© 2021 MJH Life Sciences and Management Healthcare Executive Officer. all rights reserved.

© 2021 MJH Life Sciences™ and managed healthcare executive. all rights reserved.

Clinical, economic, and payer considerations for atopic dermatitis-episode 2

Atopic dermatitis (AD), also known as atopic eczema, is a pruritic inflammatory skin disease. 1-3 It is characterized by recurring eczema skin lesions with redness, blistering, crusty or exuding skin; lichenification; 1 although the prevalence of AD in the United States is higher in children (about 11%- 13%),4,5 Recent estimates indicate that a significant percentage of adults are affected (approximately 7%)6.

The clinical manifestations of AD are heterogeneous. 1 AD may follow a relapse-remitting process, accompanied by an acute attack or as a chronic persistent disease. 7,8 AD can appear on any part of the body, but most often occurs on the inside of the elbows, the back of the knees, the back of the feet and the lower legs. 9

The pathogenesis of AD is multifaceted, involving epidermal barrier dysfunction and immune system activation, and it is likely to be affected by environmental factors. 1 The strongest risk factor for AD is the family history of atopic diseases, especially AD. 1

AD is diagnosed based on clinical signs, medical history characteristics, morphology, and distribution of skin lesions. Currently, there are no biomarkers for AD. 3 Itching is a significant feature of AD and can cause patients to bear a large burden of disease. 2,10 In a study of 380 adults with moderate to severe AD, most reported daily itching, and about 60% said itching was "unbearable" or "severe". 11

The severity of the disease may be difficult to determine because the symptoms of AD fluctuate over time and depend on the location of the body; darker skin indicates less skin involvement, and assessment tools have different severity categories. Similarly, some severity assessment tools require the subjective judgment of the patient (for example, regarding the intensity of itching and insomnia)2,7,12.

There are four validated tools that can be used to measure the severity of AD; however, two of them are most commonly used in clinical trials and may take too much time for healthcare providers to use: Atopic Dermatitis Score (SCORAD) Index and Eczema Area Severity Index (EASI). The SCORAD composite score is based on the extent and severity of AD and the symptoms reported by the patient (pruritus and lack of sleep). 1,7 EASI is used to determine the scope and severity of AD, and focuses on the four body parts (head and neck, trunk and upper and lower limbs. 7,13 EASI grades the four main clinical symptoms of AD: erythema (redness) ), induration/papules (thick), exfoliation (eg scratching) and lichenoid changes. 13

In the United States, there is a significant association between AD and immune-mediated comorbidities (such as ulcerative colitis, pernicious anemia). 14 Adults with AD in the United States have cardiovascular disease (for example, heart disease, hypertension), psychological (for example, depression and anxiety), and other chronic disease risks compared to those without AD. 15 Data from the 2013 US National Health and Wellness Survey (NHWS) determined that adults with AD are more than twice as likely to report sleep problems as compared with matched controls without AD, disorders, depression, and/or anxiety (All P <.001) 16.

Itching can trigger and exacerbate a series of AD symptoms and reduce the quality of life (QOL) of AD patients. 1 A study using a self-managed Internet-based questionnaire showed that adult patients with moderate or severe AD had significantly more sleep difficulties and longer sleep periods. Compared with mild AD patients, sleep latency, sleep disturbances, and sleep disorders were more frequent. Increased demand for over-the-counter (OTC) sleep medications (all P <.001). 17 A population-based study showed that AD and significant QOL-related obstacles in American adults restrict the lifestyle of patients (51.3%), cause them to avoid social interaction (39.1%) and affect their activities (43.3%) . 18

In the United States, the cost associated with AD is approximately US$7 billion (US$2020) per year. The direct cost is approximately US$1.7 billion, and the indirect cost is estimated to be US$1.04 billion. The estimated intangible cost based on the patient's willingness to pay for symptom relief is about 4.37 billion U.S. dollars. 19-21

Compared with adults without AD, adults with AD use more medical resources, and the higher the severity of the disease, the higher the utilization rate. 22,23 The analysis of health care claims data from three different groups (commercial, medical insurance and Medi-Cal) determined that the number of emergency visits, outpatient visits and pharmacy prescriptions of adults with AD each year The average number of times was significantly higher than that of adults without AD (all P <.05). 22 These results are consistent with the 2013 data analysis NHWS, which shows that the average number of visits (P <.001), emergency department visits (P <.001) and hospitalizations (P = .004) of AD adults are higher than the matched control group . twenty three

The management goals of AD include improving the skin, minimizing flares, and reducing the burden of comorbidities and symptoms (ie sleep disturbance and itching). 1,24 Interventions aimed at avoiding triggers, improving the skin barrier, and reducing inflammation are central to achieving these goals. 2

As mentioned earlier, validated tools (such as EASI) can be used to measure the severity of symptoms and response to treatment. The validated global assessment of AD investigators (vIGA-AD) frequently used in clinical trials is another tool for measuring the effectiveness of treatment. The vIGA-AD scale is used to measure the improvement of clinical symptoms and has different categories (erythema, induration/papules, lichenification, exudation and/or scab) to assess the severity of the disease in AD. 25

The AD guidelines suggest a multifaceted approach. It is recommended to take basic non-pharmacological measures (for example, bathing, moisturizing, and avoiding triggers) for all severity of AD. Medication follows a gradual progression based on the severity of the disease. 1,2

Humectants are essential in AD. They can lubricate and soften the skin, reduce water evaporation, and attract and retain water. 24 They can reduce the signs and symptoms of AD, and reduce inflammation and severity. 24 Severe attacks or persistent diseases may require wet compress therapy, whereby a wet first layer of tubular bandage or gauze is applied to the topical medication, and a dry second layer is used as an outer barrier. twenty four

Step-by-step treatment recommendations for AD suggest topical treatment (for example, topical corticosteroids) when proper skin care and moisturizers are no longer sufficient to control the disease. 24 Topical drugs are used to provide symptom management during acute attacks and as maintenance treatment for moderate to severe AD. The effectiveness and dosage of TCS can be increased according to the severity of symptoms. 2 However, long-term daily use of TCS is not recommended because it may cause systemic adverse reactions (for example, hypothalamic-pituitary-adrenal axis inhibition), skin atrophy, telangiectasia, dermatoglyph, worsening acne, and allergic reactions. After stopping TCS, some of these adverse reactions may last for several months. 2,24,26 Topical calcineurin inhibitors (TCIs) (such as Elidel, or pimecrolimus cream 1%; or Protopic, or tacrolimus ointment 0.03%, 0.1%) represent a class that does not Steroid anti-inflammatory drugs can be used for the onset or maintenance of moderate to severe AD. 2 They are recommended for patients who do not respond to other topical treatments or who are not suitable for other topical treatments. 24 However, they are generally not as effective as intermediate TCS. Their prescription labels carry a black box warning about the risk of malignancy, and burning or itching may occur during early use. 24,27 Eucrisa, or 2% crisaborole ointment, a non-steroidal anti-inflammatory PDE4 inhibitor, has good safety2, but has limited efficacy in patients with mild to moderate disease. 12

Some patients with insufficient response to local treatments or severe illness may require phototherapy or systemic corticosteroids or other systemic immunosuppressive therapy, such as cyclosporine A, methotrexate, azathioprine, or mycophenolate mofetil. 2 Dupixent (dupilumab), a human monoclonal antibody that inhibits interleukin (IL)-4 and IL-13 signal transduction, is approved by the FDA for the treatment of moderate to severe AD patients 6 years of age and older. Prescribed therapies adequately control or do not recommend the use of these therapies. 28 Although Dupixent has shown good efficacy and good safety, it does not require clinical laboratory monitoring, it takes time to start working, and the subcutaneous route of administration may limit its use. 12,29,30 Although there are many treatment options, there is an additional unmet need to provide AD patients with safe and effective drugs.

A study using 2015 data from the Truven Health Analytics MarketScan commercial and medical insurance supplementary database showed that the use of TCS or TCI to treat AD will affect pharmacy budgets regardless of treatment options. 31 There are significant differences in the mechanism of action (TCI and TCS) and the intensity of TCS in the annual prescription cost of each patient. 31 With the emergence of new drugs and new therapies being developed in recent years, AD prescription decisions will become more complicated.

The barriers to safe and effective AD treatment remain high. Access to certain agents is limited, and the payer has a request to change the treatment.

Obtaining new drugs can be a challenge for healthcare providers, which may depend on the patient’s insurance company and prescription drug coverage. 2 In addition, the payer may restrict the prescription of new drugs, such as biological agents and small molecules (such as Janus kinase or JAK, inhibitors), to experts such as dermatologists or allergists, because their use may require more than primary care Doctors can provide more knowledge bases. 32 Lack of medical insurance may also limit patients' access to specialists and the new treatments they may prescribe. In addition, the cost of updating medications or out-of-pocket expenses may limit patients' access to the most beneficial treatments. 32

Ladder therapy may require doctors to try multiple options before they can find a solution that can adequately control the disease. 32 This may cause a significant time delay in the relief of AD symptoms. For example, before considering other therapies, the payer usually requires a 30-day topical TCS or TCI treatment trial. 32 Payer’s step-by-step therapy requirements may also restrict the use of certain drugs, thus hindering the safest and most effective treatment for certain patients with AD. 32

The affordability of TCS has prompted off-label prescriptions for these drugs. However, the medium and high-efficiency TCS is not suitable for daily and long-term use. 2 At the same time, lack of insurance and the cost of TCI and Dupixent may limit its use. 2,27 The cheaper options of prescription drugs may not be as effective as the newer but more expensive therapies. The high cost of new treatments may require the payer to set pre-authorization standards or other usage restrictions. 32

Severe diseases may require systemic treatment, especially when it negatively affects QOL. Older systemic drugs are immunosuppressive and non-specific. They require a high level of monitoring, including blood tests, and carry risks associated with systemic immunosuppression. They are not the best option for long-term treatment. 33

The landscape of AD therapy is changing. Targeted drugs provide better safety and effectiveness characteristics, can change the course of the disease, quickly resolve symptoms and enable patients to enter the maintenance phase. 34 Importantly, the new AD therapies under development address some of the most important symptoms that affect QOL (ie itching and sleep disturbance). Emerging systemic therapies for AD include biological agents and oral JAK inhibitors. Promising new topical drugs, such as JAK inhibitors that inhibit key regulators of pro-inflammatory signals, are in clinical development. 35

The JAK family includes JAK1, JAK2, JAK3 and tyrosine kinase 2. The JAK-STAT pathway regulates the differentiation of T helper 2 cells. In addition, several cytokines (eg, IL-4, IL-31) that are thought to play a role in the pathogenesis of AD utilize the JAK-STAT pathway of signal transduction. The hyperimmune response in AD, especially the up-regulation of IL-4, plays a key role in skin barrier dysfunction. IL-31 is also related to the development of AD because its production is related to nerve crosstalk (ie, itching) and worsening of itching. 36

JAK inhibitors represent a new direction for AD treatment. JAK inhibitors target the itchy cycle by suppressing sensory neurons and improving the skin barrier by reducing inflammation. 37 Inhibitors selectively bind to different JAK proteins. 30

Oral JAK inhibitors under study for AD include Olumiant (baritinib in combination with JAK1/2) and Rinvoq (upadacitinib) and abrocitinib (in combination with JAK1). 29,30 Concerns about the safety of oral JAK inhibitors approved for other indications (Xeljanz or tofacitinib; Olumiant; Rinvoq) due to adverse reactions such as severe infections, vascular diseases, and malignant tumors, the FDA prolonged AD Review period for indications. It is worth noting that the prescription information for Xeljanz, Olumiant, and Rinvoq includes boxed warnings about serious infections, malignancies, and thrombosis; Xeljanz's boxed warnings also include the risk of death. 12,38-40

In September 2021, the FDA approved Opzelura (ruxolitinib cream 1.5%) for the short-term and non-continuous chronic treatment of mild to moderate AD in non-immune-compromised patients 12 years of age and older, whose diseases cannot be prescribed locally Therapies are adequately controlled, or are not advisable when these therapies cannot adequately control the disease. This is the first topical JAK inhibitor approved for this indication. 41,42 Although Opzelura’s prescription information has the same black box warning as oral JAK inhibitors, in the clinical trials supporting FDA approval of TruE AD1 and TruE AD2, are there any safety signals attributable to systemic JAK inhibition. 43,44 The safety problem of this topical drug may not be as serious as the safety problem of oral JAK inhibitors. 12

Ruxolitinib cream has a dual mode of action, targeting the itching and inflammatory effects of AD, delivered directly to the skin. 44 The efficacy and safety of ruxolitinib cream in patients with mild to moderate AD at least 12 years of age are in two large, double-blind, vehicle-controlled phase 3 trials of TruE AD1 and TruE AD2. 44-46 Patients must have had AD for at least two years, the investigator’s overall assessment (IGA) score is 2 or 3, and 3% to 20% of their body surface area is affected. A total of 1,249 patients were randomly (2:2:1) receiving 0.75% ruxolitinib, 1.5% ruxolitinib or carrier cream twice a day for eight weeks. 44 The primary endpoint of the two studies was the percentage of patients who achieved IGA treatment success, defined as clear or almost clear skin at week 8, an improvement of at least two grades from baseline. 44 Ruxotinib was given significantly more patients in TruE-AD 1 and TruE-AD 2 (0.75%, 50.0%, and 39.0% for ruxotinib; and 1.5% for ruxotinib, 53.8% and 53.8%). 51.3%) reached the primary endpoint, while those who were given the vehicle (15.1% and 7.6%, respectively) (P <.0001). 44 Ruxolitinib 1.5% cream was associated with a significant reduction in itching for 12 hours, and the reduction reported within 8 weeks was even greater. 44 Ruxolitinib cream also has good safety. 44 The treatment group and the two studies had similar adverse reaction percentages. The most common treatment-related adverse reaction was burns at the application site, which occurred most frequently in the vehicle group. There are no safety signals attributable to systemic JAK suppression. The 44-week extension of the two studies is currently evaluating the long-term safety of ruxolitinib. 44

In August, the Institute of Clinical and Economic Review issued final policy recommendations on the effectiveness and value of JAK inhibitors and monoclonal antibodies in the treatment of AD. Compared with the use of topical emollients alone, the New England Comparative Effectiveness Public Advisory Committee voted 12-1 to support Ruxotinib cream for the treatment of mild to moderate AD. 32

Delgocitinib is a pan-JAK inhibitor (JAK1/2/3, TYK2), approved as an AD ointment in Japan. 47 Two phase 3 trials, DELTA 1 and DELTA 2, are currently recruiting patients with moderate to severe chronic hand eczema. 48,49

The efficacy, safety, tolerability and pharmacokinetics of topical ATI-1777 (a JAK1/3 inhibitor) in 50 moderate to severe AD patients in phase 2a, multi-center, randomized, double-blind, vehicle-controlled Research was conducted in the experiment. 50 The primary efficacy endpoint is the percentage change in the modified EASI (mEASI) score from baseline, excluding the untreated body surface in the trial. At week 4.50, ATI-1777 reduced the mEASI score by 74% (41%) compared with vehicle. (P <.001).50

ATI-1777 has good security. The incidence of adverse reactions between the two groups was similar. The most common adverse reactions in the ATI-1777 group were elevated serum creatinine phosphokinase and headache. There are no cases of thrombosis. 50

AD is associated with a considerable clinical and economic burden. Itching and sleep disturbance are the two most disturbing symptoms of AD, and they have a major impact on the patient's QOL. JAK inhibitors represent a new direction for AD treatment. Their mechanism of action directly targets the itching and inflammatory effects of AD. Topical JAK inhibitors, such as Ruxotinib cream, can provide these benefits without the systemic effects associated with oral JAK inhibitors.

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20. Medical Consumer Price Index (CPI). Health Resources and Services Administration. Update in June 2021. Visited on September 20, 202. https://www.hrsa.gov/get-health-care/affordable/hill-burton/cpi.html

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50. Aclaris Therapeutics announced positive preliminary top-line data from the Phase 2a trial of ATI-1777 for the treatment of moderate to severe atopic dermatitis. Aclaris therapy. June 8, 2021. Visited October 4, 2021. https://investor.aclaristx.com/news-releases/news-release-details/aclaris-therapeutics-announces-positive-preliminary-topline-0