All About Anti-VEGF & Novel Treatments

July 04, 2022

It was long theorized that regions of ischemic retina released some type of unknown factor that promoted growth of new vasculature (i.e., neovascularization).

The molecule now known as vascular endothelial growth factor (VEGF) was discovered and found to be present in much higher concentrations in eyes with neovascularization than in those without.

Animal models also revealed that artificially creating a hypoxic retina led to increased VEGF and that injecting VEGF into the eye induced iris neovascularization and neovascular glaucoma.

The development of anti-VEGF injections has provided a medical option to patients with certain posterior segment issues that simply didn’t exist before. New compounds continue to be developed and tested to better resolve retinal issues.

Several ocular diseases are characterized for an excessive angiogenesis, which causes severe visual loss and ocular morbidity worldwide. The most common ones are age-related macular degeneration (AMD), diabetic retinopathy (DR) and retinal vein occlusion. 

These diseases present ocular neovascularization triggered by a pathologic angiogenesis process that involves degradation of the basement membrane, extracellular proteolysis and abnormal blood vessels growth. 

AMD implies choroidal neovascularization as a consequence of hypoxia, ischemia, and inflammation, causing macular thickening and edema. 

In DR, the hyperglycemia seems to have a structural and physiological effect: retinal capillaries become blocked and this results in early stages of the pathology where micro aneurism are formed. 

Then, it usually progresses to hypoxia that stimulates the generation of new blood vessels. Diabetic macular edema (DME) is the most common cause of vision loss in patients with DR. Based on these facts, the angiogenesis control is the main focus for these diseases therapy.

One of the key aspects of the angiogenesis therapy is targeting of the vascular endothelial growth factor (VEGF) whose family consists in five related glycoproteins that play critical roles in the development, progression, and regularization of new blood vessels both in normal physiological and pathological conditions. 

VEGF binding to its receptors, VEGFR1 and VEGFR2, on the surface of endothelial cells induces intracellular calcium increase and production of vasodilatory mediators like nitric oxide. 

Thus, VEGF promotes endothelial cell proliferation, vascular leakage, and formation of new blood vessels. Therefore, blockage of VEGF activity has become the main strategy in the treatment of neovascular ocular pathologies.

Conventional therapies targeting VEGF are based on biological drugs (BD) also known as biological medicine or biotherapeutic agent. Its definition has changed over time and it may differ from one author to another. 

However, in a broad sense, they are described as drugs obtained from living natural resources. 

Moreover, it is also referred as biotechnological drugs when BD are obtained through living-organism modification by taking advantage of the their biological mechanics; for example, using recombinant DNA techniques or the hybridoma technique.

Currently, biological drug therapy for ocular angiogenesis treatment is based on the administration of anti-VEGF agents via intravitreal route.

The molecules approved with this purpose for ocular use include pegaptanib, ranibizumab, and aflibercept, whereas bevacizumab is commonly off-label used in the clinical practice.

The schedule dosage involves repeated intravitreal injections of anti-VEGF agents to achieve and maintain effective concentrations in retina and choroids, which are administrated as solutions form.

In this review article, we describe the features of different anti-VEGF agents, major challenges for their ocular delivery and the nanoparticles in development as delivery system of them.

In this way, several polymeric and lipid nanoparticles are explored to load anti-VEGF agents with the aim of achieving sustained drug release and thus, minimize the number of intravitreal injections required.

The main challenges were focused in the loading the molecules that maintain their bioactivity after their release from nanoparticulate system, followed the evaluation of them through studies of formulation stability, pharmacokinetic, and efficacy in in vitro and in vivo models.

The analysis was based on the information published in peer-reviewed published papers relevant to anti-VEGF treatments and nanoparticles developed as ocular anti-VEGF delivery system.

Since the introduction of bevacizumab (Avastin, Genentech) as an off-label treatment in 2005, and the FDA approval of ranibizumab (Lucentis, Genentech) in 2006, intravitreal injection (IVI) of antibodies to vascular endothelial growth factor (anti-VEGF) have been the mainstay of treatment for a multitude of ocular conditions including neovascular age-related macular degeneration (nAMD), diabetic retinopathy (DR), retinal vein occlusion (RVO), and diabetic macular edema (DME).

The treatment burden on patients has been relatively high, consisting of injections as frequently as every 28 days.

With the introduction of pharmaceutical variations, the treatment burden has been decreased in some patients, with aflibercept (Eylea, Regeneron) as long as 8 weeks and brolucizumab (Beovu, Novartis) as long as 12 weeks between injections with continued efficacy.

However, many patients with less responsive disease variants need to come in consistently every 4 weeks to maintain their current vision.

This places a strain on both the healthcare system and on each individual patient, many of whom drop out of treatment and consequently suffer permanent vision loss.

Novel treatments aim to decrease this high level of treatment burden on patients, with some potentially extending time between injections as far as 6 months.

A variety of modalities are being employed in this attempt, including constructing a more effective anti-VEGF molecule, inserting a mechanism for sustained medication delivery, and targeting a new mechanism of action in the inflammatory disease cascade.

The number of needles in a patient’s eye is reduced while maintaining treatment efficacy and visual outcome. This impacts practice scheduling as decreased treatment frequency would allow the practice to see a greater number of total patients.

For physicians and technicians, days could be less hectic with fewer scheduled daily injections. Still, staff would need to adjust to some of the nuances of these new treatment possibilities.

Scheduling A current “injection only” visit for a patient can be completed in as little as 30 minutes and facilitates as many as 40-50 appointments per day for each physician in the practice. At least one novel treatment, Roche’s faricimab, would maintain this methodology.

A bispecific antibody against VEGF and angiopoietin-2 (Ang2), faricimab would be drawn up and injected similarly to anti-VEGF medications currently utilized; however, faricimab has the added benefit of halting the disease process via two separate mechanisms of actions.

Phase 2 AVENUE and STAIRWAY trials demonstrated noninferiority to current treatment protocols.

Early results of Phase 3 TENAYA and LUCERNE as well as YOSEMITE and RHINE studies results suggest >70% of patients being able to extend time between injections to 12 weeks and >50% to 16 weeks after initial loading doses.

In addition to this novel medication, the Phase 3 PULSAR and PHOTON studies are investigating an increased dose of aflibercept (8 mg compared to 2 mg) at 12-16 week intervals, which would be administered without any changes to the current methodology.

Preparation Some of these novel treatments would require more effort and time on behalf of the technicians preparing them. The first of these, Opthea’s OPT-302, is a VEGF C/D trap molecule designed to be used in conjunction with current anti-VEGF-A treatments.

As it comes frozen, it requires 40 minutes to defrost in the refrigerator prior to injection and would require each facility to have a freezer and maintain an appropriate cold chain.

Additionally, it is given in conjunction with standard of care anti-VEGF, so the patient receives two injections with a 15-minute period between to ensure IOP stabilization, which lengthens the visit.

Phase 3 ShORe and COAST studies are currently analyzing OPT-302’s efficacy treating nAMD in combination with ranibizumab and (aflibercept, Regeneron), respectively.

Kodiak Science’s KSI-301 is an antibody biopolymer conjugate, a novel method of attaching the anti-VEGF molecule to a polymer that would last longer in the eye, thus increasing both bioavailability and durability.

Early results also suggest a decreased systemic absorption of anti-VEGF and a decreased half life in the body, thus decreasing any potential adverse effects.

However, this polymer causes the medication to be extremely viscous, which roughly doubles the amount of time required to both draw up and actively inject.

There are a variety of active Phase 2/3 studies including DAZZLE for nAMD, GLEAM/GLIMMER for DME, BEACON for RVO, and GLOW for diabetic retinopathy analyzing its efficacy in each of the different diseases entities treated.

Education Two of the proposed novel treatments are enacted via gene therapy in a viral vector, which would require increased patient education.

Adverum’s ADVM-022, an adeno-associated virus, contains complimentary DNA to generate an aflibercept medicine and can be administered in a standard intravitreal injection.

Regenxbio’s RGX-314 is an adeno-associated virus coding for a ranibizumab-like medicine, which requires vitrectomy and intraoperative injection via cannula into a subretinal bleb.

Techs will need to educate patients on the surgical intervention for treatment (which also requires OR scheduling) along with the need for close immediate follow-up and an initial increase in their treatment burden.

Alternative technology, Another surgical alternative being proposed is Genentech’s port delivery system, or PDS, which is an apparatus installed in the OR with a reservoir of anti-VEGF medication.

Current studies utilize ranibizumab, with recruited patients having shown a positive response to IVI but with need for frequent injections. This novel system releases medication slowly into the vitreous over a period of months.

The Phase 2 LADDER study’s high-dose arms suggest a refill as infrequently as every 15 months, and 98% of the study participants are able to go 6 months without an injection. Phase 3 ARCHWAY and PORTAL are currently underway to analyze its efficacy.

Although it is necessary to undergo implantation in a surgical suite using vitrectomy equipment, the refill would be performed in a clinic setting, providing overall decreased treatment burden moving forward for the patient.

Advancing treatment With the prevalence of nAMD alone at roughly 1% in the United States, roughly 3 million patients rely on regular injections for sustained vision. Combined with DR, RVO, and DME, this number rises dramatically.

This burden on both the patient and healthcare system stands to be greatly reduced with an improvement in therapy that results in an increase in time between each required treatment.

More treatment options with varying procedures in storing, preparing, and applying may translate to decreased efficiency relative to the current homogenous process for anti-VEGF treatment.

Standardization across these new processes will be a challenge but is needed for maintaining safety. The variability and treatment options may require more time to select optimized treatment, as well as chair time with the patient regarding individualized risks and benefits of each treatment.

With proper scheduling, technician training, and patient education, these described novel treatments are our most promising upcoming possibilities to take the next step in advancing treatment.