From OSN Europe

Lampalizumab offers realistic hope for atrophic AMD

The phase 3 Chroma and Spectri trials are attempting to replicate the good results of the phase 2 MAHALO study.

Lampalizumab may offer hope for people affected by atrophic age-related macular degeneration. Phase 3 trials are ongoing, and research is focusing on identifying patients who may better respond to the treatment.

“We should be grateful for every small step forward, as atrophic AMD is the most difficult form of the disease. In wet AMD we treat to destroy something abnormal, while here we are trying to move forward the internal clock of cells that are programmed to die, which is an infinitely greater challenge,” Jordi Monés, MD, PhD, said in an interview with Ocular Surgery News.

Monés is one of the investigators of the Chroma trial, which, together with the Spectri trial, is evaluating lampalizumab (Roche) for the treatment of geographic atrophy (GA) in atrophic AMD. The phase 2 proof-of-concept MAHALO study showed a 20% reduction in the area of geographic atrophy with monthly treatment, rising to 44% in a biomarker-defined subset.

“If the results of MAHALO can be replicated in a larger group of patients, Roche will start the procedure to register this drug for the treatment of geographic atrophy,” Monés said.

Jordi Monés

Defining the target

In the last 10 years, there has been evidence that overactivation of the complement pathway is involved in the pathogenesis of AMD, both wet and atrophic. Gene mutations lead to overactivation of the complement pathway and to “an abnormal, constant anti-inflammatory reaction,” which destroys normal cells, Monés explained. Lampalizumab inhibits the complement factor D, thus interfering with the activation of the complement pathway.

The MAHALO study also found that treatment efficacy is correlated to specific genetic factors. Patients who are complement factor I-positive have by natural history a much worse outcome but benefit more from the treatment.

“GA reduction in this specific group was 44% with monthly injection,” Monés said.

The target population for lampalizumab is patients at risk of losing vision in a relatively short term because of fast disease progression.

“We don’t want to treat end-term patients that already have 20/200 vision because it would make no sense to avoid these lesions to get larger. We want to intervene relatively early, but not on someone with almost no GA that will take years to develop. We want patients with small to medium lesions that we anticipate will progress fast and can still benefit from the treatment,” he said.

Studies are ongoing to identify fast progressors based on genetic and biological markers, phenotyping and morphological tests.

“There is still a lot to do in terms of defining who are the patients at a high risk of progression. We don’t want to mix slow and fast progressors. We are already addressing this in the trials but need to further improve our criteria,” Monés said.

Promising treatment

Lampalizumab is the only treatment for atrophic AMD that is in phase 3, and it will be in a good position if phase 2 results are proven. Several other drugs have failed or are still in phase 1 or 2.

“We are trying to identify what can prevent progression when AMD is still in the drusen stage, but nothing has yet been found,” Monés said. “With lampalizumab we are addressing the late stages, and the idea is not to stop the progression but slow it down as much as possible.”

The Chroma and Spectri trials are identically designed to compare the safety and efficacy of 10-mg lampalizumab injections every 4 or 6 weeks vs. sham injections. Each study is aimed at enrolling nearly 1,000 patients from approximately 300 sites in 24 countries worldwide. Study completion is expected by September 2018.

With 12 patients, Monés is one of the highest recruiters, but due to the masked nature of the study, he has no access to interim results.

“What I can say is that we haven’t had any major adverse event, any alarm or warning. Lampalizumab appears to be a very safe drug. Minor complications may be related to the injection procedure, but we are so used to injecting eyes that the chances of infections are probably one out of 3,000,” he said.

Two other trials, the Proxima A and Proxima B observational trials, are collecting additional scientific data on the progression of geographic atrophy and on the relationship between genetics and progression.

“There is still a lot be learned. At this time we have got to be humble. This drug does not have a ‘wow’ effect, but we should be grateful to have something that gives us hope,” Monés said. – by Michela Cimberle

Disclosure: Monés reports he is a consultant for Alcon, Bayer, Novartis and Roche.

Lampalizumab may offer hope for people affected by atrophic age-related macular degeneration. Phase 3 trials are ongoing, and research is focusing on identifying patients who may better respond to the treatment.

“We should be grateful for every small step forward, as atrophic AMD is the most difficult form of the disease. In wet AMD we treat to destroy something abnormal, while here we are trying to move forward the internal clock of cells that are programmed to die, which is an infinitely greater challenge,” Jordi Monés, MD, PhD, said in an interview with Ocular Surgery News.

Monés is one of the investigators of the Chroma trial, which, together with the Spectri trial, is evaluating lampalizumab (Roche) for the treatment of geographic atrophy (GA) in atrophic AMD. The phase 2 proof-of-concept MAHALO study showed a 20% reduction in the area of geographic atrophy with monthly treatment, rising to 44% in a biomarker-defined subset.

“If the results of MAHALO can be replicated in a larger group of patients, Roche will start the procedure to register this drug for the treatment of geographic atrophy,” Monés said.

Jordi Monés

Defining the target

In the last 10 years, there has been evidence that overactivation of the complement pathway is involved in the pathogenesis of AMD, both wet and atrophic. Gene mutations lead to overactivation of the complement pathway and to “an abnormal, constant anti-inflammatory reaction,” which destroys normal cells, Monés explained. Lampalizumab inhibits the complement factor D, thus interfering with the activation of the complement pathway.

The MAHALO study also found that treatment efficacy is correlated to specific genetic factors. Patients who are complement factor I-positive have by natural history a much worse outcome but benefit more from the treatment.

“GA reduction in this specific group was 44% with monthly injection,” Monés said.

The target population for lampalizumab is patients at risk of losing vision in a relatively short term because of fast disease progression.

“We don’t want to treat end-term patients that already have 20/200 vision because it would make no sense to avoid these lesions to get larger. We want to intervene relatively early, but not on someone with almost no GA that will take years to develop. We want patients with small to medium lesions that we anticipate will progress fast and can still benefit from the treatment,” he said.

Studies are ongoing to identify fast progressors based on genetic and biological markers, phenotyping and morphological tests.

“There is still a lot to do in terms of defining who are the patients at a high risk of progression. We don’t want to mix slow and fast progressors. We are already addressing this in the trials but need to further improve our criteria,” Monés said.

Promising treatment

Lampalizumab is the only treatment for atrophic AMD that is in phase 3, and it will be in a good position if phase 2 results are proven. Several other drugs have failed or are still in phase 1 or 2.

“We are trying to identify what can prevent progression when AMD is still in the drusen stage, but nothing has yet been found,” Monés said. “With lampalizumab we are addressing the late stages, and the idea is not to stop the progression but slow it down as much as possible.”

The Chroma and Spectri trials are identically designed to compare the safety and efficacy of 10-mg lampalizumab injections every 4 or 6 weeks vs. sham injections. Each study is aimed at enrolling nearly 1,000 patients from approximately 300 sites in 24 countries worldwide. Study completion is expected by September 2018.

With 12 patients, Monés is one of the highest recruiters, but due to the masked nature of the study, he has no access to interim results.

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“What I can say is that we haven’t had any major adverse event, any alarm or warning. Lampalizumab appears to be a very safe drug. Minor complications may be related to the injection procedure, but we are so used to injecting eyes that the chances of infections are probably one out of 3,000,” he said.

Two other trials, the Proxima A and Proxima B observational trials, are collecting additional scientific data on the progression of geographic atrophy and on the relationship between genetics and progression.

“There is still a lot be learned. At this time we have got to be humble. This drug does not have a ‘wow’ effect, but we should be grateful to have something that gives us hope,” Monés said. – by Michela Cimberle

Disclosure: Monés reports he is a consultant for Alcon, Bayer, Novartis and Roche.