Development Trends of Janus Kinase Inhibitors (JAKi) Over Three Decades: From Common to Rare Diseases

Introduction

The Janus Kinase-Signal Transducer and Activator of Transcription (JAK/STAT) signaling pathway is a key regulator of cytokine communication. It is activated by multiple cytokine interactions with cell membrane receptors, leading to JAK autophosphorylation and transmembrane phosphorylation. Subsequently, phosphorylated STATs (pSTATs) either homo- or heterodimerize via intermolecular Src Homology 2 (SH2) phosphotyrosine interactions and bind to DNA regulatory elements to generate physiological effect.¹ Overexpression of cytokines and mutations in JAKs and STATs can lead to pathological disorders, including cytokine-dependent autoimmune diseases, inflammatory diseases, and cancers, which can be targeted therapeutically using Janus Kinase inhibitors (JAKi). JAKi are small-molecule drugs that binds to JAK receptors, inhibit the phosphorylation of downstream effector proteins, block cytokine signaling, and disrupt the signaling cascade for key pathways.² To date, JAKi have been extensively applied in numerous diseases such as rheumatoid arthritis (RA), ulcerative colitis (UC), Crohn’s disease (CD), alopecia areata (AA), atopic dermatitis (AD), and myelofibrosis (MF).³

Notably, JAKi have emerged as a transformative therapeutic class despite well-recognized safety concerns. This stems from their unique mechanistic properties, as the JAK/STAT pathway functions as a convergent signaling node for nearly all proinflammatory cytokines.⁴ Additionally, JAKi’s oral bioavailability and favorable pharmacokinetic (PK) profile provide a more convenient treatment option than injectable biologics for chronic conditions,⁵ further supporting extensive research and development (R&D) investment in these agents. Nevertheless, JAKi development faces widely reported core safety and translational challenges. Non-selective JAKi disrupt homeostatic cytokine signaling and trigger adverse events including myelosuppression, thrombotic risk and infections.⁶ Interindividual PK variability also complicates the design of optimal dosing regimens, and poor target selectivity remains a major hurdle to improving the benefit-risk ratio.⁷

In 1995, the first preclinical study on JAKi for cancer treatment was conducted.^1,3 More than a decade later, ruxolitinib (Jakafi^®), an immunosuppressive agent, as the first JAKi was approved by the United States (US) Food and Drug Administration (FDA) for the treatment of patients with intermediate or high-risk primary myelofibrosis (PMF) in 2011.^3,8 Following the development of numerous targeted therapies, JAK has emerged as one of the most prominent therapeutic targets in oncology and immunology, with substantial clinical and commercial potential. As JAKi R&D has matured over three decades, rare diseases have emerged as a central and irreplaceable focus in the current JAKi landscape. Most rare diseases, particularly rare immune-mediated and hematologic disorders, are driven by dysregulated JAK/STAT signaling with limited or no approved therapeutic options.⁹ Furthermore, regulatory incentives like orphan drug designations from FDA lower the development barrier for JAKi in rare diseases,¹⁰ while clinical data from rare disease trials also enriches the understanding of JAK/STAT pathway biology, facilitating the iterative optimization of JAKi for both rare and common diseases.

On the occasion of the 30th anniversary of JAKi research, our study aimed to systematically analyze the global development trends of JAKi and clarify the underlying rationales driving these efforts. Through retrospective data mining, we further conducted a comprehensive assessment of target and indication landscapes, with a specific focus on the evolutionary shift from common diseases to rare orphan indications. To our knowledge, this represents the first comprehensive review to the entire three-decade R&D journey of JAKi. Despite the long-standing and ongoing interest in JAKi as a key therapeutic target, a holistic analysis of their global development trends remains lacking. Hence, we performed this review to identify key challenges and outline future directions for JAKi research and clinical translation.

Overall Development Trends in JAKi

Over the past 30 years (1995–2025), 271 JAKi with 2035 clinical trials had been conducted (Supplementary Figure S1). The development process was slow during the first decade. In the second decade, the number of trials increased five-fold from 11 trials in 2005 to 61 trials in 2015. In the third decade, beginning in 2016, there was a pronounced acceleration, with the number of global trials peaking at 206 by 2024 (Figure 1A). Evolving trends in JAKi are intrinsically linked to broader transformations in the pharmaceutical industry.

Figure 1 Trends in JAKi development during the past 30 years. (A) Global annual numbers of preclinical and clinical trials devoted to JAKi development from January 1st, 1995, to August 31, 2025. (B) Evolution of trials in development comparison between the US and China (including Hong Kong and Taiwan regions). Because year information in some trials is not available, the total number in this graph is 597 for China and 578 for the US. (C) Top 20 JAKi ranked by clinical trials (red columns are market drugs, blue columns are investigational products).

During the initial decade (1995–2005), progress in foundational research was limited because technologies constrained the efficiency of drug structure design. The scientific community required time to validate that JAK may be a valuable therapeutic target.^11,12 The subsequent decade (2006–2015) witnessed accelerated development, driven by industrial paradigm shifts and clinical demands. The milestone of imatinib approval in 2001 catalyzed pharmaceutical investment in small-molecule targeted drugs, which promoted the appeal of intracellular targets such as JAK.¹³ Subsequently, the clinical success of tofacitinib (Xeljanz^®) in autoimmune diseases in 2012 created market opportunities for JAKi.¹⁴ The most recent decade (2016–2025) experienced exponential growth in clinical trials fueled by technological synergies, indication expansion, and policy assistance. Advances in artificial-intelligence-assisted drug design facilitated the development of highly selective JAKi.¹⁵ Clinical applications have diversified beyond rheumatology and hematologic proliferation neoplasms to encompass dermatologic diseases such as AD, AA, psoriasis (PsO), and even COVID-19 cytokine storms in special stages (eg, emergency authorization for baricitinib).^16,17 Advancements in precision medicine through molecular diagnostics have promoted targeted therapies and reduced development risks.¹⁸ In addition, regulatory reforms, such as FDA breakthrough therapy designation, accelerated JAKi approval timelines.¹⁹ Noticeablely, during this period, the rapid increase in clinical trials in China was also an important contributor.

By analyzing the R&D states of different countries, we found that 70 countries and regions participated in JAKi development. China (including Hong Kong and Taiwan regions) and the US significantly led the research magnitude over others, with 612 and 594 trials, respectively. China started JAKi research in 2010, approximately 15 years later than the US. However, China has shown a rapid increase, equal to that of the US after eight years in 2018. Over the past seven years (2019–2025), China’s average annual trials approximately doubled compared to those of the US (73 versus 39) (Figure 1B), which could be attributed to the rapid innovation of China’s pharmaceutical industry during the transition period from 2015 to 2025.²⁰ During this period, a revolutionary breakthrough in China’s regulatory policy reshaped the pharmaceutical landscape. For example, in the 2015 policy, Opinions on the Reform of the Drug and Medical Device Review and Approval Process, marked a turning point by initiating reforms that reduced application backlogs and encouraged innovation.²¹

The top 20 JAKi ranked by clinical trial are shown in Figure 1C, in which 15 products have been approved. The other five investigational drugs, Itacitinib, Zasocitinib, Brepocitinib, Povorcitinib, and Tinengotinib, have promising potential for marketing approval.

Phase Analysis of Investigational JAKi

JAKi pipelines have shown significant progress at various developmental stages. Specifically, there were 24 New Drug Application (NDA) submissions, 533 Phase III trials, 594 Phase II trials, 460 Phase I trials, 65 Investigational New Drug (IND) applications, and 359 preclinical studies (Figure 2). This distribution highlights the substantial efforts invested in advancing JAKi development.

Figure 2 Breakdown of all JAKi by stage of development. (A) Distribution of JAKi by clinical development phase. (B) Trends in clinical trial phases of JAKi by year.

The high proportion of Phase II/III clinical trials (54%) indicates that JAKi pipelines have entered the late development phase with intensive commercial competition. However, a significant disparity remained between the number of NDA and phase III (approximately 1:23). This indicates a high failure rate in Phase III. On the one hand, efficacy failed to meet the primary or secondary endpoints. Baricitinib has registered 58 Phase III trials according to the data in clinicaltrials.gov, but only three NDA submissions in the FDA and one in the European Medicines Agency (EMA).^22–24 A double-blind, randomised, placebo-controlled, Phase 3 trial for Baricitinib for systemic lupus erythematosus indicated that although baricitinib is a potential treatment for SLE, it did not meet the primary efficacy outcome of improved SLE Responder Index (SRI)-4 response. In addition, none of the key secondary endpoints, including glucocorticoid tapering and time to first severe flare, were achieved.²⁵ Moreover, an additional burden was derived from safety trials. Because of the FDA box warning associated with an increased risk of serious heart-related events, cancer, blood clots, and death due to tofacitinib in the treatment of certain chronic inflammatory conditions, additional Phase III safety investigations were imposed by the registration demand.²⁶ These events were jointly attributed to the high Phase III-to-NDA ratio.

The high proportion of Phase I and preclinical trials (41%) indicates the sustainability of JAKi development and the industry desired to explore new chemical entities and novel mechanisms in the JAK pathway. We measured the IND transition success rate (IND ratio) as approximately 18%, which was determined by dividing the number of IND applications by preclinical studies. This suggests challenges in the target selection. The high homology among JAK family subtypes leads to a high elimination rate in early compounds selection. To deal with the failure issue and low IND ratio, precise mutation target screening, such as JAK2^V617 inhibitors, is key to success. Additionally, safety issues have become more stringent owing to lessons learned from box-warning adverse effects (AEs). Consequently, preclinical models should incorporate enhanced assessments of cardiovascular risk to ensure more rigorous evaluation of candidate compounds before clinical trial.²⁶

Development Evolution in Targets

Core Targets

JAKs are a group of intracellular non-receptor tyrosine kinases (TYKs) including JAK1, JAK2, JAK3, and TYK2. In this study, 271 JAKi agents were identified as 38 targets (Supplementary Table S1). Frequency (freq.) of the top five targets were the core components of the JAK/STAT pathway: JAK1 (1194 freq. /90 products), JAK2 (including JAK2^V617F) (854 freq. /80 products), TYK2 (340 freq. /60 products), JAK3 (335 freq. /61 products) and non-selective JAK (Pan-JAK) (178 freq. /50 products). The core target strategy shifted from broad-spectrum first-generation Pan-JAK to precision second-generation selective JAKi (Figure 3A), but 61% (n=11) of approved JAKi were still Pan-JAKi. This indicates that the development of highly selective targets and target druggability still present challenges.

Figure 3 Evolution of targets for JAKi development. (A) Temporal trends in R&D of core targets over time. (B) Top15 typical non-core target preferences for JAKi over time.

JAK1 is the cornerstone of immune and inflammatory diseases and the most extensive and time-consuming target. However, the extensive inhibitory effect of JAK1 will affect the normal immune surveillance and increase the risk of infection.² Five approved elective JAK1 inhibitors (Table 1) are used to treat inflammatory diseases, such as RA, AD, AA, and UC.^27–29 Only Golidocitinib has been developed for the treatment of relapsed or refractory peripheral T cell lymphomas (r/r PTCLs).^30,31 For JAK1, the key priority is to identify precise mutation profiles to enhance the specificity of its anti-inflammatory effects. Jeanpierre et al used in silico modeling to identify novel JAK1 variants associated with immune dysregulation.³² They applied this approach to identify five novel gain of function (GOF) variants in key cis-regulatory and catalytic domains. Furthermore, they administered a pan-inhibitor, tofacitinib, which reversed these molecular abnormalities and improved the clinical symptoms in two patients. These findings suggest diverse mechanisms of JAK1 GOF and underscore the importance of precise variant characterization for effective personalized therapy.³²

Table 1 Information on Marketing JAKi, Ranked by the First Data Approved and Orphan Drug Designation & Approved by the FDA

JAK2 represents a well-defined therapeutic target with actionable variants. Researchers have found that JAK2^V617F mutations occurred in most myeloproliferative neoplasms (MPNs) patients, specifically in over 90% of polycythemia vera (PV) cases and about 50% of essential thrombocythemia (ET) and PMF cases.^33,34 Ruxolitinib is an effective front-line JAK1/JAK2 inhibitor approved for the treatment of patients with MF.^35,36 However, its mechanism of action is better characterized as a highly effective symptom controller than a direct inhibitor of the JAK2^V617F target within malignant cells.³⁷ Some researchers believed that the clinical efficacy of ruxolitinib primarily stem from reducing the levels of key pro-inflammatory cytokines, such as TNF-α and interleukin (IL)-6, leading to the modulation of the tumor microenvironment.³⁷ Therefore, ruxolitinib will cause dose-dependent anemia and thrombocytopenia, and approximately 10% of patients experienced non-hematologic AEs.³⁸ To date, selective JAK2^V617F inhibitors will be the most intriguing and promising approaches.³⁷

JAK3 is exclusively expressed in hematopoietic cells, whereas the other members are widely expressed in various tissues.^33,39 However, JAK3 inhibitors have not been successful in the treatment of hematopoietic diseases because of their poor druggability. A recent study has shed new light on the potential of JAK3 inhibitors in treating hematological malignancies.⁴⁰ They revealed JAK3^A573V and JAK3^M511I mutations could mediate resistance to anti-PD-1 therapy through the STAT3/PD-L1 pathway in patients with r/r PTCL. Their in-vivo study demonstrated that cells with JAK3 mutations exhibit greater sensitivity to tofacitinib, indicating that tofacitinib will be a promising therapeutic strategy for JAK3 mutant r/r PTCLs. Although golidocitinib, a JAK1 inhibitor, has recently been approved for r/r PTCL,³⁰ JAK3, which is specifically expressed in hematopoietic cells, demonstrates greater theoretical therapeutic potential. To date, peficitinib, a pan-JAK inhibitor, has significantly inhibited JAK3 targets and was approved for the treatment of RA in 2019.⁴¹ But the first truly selective JAK3 inhibitor is ritlecitinib, a selective dual JAK3/Tec family kinase inhibitor approved for the treatment of AA in 2024.⁴² Decernotinib, a novel JAK3-selective inhibitor, is currently under development and considered efficacious against RA.⁴³ The development of JAK3 inhibitors is currently focused on autoimmune diseases, but their application in hematological diseases still holds promise.

TYK2 primarily transmits downstream signals by forming dimers with JAK1/JAK2.³ Unlike traditional JAKi, TYK2 inhibits the JH1 kinase domain and blocks signaling pathways such as IL-12, IL-23, and type I interferon (IFN) by specifically binding to the JH2 pseudokinase domain of TYK2, without interfering with other JAK pathways, which could prevent cardiovascular events or venous thrombosis risk related to JAK1/JAK2/JAK3 impaction.^3,44,45 Deucravacitinib is an oral, selective, allosteric TYK2 inhibitor approved by the FDA for the treatment of moderate-to-severe plaque psoriasis (PP) in September 2022.⁴⁶ It was the first de novo deuterated drug and JAKi without being subjected to an FDA box warning. Building on the success of deucravacitinib, several novel allosteric inhibitors have been developed, showing promising therapeutic outcomes in diseases linked to the JAK-STAT pathway.^47,48

Non-Core Targets

After a 15-year effort beginning in 2010, JAKi initiated a new era of dual- and multi-targeting. Because the pathogenesis of cancer and immune-mediated diseases is highly complex, JAK/STAT-targeted monotherapy is insufficient to effectively control or cure these conditions. Combination strategies targeting additional pathways have been shown to improve clinical responses.^49,50 Our study elucidated some hotspot non-core targets, such as TEC protein tyrosine kinase (TEC) and spleen tyrosine kinase (Syk) (Figure 3B). TEC is primarily expressed in hematopoietic cells and plays an important role in leukocytes.⁵¹ Moreover, inhibition of TEC kinases can expand the mechanism of action of JAK3 to other cell types, such as lymphocytes.⁵² PF-06651600 is unique in that it inhibits only cytokine receptors that use the common γ-chain, so it not only selects for JAK3 but also inhibits the TEC family, leading to joint anti-immune effects.⁵² Syk is a typical non-core target (freq.39) that belongs to Glycoprotein VI/immunoreceptor tyrosine-based activation motify (GPVI/ITAM) pathway, a parallel pathway of JAK/STAT.⁵³ Syk inhibitors have been developed to treat hematological malignancies such as B-cell lymphomas and allergic, inflammatory, and autoimmune diseases.^53–55 Therefore, joint development with JAK can not only compensate for AEs caused by JAK inhibition alone but also produce synergistic anti-inflammatory effects. SYHX-1901 has the most trials in JAK/Syk dual target investigated by CSPC Pharma of China. To date, its highest development phase is the Phase III study in PsO, Phase II study in AA and Vitiligo.⁵⁶

Given their highly conserved ATP-binding sites, JAKi produce a wide range of effects and cause side effects. Therefore, the development of dual- or multiple-target inhibitors with enhanced specificity and fewer AEs are key considerations for drug development. Optimization of the four core JAK targets is key to improving safety profiles, whereas the introduction of non-core targets facilitates multi-target combination therapies. However, future breakthroughs need to depend on a clearer mechanistic understanding of the JAK/STAT signaling network and precise regulation of cross-target synergistic effects.

Therapeutic Areas & Indications Evolution

Based on the International Classification of Diseases 11th revision (ICD-11) and the European Alliance of Associations for Rheumatology (EULAR) expert consensus on rheumatic and immune diseases,^57–59 therapeutic areas of under-developed JAKi were categorized into seven domains, involving 109 indications with 1844 valid trials. The main areas were immune-mediated inflammatory diseases (IMIDs) (69.3%, n=1277) and oncology (accounting for 21.7%, n=400). Respiratory system diseases (predominantly COVID-19), ophthalmological diseases, neurological disorders, and genetic diseases accounted for a small proportion (Figure 4A and Supplementary Figure S2). It is noteworthy that among all indications, 35.8% were rare diseases (n=39) (as defined by the Orphanet database of European and Chinese rare disease catalog announced by the National Health Commission of China^60,61), which involved 20.4% of the trials (n=376). From the heat map of indications (Figure 4B and C), in the field of hematological neoplasms, rare diseases witnessed the earliest and highest number of trials. However, in IMIDs area of IMIDs, early efforts focused on common IMIDs, and it is only in the recent decade that research has begun to gain momentum in rare immune system disorders, such as juvenile idiopathic arthritis (JIA), psoriatic arthritis (PsA), and graft versus host disease (GVHD).

Figure 4 Heatmap of therapeutic areas and cluster distribution map of indications. (A) Distribution of JAKi R&D trials in immune-mediated inflammatory diseases (IMIDs), oncology and other therapeutic areas. (B) Cluster distribution of indications in IMIDs area and comparison of common and rare diseases in this field. (C) Cluster distribution of indications in oncology area and comparison of common and rare diseases in this field.

From Common to Rare in IMIDs

IMIDs’ scope of IMIDs included inflammatory dermatological diseases (43.7%, n=558), inflammatory rheumatic diseases (30.8%, n=393), inflammatory bowel diseases (IBDs) (11.0%, n=141), and other IMIDs (14.5%, n=185). This confirms the central role of the JAK/STAT pathway in immune regulation. Notably, dermatological diseases even surpass traditional rheumatic diseases, which is probably due to the lower risk of systemic side effects, higher market acceptance, patient compliance, and development of external topical JAKi.^62,63 For example, delgocitinib cream treatment for chronic hand eczema (CHE) can effectively treat AD and PsO. Ruxolitinib 1.5% cream in a Phase II clinical trial was shown to be more effective at reducing pruritus in patients with AD than oral JAKi.⁶⁴ The introduction of JAKi makes dermatology a novel therapeutic strategy with the potential to significantly improve the outcomes of inflammatory dermatoses.

From the two representative IMIDs, RA and SLE, we could see the indication challenge and the change from common to rare. RA was the most popular indication for JAKi therapy, with 234 trials. Given the success of Tocilizumab, JAKi has become an alternative drug for the treatment of RA, especially for those who fail initial treatment with methotrexate (MTX) or disease-modifying anti-rheumatic drugs (DMARDs).⁶⁵ Currently, six JAKi products are approved for RA treatment, half of which are selective JAK1 inhibitors (Table 1), addressing the safety and off-target deficiency induced by Pan-JAK. Despite the established role of JAKi as a key therapeutic option for RA, several critical challenges persist in their development. Approximately 30–40% of patients exhibit an inadequate response to JAKi treatment,⁶⁶ especially in patients with difficult-to-treat RA (D2T RA), and respond poorly to multiple existing targeted therapies.⁶⁷ A lack of reliable predictive biomarkers for efficacy is crucial. From a long-term perspective, scientists are exploring novel mechanisms of action beyond the JAK-STAT pathway. Wj1113 is a promising dual-target therapeutic candidate for RA that inhibits BTK/JAK3 signaling in vivo, alleviates arthritis in joints, and can address both B-cell-and cytokine-driven pathogenic pathways.⁶⁸

SLE was the second most popular indication for IMIDs in 54 trials. In December 2018, FDA granted the “Fast Track” status for baricitinib use in SLE treatment.⁶⁹ However, the development of JAKi for SLE is challenging because of its inherent complexity and heterogeneity, and not all patients with SLE are dependent on the IFN pathway. Recently, Szebeni et al revealed that baricitinib could dampen IL-6- and IL-15-mediated STAT3 activation in key immune cell subsets.⁷⁰ This result supports a precise medical approach to JAKi in SLE and reinforces its potential. JAKi development in SLE therapy, including upadacitinib, filgotinib, deucravacitinib, solcitinib, SYHX-1901, and TLL-018, is currently being investigated in phase II and III trials.

Overexpression of type 1 IFN is considered to be the main characteristic of SLE.⁷¹ Coincidentally, the JAK/STAT pathway was first discovered in the early 1990s when researchers investigated IFN-induced transcription activation.⁷² According to the principle of common mechanism, type I IFN plays a critical role in both SLE and type I interferonopathies (IFN-I). Type IFN-I first proposed by Crow in 2011, is a group of rare diseases characterized by the excessive upregulation of type I IFN due to monogenic inherited deficiency, which leads to multi-systemic inflammatory reactions.^73,74 JAKi is administered by blocking the IFN-I signaling pathway, but most applications are off-label in type IFN-I treatment. We found that there are two completed trials of baricitinib for type IFN-I disease (NCT03921554 and NCT04517253).^75,76 Nobuo et al reported that baricitinib has potential therapeutic effects in adult and Japanese pediatric patients with STING-associated vasculopathy, infantile onset (SAVI), Aicardi-Goutières syndrome (AGS).⁷⁵ From this perspective, SLE and type IFN-I are typical indication expansions, suggesting that type IFN-I could be an interesting rare indication for JAKi development.

As time passes, the indication scope in IMIDs experiences a significant change, from common IMIDs such RA, AA and vitiligo before 2010 to a surge exploration in rare IMIDs such as PsA, JIA, Giant Cell Arteritis (GCA), Behçet Syndrome (BS), from 2013 to 2025 (Figure 4B). However, indication extrapolation cannot be directly applied. This requires case-by-case consideration based on the drug’s mechanism of action, pathological and physiological similarities between the studied and extrapolated indications, consistent PK profiles, and comparable adverse reactions across different diseases.⁷⁷ For instance, studies have revealed elevated levels of cytokines such as IFN-γ and IL-6 in several rare diseases, such as BS, GVHD, and GCA, suggesting aberrant activation of the JAK/STAT pathway. Based on this mechanistic similarity, repurposing approved JAKi for these rare conditions has become a risk-controlled and potentially highly successful R&D strategy.

From Common to Rare in Oncology

Oncology is the second largest therapeutic area, in which hematologic malignancies occupy a dominant position, with 285 trials (accounting for 71.3% in the oncology area) far ahead of other solid tumors, in which 71.6% are rare hematologic tumor, including (PMF, PV, and ET), myelodysplastic syndromes/myeloproliferative neoplasms (MDS/MPNs), multiple myeloma (MM), and Waldenström Macroglobulinemia (WM) (Figure 4B), only lymphoma and leukemia are common hematologic tumors. These six rare MPNs accounted for 15.4% of the total rare indications (n=39) and 50.5% (n=190) of the total number of rare trials (n=376).

Subtypes of JAK2 and JAK3 play critical roles in the proliferation, differentiation, and survival of hematopoietic cells, and their mutations or abnormal activation are directly related to various bone marrow proliferative tumors and leukemia.^78–80 Moreover, mutations in the SH2 domains of STAT3 and STAT5 are often observed in hematopoietic malignancies.⁸¹ PMF is the first and most rare indication for approved JAKi, a total of five JAKis were approved for treatment of PMF, from first-generation ruxolitinib, fedratinib, pacritinib, to the second-generation momelotinib and jaktinib. The discovery of JAKi has been pivotal in the treatment of symptomatic MF by reducing spleen size and alleviating the cytokine-related symptom burden. Despite this, up to 50% of MF patients discontinue JAKi after 2–3 years, and only one-quarter of patients remain on treatment at 5 years.⁸² On one hand, due to the intrinsic hematopoietic impairment in MF patients and the inhibitory effect of JAKi, 61% of patients develop anemia after treatment with ruxolitinib, and 69% of the anemia worsened, forcing them to interrupt treatment.⁸³ On the other hand, somatic mutations are associated with inferior survival following JAKi failure. England et al reported 21% of frequent emergent mutations in ASXL1 and KRAS in failure patients, but among the six patients with ongoing benefit from therapy, three patients had the same variants detected, two patients had dropout of mutations, and one patient had two emergent mutations (NRAS, BCORL1) and dropout of JAK2.⁸² This finding suggests that the focus of JAKi development, based on molecular typing, is the next step.

Although mutations in JAKs and STATs are relatively uncommon in non-hematopoietic tumors, including those affecting the breast, lung, and intestine, this does not mean that the pathway is irrelevant for solid tumors.³ In addition to mutations, the activation of STAT3 and STAT5 is frequent in solid tumors. They can promote tumor growth and chemoresistance and alter immune cell function.⁸⁴ In our study, non-hematopoietic tumors accounted for a certain proportion (30%, n=120), including hepatocellular carcinoma (HCC), breast cancer, lung cancer, and rare nervous system cancers such as glioblastoma (GBM), gliosarcoma (GS), astrocytoma, and neuroblastoma.

JAKi are among the few drug classes that demonstrate blockbuster potential in both autoimmune diseases and oncology, reflecting the fundamental and broad nature of their mechanism of action. Future directions for expanding JAKi indications include several strategies: optimizing established indications through combination therapies and novel delivery systems; investigating emerging diseases such as GBM, pulmonary sarcoidosis, and uveitis, along with well-studied but unapproved areas such as lymphoma; and targeting rare diseases by leveraging shared mechanistic pathways for clinical trials. However, safety concerns remain a significant constraint in indication expansion. Rare diseases and niche tumors are likely to become key areas of differentiated competition in an evolving market.

Approved and Orphan Drug Designated in JAKi

Over the past three decades, 18 JAKi have been approved globally, covering 18 indications and 9 targets (Table 1). Among the 142 candidates (from Phase I to approval) in our study, the clinical development success rate was 12.7%, which was higher than the industry 7.9%.⁸⁵ JAKi is primarily used to treat intermediate- or high-risk MF, including primary and secondary MF (secondary MF consists of post-polycythemia vera MF (PPV-MF) and post-essential thrombocythemia MF (PET-MF)), moderate-to-severe active RA in adult patients who show an inadequate response to one or more DMARDs, severe AA and severe AD. Approved targets include JAK targets that regulate the efficiency, as well as additional targets aimed at reducing adverse drug reactions, such as bone morphogenic protein receptor kinase activin A receptor type I ACVR1 (to improve iron metabolism and anemia by Jaktinib) and interleukin-1 receptor-associated kinase 1 (IRAK1) (to improve thrombocytopenia by Pacritinib).^86,87

Among the approved JAKi, five drugs acquired the FDA orphan drug designation (ODD) with a total of seven indications, including GVHD, PV, PMF, PPV-MF, PET-MF, GCA, and Pediatric JIA (excluding systemic JIA) (Table 1). However, pediatric SLE (pSLE) with baricitinib, pediatric CD and UC in Filgotinib, pediatric UC and pediatric systemic JIA in Upadacitinib were not approved by ODD in FDA.⁸⁸ Because the deficiency letters to the sponsor are confidential, we can only speculate the reason for refusal based on literature citations or epidemiological information. For example, the application of upadacitinib for pediatric UC designation was refused in 2019, which might be associated with a population of over 200,000, inconsistent with the standard of rare diseases in the US. In most European countries and in the USA, the incidence of UC new cases among children is estimated to be 1–4 per 100,000 per year.⁸⁹ In 2019, the population of the whole US was approximately 337,790,066, given that the prevalence of pediatric UC will be over 200,000 persons.⁹⁰ Thus, when a company applies ODD, a thorough investigation of assessment standards is critical. Both the European Union (EU) and the US have designation standards that include epidemiological criteria, expected cost-benefit criteria, precision medicine criteria, and clinical advantages over existing drugs of the same type.^91,92

Challenges and Future Directions

Based on the above analysis, highly selective mutation targets, target tolerance, reliable biomarkers based on disease genotyping, and safety issues constitute primary obstacles in drug development.

Regardless of whether JAK is targeted, patients who are relapsed or refractory are intolerant to JAKi, limiting effective treatment options, and the outcome after discontinuation of JAKi is poor.³⁵ Research on JAK1 GOF mutations and the discovery of JAK3 mutations provides guidance for precise development.^32,40 Another direction is to develop joint targets based on other pathways. Rovadicitinib (TQ05105) is a novel, orally administered, small-molecule inhibitor of JAK2/Rho-associated kinase (ROCK),⁹³ which has demonstrated significant clinical benefits for spleen or symptom response in intermediate-risk or high-risk MF patients (NCT04339400 and NCT05020652).³⁵ The increasing number of JAK variants identified in patients has resulted in new diagnostic and therapeutic directions.

Safety risk is another important factor that affects development. Most of the AEs observed so far can be explained by the known mechanism of action of specific cytokines in infections, anemia, neutropenia, and secondary malignancies, and these safety profiles are largely comparable with those of biologics.³ However, additional adverse effects remain unknown. However, the toxicity of dosage restrictions is an obstacle. Spracklen et al reported that, in a South African child with RNU7-1-Associated Aicardi-Goutières Syndrome, liver function, dystonia, and neurological function did not improve even after increasing the baricitinib dose, and baricitinib was eventually discontinued because of persistent and worsening adverse effects eventually.⁹⁴ Another safety challenge is the serious AE announced by FDA box warning regarding JAKi. This warning highlights the increased risks of serious infections, mortality, malignancy, MACE, and thrombosis in tofacitinib, which compels sponsors to integrate rigorous safety assessments from the earliest stages of research and clinical trial design.²⁶ It also promotes the development of a novel and safe JAKi. Because the total treatment cost for MF patients with severe anemia increased by nearly two times and the median survival period decreased by nearly 60% (only 2.1 years),⁹⁵ GSK developed a new JAK1/JAK2/ACVR1 inhibitor for MF patients with anemia, called Momelotinib, which was recently approved by FDA. Its inhibition of ACVR1 improves iron availability, mitigating the effects of anemia associated with this disease or JAKi.⁹⁶

In addition, JAKi has significant PK interindividual variability and a narrow therapeutic window,⁹⁷ which affects the frequency of administration and dosing regimen design, especially for special populations. Hepatic metabolism of JAKi is predominantly metabolized by cytochrome P450 (CYP)3A4 and to a lesser extent by CYP2C19, CYP2C9, or CYP2D6,^98,99 which induces susceptibility to drug-drug interactions (DDI). Co-administration of moderate-to-potent CYP3A4 inhibitors increases systemic exposure and therefore requires appropriate dosage adjustments or restrictions. Gupta et al reported that the area under the curve (AUC) and maximal plasma concentration (C_max) increased by 79% and 27%, respectively, with fluconazole co-administration and by 103% and 16%, respectively, with ketoconazole respectively.⁹⁸ Patients with impaired hepatic function require longer dosing intervals or lower total daily dose. Manna Zhao et al reported that exposure to Jaktinib is approximately 2-fold in patients with mild and moderate hepatic impairment compared to normal hepatic function in subjects with hepatic impairment in a phase I trial.¹⁰⁰ The main route of excretion is in urine, with only a small percentage excreted in feces, and half-lives mostly between 4 and 10 hours.^101–103 The same precautions should be applied in patients with end-stage renal disease, as suggested by the finding of minimal ruxolitinib clearance and high binding to plasma proteins in hemodialysis patients.¹⁰¹ Currently, model-informed drug development (MIDD) strategies such as PBPK modeling and population PK analysis can significantly enhance R&D efficiency while reducing clinical trial costs and timelines.¹⁰⁴ Pediatricians represent a frequent user population for JAKi with approved or investigational applications in conditions such as JIA, type IFN-I disease, and pediatric IBD. Extrapolation of pediatric doses is also a key step in the development of dose design. It was employed for selecting the initial pediatric doses for Upadacitinib by combining population PK (popPK) models and the assumption of typical allometric values for body weight based on adult data.¹⁰⁵ The PK profile not only directly influences the clinical convenience and safety of the drug but also necessitates further optimization of selective inhibition and local delivery technologies in future research to balance efficacy with long-term safety. Thus, laboratory monitoring and exploration of biomarker-guided drug development is necessary.

Conclusions

Over the past 30 years, JAKi have achieved remarkable clinical success and broad regulatory approval, with indications spanning a wide spectrum of immune‑mediated inflammatory diseases, dermatologic disorders, hematological malignancies and an expanding range of rare diseases. Despite notable limitations and unresolved challenges remain, including off‑target adverse events, interindividual PK variability, suboptimal target selectivity, and remaining uncertainties in long‑term safety, JAKi continue to represent an indispensable and widely used therapeutic class, with steady growth in global R&D activity. Future investigations should prioritize improved drug tolerability and safety profiles, the rational design of highly selective JAKi optimized for precise mutational profiles, and further exploration of rare disease indications. Such advances will help refine the benefit–risk balance, streamline clinical development and regulatory approval, and ultimately expand patient access to effective targeted therapies.