved amniotic membrane product on the market designated for wound healing and regeneration of the ocular surface via its anti-inflammatory, anti-scarring, and anti-angiogenic properties.
Treatment
The Prokera membrane comes from human placental tissue and is attached to a plastic ophthalmic conformer which is inserted onto the ocular surface. It is indicated for corneal ulcers, neurotrophic keratitis, exposure keratitis, filamentary keratitis, anterior basement membrane dystrophy, recurrent corneal erosions, band keratopathy, nodular corneal degeneration, chemical or thermal burns, and Stevens-Johnson syndrome.
Mechanism of action
The Prokera membrane contains growth factors, fibronectin, collagen, anti-inflammatory cytokines, and hyaluronic acid; all of which promote healing and regeneration of the ocular surface.
Contraindications and risks
The contraindications to Prokera placement are known hypersensitivity reactions to ciprofloxacin and amphotericin B as the membrane is processed with these antimicrobials.22-26
Dehydrated amniotic membranes
Ambiodisk (Corza), BioDOptix (Integra Life Sciences), Aril (Seed Biotech), and Apollo (Atlas) are all dehydrated amniotic membranes processed from human placental tissue.
Treatment
Similar to the cryopreserved membrane, the dehydrated membranes act to heal and regenerate the ocular surface via reducing inflammation, scar tissue, and angiogenesis. These membranes must be secured in place with a bandage contact lens.
Contraindications and risks
Dehydration of the amniotic tissue allows it to be shelf-stable but may have reduced potency of the growth factors and anti-inflammatory proteins and cytokines when compared to cryopreserved membranes.22-26
Blood biologic eye drops
Autologous serum eye drops
Autologous serum tears are eye drops made from a patient’s own blood serum to provide lubrication, antioxidants, lysozyme, lactoferrin, albumin, immunoglobulins, growth factors, and other anti-inflammatory cytokines to help heal a damaged ocular surface. They are known to improve tear film breakup time, corneal punctate epithelial erosions, persistent epithelial defects, and subjective symptoms.
In addition, autologous serum eye drops are preservative-free, which is clinically relevant when treating moderate to severe ocular surface disease.
Dosing
Autologous serum tears are made to order from compounding pharmacies and companies like Vital Tears, and are typically ordered at concentrations of 20 to 50%, dosed anywhere from two to eight times per day, depending on clinical signs and symptoms.
Mechanism of action
Autologous serum tears assist with corneal epithelial wound healing and increase the concentration of goblet cells and mucin production.
Additional notes
They were first used in 1975 to treat ocular burns and Stevens-Johnson syndrome. Since then, they have been proven useful for other etiologies of ocular surface disease, especially autoimmune-related dry eye syndrome (Sjogren's syndrome, mucous membrane pemphigoid, GVHD, and rheumatoid arthritis), limbal stem cell deficiency, and superior limbic keratoconjunctivitis.27-29
Platelet-rich plasma eye drops
Platelet-rich plasma tears are similar to autologous serum tears, but as the name says, the manufacturing process includes platelets from the patient’s blood.
Mechanism of action
Platelets may be a more potent source of growth factors and cytokines and thus may be more effective as a treatment.30 However, platelet-rich plasma tears are not superior to autologous serum tears in clinical practice.
Additional notes
Autologous serum tears and platelet-rich plasma tears are not FDA-approved treatments for ocular surface disease and are not covered by insurance.
Biologic therapies on the horizon
The value of biologic pharmaceuticals and biosimilars in primary and sub-specialty eyecare cannot be overrated due to the clinically meaningful impact they have had on maintaining and improving vision and quality of life.
Optometrists should be on the lookout for new treatments in the near future. In the pipeline for vasoproliferative retinal disease, we can expect to see more biosimilars for ranibizumab and aflibercept. There are also new biologic therapies in development for the treatment of dry eye and ocular surface disease.
These developing treatments include:
- HBM9036 (Harbour BioMed) which is tanfanercept, a TNFα blocker
- RGN259 (RegeneRx) which is Tβ4, thymosin-beta 4, a protein that reduces pro-inflammatory cytokines and allows tissue healing and regeneration31
Conclusion
Biologics provide target-specific therapies to reduce ocular inflammation and tissue damage with fewer side effects than historical treatment options. As these therapies improve, it is hopeful that with the introduction of biosimilars, patients will be able to benefit from these novel technologies with less financial burdens and other barriers to access.
