Inside the FDA: Valeant Pharmaceuticals Intl Inc (NYSE:VRX)’s Psoriasis Drug, Brodalumab.

FDA

On July 19, the Dermatologic and Ophthalmic Drugs Advisory Committee (DODAC) advisory panel for the FDA met to discuss the merits and downfalls of Valeant Pharmaceuticals Intl Inc (NYSE:VRX)’s psoriasis drug, Brodalumab. There has been a lot of uncertainty surrounding the risk benefit profile of the drug, and an approval is far from certain. Here’s a look into what went on in the panel review, and what it says about the drug’s chances of approval come FDA decision day.

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Before we get into the review, let’s take a look at the drug itself.

Brodalumab is part of a family of drugs called human monoclonal antibodies. Specifically, it is an interleukin-17 (IL-17) receptor inhibitor. The IL-17 receptor is a cytokine receptor, which binds to a cytokine called (not surprisingly) IL-17.

IL-17, when bound, stimulates the recruiting of what are called monocytes (as well as certain neutrophils) to the binding site. Monocytes, as part of this system, are responsible for inducing inflammation, which in a correctly working system (a healthy patient) is a good thing, as the inflammation helps to mitigate the impact of pathogens. When the system is not working correctly, however, overstimulation of IL-17 receptors leads to unnecessary monocyte recruitment, and in turn, excessive inflammation. Psoriasis is the result of this inflammation, and through the inhibition of the IL-17 receptor, Valeant is attempting to prove that Brodalumab can treat plaque psoriasis.

The biologics licensing application (BLA) was submitted in place of an NDA by AstraZeneca plc (ADR) (NYSE:AZN), which is partnered with Valeant on the drug, at the end of last year. It’s based on data from a phase III trial called AMAGINE. The trial showed that Brodalumab was superior to a current SOC in the space – ustekinumab, which is marketed under the name Stelara, and is also a IL-12 receptor inhibitor – against a primary endpoint of total skin clearance in patients with moderate to severe plaque psoriasis.

The issue is this: In the psoriasis development program, 34 subjects were observed to have suicidal ideation and behavior events. In particular, six completed suicides were observed, and this raised concerns about a potential association of Brodalumab with these events. While there’s no hard evidence that the suicide came as a direct result of the patients’ taking of the drug, there’s enough of a question surrounding the matter that it will almost certainly necessitate some degree of warning or follow up if the drug is approved. If not approved, it’s going to be based on this potential for suicidal thoughts (ideation, if we are going to use the technical term).

Here’s a quote from the meeting transcript that’s worth keeping in mind as we move forward through this analysis:

“For the purposes of our discussion today and for the purposes of data analysis, suicidal ideation and behavior is defined as any event of suicidal ideation, preparatory action towards suicide, which is termed “suicidal behavior,” suicide attempts, and completed suicide.”

Of all the six suicides, five were male, and all ranged in age from 39-57. The suicides occurred at a pretty wide post-doing frame, between 97 and 952 days after first dosing. Now, psoriasis is a tough condition to live with and there’s plenty of evidence that suicidal ideation is common in the condition, with or without treatment. Given this fact, the suggestion that Brodalumab might be playing a part in the ideation might not normally have come in to question. However, of the six patients that committed suicide, only two had ever expressed any sort of suicidal ideation.

That’s two thirds of the trial candidates that committed suicide having no history of suicidal ideation. That’s pretty significant, and this doesn’t include a number of events that were judged as non-suicidal, but there’s some uncertainty of whether his judgment is correct.

Another major issue is the difficulty a physician faces when trying to ascertain whether a patient is suicidal or not. There are a number of cultural stigmas attached with admitting things like suicidal thoughts, and this can play into treatment or diagnosis. Fifty percent of the patients that committed suicide where in the US, and only forty percent of the overall patient population derived from the US.

So, let’s get to the nitty gritty.

The panel posed three questions to the members of the advisory committee:

Discussion question 1: Discuss the safety data for Brodalumab. Do the safety data suggest a signal for suicidal ideation and behavior, major adverse cardiac events? If you believe there is a safety signal for SIB or MACE, comment on possible approaches to further evaluate these signals.

The general response to this one was that the drug is very efficacious, and that while there are certain concerns, it should be approved as a treatment option for psoriasis because the currently available treatments are often only efficacious for a certain period of time.

There were a number of cardiologists on the panel, and the consensus regarding MACE (which for those unfamiliar with the term, simple relates to cardiovascular events) was that the drug doesn’t have any real MACE concerns associated with it. This is a big win for Valeant, as MACE has been a concern across pretty much the entire development spectrum for this drug.

The opinion of SIB (Suicidal Ideation and Behavior), of course, differed considerably from that of MACE. The fact that six patients committed suicide was universally regarded as a signal for SIB, and the necessitation of some degree of follow up for patients to assess the potential for drug induced SIB was universally agreed upon.

A further issue arose on the back of this latter mentioned point. Specifically, how can you effectively implement some sort of follow up program for the standard patient-physician interaction, when the physicians (in the vast majority of instances) won’t be qualified psychiatrists and – as such – aren’t able to judge effectively the risk, or development, of SIB in patients.

The bottom line for this question – yes, the drug should be approved, but there needs to be some degree of follow up. MACE isn’t a risk, SIB might be but a) it shouldn’t stop the drug being prescribed and b) we’re not sure how to approach a follow up program.

The panel were then asked to vote on the following question:

Is the overall benefit/risk profile of Brodalumab acceptable to support approval for the treatment of moderate to severe plaque psoriasis in adult patients who are candidates for systemic therapy or phototherapy.

  1. Yes, with labeling alone to manage the risks
  2. Yes, but only if certain risk management options for SIB beyond labeling are

implemented

  1. No

Please provide a rationale for your vote. If you voted for A, please describe the labeling you would recommend to manage the risks. If you voted for B, describe the interventions or tools you believe would help mitigate the risk of SIB, in addition to labeling.

Four of the panel voted in favor of option A, suggesting labelling will be enough to cover the potential for SIB. Fourteen went for option B, and the overwhelming opinion on this was that the prescribing physicians should implement some degree of registry to keep track of patients, efficacy and SIB. For those not familiar with the term, a registry study is basically the same as a follow up clinical trial, with one major difference – registry studies are observational and clinical studies are investigational.

None of the panel voted in favor of C, mirroring the opinion that the drug is effective enough to mitigate any potential safety issues from a risk benefit perspective.

The final question was as follows:

If you voted for approval in question #2, please comment on post-marketing studies/trials that are needed to further define the safety of Brodalumab, including, but not limited to, the need for long-term studies to evaluate suicidality and cardiovascular events.

Again, this one pretty much focused on the requirement for a registry trial. Essentially, two opinions came to light. The first, yes, a registry trial needs to be put in place, and this can be used to asses the risk post administration. The second, that if this sort of trial came in to effect, it may serve as a barrier to administration, and this might be an issue for physicians and patients. Basically, a patient might not want to take the drug if he or she has to be part of a registry trial.

The outcome on this one was that the registry trial is a good idea, but if it is going to be implemented then it should be voluntary – i.e. give the patients the choice as to whether they want to take part in the trial. If they don’t still give them access to the drug.

So, let’s move on to a final analysis.

Our take is this:

We have no doubt that the drug is going to get approved. Efficacy is non debatable, and it seems (and a panel seems to agree) that the efficacy far outweighs the safety concerns from a risk benefit perspective.

Having said this, Valeant might be held back from a revenues perspective depending on the post marketing outcome. A black box label will be a great outcome, but we are pretty much certain that a registry trial will be put in place to assess patients post administration. With that being the case, there is a good and a bad outcome for Valeant. The good is a voluntary registry, whereby patients aren’t forced into a trial if they want the drug. The bad is a mandatory registry. This could massively inhibit Valeant’s Brodalumab sales potential, and will be a serious hit for the company if it comes to pass.

PDUFA is November 16.

Resources:

Meeting Transcript

FDA Presentation

Valeant’s Presentation

Questions

Answers

 

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