• Faricimab (Vabysmo) is the first approved bispecific antibody uniquely engineered to block two key pathways driving retinal vascular disease by neutralizing Ang-2 and VEGF-A
• Absence of retinal fluid (RF) was achieved faster with faricimab vs aflibercept in TENAYA and LUCERNE trials^1,2
• ~80% of faricimab patients were maintained on every 12- or 16-week treatment intervals at year 2¹
• Faricimab is approved in more than 90 countries, with 2 million doses distributed worldwide³

The advent of anti-vascular endothelial growth factor (anti-VEGF) agents some two decades ago has revolutionized the treatment regimen of retinal diseases. However, the key challenge with currently available anti-VEGF therapies is the need for frequent injections to maintain initial vision gains. Although anti-VEGF therapy targets pathological neovascularization, it does not address other features of retinal diseases such as inflammation and fibrosis.

In multifactorial retinal diseases such as neovascular age-related macular degeneration (nAMD) and diabetic macular edema (DME), the disease pathologies are not completely addressed by anti-VEGF alone – which only effectively addresses vascular leakage and neovascularization – but not other aspects of retinal disease, such as inflammation and fibrosis.⁴ Hence, novel targets beyond the VEGF pathway are needed to promote optimal vessel stability for improved patient outcomes.

A pivotal pathway in this context is angiopoietin-2 (Ang-2), a ligand that plays a key role in vascular destabilization and inflammation. Neutralizing Ang-2 holds significant promise in the restoration of vascular stability through reduction of vascular leakage, neovascularization and inflammation, and enhancing vascular responsiveness to the effects of VEGF-A. This intervention, aimed at modulating Ang-2, has emerged as a strategic approach to address the multiple facets of vascular dysfunction, hence providing stability and responsiveness in balancing angiogenic processes.

But what if one molecule could target both pathways? In preclinical studies, dual Ang-2 and VEGF-A inhibition demonstrated the potential for increased vascular stability, with greater reductions in vascular leakage, neovascularization and inflammation versus VEGF inhibition alone.

At the recently held 16th Congress of the Asia-Pacific Vitreo-retina Society (APVRS 2023) in Hong Kong, faricimab (Vabysmo^TM; Roche) took center stage as vitreoretinal specialists showcased and deliberated on pre-clinical, clinical trials and real-world data, providing robust evidence of faricimab’s efficacy and safety profile in treating nAMD and DME. The revolutionary dual pathway inhibition offered by faricimab marks a paradigm shift in this field. Roche and faricimab’s active participation at APVRS 2023 has undeniably heightened the enthusiasm surrounding medical retina innovations within the Asia-Pacific ophthalmic community.

Results from TENAYA and LUCERNE Trials

Faricimab demonstrated durable efficacy through disease control with up to Q16W dosing in nAMD

TENAYA and LUCERNE⁵ are the first phase 3 clinical trials that evaluated the dual pathway inhibition of Ang-2 and VEGF-A for the treatment of nAMD. The primary results support faricimab as a bispecific inhibiting agent that addresses multiple pathological features of nAMD beyond neovascularization alone.

TENAYA and LUCERNE investigators have reported that the visual benefits with faricimab given at up to 16-week intervals demonstrates its ability to meaningfully extend the time between treatments without compromising vision outcomes, hence resulting in less burdensome treatment regimens for both patients and clinicians.

Faricimab demonstrated extended durability, with approximately 80% of faricimab-treated patients on extended dosing intervals of every 12 weeks or more, and nearly 45% of patients on dosing intervals of every 16 weeks.

The TENAYA and LUCERNE trials were designed to assess the efficacy, safety and durability of faricimab versus aflibercept in patients with nAMD.

At the APVRS Congress in December 2023, Dr. Adrian Koh (Singapore), exploring first line use of dual Ang-2/VEGF-A inhibition, presented a few of his own patient cases, which echoed the clinical trial results. “After the fourth loading dose, you can see that the macula is now dry and subretinal fluid has resolved completely… and then I wait… there is no disease activity both at week 20 and week 24,” he shared. In this particular treatment-naïve case, according to Dr. Koh, the patient at this point is now eligible to jump from 4-weekly treatment to Q16W. “I call this the fast-track treat-and-extend – an excellent initial treatment response for a treatment- naïve case,” he summarized. There was no recurrence, no aggravation, according to Dr. Koh. “The patient [treated eye condition] remains very quiet and dry,” he added.

The session’s co-speaker, Dr. Tai-Chi Lin (Taiwan), agreed with Dr. Koh. “I don’t see why not [use faricimab as the first line treatment], seeing that it has shown promising visual and anatomical outcomes. I think both clinical trials and real-world data, including my own clinical experience, show that using faricimab can achieve rapid improvement in anatomical results – such as retinal fluid drying and reduction of CST,” shared Dr. Lin.

“We are looking at an agent that will bring disease control as quickly as possible to prevent neovascularization. The faster we bring that under control with everything we’ve got, the better the chance we have of extending treatment. And I believe that the durability is the result of superior disease activity control, in part that would be Ang-2- related, not just VEGF,” Dr. Koh explained, emphasizing that not only treatment- naïve patients will benefit from faricimab, but patients switched from other agents as well.

“In patients who have consistent fluid even after anti-VEGF treatment, it’s good to load them with faricimab – 4 initial injections, until they achieve drying and then slowly push them up to the 16-week interval,” he added.

“Treatment with faricimab led to marked PED (pigment epithelial detachment) regression, rapid improvements in vision and corresponding anatomical outcomes,” Dr. Koh summarized.

“But for switch patients, don’t be disheartened if you don’t get quick results, as these patients are on other agents for a long time, it will take a while to see results”, warned Dr. Koh.

Results of short-term study in Japan

Is faricimab a potential monotherapy against PCV?

Dr. Keiko Kataoka (Japan) is impressed with the rapid anatomical response of treatment-naïve patients treated with faricimab. “The rapid subretinal fluid drying in faricimab is really impressive, especially in pachychoroid diseases. It is always more difficult for us to control the subretinal fluid drying, but with faricimab… faricimab is really effective, especially in treatment- naïve patients”, she shared.

In her part during the symposium, Dr. Kataoka presented evidence that supports faricimab’s extended durability. She presented on the three-month outcomes of a multicenter study that assessed the short-term effectiveness and safety of faricimab in treatment- naïve Japanese patients with wet age-related macular degeneration (wAMD). The study retrospectively reviewed 63 eyes of 61 patients with wAMD, including types 1, 2, and 3 macular neovascularization as well as polypoidal choroidal vasculopathy (PCV).⁶

The panelists then proceeded to discuss faricimab’s potential against PCV based on their own clinical experiences. “We still don’t know a lot about how faricimab behaves in PCV, but we now have a good idea based on results of TENAYA and LUCERNE and the outcomes of the Japanese sub-group – the initial indication is that [faricimab] is very good in disease control, at least we know that we’ll be able to dry the macula, that we’ll be able to extend similar to choroidal neovascularization. What we don’t know is how long this effect lasts and what is the effect on polyp closure,” shared Dr. Koh.

“My experience, [in polypoidal] especially in switched patients, they need possibly 3 to 6 months of faricimab exposure before we start to see the beneficial effects. What I mean is that these polyps perhaps may have been hydrolyzed and fibrous over a period of time so you’re not going to see an immediate response to some of these persistent fluids. But I believe that the Ang-2 effect has a beneficial role in not just stabilizing the branching vascular network but actually closing polyp stamp,” he added.

“In terms of PCV, our multicenter study results reported that about 52% of patients with PCV had complete regression of polypoidal lesions. This is 52%… we still need more detailed study, but that result is not bad,” said Dr. Kataoka. “We will know more when [SALWEEN] finishes recruiting and we’ll have initial data,” added Dr. Koh, referencing the single-arm multicenter phase 3b/4 study of faricimab for PCV that is currently under way.

Results from YOSEMITE and RHINE Trials

Stable Q16W durability with faricimab through 2 years in DME

The combined results of the YOSEMITE and RHINE7 trials showed that robust vision gains and anatomical improvements with faricimab were achieved also for DME patients.

In the largest head-to-head phase 3 trials in DME, faricimab as compared to aflibercept Q8W achieved comparable vision gains, with faricimab patients receiving a median of 3 injections versus 5 injections of aflibercept in year 2.⁹ Fifty percent (50%) of patients treated with faricimab achieved first absence of intraretinal fluid (IRF) 36 weeks earlier than with aflibercept and with fewer injections.¹⁰

Faricimab’s protocoled treat-and-extend (T&E) approach with adjustable dosing up to every 16 weeks is the first individualized treatment regimen to be examined in a double-masked manner. The protocoled T&E approach was used to reflect real-world practice, to achieve maximum vision gains while minimizing patient burdens (i.e. frequency of visits and injections) based on the individual patient’s anatomic, functional and visual responses to treatment.

In Singapore, Dr. Colin Tan has been using faricimab in his clinical practice for more than a year now. Presenting his cases at the APVRS 2023 Congress, Dr. Tan provided evidence of quick anatomical response and vision gains in treatment-naïve patients after the 4 initial every-4-week doses, reflecting clinical trial results. “Faricimab demonstrated a very rapid anatomic improvement after the first injection and then was able manage on the treat-and-extend regimen,” he summarized. Eventually, his patients [in cases presented] are put on the 16-week interval fixed dosing.

“Treatment with faricimab led to rapid improvements in vision and anatomic outcomes. I am very happy with this response,” shared Dr. Tan.

Dr. Michael Singer (USA) referred to faricimab as the “stronger and longer phenomena” in the treatment of DME. “Having an agent that has dual pathway, I sleep better at night,” said Dr. Singer.

Dr. Mali Okada (Australia) whose patients often have complex issues couldn’t agree more with her co-speakers. “DME is a multifactorial disease and we do need different ways of treating them,” she shared. “When the patient is not improving, regardless… have another step back and see what the other contributing factors are… and make sure you did not miss anything,” explained Dr. Okada of her approach in treating complex cases.

In Australia, where patients have access to all drugs equally, Dr. Okada is advocating to be braver and give patients the best option available. “If [patients] do sub-optimally with another drug, and you tell them, oh I’ve got a potentially better one for you, and they’d say then why didn’t you start off with that in the first place? We should be braver in using this [faricimab] as the first line,” she concluded.

Dual pathway for better disease control and treatment durability

Faricimab is changing the treatment paradigm in retinal diseases. In both nAMD and DME, clinical and real- world data suggest that individualized faricimab dosing up to Q16W controls anatomic outcomes and maintains vision, with fewer injections vs aflibercept Q8W, through 2 years.^5,7 Data from clinical trials showed that faricimab was well tolerated with a safety profile comparable to aflibercept. Based on real-world experience so far, faricimab’s benefit- risk profile remains favorable.

Faricimab is now approved in more than 90 countries worldwide, including Singapore, for the treatment of nAMD and DME, with more than 2 million doses distributed.³

Scan or click here www.roche.com.sg/pharma/vabysmo to get in touch with Roche Singapore, for more information about Vabysmo (faricimab).

Editor’s Note: The 16th Congress of the Asia-Pacific Vitreo-retina Society (APVRS 2023) was held from 8 to 10 December in Hong Kong. Reporting for this story took place during the event. 

References

1. Chaudhary V, Kotecha A, Willis J, et al. Individualized faricimab dosing up to every 16 weeks maintains robust anatomic and vision outcomes through 2 years in nAMD. (ARVO Annual Meeting Abstract, June 2023). Investig Ophthalmol Vis Sci. 2023; 64(8):5056.
2. Querques G, London N, Kotecha A, et al. Faricimab rapidly improves fluid parameters in patients with nAMD. (ARVO Annual Meeting Abstract, June 2023). Investig Ophthalmol Vis Sci. 2023;64(8):2185.
3. Roche data on file.
4. Lambert NG, ElShelmani H, Singh MK, et al. Risk factors and biomarkers of age-related macular degeneration. Prog Retin Eye Res. 2016;54:64-102. 
5. Heier JS, Khanani AM, Quezada Ruiz C, et al; TENAYA and LUCERNE Investigators. Efficacy, durability, and safety of intravitreal faricimab up to every 16 weeks for neovascular age-related macular degeneration (TENAYA and LUCERNE): two randomised, double-masked, phase 3, non-inferiority trials Lancet. 2022;399(10326):729-740. 
6. Mukai R, Kataoka K, Tanaka K, et al. Three-month outcomes of faricimab loading therapy for wet age-related macular degeneration in Japan. Sci Rep. 2023;13(1):8747. 
7. Wykoff CC, Abreu F, Adamis AP, et al; YOSEMITE and RHINE Investigators. Efficacy, durability, and safety of intravitreal faricimab with extended dosing up to every 16 weeks in patients with diabetic macular oedema (YOSEMITE and RHINE): two randomised, double-masked, phase 3 trials. Lancet. 2022;399(10326):741-755. 
8. Wong TY, Haskova Z, Asik K, et al; YOSEMITE and RHINE Investigators. Faricimab Treat-and-Extend for Diabetic Macular Edema: 2-Year Results from the Randomized Phase 3 YOSEMITE and RHINE Trials. Ophthalmology. 2023:S0161-6420(23)00933-8. 
9. Lim JI, Chen S-J, Steinle N, et al. Durable vision gains and greater fluid control with extended faricimab dosing vs aflibercept in patients with DME. (ARVO Annual Meeting Abstract, June 2023). Investig Ophthalmol Vis Sci. 2023; 64(8):2815.
10. Pollreisz A, Camino C, Gibson K, et al. Faster time to retinal fluid control with faricimab versus aflibercept in patients with DME in the phase 3 YOSEMITE/RHINE trials. (ARVO Annual Meeting Abstract, June 2023). Investig Ophthalmol Vis Sci. 2023; 64(8):2817.

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