Angiogenesis 2022 – Regeneron and Bayer see positive signs for long-acting Eylea
The omens look good for the upcoming Pulsar readout, but can Eylea keep its wet AMD stranglehold?
Roche recently got approval for a new wet age-related macular degeneration drug, Vabysmo, but Regeneron and Bayer are not ready to give up their crown. The companies’ strategy of developing a high-dose, long-acting version of their blockbuster Eylea got a boost over the weekend with full data from the phase 2 Candela study.
The data bolster confidence before readout of the phase 3 Pulsar study in wet AMD, due in the second half. Regeneron and Bayer are not only fending off other long-acting contenders, including Kodiak Sciences, whose pivotal data are imminent, but also biosimilar competition: Eylea’s patents are set to start expiring in 2023.
However, the question is whether dosing every 12 or 16 weeks, versus every eight weeks currently with Eylea, will really make a difference for patients in the absence of clearly better efficacy – something the companies have yet to show even with this new readout. And whether the intellectual property over the high dose is enforceable will only become apparent if and when a challenge emerges.
Candela in the wind
Eylea is approved at 2mg, which is given every eight weeks after an initial loading period. The high-dose version comprises 8mg of Eylea’s active ingredient, aflibercept, in a novel formulation, which the groups hope could be dosed as infrequently as every 16 weeks.
The aim is at least to show similar efficacy to standard-dose Eylea, with a more convenient dosing schedule, and the companies seem to be on track here: as Regeneron disclosed in August, the high-dose version numerically outperformed standard Eylea in the 106-patient Candela trial in terms of the proportion of subjects without fluid in the macula of the eye at 16 weeks.
However, this assessment came after a more conventional dosing schedule: both doses were being given monthly for the first two months.
Only then was less frequent dosing implemented, again for both cohorts, which received therapy every 12 weeks, at weeks 20 and 32.
Thus the long-term data, presented on Saturday at the Angiogenesis annual meeting, gave the first clues about how high-dose Eylea will fare with less frequent dosing.
Perhaps most intriguing were data on best-corrected visual acuity. At 44 weeks those in the high-dose group showed an improvement of 7.9 letters, versus a 5.1-letter gain with standard Eylea. However, this was far from statistically significant, and it is unclear whether high-dose Eylea would need to be superior to standard Eylea to gain a foothold in the market, especially once biosimilars are available.
The primary endpoint of the upcoming Pulsar trial, which is testing high-dose Eylea dosed at 12 and 16 weeks versus 2mg Eylea dosed every eight weeks, is BCVA at week 48.
|Low vs high-dose Eylea: data from the phase 2 Candela trial|
|Endpoint||High-dose Eylea (8mg)||Standard Eylea (2mg)||p value|
|Proportion of eyes without fluid in the centre subfield at wk 16*||51%||34%||0.0770|
|Proportion of eyes without fluid in the macula at wk 16||43%||26%||0.0667|
|Proportion of eyes without fluid in the centre subfield at wk 44||40%||28%||0.2185**|
|Mean change from baseline in BCVA at wk 44||7.9 letters||5.1 letters||0.1957**|
|*Primary efficacy endpoint; **Nominal p value. Source: company presentation.|
Safety will be just as important as efficacy, and Candela also appears to bode well here. Rates of adverse events were similar between high and low-dose Eylea, and there were no cases of serious intraocular inflammation.
However, in the 8mg cohort there were two retinal tears and four cases of vitreous detachment, versus none and two respectively in the 2mg arm, so investors will no doubt be keeping an eye on these.
The next big event in wet AMD is readout of Kodiak Sciences’ pivotal Dazzle trial of its long-acting project KSI-301, due this quarter. The group hopes to extend dosing to every 20 weeks.
Others are looking to go even further, with several potential one-time therapies in development. The most advanced is Regenxbio’s gene therapy RGX-314, recently partnered with Abbvie.
Still, these groups will have a hard task going up against Eylea. As Regeneron’s chief executive officer, Len Schleifer, said during the group’s fourth-quarter call: “It seems like every single year for the last decade there has been a threat to Eylea that a variety of number of people have predicted would be the next thing to displace Eylea.” Maybe the only thing that can replace Eylea is Eylea itself.
|Selected long-acting wet AMD projects|
|KSI-301||Kodiak Sciences||Intravitreal VEGF-A inhibitor||Up to 20 weeks||Ph2/3 Dazzle: Q12-20W KSI-301 vs Q8W Eylea; data due Q1 2022; ph3 Daylight: Q8W KSI-301 vs Q8W Eylea; data due Q1 2023|
|8mg Eylea||Regeneron/Bayer||Intravitreal VEGF-A inhibitor||Every 12 & 16 weeks||Ph3 Pulsar: 8mg Q12-16W vs 2mg Q8W; data due H2 2022|
|RGX-314 Subretinal||Regenxbio/Abbvie||Subretinal AAV8 anti-VEGF gene therapy||One-time therapy||Ph2/3 Atmosphere: RGX-314 vs Q4W Lucentis completes Mar 2023; ph3 Ascent began Jan 2022|
|RGX-314 Suprachoroidal||Regenxbio/Abbvie||Suprachoroidal AAV8 anti-VEGF gene therapy||One-time therapy||Ph2 Aaviate cohort 2 data reported Nov 2021; high-dose cohort 4 data due 2022|
|GB-102||Graybug Vision||Microparticle depot formulation of pan-VEGF inhibitor||Every 6 months||Ph2 Altissimo disappointed; seeking partner for additional trials|
|CLS-AX||Clearside Biomedical||Suprachoroidal pan-VEGF inhibitor||Every 6-12 months||Ph1/2 Oasis cohort 2 data reported Dec 2021; high-dose cohort 3 data due mid-2022|
|4D-150||4D Molecular Therapeutics||Intravitreal R100 vector (AAV) anti-VEGF/PlGF gene therapy||One-time therapy||Ph1/2 began Jan 2022|
|ADVM-022||Adverum Biotechnologies||Intravitreal AAV.7m8 anti-VEGF gene therapy||One-time therapy||Ph2 wet AMD trial planned for Q3 2022 despite toxicity signal in diabetic macular oedema|
|EYP-1901||Eyepoint Pharmaceuticals||Intravitreal sustained-delivery system with VEGF inhibitor||Every 6 months||Ph1 Davio data reported Feb 2022; ph2 to start Q3 2022|
|OTX-TKI||Ocular Therapeutix||Intravitreal implant, pan-VEGF inhibitor||Every 6 months or longer||Ph1 Australia trial completes Dec 2022; ph1 US trial enrolling|
|Source: Evaluate Pharma & clinicaltrials.gov.|