Evolving Therapies for Clearer Skin Could be a Game Changer
The current late-stage pipeline is driving intense competition for patient share
- August 2022
Ashish Khandizod, Associate Research Manager; Bhavani Nelavelly, Research Manager; Nishika Bhan, Director; Dr. Gaurav Sharma, Director; and Dr. Aviral Maheshwari, Vice President
Introduction
Over the past two decades, substantial progress has been made to circumvent the challenges posed by the complex immune disease psoriasis. Improved understanding of the pathogenesis of psoriasis and innovations around effective drug therapies have improved patients’ quality of life (QoL), but a substantial need for enhanced treatment remains.
Psoriasis is a debilitating chronic inflammatory autoimmune disease affecting ~7.4 million adults in the US alone (as of 2021)1, with the most common manifestation being plaque psoriasis, affecting 80-90% of patients. The disease is primarily categorized as mild-to-moderate or moderate-to-severe, affecting ~80% and 15-20% of psoriasis patients, respectively2. Psoriasis is a cause of anxiety, depression and social isolation, and several unmet needs persist, such as the need for more oral treatments with an improved clinical profile. In addition, prescribers lack confidence when prescribing drugs to pediatric and cancer patients and pregnant women with psoriasis, primarily due to a lack of long-term safety data on approved therapies in these sub-segments. The physical, psychological, social and economic impacts of psoriasis, in tandem with the stigma of the disease, cause poor patient QoL.
The psoriasis market was valued at $18.3 billion in 2020 and is expected to reach $23.3 billion across the US, France, Germany, Italy, Spain and the UK by 2030, with a CAGR of ~2% (Exhibit I). Psoriasis prevalence is high in the US and Europe due to environmental factors and genetics, while access to better healthcare systems and increased awareness of psoriasis has resulted in improved rates of diagnosis.
Impact of COVID-19
In 2020, research findings from the Perelman School of Medicine in collaboration with the National Psoriasis Foundation (NPF) suggested that COVID-19 had minimal to no effect on psoriasis patients3. Relaxation in telehealth and telemedicine regulations by governments has led to further market growth. With COVID-19 restrictions limiting face-to-face appointments, patients and practitioners have been increasingly using digital platforms for healthcare access.
Patient Journey and Pain Points
The psoriasis patient journey is painful and complex. It starts as a general skin plaque that is often initially ignored by the patient, assuming it is caused by other skin conditions such as eczema or itching. Raised patches covered with silvery-white scales are the hallmark of psoriasis.
Psoriasis diagnosis is generally clinical, and based on the morphology, distribution and histology of skin lesions. In a few cases, differential diagnosis is needed, as psoriasis is mimicked by several other conditions, such as pityriasis rosea.
An overview of the psoriasis patient journey and pain points is shown in Exhibit II. During the diagnosis phase, the psoriasis patient goes through panic and confusion, and misdiagnosis or delayed diagnosis, which may be a result of general practitioners (GPs) and family physicians not having sufficient training or education for disease diagnosis, may lead to greater symptom severity.
The psoriasis patient’s treatment phase is associated with low QoL, with stress, anxiety and depression being common. Approved treatments mainly include biologics and single oral therapy, and intense trial and error is needed to identify the most effective treatment. Lifestyle changes, as well as the wait for symptoms to resolve, are complex and difficult aspects of the psoriasis patient journey.
Furthermore, in the treatment management phase, some patients do not adequately respond to the therapies, resulting in disease relapse. In these cases, the patient may give up hope of relief. Some patients lack insurance or cannot afford the treatment cost. Further, 4-30% of psoriasis patients are affected by psoriatic arthritis, a painful and difficult-to-manage comorbidity.4
In the support phase, some of the key challenges include identifying the triggers of the psoriasis, reinitiating previously used treatments or seeking alternative or new treatment options for better disease control.5,6
Evolving Psoriasis Landscape
The treatment guidelines for moderate-to-severe psoriasis have evolved significantly over the last two decades. For instance, the International Psoriasis Council in the US does not consider the mild, moderate and severe classifications of psoriasis severity, instead classifying patients as suitable for topical therapy or systemic therapy. In some countries, including the US, guidelines for moderate-to-severe psoriasis have shifted from step therapy, which consists of treatment initiation with phototherapy followed by oral agents and further biologics, to concurrently offering biologics, oral agents and phototherapy.
Psoriasis has myriad treatment options, ranging from topical treatment with emollients and corticosteroids for mild psoriasis, to systemic therapy with methotrexate, fumaric acid esters or biologics for severe psoriasis; however, these can only control the symptoms of the disease.
Enbrel (Amgen), a TNF-α inhibitor, was the first approved biological drug for psoriasis in 2004. Humira, another TNF-α inhibitor, that was approved in 2008, remains the mainstay of psoriasis treatment. Dermatologists and rheumatologists have shown high confidence in Humira, primarily due to the familiarity with its safety profile. As per 2018 IQVIA data, Humira remains one of the most prescribed drugs in dermatology.
In 2009, after a couple of years of TNF-α inhibitor dominance, Stelara (J&J), an IL-12/23 p40 inhibitor, became the first new approved drug for psoriasis. IL-17 inhibitors entered the market next, with Cosentyx (Novartis), Siliq (Bausch Health-Leo Pharma) and Taltz (Eli Lilly) launching in 2015-2017.7 Uptake of these newer classes is anticipated to rise by 2030 due to their improved efficacy and minimal side effects, as shown in Exhibit III.
Companies are exploring highly innovative MoAs to address the intricacies of psoriasis. One such example is Bimzelx (UCB), which selectively inhibits both IL-17A and IL-17F. This next-generation drug has set a new standard for psoriasis treatment, with the majority (~68%) of patients achieving 100% skin clearance in clinical trials.
In addition, BMS’ deucravacitinib and Pfizer’s ropsacitinib (TYK2 inhibitors) and brepocitinib (TYK2/JAK1 inhibitor) are new oral agents in development that are expected to deliver better efficacy and fewer side effects than the other available options. Other novel MoAs in the pipeline include RIP1 inhibitors, TRK inhibitors and RORγ antagonists.
Currently, the only drug developer that has both marketed and late-stage pipeline products specifically for psoriasis is UCB, which has the TNF-α inhibitor Cimzia on the market and is hoping to gain approval for the IL-17A/F inhibitor Bimzelx in the US by Q3 2022. Meanwhile, Merck, Affibody, Arcutis, BMS and Can-Fite are all developing their first product in the psoriasis space with expected launches from 2022 to 2027.
Remicade (J&J) is the only drug with an IV route of administration in the psoriasis space; most other products are delivered either subcutaneous or orally. While the psoriasis space has long been dominated by large pharmaceutical companies such as AbbVie and Pfizer, the current late-stage pipeline features newer companies as well, with intense competition for patient share driving innovation.
Effective Therapies for Refractory Patients
Although the most severe psoriasis is adequately managed by the available therapies, some patients with exceptionally severe diseases remain refractory to therapy (10-15% of severe patients). Several non-biologic therapies in development, including TYK2 inhibitor deucravacitinib and A3AR agonist piclidenoson, could present good options for patients who are refractory to biologic treatment. These therapies could be administered as either monotherapies or adjunctive to the current standard of care due to their lower price compared to biologics. Additionally, KOLs are optimistic about small-molecule agents as there is a negligible risk of drug immunogenicity compared to their biological counterparts.
A few companies such as Aristea Therapeutics, vTv Therapeutics and BMS, are exploring the oral route of administration to offer patients greater convenience and improved treatment adherence. Some companies are also exploring novel and evolving MoAs, such as S1P modulators (e.g., SCD-044 by Sun Pharma) and microbiome modulators (e.g., EDP-1815 by Evelo Biosciences). Although the current psoriasis market has a plethora of drugs, the intense activity of several companies suggests that there will be more innovative and promising therapies in the near future.
Robust Clinical Endpoints Towards Clearer Skin and Improved QoL
While a 75% reduction in the Psoriasis Area and Severity Index (PASI 75) has been widely evaluated as a standard psoriasis trial endpoint so far, recent data show that this is no longer sufficient to be competitive in the current market. Primary endpoints have evolved progressively from PASI 50 to PASI 100 for psoriasis treatment, and the use of biologics as active comparators is now incorporated following regulatory requirements and for marketing purposes (Exhibit IV). To verify long-term safety, randomized controlled pivotal studies with subsequent open-label extensions into five years have become the standard.
In earlier trials, anti-TNF-α biologics adopted PASI 50 and PASI 75 as clinical endpoints for efficacy data; with the subsequent introduction of more effective biologics (anti-IL-17s and anti-IL-23s) and small molecules (TYK2 inhibitors), companies have adopted more stringent endpoints, such as PASI 75 and PASI 90, to manifest results with better skin clearance. While the importance of the PASI 100 endpoint has been increasing, it remains the least used PASI endpoint, primarily because all the drugs under evaluation are unable to manifest total resolution of skin plaques.8
Many pivotal and post-marketing trials also incorporate the Investigator’s Global Assessment (IGA) or Static Physician Global Assessment (sPGA) as co-primary endpoints in addition to the PASI system. These are more widely understood by non-researching clinicians, which indicates the competitive nature of the field and the need to stake a claim both in the minds and on the prescription pads of community prescribers.
In previous clinical trials evaluating biologics such as Humira and Remicade, patients were at an increased risk of hepatitis B and tuberculosis; this has led to the incorporation of hepatitis B DNA and hepatitis C RNA testing as pre-trial screening tools in newer clinical trials.9 In contrast, there is still an unmet need for pediatric, cancer patients, pregnant women, and patients with depression, as most trials exclude these patients for better outcomes.9
Aggressive LCM Strategies to Cover a Spectrum of Psoriasis Treatments
Once a drug is approved for the originally pursued indication, or even during the evaluation of a primary indication, companies have started to leverage other allied or niche indications, which can lead to an increase in the market share by garnering a greater patient population. Companies often try to get patent exclusivity over these newly added indications, leading to a monopoly.
Skyrizi, which was initially approved for adult patients with moderate-to-severe psoriasis, is now being studied by AbbVie in palmoplantar (non-pustular) plaque psoriasis (PPPsO). Boehringer Ingelheim is developing a novel anti-IL-36R, spesolimab for generalized pustular psoriasis (GPP); the company has recently filed this drug in the US. BMS’ deucravacitinib is in the registration phase for pustular psoriasis (PP) and erythrodermic psoriasis in Japan. An overview of LCM strategies adopted by various companies is shown in Exhibit V.
Companies are increasingly focused on patient convenience through patient centricity, with Humira leading this approach. Initially, it was available as an SC vial, prefilled pen (PFP) or prefilled syringe (PFS) with a 27-gauge, half-inch needle. Over time, to achieve better patient compliance and treatment adherence, AbbVie launched Humira in a citrate-free PFS and auto-injector (AI). It also changed the needle size from 27 gauge to 29 gauge, which requires 50% less liquid per injection compared to the original version.
The citrate-free formulation also causes less pain compared to the original Humira formulation, primarily due to removal of the citrate buffers that are associated with pain on injection along with other inactive ingredients. Additionally, the Humira Complete app aids adherence by offering injection site recording, symptom tracking and medication reminder functions.
While Enbrel was initially available as an SC formulation, it was subsequently launched in PFS and AI forms. Likewise, while Skyrizi was first available as a PFS, it is now available as a PFS, PFP, IV infusion and prefilled cartridge with supplied on-body injector. Similarly, Stelara, originally available as a single-use glass vial, is now available both as a PFS and vial, and Tremfya, first available as a PFS, is now available both as a PFS and a single-dose, One-Press patient-controlled injector. These newer and modified administration techniques simplify self-administration so that patients can take them at home or at work after proper training.
Digital Technology Adoption
Digital intelligence is paving the way for increased stakeholder engagement. As the pharmaceutical industry is heavily regulated, companies have been slow in digital adoption; however, several biopharma companies have shown interest in leveraging digital technology recently. In January 2021, UCB established a Digital Care Transformation (DCTx) team with the intent of developing digital care solutions for patients, and other companies are embracing digital adoption at a rapid pace. For example, one study revealed an 81% growth in dermatology apps from 2014 to 2017, evidence of the increased adoption of mobile technology by patients and providers evolving in the dermatology landscape.10
Companies have developed tools or apps available in multiple languages to bridge the gap between patients and physicians, enabling patients to track their symptoms, document the treatment effects, and share their progress with physicians. For instance, Almirall collaborated with Popit, a Finnish start-up, to develop an electronic device that attaches to push-through pill packages and monitors dosing alongside an app. Almirall also joined forces with Happify Health in January 2021 to develop digital therapeutics; in June 2022, the companies launched Claro, a platform aimed at improving the mental health of psoriasis patients by leveraging cognitive behavioral therapy, positive psychology and mindfulness, in Spain, the UK and Italy, with the language options of Spanish, English, Italian and French.11
AbbVie is also exploring the digital space and has developed apps like the PSOdisk app, which tracks psoriasis symptoms, and Complete – Medication Tracker to spread awareness about psoriasis, which also enables patients to follow the dosing routines for Humira and Skyrizi.
Novartis has launched Medisafe, a free medication reminder app that keeps track of prescriptions and doctor appointments, sends alerts for any missed doses and helps patients learn more about Cosentyx. A few companies are also assisting patients with various insurance programs through their websites or apps, such as UCB’s CIMplicity Savings Program for Cimzia, Janssen’s CarePath program for Tremfya, and Eli Lilly’s Taltz Together™, Companion in Care™ and “Lilly Together” programs. Through these platforms, patients can receive such benefits as insurance investigation, injection training and field reimbursement support.
Further, companies are developing platforms for accurate disease prediction and treatment fit. For instance, AMPEL BioSolutions is working on precision and personalized medicine and has developed clinical genomic tests that use machine learning to predict flares and drug options for a patient based on their gene expression. DermaGENE®, a skin biopsy test for lupus, psoriasis, atopic dermatitis and scleroderma, is one such product.
By adopting digital technology, companies are leveraging digital platforms to develop apps, AI tools and websites to enhance disease awareness, diagnosis, and treatment fit, and offer more information regarding insurance, symptom tracking and dosing reminders. This is expected to dramatically improve patient treatment adherence and compliance, resulting in higher market shares and brand value.
Outlook
Psoriasis does not have a cure; however, management should aim to minimize physical and psychological burdens. This can be achieved through early diagnosis, treating patients in the initial stages, addressing comorbidities with the right drug choice and lifestyle modifications, improving patient convenience, and employing a personalized approach to treatment.
Anti-IL-17s have raised the efficacy bar set by the anti-TNFs; however, anti-IL-23 therapies are raising the bar even further. Assets with better efficacy at PASI 100 will enjoy significant opportunities in the future. There will be major competition between the anti-IL-17s and anti-IL-23s in terms of dosing and formulation, with anti-IL-17 drugs having the advantage of auto-injectors (AI), while anti-IL-23 therapies have the benefit of less frequent, Q8W/Q12W dosing.
Drugs with higher efficacy and safety and a more convenient route of administration, such as the registrational-stage novel oral asset deucravacitinib, will have an edge due to improved patient adherence and compliance. Meanwhile, Zoryve (roflumilast cream), which was approved in July 2022, is the first and only topical PDE4 inhibitor for patients aged 12 years and older for the treatment of psoriasis, including intertriginous psoriasis.
Lastly, pharma majors now realize the substantial potential of social media, given its rapid usage and adoption, and are now significantly leveraging all the main social media platforms such as Facebook, Twitter, Instagram, LinkedIn, and YouTube to raise awareness of their assets. Additionally, medical apps may lead to an increase in psoriasis diagnosis as well as improved adherence to specific treatments, which has been a major challenge for psoriasis patients.
As the landscape continues to evolve, we can expect to see improved treatment options and QoL for patients with this incurable disease.
References
- Psoriasis Prevalence in Adults in the United States https://jamanetwork.com/journals/jamadermatology/fullarticle/2781378#:~:text=Based%20on%20the%202020%20US,%25%2D3.3%25)%20in%20men. (June 2021)
- Psoriasis Prevalence and Severity by Expert Elicitation https://link.springer.com/article/10.1007/s13555-021-00518-8 (April 2021)
- Patients with Psoriasis and Psoriatic Arthritis Should Continue Treatment Amidst the COVID-19 Pandemic
https://www.pennmedicine.org/news/news-releases/2020/september/patients-psoriasis-psoriatic-arthritis-should-continue-treatment-amidst-covid19-pandemic (September 2019) - Psoriatic Arthritis https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6758836/ (September 2019)
- Contemporary Management of Moderate to Severe Plaque Psoriasis
https://www.ajmc.com/view/contemporary-management-of-moderate-to-severe-plaque-psoriasis (December 2017) - Joint AAD-NPF guidelines of care for the management and treatment of psoriasis with biologics
https://pubmed.ncbi.nlm.nih.gov/30772098/ (February 2019) - Old and New Biological Therapies for Psoriasis https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5713267/ (November 2017)
- Evaluation of the fragility of pivotal trials used to support FDA approval for plaque psoriasis https://www.themillerlab.io/publication/fragility-of-pivotal-trials-in-psoriasis/ (April 2020)
- Evolution of the inclusion/exclusion criteria and primary endpoints in pivotal trials of biologics and small oral molecules for the treatment of psoriasis
https://pubmed.ncbi.nlm.nih.gov/32167790/ (March 2020) - Growth of mobile applications in dermatology – 2017 update https://escholarship.org/uc/item/3hs7n9z6 (February 2018)
- Happify Health and Almirall Go Live with Digital Solution to Support Psoriasis Patients https://www.almirall.com/newsroom/news/happify-health-and-almirall-go-live-with-digital-solution-to-support-psoriasis-patients (June 2022)
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