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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 burdens and ultimately improving clinical outcomes. 

Polymer Microparticle Depot Promote Controlled, Sustained Drug Delivery

Graybug’s microparticles are designed to aggregate after intravitreal (IVT) injection to form a depot near the bottom of the eye, outside of the visual axis. Our biodegradable microparticles then gradually release the active ingredient at a rate dependent on the composition of the polymers. They then biodegrade into lactic acid, glycolic acid and polyethylene glycol, all of which are then naturally cleared from the body.

Applying Our Proprietary Depot Technology to Our Pipeline
  • We are developing our lead product candidate, GB-102, as a twice-per-year intravitreally delivered microparticle depot formulation of sunitinib for the treatment of wet age-related macular degeneration (wet AMD) and diabetic macular edema (DME). 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 and DME, better patient quality-of-life and reduced disease-monitoring requirements.
  • We are also developing GB-103, designed to be a once-per-year intravitreally delivered microparticle depot formulation of sunitinib. This potentially longer duration of clinical benefit, and consequently less frequent need for intravitreal injections, may be more conducive to maintaining a typically asymptomatic patient with diabetic retinopathy on an effective anti-VEGF therapy regimen. If approved, GB-103 could provide a paradigm shift in the treatment of patients with diabetic retinopathy (DR) who are currently managed either by observation alone, pan-retinal laser photocoagulation or, in rare instances, with short-acting anti-VEGF injections.
  • We are applying our proprietary technologies to develop GB-401, 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.

We believe our proprietary technologies will allow us to develop other novel therapeutics, either alone or in combination, that can achieve extended durations of effectiveness and, thus improve the care and quality of life for patients with chronic diseases and disorders of the eye.

Our pipeline of long-acting ocular drug candidates

The following chart summarizes the status and development plan for the product candidates in our pipeline. We own worldwide rights to each of our programs. 

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 (PIGF) 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 1/2a 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 reduced injection frequency by 80% while maintaining retinal thickness and visual acuity

GB-102 1 mg reduced injection frequency by 80% while maintaining retinal thickness and visual acuity

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)

Having optimized the formulation, 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

These results provided additional support for the potential advancement of GB-102 1 mg dose into pivotal trials.

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

ALTISSIMO is a 12-month, multicenter, prospective, double-masked, randomized (3:3:2), 3-parallel arm trial comparing two doses of GB-102 (1 and 2 mg) administered every six months to aflibercept administered every two months in patients with anti-VEGF-responsive wet AMD.

Similar to the population in our ADAGIO trial, 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 will be 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. The re-dosing of patients with GB-102 1 mg at 6 months has been completed.

GB-102 Phase 2b trial in wet AMD: Re-dosing of patients at 6 months has been completed

The results of the ADAGIO and ALTISSIMO trials, together with published clinical data in wet AMD, will inform the trial design of our pivotal Phase 3 trials.

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