Target Disease: Retinal Diseases

The retina is a neuronal tissue located at the back of the eye. Its primary function is the perception of light, the processing of light induced stimuli, and the transmission of light-dependent information to the brain.

Retinal diseases like wet age-related macular degeneration (wet AMD), diabetic retinopathy (DR) and geographic atrophy (GA) can lead to permanent vision loss. VEGF is a protein produced by cells which stimulates the formation of new abnormal blood vessels, a process called neovascularization, and induces vascular permeability, leading to leakage and swelling of the retina. Swelling of the retina leads to vision decline and death of the retinal cells, which can irreversibly cause blindness if not adequately treated.

In addition, a large number of hereditary diseases affect the retina and can result in severe vision impairment or blindness.

Wet AMD

About Wet Age-Related Macular Degeneration (wet AMD)

Wet AMD is caused by the growth of abnormal blood vessels known as choroidal neovascularization (CNV) and subsequent leakage of fluid in the macula, the portion of retina used for more precise vision. The choice of treatments depends on the size, location, and type of neovascularization. Intravitreal injections with anti-VEGFs have proven to be safe and effective in reducing the risk of vision loss and in restoring reading vision in up to one third of patients. Early intervention is essential to treat wet AMD; without treatment, vision rapidly declines. The below graphic illustrates the primary effects of wet AMD compared to a healthy eye.
Wet AMD is caused by the growth of abnormal blood vessels known as choroidal neovascularization (CNV) and subsequent leakage of fluid in the macula, the portion of retina used for more precise vision. The choice of treatments depends on the size, location, and type of neovascularization. Intravitreal injections with anti-VEGFs have proven to be safe and effective in reducing the risk of vision loss and in restoring reading vision in up to one third of patients. Early intervention is essential to treat wet AMD; without treatment, vision rapidly declines. The below graphic illustrates the primary effects of wet AMD compared to a healthy eye.
PREVALENCE OF AMD
Age-related macular degeneration (AMD) is the leading cause of visual disability in the elderly in the industrialized world and the third leading cause globally. It is estimated that 11 to 15 million people in the US and 170 million people worldwide have AMD. Aging is the greatest risk factor; therefore, the prevalence of AMD in the U.S. is anticipated to increase to 22 million by the year 2050, while the global prevalence is expected to increase to 288 million by the year 2040.
Age-Related Macular
Degeneration
11 / 170
Million
us
Million
worldwide
Age-related macular degeneration (AMD) is the leading cause of visual disability in the elderly in the industrialized world and the third leading cause globally. It is estimated that 11 to 15 million people in the US and 170 million people worldwide have AMD. Aging is the greatest risk factor; therefore, the prevalence of AMD in the U.S. is anticipated to increase to 22 million by the year 2050, while the global prevalence is expected to increase to 288 million by the year 2040.
The prevalence of the disease is broken down into approximately 85 to 90% nonexudative, or dry, AMD and 10 to 15% wet AMD, which represents about 25 million people worldwide and 1.7 million in the United States. Geographic atrophy is considered the late stage of dry AMD and is less common than wet AMD.

The Unmet Need of wet AMD
Patients

Despite the significant benefits of existing therapeutic options to treat wet AMD, the need for frequent intravitreal injections is burdensome for patients and their caregivers, retinal specialists and the overall healthcare system.

An annual survey conducted with retinal specialists by the American Society of Retinal Specialists (ASRS) reported that in wet AMD therapeutics, the two greatest unmet needs are:
The two greatest unmet needs from a retinal specialist perspective
Need for longer-acting/sustained delivery therapies
Reduced treatment burden
Some of the challenges patients experience when on anti-VEGF therapy include:
Psychosocial burden of repeated intravitreal injections
Time burden of both treatment and monitoring visits
In clinical trials, intravitreal injections of anti-VEGF drugs resulted in significant gains in visual acuity for patients with retinal diseases. However, in settings outside of clinical trials, patients often receive less frequent injections than in clinical trial settings. Long-term observational studies in the United States, Europe and Japan have demonstrated that many patients with wet AMD lose visual acuity due to the challenges associated with receiving anti-VEGF injections at an optimal frequency.

This diagram shows the declining visual acuity (VA) results over four years after the first anti-VEGF injection in patients with wet AMD in the United States.

This diagram shows the declining visual acuity (VA) results over four years after the first anti-VEGF injection in patients with wet AMD in the United States.

GB-102 Clinical Trial Overview
GB-102 has been evaluated in three Phase 1/2 trials to assess dose levels, safety, tolerability, durability and pharmacodynamic effects, as well as to identify the optimal dose.
ADAGIO trial:
An 8-month, Phase 1, open label, multi-center, dose ranging trial to assess the safety, durability and pharmacodynamic effects of a single injection of GB-102 in patients with wet AMD who had received prior injections of anti-VEGF.
VIEW THE ADAGIO trial results summary
ADAGIO clinical trial results summary
The primary endpoint of safety and tolerability of four dose levels of GB-102 (N=32, 8 patients per dose level) was met, with no ocular serious adverse events (SAEs) or dose limiting toxicities. No patients discontinued treatment because of any drug-related adverse event. Four patients discontinued due to reasons unrelated to the drug. There were no detectable plasma levels of sunitinib in any patient. All drug related adverse events (AEs) were mild or moderate. Out of the four dose levels studied, GB-102 1 mg dose showed the best safety profile.
Seven out of eight patients who received GB-102 1 mg did not need any additional supportive therapy for six months and four out of eight patients exited the trial at month eight without additional supportive therapy. On average, patients maintained the pre-trial central subfield thickness (CST) and best corrected visual acuity (BCVA).
However, some patients experienced presence of microparticles in the anterior chamber in a dose-dependent manner, leading to the development of an improved version of GB-102. This improved version was used in subsequent trials.
Macular Edema (ME) trial
A 6-month, Phase 2a, open-label, multi-center, parallel group, dose ranging trial to assess the safety, tolerability and pharmacodynamic response of two dose levels of GB-102 (N=21) in patients with ME secondary to diabetic macular edema (DME) and branch or central retinal vein occlusion (RVO) who had received prior injections of anti-VEGF.
VIEW THE GB-102 ME clinical trial results summary
GB-102 ME clinical trial results summary
The trial met its primary endpoint of safety and tolerability for the GB-102 1 mg dose with seven out of ten patients demonstrating no adverse events. None of the patients had inflammation and all adverse events were mild to moderate and resolved without long-term consequences. As seen in the image below, the microspheres aggregated well in the 1 mg dose and formed a depot at the bottom of the eye. As the depot eluted drug, the size decreased and at six months there was only a small amount of the depot left. There were no drug related non-ocular adverse events in the trial.
Particle aggregation and bio absorption with GB-102 1 mg observed over 6 months
GB-102 depot images using wide field color fundus photography throughout the six-month observation period in the ME study
ALTISSIMO trial:
A 12-month, Phase 2b, randomized, double-masked, prospective, multi-center, dose ranging, parallel arm trial to assess safety, durability and pharmacodynamic effects of repeat injections of either 1 or 2 mg GB-102 every six months vs aflibercept bi-monthly as per label in patients with wet AMD who had received prior injections of anti-VEGF. Patients who completed the 12-month core study period and were willing and qualified, entered an additional 6-month observational extension period.
VIEW THE ALTISSIMO trial results summary
VIEW THE ALTISSIMO trial results summary
GB-102 ALTISSIMO 12-month clinical
trial results summary
The ALTISSIMO full-data analysis focused on the GB-102 1 mg arm as compared to aflibercept and the pre-enrollment period, excluding results from the GB-102 2 mg arm. The development of GB-102 2 mg was terminated in 2020 following an interim safety analysis. The trial was not powered to assess non-inferiority to aflibercept.

Overall, GB-102 1 mg was safe and well-tolerated. No drug-related serious adverse events or vision-threatening inflammation were reported. Most drug-related adverse events were mild to moderate. Particle migration to the anterior chamber in patients treated with GB-102 1 mg was reduced by 79% as compared to GB-102 1 mg patients in the ADAGIO Phase 1/2a trial (4/51 injections vs. 3/8), and no surgical interventions were required.
Patients in the GB-102 1 mg trial arm (n=21) had a median time to first supportive therapy of five months, and 48% of patients did not require supportive therapy for at least six months. An additional analysis showed the injection frequency was reduced by 58% compared to patients’ treatment prior to enrollment in the trial.

Although ALTISSIMO was not powered to show statistical significance, control of CST in patients treated with twice-a-year GB-102 1 mg compared with baseline was similar to bi-monthly aflibercept, while BCVA trended lower in GB-102 1 mg patients as compared with aflibercept.
This trend in visual acuity was primarily driven by four patients who had a combination of high anti-VEGF need prior to enrollment, particle dispersion during the study, or adverse events unrelated to the drug.
ALTISSIMO six-month extension
trial summary
The ALTISSIMO Extension Study provided up to an additional six months for patients to demonstrate longer duration, which resulted in 55% of GB-102 1 mg patients (6/11) who entered the Extension Study experiencing a treatment duration of 12 months or longer, while maintaining visual acuity and central retinal thickness. This is the longest duration ever achieved with an intravitreal injection in a randomized, masked, and controlled clinical trial in wet AMD. In addition, the injection burden was reduced by 73% for those GB-102 1 mg patients who participated in the six-month Extension Study.

As in the 12-month Core Study, GB-102 1 mg continued to be well-tolerated and maintained a favorable safety profile during the Extension Study. No drug-related adverse events or vision-threatening inflammation were reported.
ALTISSIMO 18-month results
summary
The 18-month ALTISSIMO data confirmed an improved and long-term safety profile of GB-102 1 mg with an unprecedented duration for an intravitreal injection beyond six months, as well as a similar effect on central retinal thickness (CST) compared to aflibercept. The reduction in visual acuity (BCVA) was primarily driven by a subgroup of patients whose disease was not controlled by frequent high-dose anti-VEGF injections prior to study entry.

GB-102 Phase 2b trial in wet AMD (ALTISSIMO) 12-month core study and 6-month extension trial design

The ALTISSIMO data confirmed an improved and long-term safety profile of GB-102 1 mg with an unprecedented duration for an intravitreal injection beyond six months.

Clear Roadmap Ahead

To capitalize on GB-102 1 mg good anatomical control and extended duration observed in the ALTISSIMO trial, Graybug has optimized its technology platform by developing an enhanced formulation (GB-102 Version 3) that has the potential to preserve the durability of GB-102 1 mg microparticles while minimizing the risk of particle dispersion. This new and enhanced formulation also simplifies the drug reconstitution process and the injection technique, both of which are sources of variability in clinical outcomes. See below the improved aggregation of GB-102 in vitro. Furthermore, Graybug has refined the entry and rescue criteria for future clinical trials based on the learnings from ALTISSIMO.

EXHIBIT: GB-102 Version 3
FORMULATION DESIGNED
TO QUICKLY FORM A
STRONGER DEPOT













Enhanced GB-102 depot remains intact after shear stress test




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