You can listen to the follow up to this article here– where we talk with XBiotech about their HS clinical trials pipeline.

TrialSite News has covered the hidradenitis suppurativa (HS) research pipeline. HS is a pervasive problem for so many. We are connected with hundreds who have sent us feedback and research requests. According to some figures, up to 4% of any population may struggle with the chronic inflammatory condition, and women are afflicted in greater numbers. Starting as a simple little nodule (often mistaken for some form of acne), it can look like a cyst. The bumps often develop into abscesses and become sizeable and painful—lasting for months. Often leaking a puss, they may scar skin in their wake. With no known cure, hundreds of thousands struggle while trying different treatments, from antibiotics (often with poor results), to powerful biologic medications such as Humira (where results are mixed). It may work some of the time, but for others it represents considerable risk, and in other cases it just doesn’t help.

A TrialSite News survey of treatments was received by our readership with mixed reviews. While some sent us hopeful comments, others expressed considerable cynicism and essentially relayed to us a sense of hopelessness. We recently curated and posted the XBiotech (NASDAQ: XBIT) phase II bermekimab results. The response was overwhelmingly positive as we tapped into the hope of many thousands struggling with HS. Is there a potential cure? If not, will there be a treatment that makes life easier with HS? We cannot be certain at this stage, but we shall not only continue to follow commercial sponsor XBiotech, but also drill deeper into HS treatments including this new investigational one covered in the news: bermekimab (MABp1 or Xilonix.™)

What is Bermekimab?

Developed by biotech venture XBiotech, bermekimab, known as MABp1 (trade name Xilonix), is a human monoclonal antibody of IgG1k isotype targeting interleukin 1 alpha (IL1A). As of March 2017, it has been in phase III clinical trials as an immunotherapy for colorectal cancer and as of September 2018, has been in Phase II clinical trials for the treatment of atopic dermatitis in addition to the hidradenitis suppurativa trials.

What is the Bermekimab Story?

According to website ADis Insight, Bermekimab was developed by XBiotech Inc. Its developers included Cedars-Sinai Medical Center, Hellenic Institute for the Study of Sepsis, Ipsen (a European biotech) and of course XBiotech.

XBiotech Inc., a pre-market biopharmaceutical venture has developed its “True Human™” monoclonal antibodies line of investigational treatment. Monoclonal antibodies are antibodies that are made by identical immune cells that are all clones of a unique parent cell. They can have monovalent affinity in that they bind to the same epitope (the part of an antigen that is recognized by the antibody). As XBiotech reports, the True Human antibodies are those which occur naturally in human beings—as opposed to being produced from animal immunization and less effective than the naturally occurring counterparts. Bermekimab is one of the products of XBiotech’s True Human pipeline and manufacturing system.

Indeed, XBiotech has primarily focused on developing their lead candidate—also known as MABp1 (Xilonix™, CA-18C3, CV-18C3, RA-18C3, and T2-18C3), a therapeutic antibody which specifically neutralizes interleukin-1 alpha (IL-1). IL-1 is a pro-inflammatory protein produced by leukocytes and other cells, where it plays a key role in inflammation. If not treated, inflammation can lead to several compounding problems including progression of various diseases such as cancer, vascular disease, inflammatory skin disease, and diabetes. XBiotech’s clinical program is starting to demonstrate that stopping IL-1 with Xilonix may in fact help the patient fight several relevant diseases including Hidradenitis Suppurative (HS).

The Road to the Present

XBiotech’s Xilonix has faced some challenges, but has come a long way since its 2005 inception. Back in June 2017, the company announced a discontinuation of its global phase III study for the treatment of advanced colorectal cancer (CRC) patients under U.S. FDA regulatory guidance after an Independent Data Monitoring Committee (IDMC) recommended early termination of the trial. Apparently, the trial’s results failed to meet enough efficacy or the threshold for continuation, which involved a prospectively defined acceptance boundary for the interim analysis. The company also received a negative opinion from the European Medicine Agency (EMA) Committee for Medicinal Products for Human Use (CHMP) for its Marketing Authorization Application (MAA) in Europe. XBiotech appealed, requesting a re-examination procedure however the CHMP maintained its initial negative option.

The company continued to pursue other treatments for MABp1 (Xilonix). Including:

  • As a therapy to reduce the need for re-intervention after treatment of peripheral vascular disease with angioplasty or other endovascular methods of treatment
  • Type 2 diabetes
  • Acne
  • Psoriasis
  • Pyoderma gangenosum (PG)
  • Hidradenitis suppurativa (HS)

In regards, to hidradenitis suppurativa (HS), the company recently published results from a phase II double-blinded, placebo-controlled investigator-sponsored study evaluating MABp1. By October 2017, the results from the study were published in the Journal of Investigative Dermatology, which highlights results of twenty patients enrolled in the study with moderate to severe HS that had progressed on standard therapies. In the study, HS patients received MABp1 for 12 weeks and were then followed up with an additional 12 weeks treatment to observe durability of the treatment. Efficacy measures include assessment of Hidradenitis Suppurative Clinical Response (HiSCR) scores—a validated method for evaluating efficacy in HS patients—in addition to quality of life assessment (Dermatology Life Quality Index or DLQI. The study results indicated a response rate in participants treated with MABp1 versus placebo of 60% vs 10% respectively (P-0.035).

Most recently, XBiotech reported the successful outcome of its multi-center, open label, confirmatory study using bermekimab (MABp1) to treat moderate to severe HS patients. Of note, the commercial sponsor reports that both primary and key secondary endpoints were met in a study including “significant, differentiating findings.” Previously, the company published data from its double-blind placebo controlled study in HS using bi-weekly, intravenous infusions of bermekimab where safety and primary efficacy endpoints were met. The most recent trial “tested a new concentrated subcutaneous formulation in convenient pre-filled syringe, confirmed and expended up the previous findings.

As recently reported, the study data show that Bermekimab was well-tolerated with no safety concerns. Moreover, “statistically significant improvement was seen for efficacy endpoints in both anti-TNF and anti-TNF naïve groups, including the Hidradenitis Suppurativa Clinical Response Score (HiSCR); Dermatology Life Quality Index (DLQI); Physician’s Global Assessment (PGA); Change in inflammatory lesion count; Disease Activity Score (DAS); and Visual Analogue Scales (VAS) for Disease Impression and Pain. These efficacy findings differentiate bermekimab from the available treatments for HS.”

The study was chaired by Dr. Alice Gottlieb, M.D., Ph.D., Clinical Professor of Dermatology, Department of Dermatology, Icahn School of Medicine at Mount Sinai, New York. Dr. Gottlieb noted, “we need more effective treatments for HS. Bermekimab provides hope for potent therapies which address novel targets. I am very excited about this drug for hidradenitis suppurativa and atopic dermatitis.” Moreover, a Dr. Gregor Jemec, MD, DMSci Professor and Chairman Dept of Dermatology, Zealand University Hospital, University of Copenhagen commented, “I am very pleased to see these promising results of a new treatment option.”

Of paramount interest, the result study evidenced a reduction in HS patient pain. HS patients are all too familiar with what can be severe pain associated with the ailment. The pain symptom has largely been unaddressed by presently approved therapies. According to XBiotech’s recent press release, “Pain was assessed with a patient questionnaire using a numerical rating scale from 0 to 10. A 30% and ≥1-unit reduction in pain score is considered a clinically important relief from pain. Remarkably, 67% and 72% of patients who had prior or no prior anti-TNF therapy achieved this endpoint at week 12, respectively.  No approved monotherapy for HS has shown a significant effect on pain

XBiotech Business

Founded in 2005, XBiotech is a biopharmaceutical company developing first-in-class antibody therapies. The Company’s lead product candidate inhibits chronic (sterile) inflammation—a condition involved in the progression of many serious and common diseases. The Company has several groundbreaking clinical trial programs in different areas of medicine, including dermatology, oncology, diabetes, cachexia and cardiovascular disease. The recent positive hidradenitis suppurative news excited market watchers. Online stock analyst Seeking Alpha reported that, “XBIT” and its anti-IL-1a antibody Xilonix) has thus far proven efficient in dermatology. Although the cancer program didn’t progress it did establish an overall safety profile of treatment…. recent phase II data in atopic dermatitis (AD) suggest that subcutaneous bermekimab formulation sets new standard in management of AD.” This potentially establishes Xilonix as a superior treatment to that of dupilumab (Dupixent®), reducing itching symptoms in twice as many patients. Some analysts expect Dupixent (Sanofi & Regeneron) to bring in $4.1 billion in revenue by 2022. Noteworthy, AbbVie has reported that Humira HS sales would peak at approximately $1 billion.

The positive bermekimab news around the HS phase II trial leads investors toward a giant target—AbbVie’s Humira. Seeking Alpha noted “intravenous administration of bermekimab showed compelling phase II data in hidradenitis suppurativa (HS). Bermekimab beat adalimumab (Humira®).” The phase II study testing subcutaneous formulation is presently in progress and all patients have been enrolled. The Seeking Alpha author called SwissBioIT notes that they believe the company’s stock price is bound to rise. It was hit hard when it failed to secure regulatory approval for phase 3 cancer studies, but with the latest clinical results, XBiotech shows “unparalleled activity in two major dermatology indications.” As highlighted above, XBiotech’s Bermekimab presents potentially superior treatments to Sanofi/Regeneron’s Dupixent for AD and to AbbVie’s Humira (HS). SwissBioIT believes that XBiotech is trading approximately 5 to 10X lower than competing companies at the same stage, same focus areas, etc.

The management appears organized and ready to manage scale in FDA regulated (GxP/GmP, GcP, etc.) environment. Most recently they passed a GMP audit. They retained prominent laboratory and quality management firm Eurofins Amatsigroup to conduct the audit related to its distribution in Europe of its U.S.-based manufactured drug product. Bermekimab is made in its Austin, Texas facility, and regularly distributes the drug to various clinics in the UK and EU. As was reported in the XBiotech news release, drugs manufactured outside of Europe are only allowed access to EU markets through a qualified organization that meets the highest quality standards (e.g. GxP). XBiotech recently built a state-of-the-art manufacturing and R&D center in Austin. The first audit of the new facility appears to be a smashing success.

TrialSite News provides some basic business and financial information for viewers to consider. Although a cursory view doesn’t look great, bleak numbers are common with fledging high risk and high potential return biotech ventures. They went public in 2015 at just over $20 and have fluctuated since then. They now at $6.07 as of this writing, and approximately 35 million shares outstanding. Insiders control approximately 43.5% according to Yahoo Finance. CEO & Founder John Simard and hedge-fund investor Thorpe Mckenzie own approximately 10 million shares or nearly 30% according to Yahoo Finance. The company posses about $20 million cash in the bank according to their latest SEC 10Q. As of their announcement, they were on track to lose slightly more than $20 million for all of 2018.  

The company has a multi-billion upside if they can secure FDA and European approvals for bermekimab for HS and AD.

The company lists the usual biotech risk suspects including:

  • Uncertainties of technological innovations
  • Dependence on key individuals
  • Development of the same or similar technological innovations by their competitors
  • Protection of proprietary technology
  • Financing its ongoing operations and clinical studies depends on the amount and timing of cash receipts from future collaboration or product sales and /or financing transactions.
  • It reports in its 10Q that its cash and cash position of $20.8 million enables it to achieve “some inflection points” including advanced clinical studies in certain indication(s) as well as ongoing R&D efforts for its’ pre-clinical pipeline
  • They believe they have enough capital to execute through 2019 though a look at finances leads to a very tight situation and they are clear that if they are incorrect on key assumptions then they may not have enough capital.
  • They have not generated any revenue. It would appear they haven’t signed on any larger biotech/pharma partners for a co-development, revenue share alliance.  All bets are on successfully commercializing bermekimab

Key intellectual property includes a patent portfolio. They reported that over the last quarter they were awarded 4 new patents and 7 patent allowances. TrialSite News lists XBiotech’s latest patent status:

Patents

  • Bermekimab patents awarded in Canada and Russia
  • European Patent for IL-1α-specific antibodies for treatment of dermatological pathologies
  • European patent for IL-1α-specific antibodies for the treatment of cancer-associated cachexia

Patent Allowances

  • Patent applications allowed in Q3 include one each in Australia, Canada, Israel, Mexico, the Philippines, Russia, and South Korea
  • The allowed Australian application relates to using IL-1α-specific antibodies to treat arthritis
  • The allowed Canadian application relates to using IL-1α-specific antibodies to reduce a subset of blood cells that contribute to inflammatory diseases
  • The allowed Israeli and Mexican applications each cover key aspects of the Company’s innovative True HumanTM antibody discovery platform. 
  • The allowed Russian application relates to using IL-1α-specific antibodies to treat vascular diseases and complications thereof
  • The allowed Philippines application relates to the Company’s antibody for treating S. aureus infections, 514G3

XBiotech reports on research and development expenses. Their bulk of costs are associated with salaries, stock, equipment, laboratory supplies, facility costs, etc.  Their clinical timelines represent the lifeblood of the venture as all is riding on the successful approval of Bermekimab. They don’t break down their R&D costs (or personnel) on an individual drug candidate basis. Rather, they leverage the resources and capital across the drug development programs—seeking efficiency and continuity. However, they do report on total R&D expenditure. From inception through the end of Q3 2018 they spent a total of $180.8 million. Their R&D expenditures have gone down since 2017. They may be reallocating capital toward ongoing clinical trials as they continue to progress with their two on-going phase II trials. Total number of employees ranges from 51, reported in Owler, to 69 self-reported in LinkedIn. TrialSite News estimates approximately 60 to 70 employees.

XBiotech includes what we think is special leadership. CEO and Founder Mr. Simard has led a brilliant career. He has invented several core technologies that eventually formed the basis of prominent commercialization programs. He is known in the industry for an efficient and effective integrated systems approach to drug development—essentially organizing pre-clinical, manufacturing and clinical regulatory activities under one roof. He drives this approach to not only carefully oversee and monitor quality, but also to conserve capital and control timelines. He was a director with MannKind Corp. for many years and has more than 140 issued and pending patents related to cancer therapy, therapeutic antibodies and vaccines. He has authored/coauthored many peer-reviewed scientific publications as well as co-authored the textbook Handbook of Immune Response Genes (Plenum Publishers 1998). Simard attended graduate studies in Medical Biophysics/Immunology at the University of Toronto and has a degree in Biochemistry from the University of Saskatchewan. There is no doubt that the leader of the company knows his business. Mr. Simard’s small, tight knit leadership includes seasoned quality veteran Norma Gonzalez and Chief Scientific Officer Sushma Shivaswamy, Ph.D. Sushma came to XBiotech during her time as postdoctorate researcher at the Center for Systems and Synthetic Biology at the University of Austin.

Their Scientific Board is a small, committed high-academic pedigree group including:

Dr. Alice Gottlieb, M.D., Ph.D. is internationally recognized for her expertise and trail-blazing work in the development of biological therapies to treat skin diseases. She has played leading roles in the clinical development of therapies including etanercept, infliximab, ustekinumab and secukinumab. Dr. Gottlieb is working to help guide development of bermekimab for the treatment of skin diseases. She currently serves as Study Chair for XBiotech’s ongoing Phase 2 study in hidradenitis suppurativa.

Dr. Peter Libby, M.D. is the Mallinckrodt Professor of Medicine at Harvard Medical School and clinical cardiologist at Brigham and Women’s Hospital. Dr. Libby is collaborating with XBiotech on basic research into the mechanism of inflammation and the use of bermekimab to treat cardiovascular disease. Pioneering research by Dr. Libby and his team was recently published in the journal of the American Heart Association, Arteriosclerosis, Thrombosis, and Vascular Biology. The breakthrough findings of this research showed that bermekimab could potentially be used to prevent heart attacks and strokes.

Conclusion

Hidradenitis suppurativa is a debilitating inflammatory skin disease. It afflicts from 1% to 4% of any given population—representing millions of people often in severe discomfort and pain. The etiology of the disease, which can cause considerable physical and psycho-social distress, remains largely not understood. Some suspect a bacterial component may be at work, others suspect a similar pathogenic mechanism to that of Crohn’s disease. There is currently no cure and limited treatments options  including antibiotics, acne washes and medicines, bleach baths and for moderate to severe cases, biologics (such as Humira) and even surgery.

Having covered HS in the past at TrialSite News, we have engaged with hundreds of patients via social networks from the United States, Canada and Europe as well as Australia and New Zealand. Our team has received reports from viewers/readers that in some extreme cases they feel hopeless because nothing on the market alleviates the considerably uncomfortable to painful symptoms. What if these phase II results translate to a successful phase III trial and FDA, EMA and another regulatory agency approval? What if this biologic works far better than the current products on the market such as Humira? In anticipation of those answers, TrialSite News will research HS biologic treatment pricing and post any findings on TrialSite News’ PriceWatch. We sincerely hope the bermekimab momentum carries on through a phase III trial to ultimate approval, potentially helping those hundreds of thousands severely afflicted HS patients. They may finally receive relief that is safer. If such a reality were to materialize the commercial sponsor, XBiotech, will be able to redeploy the economic windfall of such a scenario into more meaningful, superior treatments for patients.

About the Author

Daniel O’Connor

Mr. O’Connor has spent nearly 20 years providing technology and services to the clinical trials and health technology industry. An entrepreneur, he has been instrumental in building different ventures focusing on FDA 21 Part 11 enterprise document management, technology-enabled patient recruitment services, clinical document and safety data exchange, as well as population health and community care coordination for at-risk populations with Eccovia Solutions. He is a co-founder of a public benefit corporation launching a global clinical research site accreditation standard–ACRES ReServ. Mr. O’Connor has developed a comprehensive clinical research site data base and intelligent clinical news curation engine with TrialSite News. He earned his combined MA and JD from the University of California (Los Angeles and Hastings College of the Law) and undergraduate from San Francisco State University.

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