TrialSite News recently published an original analysis titled “Hidradenitis Suppurativa Trials Analysis” which received considerable interest from our readers. As we analyzed the traffic, in part by engaging via social media where we have connected with Hidradenitis Suppurativa (HS) patients, it became clear to us that there was a great disappointment. Our analysis covered most of the clinical trials currently underway (all phases) and most of the investigational drugs constituting biologics (e.g. monoclonal antibodies, etc.). Although the scientific and medical literature clearly demonstrates that this class of drug can have a positive impact in reducing HS symptoms, there are well-known side effects—some of which can be severe.
We sensed from several interactions with the HS community that many who visit TrialSite News are seeking more information. They need to understand what other options exist. Is there something else that could help them that isn’t a monoclonal antibody based biologic drug with the potential for debilitating side effects? Unfortunately, we are not sure that there is here at TrialSite News, but we are committed to clinical research transparency with focus on research sites and staff. We have number of readers that have expressed interest in learning more. Consequently, we aim to provide as much relevant information as possible to individuals struggling with HS.
What follows is a recent literature survey for our readers struggling with HS. Here we cannot pretend to provide good news or any great insight, rather, we aim for transparency for those struggling with this condition. Over the past couple of years what has been written about HS? What has been the true aim of the author(s)? Who are the authors? What organizations are they connected to? What does the general literature review point to in terms of standard of care now?
With that in mind, what follows is a brief literature review with commentary for what we hope provides some value to our readers. We invite our readers with HS to send us comments— if there are research angles you have heard about that hold promise, let us know and we will surely consider our own investigation.
HS Literature Review
What follows is a brief literature review of the past couple years. With an aim of capturing the essence of current thinking, research, occurrence and standards of care, we provide a rudimentary summary to keep information at its basic level for ease and speed of read.
Current Medication for HS
Interestingly, 2018 analyst firms reported on size of HS market for pharmaceutical company revenue. The consensus market size is $572.5 million and is predicted to grow to $763.6 million by 2023. Key pharmaceutical companies include AbbVie, Allergan, Pfizer, AstraZeneca, and Johnson & Johnson. Other players mentioned include those TrialSite News covered in the trial’s analysis, including: InflaRX, XBiotech and Incyte Corporation. All companies are developing primarily monoclonal anti-body based biologic treatments. The biopharmaceutical industry segments the HS market based on skin condition which is comprised of pimples, folliculitis, deep-acne, boils and others. Humira, the number one prescribed treatment today, commands $16 billion in revenue. As a total, the HS targeted market is on the smaller side for the global biopharmaceutical sponsors. To date, the market treatment segmentation includes medications, surgery, laser treatment, photodynamic therapy (PDT), and others. Medication is further segmented into antibiotics, antiandrogens, immunosuppressive drugs, hormones, pain medication, zinc supplements, sulfones, and retinoids.
In September 2018 Sheila Jacobs, writing for Dermatology Advisor, wrote a piece about the possibility of lower-dose spironolactone (hormone sub category) as a treatment for HS with tolerability issues. The summary was based on a single center study and was authored by NM Golbari, ML Porter and AB Kimball, titled “Antiandrogen therapy with spironolactone for the treatment of hidradenitis suppurativa,” published in American Academy of Dermatology in 2018. So, what is Spironolactone? We refer to standard definition in Wikipedia:
“Spironolactone, sold under the brand name Aldactone (Pfizer is manufacturer) among others, is a medication that is primarily used to treat fluid build-up due to heart failure, liver scarring, or kidney disease. It is also used in the treatment of high blood pressure, low blood potassium that does not improve with supplementation, early puberty in boys, acne and excessive hair growth in women, and as a part of feminizing hormone therapy in transgender women. Spironolactone is taken by mouth.
Common side effects include electrolyte abnormalities, particularly high blood potassium, nausea, vomiting, headache, rashes, and a decreased desire for sex. In those with liver or kidney problems, extra care should be taken. Spironolactone has not been well studied in pregnancy and should not be used to treat high blood pressure of pregnancy. It is a steroid that blocks the effects of the hormones aldosterone and testosterone and has some estrogen-like effects. Spironolactone belongs to a class of medications known as potassium-sparing diuretics. “
We breakdown the authors and their affiliation:
Nicole Golbari, Medical Student, Stony Brook University
Martina Porter, MD, Harvard, BIDMC
Alexa B. Kimball, President, CEO Harvard Medical Faculty Physicians
Their study was retrospective, and included limited sample size as well as variation in documented severity measures. The authors noted that in cases with HS tolerability issues spironolactone appeared to be an effective option. In 2018, Danish researchers undertook a comprehensive survey of HS investigational drugs under study. They noted that the only Adalimumab (AbbVie’s Humira) is a registered indication. Performing a review like the TrialSite News effort recently, they summarized “Currently, MABp1, Secukinumab (immunosuppressive from Novartis), CJM112 (immunosuppressive from Novartis), Apremilast (anti-inflammatory by Celgene) and IFX-1(antibiotic/inflammatory by InflaRX) are being investigated in Phase I and II trials and offer theoretical and promising new treatment options. A trial with the drug MEDI8968 (immunosuppressive by Amgen) has been terminated with disappointing results. Metformin (anti-diabetic), Botulinum Toxin B (University Hospital Northern Norway), Provodine, Benzoyl Peroxide and intralesional triamcinolone are being tested as well. Treatment of Hidradenitis remains a challenge and quality RTCs (return to clinics) are needed. Studies indicates a range of potential targets for therapy such as interleukin-1 and interleukin-17, but ‘broad-spectrum’ immunosuppressants like phosphodiesterase-4 inhibitors are being examined as well. A range of outcomes, including Physician Global Assessment, Sartorius scores and hidradenitis suppurativa clinical response are used in these trials, making future meta-analysis of the data difficult.” Translated for the layperson, there are a range of experimental drugs under investigation. However, they are addressing different specific challenges, under differing conditions and it would be all but impossible for a harmonized analysis providing universal understanding.
AbbVie, the makers of Humira, are active agents in the publication arena over the past two years. In an Australian-focused study titled “Hidradenitis Suppurativa (HS) prevalence, demographics and management pathway in Australia, a population-based cross-sectional study” the Australian authors included a few employed by AbbVie.
The authors concluded first on the prevalence of HS in Australia at 0.67%. They observed that diagnosis rates were low due to “a combination of patients not seeking help and decentralization of care.” They did note that targeted HS patients were more likely female, young, obese, smokers and unemployed or active with home duties with lower income. This study appeared to be an attempt to understand how individuals with HS were being diagnosed, treated, etc. It did not propose any alternative treatments. In June of 2018, AbbVie announced that it would team with patients to created “Voices of HS Unite” to address HS.
They announced a social network platform “Thunderclap” which wasn’t available at time of this writing. However, in their 2018 press release, AbbVie Vice President, Global Medical Affairs noted “AbbVie is committed to supporting those affected by HS. Voices of HS Unite aims to bring the community together by shining a light on their stories and elevating their voice so they can receive the best possible support during all phases of their journey.” TrialSite News does monitor and engage with some members of the HS community via Facebook, some user groups as well as direct interaction via private comments to our site staff and we certainly believe what the HS community wants is a cure or at least innovative approaches that reduce the pain and suffering while minimizing debilitating side effects.
In 2017 it was promoted by Innovation Pharmaceuticals via a business press article that Brilacidin could potentially be applied to treat HS.
The authors’ noted that even a principal investigator, Dr. Alexa Kimball, of Harvard Medical School, said about Humira HS studies, “the magnitude of improvement with adalimumab (Humira) treatment in our patients was relatively modest as compared with adalimumab treatment in patients with other diseases, and our patients were unlikely to have complete resolution of their symptoms.” The prognosis of Humira for HS is not great. Given the potential side effects of this powerful biologic, the gains may just not be worth it. Hence the introduction of Brilacidin (formally PMX-30063) as potential investigational new drug. It is a polymer-based antibiotic currently in human trials. It purports to work by disrupting cell membranes, mimicking defensins that play a role in innate immunity. See a company presentation that promotes the potential of Brilacidin (and other treatments) to investors.
As promising as some of this investigational activity sounds, there are considerable risks with Innovative Pharmaceuticals. Essentially a penny stock, they have just a handful of employees. With no real revenues and a burn of at least $16 million per annum, drug development is an expensive business. Based on a review of Yahoo Finance, a couple of the key executives are taking salaries over $450,000 annually— while the venture is thinly capitalized. How will this company get through all phases of clinical trials toward commercialization to compete against multi-national AbbVie? As stated in their own annual statement to the SEC (10K) “Phase 3. If Phase 2 clinical trials of a compound yield promising data regarding safety and effectiveness, the compound may be advanced to Phase 3 clinical trials to confirm those results. Phase 3 clinical trials typically are long-term, involve a significantly larger population of patients, are conducted at numerous sites in different geographic regions, and are carefully designed to provide reliable and conclusive data regarding the safety and benefits of a drug and to form the basis for labeling. It is not uncommon for a drug that appears promising in Phase 2 clinical trials to fail in the more rigorous and reliable Phase 3 clinical trials.” Of note, Phase 3 trials can cost in the tens of millions to hundreds of millions of dollars. Innovative Pharmaceuticals will need significant sources of fresh capital.
A Severe Case of HS
We review another publication from 2017 covering a case documented by Dr. Birgit Khandalavala, based in Nebraska and affiliated with the University of Nebraska. In this extreme case, Dr. Khandalavala treated a 19-year old female with an 8 year history of progressively debilitating cicatricial HS disease involving obesity, severe anemia, leukocytosis, increased platelet count, hypoalbuminemia, and elevated liver enzymes. The physician treated the case with a combination of metformin, liraglutide, levonorgestrel-ethinyl estradiol, dapsone and finasteride was initiated. Acute antibiotic use for recurrences and flares would be slowly discontinued. Over the course of thee years on this regimen, the liver enzymes normalized in one year, followed in two years by complete resolution of most of the hematological and metabolic abnormalities. The sedimentation rate reduced from over 120 to 34 mm/h. She required 1 surgical intervention for perianal disease after nine months on the regimen. Flares greatly diminished in intensity and duration, with none in the past six months. Right axillary lesions had completely healed with residual disease greatly reduced. Chiefly abdominal lesions were persistent. She was able to complete high school from home, start a job, and resume a normal life. Initial weight loss of 40 pounds was not maintained. The current regimen was being well tolerated and continued. Dr. Khandalavala was able to get this severe case of HS under control to an extent.
A Current Understanding of HS
In a Michigan-based report in 2017, the authors included the following:
They reiterated the devastating nature of HS and reported that some progress in terms of disease pathogenesis, noting, “HS pathology runs much deeper than the cutaneous manifestations. It is not believed that HS is a systematic inflammatory disease that gives rise to the characteristic cutaneous manifestations.” They emphasized all too well what HS patients already know that the disease is difficult to manage. The purpose of the Michigan author’s report was “to provide updates on the current understanding of HS to increase awareness and improve management.” After a medical and scientific survey, they summarized that “treatment is guided by disease severity and symptomatology.
While the medical, surgical, and laser management sections are separated for ease of discussion, these treatment options are not exclusive but rather exist on a continuum, and are often combined to optimize treatment response. Additionally, it is important to address and properly treat underlying medical conditions to comprehensively manage patients. To date, there is no widely accepted, evidence-based treatment algorithm, although evidence-based treatment ladders have been suggested. The Henry Ford Health System in Detroit, Michigan proposed an algorithm of HS management based on the treatment of more than 1,000 patients in a dedicated follicular disorders clinic—see the Ford Hospital HS Treatment Algorithm below:
Writing in 2017 via Swiss publisher Karger, authors D.E. Lee (Creighton University School of Medicine); A.K Clark (University of California Davis School of Medicine); and V.Y Shi (University of Arizona) discuss in “Hidradenitis Suppurativa: Disease Burden and Etiology (Cause)in Skin Color.”
The authors summarized what patients already know all too well—that “HS is a chronic, debilitating skin disease.” The authors reported that the research has focused on Caucasian (white) populations, but that evidence points to the reality that African American and Hispanic (Latino) populations experience a much higher prevalence. The authors noted that the “paucity of research” in these populations and conditions may be worse for the population experiencing HS—magnifying the challenge with less general health care system access for minority groups within the United States.
Additionally, in 2017 “Review of Current Immunologic Therapies for Hidradenitis Suppurativa” was published in the International Journal of Rheumatology, by Victor K. Shanmugam (George Washington University, School of Medicine and Health Sciences); Nadia Meher Zaman (Shanmugam (George Washington University, School of Medicine and Health Sciences); Sean McNish Shanmugam (George Washington University, School of Medicine and Health Sciences); and Faye N. Hant (University of South Carolina Medical University).
The authors reported that HS affects approximately 1-4% of the population or as many as 13 million people. They reiterated that the disease is more common with women and African Americans and that approximately 1/3 of patients reported a family history—obesity and smoking are known risk factors as are associations with other immune disorders such as inflammatory bowel disease. The origin and cause are “poorly understood” but there are several factors involved including “host innate or adaptive immune response, defective keratinocyte function, and the microbial environment in the hair follicle and apocrine gland have all postulated to play a role in the disease activity.” They noted a high recurrence rate with surgical interventions (although they provided some help in extreme cases). The purpose of the author’s study was “to outline the current data supporting use of targeted immune therapy in HS management.”
The study was not funded by commercial sponsors and was supported by the National Institutes of Nursing Research and by the National Center for Advancing Translational Science as well as the National Institutes of Health through the Clinical and Translational Science Awards Program (CTSA). The authors concluded that the immune system role is of prime suspect in driving HS. They summarized that a number of “therapies are under investigation for efficacy as treatment for HS. Based on data from randomized controlled clinical trials, the TNFα inhibitor adalimumab recently received orphan drug designation for HS. As new immune pathways driving disease pathogenesis are recognized, there is a significant need for ongoing clinical studies investigating adjunctive immune therapies in HS.” TrialSite News points back to our comprehensive summary of trials for the readers review.
We also noted a 2017 report in Spain titled, “Strategic Health Initiative to Determine the Standard of Care for Patients with Hidradenitis Suppurativa,” which was authored by a prominent Spanish HS focused medical group. TrialSite News Research found this 148 page report interesting and useful and hopes viewers can review at length. The authors report that almost 450,000 individuals in Spain struggle with HS (although we think this may be a larger number based on Spain’s population of nearly 47 million people and as the authors note many patients “still do not know this, since they lack a diagnosis that puts a name to what is happening to them.” The Spanish Hidradenitis Suppurativa Patient Association (ASENDHI) and 20 scientific associations all supported this report.
Some insightful metrics:
- The departments most commonly visited by patients with HS were emergency departments (58.2% of the times that they went to the doctor due to HS), followed by dermatology departments (16%) and primary care departments (13.8%).
- The patients who were interviewed stated that they had undergone an average of six surgical procedures since the onset of their first symptom (5 years for women and 9 years for men).
- Those interviewed indicated that they had been hospitalized in the last year for two days on average due to their HS and had gone to the doctor on seven occasions.
- Of them, 87.4% stated that HS affected their daily life, and more than 31% stated that it seriously affected their daily life. The main symptoms that they experienced were: pain, discharge, impaired mobility and foul odor.
- The general aspects of their lives that the patients found to be most affected by the disease were: • Emotional and psychological problems (20.5%) • Sexual relationships (19.9%) • Social relationships (16.1%) • Occupational problems (15.8%)
- Average Diagnosis time: 9 Years
- Average Physician Visited Before Diagnosis 14.6
- Average # Surgeries 6
- Number in Survey Noting HS materially impacted daily life 87.4%
- Average amount of Occupational Leave due to HS 35 days
Overall, there is a lack of suitable healthcare process for HS, which would enable and approach that would ensure optimal standard of care for HS patients. Moreover, there is a lack of awareness of HS in Spain which adversely impacts patients on healthcare, social and institutional levels. See “Proposed Interventions” in the report for additional information.
Possible Dietary Concerns
Dr. Greger noted that an estimated of 1% to 4% of the US population faces HS. He cautions that there are surgical options, chemotherapy and others, but asks why not think of diet as a possible answer. He states that there is a potential link between HS and Crohn’s Disease—that there may be an immunopathogenic link between the two. He reports that there has been some positive correlation between patients eliminating yeast from their diets (bread, beer, etc.) and relief from Crohn’s Disease symptoms. He asked the question: “why not consider yeast elimination to combat HS—for those facing debilitating struggles what is there to lose?” In one non-clinical trial Dr. Greger reported of the 12 HS patients that eliminate yeast 12 patients benefited. Note that the Michigan group study reported earlier in this TrialSite News article identified this study involving Brewer’s yeast, making this other dietary component of interest. “One study followed 12 patients who eliminated foods containing brewer’s yeast, such as breads, beer, black tea, fermented cheese, and more, after the completion of HS surgery. Stabilization and eventual regression of HS throughout the one-year study period was reported 18. However, because of the small sample size, future studies are needed to further elucidate the role of brewer’s yeast in HS management.”
Dr. Greger further articulated that the removal of dairy products may also yield results. TrialSite News encourages readers to study up on yeast and even dairy removal as a potential alternative approaches to explore. Of course, this should be undertaken with the guidance of a trained and certified medical professional.
A Need For More Studies
In December 2016 an article was included in Consultant 360 titled “Treatment of Hidradenitis Suppurativa: A Desperate Need for Comparative Studies.”
The authors noted what HS patients are becoming all too familiar with—that the treatment is not standardized and “no well-defined, accepted evidence-based guidelines exist.” In 2015 authors from May Clinic reported that “No ideal treatment regimen has been defined, but several therapies have been found to reduce lesion severity and improve symptoms.” We reviewed the literature through July 2014 for existing treatments. Published articles were obtained via systematic review of medical databases (PubMed, Embase, Google Scholar) and scrutiny of citation lists using the search terms “hidradenitis suppurativa” and “acne inversa.” Given the scarce literature on treatment strategies, we also reviewed data from any case reports or prospective and retrospective studies that were located. On the basis of the existing literature, we provide an evidence-based algorithm for the management of this disease in the primary care setting. More research is needed to evaluate the comparative effectiveness of topical and systemic treatments and to better understand the pathogenesis, natural history, and subtypes of hidradenitis suppurativa.
The authors’ proposed an evidence-based algorithm and it may be worthwhile for patients to review these professionals’ work. TrialSite News clinical research service can facilitate and broker communications with these professionals.
The researchers include:
Carina M Woodruff
In 2016 authors Amit Garg, MD; Justin Besen, MD; Aaron Legler, MPH and Christina S. Lam MD published “Factors Associated with Point-of-Care Treatment Decisions for Hidradenitis Suppurativa” which was published in JAMA Dermatology. The work represents a retrospective cohort analysis identifying the clinical and demographic factors that patients and clinicians should consider in developing partnered short and long-term support strategies for HS. See the link. A summary of the report can be seen here.
TrialSite News conducted a comprehensive survey of all relevant commercial and academic HS trials inclusive of all trial phases. The results were sobering for many HS patients we thereafter engaged with. They reported that they wanted more general information about what they can do in the alternative to taking powerful biologic drugs such as Humira or similar immunosuppressive competitive drugs in investigational stages. Their concern includes the fact that prominent investigators are on the record that Humira may only have nominal value for many struggling with HS when one considered cost and the potential for severe side effects. TrialSite News introduces this literature review covering the past couple of years. We summarized various reports from a wide array of authors from academic, European consortium in Spain, alternative approach possibilities to another commercial sponsor comparable investigational drug survey.
Patients face severe problems with HS. The costs in terms of quality of life, pain and suffering and economics are real. Women and minority groups may fare even worse with HS and there are clearly no known cures. The medical community lacks a unified understanding of cause or even standard of care (although many are developing such algorithms such as the one from Michigan included in this article). However, we found an insight that yeast and dairy could be eliminated to possibly and hopefully reduce symptoms for some HS sufferers, but any patient should still consult with medical professional for any action with this serious disease. Finally, we remind TrialSite News community that our tailored clinical research services are available for patients—simply submit a request and our research team will seek guidance and direction based on our research capabilities; access information as well as a network of medical professionals; and offer the possibility of brokering introductions to select medical professionals working to understand this debilitating disease.