Biotech Values

[DewDiligence]

Re: AAVL CC post-mortem (addendum to #msg-114621453)

What will it take for AAVL to resuscitate the AVA-101 program in wet AMD and move forward to phase-2b?

At a minimum, AAVL will have to show that the increase in retinal thickness relative to baseline for patients in the AVA-101 arm (relative to the control arm) is not a material safety concern. Generally, in anti-VEGF treatment, an improvement in visual acuity is accompanied by a reduction in retinal thickness, not necessarily for every patient, but rather for a treatment group as a whole. That this pattern didn’t hold in AAVL’s phase-2a trial is disconcerting and suggests that the gene-therapy injection procedure may be causing the increased retinal thickness.

If the gene-therapy procedure is indeed responsible for the increased retinal thickness, AAVL will probably have to redesign the procedure or even alter the content of the GT vector, which would essentially take the program back to phase-1 and result in a substantial delay.

If, on the other hand, AAVL can offer a plausible explanation for the OCT retinal-thickness data, they would still (IMO) need another phase-2 trial to demonstrate efficacy more convincingly than was done in the phase-2a trial that just reported. Bona fide efficacy, as I’m defining it, means an absolute improvement in VA for the AVA-101 arm relative to baseline of at least 7.5 letters (in contrast to the 2.5-letter absolute improvement in the phase-2a trial) as well as a statsig improvement for the AVA-101 arm relative to the control arm.

Moreover, from a practical standpoint, the AVA-101 arm has to reduce the mean number of total injections relative to the control arm during the 12-month observation period by much more than the 1-injection reduction (5* vs 6) seen in phase-2a. A mean reduction of 3+ injections would be meaningful from a practical (and reimbursement) standpoint, IMO.

All told, I think AAVL has more work to do before advancing the program to a large and expensive phase-2b trial. However, based on the CC yesterday, AAVL’s management team appears to be in denial about the phase-2a data, and Zebra’s Law may end up dictating the next move.

*Counting the GT procedure itself as an injection.