Avalanche crashes down as gene therapy disappoints

After results of the phase IIa trial of its wet AMD gene therapy AVA-101 Avalanche Biotechnologies is considering partnering the project. But interested parties should be warned: so promising are the data that the company says it will entertain only the most generous offers.

Don’t all rush at once. Avalanche’s management put on a brave show on a conference call yesterday but could not disguise how disappointing the results actually are. The trial only hit its efficacy endpoint thanks to an unusually poor showing in the control group, and with other worrying clinical signs, not to mention several executives including the chief executive selling shares before the read-out, potential partners are likely to be as keen as Avalanche’s shareholders – and its shares are down 51%.


The study met its primary endpoint, safety, with little trouble, but it was the secondary efficacy criteria that have caused problems.

All the patients in the trial received two injections of Lucentis, at weeks 0 and 4. In the 21-strong treatment group a single injection of AVA-101 improved patients’ vision by an average of 2.2 letters on an eye chart from baseline at one year, whereas the 11 control patients worsened by 9.3 letters on average.

A 2.2-letter improvement in visual acuity is poor compared with both Lucentis and Regeneron’s Eylea, which have shown mean improvements in the mid to high teens. But it is even worse considering the alarmingly bad showing in the control group, which having been treated with Lucentis should not have declined so precipitously.

Also worrying was a seemingly inexplicable increase in retinal thickness in ’101 recipients. Wet AMD treatments ought to reduce this, as indeed Lucentis did in the trial – despite its lack of effect on acuity. Analysts at Chardan Capital Markets said that the increase in retinal thickness raised the question of whether AVA-101 was harming patients.

All current AMD therapies have been approved on improvements in acuity, the company acknowledged on its conference call. Touting a reduction in Lucentis injections is unlikely to swing approval.

The promise of gene therapy is that a single administration results in a cure. AVA-101 is injected directly into the retina, which requires an operation; Avalanche surely knows that this is only going to fly commercially if it vastly reduces or ideally eliminates the need for further intravitreal injections.


According to the Chardan analysts ophthalmologists would look for a far greater improvement in acuity – at least 10 letters – and the need for no more than two anti-VEGF injections per year. There are also concerns that the intravitreal injection could cause cataracts and glaucoma, and few surgeons are comfortable with the procedure.

Undeterred, Avalanche plans to start a phase IIb trial looking at the efficacy of ’101 by the end of this year. This will have to show pretty spectacular results if the company is to get back on track. The results of the phase IIa trial have already shaken the developers of other ophthalmic gene therapies: Spark Therapeutics is down 6% and Oxford BioMedica 3% so far today (Gene therapy investors should keep eye out for ophthalmic data, April 30, 2015).

As for partnership, Regeneron has right of first refusal to AVA-101. Given that it already has a blockbuster in Eylea it would not be greatly astonishing if it passed. Avalanche would then be free to choose between the huge variety of other suitors that it seems to believe will now come calling.

Study Trial ID
Phase IIa trial of AVA-101 in 32 patients with wet AMD NCT01494805 

To contact the writer of this story email Elizabeth Cairns in London at elizabethc@epvantage.com or follow @LizEPVantage on Twitter

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