Livermore, can you comment on the 4 times a day doing for the PDR? Since squalamine is tightly bound to calmodulin, Can we just increase the concentration of the drops and make it twice a day for this indication? Thanks for your thoughts?
The squalamine eye drop is 0.2% or 2mg per 1000mg which is the same as 2mg/ml;. for comparison, the Glaxo drop ranged from 5mg/ml to 10mg/ ml.. Squalamine is water soluble at a pH of 7 whereas pazopanb isn't and thus had to complexed with cyclodextrin, yet still Glaxo had to go to the higher concentraton.
I think squalamine could and probably should be raised to 0.3% or 0.4%; however; Ohr used the concentration that Genaera infused patients which was 0.2%; they were hesitant to change it since their data showed that this formulation inhibited angiogenesis in cell cultures. Genaera tried higher strength solutions but there was some discomfort to the patient when the higher strength was infused (burning sensation?); however an single eyedrop is completely different than a long infustion and I dont' think there would have been any irritation to the patient if the eye drop concentration were raised to 0.4%. Perhaps Ohr didn't change the strength in order to simplify the FDA's review of their trial.
I did some calculatons awhile back and felt that Ohr should have gone with a 0.4% squalamine solution
(4mg/ml) dosed twice per day just to increase the odds. Right now, they have a margin of about 7 x more squalamine then then need to just counter new angiogenesis (but not reverse old angiogenesis), and a margin of about 3 x more squalamine then they need to reverse angiogenesis. I would rather see them have a margin of about 6 x more than needed to reverse angiogenesis.
I even contacted Ohr about 18 months ago asking them about raising to dose but Sam said that Dr. T. had chosen the dose and they were going to tick with the 0.2% concentration. I think that the 'amazing results' that Dr. Katz saw should tell us that the drops are working as they are in the vast majority of people. There will be occasional patients that need 4 x per day; this would be needed to reverse angiogenesis but after angiogenesis is reversed and the lesion regressed, the dose could be lowered to twice per day as this would be sufficient to prevent the regrowth of the lesion.
The patient was seen weekly and per Dr. Elmans protocall, had to have the dose increased to 4 x per day if the lesion hadn't responded sufficiently by the 8th day. However we know that it takes 20 days for squalamine drops dosed twice per day to build up to a maximum concentration so if Dr. Elman had just waited, the patient would have responded on just the twice per day. But once the dose was increased to 4 x per day, there was no mechanism in the protocol to lower it back to twice per day
This problem is not going to occur in the wet amd trial since they are seen 1 month later and squalamine dosed twice per day has had a chance to build up
A good thing about treating PDR with squalamine compared to an anti-vegf injection, is that the squalamine, choroid concentration slowly builds up which allows the leaky capillaries to gradually decrease over 20 days, rather than to suddenly 'dry up' as the anti vegf does. Thus squalamine allows the 'air to slowly leave the balloon' rather than popping the balloon as an antivegf does. By allowing the fluid buildup to gradually subside, squalamine prevents the problem that occurs from antivegf injections causing retinal traction and detachment as sometimes occur when they are used to treat PDR and ROP
Also, in wet AMD trial patients, not only are the VEGF levels much lower, but the Bruch's membrane has been breached, so the drug can penetrate better than in the PDR patients. So smaller doses and lower twice daily frequency will presumably work in AMD.