X82-OPH-102

24 evidence topics · 4 sources

Objective

Primary objective

“To undertake safety testing of oral X-82 administered for the treatment of neovascular AMD.” (opens the source at this quote in a new tab)

Location and study date

Sites and study period

“Subjects with wet age related macular degeneration were enrolled at 5 US retinal clinics between November 2012 and March 2015” (opens the source at this quote in a new tab)

Study design

Open-label dose escalation

“Phase 1, open-label, uncontrolled, dose-escalation study at 5 US retinal clinics between November 2012 and March 2015” (opens the source at this quote in a new tab)

Dose escalation rules, dose-limiting toxicity definition, and maximum tolerated dose

“The dose escalated from one level to the next in the absence of any DLT.” (opens the source at this quote in a new tab)
“Dose-limiting toxicity was defined as a drug-related safety event during the first 2 weeks of treatment that was severe enough to require removal of the participant from the study.” (opens the source at this quote in a new tab)
“The maximum tolerated dose was the maximum dose at which no DLT occurred in a group of 3 participants or no more than 1 DLT in a group of 6.” (opens the source at this quote in a new tab)
“Participants attended for screening, day 14, and then monthly for 7 months (210 days).” (opens the source at this quote in a new tab)

Eligibility criteria

Key inclusion criteria

“No previous treatment with anti-VEGF therapy or prior anti-VEGF therapy with evidence of response to treatment and the need for additional treatment.” (opens the source at this quote in a new tab)
“Early Treatment Diabetic Retinopathy Study (ETDRS) BCVA 20/32 to 20/320 in the study eye(s).” (opens the source at this quote in a new tab)

Treatment

Oral X-82 dose cohorts

“Participants received oral X-82 for 24 weeks at 50 mg alternate days (n = 3), 50 mg daily (n = 8), 100 mg alternate days (n = 4), 100 mg daily (n = 10), 200 mg daily (n = 7), and 300 mg daily (n = 3), with intravitreous anti-VEGF therapy using predefined retreatment criteria.” (opens the source at this quote in a new tab)

Criteria for anti-VEGF rescue therapy and choice of agent

“Rescue anti-VEGF therapy was permitted if predefined criteria were met, including any increase in macular fluid or thickness on SD-OCT compared to baseline, new or increased SRF or IRF, enlargement or new PED, or new or worsening macular hemorrhage.” (opens the source at this quote in a new tab)
“Rescue agents were matched to each patient’s prior treatment regimen.” (opens the source at this quote in a new tab)

Study outcomes

Rationale for using adverse events as the primary endpoint

Main outcome measures

“The main outcome was adverse events. Other outcomes included visual acuity, central subfield retinal thickness, and number of anti-VEGF injections.” (opens the source at this quote in a new tab)

Statistical analysis description

Number of participants (Planned and analyzed)

Enrolled and completing participants

“Thirty-five participants with neovascular age-related macular degeneration, 7 of whom were treatment naive.” (opens the source at this quote in a new tab)
“Of 25 participants (71%) who completed the 24 weeks of X-82 treatment, all except 1 maintained or improved their visual acuity (mean [SD], +3.8 [9.6] letters).” (opens the source at this quote in a new tab)

Description of analysis sets

Efficacy analysis restricted to completers

“The mean and standard deviation was calculated for all subjects who completed 6 months of treatment with oral X82” (opens the source at this quote in a new tab)

Statistical approach and efficacy population

“No formal hypothesis testing was performed.” (opens the source at this quote in a new tab)
“The efficacy population comprised all those who completed the course of X-82 treatment.” (opens the source at this quote in a new tab)

Results

Participant disposition

Withdrawals

“Ten participants withdrew consent or discontinued prematurely, 6 owing to adverse events attributed to X-82 including leg cramps (n = 2), elevated alanine aminotransferase (n = 2), diarrhea (n = 1), and nausea/anorexia (n = 1).” (opens the source at this quote in a new tab)

Completion at 3 and 6 months and discontinuations by dose group

“Twenty-eight participants completed 3 months, and 25 completed 6 months.” (opens the source at this quote in a new tab)
“Of 35 participants, 25 completed 24 weeks of treatment. Six discontinued X-82 owing to AEs potentially related to X-82 (2 in the 50 mg daily group, 1 each in the 100 mg daily and 200 mg groups, and 2 in the 300 mg group). Four discontinued owing to unrelated events” (opens the source at this quote in a new tab)

Baseline characteristics

Demographics

“Of the 35 participants, the mean age was 76.8 years, 16 were men and 19 were women, and 33 were white and 2 were nonwhite.” (opens the source at this quote in a new tab)

Efficacy results

Visual acuity, retinal thickness, and anti-VEGF injections among completers

“Fifteen participants (60%) required no anti-VEGF injections (mean, 0.68).” (opens the source at this quote in a new tab)
“Mean [SD] central subfield thickness reduced by −50 [97] μm, with 8 participants (all receiving at least 100 mg daily) demonstrating sustained reductions despite no anti-VEGF injections.” (opens the source at this quote in a new tab)

Anti-VEGF rescue injections among completers and pre-enrollment injection rate

“The mean number of anti-VEGF injections in the 25 participants who completed 24 weeks of treatment was 0.68 (median, 0; range, 0-4; interquartile range, 0-1), with 15 (60%) not requiring any anti-VEGF rescue injections.” (opens the source at this quote in a new tab)
“The mean time to the first rescue injection was 130 days in the 10 participants who completed the study and required an injection.” (opens the source at this quote in a new tab)
“None of those assigned to 300 mg daily required intravitreous injections while receiving X-82.” (opens the source at this quote in a new tab)
“Previously treated participants who completed 24 weeks of X-82 treatment had a mean (SD) of 9.0 (4.1) injections yearly prior to enrollment.” (opens the source at this quote in a new tab)

Visual acuity change across all participants and by dosing frequency

“Mean BCVA change across all 35 patients was +3.5 (9.7) letters.” (opens the source at this quote in a new tab)
“A gain of +4.3 (9.2) letters was seen in the 28 patients who were dosed at least daily.” (opens the source at this quote in a new tab)
“In 3 patients (8.6%) dosed with 100 mg on alternate days, 200 mg daily, and 300 mg daily, an at least 5-letter worsening was seen.” (opens the source at this quote in a new tab)

Central subfield thickness response at higher doses and fellow eye outcomes

“Five of 7 participants receiving 200 mg had a reduction in thickness, as did 2 of 3 receiving 300 mg.” (opens the source at this quote in a new tab)
“No participants developed new neovascular AMD in the fellow eye, but 1 (receiving 50 mg daily) developed new exudation from a previously treated fellow eye CNV.” (opens the source at this quote in a new tab)

Health-related quality of life and patient-reported outcomes

No evidence found.

Safety results

Adverse events attributed to oral X-82

“The most common adverse events attributed to X-82 were diarrhea (n = 6), nausea (n = 5), fatigue (n = 5), and transaminase elevation (n = 4). A dose relationship to the transaminase elevations was not identified; all normalized when X-82 was discontinued.” (opens the source at this quote in a new tab)
“X-82 can be associated with reversible, elevated liver enzymes; hence, liver function testing is needed to identify those unsuited to treatment.” (opens the source at this quote in a new tab)

Registry adverse event totals

Category	All participants
Serious adverse events	“3/35 (8.57%)”
Other adverse events	“28/35 (80.00%)”
Diarrhoea	“5/35 (14.29%)”

Ocular adverse events, severe events, and serious adverse events

“There were 4 ocular AEs in 4 of 35 participants (11.4%)” (opens the source at this quote in a new tab)
“Three AEs (8.6%) were considered severe: 1 case of multiple myeloma, 1 of pulmonary hypertension, and 1 with an isolated, 5-fold increase in serum transaminase, which was reversible and not associated with other abnormalities (hence, not considered an SAE).” (opens the source at this quote in a new tab)
“Of 94 systemic AEs, 32 were considered related to X-82” (opens the source at this quote in a new tab)

Incidence of liver enzyme elevation and gastrointestinal symptoms

“Liver enzyme elevations were reported as AEs 10 times across 5 participants.” (opens the source at this quote in a new tab)
“The main downside of treatment was elevated liver enzymes and gastrointestinal symptoms, which occurred in 11% and 14% of participants, respectively.” (opens the source at this quote in a new tab)
“Of 35 participants, 6 (17%) did not tolerate X-82, and an additional 4 failed to complete the study.” (opens the source at this quote in a new tab)

Study limitations

Summary

X82-OPH-102 evaluated oral vorolanib (X-82), not the intravitreal insert, in 35 participants across 6 dose cohorts of 3 to 10 participants, without a control arm or masking. Efficacy outcomes were reported only for the 25 participants (71%) who completed 24 weeks, and 6 participants (17%) discontinued because of adverse events attributed to X-82, so the efficacy estimates are subject to attrition bias. Its relevance to this report is the systemic adverse event profile of vorolanib at oral exposures, including transaminase elevations. The study was funded by Tyrogenex, and 3 authors were Tyrogenex employees.

Author-stated limitations

“The main weaknesses, inherent to most open-label phase 1 studies, are a small sample size and lack of both masking and a control group.” (opens the source at this quote in a new tab)
“This study cannot determine the level of patient compliance with X-82 in a clinical setting.” (opens the source at this quote in a new tab)
“Because 80% of the participants were already receiving anti-VEGF therapy at enrollment, this may reduce the potential for clinical improvement.” (opens the source at this quote in a new tab)