FDA Whiplashes This Biotech

The Food and Drug Administration is making me dizzy whiplashing Chelsea Therapeutics  (NASDAQ: CHTP  ) all over the place. Perhaps I'll be able to take Northera for the dizziness someday.

Last March, the FDA rejected Northera, its drug for treating neurogenic orthostatic hypotension, a disease characterized by a sudden decrease in blood pressure when standing that can cause lightheadedness and even fainting. But there was a possibility that the company's ongoing trial, dubbed 306B, could satisfy the FDA's concerns.

The 306B trial was positive, but the FDA said it wasn't sufficient for approval. Chelsea was stuck running another longer trial.

Except, now Chelsea says that the FDA tells the company the 306B trial might be sufficient for approving the drug as a short-term treatment. Chelsea would likely have to run a longer trial after approval to confirm that the drug has a long-term effect without any major safety issues if used for an extended period.

Normally, I'd recommend taking the FDA changing its mind with a grain of salt. Cell Therapeutics (NASDAQ: CTIC  ) made that claim about its non-Hodgkins lymphoma treatment Pixuvri, but the drug's U.S. prospects seem to be going nowhere fast. The approval of Gilead Sciences' (NASDAQ: GILD  ) Cayston is one of the only times I know of that the FDA reversed its initial decision.

The difference for Chelsea is that it has additional data beyond what it submitted originally. Cell Therapeutics and Gilead resubmitted without any new data.

It's curious that the FDA said the data from the 306B trial wasn't sufficient and then that it might be. Investors need to be careful because there's a fine line between the FDA saying "please submit the data, we think it'll make the drug approvable" and "submit the data and we'll take a look and see if it's approvable." In both cases, the company can say, "the FDA told us to submit the data" and not be lying to investors.

Chelsea seems to be trying to put investors at ease, quoting guidance from the FDA that "data strongly demonstrating a short-term clinical benefit (e.g., improvement in symptoms or ability to function) of droxidopa in patients with NOH would be adequate for approval, with a possible requirement to verify durable clinical benefit post-approval." While that sounds positive, it still hinges on strong data. In the 306B trial, Northera showed an effect after one week, but wasn't statistically significant through week eight.

Whether that's strong enough for approval remains to be seen. Chelsea plans to resubmit late in the second quarter, which would put a decision toward the end of the year.

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  • Report this Comment On February 22, 2013, at 2:29 PM, NoFoolInvest wrote:

    Great article! I will like to share more insight about this company:

    Chelsea-Recently the company announce that FDA will review their P306B data. The stock price went 153% at that day. They also had conference calls with very positive tone. After they failed in P306A, they released only preliminary results of P306B on Sep 2012: 1)Northera was more effective than a placebo at reducing dizziness and lightheadedness after a week of treatment. However it said the results after more than a week were not significantly different. 2)The company also said the Northera patients fell less frequently and were injured in falls less often, but that difference between Northera patients and the placebo group wasn't statistically significant. At that time FDA required more clinical trial. But now FDA director allowed to review their data. Why? Dr. Schwieterman, their CMO, explained in their conference call said:"...I think that when they saw that and recognized the value of that particular study (306B), they agreed that we should be looking at the totality of the data overall with this particular NDA...". However, FDA hasn't reviewed their P306B data yet. How did FDA recognized P306B value even before their review? I felt my head started spinning. So let's review "totality" of their previous clinical trials and some fine prints in their P306B.

    Chelsea has done 6 clinical trials submitted . Five studies addressed efficacy and safety (301, 302, 303 and 306A and 306B), whereas the last two address safety only (304 and 305). Clinical study 301 is the only study in this NDA that won on its primary endpoint: the Orthostatic Hypotension Questionnaire (OHQ) - which is essentially a composite endpoint because it includes 10 separate questions. However, SEALD team reviewer, Dr. Elektra Papadopoulos, found their primary point in P301 lacking in content validity.

    Only their clinical study 306B won on its primary endpoint when they changed their primary endpoint back to address only the first question in OHQ (headache, dizziness and Nausea) as FDA required. However, all studies failed to show not only efficacy durability but also patient postural changes (i.e. fall rate after certain patient standing time), one of the most critical measure of clinical benefit for this disease. FDA asked for it but they use all execuses to avoid it as primary endpoint or second endpoint.

    In their P306B,they claimed that the preliminary safety data show Northera was well tolerated at all dosages tested in one week or so. Remember that FDA asked for more than 3 months of durability test but Chelsea executives insisted to do it after it is approved. Adverse events in one week of P306B were headache (Northera=13.5% vs. placebo=7.3%), an event of dizziness (10.1% v. 4.9%), nausea (7.9% v. 2.4%) and hypertension (7.9% v. 1.2%).

    So they haven't really addressed FDA issues in their CRL: 1)Adverse events in the longer term (at least three to six months), Currently They have adverse events comparison in the first week of their clinical trial P306B which made me dizzy. They have more than double percentage of patients with adverse events of headache, dizziness, and nausea comparing with patients in placebo. On the other hand, they claimed that Nothera significantly improved diziness and naursea symtom in week one. 2) Northera doesn't have any significant efficacy after one week. There still are not much durability of efficacy of Northera to pass FDA requirement.

    FDA specifically paid attention to hypertension adverse event of Northera. In this trial, it showed Northera has four times incidences of hypertensions than placebo; FDA Previously advised Chelsea Study 306B is Unlikely to Provide Sufficient Confirmatory Evidence to Support Northera' approval but CHTP Executive still persisted to do it. Although Executives spined news to a positive note that the head of FDA allowed to review it with great chance to approve it. Well, FDA allow to review the data but it doesn't mean that they will approve it. After I reviewed more about their data, my head is getting dizzier.

    Shire is going to withdraw midodrine from Market which also is vasocontrictor like Northera due to lack of clinical benefit and some severe side effects. Midodrine is the only approved drug for symptomatic neurogenic orthostatic hypotension, is a vasoconstrictor. It was given accelerated approval based on a surrogate endpoint, standing systolic blood pressure, which was thought at the time to be reasonably predictive of a therapeutic benefit. Many years have passed since initial approval (1996) and no studies have convincingly shown that there is symptom relief associated with midodrine use.

    There is no more clinical trial that Shire is going to further test its clinical benefit and side effect for NOH. However, CHTP's CEO told us in recent conference call that Shire had two clinical trials going on for the same purpose.

    CHTP executives, including Dr. Schwieterman, got law suit for their mislead and conditioned info for Northera previous clinical trials (Case No. 3:12-cv-213 v.). In addition, recently you may also found that their CEO and CMO conditioned their results and FDA intention in their news conference their transcript on 20Feb2013 in SA.

    During the longer term open-label experience with Northera (droxidopa), there were several deaths, SAEs, many discontinuations for AEs, and events of hypertensive crisis, strokes, and myocardial infarction. There were also several patients with worsening of their movement disorders. Of utmost concern reports of neuroleptic malignant syndrome from Japan that aren't clearly explained. During a 10-year reporting period, there were 9 cases of neuroleptic malignant syndrom reported while patients were taking droxidopa. Executives in CHTP have not been honest during clinical trials. They conditioned their statement and hide negative information.

    Dr. Melanie Blank, MD. concluded in her Advisory Committee Briefing Document on Feb 2012: "In summary, in support of approval, the strength of evidence of short-term efficacy for droxidopa is adequate and the safety demonstrated in the short double-blind trials was relatively good. Against approval, durability of effect of droxidopa has not been demonstrated. Additionally, the safety data base was small considering the worrisome safety signals that arose during the open-label phases of the trials which included deaths, strokes, myocardial infarction, progression of underlying disease and hypertensive crisis. Also very worrisome are the Japanese postmarketing cases of neuroleptic malignant syndrome. Some of those cases do not appear to be explicable on the basis of other drugs known to cause the syndrome."

    "On the basis of the safety concerns compounded by absence of evidence of durability of effect, my regulatory recommendation is that we should not grant approval for droxidopa at this time"

    Now after almost one year CHTP Executive received CRL, they haven't really provided solid data and valid results to show durability of Northera efficacy and resolve safety issue according to FDA request in their P306B results So it is very dizzy if FDA will approve it despite that Chelsea executives may again pay some patients to appeal in FDA advisory committee meeting.

    Themes: Biotech investment, BioPharma, Northera, Chelsea, Healthcare, droxidopa, neurogenic orthostatic hypotension Stocks: CHTP

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