Replies to post #6744 on Biotech Values

[randychub]

Are we splitting statistical hairs in looking at averages across N=6 populations?


There is a very obvious reason that clincal trial are not run with 6 patients. If a fair number of these six patients vision continued to decline I would be worried. If 2 out of 6 patients had 5-6 lines of improvement I would be surprised simply because with the size of the eyet trial and the lack of the number of patients with similiar benefit.

They eyet trial had 809 patients that received macugen. Of those only 6 patients had >=+3 lines of vision improvement. I'am assuming no one had greater then 3 lines or they would have mentioned that fact. Somone correct me if I'am wrong.

In the mexio trials with just 40 patients we seen 10 patients with >=+ 3 lines of vision with no maintence therapy just 4 weeks of treatment

In the most recently completed 40mg trial, in the 2nd eye 2 patients had >=+ 3 lines of vision.

In the 10mg trial, i can't find the press release but I believe 1 patient had vision improvement of >=+ 3 lines of vision.

That makes 13 out of 52 patients compared to 6 out of 809. I'll take squalamine with my amd please.

Randy

[DewDiligence]

rkc: Let’s look at each of your points in order:

>>1. Are we splitting statistical hairs in looking at averages across N=6 populations? <<

Since GENR did not release the individual data points, the sample averages are the best gauge we have. Also, N=12 when you include the non-study eyes, so looking at averages is not quite as silly as with N=6.

>> 2. It seems that much of your disappointment and concern is due to comparisons with the Mexican trial. OK, there are differences. But are not the 207 40mg results still some of the best wet AMD results ever seen? Can they not stand alone? <<

The “207” results at 40mg are still fairly impressive, but I’m not sure if it makes sense to say that results from a tiny trial with no control arm can stand on their own.

>>3,4. Clearly the 2-Month results are important, but they do not render the EOT values meaningless. For example, the 2-Month results seem to point to issues regarding the need for maintenance therapy, rather than saying that squalamine is ineffective. It’s a treatment, not a cure, right?<<

I disagree. End-of-treatment (EOT) readings don’t have much relevance on their own; they are useful mainly for establishing how quickly vision deteriorates over time.The “2 month” results are actually one month from EOT (2 months from baseline), so this is the best measure we have so far of how Squalamine will fare when patients are retreated monthly. (It is impractical to consider retreatments more often than monthly, IMHO.)

>>5,6. An issue I have not yet seen discussed much is Baseline Visual Acuity. As noted earlier, I believe 207 required 20/200 or better Baseline in the Study Eye. Does the EDTRS chart fully equalize results across all VA? In other words, is one line of improvement the equivalent at 20/80 and at 20/320? <<

The EDTRS chart is constructed so that a given number of lines represents the same change in the subtended angle regardless of the position on the chart. For instance, moving up the chart by three lines represents a doubling of the visual angle regardless of the starting line on the chart.

>>7. …Isn’t this still where we are? <<

Yes, and that’s part of the problem: progress has been dismally slow since GENR released the final Mexican results 15 months ago. The “207” trial is not even intended to be an efficacy trial, but it’s the only trial where we have seen data. The “208” trial was delayed half a year (supposedly to include the 10mg dose, although I find this explanation hard to believe) and there has been no interim look in the “209” trial that management originally promised to provide by now. All in all, it’s reasonable to infer that enrollment is not proceeding as quickly as expected, and I think it’s unlikely GENR will meet it’s stated goal of starting phase 3 during 1H05.

Meanwhile, the long-term safety issue, which did not seem a major concern a year ago, has moved to center stage. You simply can’t ignore the impact of the Vioxx debacle and pretend that the FDA’s mindset hasn’t changed. The FDA is going to examine Squalamine’s two-year safety data with fine-tooth comb, and I believe the Agency will be disinclined to accept any hint of cardiotoxicity in an anti-angiogenesis drug that is systemically administered over an extended duration.

Squalamine could still make it to market and become a big-selling drug, but the odds of this are worse than they were a year ago. I’ll reassess as more information becomes available. Regards, Dew