Registered study summary

“To evaluate the safety, tolerability and efficacy of OTX-TKI for intravitreal use, in subjects who have neovascular age-related macular degeneration (AMD).” (opens the source at this quote in a new tab)

Research question and objectives

“Research Question: Does axitinib (tyrosine kinase inhibitor) have biological activity in wet AMD subjects with retinal fluid when administered intravitreally?” (opens the source at this quote in a new tab)

“This Phase 1 clinical trial was designed to evaluate the safety, durability and tolerability of AXPAXLI.” (opens the source at this quote in a new tab)
“In this trial, we evaluated whether AXPAXLI can reduce existing fluid levels.” (opens the source at this quote in a new tab)

Registry dates

Milestone	Registry record
Study start (actual)	“2019-02-18”
Primary completion (actual)	“2024-01-10”
Study completion (actual)	“2024-01-10”
Last update posted	“2024-07-10”

Regulatory submission in Australia

“Our Phase 1 clinical trial of AXPAXLI in Australia was submitted to the Therapeutic Goods Administration, Australia’s regulatory authority for therapeutic goods, in July 2018 and was being conducted at multiple sites in Australia.” (opens the source at this quote in a new tab)

Number of sites: six in the registry

“This study has 6 locations” (opens the source at this quote in a new tab)

Number of sites: five in the 2021 presentation

“5 sites in Australia” (opens the source at this quote in a new tab)

Interim data cutoff dates

Presentation	Data cutoff
ARVO 2021	“Data cut on April 12th, 2021”

Presentation	Data cutoff
AAO 2021	“Data cut off October 15, 2021”

Presentation	Data cutoff
Angiogenesis, Exudation, and Degeneration 2022	“Data cut off January 11, 2022”

Presentation	Data cutoff
AAO 2022	“Data cut off August 5, 2022”

Registered design

“A Phase 1 Open-Label, Dose Escalation Study of OTX-TKI for Intravitreal Use in Subjects With Neovascular Age-Related Macular Degeneration (AMD)” (opens the source at this quote in a new tab)

Field	Registry record
Allocation	“Randomized”
Interventional model	“Sequential Assignment”
Masking	“None (Open Label)”

Company-described design

“We have conducted an open-label, multi-center, proof-of-concept, dose-escalation Phase 1 clinical trial of AXPAXLI for the treatment of patients with wet AMD.” (opens the source at this quote in a new tab)

Dose cohorts, data and safety monitoring committee review, and follow-up

“Cohort 2; 400 μg” (opens the source at this quote in a new tab)
“(2 x 200μg implants); N=7” (opens the source at this quote in a new tab)
“Cohort 1; 200 μg” (opens the source at this quote in a new tab)
“(1 x 200μg implant); N=6” (opens the source at this quote in a new tab)
“Cohort 3a; 600 μg” (opens the source at this quote in a new tab)
“(3 x 200μg implants); N=6” (opens the source at this quote in a new tab)
“Cohort 3b; 400 μg” (opens the source at this quote in a new tab)
“(2 x 200μg implants) + anti-VEGF; N=4” (opens the source at this quote in a new tab)
“Cohort 4a*; 600 μg single implant; N=1” (opens the source at this quote in a new tab)
“Cohort 4b*; 600 μg single implant + anti-VEGF ; N=5” (opens the source at this quote in a new tab)

“Monthly Follow-up to Month 17” (opens the source at this quote in a new tab)

Rescue criteria

“If needed, any subject in any treatment arm may receive rescue therapy (i.e., anti-VEGF) at the investigator’s discretion regardless of meeting rescue criteria” (opens the source at this quote in a new tab)
“The following criteria were used to identify subjects who will likely require rescue therapy: 1) loss of ≥15 letters from best previous BCVA due to AMD, with current BCVA not better than baseline; or 2) loss of ≥10 letters on 2 consecutive visits from best previous BCVA due to AMD, with current BCVA score not better than baseline; or 3) evidence of worsening disease activity manifest by >75 microns CSFT from previous best value” (opens the source at this quote in a new tab)

Registered inclusion criteria

“Are at least 50 years of age” (opens the source at this quote in a new tab)
“Are eligible for standard therapy” (opens the source at this quote in a new tab)
“Have active primary CNVM secondary to AMD, either newly diagnosed or previously treated with documented response to anti-VEGF therapy in the study eye [primary subfoveal CNV secondary to AMD including juxtafoveal lesions that affect the fovea] documented by FA and SD-OCT” (opens the source at this quote in a new tab)

Registered exclusion criteria

“Have previous laser photocoagulation to the center of the fovea in the study eye” (opens the source at this quote in a new tab)
“Have participated in any study involving an investigational drug either in the U.S. or outside the U.S. within the past 30 days” (opens the source at this quote in a new tab)
“Have a presence of a disease other than 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)

Pre-existing retinal fluid required

“Presence of retinal fluid” (opens the source at this quote in a new tab)

“The Phase 1 clinical trial was comprised of four cohorts consisting of subjects with wet AMD and pre-existing intraretinal and/or subretinal fluid” (opens the source at this quote in a new tab)

Dose cohorts

“The Phase 1 clinical trial was comprised of four cohorts consisting of subjects with wet AMD and pre-existing intraretinal and/or subretinal fluid: a lower dose cohort of 200 µg with six subjects; a higher dose cohort of 400 µg with seven subjects; a third cohort with two parallel arms, one arm of four subjects receiving a concomitant anti-VEGF injection with 400 µg of AXPAXLI and the other arm of six subjects receiving a 600 µg of AXPAXLI with no anti-VEGF injection; and a fourth cohort with two parallel arms, one arm of one subject receiving a 600 µg single dose of AXPAXLI and the other arm of five subjects receiving a 600 µg single dose of AXPAXLI with anti-VEGF injection.” (opens the source at this quote in a new tab)

Implant configuration

“Cohorts 1-3 used one to three 0.2 mg (200 μg) implants to achieve different dose levels (0.2, 0.4 and 0.6 mg)” (opens the source at this quote in a new tab)

“OTX-TKI is a dried polyethylene glycol-based hydrogel fiber containing dispersed microcrystals of a small molecule tyrosine kinase inhibitor (TKI).” (opens the source at this quote in a new tab)

Registered anti-VEGF agents for combination cohorts

Field	Registry record
Anti-VEGF description	“Standard of care therapy used to block vascular endothelial growth factor”
Other names	“aflibercept”
Other names	“bevacizumab”
Other names	“ranibizumab”

Formulation compared with phase 3 trials

“We conducted the two Phase 1 trials of AXPAXLI for the treatment of wet AMD with different formulations of axitinib.” (opens the source at this quote in a new tab)

Registered primary outcome measure

Field	Registry record
Outcome measure	“Incidence of treatment emergent adverse events for each subject”
Description	“All adverse events from screening through end of study will be captured”
Time frame	“9 months”

Registered secondary outcome measure: maximum tolerated dose

“A Central Reading Center will evaluate multiple imaging modalities to confirm evidence of biological activity for subjects that have been treated with the OTX-TKI injection. If all subjects tolerate lower dosages, additional subjects will be treated at higher dosages. All data will be evaluated by the DSMC who, in concert with the Medical Monitor, will determine the Maximally Tolerated Dose.” (opens the source at this quote in a new tab)

Biological activity measures

“Biological activity: mean change in central subfield thickness measured by SD-OCT, BCVA, and clinically-significant leakage on FA and/or OCT-A” (opens the source at this quote in a new tab)

“In the Phase 1 clinical trial of AXPAXLI conducted in Australia, we evaluated biological activity by measuring CSFT, using spectral domain optical coherence tomography, or OCT, and following visual acuity over time as measured by BCVA.” (opens the source at this quote in a new tab)

Registry enrollment

Field	Registry record
Enrollment (actual)	“29”

Participants dosed

“29 subjects dosed with OTX-TKI” (opens the source at this quote in a new tab)

Participants in the published interim analyses (cohorts 1 to 3)

“Cohorts 1-3 Subjects” (opens the source at this quote in a new tab)
“(Pooled; N=23)” (opens the source at this quote in a new tab)

Participants remaining in follow-up by cohort (January 2022)

“Cohort 1: n=6 until Month 9; Cohort 2: n=7 until Month 12, n=6 for Month 14, n=5 for Month 16 and 17” (opens the source at this quote in a new tab)
“Cohort 3a: n=6 until Month 11, n=5 for Month 12, n=2 for Month 14, n=1 for Month 16 and 17; Cohort 3b: n=4 until Month 7.5; n=3 for Month 9, n=2 for Month 11 to 14; n=1 for Month 16” (opens the source at this quote in a new tab)

Interim, unmonitored data

“NOTE: Interim review, unmonitored data; Data cut off August 5, 2022” (opens the source at this quote in a new tab)

Rescue counting rule

“If subjects received rescue anti-VEGF therapy at a study visit, they were counted as rescued at the following study visit in the table above.” (opens the source at this quote in a new tab)

Analysis of cohort 4 and final analysis

No evidence found.

Trial completion

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

Discontinuations and reasons

No evidence found.

Cohorts 1 to 3, data cutoff January 11, 2022

Characteristic	Cohort 1, 200 µg (n=6)	Cohort 2, 400 µg (n=7)	Cohort 3a, 600 µg (n=6)	Cohort 3b, 400 µg plus anti-VEGF (n=4)	All participants (n=23)
Age, years, mean (SD)	“75.8 (3.7)”	“74.7 (5.4)”	“77.3 (5.4)”	“78.3 (8.1)”	“76.2 (5.3)”
Male, n (%)	“5 (83.3%)”	“4 (57.1%)”	“5 (83.3%)”	“3 (75.0%)”	“17 (73.9%)”
Female, n (%)	“1 (16.7%)”	“3 (42.9%)”	“1 (16.7%)”	“1 (25.0%)”	“6 (26.1%)”
BCVA, ETDRS letters (Snellen equivalent), mean ± SEM	“48 (20/110) ± 12.0”	“62 (20/63) ± 8.5”	“46 (20/125) ± 6.4”	“47 (20/125) ± 11.8”	“51 (20/100) ± 4.7”
CSFT, µm, mean ± SEM	“680 ± 159”	“450 ± 29”	“521 ± 68”	“435 ± 58”	“526 ± 49”

Treatment history by subgroup

“Baseline CSFT and BCVA ± SEM for treatment naïve subjects was 571 ± 88.7 μm and 46 ± 5.6 letters, respectively. Baseline CSFT and BCVA ± SEM for previously treated subjects was 485 ± 47.6 μm and 57 ± 7.4 letters, respectively.” (opens the source at this quote in a new tab)

“Number of treatment-naïve subjects in each cohort. Cohort 1 (n=2), Cohort 2 (n=2), Cohort 3a (n=5), and Cohort 3b (n=2)” (opens the source at this quote in a new tab)

Month 6 change in CSFT and BCVA (data cutoff August 5, 2022)

Population	Baseline CSFT	Change in CSFT at Month 6	Baseline BCVA	Change in BCVA at Month 6
All participants (n=23)	“526 ± 49 μm”	“-101.3 ± 32.0 μm”	“51 ± 5 letters”	“+1.1 ± 2.0 letters”
Treatment-naive participants (n=11)	“571 ± 89 μm”	“-143.2 ± 45.6 μm”	“46 ± 6 letters”	“+2.6 ± 3.6 letters”

Participants without rescue anti-VEGF injections by cohort (data cutoff January 11, 2022)

Cohort	Month 1	Month 3	Month 6	Month 7.5	Month 9	Month 12
Cohort 1 (200 µg)	“100% (6/6)”	“67% (4/6)”	“50% (3/6)”	“50% (3/6)”	“50% (3/6)”	“NA”
Cohort 2 (400 µg)	“86% (6/7)”	“71% (5/7)”	“57% (4/7)”	“43% (3/7)”	“43% (3/7)”	“29% (2/7)”
Cohort 3a (600 µg)	“100% (6/6)”	“83% (5/6)”	“83% (5/6)”	“50% (3/6)”	“17% (1/6)”	“20% (1/5)*”
Cohort 3b (400 µg plus anti-VEGF)	“100% (4/4)”	“100% (4/4)”	“50% (2/4)”	“50% (2/4)”	“33% (1/3)*”	“0% (0/2)*”
All cohorts (pooled)	“96% (22/23)”	“78% (18/23)”	“61% (14/23)”	“48% (11/23)”	“36% (8/22)*”	“21% (3/14)*”

Earlier rescue-free rates in cohort 3a at Month 6: 66.6% (October 2021)

“Cohort 3a” (opens the source at this quote in a new tab)
“(600 μg)* 83.3 (5/6) 83.3 (5/6) 66.6 (4/6) 66.6 (4/6) 40 (2/5)* 100 (1/1)* 100 (1/1)* TBD” (opens the source at this quote in a new tab)
“OVER 50% OF SUBJECTS DID NOT RECEIVE ANTI-VEGF THERAPY OUT TO 6 MONTHS” (opens the source at this quote in a new tab)

Rescue-free rates at 6 months by cohort (August 2022)

“Cohort 1 50% of subjects rescue-free up to 6 months” (opens the source at this quote in a new tab)
“Cohort 2 57% of subjects rescue-free up to 6 months” (opens the source at this quote in a new tab)
“Cohort 3a 83% of subjects rescue-free up to 6 months” (opens the source at this quote in a new tab)
“Cohort 3b 50% of subjects rescue-free up to 6 months” (opens the source at this quote in a new tab)
“Over ~60% of all subjects did not receive anti-VEGF rescue injections for 6 months” (opens the source at this quote in a new tab)

Median time to first rescue

“After treatment with OTX-TKI, median time to first rescue with anti-VEGF was 7 months” (opens the source at this quote in a new tab)

Duration of activity and early fluid reduction

“Some subjects showed a decrease in intraretinal or subretinal fluid by two months in cohorts 2 (400 µg) and 3a (600 µg). In cohort 3b (400 µg dose plus anti-VEGF induction injection of aflibercept), two subjects showed a decrease in intraretinal or subretinal fluid as early as a week after treatment. We observed extended duration of activity of six months or more for over 60% of subjects across all cohorts and for over 80% of subjects in cohort 3a, in which we administered a 600 μg dose.” (opens the source at this quote in a new tab)

“Approximately 50% of all subjects showed durability of 7.5 months or longer” (opens the source at this quote in a new tab)

Implant biodegradation and movement

“In addition, the AXPAXLI doses in cohort 1 (200 µg single dose) were observed to have biodegraded in all subjects within nine to 10.5 months of injection. It has also been observed in the trial that the hydrogels were able to be adequately monitored and that there was limited to no movement of the hydrogel and no migration into the anterior chamber has occurred.” (opens the source at this quote in a new tab)

Results for cohort 4 (600 µg single implant with or without anti-VEGF)

No evidence found.

Adverse events in the study eye by cohort (data cutoff August 5, 2022)

Event, n	Cohort 1, 200 µg (n=6)	Cohort 2, 400 µg (n=7)	Cohort 3a, 600 µg (n=6)	Cohort 3b, 400 µg plus anti-VEGF (n=4)	Total (n=23)
Vitreous floaters	“0”	“1”	“0”	“2”	“3”
Endophthalmitis	“0”	“0”	“0”	“0”	“0”
Retinal detachment	“0”	“0”	“0”	“0”	“0”
Implant migration into anterior chamber	“0”	“0”	“0”	“0”	“0”
Elevated IOP	“0”	“0”	“0”	“0”	“0”
Ocular inflammation	“0”	“0”	“0”	“1”	“1”
Subconjunctival hemorrhage	“1”	“3”	“5”	“4”	“13”
Eye pain	“0”	“2”	“2”	“0”	“4”
Worsening cataract	“0”	“1”	“2”	“1”	“4”
Pigmented keratic precipitates	“3”	“0”	“0”	“0”	“3”
Dry eye	“1”	“0”	“1”	“1”	“3”

Ocular adverse events by maximum severity (data cutoff August 5, 2022)

“Ocular AEs 4 7 6 3 20” (opens the source at this quote in a new tab)
“Mild 4 4 3 2 13” (opens the source at this quote in a new tab)
“Moderate 0 3 2 1 6” (opens the source at this quote in a new tab)
“Severe 0 0 1a 0 1a” (opens the source at this quote in a new tab)
“Serious AEs 0 0 0 0 0” (opens the source at this quote in a new tab)
“a Severe ocular AE in Cohort 3a was worsening of cataract” (opens the source at this quote in a new tab)

Adverse event counts and serious non-ocular events (data cutoff October 15, 2021)

“Adverse Events (AEs) 14 27 31 13 85” (opens the source at this quote in a new tab)
“Suspected Relationship to Study Product 1 2 3 3 9” (opens the source at this quote in a new tab)
“Suspected Relationship to Injection Procedure 1 5 10 4 20” (opens the source at this quote in a new tab)
“Ocular AEs (Study Eye) 6 15 20 9 50” (opens the source at this quote in a new tab)
“Serious Ocular AEs 0 0 0 0 0” (opens the source at this quote in a new tab)
“Serious Non-ocular AEs† 1 0 1 0 2” (opens the source at this quote in a new tab)
“† Serious non-ocular AEs: atrial fibrillation (Cohort 1) and ureterovesical stone (Cohort 3a)” (opens the source at this quote in a new tab)
“‡ Severe AE: ureterovesical stone” (opens the source at this quote in a new tab)

Uveitis and implant affecting vision (data cutoff October 15, 2021)

“No IOP elevations were reported” (opens the source at this quote in a new tab)
“Uveitis was reported in one subject (Cohort 3b) which resolved with treatment” (opens the source at this quote in a new tab)
“OTX-TKI implant affecting vision 0 1 3 0 4” (opens the source at this quote in a new tab)

Vitreous floaters count in January 2022

“Vitreous floaters 0 1 0 1 2” (opens the source at this quote in a new tab)

Drug-related serious adverse events over 9 months

“In the clinical trial, intravitreal injections of AXPAXLI at 200 μg, 400 μg, and 600 μg, with and without concurrent administration of anti-VEGF, were generally well tolerated. There were no drug-related serious treatment-emergent adverse events reported in any of the AXPAXLI dose cohorts over the 9-month study period.” (opens the source at this quote in a new tab)

Systemic pharmacokinetics: plasma axitinib below the limit of quantification

“Plasma concentrations of axitinib were below the limit of quantification of assay (BLQ) <0.1 ng/ml at all sampled timepoints in all subjects in Cohorts 1, 2, 3a and 3b” (opens the source at this quote in a new tab)

“Plasma levels of the active drug, axitinib, were below the limit of quantification at all doses, indicating that systemic exposure to intravitreal delivery of axitinib by AXPAXLI up to 600 μg was negligible.” (opens the source at this quote in a new tab)

Summary

CLN-0046 was an open-label, uncontrolled, dose-escalation trial; efficacy and safety were presented only as interim, unmonitored analyses of cohorts 1 to 3 (23 of 29 participants), and no results for cohort 4 (6 participants), no final analysis, no peer-reviewed publication, and no registry results were identified. Cohort sizes were 4 to 7 participants, cohorts mixed treatment-naive and previously treated eyes, and rescue anti-VEGF injections could be given at investigator discretion without meeting rescue criteria. The trial used first-generation implants (one to three 200 µg implants in cohorts 1 to 3), which differ from the 450 µg formulation used in phase 3 trials. Reported values changed across data cutoffs: the Month 6 rescue-free rate in cohort 3a was 66.6% (4 of 6) in October 2021 and 83% (5 of 6) in January 2022; the severe adverse event was attributed to a ureterovesical stone in October 2021 and to worsening cataract in the study eye in a 2023 presentation; vitreous floaters totaled 2 in January 2022 and 3 in August 2022. The registry lists 6 sites, whereas a 2021 presentation lists 5. Plasma axitinib was below the limit of quantification (less than 0.1 ng/mL) in cohorts 1 to 3.