The introduction of medications has had a revolutionary impact on the practice of
For many patients with blinding eye conditions like and , provided the first hope for meaningful visual recovery.
and DME are two leading causes of vision loss among adults worldwide. The BLA submission is based on positive results across four phase III studies in nAMD and DME.
The studies consistently showed that faricimab, given at intervals of up to four months, offered non-inferior vision gains compared with aflibercept, given every two months.
Approximately half of people eligible for extended dosing with faricimab were able to be treated every four months in the first year in the in nAMD and the YOSEMITE and RHINE studies in DME.
Faricimab is the first injectable eye medicine to achieve this length of time between treatments in phase III studies for nAMD and DME.
Furthermore, approximately three-quarters of people eligible for extended dosing with faricimab were able to be treated every three months or longer in the first year.
Faricimab was generally well-tolerated in all four studies, with no new or unexpected safety signals identified.
Faricimab will be the first and only bispecific antibody designed for the eye, if approved. It targets two distinct pathways – via and – that drive a number of retinal conditions that can cause vision loss.
In ophthalmology, many diseases are related to vascular abnormalities. For example, and which are the leading causes of visual loss, are due to abnormal retinal or , respectively.
serves as a therapeutic principle in ophthalmology. A popular strategy is to block signaling pathways involved in or in eyes.
or block the same pathway at two points. Therefore BsAbs are great drug formats for next-generation therapeutics in the pharmaceutical industry for ocular disease treatment.
ushers in a new era for retina specialists and their patients with the potential to have a triple effect: inhibition of the disease processes of and improvement of visual acuity, and reduction of patient treatment burden.
Faricimab, the only injectable treatment simultaneously approved by the FDA to treat both wet AMD and DME, facilitates flexible dosing regimens based on the patient’s anatomy and their visual outcomes.
“Vabysmo represents an important step forward for ophthalmology. It is the first bispecific antibody approved for the eye,” noted Charles Wykoff, MD, PhD, director of research at Retina Consultants of Texas in Houston and a faricimab phase 3 investigator.
“With Vabysmo, we now have the opportunity to offer patients a medicine that could improve their vision and potentially lower the treatment burden with fewer injections over time.” The hope is that faricimab will be available to be prescribed to patients in the coming weeks.
The mechanism of faricimab - The beauty of the formulation lies in the drug’s dual activity. “It does more than block a single cytokine,” Wykoff said.
“The current VEGF agents such as , and block only the VEGF pathway.
Vabysmo is unique in that in addition to blocking the same VEGF pathway, it also blocks a separate one, the . With the neutralization of Ang-2, the is activated.”
This scenario differs from the activity of the anti-VEGF therapies. When VEGF is inhibited, signaling through its receptors is decreased. The blocking of Ang-2 allows activation of a specific pathway moderated by Tie-2, a very different cellular response.
“The thought is that inhibiting both VEGF and Ang-2 is complementary and can achieve improved anatomic outcomes,” Wykoff said.
These disease pathways seem to work by destabilizing the blood vessels, which can result in the formation of new leaky blood vessels and increased ocular inflammation.
According to Wykoff, the process of inhibiting both pathways results in stabilization of the blood vessels and subsequent decreased leaking and inflammation.
The activity of these 2 pathways resulting from faricimab is responsible for the increased intervals between treatments in most study patients compared with patients receiving the anti-VEGF therapies.
With the individualized dosing of patients across 4 phase 3 trials, Wykoff said approximately 50% of patients could go 4 months between treatments and approximately 75% could go 3 months or more between treatments.
Wykoff also noted that although not definitive at this point, faricimab appears to have increased durability.
The approval of faricimab was based on results from 4 randomly assigned, multicenter, double-masked, global phase 3 studies, all of which showed consistent beneficial treatment effects in patients with wet AMD and DME.
After patients received the first 4 monthly doses of faricimab, when the drug was administered at up to 4-month intervals, the results equaled those achieved with aflibercept administered every 2 months during the first treatment year.
Patients generally tolerated faricimab well. The most frequently seen adverse effect was conjunctival hemorrhage in 7% of patients. Patients treated monthly with faricimab and aflibercept did not show increased retinal toxicity.
In clinical practice, treatment will consist of a series of 4 initial monthly injections, followed by a flexible treatment schedule from 1 to 4 months apart based on a physician’s evaluation of the patient’s anatomy and vision outcomes.
“The package insert is relatively inclusive,” Wykoff said. “When needed, patients can be treated on a monthly basis, and there certainly is the option for less frequent dosing. In most cases, physicians can use Vabysmo as required by the patients.”
TENAYA and LUCERNE trials - The TENAYA (NCT03823287) and LUCERNE (NCT03823300) studies included 1329 patients with wet AMD.
The results of these trials showed average increases in the visual acuity of +5.8 and +6.6 letters, respectively, in patients treated with 6.0-mg doses of faricimab at the 1-year evaluation compared with +5.1 and +6.6 letters in patients treated with 2.0-mg doses of aflibercept.
Wykoff said the results also highlighted the decreased treatment burden in patients who received faricimab: Forty-six% in the TENAYA study and 45% in the LUCERNE study were treated every 4 months during the first year; another 34% and 33% of patients, respectively, were treated every 3 months.
Those data indicated that 80% of patients did not require treatment for 3 months or more during the fi rst year. The visual results showed that the central subfield thickness (CST) decreased comparably, as did the size and area of the choroidal neovascularization, along with the visual improvements.
“The visual benefits with Vabysmo given at up to 16-week intervals demonstrate its potential to meaningfully extend the time between treatments with sustained effi cacy, thereby reducing treatment burden in patients with ,” the study’s authors concluded.
In the YOSEMITE (NCT03622580) and RHINE (NCT03622593) studies that included 1891 patients with DME, the faricimab results achieved with the 6.0-mg doses were comparable with those achieved with the 2.0-mg doses of afl ibercept, with average letter gains of +11.6 and +10.8 in the faricimab treat-and-extend (TAE) arms, +10.7 and +11.8 letters in the 2-month arms, and +10.9 and +10.3 letters in the afl ibercept arms, respectively.
Regarding the treatment burden, 53% of those in the faricimab TAE arm in the YOSEMITE study and 51% in the RHINE study were treated every 4 months during the fi rst year; an additional 21% and 20%, respectively, were treated every 3 months.
This again indicated most patients (70%) in the TAE faricimab arm required dosing after 3 months or more during the first year. The CST decrease and resolution of intraretinal fluid that occurred throughout the first year favored faricimab versus aflibercept.
In addition to the treatment regimens described, another approved regimen for DME involves 6 monthly loading doses, followed by treatment every 2 months.
Patients with wet AMD and DME also can undergo monthly treatments as needed, although the study investigators pointed out that additional efficacy was not observed with monthly dosing.
“Robust vision gains and anatomical improvements with Vabysmo were achieved with adjustable dosing up to every 16 weeks, demonstrating the potential for Vabysmo to extend the durability of treatment for patients with .”
Extension studies Extension studies are under way: AVONELLE-X (NCT04777201), the extension study of TENAYA and LUCERNE, is evaluating the long-term safety and tolerability of faricimab in wet AMD.
RHONE-X (NCT0443283), the extension study of the YOSEMITE and RHINE studies, is investigating the long-term safety and tolerability of faricimab for DME. Investigators are also considering the potential benefi ts of faricimab for other retinal diseases.
The COMINO (NCT04740931) and BALATON (NCT04740905) trials are evaluating the efficacy and safety of the drug in patients with macular edema subsequent to retinal vein occlusion.
“The most exciting consideration is that we now have a next-generation pharmacotherapy that achieves what we know to be important in the treatment process, namely, inhibition of VEGFA, that also blocks a new cytokine, Ang2,” Wykoff concluded.
“There is a tremendous amount of preclinical data and strong clinical rational implicating Ang-2 in the pathophysiology of exudative retinal diseases, including DME and neovascular AMD.
We now have a molecule that can block both pathways. There is tremendous promise that patients can achieve optimal outcomes with fewer injections over time.”