Regeneron brushed off the phase II failure of its co-formulation of Eylea and rinucumab and is already looking towards a new combination for wet age-related macular degeneration. But Ophthotech, which is eagerly awaiting results with a similar combination approach using its AMD drug Fovista, saw its stock fall 15% on the news. Regeneron was down just 1% on Friday.
Some analysts remained optimistic that Regeneron’s failure was not bad news for Ophthotech. But the latest results are a dent in the theory that a dual anti-VEGF/PDGF approach could provide additional benefit over anti-VEGF therapy alone.
Capella falls flat
In fact the data suggest the opposite, with the Capella trial favouring Eylea over the co-formulation of Eylea and rinucumab. There was a greater improvement in best corrected visual acuity (BCVA), the primary endpoint, in the patients that received Eylea alone: 7.5 letters, versus a 5.8 letter improvement in the combination arm.
There were also more adverse events in the patients receiving the combo, known as REGN2176-3, driven by an increase in conjunctival haemorrhage, eye irritation and eye pain.
All of this does not bode well for Ophthotech, which is set to report results from two phase III studies in the fourth quarter, testing its PDGF inhibitor Fovista in combination with the VEGF inhibitor Lucentis (Upcoming events – Fovista results could see Novartis dig deep, and Gilead’s NASH data, September 23, 2016).
Evercore ISI analyst John Scotti put a positive spin on what Regeneron’s results might mean for Ophthotech, citing “three key differences” between Fovista and rinucumab. First, Fovista is an anti-PDGF-B aptamer, while rinucumab is an anti-PDGF MAb; second, Ophthotech’s drug is given as a separate injection, whereas REGN2176-3 involves Eylea and rinucumab being administered via a single injection; and third, the Capella trial measured outcomes at 12 weeks, while the Fovista trials have a 12-month primary endpoint.
Mr Scotti added that Fovista has shown an improvement at 24 weeks in phase II, so presumably a longer-duration trial might favour the drug. But the first two points look like a reach – both drugs inhibit PDGF and it is unclear what advantage, if any, Fovista would gain from being an aptamer rather than a MAb. The same goes for the single over combination injection.
|Fovista phase IIb after 24 weeks||Capella phase II after 12 weeks|
|Drug/dose||Lucentis 0.5mg||Fovista 0.3mg + Lucentis 0.5mg||Fovista 1.5mg + Lucentis 0.5mg||Treatment difference||Eylea + rinucumab||Eylea alone||Treatment difference|
|Mean change in BCVA||6.5 ± 1.09||8.8 ± 1.09||10.6 ± 1.07||4.1 (p=0.019)||5.8||7.5||-1.7|
|Source: Evercore ISI|
Ophthotech is also testing Fovista in combination with Eylea or Avastin, with data expected in mid-2017, but this is another anti-VEGF/PDGF approach so might run into the same hurdles.
Regeneron, meanwhile, has already shifted its attention to a co-formulation of Eylea and the anti-angiopoietin-2 (ANG2) MAb nesvacumab, known as REGN910-3. Like Eylea, this is partnered with Bayer.
Regeneron seems more convinced of the rationale behind the combination of an anti-Ang2 and an anti-VEGF, and this will soon be put to the test with results from phase II trials of REGN910-3 in both AMD and diabetic macular oedema due next year.
Roche also has an anti-VEGF/ANG2 bispecific antibody, called RG7716, in phase II for wet AMD.
Ophthotech's backup plan, Zimura, is two years away from a clinical milestone. Those who had hoped for the Fovista readout to spur a takeout by Novartis, which has ex-US rights to Fovista, now face a nervous wait.
|REGN2176-3||Capella||Eylea co-formulated with rinucumab||NCT02418754|
|REGN910-3||Onyx||Eylea co-formulated with nesvacumab; AMD||NCT02713204|
|REGN910-3||Ruby||Eylea co-formulated with nesvacumab; DME||NCT02712008|
|Fovista||OPH1002||In combination with Lucentis||NCT01944839|
|Fovista||OPH1003||In combination with Lucentis||NCT01940900|
|Fovista||OPH1004||In combination with Eylea or Avastin||NCT01940887|