Failure of first lampalizumab Phase III study could delay availability

19th September 2017 (Last Updated September 19th, 2017 05:29)

Roche’s announcement of the failure of its first Phase III trial of lampalizumab, named SPECTRI, is disappointing following its successful Phase II trials.

Roche’s announcement of the failure of its first Phase III trial of lampalizumab, named SPECTRI, is disappointing following its successful Phase II trials. Lampalizumab’s potential to become the first ever treatment for patients with geographic atrophy (GA), the advanced form of dry age-related macular degeneration (AMD), is now uncertain.

Millions of people who suffer from GA are awaiting an effective therapy that could prevent them from losing central vision as a result of atrophy of photoreceptor cells in the central retina, or macula. According to GlobalData’s epidemiologists, over 2.5 million people have GA within the seven major markets (7MM:  US, France, Germany, Italy, Spain, the UK, and Japan).

Unlike for wet AMD, where effective treatments have been available for over a decade, dry AMD patients have no treatments to stop or slow the progression of this vision-threatening disease.

Over activation of the complement pathway has been implicated in the pathogenesis of AMD, and lampalizumab is a complement factor D inhibitor. Despite this pathway’s role in the progression of AMD, however, a number of complement inhibitors have already failed clinical development in AMD, including Alcon’s POT-4 (also known as APL-1), and Alexion’s C5 antibody, Soliris.

The Phase II lampalizumab study (MAHALO) showed a 20% reduction in GA lesion progression in GA patients treated monthly with intravitreal injections of lampalizumab, as compared with sham injections, and a 44% reduction in the subpopulation of GA patients who were positive for complement factor I (CFI), an exploratory biomarker, at 18 months of the trial. The first Phase III trial of lampalizumab, however, did not meet the primary endpoint of reducing mean change in GA lesion area in patients treated with lampalizumab compared with sham treatment. Subgroup analysis based on the CFI marker has not been reported.

According to KOLs interviewed by GlobalData, the efficacy of lampalizumab will likely be limited to those GA patients with CFI mutation, considerably narrowing the patient pool. Therefore, GlobalData believes that further evaluation of the SPECTRI trial is warranted before conclusions can be drawn. The company announced that it will stop further dosing of patients until the results from the second Phase III study, CHROMA, are evaluated, anticipated in November this year.

There are two other complement inhibitors, Ophthotech’s Zimura, and Apellis’ APL-2, that have reported positive Phase IIa results and that could potentially be suitable for those GA patients who do not benefit from lampalizumab. Zimura is a complement 5 inhibitor and APL-2 is a reformulated version of APL-1, which binds to complement 3. Both of these agents potentially block all downstream complement cascades, including classical, lectin, and alternative complement pathways.

Considering that dry AMD is a multifactorial disease, GlobalData believes that different subgroups of patients may benefit from agents targeting different pathways involved in the pathogenesis of AMD, and that the treatment of this disease will ultimately be moving towards the use of combination therapies.

Allergan’s Brimo DDS (brimonidine tartrate) is currently the only agent in late-stage development for dry AMD that is not a complement inhibitor. Brimo DDS is a neuroprotective drug, formulated as an implant, which is aimed to preserve macular function by preventing apoptosis of viable photoreceptors in patients with GA due to AMD. Based on KOL interviews, GlobalData foresees the use of this agent in combination with complement inhibitors, if any of them proves to be effective for these patients.

Whether or not lampalizumab makes it to market, it is clear that more efficacious treatments and/or combinations of these treatments will be necessary to effectively reduce GA progression in AMD patients. Furthermore, self-administered treatments that can prevent the development of late-stage AMD, GA, and wet AMD, and ultimately agents that can restore photoreceptor function, will need to be developed.