Why wet AMD drug Izervay’s eligibility became limited in Korea

Restriction reflects exclusion of patients with central foveal involvement from clinical trials

Indication specifies ‘slowing progression’ rather than ‘treatment’

The specific rationale behind the strict restriction of Izervay’s eligible patient population to those with a preserved foveal center has been disclosed following the drug’s approval on Sept. 23 as Korea’s first treatment to slow the progression of geographic atrophy (GA) secondary to dry age-related macular degeneration (AMD).

According to minutes of the June 10 meeting of the Central Pharmaceutical Affairs Council released by the Ministry of Food and Drug Safety (MFDS), council members closely reviewed the pivotal clinical trial design and adverse event monitoring data before ultimately endorsing the MFDS’ proposed indication, which was more restrictive than that initially sought by Astellas Pharma Korea. The council nevertheless supported the approval, concluding that the drug’s benefits outweighed its risks.

Clinical trial design leads to ‘preserved foveal center’ restriction...‘treatment’ replaced with ‘slowing progression’

One of the central issues in the review was the scope of the patient population covered by the indication. The MFDS proposed limiting the indication to ‘patients whose foveal center had not been involved (preserved).’

When a council member questioned whether this would restrict the eligible population too narrowly, the MFDS explained, “We proposed the revised indication in consideration of the fact that patients with central foveal involvement were excluded from the clinical trials.”

Ophthalmology specialists on the council agreed, noting that “given the nature of the disease, in which geographic atrophy lesions progressively expand and central vision is lost once they reach the foveal center, it is appropriate to limit the indication to patients with a preserved foveal center.”

The council also agreed to replace “treatment” with “slowing progression” in the indication, reflecting the drug’s pharmacological effect of slowing lesion expansion rather than restoring vision that has already been lost.

No improvement in vision, CNV risk debated...benefits outweigh risks in 6-2 vote

The risk-benefit assessment of Izervay prompted extensive debate, particularly over the risk of choroidal neovascularization (CNV) observed in clinical trials and the ‘absence of improvement in central vision.’

Some council members argued, “What patients actually experience is their vision. If the drug does not improve vision and the development of CNV requires additional anti-VEGF injections, it is difficult to say there is no associated harm. The differing conclusions reached by the US FDA and European EMA should also be taken into consideration.”

Most members, however, took the view that “with no adequate treatment available for dry AMD, the drug should be approached as a therapy that slows disease progression, similar to treatments for dementia. The ability to inhibit the growth of GA lesions and thereby help preserve central vision provides sufficient clinical benefit.” Ultimately, the council voted 6-2 that the drug’s benefits outweighed its risks.

The dosing regimen and risk-management measures were also strengthened to further ensure safety.

Council members noted data showing that after 12 months, when dosing switched to every other month, the incidence of CNV declined to a level similar to that in the placebo group. To minimize the drug’s risks, the council therefore finalized a dosing regimen requiring ‘administration every 2 months after the first year’

Given that Izervay is administered by invasive intravitreal injection and requires careful management of adverse-event risks, the council also decided to strengthen its Risk Management Plan (RMP), including additional educational materials for experts (healthcare professionals).

Izervay has therefore entered the Korean market as the country’s first therapy to slow GA progression in patients with a ‘preserved foveal center,’ following a rigorous scientific review by the MFDS and the Central Pharmaceutical Affairs Council aimed at delaying the risk of vision loss.