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Regeneron's Asthma Biotech Drug May Be The Best In Class

|Includes: AMGN, AZN, GSK, NVS, PFE, Regeneron Pharmaceuticals, Inc. (REGN), RHHBY, TEVA, VRX

For what it's worth, here's a few thoughts about Regeneron's (NASDAQ:REGN) asthma/allergy biotech drug, dupilumab, from a board-certified allergist.

1) The article published in New England Journal of Medicine (very respected journal) in July, 2013, was very positive. Dupilumab showed a 90% reduction in asthma exacerbations compared to placebo.

Being published in NEJM is awesome, but being the #1 original article of the week is a bigger honor. The trifecta is the honor of also having an editorial written about your article.

The primary end point of this study was asthma exacerbation, either from needing to use the rescue inhaler (e.g. Ventolin or ProAir), or from a reduction in the peak flow (to see how fast the asthmatic can blow air out). Since asthma causes lung obstruction, most asthmatics can get air out; it just takes them longer. Imagine breathing thru a straw instead of your nose or mouth. A peak flow measures how many liters you can get out per minute. Thus, if your peak flow drops, it may be the asthma getting worse.

In the study, 52 patients got placebo and 52 got the active medication. Asthma exacerbations occurred in 26 of the placebo patients (44%), but only 3 of the Dupilumab patients (6%).

My comments on this study:

(a) It was a phase IIb study, so they still have to go thru phase 3 studies before the FDA will consider it. There are lots of other companies with biologics in phase II or III studies, such as:

o Genentech (NVS and RHHBY), with lebrikizumab. Note--they currently own the entire biologic market in asthma with Xolair {omalizumab}, and Xolair just got FDA approved for chronic urticaria {hives}, making a lot of my patients happy),

o Aerovance (privately held company in Berkeley CA), with pitrakinra

o Amgen (NASDAQ:AMGN), with AMG-317 and with altrakincept

o Astra Zeneca (NYSE:AZN), with tralokinumab

o Wyeth (now Pfizer PFE) with anrukinzumab

o Medimmune (now Astra Zeneca AZN), with benralizumab

o Teva (NYSE:TEVA) with reslizumab

o GlaxoSmithKline (NYSE:GSK) with mepolizumab

o Medicis (now Valeant VRX), with imiquimod

Xolair (Novartis and Genentech/Roche) targets human Immunoglobulin E and binds it up, preventing it from causing allergic reactions. Regular use of Xolair also reduces production of one of the IgE receptors (which is probably why it also works in hives). It has been great to use in severe asthma the past 11 years, but there are a lot of patients with continued symptoms in spite of using it, along with other aggressive medical treatment. So having other biologics in my field will be helpful.

(b) Of note, in the 10 months since this manuscript was published in NEJM, it has been cited by 55 other articles, including some pretty important review articles (at least important to us lowly allergists). For instance, Tony Montanaro's review of biologic agents for asthma in the February, 2014, Annals of Allergy:

and Stan Szefler's Advances in pediatric asthma in 2013: Coordinating asthma care. Published March, 2014, in Journal of Allergy and Clinical Immunology

By comparison, the March 21, 2013 NEJM article showing Xolair was effective for hives has only been cited 45 times, and the September 27, 2012 article showing tiotropium was effective in asthma has only been cited 40 times.

(c) The two lead authors of this NEJM article, Sally Wenzel and Linda Ford, don't publish studies on every new allergy or asthma drug coming down the pike. They stick to reporting important medical progress. Thus, in my opinion, they are not "drug-company whores." No offense to my close friends and colleagues who were involved in studies for me-too drugs like Dymista, Dulera, and Veramyst.

(d) The two letters to the editor did not criticize the study or its methods. One discussed injection site reactions and one discussed how obesity can be a confounding variable.

(e) Of the three comments posted to the article's web page, only one merits consideration. It points out that comparing this drug to placebo is ridiculous. As I read the article for Baylor College of Medicine's allergy journal club last year, I also found it odd that to prove its efficacy, they tapered all patients off recommended, moderately effective current treatment (inhaled steroids and long-acting beta agonists (bronchodilators) over a 5 week period. First they stopped the LABA, and then they reduced the dose of the inhaled steroid. A competent doctor would never do this.

In the accompanying editorial, they said:

"Furthermore, although this therapy appeared to be effective in reducing exacerbations as LABAs and inhaled glucocorticoids were withdrawn, in clinical practice, physicians do not withdraw therapy to induce exacerbations. Thus, the apparent reduction in deleterious asthma outcomes as therapies were withdrawn only serves to tell us that this biologic therapy appears to work, as a proof of concept, but may not be advantageous in a "real world" situation, and thus the finding offers little direction for clinical practitioners."

Still, one comment I heard from the BCM allergy group was, "Wow, nearly a 90% reduction in exacerbations. (86.7%, actually). You just don't see that in human studies".

So, what's the downside? This drug, which neutralizes the alpha subunit of the interleukin 4 receptor, would only be effective in the subset of patients with asthma driven by interleukin 4 or interleukin 13 (IL-4 or IL-13). Why also IL-13? The IL-13 receptor includes the alpha sub-unit of the IL-4 receptor, so this drug hits both.

But, IL-4 and IL-13 are not the only troublemakers causing difficult-to-treat asthma. In the NEJM editorial accompany this article, the Dr. Wechsler (from National Jewish in Denver, a top notch allergy/asthma research center) wrote:

"Only 21% of those screened for the study met the inclusion criteria, probably

because of the requirement for persistent symptoms and eosinophilia in the presence of treatment with inhaled glucocorticoids. We do not know whether dupilumab will be effective in other patient populations, such as the much larger population of patients who use inhaled glucocorticoids and LABAs and do not have eosinophilia."

Other biologics for asthma go after Interleukin 5 (IL-5), which is important for eosinophils, basically an allergic white blood cell, or after Toll Like Receptor TLR-7 or TLR-9, which are other proteins involved in the immune system.

With biologics and monoclonal antibodies targeting specific parts of the immune system, we have to identify which patients will benefit from which drug. We try to do this by looking at biomarkers. IgE (the allergic antibody) is one biomarker, and is easily obtained with a blood test. Exhaled nitric oxide (eNO), measuring lung inflammation, is another biomarker. No biomarker is perfect, though, so some of the choice is still through the doctor's clinical judgment.

In spite of all this, at the time of this writing, dupilumab seems to me to be the best of this bunch. If future studies have equally good outcomes, this may be a money maker for Regeneron.

Disclosure: I am long REGN, GSK.