Regeneron’s Eylea is the dominant drug in wet age-related macular degeneration – and phase III data from a rival project, Allergan/Molecular Partners’s abicipar, look set to do little to change this.
Two pivotal trials of abicipar, Sequoia and Cedar, did meet their primary endpoints, showing non-inferiority over Roche’s older AMD therapy Lucentis on vision stability. But questions over how vision loss was evaluated, as well as a higher incidence of intraocular inflammation with abicipar, raise doubts over whether Allergan’s project is approvable – and, if it is, whether it will be able to compete.
At the moment, abicipar’s main advantage is that it can be administered every 12 weeks, versus Eylea’s approved dosing schedule of every eight weeks; this is not an incidental issue for drugs that are injected into the eye. But this edge might not last for long, with a 12-week dosing schedule for Eylea due a US approval decision by August 11.
True, Eylea, which is set to come off patent in 2023, faces other threats including biosimilars and new contenders like Novartis’s brolucizumab, which has shown non-inferiority to Eylea in phase III.
But after a surprisingly strong performance from Regeneron's star drug in the first quarter, the company will hope that Eylea can prop up its business for a bit longer while it awaits new projects to pick up the slack (Eylea saves Regeneron’s skin, May 3, 2018).
On the latest showing, abicipar looks unlikely to hurt Regeneron’s mega-blockbuster. For a start, the Allergan project has only shown non-inferiority to Lucentis, which itself is inferior to Eylea.
|Abicipar vs Lucentis|
|% of patients with stable vision||% of patients with intraocular inflammation|
|Abicipar Q8||Abicipar Q12||Lucentis Q4||Abicipar Q8||Abicipar Q12||Lucentis Q4|
|Q4=every 4 weeks; Q8=every 8 weeks; Q12=every 12 weeks. Source: company press release.|
Lucentis’s numerically better performance has also raised eyebrows, as have the primary endpoints used in the two trials. Stable vision was defined as the proportion of patients with vision loss of 15 letters or fewer than in best-corrected visual acuity (BCVA) at one year.
Within this definition there could be a broad spread of results, and Evercore ISI’s Umer Raffat noted that 15 points on this scale represented “a lot of vision deterioration”.
It is impossible to know how abicipar really stacks up against Lucentis until absolute BCVA scores are available, but Allergan is not giving details of these, saying it will present full results at an upcoming conference.
Even without these efficacy doubts, the high risk of intraocular inflammation means abicipar might already be done for. Rates of around 15% in both phase III trials are much greater than those seen with Lucentis and Eylea – the latter has inflammation rates of 2-3%, according to its label.
David Nicholson, Allergan’s chief R&D officer, pointed out on a conference call yesterday that earlier formulations of Lucentis had been linked with higher incidences of inflammation, adding that rates of around 13% in AMD were detailed on its label.
Allergan believes that it can also bring down inflammation rates with abicipar, and to this end is testing a new formulation in a 100-patient open-label trial called Maple, which is due to read out in the first half of next year.
The company is not waiting for these data before filing abicipar, with a submission planned in early 2019. Mr Nicholson added that both formulations – that used in Sequoia and Cedar, and the new version administered in Maple – would be included in the original filing.
Mr Nicholson would not be drawn on what level of inflammation incidence would be acceptable in Maple. However, on the same call, Dr Raj Maturi of Indiana University School of Medicine, who was involved in the Cedar study, noted: “If inflammation rates stay at this level or higher I’d have some questions about use.” But he added that he did not expect this to be the case.
Even if inflammation rates do come down significantly abicipar will at best be similar to existing AMD therapies. The drug will have to do better if it is to threaten Eylea.
|Top five wet AMD drugs in 2024|
|Indication sales ($m)|
|Eylea||Regeneron Pharmaceuticals/Bayer||VEGFr kinase inhibitor||Marketed||3,823||3,772|
|Brolucizumab||Novartis||VEGF antibody fragment||Phase III||-||1,480|
|Abicipar||Allergan/Molecular Partners||VEGFr A kinase inhibitor||Phase III||-||328|
|Fovista||Ophthotech||PDGFr B aptamer||Phase III||-||124|