Registered study summary

“Evaluate the safety, tolerability, and efficacy of OTX-TKI for intravitreal use in subjects with Neovascular Age-Related Macular Degeneration” (opens the source at this quote in a new tab)

Company-stated objectives

“In this trial, we evaluated how long we are able to maintain subjects who have been previously treated with anti-VEGF therapy without the need for retreatment.” (opens the source at this quote in a new tab)
“The trial was designed to assess the safety, durability and tolerability of AXPAXLI as well as to assess preliminary biological activity in subjects by measuring anatomical and functional changes.” (opens the source at this quote in a new tab)

Registry dates

Milestone	Registry record
Study start (actual)	“2021-07-28”
Primary completion (actual)	“2023-02-06”
Study completion (actual)	“2023-12-18”
Last update posted	“2024-01-26”

Registry sites

Site location
“Bakersfield, California, United States, 93309”
“Oxnard, California, United States, 93036”
“Altamonte Springs, Florida, United States, 32701”
“St. Petersburg, Florida, United States, 33711”
“Reno, Nevada, United States, 89502”
“The Woodlands, Texas, United States, 77384”

Number of sites and participants

“The clinical trial enrolled a total of 21 subjects at six clinical sites in the United States, who were randomized 3:1 to an arm receiving a single OTX-TKI implant, with a 2 mg aflibercept injection four weeks after implant injection, and an arm receiving aflibercept injections every 8 weeks.” (opens the source at this quote in a new tab)

Interim and final data cutoff dates

Analysis	Data cutoff
7-month interim analysis	“Interim review: data cut off August 24, 2022”

Analysis	Data cutoff
10-month interim analysis	“Interim review: data cut off December 12, 2022”

Analysis	Data cutoff
12-month analysis	“Data cut off April 14, 2023”

Registered design

“A Prospective Multicenter, Double-Masked, Randomized, Parallel-Group, Study to Evaluate the Safety, Tolerability, and Efficacy of OTX-TKI (Axitinib Implant) for Intravitreal Use in Subjects With Neovascular Age-Related Macular Degeneration (nAMD)” (opens the source at this quote in a new tab)

Field	Registry record
Allocation	“Randomized”
Interventional model	“Parallel Assignment”
Interventional model description	“3:1”
Masking	“Triple (ParticipantCare ProviderInvestigator)”

Company-described design and regulatory pathway

“We have conducted a prospective, multi-center, randomized, controlled Phase 1 clinical trial in the United States to evaluate a single 600 µg dose of AXPAXLI with an anti-VEGF injection in comparison with a 2 mg dose of aflibercept. This trial was initiated under an exploratory investigational new drug, or eIND, application, and subsequently transitioned to a traditional investigational new drug, or IND, application.” (opens the source at this quote in a new tab)

Sham injections to maintain masking

“Sham injection was given at Week 0 in the Aflibercept Arm and at Weeks 12, 20, 28, 36 and 44 in the OTX-TKI Arm (not shown).” (opens the source at this quote in a new tab)

Rescue anti-VEGF injection criteria

“Loss of ≥10 letters from best previous BCVA with current BCVA worse than baseline, or” (opens the source at this quote in a new tab)
“Evidence of ≥75μm CSFT increase from previous best value and ≥5 letters loss from best previous BCVA, or” (opens the source at this quote in a new tab)
“New macular hemorrhage” (opens the source at this quote in a new tab)

Follow-up beyond Week 52

“OTX-TKI subjects are followed past Week 52” (opens the source at this quote in a new tab)

Registered inclusion criteria

“Have a diagnosis, within 3 years of screening, of previously treated subfoveal neovascularization (SFNV) secondary to nAMD with leakage involving the fovea, previously treated with documented evidence of an initially favorable clinical response to anti-VEGF therapy (i.e. aflibercept, ranibizumab, brolucizumab, or bevacizumab).” (opens the source at this quote in a new tab)
“The macular appearance on OCT is considered to be free of excess intraretinal and/or subretinal fluid as judged by the investigator.” (opens the source at this quote in a new tab)
“Must have received at least 3 anti-VEGF injections in the past year.” (opens the source at this quote in a new tab)
“Have received the most recent anti-VEGF injection within the past 1-4 weeks prior to screening visit.” (opens the source at this quote in a new tab)
“BCVA ETDRS score between 24 and 83 letters (~20/25 to ~20/320 Snellen equivalent)” (opens the source at this quote in a new tab)

Registered exclusion criteria

“Have evidence of a scar, fibrosis or atrophy of >50% of the total lesion in the study eye” (opens the source at this quote in a new tab)
“Have presence of a disease other than choroidal neovascular membrane (CNVM) due to AMD in the study eye that could affect vision or safety assessments” (opens the source at this quote in a new tab)
“Have monocular vision (fellow eye Snellen BCVA is 20/200 or worse” (opens the source at this quote in a new tab)

Age

Field	Registry record
Ages eligible for study	“50 Years and older”

Population compared with the Australian phase 1 trial

“The population we studied in this U.S.-based clinical trial was different than the population we studied in our Phase 1 clinical trial of AXPAXLI in Australia.” (opens the source at this quote in a new tab)

Axitinib implant 600 µg with aflibercept at Week 4 compared with aflibercept every 8 weeks

“The U.S.-based Phase 1 clinical trial is a prospective, multi-center, randomized, controlled study in subjects previously treated with anti-VEGF therapy that is evaluating a 600 μg dose of OTX-TKI in a single implant, with a 2 mg aflibercept injection four weeks after the implant, compared to 2 mg aflibercept injections administered every 8 weeks.” (opens the source at this quote in a new tab)

Registered interventions

Arm	Registered intervention description
OTX-TKI	“OTX-TKI is one dose so subsequent visits will be sham to maintain the mask”
Aflibercept	“Aflibercept administered every 8 weeks”

Implant characteristics and administration

“Single implant” (opens the source at this quote in a new tab)
“Administered by a 25G needle” (opens the source at this quote in a new tab)
“Target release for 9-12 months” (opens the source at this quote in a new tab)
“Completely bioresorbable” (opens the source at this quote in a new tab)

First-generation formulation differs from the phase 3 formulation

“We are currently conducting the SOL-1, SOL-R and HELIOS-3 trials, and we plan to conduct the SOL-X trial and, if needed, the HELIOS-2 trial with a 450 µg axitinib dose of AXPAXLI, or AXPAXLI 450 µg, which is a different formulation than we used in either of the two Phase 1 trials of AXPAXLI that we have completed for the treatment of wet AMD. This optimized configuration provides for an increased daily release of the drug and improved synchronization of axitinib drug release with hydrogel bioresorption.” (opens the source at this quote in a new tab)

Registered primary outcome measure

Field	Registry record
Outcome measure	“Safety and Tolerability”
Description	“Incidence and severity of treatment emergent adverse events”
Time frame	“Through study completion, an average of 1 year”

Registered secondary outcome measures

Outcome measure	Registered description
BCVA changes	“BCVA Changes from Baseline”
Central subfield thickness changes	“Central subfield thickness changes from baseline”
Rescue therapy	“Proportion of subjects receiving rescue therapy”
Absence of fluid	“Proportion of subjects with absence of foveal fluid”
Number of injections	“Number of injections from baseline”

Measures of biological activity

“The trial is designed to assess the safety, durability and tolerability of OTX-TKI, and to assess biological activity in subjects by measuring best corrected visual acuity (BCVA) and central subfield thickness (CSFT) of the retina.” (opens the source at this quote in a new tab)

Definition of reduction in treatment burden

“Overall, a 92% reduction in treatment burden (average percent decrease in injections over the period compared to a standard monthly injection regimen) was observed in AXPAXLI treated subjects for up to 10 months.” (opens the source at this quote in a new tab)

“Reduction in treatment burden calculation includes all rescue injections” (opens the source at this quote in a new tab)

Registry enrollment

Field	Registry record
Enrollment (actual)	“21”

Participants by arm and analysis

“The trial enrolled a total of 21 subjects at six clinical sites, comprising two arms consisting of subjects previously treated with, and who were responsive to, standard of care anti-VEGF therapy: a 16-subject arm receiving AXPAXLI in combination with a single anti-VEGF injection at month one and a five-subject arm receiving on-label aflibercept at eight-week intervals.” (opens the source at this quote in a new tab)
“Since this subject was not treated according to protocol, the subject was excluded from the analysis of biological activity, which comprised 15 out of the 16 subjects in the AXPAXLI arm and all five subjects in the aflibercept arm, but the subject was included in the safety analysis which comprised all 16 subjects in the AXPAXLI arm and all five subjects in the aflibercept arm.” (opens the source at this quote in a new tab)

Participants analyzed after censoring rescued participants

“Sample size for OTX-TKI (censoring rescued subjects): n=15 at Baseline and Weeks 4 and 12; n=14 at Week 8 (missed visit) and Weeks 16 and 20; n=12 at Week 24 and n=11 at Weeks 28, 32, 36 and 40; n=10 at Week 44; n=9 at Weeks 48 and 52” (opens the source at this quote in a new tab)

Exclusion of one participant from the efficacy analysis

“There was one subject randomized to the AXPAXLI arm who was inadvertently given aflibercept instead of sham injections at the subject’s month three and month five visits.” (opens the source at this quote in a new tab)

Per protocol analysis and rescue-free rate calculation

“Data cut off April 14, 2023; per protocol analysis” (opens the source at this quote in a new tab)
“Rescue-free rate calculations: If subjects received rescue anti-VEGF therapy at a study visit, those were reflected to count at the following study visit in the graph above” (opens the source at this quote in a new tab)
“Percentages presented in the graph above represent rescue-free rates up to each study visit, except for the 33% at Week 52 which includes rescue injections given at the Week 52 study visit” (opens the source at this quote in a new tab)

Statistical testing

No evidence found.

No dropouts through the 12-month data cutoff

“There were no retinal detachment, retinal vasculitis, or implant migration into the anterior chamber adverse events observed in the OTX-TKI arm, and no subjects had dropped out of either arm as of the data cutoff.” (opens the source at this quote in a new tab)

Trial completion

“All enrolled subjects have completed this Phase 1 clinical trial.” (opens the source at this quote in a new tab)

Missed visits

“n=14 in OTX-TKI arm at Weeks 8, 28, 40 and 48 due to missed visits” (opens the source at this quote in a new tab)

Safety population, data cutoff April 14, 2023

Characteristic	Axitinib implant 600 µg (N=16)	Aflibercept 2 mg every 8 weeks (N=5)
Mean (SD) age, years	“76 (8)”	“84 (8)”
Male, n (%)	“8 (50)”	“3 (60)”
Female, n (%)	“8 (50)”	“2 (40)”
Mean (SD) months since wet AMD diagnosis	“18 (12)”	“18 (12)”
Mean (SD) number of anti-VEGF injections within 12 months prior to baseline (annualized)	“8 (3)”	“8 (4)”
Mean (SD) BCVA, ETDRS letters	“70.9 (17.7)”	“73.8 (9.0)”
Mean (SD) CSFT, µm	“273.8 (43.0)”	“240.6 (29.6)”

Efficacy population baseline BCVA and CSFT

“Mean baseline CSFT” (opens the source at this quote in a new tab)
“OTX-TKI: 269.2 (40.3) μm” (opens the source at this quote in a new tab)
“Aflibercept Q8W: 240.6 (29.6) μm” (opens the source at this quote in a new tab)
“Mean baseline BCVA” (opens the source at this quote in a new tab)
“OTX-TKI: 73.7 (14.4) letters” (opens the source at this quote in a new tab)
“Aflibercept Q8W: 73.8 (9.0) letters” (opens the source at this quote in a new tab)

Week 52 mean change in BCVA and CSFT

Outcome, mean (SD) change from baseline to Week 52	Axitinib implant 600 µg (n=15)	Axitinib implant 600 µg, censoring rescued participants	Aflibercept 2 mg every 8 weeks (n=5)
BCVA, letters	“OTX-TKI: -1.0 (6.0) letters”	“OTX-TKI: +0.6 (2.6) letters”	“Aflibercept 2mg Q8W: +2.0 (7.2)”
CSFT, µm	“OTX-TKI: +20.2 (41.6) μm”	“OTX-TKI: +17.2 (47.6) μm”	“Aflibercept 2mg Q8W: -2.2 (8.5)”

Rescue-free participants in the axitinib implant arm up to each visit (n=15)

Visit	Rescue-free, %	Rescue-free, n/N
Week 8	“100%”	“15/15”
Week 12	“100%”	“15/15”
Week 16	“93%”	“14/15”
Week 20	“93%”	“14/15”
Week 24	“80%”	“12/15”
Week 28	“73%”	“11/15”
Week 32	“73%”	“11/15”
Week 36	“73%”	“11/15”
Week 40	“73%”	“11/15”
Week 44	“67%”	“10/15”
Week 48	“67%”	“10/15”
Week 52	“60%”	“9/15”

Rescue-free rate including rescue injections given at the Week 52 visit

“33% inclusive of Week 52” (opens the source at this quote in a new tab)
“Percentages presented in the graph above represent rescue-free rates up to each study visit, except for the 33% at Week 52, which includes rescue injections given at the Week 52 study visit.” (opens the source at this quote in a new tab)

Month 12 rescue and treatment burden reduction

“60% of OTX-TKI subjects were rescue-free up to Month 12. At the Month 12 visit, an additional four of the subjects were rescued. Overall, an 89% reduction in treatment burden was observed in OTX-TKI treated subjects at 12 months.” (opens the source at this quote in a new tab)
“Approximately 73% of patients either required no or only one supplemental anti-VEGF injection through Month 12, which is clinically meaningful and highlights the possibility of OTX-TKI being widely adopted in the management of wet AMD.” (opens the source at this quote in a new tab)

No rescue injections meeting protocol criteria before 6 months

“100% Rescue Free Per Protocol up to 6 months1” (opens the source at this quote in a new tab)

Injections compared with the year before baseline and with aflibercept

“There were fewer injections over 52 weeks in subjects with AXPAXLI compared with the annualized number of anti-VEGF injections in 52 weeks prior to baseline. Furthermore, there were fewer injections over 52 weeks received in subjects from AXPAXLI treatment compared to those received in aflibercept 2 mg treatment arm.” (opens the source at this quote in a new tab)

Month 10 interim analysis

Outcome, mean (SD) change from baseline to Month 10	Axitinib implant 600 µg	Axitinib implant 600 µg, censoring rescued participants	Aflibercept 2 mg every 8 weeks
BCVA, letters	“OTX-TKI: -0.3 (5.1) letters”	“OTX-TKI: -0.1 (5.3) letters”	“Aflibercept Q8W: -0.8 (2.8) letters”
CSFT, µm	“OTX-TKI: -1.3 (23.7) μm”	“OTX-TKI: -2.1 (26.9) μm”	“Aflibercept Q8W: -4.5 (4.4) μm”

“Treatment Reduction” (opens the source at this quote in a new tab)
“Up to 10 Months: 92%” (opens the source at this quote in a new tab)

“92% reduction in anti-VEGF treatment burden in OTX-TKI patients up to 10 months” (opens the source at this quote in a new tab)

Rescues up to Month 10 initiated at investigator discretion

“Four subjects were rescued in the AXPAXLI arm up to Month 10. One subject, the subject who experienced endophthalmitis, was rescued twice. None of these rescues met the pre-established rescue criteria set forth in the clinical trial protocol and were instead initiated at investigator discretion. One additional subject, who met the established rescue criteria at such subject’s Month 10 visit, was rescued at the end of Month 10.” (opens the source at this quote in a new tab)

Month 7 interim analysis

“Mean change in CSFT from baseline to Month 7:” (opens the source at this quote in a new tab)
“OTX-TKI: +9.2 (38.6) μm” (opens the source at this quote in a new tab)
“Aflibercept: +0.4 (9.1) μm” (opens the source at this quote in a new tab)
“Mean change in BCVA from baseline to Month 7:” (opens the source at this quote in a new tab)
“OTX-TKI: -1.3 (5.2) letters” (opens the source at this quote in a new tab)
“Aflibercept: -1.0 (5.3) letters” (opens the source at this quote in a new tab)
“80% of subjects were rescue-free up to 6 months and 73% of subjects were rescue-free up to 7 months” (opens the source at this quote in a new tab)

Hydrogel bioresorption timing: about 9 months (10-month analysis)

“Interim data suggests OTX-TKI 0.6mg hydrogel implant bioresorbs at an average of ~9 months” (opens the source at this quote in a new tab)

Hydrogel bioresorption timing: about 8 to 9 months (12-month analysis)

“We are encouraged by the 12-month data as the performance of the OTX-TKI drug product continued to demonstrate that the implant bioresorbs at an average of about eight to nine months with axitinib remaining longer in the eye, potentially providing a window to re-dose patients before disease reactivation starts” (opens the source at this quote in a new tab)

Variability in CSFT over 52 weeks

CSFT standard deviation quartile	Brolucizumab phase 3 trials HAWK and HARRIER (N=1752), Week 12 to Week 96	Axitinib implant (N=15), baseline to Week 52
Q1	“<8”	“<9”
Q2	“8-18”	“9-17”
Q3	“18-39”	“17-33”
Q4	“>39”	“>33”

Adverse events in the study eye at 12 months (data cutoff April 14, 2023)

Event, n (%)	Axitinib implant 600 µg (N=16)	Aflibercept 2 mg every 8 weeks (N=5)
Elevated IOP	“2 (12.5)”	“1 (20.0)”
Retinal detachment	“0”	“0”
Retinal vasculitis	“0”	“0”
Implant migration into the anterior chamber	“0”	“N/A”
Acute endophthalmitis	“1 (6.25)”	“0”
Ocular AEs	“16 (100.0)”	“3 (60.0)”
Mild	“14 (87.5)”	“2 (40.0)”
Moderate	“2 (12.5)”	“1 (20.0)”
Severe	“0”	“0”
SAEs	“1 (6.25)”	“0”

Serious adverse event percentage reported as 12.5% (June 2023 presentation)

“Serious AEs 1 (12.5)* 0” (opens the source at this quote in a new tab)

Endophthalmitis after protocol-mandated aflibercept injection

“aModerate and serious ocular AE in OTX-TKI arm was acute endophthalmitis 6 days after mandated aflibercept injection at Month 1.” (opens the source at this quote in a new tab)
“Injection procedure related, unrelated to study drug” (opens the source at this quote in a new tab)
“Resolved after IVT antibiotic injection, with vision returning to baseline” (opens the source at this quote in a new tab)

Moderate events other than endophthalmitis

“Acute endophthalmitis SAE (moderate and resolved) and worsening of cataract (moderate) in OTX-TKI arm” (opens the source at this quote in a new tab)
“Elevated IOP in aflibercept arm (moderate and resolved)” (opens the source at this quote in a new tab)

Elevated intraocular pressure: none in the axitinib implant arm at the 10-month cutoff

“There were no instances of elevated intraocular pressure, or IOP, retinal detachment, retinal vasculitis, or hydrogel implant migration into the anterior chamber observed in the AXPAXLI arm, and no subjects had dropped out of either arm as of the data cutoff.” (opens the source at this quote in a new tab)

“Elevated IOP 0 1” (opens the source at this quote in a new tab)
“1Interim review: data cut off December 12, 2022: includes n=4 subjects in the OTX-TKI arm past Month 12” (opens the source at this quote in a new tab)

Drug-related serious adverse events

“As of the data cutoff of April 14, 2023, there were no drug-related ocular or systemic serious adverse events (SAEs) observed in the OTX-TKI arm.” (opens the source at this quote in a new tab)

Systemic pharmacokinetics

No evidence found.

Summary

OTX-TKI-2020-101 randomized 21 participants (16 axitinib implant, 5 aflibercept), and efficacy analyses included 15 implant participants after one participant received aflibercept instead of sham injections at Months 3 and 5; no statistical comparisons, peer-reviewed publication, or registry results were identified. All implant participants received protocol-mandated aflibercept at Month 1, so outcomes reflect combination exposure rather than implant monotherapy, and the population was limited to previously treated, anti-VEGF-responsive eyes without excess fluid. The trial used a first-generation 600 µg implant, whereas phase 3 trials use a different 450 µg formulation. Sources disagree on elevated IOP in the implant arm: none at the December 12, 2022 cutoff (10-K and 10-month presentation) and 2 of 16 participants (12.5%) at the April 14, 2023 cutoff; the serious adverse event percentage for the single endophthalmitis event is reported as 12.5% in the June 2023 presentation and 6.25% in the October 2024 presentation. Reported bioresorption time was about 9 months at the 10-month analysis and about 8 to 9 months at the 12-month analysis. No systemic pharmacokinetic data were reported for this trial.

Independent review notes a waning implant effect near week 52 and protocol aflibercept exposure

“By week 48, 67% of AXPAXLI-treated patients remained rescue-free, but this declined to 33% by week 52, suggesting a waning therapeutic effect near the end of the implant’s duration of action.” (opens the source at this quote in a new tab)
“In the OTX-TKI arm, patients received 0.6 mg OTX-TKI at week zero followed by aflibercept 2 mg at week 4. Patients then received sham injections every 8 weeks through week 52.” (opens the source at this quote in a new tab)