Neovascular Age-Related Macular Degeneration (nAMD) is a leading cause of vision impairment and blindness among the elderly population worldwide. The current standard of care (SoC) in the first-line of treatment for nAMD involves anti-VEGF (vascular endothelial growth factor) therapy, which has significantly improved outcomes, but comes with treatment burden with frequent intravitreal injections. These painful, intimidating, and tricky to master injections into the eye beg the question, is there a way to reduce patient burden and eliminate injections?
Enter gene therapy (GT), an emerging advancement that is growing optimism among researchers and healthcare professionals as a potential new SoC for nAMD patients. Data from >1000 ophthalmologists suggested that GT for nAMD was equally anticipated vs. more durable anti-VEGF treatment in the US [1], showing willingness to adapt to a novel treatment. But can GT eventually supersede anti-VEGF as a SoC treatment in ophthalmic care?
Anti-VEGF Therapy: The Current Gold Standard
Anti-VEGF therapy, a breakthrough in nAMD treatment, hinders abnormal blood vessel growth in the retina. Ranibizumab, aflibercept, and the newer faricimab all show efficacy in slowing progression and preserving vision. However, frequent intravitreal injections with some experiencing sub optimal outcomes pose challenges, burdening patients, and healthcare systems, highlighting the demand for alternative therapies. Despite successes, limitations underscore the need for ongoing exploration and development of innovative treatment approaches in nAMD.
The Promise of Gene Therapy
GT represents a revolutionary paradigm shift in the treatment of various genetic and degenerative disorders. Recent GT successes include Spark Therapeutics’ LUXTURNA for blindness and Novartis’ ZOLGENSMA for spinal muscular atrophy, showcasing transformative advancements in treatment options in these populations where options are limited.
The premise of GT for nAMD involves delivering therapeutic genes into retinal cells to regulate the production of proteins involved in angiogenesis, the process of new blood vessel formation [1]. With multiple intravitreal candidates from 4D Molecular (R100) and Adverum (Ixo-vec) to subretinal candidates from REGENXBIO/AbbVie (RGX-314), the pursuing of GT, even when there are existing treatments, aligns with broader goals of medicine of improving patient outcomes, reducing long-term costs, and pushing the boundaries of scientific knowledge.
Potential Advantages of Gene Therapy over Anti-VEGF
Sustained Therapeutic Effect: To be able to draw comparisons between the current SoC, all companies involved must demonstrate non-inferiority outcomes to anti-VEGF Tx. Using well-established SoC EYLEA from Regeneron/Bayer as a comparator, Ocular and 4DMT designed its Ph3 trials to have an EYLEA comparator arm (REGENXIO’s subretinal delivery trials [1,2] have LUCENTIS/EYLEA comparator arms), a well-received move from the FDA and investors [2,3]. Companies pursuing a more typical non-inferiority pivotal design such as Adverum may struggle benchmark against anti-VEGF treatment in comparison.
Potential for Disease Modification: To eliminate the need for frequent injections on the current SoC treatment pathway, pivotal data must show promising rescue-free rates (not requiring a rescue SoC injection). Data from Adverum currently exceeds the pack, with 80% of patients being rescue free at ~6 months, with Ocular not far behind with 73% being rescue free, vs. 4DMT and REGENXBIO seeing rates from 53-55% [4]. In exploring the impact of trial design, Adverum’s elevated rescue-free rates may be linked to its extended steroid regimen, (to be discussed further below). Furthermore, companies like Ocular are delving into GT for treatment-naïve eyes, while 4DMT and Adverum are focusing solely on patients who have previously shown positive responses to anti-VEGF therapy. Importantly, these baseline characteristics and wider treatment regimens could skew perception of the respective GT’s disease modifying capability, stressing a need for predictive responder identification for commercial viability.
Benefits for younger, nAMD patients: In theory, GT should be offering targeted and long-lasting treatment for a patient, a benefit that would be maximized in younger cohorts. With early intervention, nAMD GT should alleviate the burden of frequent clinic visits and injections and preserve and potentially improve vision. Using Spark Therapeutics’ LUXTURNA as an example, GT in ophthalmologic care has been seen to benefit patients as young as 3. Whilst the general population age range for wet AMD is >50, with age being a main risk factor for developing nAMD, it early-onset macular degeneration can be seen in patients <30. Potentially targeting even a slightly younger population with nAMD could be attractive for both the patient’s perspective (relieving patient burden with reduced injections), but also from a payer perspective (likelihood of increasing cost-effectiveness of GT).
Challenges and Considerations
Safety Concerns with Steroids: To address inflammatory responses to high vector loads in nAMD GT not associated with the current SoC, various players employ prophylactic steroid regimens. REGENXBIO’s/AbbVie’s RGX-314 subretinal delivery may boast a favorable “no steroid” regimen, however, there is a high risk of developing a cataract, surgery for which suits the elderly but may deter younger wet AMD patients [6]. RGX-314’s suprachoroidal delivery boasts a favorable 7-week regimen (using topical corticosteroid paper), avoiding intraocular inflammation. In contrast, 4DMT (using topical corticosteroid paper) and Adverum (using eye drops +/- oral prednisone) require a minimum of 20/21 weeks [4]; whilst this improves efficacy of the products, this potentially increases patient burden/risk. While prophylactic steroids carry long-term risk, they could offer a viable solution if GT fulfills their “one-and-done” promise, which is yet to be confirmed.
Acceptance of the current SoC: Whilst the current SoC has its drawbacks, HCP familiarity with the “treat and extend” approach which maximizes treatment intervals with anti-VEGF will challenge GT uptake. With introduction of high-dose EYLEA and Genentech’s VABYSMO (faricimab), both with potential to offer >Q16W regimens, the “unpredictability” of GT underscores its efforts to advance the space. Risks including long-term drying, potential development of geographic atrophy, and the unpredictability of outcomes raise caution [4]. Contrastingly, established safety data profiles, across originators and biosimilars, support the benefit-risk profile of anti-VEGF Tx, where an ophthalmologist can have confidence in treating reactively. The need for comprehensive safety assessments, at least in early launch phase, may deter HCPs from recommending GT to patients.
Reimbursement and Revenue Questions: GT will not just have to compete on efficacy, but on costs also. The typical price level of a gene therapy (≥$1M) could severely limit nAMD market uptake [5] due to the availability of competitively priced originators, and biosimilars. Key opinion leaders note GT emerges as a potential “disruptor” to their current practices [7]. However, with around 200,000 new cases of nAMD annually in the US, there’s room for a reasonably priced GT to coexist alongside less frequent anti-VEGF injections. Current anti-VEGF Tx like EYLEA cost $10,000 to $12,000 per patient yearly. Considering most wAMD patients are diagnosed in their late 60s to early 70s and US life expectancy extends into the late 70s, the total lifetime cost of EYLEA per patient could reach $100,000 to $150,000. Analysts estimate Adverum’s GT could cost only $30,000; with a peak penetration of around 50,000 wAMD patients by 2034, this could yield an estimated revenue of $1.6 billion [7]. ICER may look conduct a cost-benefit analysis and suggest pricing, but $30,000 for a GT seems compelling given past spending patterns. Whilst this is an attractive option for payers, the feasibility of implementing GT hinges on various factors, including the pricing strategies adopted by GT players. Key considerations include the potential need to revert to anti-VEGF treatments, the potential rise in biosimilar usage, logistical challenges in GT delivery, and the implications for ophthalmologists’ revenue streams.
Multiple Players: The surge of GT players in the nAMD treatment landscape fuels innovation but poses challenges in differentiation and benchmarking efficacy. Factors that affect pivotal results include the patient population’s baseline BVCA, the length of steroid treatment with its effect on the final efficacy outcome, and trial design [4]. And it’s not only other GT players that need to be concerned, but also players with a historical, invested focus in anti-VEGF Tx that have established safety profiles. Should the class of GTs want to establish itself as a first-line treatment option over anti-VEGF, not only will transparency in result reporting be essential to understand the potential of the GT, but also demonstrating a safety profile that isn’t overly risky vs. anti-VEGF Tx.
Conclusion
GT holds the promise of reshaping the landscape of nAMD treatment, offering a sustained and potentially disease-modifying effect. As companies like 4DMT, REGENXBIO, and Ocular continue to innovate, with regulatory action expected in the next ~2 years, the opportunity for GT to become the new SoC in nAMD is tangible. However, success will require focused positioning and strategic differentiation, especially in an environment dominated by anti-VEGF treatments. Companies must work to distinguish their GTs not only from existing treatments but also from other GT contenders. Addressing safety, trial design, and pricing concerns is also critical, to demonstrate GT value to both patients and payers. The goal is clear: redefine the SoC for nAMD and improve the lives of those affected by this challenging condition.
Sources
1. 25th Annual ASRS PAT Survey Respondents Data, 2023 [N = 1014]
2. Wolleben, Jonathan. Ocular Therapeutix, Inc. [OCUL] SPA for SOL Wet AMD Trial INVESTMENT HIGHLIGHTS • the FDA Signs off Quickly on an SPA for Ocular’s Innovative Phase 3 SOL Trial of Axpaxli [Formerly OTX-TKI] Designed to Show Superiority to Eylea; We Reiterate Our Market Outperform Rating and $12 Risk-Adjusted, DCF. 2023.
3. Tejavibulya, Nalin. Management Discussion on Ph2 Data for 4D150 in Wet AMD; Ph3 Initiation in 1Q25. Jefferies, 5 Feb. 2024.
4. JPM, Biotechnology Wet AMD Download After a Busy Week, Industry Overview – Industry Update 12 Feb. 2024.
5. Yi Chen, Advancing Gene Therapies in Ophthalmology and Rare Diseases; Initiating Coverage at Buy and $36 PT, HC Wainwright, 11 Mar. 2024.
6. Danielle Brill, Resume Coverage at Outperform: Derisked, Diverse Gene Tx Platform w/ Many Near-Term Catalysts, Raymond James, 20 Feb. 2024.
7. Joon Lee, Laying Down the Bull Case For ADVM, Truist Securities, 19 Jun. 2023.