Phase 1 dose-escalation study of IBI324, a VEGF-A/Ang-2 bispecific antibody, for the treatment of diabetic macular oedema

Abstract

Objective

To evaluate the safety, tolerability and preliminary efficacy of IBI324, a vascular endothelial growth factor-A/angiopoietin-2 bispecific antibody, in participants with diabetic macular oedema (DME).

Methods and analysis

This multicentre, open-label, phase 1 dose-escalation clinical trial consisted of a single ascending dose (SAD) stage and a multiple ascending dose (MAD) stage. 24 participants with fovea-involving DME were enrolled. SAD participants received a single intravitreal injection (IVT) of 0.5 mg, 2 mg or 4 mg IBI324 and were followed up until Day 42 post injection. In the MAD stage, six participants each received 3 monthly IVTs of 2 mg or 4 mg IBI324 and were followed up until determined as ‘treatment needed’ per prespecified criteria or until 24 weeks after first dose. The primary endpoints were incidence of dose-limiting toxicities (DLTs), adverse events (AEs) and changes in vital signs and laboratory test findings.

Results

No DLT, treatment-related AE, AE of special interest or ocular serious AE was reported. Treatment-emergent adverse events (TEAEs), all mild or moderate in severity, were observed in 4 (33.3%) SAD participants and 11 (91.7%) MAD participants. TEAEs of the study eye included intraocular pressure increased, conjunctival haemorrhage, allergic conjunctivitis, posterior capsular opacification and visual acuity decreased. Mean best-corrected visual acuity increase and mean central subfield thickness decrease from baseline in the study eye were observed in all dose groups, accompanied by intraretinal fluid/subretinal fluid improvements. 16 weeks after the last dose, 7 (58.3%) MAD 2 mg and 6 (50.0%) MAD 4 mg participants remained free of ‘treatment needed’.

Conclusion

IBI324 was well tolerated with evidence of functional and anatomical improvement in patients with DME.

Trial registration number

NCT05489718.

WHAT IS ALREADY KNOWN ON THIS TOPIC

• Anti-vascular endothelial growth factor (VEGF) agents are established as first-line therapy for diabetic macular oedema (DME), although limitations such as frequent intravitreal injections and poor response to the therapy still exist. Bispecific antibodies targeting both VEGF and angiopoietin-2 (Ang-2) pathways may serve as a different treatment option for patients with DME.

WHAT THIS STUDY ADDS

• This study assesses the safety and efficacy of IBI324, a VEGF-A/Ang-2 bispecific antibody, in patients with DME. Results showed that patients were safe and well tolerated. Best-corrected visual acuity increase and retinal thickness decrease were observed in all groups from both single and multiple ascending doses stages. Over 50% of patients in the IBI324 2 mg and 4 mg groups maintained free of ‘treatment needed’ after three loading doses and followed until week 24, indicating a potential dosing interval of 16 weeks.

HOW THIS STUDY MIGHT AFFECT RESEARCH, PRACTICE OR POLICY

• IBI324 demonstrated favourable safety profiles with preliminary efficacy and potential in long dosing interval, suggesting its further development as a promising treatment option for patients with DME.

Introduction

Diabetic macular oedema (DME), characterised by retinal vascular leakage and fluid accumulation, disrupting the macular structure, is a leading cause of avoidable vision impairment and blindness worldwide.¹ Anti-angiogenic therapy, such as intravitreal injection (IVT) of anti-vascular endothelial growth factor (VEGF) drugs, is usually the first-line treatment for centre-involving DME. However, 20–40% patients do not respond to anti-VEGF treatment,^{2 3} and alternative options such as IVT of corticosteroids and laser photocoagulation are associated with significant adverse reactions, such as cataract formation, and less pronounced efficacy.⁴

Faricimab, a novel bispecific antibody inhibiting VEGF-A and angiopoietin-2 (Ang-2), was first approved for DME in 2022.⁵ The synergistic role of Ang-2 and VEGF-A in vascular de-stabilisation has been demonstrated.⁶ In the YOSEMITE and RHINE studies, a total of 1891 adults with fovea-involving DME were randomly assigned to intravitreal faricimab 6 mg every 8 weeks, faricimab 6 mg per personalised treatment intervals or aflibercept 2 mg every 8 weeks. In addition to comparable incidences of ocular adverse events (AEs), both studies showed non-inferiority to aflibercept, with mean best-corrected visual acuity (BCVA) increases ranging from 10.3 to 11.8 Early Treatment Diabetic Retinopathy Study (ETDRS) letters.⁷ Given that faricimab is the only globally marketed VEGF/Ang-2 bispecific antibody and was not approved for treating DME in China until December 2023, the development of novel agents targeting VEGF and Ang-2 to treat DME remains an unmet medical need.

IBI324 is a recombinant bispecific antibody developed by Innovent that targets both VEGF-A and Ang-2. Its C-terminal domain is the Ang-2 binding domain, consisting of a single-domain antibody against Ang-2 independently identified by Innovent. In this study, we report the safety, tolerability and preliminary efficacy results from a phase 1 dose-escalation study of IBI324, a VEGF-A/Ang-2 bispecific antibody composited of single-chain fragment variable targeting VEGF-A and one variable domain of a heavy-chain targeting Ang-2 with potent in vitro inhibition of both targets. IBI324 is markedly smaller (41 kD) compared with faricimab (149 kD) due to the above format. In this multicentre, open-label, phase 1 dose-escalation study, a total of 24 participants with fovea-involving DME were treated with single or multiple IVTs of IBI324 at 0.5 mg, 2 mg or 4 mg per eye. Analyses of incidence of dose-limiting toxicities (DLTs) and AEs, along with functional, anatomical and durability efficacy parameters, are presented.

Methods

This study was approved by institutional review boards at all study sites and complied with the Declaration of Helsinki, Good Clinical Practice and local regulatory requirements. All participants provided written informed consent before participating in the study. The study was registered at ClinicalTrials.gov (NCT05489718).

Study design and treatment

This multicentre, open-label, phase 1 dose-escalation clinical trial enrolled patients with fovea-involving DME. The trial consisted of a single ascending dose (SAD) stage and a multiple ascending dose (MAD) escalation stage (online supplemental figure S1). One eye per participant was designated as the study eye. If both eyes met eligibility criteria, the eye with worse BCVA was designated as the study eye. The SAD stage used a canonical 3+3 design, in which IVT IBI324 at 0.5 mg (50 µL), 2 mg (50 µL) or 4 mg (100 µL) per eye were evaluated. At each dose level (0.5 mg, 2 mg, 4 mg), an initial cohort of three participants was enrolled; the first participant was dosed alone, and the remaining two were treated only after the first completed the DLT observation period. If no DLTs occurred, the dose was escalated to the next level; otherwise, the cohort was expanded by enrolling three additional participants at the same dose. Study visits were scheduled for screening, study treatment and post-treatment follow-up on Days 1, 3, 5, 14, 28 and 42. The DLT period was defined as the first 5 days after IBI324 administration. At each dose level, only after the first participant completed the DLT period were the subsequent participants allowed to receive the study treatment.

In MAD escalation, 3 monthly doses of 2 mg or 4 mg IBI324 per eye were evaluated. Study visits were scheduled for screening, study treatments (Weeks 0, 4 and 8), and post-treatment follow-up at Weeks 12, 16, 20 and 24. At each level, six participants were sequentially enrolled; a minimum of 2 days apart between each enrolment was required for the first three participants of each dose group for safety reasons. Dose escalation would be terminated and the corresponding dose considered as intolerable if ≥2 participants experienced a DLT. The DLT period was defined as the first 33 days since the first dose. During post-treatment follow-up, participants would complete the end-of-study visit if she/he met the criteria of ‘treatment needed’, which were defined as BCVA decrease by ≥5 ETDRS letters accompanied by an increase in central subfield thickness (CST) on optical coherence tomography (OCT) compared with the previous visit, and/or CST increase by >50 µm compared with the previous visit due to DME.

A DLT was defined as any of the following IBI324-related AEs during the DLT period: (1) intraocular inflammation of grade 3 or above, (2) intraocular pressure (IOP) >30 mm Hg for more than 240 min after administration, (3) acute vision loss ≥15 letters not related to intraocular inflammation, (4) vitreous haemorrhage of grade 2 or above, (5) intracranial haemorrhage or other clinically significant non-ocular haemorrhage or (6) an IBI324-related serious adverse event (SAE).

An adverse event of special interest (AESI) included intraocular inflammation of any grade, BCVA decrease ≥30 letters compared with previous visit and lasting >1 hour, IOP ≥30 mm Hg and increase >10 mm Hg compared with before study treatment and lasting for >24 hours, or any AE requiring surgery or other medical interventions to prevent permanent visual loss.

Patient and public involvement

Patients and the public were not involved in the development, design, implementation or dissemination plans of the study.

Participants

Eligible patients of either gender had to be 18–80 years of age with a confirmed diagnosis of fovea-involving DME in the study eye; CST of ≥320 µm on OCT; BCVA of 24–73 (inclusive) ETDRS letters in the study eye; either previous treated or treatment naive. A washout period of no less than 90 days is required for patients previously treated with anti-VEGF therapies, retinal photocoagulation or corticosteroids.

Participants, as determined by the investigator, having ocular disease other than DME (eg, choroidal neovascularisation) that may confound macular assessment, affect central vision or cause irreversible vision loss of the study eye were excluded. Key additional exclusion criteria included presence of proliferative diabetic retinopathy, tractional retinal detachment, preretinal fibrosis, vitreomacular traction, epiretinal membrane involving the fovea or disrupting the macula, iris neovascularisation, aphakia, spherical equivalent ≤−8.00 D, IOP >21 mm Hg, active intraocular or periocular infection or inflammation in the study eye; confounding treatments or procedures prior to baseline, such as anti-VEGF therapy, intraocular or periocular corticosteroid, panretinal or macular laser photocoagulation, any intraocular surgery within 90 days and laser posterior capsulotomy, laser trabeculoplasty or laser iridectomy within 30 days; uncontrolled diabetes or hypertension; glycated haemoglobin >10% within 28 days; and not receiving antidiabetic medication, or receiving antidiabetic medication for less than 90 days prior to IBI324 administration.

Endpoints and assessments

The primary endpoints were number, incidence, severity and correlation with the investigational drug or treatment of all ocular and systemic AEs, changes in vital signs, physical examinations, laboratory tests and electrocardiograph before and after administration in each dose group, and incidence of DLT in each dose group. Definitions of the severity of AEs, serious AEs and relationship between AEs and the investigational drug are included in online supplemental protocol. Secondary endpoints included change in BCVA from baseline, proportion of participants with BCVA increase (≥0, 5, 10 and 15 ETDRS letters) or decrease (≥0 and 5 letters), change in CST on OCT from baseline, proportion of participants without intraretinal fluid (IRF) and/or subretinal fluid (SRF) in the study eye on Days 14, 28 and 42 for SAD participants or at Weeks 12, 20 and 24 for MAD participants, pharmacokinetics and immunogenicity. Time to ‘treatment needed’ was also an endpoint for MAD participants. A safety evaluation committee comprising the principal investigator and sponsor safety/medical representatives determined progression to subsequent dose levels based on safety monitoring, while independent monitors conducted source data verification.

Statistical analyses

No formal sample size calculation was performed. The sample size was determined based on dose escalation decision. Frequency and incidence of DLT events in the DLT analysis set were summarised by dose-escalation type (SAD vs MAD) and dose level. Incidence, relatedness to the IBI324, relatedness to IVT injection and severity of AEs were summarised by dose-escalation type and dose level. Descriptive statistics were used to summarise changes in results of vital sign, physical examination and ECG examinations and laboratory tests. For BCVA and CST parameters, number of participants, mean, SD, median, first and third quartiles, and range were used to analyse continuous variables and frequencies and percentages were used to analyse categorical variables. The Clopper-Pearson method was used to calculate 95% CIs for proportions. All statistical analyses were performed using SAS V.9.4 or higher.

Results

Participant disposition and baseline characteristics

This study was conducted at six study sites in China between 21 July 2021 and 5 June 2023, and at least one participant was enrolled at five of these sites. As illustrated in figure 1, 24 participants were enrolled. For SAD, all but the highest dose-level group (4 mg IBI324 per eye, six participants) enrolled three participants per dose group. Each of the two MAD groups enrolled six participants. All 24 participants received planned IBI324 injections. Eight (8/12) MAD participants (2 mg group: n=3, 4 mg group: n=5) completed the study before Week 24 due to ‘treatment needed’ (online supplemental table S1).

Figure 1. Flow diagram of participants.

Demographics and baseline characteristics are summarised in online supplemental table S2. Mean±SD baseline BCVA were 61.0±5.3, 48.7±14.1 and 56.5±10.6 ETDRS letters for SAD 0.5 mg, 2 mg and 4 mg dose groups and 43.0±14.5 and 61.3±8.0 letters for MAD 2 mg and 4 mg groups, respectively. The mean baseline CST ranged from 511.7 to 550.0 µm. IRF was present in all participants. The majority (58.3%, 14/24) had received anti-VEGF treatment prior to screening, with the highest prevalence in MAD 4 mg (83.3%). Agents included ranibizumab, aflibercept and conbercept across cohorts. The intensity of prior treatment was heterogeneous, ranging from 1 to 14 injections.

Safety analysis

IBI324 was generally well-tolerated. No DLT was reported. Online supplemental table S3 showed all adverse events occurred during the study. Treatment-emergent adverse events (TEAEs) were observed in 4 (33.3%) SAD participants and 11 (91.7%) MAD participants. All TEAEs were mild or moderate in severity. TEAEs in the study eye were reported for 2 (16.7%) SAD and 3 (25.0%) MAD participants. The study-eye TEAEs included IOP increased, conjunctival haemorrhage, allergic conjunctivitis, posterior capsular opacification and visual acuity decreased, each occurring once (table 1). In the one MAD participant who experienced visual acuity decrease, baseline BCVA was 55 letters, which reduced to 41 letters on Day 28 and rose to 60 letters on Day 33, with no treatment administered in the interim. Also, this AE was considered by the treating investigator as not related to IBI324 treatment.

Table 1. Serious adverse events and ocular treatment-emergent adverse events in the study eye.

Adverse event n (%) of participants with events	SAD			MAD
	0.5 mg (n=3)	2 mg (n=3)	4 mg (n=6)	2 mg (n=6)	4 mg (n=6)
Ocular SAE	0	0	0	0	0
Systemic SAE	0	0	0	1 (16.7)*	0
Ocular TEAE in the study eye	1 (33.3)	0	1 (16.7)	1 (16.7)	2 (33.3)
IOP increased	1 (33.3)	0	0	0	0
Conjunctival haemorrhage	0	0	1 (16.7)	0	0
Allergic conjunctivitis	0	0	0	1 (16.7)	0
Posterior capsular opacification	0	0	0	0	1 (16.7)
Vision acuity decreased	0	0	0	0	1 (16.7)

IOP, intraocular pressure; MAD, multiple ascending dose; SAD, single ascending dose; SAE, serious adverse event; TEAE, treatment-emergent adverse event.

No ocular SAE was reported. One participant in the MAD 2 mg group experienced a systemic SAE (preferred term: localised infection). No TEAE was related to study treatment per the investigators. No TEAE requiring dose interruption or discontinuation was reported for MAD participants. No AESI was reported.

Visual and anatomical outcomes

BCVA increase from baseline in the study eye was observed at almost all visits in all dose groups. Individual changes of BCVA from baseline were presented in online supplemental figure S2 and online supplemental table S4. In SAD, mean BCVA was increased at all six study visits since Day 1 post-treatment for all but the 0.5 mg group (figure 2A). Single doses of IBI324 at all dose levels resulted in BCVA gain that generally increased over time and lasted through the remaining visits. Respective mean±SD BCVA change from baseline on Days 14, 28 and 42 were 15.0±6.56, 15.0±6.08 and 15.0±6.08 ETDRS letters for SAD 2 mg, 6.3±6.56, 8.0±6.23 and 8.7±5.92 letters for SAD 4 mg and 3.7±3.06, 5.7±6.66 and 6.7±9.50 letters for SAD 0.5 mg participants. A similar trend of improvement in BCVA was observed during MAD escalation, in which the participants showed an increase from baseline in mean BCVA at all six visits except for MAD 4 mg at Weeks 4 and 24 (figure 2B). The two dose levels resulted in comparable maximal BCVA gain. For MAD 2 mg, mean BCVA gain was evident after the first dose and remained stable for 12 weeks before decreasing. Mean±SD BCVA change from baseline at Weeks 12 (n=6), 20 (n=3) and 24 (n=3) were 6.7±5.43, 4.0±7.81 and 1.0±10.44 letters, respectively. For MAD 4 mg, mean BCVA gain plateaued from Weeks 8 to 20. Mean±SD BCVA change from baseline was 8.2±7.36, 7.0±9.90 and −4.0 letters at Weeks 12 (n=6), 20 (n=2) and 24 (n=1), respectively. On the other hand, the eight MAD participants who completed the study before Week 24 had a mean of 1.0±5.18 letters BCVA change from baseline at the end-of-study (EOS) visit.

Figure 2. Mean BCVA change from baseline over time in (A) single ascending dose and (B) multiple ascending dose participants. Error bars represent SD. BCVA, best-corrected visual acuity; ETDRS, Early Treatment Diabetic Retinopathy Study.

Seven (58.3%) SAD participants gained ≥5 letters on Day 14, 8 (66.7%) on Day 28 and 9 (75.0%) on Day 42, of whom 5 (41.7%), 6 (50.0%) and 6 (50.0%) participants gained ≥10 letters, and 2 (16.7%), 2 (16.7%) and 4 (33.3%) gained ≥15 letters at respective visits (online supplemental figure S3). One SAD 4 mg participant on Day 14, one SAD 0.5 mg participant on Day 28 and one SAD 0.5 mg participant on Day 42 showed BCVA loss of >0 letters from baseline (online supplemental figure S4). No BCVA decrease of ≥5 was observed during SAD escalation. For MAD participants, 7 (58.3%), 2 (16.2%) and 1 (8.3%) gained ≥5 letters during post-treatment follow-up at Weeks 12 (n=12), 20 (n=5) and 24 (n=4), of whom 5 (41.7%; with one gaining ≥15 letters), 2 (16.7%) and 1 (8.3%) BCVA gained ≥10 letters at the respective visits (online supplemental figure S5). One participant (16.7%) from the MAD 4 mg group lost ≥0 letters at Week 12, 1 (16.7%) from the MAD 2 mg at Week 20 and 2 (33.3%) from the MAD 2 mg and 1 (16.7%) from the MAD 4 mg at Week 24. No MAD participant had BCVA loss ≥5 letters during post-treatment follow-up except for one from the MAD 2 mg at Week 24, who lost ≥5 and <10 letters (online supplemental figure S4B). Among those who completed the study early due to ‘treatment needed’, one gained ≥5 letters and one lost ≥10 letters at the EOS visit.

Consistent with anatomical response, changes in CST were consistent with those in the visual outcome. Online supplemental figure S2 and online supplemental table S5 showed individual changes of CST from baseline. CST decrease was evident in all SAD dose groups at all visits except for 0.5 mg on Day 1 (figure 3A). Similar to BCVA improvement, durable CST reduction was seen in both SAD and MAD participants (figure 3). On Days 14, 28 and 42, the mean±SD CST decreases were 123.3±173.07 µm, 167.7±153.26 µm and 181.7±156.51 µm for SAD 0.5 mg, 241.0±247.19 µm, 268.3±215.86 µm and 273.0±211.13 µm for SAD 2 mg, and 205.3±149.93 µm, 232.3±138.86 µm and 257.5±146.27 µm for SAD 4 mg. Among MAD participants, mean±SD CST decreases at Weeks 16, 20 and 24 were 343.0±178.11 µm (n=6), 237.7±192.79 µm (n=3) and 59.0±181.87 µm (n=3) for 2 mg, and 233.8±135.56 µm (n=6), 128.5±98.29 µm (n=2) and −261 µm (n=1) for 4 mg. For the early-completion participants, mean±SD CST decrease was 29.9±201.76 µm at the EOS visit.

Figure 3. Mean CST change from baseline over time in (A) single ascending dose and (B) multiple ascending dose participants. Error bars represent SD. CST, central subfield thickness.

Varying degrees of IRF/SRF improvements were observed at different dose levels (online supplemental figure S6). Although present in all participants at baseline, no one from the SAD 2 mg had IRF nor SRF from Days 14 to 42; neither did any MAD participant at Week 12. The proportions of MAD participants with no IRF and SRF decreased over time at both examined dose levels, with the 2 mg group decreasing at a lower rate. Among early-completion participants, absence of both IRF and SRF was observed in 33.3% (2 mg/eye) and 83.3% (4 mg/eye) participants at the EOS visit.

In terms of time to meeting the predefined criteria of treatment needed, 75% (9/12) and 58.3% (7/12) MAD 2 mg participants remained free of ‘treatment needed’ at 12 weeks (ie, Week 20) and 16 weeks, respectively, after the last dose, and 58.3% (7/12) and 50% (6/12) from MAD 4 mg group, respectively.

Pharmacokinetics

The pharmacokinetic parameters of IBI324 during SAD and MAD stages are summarised in online supplemental table S6. Following repeated intravitreal dosing, C_max, AUC_0–672, AUC_last and AUC_inf increased with dose across the 2–4 mg range. Systemic exposure after intravitreal administration was low.

Discussion

This phase 1 dose-escalation clinical trial evaluated the safety, tolerability and efficacy of IVT IBI324, a bispecific antibody targeting both VEGF-A and Ang-2, in a total of 24 participants with fovea-involving DME with CST ≥320 µm and BCVA of 24–73 (inclusive) ETDRS letters. Occurrences of DLTs and AEs were the primary endpoints. IBI324 was generally well-tolerated at the three dose levels examined (0.5 mg, 2 mg and 4 mg per eye). No DLT, treatment-related adverse event (TRAE) or ocular SAE was reported during either SAD (n=12; all three dose levels) or MAD (n=12; 3 monthly doses at 2 mg or 4 mg) escalation. All TEAEs, whether in the study eye or systemic, were mild or moderate in severity. There were no cases of intraocular inflammation or retinal vasculitis, supporting a favourable ocular safety profile for IBI324.

This study also provided data suggesting durable functional and anatomical outcomes. Improved BCVA and CST in the study eye were evident as early as 1 day after IBI324 administration and lasted for 7 weeks until EOS among SAD participants (figures 2A and 3A), when IRF and SRF were both absent in 75% (9/12) participants (online supplemental figure S6A). In MAD, BCVA and CST responses persisted up to 12 weeks after the last dose (figures 2B and 3B). Absence of IRF and SRF was achieved in all MAD participants at 4 weeks after last dose (online supplemental figure S6B). These results, along with findings from the YOSEMITE and RHINE studies, suggest that targeting both VEGF and Ang-2 pathways can effectively reduce leakage. Patients treated with faricimab showed a higher proportion of IRF absence at week 56 compared with those treated with active comparator, aflibercept.⁷ Blocking the Ang-2 pathway may synergise with VEGF inhibition, potentially enhancing vascular stabilisation. This hypothesis warrants further validation in subsequent clinical trials of IBI324. IBI324 also demonstrated a reduction in CST in both SAD and MAD patients. Caution is warranted in interpreting these improvements due to the small sample size. Additionally, mean baseline CSTs were approximately 550 µm for MAD 2 mg and 530 µm for MAD 4 mg in this study. The notably high baseline CSTs may have contributed to the significant extent of the observed reduction. Taken together, the visual and anatomical improvements in this study suggest preliminary efficacy and support further investigation in larger populations.

Evaluation of time to treatment needed suggested a potential dosing interval of 12 weeks and beyond for IBI324. The phase 2 BOULEVARD trial in patients with DME adopted a similar approach in assessing the durability of treatment effect.⁸ Kaplan-Meier survival probability estimates were calculated from the length of time to meeting the BCVA loss criteria (≥5 letters), the CST increase criteria (≥50 µm) or a more stringent combination of both, which required BCVA and CST to be simultaneously met. In our study, treatment needed was more leniently defined as meeting either one of the BCVA (loss of ≥5 letters) or CST (> 50 µm) criteria. Conversely, a participant would have to have neither condition in order to be considered as having avoided ‘treatment needed’. Among the MAD participants, 75% had a history of anti-VEGF therapy, and the proportions of those without ‘treatment needed’ were 75% (2 mg group) and 58.3% (4 mg) at 12 weeks after last dose and 58.3% (2 mg) and 50% (4 mg) at 16 weeks after. These results suggest that anti-VEGF/anti-Ang-2 bispecific antibodies may hold promising potential for enabling dosing interval of 12 weeks or longer, thereby potentially improving patient adherence. However, this potential requires further investigation and validation.

This study has some limitations. Assessment of antidrug antibodies to IBI324 was not performed in this study due to sample-testing limitations; the immunogenicity of IBI324 will be evaluated in subsequent studies. In addition, the absence of masking and centralised standardisation in efficacy assessments may weaken the robustness of the results; however, it is unlikely to alter the study’s overall conclusions. Masking procedures and independent imaging will be implemented in the further proof-of-concept trials.

Conclusion

In summary, no DLT or TRAE was reported after single or multiple doses of IVT IBI324 across all dose levels in this phase 1 study in patients with DME. No new safety signal was observed compared with agents of similar mechanisms of action. BCVA, CST, IRF/SRF and time to ‘treatment needed’ outcomes suggested durable vision improvement accompanied by anatomical changes. Considering the safety, tolerability and preliminary efficacy of IBI324 for treating fovea-involving DME in this study, further clinical characterisation of this VEGF-A×Ang-2 bispecific antibody is warranted.

Data availability statement

Data are available upon reasonable request.