Regeneron’s efforts to extend the lifespan of its blockbuster Eylea franchise via combinations have fallen flat again, raising the question of whether it can find anything that can best Eylea alone.
With competition on the horizon from Novartis’s rival wet age-related macular degeneration (AMD) project, brolucizumab, Eylea sales are forecast to flatten after 2020 – something that Regeneron cannot now counter with combos (see table below).
Regeneron’s stock was down 3% in premarket trading this morning, but the shares opened down just 1%.
Investors might have been reassured by the fact that full data from the Hawk and Harrier studies of brolucizumab, released earlier this month, were not the smash hit that Novartis had hoped for. This could allow Eylea to keep its dominant position in the wet age-related macular degeneration (AMD) market for some time to come.
|Top wet AMD drugs in 2022|
|Annual indication sales ($m)|
And if positive, the phase III Panorama study of Eylea monotherapy in diabetic retinopathy, due to report in the first half of next year, could open up another avenue for growth for the company’s most valuable product.
But even the most optimistic Regeneron bulls will have to admit that Eylea’s sales are likely to be eroded by the market entry of brolucizumab, expected in 2019 or 2020.
Although the Novartis project has merely shown noninferiority to Eylea, it could have the advantage of being dosed every 12 weeks, compared with every eight weeks for Eylea (Brolucizumab provides some comfort for Novartis, June 20, 2017).
This is not incidental for drugs that are injected into the eye; Regeneron plans to file for FDA approval of every-12-week dosing for Eylea in AMD by the end of the year.
How Novartis chooses to price brolucizumab could also be a big factor affecting its uptake.
EvaluatePharma sellside consensus has Eylea sales peaking at $7bn in 2020, before declining – and this trajectory can only get worse for Regeneron once the product loses patent protection in 2023.
|The rise and fall of Eylea|
|Annual Eylea sales ($m)|
|Regeneron Pharmaceuticals||3,323||3,889||4,108||4,184||USA; Japan (33.5-40% royalties); WW ex USA & Japan (50:50 profit-share with Bayer for eye diseases)|
|Bayer||1,798||2,172||2,444||2,191||WW ex USA & Japan (50:50 profit-share with Regeneron Pharmaceuticals); Japan (co-promotion with Santen Pharmaceuticals)|
|Santen Pharmaceutical||418||474||464||452||Japan (co-promotion with Bayer)|
This helps explain why the company has been so keen on carrying out combo studies. This long-term life-cycle management strategy seemed sensible, but has failed to pay off.
The latest disappointment came from the pairing of Eylea and the anti-angiopoietin-2 (ANG2) MAb nesvacumab, which was being tested in the phase II Ruby and Onyx trials in diabetic macular oedema and wet AMD respectively.
The studies compared the Eylea/nesvacumab combination versus Eylea monotherapy; both had a primary endpoint of change in best-corrected visual acuity (BCVA) between weeks 12 and 36.
Regeneron did not disclose any data, but did say that there were no new safety signals, so presumably the combination was no more effective than Eylea alone.
The failure could be bad news for Roche, which has an anti-VEGF/ANG2 bispecific antibody, called RG7716, in mid-stage development in various eye disorders including wet AMD.
The Eylea/nesvacumab combo had been Regeneron’s plan B after the failure of the Capella trial of Eylea plus rinucumab, an anti-PDGF MAb, just over a year ago (Regeneron failure is one in the eye for Ophthotech, October 3, 2016).
A similar approach, combining Ophthotech’s Fovista with Lucentis, Avastin or Eylea, flunked soon after, leaving Ophthotech to focus on Zimura, which is in trials in both dry and wet AMD.
Other potential rivals to Eylea include OHR Pharmaceutical’s squalamine eye drops, which are due to report phase III data early next year. Previously, though, eye drops have had trouble reaching the back of the eye where abnormal blood vessel growth occurs.
|Upcoming competitor readouts in ophthalmology|
|Squalamine||OHR Pharmaceutical||Mako, squalamine + Lucentis in wet AMD||NCT02727881||Jan 2018|
|RG7716||Roche||Avenue, AMD patients with choroidal neovascularisation||NCT02484690||2018|
|RG7716||Roche||Boulevard, diabetic macular oedema||NCT02699450||2018|
|RG7716||Roche||Stairway, wet AMD||NCT03038880||2018|
|Abicipar||Molecular Partners/Allergan||Sequoia, vs Lucentis in wet AMD||NCT02462486||H2 2018|
|Abicipar||Molecular Partners/Allergan||Cedar, vs Lucentis in wet AMD||NCT02462928||H2 2018|
Meanwhile, Molecular Partners/Allergan’s abicipar is up against Lucentis in two ongoing phase III trials that could report initial data as early as 2018. Biosimilar Avastin could also take a chunk of Eylea sales – Avastin is not approved for AMD but is used off-label.
For now, the biggest threat comes from brolucizumab. While this might not turn out to be the fearsome competitor some had feared, the faltering combo strategy means that Regeneron will now have a harder time defending its Eylea franchise as it waits for other products to pick up the slack.
|Ruby||Phase II, Eylea + nesvacumab in diabetic macular oedema||NCT02712008||Failed|
|Onyx||Phase II, Eylea + nesvacumab in wet AMD||NCT02713204||Failed|
|Panorama||Phase III, Eylea monotherapy in diabetic retinopathy||NCT02718326||H1 2018|