Monday, May 11, 2009

Fanapt: The Little Drug That Could

Last week, the FDA announced the approval of a novel second generation antipsychotic drug for use in the acute treatment of schizophrenia (1). I believe that this drug has been in development since 1995 (2) and was suppose to hit the market in 2001 (3, 4). It also has a very similar pharmacological profile to Risperdal, which means that there is nothing novel about this drug. Except for the name; first it was called "Fiapta," and then "Fanapta." Now it's called "Fanapt," which kind of sounds like that thing I did to my penis last night.

Alas, this drug, much like my uncle Arlen, has a checkered past. "Hoechst Marion Roussel Inc. made initial inquiries into the drug; however, in May 1996, they discontinued research, and in June 1997 gave research rights to Titan Pharmaceuticals. Titan then handed over worldwide development, manufacturing and marketing rights to Novartis in August 1998. On June 9, 2004, Titan Pharmaceuticals announced that the Phase III development rights have been acquired by Vanda Pharmaceuticals. The original launch date was scheduled for 2002. On November 27, 2007, Vanda Pharmaceuticals announced that the US FDA had accepted their new drug application for iloperidone, confirming the application is ready for FDA review and approval. On July 28, 2008, the FDA issued a "Not Approvable" (here) letter to Vanda Pharmaceuticals concerning the drug, stating that further trials are required before a decision can be made concerning marketed usage of iloperidone" (5). Other development problems can be read here (6).

So the drug is almost 15 years old and has been passed around more than Harry "Suitcase" Simpson. That means we should know a lot about this drug, since the peer-review processing is the "gold standard" of scientific integrity. CLpsych has been following the progress of this drug since 2006. Over three years, this is what he has said regarding the available research:

"I could find not a single published trial of ilopderidone in either PubMed or"

"iloperidone, [has] languishing for years in development and [does] not [have] a single publicly available efficacy trial."

"It is now 2008 and I cannot find a single published clinical trial on the drug."

"So this drug has been in the clinical trials phase of development for nearly a decade, and there is no published data to show its efficacy."

As of April 2008, that is no longer the case. I was able to track down all (1o years worth) the published research in the Journal of Clinical Psychopharmacology Vol. 28, No.2, Supplement 1. If you recall, the "Not Approvable" letter was in July 2008. This issue came out in April 2008. Clearly, the drug maker was so confident of FDA approval, they put out a truncated version of the research so they could begin marketing it (most of this research took place between 1998-2002).

As a side note, a "supplement" issue is an issue that was paid for directly by a sponsor (e.g., Vanda Pharmaceuticals), which allows the sponsor to publish almost anything, as long as it looks "scientific." Last week, some people were upset when Merk was revealed to have published a "fake journal" (7a, 7b). Supplements are basically the same thing, though they don't elicit as much outrage.

In this "issue" are five articles: an introduction, one paper that summarizes three phase 3 trials (8), one paper that is a "pooled analysis" of the same three phase 3 trials aimed at discussing the safety profile (9), one 4-week comparator trial against ziprasidone (10), and one paper that summarizes three long-term efficacy trials (11). In the entire issue, four articles cover a total of 7 different clinical trials. This was done to make the database "accessible for better understanding of the overall clinical profile of iloperidone"(9).

All five of these articles have many of the same authors including Mihael Polymeropoulos, the CEO of Vanda Pharmaceuticals; and Peter Weiden, a board member for Vanda. As a matter of fact, all the researchers, with the exception of one (Andrew J. Cutler) are employees of Vanda. I'm assuming the "better understanding" they want to provide to us is the most marketable understanding.

In the Vanda press release (1) it is mentioned that two clinical trials were the bases for the FDA's approval. One 4-week study against zirprasidone (N=604) and one 6-week study against Risperdal (N=706). It appears as if this article (10) from the supplement issue is the 4-week study; however, the N in that study is 606. I believe it is study 3 in this paper (8), which is the 6-week study.

To the best of my knowledge, no new trials have been completed since 2006. I thought new trials were supposed to be conducted in order to obtain approval. So what did Vanda do to receive FDA approval after initially being rejected? I don't fuckin' know.

When I read each of these papers, I came across this sentence multiple times, "Iloperidone is a novel antipsychotic in clinical development." At what point does "more of the same" stop being "novel?" The drug has been around for 15 years, and it's another "me too" drug.

Below is a picture pertaining to the receptor affinities (12)

To understand this, you might want to read the four most important articles on psychiatry, ever! (13, 14, 15, 16) All second generation antipsychotics hit up these receptors, but in different combinations and strengths. Here we can see that iloperidone is a potent alpha-2 blocker, 5HT2a blocker, and a Dopamine-2 and -3 blocker. Based on this image, in order to get to a therapeutic dose (defined as 70% D-2 blockage), many other receptor systems will have been brought on board. Can you say "side effects?"

"And side effects this drug has," said Yoda. But we all knew that, the question is, are the side effects any different, worse, or better than other second generation antipsychotics? According to the phase-3 studies, it depends on the dose (9):
For those who cannot see the image clearly, as the dose increases from 4-8mg/d to 20-24mg/d, the percentage of people experiencing severe adverse events rose from 09.% to 2.4%, which is similar to Haldo and Risperdal (2.4% & 2.0%). It's important to note that Haldol was dosed at 15mg/d, which is quite high (> 90% D-2 blockage) and Risperdal was dosed 4-8mg/d (70-90% blockage). Since no data are available for dosage of iloperidone and percentage of D-2 blockage, we have to guess. Since 20-24mg/d had a similar profile as the comparator drugs, we can hypothesize that 20-24mg of iloperidone blocks close to 80-90% of D-2 receptors.

Here are results from 3 efficacy studies (8) - Negative values indicate improvement:
Trial 1
Trial 2

Trial 3 (submitted to FDA)
Pooled data
What do you notices in all four charts? Both Haldol and Risperdal led to greater symptom reduction than iloperidone at all doses. Note that all P-values are versus placebo, so I have no idea if any inter-drug differences were statistically significant. Based on these data, iloperidone doesn't offer anything of value over what's already on the market. Weight gain was comparable to Risperdal. The 4-week study with ziprasidone produced similar results (also submitted to the FDA):

Both drugs were dosed at the upper limits (24mg/d & 160mg/d). Iloperidone also produced a larger change in QTc interval than ziprasidone (that's strike two). Overall, it appears that iloperidone produces results more slowly than other drugs. In long term (1 year) trials, rates of relapse were comparable to Haldol. Keep in mind that all of these studies are plagued by the same methodological problems I have spoken about before (17, 18).

Of course, none of this has to do with patient care or quality of life. If it did, Fanapt would have actually been a better drug. What this is about is money:

“Shares of Vanda Pharmaceuticals Inc. soared to a new 52-week high after the Rockville, Md.-based biotech drug maker reported early Thursday its schizophrenia treatment, iloperidone, was effective in a late-stage clinical trial. Vanda shares jumped $10.95, or 70.7 percent, to $26.45 in afternoon trading on 28 times their average volume. Shares, which reached a new year-high of $28.67 earlier in the session, had traded between $7.21 and $17 over the past 52 weeks” (19).

"Vanda's stock price reportedly
exploded 824 percent higher in after hours trading" (20).

When the television commercials and journal ads begin rolling out, just remember this motto: "Fanapt! It's just like everything else!"

Potkin, S., Litman, R., Torres, R., & Wolfgang, C. (2008). Efficacy of Iloperidone in the Treatment of Schizophrenia Journal of Clinical Psychopharmacology, 28 (Suppl. 1) DOI: 10.1097/JCP.0b013e3181692787

Update: (February 22, 2010). The current issue of the medical letter (Vol. 52, Iss. 1332) has a piece on Fanapt.
"ADVERSE EFFECTS — Common adverse effects that have occurred in at least 5% of patients taking iloperidone and at least twice as often as with placebo include dizziness, dry mouth, somnolence, fatigue and nasal congestion (REF 8). In clinical trials, the incidence of extrapyramidal symptoms with iloperidone did not differ from those with placebo. At an iloperidone dose of 20-24 mg/d, 4.8% of subjects developed sustained orthostatic hypotension and the QT interval increased by a mean of 9.1 msec. In short-term studies, subjects treated with iloperidone gained a mean of 2.0 kg body weight; high-dose (24 mg/d) iloperidone produced >7% weight gain in 18% of subjects."
"DRUG INTERACTIONS — Strong inhibitors of CYP2D6, such as paroxetine (Paxil, and others), or of CYP3A4, such as clarithomycin (Biaxin, and others), increase serum levels of iloperidone and further increase the effect of the drug on the QT interval. The manufacturer recommends lowering the dose of iloperidone by half when taken with such drugs. Iloperidone should not be used with other drugs that prolong the QT interval."
"CONCLUSION — The efficacy of iloperidone (Fanapt) for treatment of schizophrenia appears to be similar to that of other second-generation antipsychotics. The risk of orthostatic hypotension requires gradual titration to an effective dose, and QTc prolongation is also a concern. Older drugs with longer records of efficacy and safety are preferred."  


Neuroskeptic said...

A masterful discussion of this me-too drug.

But I wonder if anyone will actually prescribe it?

Just one thing though, from the receptor profile it looks rather like mirtazapine (alpha2, 5HT2 antagonist).

Mirtazapine is a pretty good antidepressant (the best post-1990 according to the Lancet) so I would say this is somewhat of a good sign... if you want to treat depression.

Although the flip side of that is that much of the supposed "antipsychotic" effect on psychosis rating scales could just be an antidepressant effect (I don't know about psychosis rating scales but if they're anything like the depression ones they're not very specific)

International Regulatory Affairs said...

Thanks for this useful post.....

Anonymous said...

I've been going through the FDA reviews the last few days. It looks like this drug induces psychosis in a substantial fraction of patients resulting in a lot of problems in getting clean efficacy data in the phase III trials. Also it appears to be causing all kinds of precancerous lesions in a variety of tissues as well as blocking pGP resulting in testicular and uterine atrophy and dilation of the cerebral ventricles. Consequently Novartis dropped it. The 4th phase III study used to justify approval used a MMRM approach rather than LOCF this way they could combine the patients who dropped out due to drug induced psychosis with those who dropped out due to lack of efficacy and fudge a statistically significant result on the patients remaining in the study.

The medical officer recommended they turn it down so they had to but then it appears they forced her out had a meeting with Vanda 6 weeks later and magically found a way to accept previously unacceptable data. (They also lowered the dose range to 12 mg so they could claim they met regulatory requirements for numbers of patients studied for safety reasons even though there is insufficient data to support this dose.


Anonymous said...

Did any of you hear what Vanda did differently the second time around when they got approved by the FDA? I do... They hired an ex-FDA employee to their board of directors. (Oh yeah, and isn't Vanda in the same city as FDA)

Silly me, that has nothing to do with anything.


Anonymous said...

Though I agree that Fanapt is not such a "novel" antipsychotic, your comment on "the drug is almost 15 years old and has been passed around more than Harry "Suitcase" Simpson" is misleading.

FDA safety parameters of cardiac risk have changed in the last 15-years -- and with them, the reason Fanapt finally found a home.

DJ Phillips