The race to find an effective treatment for geographic atrophy (GA), an advanced form of age-related macular degeneration (AMD) for which no approved treatment exists, has zeroed in on the complement pathway – and among the three lead candidates in this space, Apellis Pharmaceuticals’ APL-2 seems to have the early lead.
Another lead contender, Ophthotech’s Zimura, is undergoing a tweaking of its ongoing Phase II/III clinical trial of monotherapy for GA thanks to the early positive Phase II results of Apellis’ APL-2 and the not-so-positive Phase III results of Roche/Genentech’s lampalizumab for treatment of GA.
To handicap the race at this early stage requires drilling down into the contenders’ performance thus far and taking a look at what’s expected. Here’s a rundown on the three.
APL-2 is a complement factor 3 (C3) inhibitor. A readout of the Phase II FILLY trial showed that APL-2 achieved its primary endpoint, which was the change in GA lesion size from baseline to month 12 in the treatment group compared with sham. APL-2 was administered as an intravitreal injection in the study eye monthly or bimonthly for 12 months, followed by six months of monitoring after the end of treatment.
A monthly intravitreal injection of APL-2 showed a 29% reduction in the rate of GA lesion growth at 12 months compared with sham (p=0.008), and a 20% reduction with bimonthly administration (p=0.067). And a post hoc analysis showed a greater effect during the second six months of the study: a reduction in the growth rate of GA lesions of 47% (p<0.001) with monthly administration, and a reduction of 33% (p=0.01) with bimonthly administration. Going forward, investigators hope to duplicate these results in Phase III trials.
Privately held Apellis secured $60 million in Series E funding days before announcing the FILLY results – boosted by a positive readout of APL-2 for treatment of paroxysmal nocturnal hemoglobinuria (PNH), for which Apellis received European Medicines Agency (EMA) orphan drug designation approval in May. The FILLY trial involves 246 patients at 40 clinical sites, in the US, Australia, and New Zealand.
A couple weeks after Apellis announced the FILLY results, Genentech reported that Spectri, the first of two Phase III trials of lampalizumab for treatment of GA, found no reduction in GA lesions in the lampalizumab group versus sham at 48 weeks. As a result, Genentech announced it was interrupting further dosing in patients until it evaluates results from Chroma, the second Phase III study. “While this result is disappointing, we will continue to evaluate results from Spectri to get a clearer understanding of the data as we await the results of our second Phase III study, Chroma, anticipated in November,” says Sandra Horning, MD, chief medical officer and head of global product development.
Lampalizumab is an antigen-binding fragment (Fab) of a humanized, monoclonal antibody that acts against complement factor D (CFD), a rate-limiting enzyme involved in the activation and amplification of the alternative complement pathway (ACP). Through numerous genetic studies, dysfunction of the ACP has been linked to the pathogenesis of AMD.
Roche Holdings, the parent company of Genentech, saw its stock price drop about 2.5% after Genentech announced the results of the Spectri trial, although the stock has since all but recovered that loss.
Shortly after Genentech reported the Spectri results, Ophthotech revealed that it would modify its ongoing Phase II/III trial of Zimura (avacincaptad pegol) monotherapy in GA. Ophthotech had originally planned to enroll 300 patients in an initial stage of the ongoing trial, with an interim analysis set for 18 months, and to potentially enroll up to an additional 600 patients afterward.
Now, Ophthotech is modifying that trial to accelerate the anticipated timeline to obtain top-line data by reducing the number of patients, shortening the time point for attaining the primary efficacy endpoint, and reducing the costs of the study. The modified study design will incorporate patients already enrolled, the company says.
Zimura targets and inhibits the complement protein C5, a central component of the complement cascade. Inhibition of C5 in the complement cascade prevents the formation of key terminal fragments (C5a and C5b-9) regardless of which of the three complement pathways (classical, lectin, or alternative) induced their generation. C5b-9 is involved in the formation of the membrane attack complex (MAC: C5b-9), which can cause cell death through disruption of the cell membrane. The goal is to inhibit the terminal steps of complement activation at the level of C5.
Ophthotech continues to move ahead with other Zimura programs. It has initiated an open-label Phase IIa trial of Zimura in combination with ranibizumab (Lucentis, Genentech/Roche) in treatment-naive patients with wet AMD. That trial will assess a range of Zimura dosing regimens. Clinical trial sites have been identified and activated.
The company is also on track to initiate two other Zimura trials by year-end: a randomized, controlled clinical trial to assess Zimura monotherapy in Stargardt disease; and an open-label Phase IIa trial evaluating Zimura in combination with anti-VEGF therapy for idiopathic polypoidal choroidal vasculopathy. In 2018, Ophthotech plans to launch a Phase IIa trial of Zimura monotherapy for intermediate/posterior non-infectious uveitis.
On the Right Track, or Pathway
Ophthotech’s stock has had a rough ride since December 2016, when disappointing Phase III results of Fovista (pegpleranib) in combination with Lucentis for wet AMD sent its stock reeling, plunging from $35.79 to around $5 a share over a weekend. Ophthotech’s stock sunk as low as $2.27 a share in May, but the latest series of announcements caused the stock to perk up to around $2.80 a share.
Regardless how you handicap this race, the contenders are all on the right track, or pathway – the complement pathway, that is. “Until now many people have thought the complement pathway may play a role in geographic atrophy, but because of results of the FILLY trial it seems like the complement system does indeed offer some ability to treat the patients to prevent progression of geographic atrophy,” FILLY trial principal investigator David Boyer, MD, of Retina-Vitreous Associates Medical Group in Los Angeles, told the magazine Retina Specialist.