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.