Intro
Dermatology, once a therapeutic category largely served by emollients, topical corticosteroids and small molecule immunosuppressants, is an increasing focus of targeted drug development. First generation products collectively generate annual revenues in the of billions of dollars, while the expanding dermatology pipeline is rich with novel candidates, attracting substantial investment and deal-making interest. According to Statista Insights, the global market for dermatology therapeutics has grown from $10.3b in 2016 to $20.2b in 2023, a healthy 10% CAGR.
Pro-inflammatory cytokine upregulation features in many dermatological conditions. That cytokine inhibition could bring clinical benefit was established in psoriasis patients around 20 years ago using anti-cytokine (anti-TNFα) monoclonal antibody therapies initially approved for rheumatoid arthritis and inflammatory bowel disease.
Growing understanding of the dysregulation in cytokine signalling and the contribution made by different cytokine networks and immune effector cells has given rise to the specialized research field “immunodermatology”, and to effective, safe and non-immunosuppressive treatments for atopic dermatitis (AD), psoriasis and chronic itching (urticaria). Similar mechanisms contribute to the pathology of a variety of non-dermatological inflammatory conditions, offering attractive label expansion possibilities.
Big numbers, big rewards
Dermatological conditions are common. The 12-month prevalence of AD (all age groups) in developed economies is close to 10%, and over 16% in the very young (0-5 years).1 The duration and severity of AD varies, but for many, the condition impacts heavily beyond cosmetic appearance, being strongly associated with increased risk of bacterial, fungal and viral infection, and with high rates of sleep disturbance, anxiety and depression.2 AD is ranked 15th among all non-fatal conditions with respect to disability-adjusted life years. Psoriasis is estimated to afflict some 2-3% of the global population, while the lifetime prevalence of chronic urticaria is estimated at close to 2%.
Big numbers and unmet needs mean big markets. Dupilumab (Dupixent®), an anti-IL4Rα antagonist which acts on both IL-4 and IL-13 signalling, was developed by Regeneron Pharmaceuticals and Sanofi. Dupixent® received FDA approval for the treatment of moderate-to-severe AD in adults in March 2017 and experienced quick prescriber acceptance (capturing 6.7% of the US AD market in the first year, around $1billion in revenue).3 Paediatric approval and subsequent approvals in asthma and a slew of inflammatory conditions (most recently becoming the first biologic approved for chronic obstructive pulmonary disease-COPD), saw Dupixent® achieve global revenue of $11.59 billion in 2023.
Tralokinumab (Adbry®/Adtralza®: Leo Pharma) an IL-13 antagonist received FDA approval for moderate-to-severe AD in December 2021, with an estimated peak sales of $1.3 billion. Another IL-13 antagonist, lebrikizumab (EBGLYSS™: Eli Lilly/Almirall), initially approved for moderate-to-severe AD in Europe and Japan and recently in the US, has estimated peak sales of $3.4 billion.
Small molecules have also made a mark, if somewhat overshadowed by the biologic cytokine antagonists. The boron-based phosphodiesterase 4 (PDE4) inhibitor, crisaborole (Eucrisa®: Pfizer) was approved for mild-to-moderate AD in 2016 and has since been followed by the PDE4 inhibitors, roflumilast, initially approved as an oral treatment for COPD, and since approved as a topical treatment (Zoryve®:Arcutis Biotherapeutics) for AD, plaque psoriasis and seborrheic dermatitis, and difamilast (Moizerto®: Otsuka) for AD (Japan only).
Upadacitinib (Rinvoq®: AbbVie), a Janus kinase (JAK) inhibitor, was first approved for rheumatoid arthritis and later for AD and psoriatic arthritis. The JAK inhibitors, abrocitinib (Cibinqo® : Pfizer) and baricitinib (Olumiant®: Eli Lilly, acquired from Incyte) are also indicated in AD, while ritlecitinib (Lifulo™: Pfizer), a JAK3/TEC kinase inhibitor is approved for severe alopecia areata (AA), an autoimmune condition causing hair loss.
Robust Pipelines
There are over 1,200 drugs in development across over 65 indications (GlobalData, 2024). By far the most active indication is atopic dermatitis, accounting for one third of the total dermatology pipeline, with the top 10 areas shown in the chart below (“unspecified” is a catch-all category for all of the smaller pipelines). There is a healthy funnel pro assets progressing through the development pipeline, ranging from over 500 discovery to preclinical stage through to some 75 at Phase 3, pointing to the possibility of significant sector growth over the coming decade.
A target-rich landscape
The precision dermatology landscape is dynamic, with existing players looking to broaden product offerings through their own endeavors, licensing and acquisition, and emerging companies looking to leverage less exploited cytokine and immune targets, or otherwise secure approval in rarer dermatological conditions. Several companies are looking to develop superior IL-4Rα and IL-13 antagonists, with other cytokine or cytokine receptor targets of interest including: thymic stromal lymphopoietin (TSLP), an IL-2-like cytokine; IL7Rα; IL-8; IL-13Rα1; IL-17 (A, C and F variants); IL-18; IL-22Rα1; IL-31; IL-33 and its receptor, ST2, and IL-36R.
Other immune targets include: the B and T cell lymphocyte attenuator (BTLA); CD1α; CD200R; glucocorticoid-induced TNFR-related protein (GITR); IL-1 receptor-associated kinase 4 (IRAK-4); OX40 and its ligand; stem cell factor (SCF); the calcium release activated channel subunit ORA│1; oncostatin membrane receptor beta (OSMRβ), and sialic acid-binding immunoglobulin ,(Ig)-like lectin 8 (SIGLEC8), several of which have been, or remain, of interest in immuno-oncology (BTLA, OX40,/L GITR, SIGLEC).
Antagonist candidates encompass whole antibodies, bispecifics such as NM26-2198 (IL-4Rα/IL-13, Numab and J&J) and J&J’s PX128 (anti-IL13/TSLP), and trispecifics such as Pfizer’s PF-07275315 (IL-4/IL-13/TLSP) and PF-07264660 (IL4/IL-13/IL-33).
Expansion and innovation
Building on the success of Dupixent®, Sanofi is bolstering its dermatology portfolio with amlitelimab, an anti-OX40L antagonist currently in Phase II development for AD, AA and hidradenitis suppurativa (HS), an autoimmune condition resulting in painful skin abscess. A TNFα/OX40L bispecific Nanobody®, SAR442970, acquired along with Ablynx is also under evaluation in HS, as is the IRAK4 degrader, SAR444656, and the oral TNFR1 signaling inhibitor SAR441566. An oral BTK inhibitor, rilzabrutinib is under evaluation in chronic spontaneous urticaria.
Recent players in the AD space also looking to broaden and diversify their offerings. Lilly is boosting its dermatology franchise (currently EBGLYSS™and TALTZ™, an IL-17A antagonist indicated in plaque psoriasis, and the JAK inhibitor, Olumiant™ ) with the clinical-stage candidates: eltrekibart (LY2041658), a CXCR1/2 receptor neutralizer, under evaluation in HS; ucenprubart (LY3454738), an agonistic antibody to CD200R, under evaluation in AD; LY3972406, a small molecule inhibitor of the Kv1.3 ion channel protein under evaluation in psoriasis, and DC-806 (LY4100504), an oral small molecule IL-17A antagonist also under evaluation in psoriasis.
Lilly’s EBGLYSS™ marketing partner, Almirall, has disclosed three “autoimmune dermatology” assets in Phase I development. A first in class IL-TRAP antagonist, SB 880 / ALM27134 was licenced from Ichonos Sciences (now Ichonos Glenmark Innovation), and is designed to abrogate multiple drivers of inflammation, including IL-1R, IL-33R, and IL-36.
The company has recently entered into several licence and collaboration agreements with Eloxx Pharmaceuticals for a preclinical oral therapy, ZKN-013, designed to overcome nonsense mutations found in rare dermatological conditions such as forms of dystrophic epidermolysis bullosa; with Novo Nordisk for NN-8828, a Phase II IL-21 antagonist; with eTheRNA for mRNA therapeutic development; with Nostrum Biodiscovery to access AI drug development capabilities, and with the Centre for Genomic Regulation to explore AD biomarkers.
AbbVie hopes to add HS and AA to the list of Rinvoq™ approved indications. Lutikizumab (ABT-981), an IL-1a/1b antagonist licenced from OneNess Biotech is under evaluation in HS. SCF248, an antibody directed against an inflammatory form of stem cell factor is in joint development with Opsido for AD. Leo Pharma is lookng to add temtokibart (LPO145), an IL-22Rα antagonist licensed from arGEN-Xto its Adbry®/Altraza® AD offer. LEO158968, an antibody designed to disrupt several IL-1 signalling pathways is in early clinical evaluation.
Amgen’s rocatinlimab (AMG 451 / KHK4083), an OX40 antagonist licenced form Kyowa Kirin is in late-stage development for AD and prurigo nodularis, a chronic dermatological condition characterized by intensely itchy nodules. Despite the failure of ligelizumab, an anti-IgE antibody in chronic inducible urticaria and AD, Novartis remains in the skin game with LOU064, an oral Bruton’s kinase inhibitor which the company plans to submit regulatory approvals for chronic urticaria. Pfizer’s trispecific cytokine antagonists, PF-07275315 and PF-07264660 are in Phase II evaluation in AD.
Targeted dermatology is far from being the provenance of only the larger pharmaceutical players. Arcutis Therapeutics is looking to add another AD topical alongside ZORVYE®, a JAK inhibitor (ARG-252), and a CD200R agonist fusion protein is in preclinical development. Cara Therapeutics is “pruritus focused”. KORSUVA®, systemically administered difelikefalin, a selective kappa opioid-receptor agonist, is approved for the relief of chronic kidney disease-associated pruritus (CDK-ap, uremic pruritus), an intractable itching which afflicts 50-80% of individuals with chronic and end-stage renal failure. Lumosa Therapeutics is pursuing the same indication with LT5001, a topical kappa agonist/mu antagonist.
AnaptysBio is evaluating a BTLA (CD272) agonist antibody (ANBO32) in AD and seeking licensees for its Phase III asset, imsidolimab, an IL-36R antagonist effective in pustular psoriasis. Celldex Therapeutics is evaluating a KIT antagonist antibody, CDX-0159 in a number of dermatological conditions, including inducible and spontaneous chronic urticaria, PN and AD.
Current AD biologics require administration by subcutaneous injection on a bi-weekly or monthly basis, imposing a burden on sufferers and carers and with a potentially detrimental effect on compliance. Apogee Therapeutics is developing an engineered anti-IL-13 antibody with extended half-life (APG777) currently under evaluation in AD, with extended IL-4Rα, OX40L and TSLP antagonists at earlier stages of development. Immagene’s OX40R-directed antibody has an engineered Fc region which prevents depletion through T cell interaction. Glen Clova Scientific is leveraging its virus-like particle platform to produce therapeutic vaccines to elicit a neutralizing antibody response to IL-13, IL-17 and other dermatology targets, with the potential to reduce dosing to only once or twice in a year.
Targeted dermatology is driving acquisition and investment
Targeted dermatology, with its additional lucrative prospect of broad label expansion across inflammatory disease à la Dupixent®, continues to drive acquisition and investment. As of August 2024, at close to $1.8 billion, “Dermatologic” is the 7th largest biopharma venture investment category.4 Organon recently announced its intention to acquire Dermavant, a Roivant subsidiary for $1.2 billion. J&J acquired the bispecific developer Proteologix for an estimated $850 million in cash, principally for its TSLP-targeting Phase I asset, PX128, a deal closely followed by the licensing of Numab’s IL-4Rα/L-31 bispecific NM26, under evaluation in AD, for a biodollar headline of $1.25 billion.
Attovia Therapeutics enjoyed an oversubscribed Series B to raise $105 million to advance its “spatially optimised biparatropic biologics”, which include a long half-life IL-13 agonist (ATTO-1310), and the anti-IL31/IL-13 bispecific ATTO-002 in AD and pruritus indications. Immunodermatology- focused Alys Pharma, founded by the healthcare fund Mediexi through consolidation of six academic start-ups, launched with $100 million seed funding. Mediexi also invested $30 million in Aldena Therapeutics to accelerate development of its topical short interfering RNA (siRNA) immunodermatology platform. Following a $92 million Series A, Triveni Bio recently closed a $115 million Series B to advance its anti-kallikrein 5 and 7/IL-13 bispecific TRIV-509 in AD.
Healthy Prospects
No longer moribund, but now revitalized by biological discoveries and combined with strong pipelines, a plethora of new targets and plenty of unmet therapeutic needs, the stage is set for a new phase of growth in dermatology drug development for the foreseeable future.
Bibliography
1 Volke A et al. 12-month prevalence of atopic dermatitis in resource-rich countries: a systematic review and meta-analysis. Sci Rep 12, 15125 (2022).
2 Global Atopic Dermatitis Atlas. 2022 Report, International League of Dermatological Societies.
3 Fenske C et al. Prescription Market Share and Treatment Patterns in Atopic Dermatitis: A Retrospective Observational Study Using US Insurance Claims. Adv Ther. 2022 May;39(5):2052-2064.
4 Senior, M. Biotech financing: darkest before the dawn. Nat Biotechnol 42, 1331–1338 (2024).
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