Replies to post #6952 on Biotech Values

[DewDiligence]

>>I think we can start by using macugen phase III as a reference point to what was expected for squal.<<

In phase 3, Macugen was tested on approximately 900 patients for two years. For Squalamine, I think the FDA will ask for 1,200 patients for two years (probably in dual trials with 600 Squalamine patients each).

If the above is correct, counting control arms the total number of patients to be enrolled is 1,500-1,800 depending on whether the randomization is 4:1, 3:1, or 2:1.

Your use of the word “presumably” is perfectly reasonable, by the way. It’s not an absolute given that enough patients will enroll in the main phase-2 study to get to phase 3 in a timely manner.

[rkcrules2001]

<< I think we can start by using macugen phase III as a reference point to what was expected for squal.>>

An excellent point. For anyone wanting to look at the details, the slides from the 8/27/04 ODAC meeting are at:
http://www.fda.gov/ohrms/dockets/ac/04/slides/2004-4053s1.htm
And the transcript is at:
http://www.fda.gov/ohrms/dockets/ac/04/transcripts/2004-4053T1.doc
And a summary is available at:
http://www.trends-in-medicine.com/Sept2004/FDAmacugen094p.pdf

Dew commented elsewhere:
“Given the degree of focus on Macugen’s systemic safety at the August 2004 ophthalmic advisory panel, I think the same panel will maintain a high degree of skepticism about any systemic anti-angiogenic treatment for AMD.”

There wasn’t much focus on systemic safety issues at the Macugen meeting, primarily because EYET showed seemingly bullet-proof statistics that there was no significant difference between Macugen and sham for VEGF-related AEs. (D’Amico slide 155, and Harris slide 37).

But even so, your main point is none the less correct – if Squalamine ever makes it to an ODAC for AMD, VEGF issues will consume the safety discussions. GENR will need to have similar ‘bullet- proof’ data, and the only way to get it will be with large 2-year studies.

In August there was a vast amount of discussion about injection-related AEs, and this probably also helped push VEGF issues into the background.

Regarding VEGF, there are only a few points at which FDA discussed AE issues. The key one is when an FDA staffer is presenting the Agency’s views of the trial data.


DR. HARRIS [FDA staffer]: ...I just want to touch a little bit on systemic VEGF and what that could or could not mean in terms of this. Obviously, having VEGF is a good thing in some instances and it is a bad thing. It is a bad thing in the eye. We want to inhibit that in cases like AMD. But we want it in the systemic circulation, mainly because it plays an active role in cardiac angiogenesis. ...

So, what we did is we looked at the whole database and we said, well, are there any events within the database, the adverse event database, that could possibly in any way be related to VEGF being inhibited in the systemic circulation?


Her answer was slide 37– there was no VEGF adverse event relationship with Macugen.

And since looking for their symptomatic appearance seems to be the only way to know if there are VEGF issues, long-term trials will clearly be required. For example --


DR. LEHMER [ODAC member]: Are there known levels for VEGF or VEGF inhibition that are clinically significant from the cardiovascular current literature?

DR. ADAMIS [EYET doc]: The short answer is no in humans. The longer answer is that the most sensitive signal of systemic VEGF inhibition is hypertension. In the Avastin trials they picked it up in their colon cancer, the renal study, their lung cancer study, and some of those were much smaller studies than ours and there was no evidence of hypertension as a function of use of pegaptanib [Macugen] in our study. So, I guess whatever that level is--and it hasn't been determined--we are probably well below that.


No one challenged Adamis on that.

Interestingly, EYET also claimed they only inhibit “bad” VEGF. Maybe GENR will have similar (or better?) arguments about Squalamine?


DR. DUNBAR [acting ODAC Chair]: As a pediatric ophthalmologist, I am interested in retinopathy prematurity. Do you have any comments about its use in that situation?

DR. ADAMIS: Theoretically it is a drug that I think may prove useful in retinopathy prematurity but the data that I showed you is that, you know, VEGF is required for normal vessel formation and the conundrum has always been, well, how can you block the bad vessels and leave the good vessels alone? But it look like by targeting 165 we may be able to do that. So, that is something we would consider doing in the context, obviously at some point in the future, as a clinical trial. We wouldn't recommend off-label use at this point.


No one challenged him on that, either.