I've talked about a lot of difficult therapeutic areas, but here's another boulevard of broken dreams: schizophrenia drugs. I was working on follow-ups to a promising clincial candidate, which has since been promising a number of times without ever delivering. It certainly missed its endpoints in schizophrenia by a mile in Phase II. That was actually my introduction to the drug industry back in 1989 - I followed that up with several years working on Alzheimer's, another notorious graveyard of good ideas, which makes me wonder why I didn't just quit at some point and open that chain of all-you-can-eat catfish restaurants that the Northeast so desperately needs.
Of course, once in a while a drug for dementia actually works a bit, and since there's a huge underserved market out there, it's a prize worth seeking (ask Lilly or J&J). But clinical success rates are absolutely horrific in the whole CNS area, and the latest company to demonstrate this is Vanda Pharmaceuticals in Maryland (I've always wondered if they're named after a spectacular, and spectacularly finicky, genus of orchid).
Vanda's drug iloperidone has been kicking around for years now. Hoechst Marion Roussel (now Aventis) seems to have discovered it in the early 1990s, and they, Novartis, and Titan have all handed it off to someone else over the years. Vanda was the last in line, but they got the dreaded "Not Approvable" letter from the FDA yesterday, and the company's stock was blitzed, down 73 per cent at the close. And the thing is, this drug got a lot closer than anything I used to work on. Vanda did hit their endpoints against placebo and against haloperidol, but the problem is, these are not necessarily the standard of care in schizophrenia:
" The FDA stated that Vanda had demonstrated the effectiveness of iloperidone at 24 mg/day in the 3101 study for which the company reported results in December, 2006, and that the efficacy was similar to the active comparator, ziprasidone (Geodon(R), Pfizer Inc.). In addition, the FDA also stated that iloperidone was superior to placebo in patients with schizophrenia at doses of 12-16 mg/day and 20-24 mg/day in a prior study. However, the FDA expressed concern about the efficacy of iloperidone in patients with schizophrenia relative to the active comparator, risperidone (Risperdal(R), Johnson & Johnson), used in prior studies. The FDA indicated that it would require an additional trial comparing iloperidone to placebo and including an active comparator such as olanzapine (Zyprexa(R), Eli Lilly & Company) or risperidone in patients with schizophrenia to demonstrate the compound's efficacy further. The FDA also stated that it would require Vanda to obtain additional safety data for patients at a dose range of 20 to 24 mg/day."
So iloperidone works, but quite possibly not well enough compared to what's already on the market. That alone won't quite sink your drug - you can always hunt for a patient cohort that benefits from a new compound, and you'll quite likely be able to find one if you have the resources. But as that last line mentions, there are additional safety concerns.
Reading between the lines, it would appear that iloperidone had the best chance of distinguishing itself in efficacy at the higher doses, but that the FDA wanted to make sure that side effects didn't start kicking in up there. This paper makes you wonder if one problem is the (dreaded) QT interval prolongation. Many other factors have looked relatively clean in some of the reported trials.
I greatly doubt if we'll see iloperidone surface again. Vanda wouldn't seem to have the resources, and too many other organizations have passed on it. At this point, it's hard to see why more money would be put into the compound. . .
1. Still Scared of Dinosaurs on July 29, 2008 9:51 AM writes...
This I don't get. "Safe and effective" doesn't mean as good or better than anything already on the market. Basically it means "clinically useful for some patients at the doses tested".
Of course different divisions play by (or enforce) different sets of rules. Maybe this is more standard in CNS.
Permalink to Comment2. HelicalZz on July 29, 2008 10:49 AM writes...
While comparative trials should certainly be run, especially if the company expects to be reimbursed by health insurers, it should not be a basis for approval in my opinion, except for safety reasons.
As pointed out, the last line in the PR implies it is indeed a safety question, but hard to know for sure.
Zz
Permalink to Comment3. Sili on July 29, 2008 11:15 AM writes...
I seem to recall reading a while back that schizophrenia is not just schizophrenia. The only bit I remember, though, is that apparently Spring children and Autumn children suffering SP are remarkably different - implying that some sort of environmental factor during development and/or infancy might be important.
The point being that attempts to make a catch-all drug for SP is pretty much doomed from the word go since the diagnosis essentially covers biologically different ailments.
Am I just making this up, or is there some truth to it?
Permalink to Comment4. milkshake on July 29, 2008 2:39 PM writes...
The safety and tolerability is a big concern. The patients have to take these over long periods of time (and they are often not very keen on sticking with it). Haloperidol is nasty in many ways - so it hardly provides the best comparison.
Permalink to Comment5. Still Scared of Dinosaurs on July 29, 2008 4:01 PM writes...
The comments are reenacting my own confusion with this issue. It seems like it's gotta be a safety issue but "The FDA indicated that it would require an additional trial comparing iloperidone to placebo and including an active comparator such as olanzapine...or risperidone in patients with schizophrenia to demonstrate the compound's efficacy further."
Long-term usage is not a reason to disapprove effective treatments even when there are other treatments that, according to the best available clinical evidence, appear to be both safer and more effective than the agent in question. This is because so many chronic conditions are treated with variants of the "rotational therapy" paradigm. The main concern is that the toxicities of the agents used are different (hopefully mechanistically different) so that switching from one to another gives the patient a rest from the long-term risk each carries on its own. A clear example is in psoriasis where patients rotate between cyclosporin, methotrexate, UV light, biologics, vitamin D, nothing, etc.
Permalink to Comment6. Monte Davis on July 29, 2008 4:49 PM writes...
I worked on Clozaril's physician communications and the launch event. There was considerable... ambivalence among the marketroids about the accompanying blood tests (to forestall the 1-2% of agranulocytosis), given patients who might well hear Joan of arc telling them to skip the test this month.
Permalink to Comment7. Sili on July 31, 2008 1:54 PM writes...
Pardon me for not translating this in full, but apparently it's been published in Nature:
Permalink to Comment8. Rick on November 20, 2008 6:08 PM writes...
It was the QtC interval prolongation that killed this drug. Every company that had this drug tried to avoid the more efficacious dose to avoid the dreaded QtC issue when developing their development strategy. I cant for the life of me figure out how and why Vanda and their Singapore investors dumped so much good money in this molecule when there are so many good viable molecules out there. A company like Novartis doesn't drop a molecule for no good reason at all.
Permalink to Comment9. Paul on May 7, 2009 3:35 PM writes...
Oops!
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