Eosinophilic Esophagitis (EoE) has been a stubborn problem for many food-allergy sufferers. The esophagus is infiltrated by white blood cells called eosinophils–the same culprit involved in cases of allergic asthma–causing constriction, difficulty swallowing, and eventual tissue remodeling. Abstinence and swallowing oral steroids have been the only recourse, with the recent addition of the the biologic dupilumab. Mr. Maskey is PhD student in the Department of Microbiology & Immunology at New York Medical College. He has been working in Dr. Xiu-Min Li’s lab since 2018. Primarily his work focuses on understanding immunological mechanisms underlying Traditional Chinese Medicine formula and natural flavonoid purified compound improving clinical GI symptoms related to EoE. He has also been actively working on other collaborative projects with his NYMC colleagues.
Dupilumab—Real World Lessons from a Blockbuster Drug
By Henry Ehrlich
We have covered this breakthrough drug for years from before FDA approval when a presentation by Dr. Emma Guttman-Yassky at a New York Allergy & Asthma Society dinner treated the audience to “before” pictures of atopic dermatitis that made patients’ legs look like rotisserie lamb and “after” pictures that looked normal. At that time, Dr. Guttman-Yassky heralded an approaching “golden era for atopic dermatitis.” Now following a couple of years on the market, we are starting to see what a blockbuster looks like in the real world.
Dr. Peter Lio wrote about dupilumab—now Dupixent—for us in December 2016. He said, “The dream of patients and providers alike–aside from preventing it in the first place or a total cure, of course!–is a medication that would work quickly to calm the itch and inflammation, to truly allow the skin to truly heal. It would do so safely, without toxic side effects to the liver or kidneys and without an increased risk of cancer and infection. It would be easy to use instead of greasy creams or cumbersome wraps. Finally, it would not simply suppress the inflammation, but would help block the escalating itch-scratch cycle and not result in a rebound flare up when stopped.”
He described the drug and its action in this way: “It is composed of monoclonal antibody–proteins that are part of our immune system normally– and, as such, is sometimes referred to as a ‘biologic’. It is specifically designed to bind to (and thus inhibit or block) two important chemical messengers in the body: interleukin-4 (IL-4) and interleukin-13 (IL-13). These messengers, called cytokines, are very important in that they seem to be overproduced in eczema. Their message, in large part, seems to be: ‘Make more inflammation and itch! Make an allergic reaction!. Thus, it follows that by very carefully quieting them down, the resulting eczema quiets down. Perhaps most importantly, it does so WITHOUT shutting down the entire immune system or poisoning the body.”
Dr. Lio has recently published two journal articles that point to problems that arise in the real world of a drug post introduction. The first is an editorial from JAMA Dermatology, published online in December of last year entitled “Considerations in Weaning or Withdrawing Dupilumab Therapy—Nothing is Forever”. It seems strange that having waited their whole lives for relief from their eczema, patients should be anxious to find an exit strategy, but that is the case, for two primary reasons. One is that they must get the shots every two weeks. Based on a description by a friend of her child’s routine on shot day, it’s not a quick in-out. The other consideration is the astonishing cost, which is north of $30,000 annually.
Delineating the line between research and real world, Dr. Lio writes, “Dupilumab was studied for 52 weeks at continuous dosing every 2 weeks to establish its safety and efficacy, but inevitably for patients who are doing well while receiving treatment (and even for those who are not), the question arises, ‘Do I have to take this medicine forever?’” Dr. Lio describes atopic dermatitis as a “waxing and waning disease. The waning cycle leads people to wonder if they are cured or if at least may require less frequent dosing for maintenance.
Given experience with biologics for other diseases, the portents are not good. Patients tend not to do as well after stopping and restarting, and they may develop antibodies to the medicine. With dupilumab specifically, researchers “found that continuing treatment with the original dosage (300 mg weekly or every 2 weeks) resulted in a better maintenance of response than a less frequent dosage and significantly better than placebo for all end points. Moreover, the less frequent dosage regimens produced some dose-dependent reduction in efficacy but no previously unreported safety events…The authors* thus concluded that continued treatment with dupilumab using the more frequent treatment regimens (ie, every 2 weeks) ensures the most consistent maintenance of treatment effect and appears to confer no greater risk than (and likely fewer risks) than less frequent administration.”
Dr. Lio’s second article, published online in Dermatology in April 2019, was co-written with two colleagues from the University of Arizona, is called “Dupilumab and Alopecia: Causative or Therapeutic.” This one had particular resonance for me because I had recently spoken to someone who experienced hair loss with Dupixent as she was trying to cope with topical steroid withdrawal and red skin syndrome. She felt the mild relief wasn’t worth the added indignity.
According to Dr. Lio and his co-authors, the door swings both ways on this. “Our literature review yielded 6 recent case reports on ‘dupilumab’ and ‘alopecia, with four describing alopecia developing after initiation of dupilumab and two reporting resolution of pre-existing alopecia.” The hair loss seems to constitute a drug reaction.
Clearly, this drug is just getting started.
Peter A. Lio, MD is an Assistant Professor of Clinical Dermatology & Pediatrics at the Northwestern University Feinberg School of Medicine, and a Diplomate of the American Board of Dermatology. Dr. Lio received his medical degree from Harvard Medical School, completed his internship at Boston Children’s Hospital and his dermatology training at Harvard. He served as a full-time faculty at Harvard (Beth Israel & Children’s Hospital Boston) from 2005-2008 before returning home to his native Chicago to join Northwestern and Children’s Memorial Hospital. He is also a trained acupuncturist and a leader in the Chicago integrative health care community.
Dr. Lio will be speaking at the 6th East-West Integrative Medical Symposium for Immunology & Wellness at the New York Medical College in Valhalla, NY on June 20, 2020.
*Worm M, Simpson EL, Thaçi D, et al. Efficacy and safety of multiple dupilumab dose regimens after initial successful treatment in patients with atopic dermatitis: a randomized clinical trial [published online December 26, 2019].JAMA Dermatol. doi:10. 1001/jamadermatol.2019.3617 7.
#deniedRX—Hashtag to Nowhere
By Henry Ehrlich
This website has covered the progress of dupilumab, a monoclonal antibody to treat eczema, since before it had a brand name. The first sighting was in a presentation by Dr. Emma Guttman-Yassky of Mount Sinai. The before and after pictures, ideal accompaniment for a chicken dinner at the Harvard Club, were dramatic. Before looked like second and third degree burns. After looked bathing-suit worthy. Apart from this miracle drug efficacy, the other subject was the retail cost of the market version “Dupixent”. At $38,000, the price tag was so high that Regeneron’s CEO Leonard Schleifer anticipated that insurance companies might reject coverage and become an issue so he created a hashtag #deniedRX that itchy patients could use to share stories of being shot down. Presumably there would be a groundswell of pressure on the insurers.
I learned about this in a biotech podcast produced by STAT, an excellent medical website, called The Readout Loud (highly recommended for anyone interested in the business of pharmaceuticals), and I looked it up. I learned it’s not as easy for a big company to go viral as it is for the typical no-talent reality TV star. It only collected 13 Tweets, the last of which was in March this year, and several of those were about scandals that bore no relation to the drug.
Who knows? Maybe Schliefer had visions of a cause celebre on the order of Mylan and EpiPen. But it’s one thing to ratchet an indispensable product up to scandalous prices over a period of years—dependent patients will be outraged–and another to start out scandalously priced and then light a match, hoping the outrage would burst out. In fact, as the folks at STAT pointed out, this stunt was generated to boost earnings. And it didn’t work; as of this past spring, when both Regeneron and its partner Sanofi lost stock market value based on disappointing Dupixent sales.
Good drug. Iffy business model.
Graphic by eczemaliving.com
Stepping Up the Inhaled Steroids: Revisiting an Asthma-Control Tactic
Interview with Dr. Purvi Parikh and Dr. Paul Ehrlich
“The study of asthma is the study of one patient” Dr. Anthony Gagliardi
Readers of Asthma Allergies Children: a parent’s guide may recall this adage, which Dr. Ehrlich is fond of quoting, referring to the fact that “asthma” is not one disease but a set of symptoms from disparate sources, and thus may not respond to familiar treatments. One cornerstone of treatment for those who experience severe exacerbations is to respond to “yellow zone” peak flows (zone 2 in the UK) by stepping up doses of inhaled corticosteroids (ICS) by multiples of 4 or 5 to stave off hospitalization and doses of oral steroids. In analyzing two new studies of this tactic, a recent editorial in the New England Journal of Medicine by Philip G. Bardin, F.R.A.C.P., Ph.D. suggests that another bit of conventional wisdom should be retired.
One study looked at children ages 5 to 11 with mild-to-moderate persistent asthma, all of whom all of whom had suffered at least one exacerbation in the previous year who were receiving low-dose ICS. Dr. Bardin concludes, “Overall, this commendable trial indicates that escalating the dose of inhaled glucocorticoids is a failed strategy to prevent exacerbations in children with early symptoms of asthma instability.” The second trial, done in the UK, involved adults and adolescents. While the methodologies were different, Bardin says, “Evidence indicates that substantial escalation of regularly used inhaled glucocorticoids, even by a factor of 4 or 5, fails to prevent most asthma exacerbations.” Add to this concerns about the safety of ICS that have emerged over time and we have problems.
What to make of this? How will allergists address this new thinking with their patients? I turned as I often do to my cousin and to Dr. Parikh, with whom he practices. – Henry Ehrlich
AAC: Purvi and Paul—thanks for taking time to help sort out this new data. Paul, I’d like to ask you the first question. You have been in practice for longer. Can you give us a feeling for how standard of care has evolved for this kind of asthma presentation over the years? And Purvi, as someone who trained much more recently than Paul (sorry Paul) could you describe how this subject was addressed in your fellowship?
Paul: Your question made me think back to my days as a house officer at Bellevue Hospital in the early 70’s. We saw many asthmatics dealing with a huge, poorer population in New York City when acute treatment consisted of theophylline given intravenously, IV fluids, oxygen and LOTS OF STEROIDS. As my good friend and former teacher Arnold Levinson said a few years ago at a meeting with the The New York Allergy & Asthma Society, things have moved slowly ever since the discovery of IgE by the Ishizakas—Japanese researchers whom I met at Johns Hopkins when I was at Walter Reed Army Medical Center. The use of theophylline has all but disappeared, and we still rely on corticosteroids. It is only in the past five years that we have added newer modes of care, but corticosteroids are still prominent.
Purvi: During my fellowship, standard of care was evolving before my eyes. There was a push for using steroid-sparing agents such as Xolair (omalizumab). I trained at an institution that was doing clinical trials with the new monoclonal antibodies. Also, anticholinergic inhalers (tiotropium; brand name Spiriva), used for decreasing steroid use for COPD, were also effective with asthma so we incorporated them in treatment.
AAC: Purvi, you said when we talked recently that this subject was discussed at the recent meeting of the American Academy of Allergy, Asthma, & Immunology. Can you summarize for our readers the general tone of those discussions?
Purvi: There was a real buzz because now there are so many new treatment modalities on the horizon that target various parts of the immune system. This is exciting because we can provide better, personalized care for our patients and get many off toxic steroid doses. There was especially a lot of promise in those steroid-resistant asthmatics who may not be allergic but still suffer quite a bit. Some of these new modalities help control their asthma quite well. Also, we are learning what tests and biomarkers will help us identify the right drug for the right patient.
AAC: Paul, you are the one who returns continually to your friend Dr. Gagliardi’s adage that the study of asthma is the study of one patient. That has been borne out over the years by the continual identification of new asthmatic phenotypes—i.e. the symptoms may look like classic allergic asthma but closer observation shows that this is not the case. The Bardin editorial points to asthma “linked to provocative factors such as viral or bacterial infections, nonadherence to treatment, allergen exposure, and environmental air pollution.” How do you tell the difference in your practice and how does it translate into asthma action plans for your patients?
Paul: That is a great question, and Dr. Parikh and I can answer that very easily. I think of Dr. Gagliardi’s comment often which stated that each case is different, and, therefore, a complete history is crucial in formulating of appropriate treatment. When does the asthma get worse? When and where is it not a problem? When we get a referral from a non-specialist we look at the medication history to see what has worked and what has not. The side effects from each medicine and so forth.
AAC: Purvi, we have seen tremendous strides in developing new biologics for asthma and other atopic diseases—the IL-5 inhibitor mepolizumab (NUCALA) comes to mind. To your knowledge what is the record of these new drugs in staving off exacerbations?
Purvi: In addition to mepolizumab, we have also seen promise with benralizumab (IL-5 receptor antagonist) that is also approved. I am excited to see what will come from studies with dupilumab (IL-4Ra) and asthma as it has already worked wonders for patients with atopic dermatitis. These new drugs appear to be helpful in avoiding exacerbations in either patients who have failed other agents such as omalizumab or a particular set of eosinophilic asthmatics who may not all be allergic/atopic. We are learning the eosinophil plays a role in NON-allergic asthmatics as well from these studies with anti-IL-5 agents. These drugs are expensive, but insurers have seen the benefits that should translate into less emergency treatment that will save money in the long run.
AAC: This is addressed to both of you. Whenever a deeply ingrained clinical approach is challenged, the question becomes how to cope in the short run. Some of our readers may be accustomed to upping their doses as described in the studies. What should they do? What should they say to their doctors? And what should their doctors say to them? (If you could just give say three takeaways for patients and doctors that would be useful.)
Purvi: Well, if you are needing even one course of oral or injectable steroid in a year whether from an ER, urgent care, or doctor you need to have a conversation with your doctor about other agents as just one exacerbation is considered uncontrolled. The same goes for nighttime symptoms, frequent rescue inhaler use, trouble with household chores etc. If your doctor keeps increasing the steroid dose in the inhaler itself, and you do not see much difference in your control you should see your doctor or an asthma or allergy specialist to see if there are better options out there for you. You may be one of these “Steroid resistant asthmatics” Asthma is not a one size fits all diagnosis.
Paul: For many years, before and after Purvi and I began to practice together, I rarely had an asthma patient require emergency treatment. For allergic patients this usually involved better housekeeping and otherwise avoiding triggers as well as diligent peakflow metering and other good habit, as well as conscientious medication use. But I also saw a lot of stress-induced asthma (that’s a big one in New York City, occupational asthma, exercise-induced asthma, viral-induced asthma, and so forth that had little to do with allergic asthma. They will not be helped by these wonderful new treatments that Purvi has described. So patients and doctors still have to play detective and arrive at the behavioral modification that can ameliorate those symptoms.
AAC: Thank you both for your time. Now get back to your patients.
Dr. Purvi Parikh is an adult and pediatric allergist and immunologist. She completed her fellowship training in allergy and immunology at Albert Einstein College of Medicine’s Montefiore medical center following her residency at the Cleveland Clinic and is board certified by the American Board Allergy and Immunology, as well as the American Board of Internal Medicine. Dr. Parikh has published articles on allergy, asthma and immunodeficiency syndromes in the Annals of Allergy, Asthma and Immunology, The Journal of Gastrointestinal Cancer and is currently writing a chapter for an otorhinolaryngology textbook. Dr. Parikh has also presented research at various national and international meetings. She is passionate about health policy and sits on the health and public policy committee for the American College of Physicians. She also is a board member and founder of the Share and Care Foundation’s young professional committee, which raises money for underprivileged women and children in India.
Dr. Paul Ehrlich is an author of Asthma Allergies Children: a parent’s guide and co-founder of this website. He works with Dr. Parikh at Asthma & Allergy Associates of Murray Hill in New York City.
Boiling Skin—the high price of medical miracles
By Dr. Larry Chiaramonte
In the South Bronx I just saw an active 11-year-old girl disfigured by flaming, weeping, itching skin on 70 % of her face and body. When you see a case like this, you really appreciate the original meaning of the word “eczema,” which is derived from the Greek word meaning “to boil over.” Poor thing, her skin was boiling over. Her allergic inflammation was being fed by interleukin-4, which has a positive feed-back loop. In other words IL-4 is causing the skin to boil, which in turn causes more IL-4 to be produced.
This girl would be a perfect candidate for the new drug DUPIXENT (dupilumab), which has just been approved for eczema. The drug is administered by injection twice a month. Patients can do it at home. It is an IL-4 receptor agonist, which blocks the IL-4 from completing its part of the mission. However, as this website has observed, it has a list price of $37,000 per year. But that’s not the immediate problem. She is 11—short of the 12 years the age that the FDA begins its approve for use.
As I was trying to explain this to the mother, she took out her cell phone, “I want you to see these pictures of my family. See my daughter hiding behind me. She did not want anyone to see her face. She cannot have this new medicine?”
This case exposes some of the terrible conflicts in our medical system. There are reasons to approve new drugs according to age. Children are not just miniature adults. But still, the age of 11 versus 12 does seem terribly arbitrary, especially when a child’s whole life has been disrupted and diminished. Still, rules are rules, and no third-party payer is going to bend them.
Then there is the mega issue of who the payer is. If it’s Medicaid, which constitutes the lion’s share of the South Bronx population, we are eventually going to collide with one of the biggest public health dilemmas of our age. Will Medicaid spring for biologic drugs this expensive forever, even if the ACA is revived? At $37,000 per annum, the cost is just below the median household income for the Borough of The Bronx, which includes many higher income households in neighborhood such as Riverdale. I suppose this girl can survive another year on a rotation of steroids and other stopgap remedies, hiding from cameras, covering herself in warm weather from the pitying eyes of strangers and friends, and scratching, scratching, scratching. At the age of 12 she will find relief. But then the questions will remain: who will pay? And for how long? Miracles have a price.
Dupilumab Goes to Market
By Henry Ehrlich
Welcome back, Dr. Peter Lio, the Chicago dermatologist who has honored this website with a number of excellent pieces on atopic dermatitis, the maddening skin condition that while not life threatening by itself can reduce patients to uncontrollable scratching and despair. Like other allergic conditions, notably asthma, the go-to medicines are forms of corticosteroids—in topical form and when things get really bad systemic steroids. These drugs produce periods of relief followed by rebound episodes that can end up worse than before, and also mood disorders. Now Peter returns with a piece on what looks to be a breakthrough drug. Indeed, as he points out, it has bee designated such by the FDA. (We have written about the “breakthrough” designation previously.)
I have been anxious to get some coverage of this new monoclonal antibody ever since I sat through a talk by Dr. Emma Guttman-Yassky at the New York Asthma and Allergy Society where we were treated to a sumptuous roast chicken dinner while watching slides of skin being transformed from what looked like second-degree burns to peaches and cream. A miracle, long overdue.
By chance, as I was preparing Peter’s article for preparation, a post came up on my Twitter feed from Investor’s Business Daily with the headline “Regeneron Could Add $604 Million to 2018 Top Line on Eczema” the estimate by a stock analyst named Adna Butt. Let’s face it. Miracles often cost a lot of money.
Butt writes that in a survey of 51 U.S. dermatologists who treat an average 4,300 patients per month, a majority said they have a pool of patients who could benefit from the drug immediately. Butt also says, “A minority expect to prescribe dupilumab to pediatric patients ahead of approval by the U.S. Food and Drug Administration, which could provide another upside,” with an eventual market around 2-million, out of 5-million eczema patients altogether. Unless some of them are cured by the drug, or achieve what Dr. Lio calls “deep remission,” or at least deep discounts, this is going to be big-ticket item for insurance companies and taxpayers, let alone individuals. Even at prices comparable to Xolair, the monoclonal antibody used for asthma and chronic urticaria, which runs $10,000 per annum compared to $32,500 for the asthma drug Nucala—well, you do the arithmetic.
(For a different perspective on treating moderate-to-severe eczema, read chapter five of Traditional Chinese Medicine, Western Science, and the Fight Against Allergic Disease.)