The latest treatment advancements for macular degeneration from ASRS 2023 -- Updated

Highlights related to macular degeneration from the American Society of Retina Specialists (ASRS) Annual Meeting 2023

The American Society of Retina Specialists is the largest organization of retina specialists in the world, representing over 3,000 physicians worldwide.

This year’s annual meeting is taking place at the Seattle Convention Center in Seattle, WA, where the latest advancements in the retina field are being presented and discussed.

In this post, you will find a quick highlight of what’s new in macular degeneration from the meeting. As I will update this page as information becomes available, please check back every one to two days.

July 29, 2023

1. Aflibercept 8 mg for wet AMD (High Dose Eylea)

Last month, the FDA didn’t approve a high-dose 8mg formulation of aflibercept (Eylea)  for the treatment of wet age-related macular degeneration (AMD). Even though the company shared that the FDA rejection was due to an ongoing review of inspection findings at a third-party filler and not the efficacy or safety, some still questioned if there is any problem with the high-dose formulation.

At ASRS this year, the efficacy and safety of the Phase 3 clinical trial was revisited again at the meeting. The study compared a high-dose 8mg aflibercept given every 12 or 16 weeks to the 2mg standard dose given every 8 weeks.

The data showed that over 48 weeks of treatment, high-dose aflibercept met the primary endpoint of non-inferior visual acuity compared to the standard dose. However, the visual acuity was numerically lower with less frequent dosing of the 8mg dose. Approximately 83% of patients maintained 12-week or longer treatment intervals with 8mg at 1 year.

Moreover, 8mg aflibercept showed better drying of fluid in the retina compared to 2mg. At 16 weeks, 63% of patients on 8mg had complete resolution of fluid versus 52% with 2mg.

No new safety signals were seen with the 8mg dose compared to the standard 2mg dose over 48 weeks and no cases of retinal vasculitis, occlusive retinitis or endophthalmitis. The safety profiles were similar between the two doses.

(Learn more about aflibercept 8mg for wet AMD) 

2. SB15 for wet AMD (Eylea biosimilar) 

With the expiration of Eylea's patents this year, several biosimilars are being developed. SB15 is an Eylea (aflibercept 2mg) biosimilar under development from Samsung Bioepis and Biogen. Results were recently presented from a Phase 3 trial comparing SB15 to Eylea in wet age-related macular degeneration (AMD).

In the 56-week trial, patients were randomized equally to receive either SB15 or Eylea every 4 weeks for 3 doses, then every 8 weeks. At 32 weeks, patients either continued their originally assigned treatment or switched from Eylea to SB15.

SB15 demonstrated equivalent efficacy, safety, immune response, and drug levels in the body compared to Eylea through 56 weeks. Patients switched from Eylea to SB15 maintained similar outcomes without any loss of efficacy, increased side effects, or increased immune reactions.

This data provides evidence that SB15 is similar to Eylea for treating wet AMD. With Samsung Bioepis and Biogen already having launched a biosimilar of Lucentis called SB11, the positive results for SB15 suggest it may emerge as a competitor to Eylea when its patent expires, providing wet AMD patients another treatment option.

(Learn more about SB15)

3. 4D-150 for wet AMD (Gene therapy)

An investigational gene therapy called 4D-150 is being developed by 4D Molecular Therapeutics for the treatment of wet age-related macular degeneration (AMD), with the aim to provide long-lasting efficacy after a single injection.

4D-150 uses an engineered viral vector to deliver two therapeutic genes to the retina. One gene encodes for aflibercept to block VEGF proteins that drive wet AMD. The other is an RNA interference gene to reduce VEGF-C levels.

Results were recently presented from a Phase 1/2 clinical trial of 4D-150 in wet AMD patients. The data showed 4D-150 was well tolerated, with no serious treatment-related adverse events.

Importantly, patients who received the highest dose had the best outcomes. 80% of these patients did not require any additional injections 36 weeks after the single injection.

Furthermore, the high dose of 4D-150 led to significant improvement in the thickness of the central retina (-92 μm on average). This anatomical improvement was accompanied by stable vision.

The ongoing Phase 2 portion of the trial is still enrolling more patients to further evaluate the optimal 4D-150 dose. The early results suggest gene therapy may provide substantial durability for wet AMD, potentially reducing the treatment burden. 

(Learn more about 4D-150)

July 30, 2023

4. ABBV-RGX-314 for wet AMD (Gene therapy)

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RegenXBio is developing a new gene therapy called ABBV-RGX-314 as a potential one-time treatment for wet AMD. This innovative therapy delivers a gene that encodes for an anti-VEGF antibody fragment using a viral vector. 

The company has started a phase 3 trial, ASCENT, to evaluate intravitreal delivery of its gene therapy ABBV-RGX-314 for wet age-related macular degeneration (wet AMD). The trial will compare two doses of ABBV-RGX-314 injected into the vitreous humor to standard-of-care Eylea injections. The 54-week trial aims to assess efficacy and safety in 465 patients. If successful, it could reduce the injection burden compared to current anti-VEGF therapies.

In addition to the phase 3 intravitreal delivery trial, RegenXBio is exploring two other approaches for delivering ABBV-RGX-314. A phase 1/2a trial showed subretinal injection, where the therapy is injected under the retina, produced stable or improved vision and retinal thickness, and reduced anti-VEGF injections over 2 years. 

A phase 2 trial found suprachoroidal injection – the second approach – between the outer eye layer and choroid also maintained stable vision and retinal thickness. The highest suprachoroidal dose led to an 85% decrease in anti-VEGF injections, and 67% of patients were injection-free at 6 months. 

The phase 3 intravitreal trial and studies of new subretinal and suprachoroidal delivery methods would provide key insights into the efficacy and safety of ABBV-RGX-314 gene therapy for wet AMD. If successful, it could provide long-term benefits with a one-time administration.

(Learn more about ABBV-RGX-314)

5. Byooviz and Cimerli (Lucentis biosimilars) 

A presentation reviewed the outcomes of two new commercially available ranibizumab biosimilars among more than 5,000 eyes treated by a large consortium of retina specialists. The two agents were ranibizumab-nuna (Byooviz) or SB-11, and ranibizumab-eqrn (Cimerli). The study aimed to identify any unexpected adverse effects of the biosimilars that may not have been observed or anticipated during clinical research trials.

Overall, the initial experience revealed no unusual adverse outcomes. The biosimilar ranibizumab agents appeared to have similar clinical efficacy to Lucentis in terms of visual acuity outcomes. Three cases of infectious endophthalmitis and 9 cases of minimal inflammation were observed. The outcomes of the 3 endophthalmitis cases are 2 regained vision after treatment and 1 experiencied vision loss. The 9 eyes with inflammation had rare to mild anterior chamber or vitreous cells but no visual loss or need to change treatment. 

This real-world experience in a large cohort of patients found the biosimilar ranibizumab agents to have similar efficacy and safety to the reference drug --Lucentis. The endophthalmitis rate was reported to be elevated but may be an anomaly related to the sample size. Overall, the biosimilar agents did not reveal any unexpected adverse outcomes compared to the originator drug.

6. CLS-AX for wet AMD

CLS-AX is a new formulation of the drug axitinib that is injected into the suprachoroidal space to treat wet age-related macular degeneration (AMD). Axitinib is a tyrosine kinase inhibitor that blocks VEGF receptors. Unlike current anti-VEGF drugs that are injected into the eye, CLS-AX is injected into the suprachoroidal space using a proprietary delivery system. This allows the drug to spread between the choroid and sclera to target affected layers.

The results from a Phase 1/2a trial and extension study showed CLS-AX has an excellent safety profile. No serious side effects or inflammation were seen even after 6 months. Higher doses also showed signs of durable treatment effects, with stable vision and retinal thickness. Patients required 77-85% fewer injections compared to current monthly anti-VEGF medicines. 

This means CLS-AX could potentially reduce the treatment burden compared to current medicines. A Phase 2b trial is now enrolling to further evaluate efficacy and duration. 

(Learn more about CLS-AX)

7. ANX007 for Geographic Atrophy

ANX007 is a new treatment for geographic atrophy under development by Annexon Inc.. It is a monoclonal antibody designed to inhibit the activation of the complement cascade. By binding to C1q and mannose-binding lectin (MBL), ANX007 blocks activation of the classical and lectin complement pathways.

The Phase 2 study, ARCHER, evaluated different doses of ANX007 administered as an intravitreal injection. Data from over 200 patients showed that after 12 months, treatment with ANX007 provided statistically significant, dose-dependent protection of visual function in GA across multiple measures.

Specifically, the highest dose of 15 mg reduced the risk of losing 15 or more letters on an eye chart by 47% compared to sham. This beneficial effect was consistent regardless of patients' baseline characteristics like lesion size and location. Additional visual function measures like low luminance visual acuity also showed dose-dependent improvements with ANX007 treatment versus sham. ANX007 was generally well-tolerated through month 12, with no increase in CNV rates between the treated and sham arms and no events of retinal vasculitis reported.

According to Annexon, the six-month off-treatment follow-up period of the ARCHER trial is ongoing, and the company plans to report final results following the study’s conclusion. Further, Annexon plans to meet with regulators later this year to determine the next steps for advancing ANX007 as a new GA treatment option.

(Learn more about ANX007)

(Continue)

8. EYP-1901 for wet AMD

EYP-1901 is a tyrosine kinase inhibitor, vorolanib, that is in a sustained delivery technology – Durasert platform – for at least six months of delivery.

Following the Phase 1 clinical trial, which demonstrated that EYP-1901 exhibits a favorable safety and efficacy profile for patients with wet AMD, the study indicated a positive safety profile along with consistent visual acuity and OCT results. Moreover, after a single dose of EYP-1901, 53% and 35% of eyes did not necessitate any supplementary anti-VEGF injections for up to six and twelve months, respectively.

The company is currently undertaking a Phase 2 trial named DAVIO2. The primary objectives of the DAVIO2 study are to demonstrate non-inferiority to EYELA in terms of equal BCBA and, most importantly, be able to show time to first supplementation, as well as total treatment burden reduction. 

An interim safety update involving masked data from the DAVIO2 study was presented at this year's ASRS conference. From a total enrollment of 160 patients, the interim update showed there are no drug-related severe adverse events due to the drug. 

The top-line data readout is expected in December.

(Learn more about Phase 2 DAVIO 2 Clinical Trial of EYP-1901)

9. Izervay (avacincaptad pegol) for geographic atropy

The treatment was approved by FDA on Aug 4, 2023. (Learn more)

Aug 1, 2023

10. OTX-TKI for wet AMD 

OTX-TKI is a bioresorbable hydrogel implant designed to provide extended delivery of axitinib, a tyrosine kinase inhibitor that reduces abnormal blood vessel growth. 

In a 12-month U.S. Phase 1 clinical trial, researchers evaluated the efficacy of OTX-TKI combined with aflibercept injections as a treatment for wet AMD in patients who had previously undergone anti-VEGF therapy. The trial enrolled 21 subjects and compared the results of a single OTX-TKI implant followed by an aflibercept injection at 4-week intervals to every 8 weeks.

No significant adverse events were linked to OTX-TKI. Participants with OTX-TKI implants maintained consistent visual acuity and retina thickness, similar to the aflibercept group. Noteworthy is that approximately 60% of OTX-TKI subjects required no additional treatment throughout the first 12 months. Furthermore, OTX-TKI demonstrated a substantial 89% reduction in the treatment burden. The company's goal is to commence a pivotal wet AMD trial in Q3 2023, subject to the acquisition of funding.

(Learn more about OTX-TKI)

11. FHTR2163 for Geographic Atrophy

The GAllego Phase 2 study aimed to investigate the potential of FHTR2163, galegenimab, an anti-High Temperature Requirement A1 (aHtrA1) antibody fragment, in slowing the progression of geographic atrophy (GA). Despite initial hopes, the study was terminated early due to a high rate of intraocular inflammation (IOI) among galegenimab-treated patients, with no significant difference in GA area change observed between the treatment and sham groups. 

(Learn more about FHR2163’ early termination)

What are the different clinical trial phases?

Phase 1: These are small-sized studies of about 20 to 50 people. These people are usually health volunteers. In general, this phase is to evaluate the safety of a new drug, and what happens to the drug in the body. 

Phase 2: These are medium-sized studies, sometimes including a few hundred patients. This phase is to find out more about the side effects, the optimal dose, and how effective the treatment is in patients.

Phase 3 (also called pivotal trials): These are large-size studies that may include hundreds or thousands of people. A Phase 3 trial compares the new treatment to the current standard of care. If the drug has demonstrated effectiveness with an acceptable safety profile in treating disease (usually, two pivotal trials are required by FDA in the US), the manufacturer can submit a new drug application. Once approved, it can be prescribed to patients.

(Note: the treatments described here may not be approved by FDA. The information is provided only for educational purposes)