pSivida’s drug Durasert might be rejected by the FDA

pSivida [$PSDV on the NASDAQ] is conducting Phase 3 trials on a drug called Durasert. PSDV hopes that Durasert will prevent the recurrence of a disease called uveitis, which is inflammation of one of the parts of the eye. Although preliminary data from Durasert’s phase 3 trials suggests that it is effective at preventing the recurrence of uveitis, I think it’s possible that the FDA will reject the New Drug Application that PSDV sends in. The drug and delivery method that Durasert is based on has consistently been shown to increase the risk of cataracts.

Worrisome Safety Data

Whenever we talk about medications in the eyeball (which I’ve found myself doing a lot more than I expected when I started this site), there’s usually one overriding safety concern: intra-ocular pressure (IOP). Intra-ocular pressure is the pressure in the eyeball, and many medications increase it. Part of what made the Eyegate Pharmaceuticals trials so exciting is that their drug might actually decrease IOP, but pSivida isn’t so lucky. Their drug increases IOP significantly, although after an initial spike, IOP appears to be fairly stable – check out the following graph.

Phase 3 Durasert trial safety data
Durasert increases intra-ocular pressure, but pressure stabilizes after an initial spike

However, even if IOP isn’t a huge safety concern for Durasert, there’s something more ominous. At the beginning of the Phase 3 trial, 51% of the eyes had already had cataract surgery. Even so, by ~1 year into the study, 45% of the eyes treated with Durasert had to have cataract surgery, while about 10% of the control eyes had to have cataract surgery. Given that the phase 3 Durasert trials are supposed to go for about 3 years, I think it’s safe to assume that the majority of patients will have needed cataract surgery by the end of the study.

Phase 3 Durasert trials show cataract growth
50% of participants already had cataracts removed, but 45% have new cataracts

The cataract issue has been a recurring problem with PSDV’s drugs.

Cataract Issues in Previous Drugs from pSivida

Durasert is a slightly weakened dose of PSDV’s drug Iluvien (Durasert has 0.18g of the active compound, “fluocinolone acetonide,” while Iluvien has 0.19g). Iluvien was rejected three times by the FDA before finally receiving approval. Each time, the rejection came down to the same issue – taking Iluvien gave the patients increased risk of developing cataracts, with little improvement over the standard of care.

Retisert, yet another formulation of fluocinolone acetonide by PSDV, had the same issue – a study pitting Retisert against a different treatment found that 100% of the Retisert-treated eyes had cataract progression (versus 50% for the other treatment) and that eyes treated with Retisert were at 4.7 times more risk of cataract progression.

Conclusion

Durasert has absolutely shown efficacy, but I think that PSDV will struggle with the cataract issue.

Data from Phase 3 Durasert study
Durasert handily beats the placebo in preventing Uveitis recurrence. The question is: is it worth it?

Now, in fairness I should mention that cataract removal is a fairly easy procedure. Still, though, given how much Iluvien struggled, I am not confident in PSDV’s ability to get a Phase 3 pass on the first go-round.

Prediction: Phase 3 Pass on primary efficacy endpoints – but NDA rejection by the FDA

Durasert is effective, but gives patients cataracts. I can’t say whether the trade-off is worth it, but I can tell you that this company isn’t worth investing in.

Eyegate Pharma’s Pipeline is Incredibly Exciting

Summary

Eyegate Pharmaceuticals [EYEG] has the most exciting pipeline I’ve seen in a long time. They currently have two very different products in the works, and both have the markings of success. The first product, currently titled “EGP-437,” is expected to submit a NDA in late 2017. The second product, “CMHA-S” (you have to love the way companies name their drugs..) is in what I would call Phase 1b trials right now, with data expected by the end of the year (so any day now.)

I don’t think it’s any secret that I tend to look at the science behind a drug first and foremost. I firmly believe that if the science is good — if a drug is truly effective — then the rest of the company will sort of fall into place. You can see this with our recent call on Achaogen Pharma. That drug was effective as all hell, so we predicted success, even though the company has some sales issues. If you had purchased AKAO’s stock on the day that article came out and sold it tomorrow, you would make over 150% profit.

I am hopeful that EYEG might be another Achaogen. Let’s talk about the drugs.

Drug One: EGP-437

EGP-437 is a corticosteroid (anti-inflammatory) designed to treat eye conditions. Currently, the standard of care is to use corticosteroid eye drops. Where EGP-437 differs is in the delivery. Instead of eye drops, EGP-437 uses something called iontophoresis. Iontophoresis uses an electric charge to gently “push” a drug through the surface of the eyeball. It’s not painful, and it means that patients don’t need to worry about the eye drops. Eyegate estimates that in a normal patient, the burden of treatment will drop from 154 eye drop treatments to 2 treatments with EGP-437.

EGP-437 is being tested on three different medical conditions. The first, anterior uveitis, is on the second Phase 3 trial. The first Phase 3 trial was a resounding success, with EGP-437 beating not just the placebo, but also the current standard of care — those eyedrops we were just talking about. (Probably because patients don’t take the drops as often as they’re supposed to.) The safety data looks good as well. At the risk of sounding too good to be true, EGP-437 actually looks a little safer than the eyedrops, because it doesn’t increase pressure in the eyeball as much (which is a common side effect of corticosteroids).

The second medical condition, cataract surgery, just finished Phase 1b/2a trials. Here, too, the drug is incredibly effective. 70% of patients were pain-free on the first day after surgery with EGP-437. 80% of patients on EGP-437 were completely recovered after four weeks. By contrast, 80% of the placebo group had to be rescued after two weeks. In this sense, “rescued” means that it was no longer safe for the placebo group not to be getting some sort of drug.

Trials for the third condition, macular edema, seemed to look good as well. The macular edema trials are in the very early stages, so all the researchers have done is to confirm that EGP-437’s delivery mechanism can safely get the drugs into the back of the eyeball. I won’t say more here, as I’m starting to get out of my depth, scientifically.

The caveat here is that in these latter two conditions EGP-437 hasn’t been directly tested against the standard of care yet. EGP-437 is performing better than the eyedrops did when they were being tested. And frankly, after the performance EGP-437 put in against eyedrops for anterior uveitis, I’m not too worried.

Drug Two: CMHA-S

CMHA-S is a totally different animal. What Eyegate has done here is make a sort of liquid eye-bandage. Initial tests were on dogs and cats, where CMHA-S was tested against a a type of eyedrop that’s probably most similar to those “liquid tears” eyedrops. CMHA-S was significantly more effective than the regular kind of eyedrop at helping the animals heal eye ulcers.

The second trial was with rabbits, and pitted CMHA-S against yet another type of regular eyedrops for treating chemical burns as well as abrasion (scraping on the eye). In this trial, the CMHA-S was even more effective than before – it beat the control in every measure.

The current study, from which we should see data soon, is on humans who have gotten PRK eye surgery. PRK is the predecessor of LASIK, and it’s still used by the military and by people who aren’t suited to LASIK.

If CMHA-S can successfully speed healing after PRK eye surgery, that would be a multi-million dollar opportunity by itself. If it can successfully speed healing after PRK, though, there will be a massive opportunity in helping to heal all kinds of traumatic eye injuries.

It’s very telling that the Department of Defense has given EYEG a fair amount of grant money (somewhere between $50k and $100k) to finish the development.

Closing

To sum up, there are a few big events coming soon.

CMHA-S should be reporting the results of the first human trial sometime in the next few weeks. The results from that study will determine the future of CMHA-S, and the animal trials leading up to it looked good.

Phase 3 confirmation data for EGP-437 should be out sometime next year, and if the second Phase 3 trial looks as good as the first Phase 3 did, the FDA has stated that they will support a new drug application.

Phase 2b trials for EGP-437 in cataract surgery should be beginning in the first half of next year.

Predictions:
EGP-437 — Phase 3 Pass 

The way EGP-437 kicked ass in the first Phase 3 trial leads me to expect another round of good data and a successful new drug application. 

CMHA-S — Initial Human Trial Pass

I’m still not really sure what “phase” to call this, but the great efficacy data from animal trials make me think this one will be a go.