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Our Technologies
and Pipeline

Our Proprietary Technologies

Our proprietary technologies are designed to allow sustained delivery of pharmacologic agents to the eye in a well-controlled and tolerable manner to achieve extended duration of effectiveness.

We aim to extend duration of effectiveness — with the goal of improving patient compliance, reducing healthcare burden and ultimately improving clinical outcomes.

Designed to Promote Controlled, Sustained Drug Delivery

Graybug’s polymer delivery systems are designed to form a depot near the bottom of the eye, outside of the visual axis, by either an injectable implant or as microparticles that aggregate after intravitreal (IVT) injection. Our biodegradable drug products gradually release the active ingredient at a rate designed to provide the desired treatment durability. They then biodegrade into lactic acid, glycolic acid and polyethylene glycol, all of which are then naturally cleared from the body.

 

Applying Our Proprietary Technologies to Our Pipeline
  • GB-102 is a twice-per-year intravitreally delivered formulation of sunitinib for the treatment of wet age-related macular degeneration (wet AMD). We believe that GB-102 is differentiated from the current standard of care which requires more frequent dosing (up to 12 times per year), and primarily targets one neovascular pathway (VEGF-A) by delivering a sustained and durable dose of sunitinib – a pan-VEGF inhibitor – to the vitreous while blocking VEGF-B, C and D in addition to VEGF-A.
We believe durable and sustained drug delivery of a single dose offered by GB-102 could provide improved visual outcomes for patients with wet AMD, better patient quality-of-life and reduce disease-monitoring requirements. In fact, the ALTISSIMO Extension Study provided up to an additional six months for patients to demonstrate longer duration, which resulted in 55% of GB-102 1mg patients 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 1mg patients who participated in the six-month Extension Study.
  • GB-401 is a sustained release beta-blocker, designed to be injected twice-per-year to reduce intraocular pressure (IOP) in patients with primary open angle glaucoma (POPG). If approved, GB-401 could represent a significant paradigm shift in the way physicians treat POAG, addressing the patient compliance problem that exists with current therapies while improving visual outcomes. Graybug is in the process of developing a GB-401 implant for intravitreal injection.
Our pipeline of long-acting ocular drug candidates

Graybug plans to enhance its technology platform to address the unmet needs in ophthalmology. The following chart summarizes the status for the product candidates currently in our pipeline. We own worldwide rights to each of our programs.

Programs in active development

GB-102 in Retinal Diseases

GB-102 is a potent small molecule multiple receptor tyrosine kinase inhibitor sunitinib malate, or sunitinib, formulated in our proprietary microparticles designed to be administered intravitreally every six months.

Sunitinib’s mechanism of action is the inhibition of receptor tyrosine kinases, specifically of VEGF receptors 1, 2 and 3, blocking all VEGF signals, including VEGF-A, -B, -C and -D and placental growth factor (PLGF) which are ligands implicated in pathologic neovascularization in patients with wet AMD. Moreover, sunitinib is a DLK-inhibitor, which may result in a neuroprotective effect.

Sunitinib is a potent pan-VEGF inhibitor and neuroprotectant

Pan-VEGF Inhibitor

  • Blocks all VEGF receptors associated with angiogenesis, vascular permeability, cellular proliferation and fibrosis
  • Could provide benefits over traditional VEGF A inhibitors

Neuroprotectant

  • DLK pathway inhibitor
  • Blocking DLK promotes retinal ganglion cell survival
DLK: Dual Leucine Zipper Kinase​
Siu (2018) Zack (2011, 2012)
GB-102 Phase 1/2a clinical trial (ADAGIO) in patients with wet AMD

We conducted an open-label, single-injection, dose ranging safety, tolerability and efficacy in patients with wet AMD who had previously been treated with short-acting anti-VEGF treatments. Thirty-two eligible patients received a single intravitreal injection of GB-102 (0.25, 0.5, 1 or 2 mg) and were followed for eight months. Monthly assessments included adverse events, best-corrected visual acuity (BCVA), central sub-field thickness (CST), slit-lamp biomicroscopy, dilated fundoscopy and plasma blood samples to detect systemic levels of sunitinib. Patients were eligible for supportive anti-VEGF treatment if certain criteria were met.

GB-102 Phase 1/2GB-102 Phase 1/2a single injection first-in-human trial in wet AMD patients previously treated with short-acting anti-VEGFs (ADAGIO)

ADAGIO clinical trial results

In the ADAGIO trial, GB-102 met its primary endpoint of safety and tolerability with no ocular serious adverse events (SAEs) or dose limiting toxicities. No patients discontinued treatment as a result 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. Since the most commonly reported ocular AE was presence of medication in the anterior chamber, we optimized the manufacturing process for GB-102 to enhance its binding affinity thus improving its ability to aggregate post injection. This optimized version is being used for subsequent trials.

Our data also demonstrated that for patients who required an average of eight injections per year to control their disease, a single injection of GB-102 was able to maintain their central retinal thickness and visual acuity for six months or more. GB-102 appeared to reduce the overall number of anti-VEGF injections through six months by over 80% in all dose groups. The overall best performing dose was GB-102 1 mg, which controlled the disease in seven out of eight patients for six months, and in four out of eight patients beyond eight months.

GB-102 1 mg single injection maintained retinal thickness for 6+ months

GB-102 1 mg single injection maintained retinal thickness for 6+ months

GB-102 1 mg single injection maintained visual acuity for 6+ months

GB-102 Phase 2a clinical trial in patients with macular edema (ME)

We conducted an open label, single injection trial in patients with macular edema due to various diseases with a primary endpoint of safety and tolerability of two dose levels of GB-102 (1 and 2 mg with optimized formulation). Six centers in the United States enrolled 21 patients who had received at least three prior injections of anti-VEGF and shown at least some response within the last 24 months. As the focus of the ME trial was safety, disease control was not a requirement at enrollment, and patient eligibility was not verified by independent third parties. On average, at enrollment, patients required eight injections per year to control their disease. Eligible patients received GB-102 (1 or 2 mg) at day 1 and were followed monthly.

A single injection, dose selection, safety and aggregation trial in patients with ME

GB-102 ME clinical trial results summary

There were no drug related non-ocular adverse events in the trial. The 2 mg dose was associated with medication present in the anterior chamber in five out of 11 patients. The majority of adverse events occurred in these patients including two serious adverse events in a single patient. We believe that the number of microparticles injected in the 2 mg dose (approximately two million) were too many to allow adequate aggregation and as a result we have terminated the development of the 2 mg dose.

The GB-102 1 mg dose met its primary endpoint of safety and tolerability 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.

Particle aggregation and bioabsorption with GB-102 1 mg observed over 6 months

GB-102 depot images using wide field color fundus photography throughout the 6-month observation period in the ME study

GB-102 Phase 2b clinical trial (ALTISSIMO) in patients with wet AMD

ALTISSIMO is a 12-month, masked and controlled Phase 2b dose-ranging study of two doses of GB-102 (1 and 2 mg) administered every six months, with a single control arm of patients on aflibercept, administered every two months, in patients with anti-VEGF-responsive wet AMD, conducted across 33 study sites in the United States.

The primary endpoint is median time to first supportive therapy with a vascular endothelial growth factor (VEGF) inhibitor, and secondary endpoints are safety and pharmacodynamics, measured as mean change of best-corrected visual acuity (BCVA) and mean change of central subfield thickness (CST) of the retina.

Key eligibility criteria include patients with wet AMD diagnosed less than 18 months prior to enrollment, who had received at least three prior injections of any anti-VEGF and demonstrated response to anti-VEGF treatment, defined as physician-reported reduction in macular thickness. In addition, those patients received an anti-VEGF injection within 21 days of screening. Eligible patients received either GB-102 (1 or 2 mg) or aflibercept at day one and have been followed monthly for 12 consecutive months.

ALTISSIMO trial design

We initially designed the ALTISSIMO trial to enroll 160 patients and started the trial in September 2019. In December 2019, we voluntarily paused enrollment as a precautionary measure following the report of a single patient experiencing SAEs with the 2 mg dose in the Phase 2a trial of GB-102 in ME patients. On the basis of the safety analysis of the ME trial and interim safety data of the ALTISSIMO trial, we terminated the development of the GB-102 2 mg dose in all of our clinical trial programs and amended the protocol of the ALTISSIMO trial. The final patient numbers in the ALTISSIMO trial are 56 patients. All patients were re-dosed with GB-102 1 mg at 6 months.

ALTISSIMO comprised two phases, the first of which was a 12-month treatment phase, or Core Study, in which GB-102 patients were dosed at Day 1 and Month 6, while a control arm received aflibercept every other month. The second phase of ALTISSIMO was a six-month extended observation phase, or Extension Study, in which patients were monitored without additional treatment to determine the duration of effect measured from their last treatment during the Core Study.

Participation in the Extension Study was voluntary, but only patients who completed all study visits, and did not require supportive therapy at their Month 12 visit during the Core Study, were eligible. 58% of the patients who completed the Core Study were eligible and agreed to enter the Extension Study, with 11 patients participating in the GB-102 1mg arm.

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

GB-102 ALTISSIMO 12-month clinical trial results summary

The ALTISSIMO full-data analysis focused on the GB-102 1mg arm as compared to aflibercept and the pre-enrollment period, excluding results from the GB-102 2mg arm. The development of GB-102 2mg was terminated in 2020 following an interim safety analysis. The trial was not powered to assess non-inferiority to aflibercept.

Overall, GB-102 1mg was safe and well-tolerated. No drug-related serious adverse events or vision-threatening inflammation were reported. The majority of drug-related adverse events were mild to moderate. Particle migration to the anterior chamber in patients treated with GB-102 1mg was reduced by 79% as compared to GB-102 1mg 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 1mg 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 1mg compared with baseline was similar to bi-monthly aflibercept, while BCVA trended lower in GB-102 1mg patients as compared with aflibercept. This trend in visual acuity was primarily driven by six patients: two patients whose disease was not well-controlled despite frequent anti-VEGF treatment prior to enrollment, two patients who experienced adverse events unrelated to GB-102, and two patients who experienced adverse events related to dispersion of GB-102 microparticles.

GB-102 1 mg reduced treatment burden by 58% while CST and BCVA was maintained

Control of CST with GB-102 1 mg given every 6 months was similar to that of bi-monthly aflibercept

BCVA trended lower in GB-102 1 mg given every 6 months as compared with bi-monthly aflibercept — high standard deviation driven by 6 patients

ALTISSIMO six-month extension study 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 1mg patients 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 1mg patients who participated in the six-month Extension Study.

As in the 12-month Core Study, GB-102 1mg 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 driven by a subgroup of hard-to-treat patients, treatment unrelated adverse events as well as events of particle dispersion. 

 

Clear Roadmap Ahead

To capitalize on GB-102 1 mg good anatomical control and extended duration observed in the ALTISSIMO trail, Graybug is in the process of optimizing its technology platform by developing additional formulations that have the potential to preserve the durability of GB-102 1mg microparticles while minimizing the risk of dispersion. These new and enhanced formulations also simplify the drug reconstitution process and the injection technique, both of which are sources of variability in clinical outcomes. Click below to see the improved aggregation of GB-102 in vitro. 

Enhanced GB-102 formulation designed to reduce interference with vision

Extensive stress testing applied to validate new formulation

Aggregation Shear Stress Test (37°C) at 5 Minutes
ALTISSIMO Formulation

Dispersed Depot
Enhanced Formulation

Intact Depot
Benefits of enhanced GB-102 formulation:
  • Instant aggregation upon injection
  • Aggregation is resistant to shear stress
  • Improved reconstitution reduces variability
  • Demonstrated safety in a GLP tox study
  • Same drug release profile

Furthermore, Graybug will refine the entry and rescue criteria in future clinical trials based on the learnings from ALTISSIMO.

Given the 12-month or longer duration observed with GB-102 in the ALTISSIMO 18-month trial, Graybug decided to stop the further development of GB-103, which was designed to maintain therapeutic drug levels in the retinal tissue for 12 months with a single injection.

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