A Novel Bispecific Fusion Protein Targeting C3b/C4b and VEGF in Patients With nAMD: A Randomized, Open-Label, Phase 1b Study

NCT04370379 | Not specified | Jia H et al. (2023)

Jia H, Li T, Sun J, et al. A Novel Bispecific Fusion Protein Targeting C3b/C4b and VEGF in Patients With nAMD: A Randomized, Open-Label, Phase 1b Study. Am J Ophthalmol, 2023; 248:8–15.

Locations

2 study centers in China

Study Period

May 26, 2020 – February 8, 2021

Study Design

Phase 1b, randomized, open-label, multiple ascending-dose study

Study Population

Characteristic:

Type of AMD:

2 (Wet AMD)

AMD Stage:

3 (Late)

Total Sample Size:

18 patients

Age:

Phase 1b, randomized, open-label, multiple ascending-dose study

Sex (Male) n%:

15 (83.3%)

Experimental Group

Intervention Therapy:

Efdamrofusp alfa (2 mg or 4 mg)

Dose & Frequency:

2 mg or 4 mg intravitreal injections at weeks 0, 4, and 8

Age (Years):

• 2 mg: 66.5 ± 8.7 • 4 mg: 68.7 ± 2.3

Number of Patients:

• 2 mg: 6 • 4 mg: 6

Male N %:

• 2 mg: 6 (100%) • 4 mg: 5 (83.3%)

Patients Followed Up:

12 (all patients completed the study)

Control Group

Intervention Therapy:

Aflibercept 2 mg

Dose & Frequency:

Aflibercept 2 mg intravitreal injections at weeks 0, 4, 8, and 16

Age (Years):

66.8 ± 5.0

Number of Patients:

Male N %:

4 (66.7%)

Patients Followed Up:

Follow-up Time: 20 weeks

Outcomes

Durability

Not reported

Vision

Best-Corrected Visual Acuity (BCVA)
The mean change in BCVA from baseline at Week 12:
• 2 mg: +4.48 (SE 3.58) letters
• 4 mg: +8.60 (SE 3.61) letters
• Aflibercept: +8.92 (SE 3.57) letters

The mean change in BCVA from baseline at Week 16:
• 2 mg: +3.48 (SE 3.23) letters
• 4 mg: +7.43 (SE 3.26) letters
• Aflibercept: +8.92 (SE 3.22) letters

The mean change in BCVA from baseline at Week 20:
• 2 mg: +5.64 (SE 3.56) letters
• 4 mg: +8.93 (SE 3.59) letters
• Aflibercept: +7.92 (SE 3.55) letters

Vision Maintaining
Gained ≥10 ETDRS letters at week 20:
• 4 mg group: 2 patients
• Aflibercept group: 2 patients

Other

Efficacy: Progression Outcome Macular Atrophy The patients with macular atrophy at Week 20:
• 4 mg group: 1/6, 16.7%
• Aflibercept group: 3/6, 50%
• The differences were numerical differences with no statistical significance

Immunognicity

Not reported

Pharmokinetics

Following intravitreal administration of 2 mg per eye of efdamrofusp alfa to patients with nAMD, the mean plasma Cmax of free efdamrofusp alfa was 14.7
pmol/L (range, 4.7-20.4 pmol/L), which was numerically lower than with aflibercept (173.9 pmol/L; range, 0-469.6 pmol/L) at the same dose.

The Peak Time (Tmax) of free efdamrofusp alfa was 4.08 hours (range, 3.78-167.5 hours).

Pharmacodynamic parameters, including plasma-free VEGF, C5a, and interleukin-6, did not show treatment-dependent changes.

Anatomic

Central Subfield Thickness (CST)
The mean change in CST from baseline at Week 12:
• 2 mg: -157.86 (SE 22.251) µm
• 4 mg: -144.61 (SE 21.479) µm
• Aflibercept: -168.02 (SE 22.835) µm

The mean change in CST from baseline at Week 16:
• 2 mg: -155.53 (SE 22.329) µm
• 4 mg: -147.61 (SE 21.560) µm
• Aflibercept: -149.69 (SE 22.912) µm

The mean change in CST from baseline at Week 20:
• 2 mg: -157.53 (SE 22.367) µm
• 4 mg: -148.61 (SE 21.599) µm
• Aflibercept: -176.69 (SE 22.948) µm

Choroidal Neovascularization (CNV)
A CNV area reduction was observed at week 12 and week 20 in all groups.

The mean CNV area reduction from baseline at Week 20:
• 2 mg: -1.02 mm²
• 4 mg: -2.39 mm²
• Aflibercept: -1.39 mm².

Subretinal Fluid (SRF)
The proportion of patients with SRF absorption from baseline to Week 20:
• 2 mg: Not reported
• 4 mg: 5/5 (100%)
• Aflibercept: 2/3 (66.7%).

Retinal pigment epithelial detachment (PED)
The proportion of patients with PED resolution from baseline to Week 20:
• 2 mg: Not reported
• 4 mg: 2/6 (33%)
• Aflibercept: 2/6 (33%).

Safety

Treatment-emergent AEs (TEAEs)
• 2 mg: 66.7%
• 4 mg: 66.7%
• Aflibercept: 100%.

Ocular TEAEs
Patients with ocular TEAEs:
• 2 mg: 33.3%
• 4 mg: 66.7%
• Aflibercept: 66.7%
• All mild or moderate in severity and related to the intravitreal injection procedure
Conjunctival hemorrhage (most common):
• 2 mg: 16.7%
• 4 mg: 66.7%
• Aflibercept: 50.0%

Serious AEs
• No ocular serious adverse event was reported.
• One patient in the efdamrofusp alfa 4 mg group reported a non-ocular serious adverse event of lumbar disc herniation, which was moderate in severity and unrelated to the treatment as judged by the investigator.

Outcomes

Conclusion

Efdamrofusp alfa (2 mg and 4 mg) was well tolerated with no serious AEs and demonstrated comparable BCVA and anatomical improvements to aflibercept. The 4 mg dose showed the largest CNV area reduction and complete SRF absorption in all affected patients.

Risk of Bias Assessment for Primary Outcome

Randomization Process

High risk

Note: No information on the method of randomization or allocation concealment. In addition, due to the small sample size, the two groups were not comparable at the baseline.

Missing Outcome Data

Low risk

Note: No missingness.

Selection of the Reported Results

Some concerns Note: the protocol is not publicly available.

Deviations from Intended Observations

Low risk Note: The primary outcome is safety. Although it is an open-label study, the assessment was unlikely to be influenced by the knowledge of the intervention. All participants were included in the final analysis (ITT).

Measurement of the Outcome

Low risk Note: The primary outcome is safety. The risk of biased measurement is low.

Overall

High risk