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Chelsea Blues: FDA Reviewer Hates Northera But Don't Head For Exit Quite Yet (Corrected)

By: Adam Feuerstein | 01/10/14 - 11:20 AM EST

Correction: My original blog post on Chelsea Therapeutics (CHTP) focused on the negative comments about Northera made by FDA reviewer Melanie Blank. In fact, Blank's review is from 2012 when FDA last brought Northera in front of an advisory panel. I missed the FDA's more updated Northera review posted today -- still negative -- conducted by Shari Targum. I apologize for my error and I've updated the blog post below. 

Update: FDA reviewer Shari Targum recommends against the approval of Chelsea Therapeutics' Northera:

This reviewer recommends a Complete Response action for droxidopain the treatment ofsymptomatic neurogenic orthostatic hypotension (NOH), becauseof inadequate evidence ofeffectiveness.

Targum elaborates here:

In summary, the applicant submitted 4 studies (301, 302, 303 and 306) in the droxidopa application; two of these studies, 301 and 306B, met their primary endpoint. Although studies 301, 302 and 303 were enriched populations (e.g., enrolling responders), studies 302 and 303, both randomized withdrawal studies, failed to meet their respective primary endpoints, and 306A (not enriched, but with a primary endpoint measured at Week8) met the criteria for futility. Of the two studies (301, 306B) that succeeded in meeting their amended primary endpoints, one site with unusually homogeneous positive results (507) contributed disproportionately to the positive result (301); the other study (306B), created after an unblinded interim analysis, met its amended primary endpoint with a statistically significant treatment effect at a single early timepoint. Additional issues affecting the interpretability of study 306B results include: the imbalance in premature discontinuations and missing data (more in the droxidopa-treated group); the small treatment effect in the face of larger intra-subject and inter-subject variability; lack of durability beyond the Week 1 time point; and the inconsistent OHQ, OHSA item-1 and standing SBP curves between study306A and 306B. Collectively,these concerns undermine this reviewer's confidence in study306B as a "strongly positive" trial supporting a benefit with droxidopa.

Chelsea faces a tough challenge Tuesday, but as I said below and still believe, it's not all doom and gloom. The Northera data have more hair on them than Chewbacca, but anyone who spent time looking seriously at the data knew this already. Chelsea did a fantastic job getting a positive panel vote in 2012, despite long odds. They will need a repeat performance Tuesday.

My original blog post is below:

The FDA posted a very harsh medical review of Chelsea Therapeutics'  (CHTP) Northera ahead of Tuesday's advisory panel meeting. The agency's reviewer, Melanie Blank, lists five reasons to approve Northera for the treatment of neurogenic orthostatic hypotension (NOH) but seven reasons against.

The "against" list is a lot longer. Not surprising, Chelsea shares are taking a beating Friday morning, down 35% to $2.29.

You can and should read Blank's entire Northera review. Here are key, summary excerpts:

In summary, in support of approval, there is one trial (Study 301) that is strongly supportive of efficacy of droxidopa and contains many of the attributes of a single trial that might stand alone to support efficacy: large and multicenter trial, improvement on multiple ordered endpoints including OHSA Item 1, OHQ and systolic blood pressure, and statistically very persuasive findings. From a post-hoc analysis of the cumulative distribution bin analysis of Study 301, there was a much larger group of patients that had a greater level of improvement (improvement of ≥4 points on the OHQ) on droxidopa than on placebo. Study 302, the OHQ hypothesis generating study for Study 301, might be considered supportive of efficacy if one considered OHQ to be a valid endpoint.

The primary reason to not recommend approval is the lack of sufficient evidence of efficacy. There is only one successful trial and it is well known that random factors can cause erroneous clinical trial outcomes. Patients with symptomatic neurogenic orthostatic hypotension are vulnerable and it is important to ensure their safety by protecting them from exposure to drugs that may not be effective, particularly drugs that have a theoretical basis for causing cardiovascular safety issues, as this drug has. Additionally, the lack of evidence of durability is particularly concerning. Patients should not be exposed to a drug chronically unless benefit is established over a reasonable amount of time - at least three months. It is possible that there is a down regulation of NE receptors in the peripheral circulation after prolonged exposure to droxidopa. If this is the case, one might consider approval but would need to label the product differently than what is being currently proposed (long-term use). Durability of effect should be studied further so that proper instructions for use can be crafted. Finally, the safety of droxidopa is still poorly characterized and another properly designed trial should be conducted to evaluate it. This development program was not properly designed to evaluate safety because of three factors: 1) the absence of a pure placebo group, 2) most of the safety data were collected in open-label trials and 3) blood pressure was collected with the head of the bed tilted at 30 degrees. Vasoconstriction is the mechanism of action of droxidopa. Therefore, without a control group, it is logical to assume that the cardiovascular adverse events, and there were many, were caused by droxidopa. There is also the concern of neuroleptic malignant syndrome. Since there were some Japanese postmarketing cases that were not explicable on the basis of other drugs known to cause the syndrome, one needs to be concerned that droxidopa may cause this sometimes fatal condition.

Like I said, harsh.

I don't believe it's time for Chelsea shareholders to panic. The Northera data have more hair on them than Chewbacca, but anyone who spent time looking seriously at the data knew this already.

I wrote a detailed review of the Northera data in November. Please go back and read it. Today's FDA review brings up all the scary bits, so I'm not necessarily surprised.

With that said, FDA reviewer Blank seems dead-set against Northera's approval. It will be up to Chelsea to convince the experts on Tuesday's panel to vote yes. Whether or not FDA ultimately heeds the recommendation of the panel is unclear.

Bottom line: Chelsea did a fantastic job getting a positive panel vote in 2012, despite long odds. They will need a repeat performance Tuesday.

TheStreet contributor Aafia Chaudhry will be live-blogging Tuesday's FDA panel of Northera for us. Please tune in, it will be very interesting.

-- Reported by Adam Feuerstein in Boston.

Follow Adam Feuerstein on Twitter.

Adam Feuerstein writes regularly for TheStreet. In keeping with company editorial policy, he doesn't own or short individual stocks, although he owns stock in TheStreet. He also doesn't invest in hedge funds or other private investment partnerships. Feuerstein appreciates your feedback; click here to send him an email.

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