In March of 2021 Lilly Dermatology held a webinar for Australian dermatologists to discuss updates in the management of psoriasis and atopic dermatitis. Dermatologist and senior lecturer Dr Diana Rubel of Woden Dermatology in Phillip (ACT) presented 5-year safety data published in 2020 on ixekizumab. Dr Lynda Spelman, founder and director of the Queensland Institute of Dermatology, Brisbane, launched a new treatment for atopic dermatitis, including lessons from experience with the treatment in rheumatology. 

Taltz (ixekizumab) for psoriasis – putting efficacy and safety into context 

Dr Rubel began by highlighting the management challenges of psoriasis and the choices dermatologists face, stating “it’s hard to quickly get your head around just how many effective treatments we now have for psoriasis.” With so much choice comes a responsibility to factor patient preferences into decision making – “an important factor to consider is what patients want most from their treatment.” Presenting data from a survey of 3000 psoriasis patients in 2016 from the German psoriasis registry, Dr Rubel explained that  the top priorities for patients were found to be clearance of psoriasis (i.e., achieving a Psoriasis Area and Severity Index [PASI] of 0 [PASI 100] ), and speed of response – that is, for their skin to get better quickly.¹ 

Although head-to-head studies are hard to come by, noted Dr Rubel, they do exist. A systematic review and network meta-analysis from 2019 of phase 3 randomised, controlled trials found interleukin (IL)-17 and IL-23 inhibitors work well when it comes to the proportion of patients achieving a PASI 100 response.² Focussing on ixekizumab, an IgG4 monoclonal antibody that inhibits IL-17A,³ Dr Rubel described the latest head-to-head results of ixekizumab vs ustekinumab (targeting IL-12 and IL-23) and guselkumab (targeting IL-23) from the IXORA-S and -R studies, published in 2019 and 2020, respectively. Dr Rubel explained how this latest evidence “showed a significant difference in clearance of psoriasis with ixekizumab versus ustekinumab that was sustained across 52 weeks.”⁴ Compared with  guselkumab, “there was a significant increase in the number of patients achieving PASI 100 from as early as week 4 with ixekizumab. By week 24 there was comparable efficacy, but the patients treated with ixekizumab achieved a PASI 100 in more patients earlier than guselkumab.⁵ These recent data indicate that ixekizumab is an option that delivers on both goals identified by patients as important – complete skin clearance that happens fairly quickly,” noted Dr Rubel.^1,4,5 

Turning to safety, Dr Rubel stated “safety is one component that we dermatologists are interested in when choosing a biologic. Over the past 5 years the safety of more than 17,000 patient-years of exposure have been monitored in the UNCOVER study series. And it’s not just ad hoc or pharmacovigilance adverse event monitoring either, but rather structured and consistent monitoring through the clinical trial program.” She highlighted how injection site reactions, allergies, discontinuation for any reason, yeast infections and malignancies mainly occurred in the first year of treatment.⁶ Dr Rubel noted “the take home message is that there have been no cumulative exposure toxicities.”

Before closing, Dr Rubel offered her advice based on managing patients with psoriasis in the midst of the pandemic. She noted there was not much published evidence for patients on treatment for psoriasis and COVID-19, but offered the following advice “patients should continue on biologic therapies, although not if they have a clinically important active infection.” When it comes to vaccination, Dr Rubel concluded “live vaccines need to be avoided, though so far only inactivated vaccines are available. Studies done on tetanus and pneumococcal vaccines indicate that patients should mount a reasonable and clinically useful response to vaccination.”

Introducing Olumiant (baricitinib) – a novel systemic treatment for atopic dermatitis

Similar to psoriasis, atopic dermatitis is associated with multiple comorbidities.⁷ Baricitinib is the first oral Janus kinase (JAK) inhibitor made available for the treatment of moderate-to-severe atopic dermatitis. Dr Spelman began by summarising its place in treatment. “Unlike other new treatments, we already know a lot about the safety and tolerability profile of baricitinib – that’s because it’s  been around since 2018 for the treatment of moderate-to-severe active rheumatoid arthritis, giving us the background data we need to give us confidence in using it to treat patients with atopic dermatitis.”⁸ 

It is well recognised that atopic dermatitis is caused by a complex dysregulation of many immune pathways. This complexity can make it difficult to know where to focus treatment efforts.¹⁰ “Current treatment options have thus far not satisfied the broad needs of these patients,” Dr Spelman explained.^9,10 “Baricitinib works by modulating the intracellular signalling of multiple cytokines involved in itch associated with atopic dermatitis. It is a reversible, selective JAK1/2 inhibitor that competes with adenosine triphosphate (ATP) for the binding site. Therefore, baricitinib selectively inhibits the kinase activity of JAK1 and 2.”^11,12 

JAK inhibitors such as baricitinib are administered once daily and are rapidly absorbed, reaching a steady-state in 2–3 days. Olumiant is available in 2 mg or 4 mg doses, with 2 mg the recommended initial dose and 4 mg reserved for patients who do not achieve sustained control.⁸ 

Baricitinib has been studied in seven phase 3 clinical trials in the BREEZE-AD program 

Altogether, there were seven studies in the BREEZE-AD clinical trial program assessing the efficacy and safety of baricitinib in atopic dermatitis. Each study assessed different aspects of treatment with baricitinib, from monotherapy at various doses to use in combination with topical corticosteroids.¹³ 

Dr Spelman presented data on BREEZE-AD7, which she explained “aimed to assess baricitinib in circumstances that mirrors clinical practice.” BREEZE-AD7 was a multicentre, double-blind, placebo-controlled, parallel arm, 16-week, phase 3 randomised clinical trial of baricitinib in combination with background topical corticosteroid (TCS) therapy in patients with moderate-to-severe atopic dermatitis who previously had an inadequate response to TCS therapy.¹⁴

Moderate-to-severe atopic dermatitis was defined as:¹³

• Investigator Global Assessment (IGA) of 3 or 4
• Eczema Area Severity Index (EASI) ≥16 
• Body Surface Area (BSA) ≥10% 
• An inadequate response or intolerance to ≥1 topical medication in the 6 months prior to screening. 

During the trial, patients were allowed to use topical corticosteroids but had to washout prior to randomisation – 2 weeks from TCS and 4 weeks from systemic therapies. 

Table 1 shows the main results from the BREEZE-AD7 trial. Dr Spelman noted that “an IGA score of 0 or 1 indicates clear or almost clear skin and EASI is now one of the strong scoring systems we have. Looking at the topical corticosteroid use, patients on placebo used more topicals than those in the active comparator arms.”

Table 1. Results from the BREEZE-AD7 clinical trial^8,13,14

*With a ≥2 point improvement from baseline at Week 16.       †At Week 16.                  ‡Key secondary endpoint. 

2mg was not statistically significant vs placebo for IGA 0,1 response.

With respect to safety, Dr Spelman explained that “although there were fewer treatment-emergent adverse events in the placebo arm, the rate of severe events was low across all three arms.” The atopic dermatitis safety profile did not reveal any new safety concerns or signals compared with the established safety profile for baricitinib.^8,13,14 She also pointed out that “experience in 3770 patients with rheumatoid arthritis exposed to baricitinib for up to 8.4 years (13,148 patient-years) maintained a safety profile that was similar to that previously reported.”¹⁵ 

Baricitinib in practice

Dr Spelman concluded with a case presentation of a 41 year old male with a history of atopic dermatitis since birth. Despite being young and fit, exercising was difficult as it caused his condition to flare. The patient had been on Imuran for 3 years and topical corticosteroids for more than 20 years, with oral corticosteroids used to control flares. Self-management, including naturopathy and sedating histamines, had become expensive. Treatment with baricitinib commenced in 2019. The box shows his progress up until a recent visit.

Case report progress on clinical trial for baricitinib

Baseline:

• IGA 4
• EASI 32.1
• DLQI 24
• BSA ~54%
• Passed mental health screening for trial inclusion

Commenced treatment with baricitinib

Week 3:

• Pruritus reduction as first evidence of improvement
• IGA 2
• Still using topical treatment, but progressively decreased by Week 3
• Erythema decrease evident – continued to improve over 3 months
• No documented adverse events

Recent visit:

• DLQI 2
• Pruritus completely resolved
• Mild erythema still present
• Sleep reported as normal
• Mental health (as assessed by C-SSRS) remained stable throughout trial

This article was commissioned by Eli Lilly Australia Pty Ltd. The content is independent and based on studies and the author’s opinion. The views expressed do not necessarily reflect the views of Eli Lilly. Before prescribing please review the Olumiant^® (link) and Taltz^® (link) full product information via the TGA website. Treatment decisions based on these data are the responsibility of the prescribing physician.

References:

1. Blome C et al Arch Dermatol Res 2016;308(2):69-78.
2. Sawyer LM et al. PLoS One 2019;14:e0220868.
3. Taltz (ixekizumab) Australian Product Information.  
4. Paul C et al J Am Acad Dermatol 2019;80:70-79.
5. Blauvelt A et al. Br J Dermatol 2020;182(6):1348-1358.
6. Armstrong A et al. Dermatol Ther (Heidelb) 2020;10(1):133-150.
7. Silverberg JL Ann Allergy Asthma Immunol 2019;123(2):144-151.
8. Olumiant Australian Product Information.
9. Weidinger S et al Nat Rev Dis Primers 2018;4(1):1.
10. Noda S et al. J Allergy Clin Immunol 2015;135(2):324-336.
11. Virlanen AT et al. BioDrugs 2019;33(1):15-32.
12. Choy EG Rheumatology 2019;58:953-962.
13. Reich K et al. 28th European Academy of Dermatology and Venerology (EADV) Congress, Madrid Spain, October 9-13 2019, Abstract 1313.
14. Reich K et al. JAMA Dermatol 2020;156(12):1333-1343.
15. Genovese MC, et al. European League Against Rheumatism (EULAR); European E-Congress of Rheumatology, from 3 June 2020; FRI0123