Ophthotech flop opens up Novartis nightmare scenario


Foresight is vital in betting on clinical trial readouts, particularly, it seems, in the case of eye disease drugs. Thus some Ophthotech investors took the hint in October, deserting the stock when a phase II study of Regeneron’s Eylea and rinucumab failed in wet age-related macular degeneration.

They were rewarded today when Ophthotech said its related approach, combining Fovista with Novartis’s Lucentis, flunked two phase III trials. The failure means that an important part of Novartis’s defence against competition for Lucentis has crumbled; things could get even worse for the Swiss firm.

This might come as a surprise since Fovista’s failure, while unequivocal, looks no different from many other R&D disappointments.

The key lies in a separate phase III trial, still ongoing, which combines Ophthotech’s Fovista with either Eylea or Avastin. This study is due to read out next year, and a positive result – a long shot, granted – would give a boost to Lucentis’s two most important challengers.

This would prove particularly galling for Novartis, which had in vain paid Ophthotech $330m in up-front and milestone payments to secure ex-US Fovista rights. Eylea is a VEGFr kinase inhibitor, while Avastin’s active ingredient is a very similar molecule to that in the anti-VEGF MAb Lucentis.


For now the disaster has hit Ophthotech, whose stock crashed 85% this morning, putting its market cap below the $320m of cash it reported at the end of the third quarter. Fovista, an anti-PDGF-B aptamer, carried sellside 2022 sales expectations of $2.2bn, as computed by EvaluatePharma.

The group did not mince its words, announcing that neither of the two phase III trials in wet AMD had demonstrated the benefit of adding Fovista on top of Lucentis, either according to the primary measure of change in visual acuity by the ETDRS chart at 12 months, or on key secondary endpoints. Indeed, one trial showed a numerical benefit favouring standalone Lucentis.

Ophthotech stock had actually risen on Friday as Point72 Asset Management disclosed that it had built a 5% equity stake in the group in anticipation of the Fovista readout. This now looks like a monumental blunder.

After all Regeneron’s phase II failure held important lessons; the Eylea plus rinucumab approach is similar to Lucentis plus Fovista, though rinucumab is an anti-PDGF MAb rather than an anti-PDGF aptamer (Regeneron failure is one in the eye for Ophthotech, October 3, 2016).


On an analyst call today Ophthotech management said it was “stunned” by the pivotal failure, especially as statistically significant phase II data, with a dose response, had strongly backed the phase III design.

Had the Lucentis combo trials returned a positive result it would not have been outlandish to see Novartis making a takeover bid for its partner. Lucentis is expected to sell $3.3bn this year (it had hit $4.3bn in 2014), versus Eylea’s $5.6bn; consensus for Avastin in wet AMD – an off-label use – is not available.

It was strange that in signing the ex-US deal with Ophthotech Novartis allowed the option of combining Fovista with its two fiercest rivals to remain open, though perhaps it had little choice. Ophthotech at the time said it was “agnostic” as to the choice of anti-VEGF agent with which Fovista was to be used.

As the clock ticks down to the readout of that third trial all Novartis can do is cling to the evidence suggesting that Fovista combos simply do not work.

Selected wet AMD trials of Fovista
Combination agent(s) Mechanism of combo Trial ID Data
Lucentis Anti-PDGF-B aptamer + anti-VEGF MAb NCT01944839 Fail
Lucentis Anti-PDGF-B aptamer + anti-VEGF MAb NCT01940900 Fail
Eylea or Avastin Anti-PDGF-B aptamer + VEGFr kinase inhibitor/anti-VEGF MAb NCT01940887 Due in 2017

To contact the writer of this story email Jacob Plieth in London at jacobp@epvantage.com or follow @JacobPlieth on Twitter

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