Much ado about Sanofi and Regeneron’s Dupixent (dupilumab)

There was much ado about Sanofi and Regeneron’s development of dupilumab—the first biologic approved to treat adults with moderate-to-severe atopic dermatitis (AD), or eczema. In fact, one couldn’t attend a dermatology conference without hearing a speaker tout its promise. Since Dupixent’s approval by the FDA on March 28, 2017, about half a week after the conclusion of Maui Derm, the excitement has been a bit more subdued. Is this just life’s ubiquitous anticlimactic effect after protracted anticipation? Or is it related to Dupixent’s efficacy, safety, or the emergence of competitors?

Atopic dermatitis and standard of care

Moderate to severe AD is a chronic, relapsing inflammatory skin disease that is characterized by persistent pruritus (itching), which can lead to sleep deprivation, anxiety, and an overall decreased quality of life. In the United States, AD impacts approximately 3-7% of adults and 11% of children.

Topical corticosteroids have been the mainstay AD treatment for the last 40 years, yet prolonged use can result in telangiectasias (spider veins), easy bruising, poor wound healing, acne, and rosacea. When used on large surface areas of skin for a long time, topical corticosteroids can also produce deleterious systemic effects including adrenal suppression. In addition to corticosteroids, calcineurin inhibitors such as Astella’s Prograf (tacrolimus) or Valeant’s Elidel (pimecrolimus) can treat AD, yet these therapies include a black box warning for risk of the development of skin cancers and lymphoma. (Both Prograf and Elidel have lost patent protection and are now available as generics.) Phototherapy is an option for those with mild AD, although it may increase the risk of skin cancer. Finally, cyclosporin offers rapid relief from recalcitrant AD, but relapses occur in almost all cases if followed up for long enough. Although there are numerous options in dermatologists’ armamentarium, none have succeeded in providing a marriage of potent efficacy and minimal risk.

In December 2016, Pfizer’s Eucrisa (crisaborole), a topical PDE-4 inhibitor, was approved for mild-to-moderate AD in adults and children as young as 2 years, which was a wise indication gambit by Pfizer since AD predominantly affects children, although its overall efficacy has been nominal. Three months later, Dupixent (dupilumab) was approved as the first biologic to treat AD in a more severe population consisting only of adults, thus far.

Dupilumab history and trajectory

Dupilumab, a human monoclonal antibody inhibiting the signaling of IL-4 and IL-13, was developed in part based on paradigm-shifting research led by Dr. Emma Guttman-Yassky of the Icahn School of Medicine at Mount Sinai. For years, it was unclear whether AD was a disease of barrier dysfunction or of the immune system. “We can show with a narrow immune targeted treatment that we can actually reverse barrier responses, finally settling the debate, and classify atopic dermatitis as primarily an immune disease,” Dr. Guttman-Yassky observed. Her findings have suggested a Th2/T22 immune polarization in chronic AD, compared to the deviation toward a Th1/Th17 phenotype in psoriasis.

psoriasis-atopic-dermatitis-cellular-mechanism

Like the PASI score for psoriasis, the EASI score quantifies the extent of disease for eczema or AD. EASI scores range from 0-72 with higher scores indicating greater severity of:

  1. Redness (erythema, inflammation)
  2. Thickness (induration, population, swelling)
  3. Scratching (excoriation)
  4. Lichenification (lined skin)

U.S. approval of Dupixent was based on SOLO 1 and 2 (monotherapies) and CHRONOS (steroid combination). At EADV 2017 in Geneva, Sanofi/Regeneron presented LIBERTY AD CAFÉ, which was unlike CHRONOS in that patients required continuous topical corticosteroids (TCS) throughout. Recall back in SOLO 1, without concomitant TCS, Dupixent hit 51% EASI-75 (placebo: 15%) after 16 weeks. With TCS, Dupixent can hit 62.6% EASI-75 (placebo + TCS: 29.6%). Due to its unique first-in-class mechanism of action, Dupixent can cause side effects such as conjunctivitis (pink eye) and keratitis (inflammation of the cornea). So far the efficacy and safety profile of Duipxent has remained fairly consistent across studies.

dupilumab-EASI75-TCS-EADV-NEJM-2017

A week before EADV, AbbVie released topline Phase 2b data for its JAK1 inhibitor, upadacitinib (ABT-494). AbbVie chose to walk away from prospective partnerships to focus on this in-house drug, convinced that they may have a blockbuster, which may be the case, as these numbers are resembling or perhaps even exceeding Dupixent’s. Indeed, upadacitinib hit 69% EASI-75 (placebo: 10%) after 16 weeks. In upadacitinib’s study, no new safety signals were detected. Unlike Dupixent, there were no side effects relating to the eyes as most common adverse events (AEs) were upper respiratory tract infections, atopic dermatitis, and acne. The safety profile of upadacitinib will be further evaluated in Phase III. Another major difference between upadacitinib and Dupixent is dosing: Dupixent is dosed every week or every other week whereas upadacitinib is dosed daily.

upadacitinib-EASI75-2017PR

Market impact and outlook

Dupixent has been priced at a wholesale acquisition cost (WAC) of $37,000/year, which is more expensive than other AD therapies because Duipxent is a biologic.

The Institute for Clinical and Economic Review (ICER), an independent non-profit research organization, estimated the cost-effectiveness of dupilumab versus standard of care over a lifetime for adult patients with AD. Compared to standard of care, the cost per additional quality adjusted life years (QALY) for dupilumab was estimated to be approximately $101,800. The QALY is used in cost-utility analysis that combines into a single measurement how much a treatment would extend a patient’s life with how much it will improve quality of life. For example, if a drug cost $50,000 more than the standard of care, but only gives the patient 6 months more of healthy life, it would cost $100,000 per QALY gained. The cost per additional QALY was lower for patients with severe atopic dermatitis ($78,300) than those with moderate atopic dermatitis ($130,800). Thus, dupilumab was projected to be more cost-effective in patients with severe atopic dermatitis, which is as expected. Even in patients with moderate atopic dermatitis, the ICER remained below the upper range of commonly cited thresholds.

The global AD treatment market is expected to grow from $7 million in 2017 to $24 million by 2027. This substantial increase can be attributed to a rising prevalence of AD as well as the introduction of novel therapies like Dupixent. Shares of $REGN gained 23% from early May through June, but have since lost speed perhaps in part to AbbVie’s promising pipeline data. “The next two to three years will be extremely important as far as how we understand and can treat this disease in a much better and specific fashion,” Dr. Guttman-Yassky noted presciently in 2015.

Amgen will not launch its biosimilar of AbbVie’s Humira in U.S. until 2023

One cannot watch a program on cable television without likely catching a commercial for Humira with its iconic mauve ribbon branding. AbbVie’s blockbuster drug, Humira (adalimumab) was the best selling drug of 2016, with net sales of over $14 billion, a 15% increase from 2015. While it was not the first approved TNFα-inhibitor, Humira was the first approved fully human monoclonal antibody in its class. The brand name Humira stands for “human monoclonal antibody in rheumatoid arthritis”. Remicade (infliximab), a mouse-human chimeric antibody, was the first approved TNFα-inhibitor and Enbrel (etanercept), a fusion protein, was the second. In 2001, pivotal results from ARMADA, AbbVie’s phase III double-blind, placebo-controlled trial involving 271 patients, showed a 50% improvement in ACR score (or, reductively, a 50% joint improvement) using Humira. Since then, Humira has become a staple in the armamentariums of rheumatologists, dermatologists, and gastroenterologists. After its original approval in RA in 2002, the timeline for indication approvals follows:

Humira-approvals-by-year

  1. Rheumatoid Arthritis (2002)
  2. Psoriatic Arthritis (2005)
  3. Plaque Psoriasis (2008)
  4. Adult Crohn’s Disease (2008)
  5. Juvenile Idiopathic Arthritis (2008)
    • Orphan
  6. Ankylosing Spondylitis (2008)
  7. Ulcerative Colitis (2012)
  8. Uveitis (2014)
    • Orphan
  9. Pediatric Crohn’s Disease (2014)
    • Orphan
  10. Hidradenitis Suppurativa (2015)
    • Orphan

In the United States, drugs qualify for orphan status if they treat a disease affecting less than 200,000 patients, thus meriting an additional 7 years of market exclusivity. With 10 indications and a few orphan designations to boot, it’s not difficult to see why Humira is one of the best selling drugs in the world. And, as of September 28, in a major win for AbbVie, their legal team successfully deterred biosimilar competitors until 2023 in the U.S. and until 2018 in Europe. Indeed, Amgen’s Amjevita was approved September 2016 in the U.S., yet it will not be commercially available any time soon.

Biosimilars 101

Most are aware of generics because most of the time, we can acquire generic drugs for a fraction of the cost of the brand-name drug. Biosimilars are essentially “the generic” of a biologic type of drug, but with a few important caveats as the analogy is imperfect.

Until the 1980s, all drugs were simple chemical entities. Take for example, aspirin, which has a very simple formula, C9H8O4. Aspirin is comprised solely of 9 carbon, 8 hydrogen, and 4 oxygen atoms. Because of its simplicity, every single time researchers synthesize aspirin, it is exactly the same with no variation. Humira is an antibody with a molecular weight 800X greater than aspirin. Biologic antibodies cannot be chemically synthesized like aspirin and the technological requirement of a cell line to produce an antibody just happens to be inherently variable.

While the U.S. pathway for the approval of generics (The Hatch-Waxmen Act of 1983) has shown considerable success in decreasing the price of drugs, the pathway for the approval of biologics (The Biologic Price Competition and Innovation Act of 2010) was likewise paved for prospective cost savings, yet requires an additional layer of scrutiny due to the inevitable variability of these cell-generated biologics. As the technology to produce antibodies like Humira is nontrivial and far more complex than the technology to produce a chemical entity like aspirin, AbbVie successfully delayed biosimilar competitors far past their market exclusivity date of 2016 to 2023 due to the dozens of formulation, manufacturing, and methods patents. As the goal of the biosimilars pathway was to facilitate cost savings, what does that mean for patients?

Cost savings of biosimilars

No one knows—no, quite literally, at least for the U.S., no one knows. Sure, there are U.S. cost savings projections in the ballpark of 15-30%. Indeed, Pfizer’s infliximab biosimilar, Inflectra, was recently introduced at a 15% wholesale acquisition cost (WAC) discount. And sure, Pharma manufacturers, insurance providers, and pharmacy benefit managers (PBMs) alike are touting in a very public relations-sensitive fashion the impending cost savings of biosimilars. The U.S. healthcare market herein is specifically differentiated as it quite unlike that of Europe, which may already be a decade ahead of the U.S. in its implementation of biosimilars. Furthermore, Inflectra is discussed not in terms of a general cost savings, but specifically a WAC discount, because the actual, effective cost savings to patients remains nebulous. Perhaps you have noticed that the American healthcare system is like a Rube Goldberg machine, where everything is intertwined, the outcome is non transparent, and Rube Goldberg, or the inventor, has left the building. There is nothing but speculation about the cost savings of biosimilars, yet the one trend emerging is the stark contrast between the U.S. and European healthcare systems.

Imagine the outcry and resistance if the United States government fully funded and mandated patients successful on Humira to switch to a trial biosimilar. Well, the Norwegian government successfully executed such an experiment/trial between 2014 and 2015 using an infliximab biosimilar, Remsima (the European counterpart to Inflectra). This aptly named NOR-SWITCH trial involving 482 patients showed that switching from infliximab originator to the biosimilar was non-inferior. By the close of the study year, in 2015, Remsima hit 80% market share at a steep 69% discount. While Inflectra only became commercially available at the close of 2016, penetration is expected to hit a nominal 10% market share in the U.S. at a 15% discount. Notably, as of August 2017, the European Medicines Agency has approved 35 biosimilars, whereas the Food and Drug Administration has only approved 6, which almost seems akin to the ratio of available cheese varietals. Aside from the ever-present concern of emergent efficacy or safety signals, it remains to be seen whether the U.S. healthcare system and all of its tentacles of complexity can pivot biosimilars into a meaningful cost savings to patients as the only thing we now for certain is that the the American leviathan in its current state has proven it is far less nimble than its European counterparts. For better or worse.

cheese

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