Abicipar Pegol

Key Points at a Glance

1. What is Abicipar Pegol?

Abicipar pegol is an anti-VEGF (vascular endothelial growth factor) drug developed by Allergan (now AbbVie). It was developed for neovascular age-related macular degeneration (nAMD) and diabetic macular edema (DME).

Abicipar belongs to a novel class of binding proteins called DARPins (Designed Ankyrin Repeat Proteins). It consists of 4 to 6 ankyrin repeat domains and has a molecular weight of 34 kDa. ¹⁾ It is smaller than ranibizumab (48 kDa), and the addition of a PEG (polyethylene glycol) chain reduces renal clearance and prolongs intraocular retention. ¹⁾

Its binding affinity for VEGF-A is 486 fM (femtomolar), approximately 87 times higher than ranibizumab’s 42.5 pM. ¹⁾ The intraocular half-life is 13 days, significantly longer than ranibizumab’s 7.2 days. ¹⁾ This long half-life allows for about 10 injections over 104 weeks of treatment (compared to 25 monthly injections of ranibizumab). ¹⁾

In June 2020, the FDA rejected approval due to a high incidence of intraocular inflammation (IOI). ¹⁾ The benefit-risk ratio was deemed unfavorable. It is also not approved in Japan.

Q Why was abicipar pegol not approved by the FDA?

In Phase 3 trials, IOI (intraocular inflammation) occurred in up to 15% of patients, and the benefit-risk ratio was deemed unfavorable. ¹⁾ See “Safety and Side Effects” section for details.

2. Mechanism of Action

VEGF-A (vascular endothelial growth factor A) plays a central role in the pathophysiology of neovascular age-related macular degeneration. It is involved in the formation of subretinal choroidal neovascularization and increased vascular permeability. ¹⁾

Abicipar binds to VEGF-A with high affinity and competitively inhibits binding to VEGF receptors (VEGFR-1 and VEGFR-2). DARPins have a smaller molecular weight compared to monoclonal antibodies or Fab fragments and are thought to have superior penetration into intraocular tissues. ¹⁾

Preclinical studies demonstrated that avicipar effectively inhibits both angiogenesis and vascular permeability. ¹⁾

Frequent intravitreal injections of anti-VEGF therapy impose a significant burden on patients and healthcare systems. ¹⁾ Avicipar was developed as the only anti-VEGF agent to show non-inferiority to monthly ranibizumab with fixed dosing every 3 months (Q12). ¹⁾

3. Clinical Trials

Avicipar was developed through a multi-phase clinical trial program.

Phase II Trials

REACH Trial

The REACH trial was a 20-week Phase II study involving 64 patients with neovascular age-related macular degeneration. Three groups were compared: avicipar 1 mg, avicipar 2 mg, and ranibizumab 0.5 mg. The avicipar groups received 3 injections, while the ranibizumab group received 5 injections.

At 20 weeks, the mean change in best-corrected visual acuity (BCVA) was +8.2 letters in the avicipar 1 mg group, +10.0 letters in the 2 mg group, and +5.3 letters in the ranibizumab group. The mean reductions in central retinal thickness (CRT) were 116 μm, 103 μm, and 138 μm, respectively.

BAMBOO Trial and CYPRESS Trial

The BAMBOO trial (Japan, n=25) and CYPRESS trial (USA, n=25) were each 20-week Phase II studies.

In the BAMBOO trial, the mean change in BCVA was +7.8 letters in the avicipar 1 mg group, +8.9 letters in the 2 mg group, and +17.4 letters in the ranibizumab group. In the CYPRESS trial, the corresponding changes were +4.4, +10.1, and +15.2 letters. The small sample sizes limit external validity.

PALM Trial (Diabetic Macular Edema)

This was a 28-week Phase II study involving 151 patients with diabetic macular edema. Four cohorts were compared: avicipar 1 mg every 8 weeks, avicipar 2 mg every 8 weeks, avicipar 2 mg every 12 weeks, and ranibizumab every 4 weeks. At 28 weeks, the mean changes in BCVA were +4.9, +7.1, +7.2, and +9.6 letters, respectively.

Phase III Trials: CEDAR and SEQUOIA

The CEDAR trial (n=939) and SEQUOIA trial (n=946) were 52-week international multicenter randomized controlled trials. They compared avicipar 2 mg every 12 weeks, avicipar 2 mg every 8 weeks, and ranibizumab 0.5 mg every 4 weeks.

The combined stable vision maintenance rates were 93.2% in the Q8-week group, 91.3% in the Q12-week group, and 95.8% in the ranibizumab Q4-week group, with both abicipar groups achieving non-inferiority to ranibizumab. ¹⁾ The number of injections was 6 to 8 in the abicipar groups and 13 in the ranibizumab group. ¹⁾

On the other hand, the incidence of IOI was 15.1% in the Q8-week group and 15.4% in the Q12-week group, compared to 0.3% in the ranibizumab group, showing a large difference. ¹⁾

Phase II Safety Study: MAPLE Study

The MAPLE study is an open-label Phase II study evaluating the safety of abicipar with an improved manufacturing process. ¹⁾ It included 123 patients with neovascular age-related macular degeneration (83 treatment-naïve, 40 previously treated) and observed them over 28 weeks. The mean age was 78.3 years. ¹⁾

The dosing schedule was a total of 5 injections at baseline, week 4, week 8, week 16, and week 24. ¹⁾

The table below shows the IOI rates from the Phase 3 studies and the MAPLE study.

Study	Q8-week group	Q12-week group	Control group
CEDAR/SEQUOIA	15.1%	15.4%	0.3%
MAPLE	8.9%	—	—

The IOI incidence in the MAPLE trial was 8.9% (11/123), lower than the 15.1–15.4% in Phase 3. ¹⁾ The breakdown of IOI was mild 2.4%, moderate 4.9%, and severe 1.6%. ¹⁾ All cases resolved with steroid treatment, and no endophthalmitis or retinal vasculitis was reported. ¹⁾

Regarding efficacy, the stable visual acuity maintenance rate was 95.9% at all visits and 97.6% at 28 weeks. ¹⁾ The mean change in best-corrected visual acuity was +3.6 letters overall (+4.4 letters in treatment-naïve, +1.8 letters in previously treated). ¹⁾ The mean reduction in CRT was −82.5 μm overall (−98.5 μm in treatment-naïve, −45.5 μm in previously treated). ¹⁾

Q How much longer is the dosing interval of avicipar compared to other anti-VEGF drugs?

Avicipar achieved non-inferiority to monthly ranibizumab with fixed dosing every 8–12 weeks. At 104 weeks, it required only about 10 injections, significantly fewer than ranibizumab’s 25 injections. ¹⁾

4. Safety and Side Effects

Intraocular Inflammation (IOI)

IOI is the greatest safety concern for avicipar. In Phase 3 trials, the IOI incidence was 15.1% in the Q8-week group and 15.4% in the Q12-week group, markedly different from 0.3% in the ranibizumab group. ¹⁾ In the MAPLE trial, it decreased to 8.9% with manufacturing improvements, but still did not reach the level of approved anti-VEGF drugs (less than 1%). ¹⁾

The clinical presentation of IOI included iritis, uveitis, vitritis, and panuveitis. In the MAPLE trial, the onset of IOI occurred after the first injection in 27.3%, after the second in 18.2%, and after the fourth in 54.5%. ¹⁾ All cases resolved with steroid treatment (topical, oral, or subconjunctival). ¹⁾ Of the 11 patients who developed IOI, 8 recovered to baseline best-corrected visual acuity or better at the end of treatment. ¹⁾

Consideration of the Cause of IOI

Host cell-derived impurities (IIRMI) from the manufacturing process are thought to be involved in inducing inflammation. ¹⁾ In vitro studies showed that improved manufacturing lots reduced IL-1β, IL-6, and TNF-α responses in peripheral blood mononuclear cells (PBMCs). ¹⁾ The cause of IOI is multifactorial, and syringe or silicone oil microdroplets may also contribute. ¹⁾

Immunogenicity

In the MAPLE trial, anti-avacincaptad pegol antibodies were detected in 30.1% (37/123) of patients. ¹⁾ Of these, 18.7% were positive for neutralizing antibodies. ¹⁾ Among patients who developed IOI, 81.8% were antibody-positive, but 75.7% of antibody-positive patients did not develop IOI. ¹⁾ Six of 8 patients with high titers (≥10,000) developed IOI. ¹⁾

Other Adverse Events

Systemic VEGF inhibition-related treatment-emergent adverse events (TEAEs) occurred in 10.6% of patients, with hypertension in 5.7%. ¹⁾ Ocular TEAEs included subconjunctival hemorrhage (4.9%), vitreous detachment (4.9%), and increased intraocular pressure (4.1%). ¹⁾

Phase 3 IOI

Incidence: Q8W group 15.1%, Q12W group 15.4%

Severity: Endophthalmitis and retinal vasculitis reported. Control: Ranibizumab group 0.3%

MAPLE Trial IOI

Incidence: 8.9% (11/123 patients)

Severity: Mild 2.4%, Moderate 4.9%, Severe 1.6%. Outcome: All cases resolved with steroids

Q If intraocular inflammation occurs, will vision recover?

In the MAPLE trial, 8 of 11 patients who developed IOI recovered to baseline best-corrected visual acuity or better at the end of treatment. ¹⁾ All cases resolved with steroids (topical, oral, or subconjunctival).

5. Comparison with Other Anti-VEGF Agents

The standard treatment for neovascular age-related macular degeneration is intravitreal injection of anti-VEGF agents, and several drugs are currently approved. ³⁾ Approved anti-VEGF agents include ranibizumab, aflibercept, brolucizumab, faricimab, and bevacizumab (off-label). ³⁾

Japanese clinical guidelines recommend an induction phase (monthly × 3–4) followed by a maintenance phase (PRN or treat-and-extend). ²⁾ The treat-and-extend regimen has been shown to yield significantly better visual outcomes than PRN. ²⁾

The unique position of avacincaptad pegol was achieving non-inferiority with fixed 3-month dosing. However, the high rate of IOI became a barrier to approval. Brolucizumab also had issues with intraocular inflammation (including occlusive retinal vasculitis), and IOI risk management has become an important issue across anti-VEGF agents. ³⁾

Notably, ranibizumab was reported to have an IOI incidence of 38.1% in Phase 1/2 trials, but this rate dramatically decreased after formulation improvements. ¹⁾

A comparison of molecular weights and maintenance dosing intervals for major anti-VEGF drugs is shown below.

Drug	Molecular weight	Maintenance dosing interval
Avastin	34 kDa	8–12 weeks (unapproved)
Ranibizumab	48 kDa	4 weeks–
Aflibercept	115 kDa	8 weeks–

Q What anti-VEGF drugs are currently used to treat neovascular age-related macular degeneration?

Ranibizumab, aflibercept, brolucizumab, faricimab, and bevacizumab (off-label) are used. ³⁾ Each has different dosing intervals, molecular weights, and side effect profiles, and is selected based on the pathology and patient background.

6. Molecular Characteristics and Manufacturing Challenges

Structural Features of DARPin

DARPin has a structure in which 4 to 6 ankyrin repeat domains are stacked, characterized by high thermal stability and selective high-affinity binding to target molecules. ¹⁾ PEG modification suppresses renal clearance and prolongs intraocular retention time. ¹⁾

Manufacturing Challenges

Avicipar is produced using an E. coli expression system. In this process, host cell proteins (HCP) and other host-derived impurities (IIRMI) may remain. ¹⁾ IIRMI is thought to induce cytokine release or act as an immune adjuvant, thereby causing inflammation. ¹⁾

Since intravitreal injection is administration into a small closed cavity, impurities are not easily diluted. Therefore, the formulation requires ultra-low levels of impurities. ¹⁾

An improved manufacturing process uses high-resolution chromatography to remove pro-inflammatory impurities derived from E. coli. ¹⁾ The effects of this improvement were evaluated in vitro (human PBMC) and are shown below.

Phase 3 Manufacturing Lot

IL-1β response rate: 2%

IL-6 response rate: 12%

TNF-α response rate: 21%

Improved Lot for MAPLE

IL-1β response rate: 0%

IL-6 response rate: 0%

TNF-α response rate: 10%

In the improved lot, inflammatory cytokine responses were significantly reduced. ¹⁾ This manufacturing improvement is thought to have contributed to the reduction in IOI rate (from the 15% range to 8.9%) in the MAPLE trial, but it did not reach the level of approved anti-VEGF drugs. ¹⁾

7. Development Status and Future Prospects (Research Stage Reports)

Abicipar pegol was denied approval by the FDA in June 2020. ¹⁾ In the MAPLE trial, the IOI rate improved to 8.9%, but it still did not reach the level of approved anti-VEGF drugs, which is less than 1%. ¹⁾

The DARPin technology platform itself continues to be researched and developed in other medical fields such as oncology and immunology. The characteristics of designed ankyrin repeat proteins—high affinity, high stability, and low molecular weight—are considered promising even outside ophthalmology.

In the treatment of neovascular age-related macular degeneration, extending the dosing interval remains an important challenge. After the development of abicipar, new-generation long-acting anti-VEGF drugs such as high-dose aflibercept (12–16 week dosing) and faricimab (up to 16 week dosing) have been approved. ³⁾

The concept demonstrated by the development of abicipar (long-acting, low molecular weight, ultra-high affinity) was significant. However, it also became clear that controlling intraocular inflammation risk is essential. In the future development of long-acting ophthalmic drugs, purification of the manufacturing process and minimization of immunogenicity will be positioned as important challenges.

8. References

Callanan D, Khurana RN, Maturi RK, et al. Impact of Modifying Abicipar Manufacturing Process in Patients with Neovascular Age-Related Macular Degeneration: MAPLE Study Results. Clin Ophthalmol. 2023;17:1367-1384.
日本眼科学会. 新生血管型加齢黄斑変性の診療ガイドライン.
Flaxel CJ, Adelman RA, Bailey ST, et al. Age-Related Macular Degeneration Preferred Practice Pattern. Ophthalmology. 2020;127(1):P1-P65.

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