GSK-1070806 (Aletekitug): A Comprehensive Clinical Development Review

1. Executive Summary

This report provides a comprehensive analysis of the clinical development program for GSK-1070806, also known by the proposed International Nonproprietary Name (INN) Aletekitug, a humanized monoclonal antibody developed by GlaxoSmithKline (GSK).[1] GSK-1070806 targets and neutralizes the pro-inflammatory cytokine Interleukin-18 (IL-18), a member of the IL-1 family implicated in various immune-mediated conditions.[1] By inhibiting IL-18, the therapy aims to reduce downstream inflammatory cascades, notably the production of interferon-gamma (IFN-γ).[6]

The clinical development of GSK-1070806 has spanned multiple indications, including Atopic Dermatitis (AD), Crohn's Disease (CD), Delayed Graft Function (DGF) following renal transplantation, and Type 2 Diabetes Mellitus (T2DM).[2] Currently, the primary focus is on Phase 2 development for moderate-to-severe AD, administered via subcutaneous injection.[1] Early Phase 1b results in AD showed promising clinical improvements and significant benefits in patient-reported outcomes, including itch and quality of life, compared to placebo.[14] A Phase 2b dose-finding study (NCT05999799) and a subsequent long-term extension study (NCT06447506) are ongoing to further evaluate efficacy and safety in this indication.[15] Development in CD reached Phase 2, but recent reports conflict regarding its current status.[3]

Conversely, development was discontinued for DGF and T2DM due to lack of efficacy demonstrated in Phase 2a trials.[3] Despite evidence of target engagement in both studies, GSK-1070806 failed to meet primary endpoints related to preventing DGF or improving glycemic control.[5] These outcomes highlight the challenge of translating IL-18 inhibition into clinical benefit across diverse conditions.

Notably, GSK-1070806 demonstrated remarkable efficacy in a compassionate use case involving a child with severe, refractory Very Early-Onset Inflammatory Bowel Disease (VEOIBD) driven by an IL-18opathy (characterized by markedly elevated IL-18 levels), leading to sustained remission.[21] This success suggests potential utility in specific, biomarker-defined patient populations where IL-18 is a primary driver.

Overall, GSK-1070806 presents a mixed development history. While setbacks occurred in DGF and T2DM, promising signals in AD and compelling efficacy in a targeted VEOIBD case warrant continued investigation. The results from the ongoing Phase 2b AD trial are critical for defining the future trajectory of this anti-IL-18 therapy.

2. Introduction to GSK-1070806 (Aletekitug)

GSK-1070806 is an investigational therapeutic agent identified by its development code from GlaxoSmithKline (GSK).[1] The proposed International Nonproprietary Name (INN) for this compound is Aletekitug.[4] INNs are unique, globally recognized generic names assigned by the World Health Organization (WHO) to facilitate clear identification and communication regarding pharmaceutical substances.[26] The suffix "-tug" in Aletekitug specifically designates it as an unmodified immunoglobulin, according to WHO INN nomenclature for monoclonal antibodies.[28] The US Food and Drug Administration (FDA) also utilizes nonproprietary naming conventions, often incorporating a distinguishing suffix, to ensure pharmacovigilance.[31]

Aletekitug is classified as a humanized Immunoglobulin G1 (IgG1) kappa monoclonal antibody.[1] It is produced using Chinese Hamster Ovary (CHO) cells and has a predicted molecular weight of approximately 147.38 kDa to 150 kDa.[4] The specific target of Aletekitug is the pro-inflammatory cytokine Interleukin-18 (IL-18).[1] GSK is the originator and developer of this therapeutic candidate.[1] GSK is a global healthcare company involved in the research, development, manufacturing, and commercialization of pharmaceuticals and vaccines across various therapeutic areas, including immuno-inflammation, respiratory diseases, HIV, oncology, and others.[2]

Table 1: GSK-1070806 (Aletekitug) Profile Summary

Attribute	Details	References
Development Code	GSK-1070806	1
Proposed INN	Aletekitug	4
Developer	GlaxoSmithKline (GSK)	1
Class	Humanized IgG1 kappa monoclonal antibody	1
Target	Interleukin-18 (IL-18)	1
Mechanism of Action	IL-18 inhibitor; neutralizes mature IL-18	1
Key Active Indication(s)	Atopic Dermatitis	1
Highest Phase	Phase 2 (Atopic Dermatitis)	1

3. Mechanism of Action: Targeting Interleukin-18

Interleukin-18 (IL-18) is a cytokine belonging to the Interleukin-1 (IL-1) superfamily, known primarily for its pro-inflammatory activities.[6] It plays a significant role in modulating both innate and adaptive immune responses.[8] A key function of IL-18 is the induction of interferon-gamma (IFN-γ) production by various immune cells, including T cells and Natural Killer (NK) cells, thereby promoting Th1-type immune responses and contributing to immune cell activation.[9] IL-18 is typically released as a mature, active cytokine from damaged or stressed cells following the activation of intracellular inflammasome complexes.[5] Elevated levels or dysregulated activity of IL-18 have been implicated in the pathogenesis of a range of chronic inflammatory conditions, autoimmune diseases, and autoinflammatory disorders.[6] Its potential role has been investigated in conditions relevant to GSK-1070806 development, such as Atopic Dermatitis (where immune system overactivity drives inflammation) [1], Crohn's Disease (gut inflammation) [33], Type 2 Diabetes (chronic subclinical inflammation) [18], and acute kidney injury (AKI) leading to Delayed Graft Function (DGF) post-transplantation, where IL-18 serves as a biomarker.[5]

GSK-1070806 (Aletekitug) functions as a specific inhibitor of IL-18.[3] As a humanized IgG1 monoclonal antibody, it binds with high affinity (reported dissociation constant, Kd​, values of approximately 30.3 pM to 46.0 pM) to mature, soluble human IL-18.[5] This binding neutralizes the biological activity of IL-18, preventing it from interacting with its receptor and triggering downstream signaling pathways.[1] The primary intended therapeutic effect is the reduction of IL-18-mediated inflammation.[1] Pharmacodynamic studies have confirmed this mechanism; ex vivo whole blood assays demonstrated that GSK-1070806 administration leads to prolonged inhibition of IL-18-induced IFN-γ production.[6]

However, the clinical development program has revealed a disconnect between this established mechanism of action and clinical outcomes in certain indications. Trials investigating GSK-1070806 for DGF prevention [5] and T2DM management [18] were discontinued due to lack of efficacy.[3] This occurred despite pharmacokinetic and pharmacodynamic data confirming target engagement, evidenced by the detection of IL18-GSK1070806 complexes and increased total serum IL-18 levels (due to antibody binding prolonging IL-18's half-life).[5] The failure in these complex conditions suggests that simply neutralizing circulating or newly released IL-18 may not be sufficient to significantly alter the disease course. The underlying pathophysiology in DGF and T2DM involves multiple inflammatory pathways and cellular processes, and IL-18 may not be the sole or dominant driver, or its critical pathological effects might occur upstream of or independent from the IL-18/IFN-γ axis targeted by GSK-1070806. Furthermore, the timing and duration of intervention (e.g., a single dose prior to kidney reperfusion in the DGF study) might have been inadequate to counteract established or rapidly progressing pathology.[5]

4. Clinical Development Program Overview

The clinical development program for GSK-1070806 has explored its therapeutic potential across several indications. According to available data, the program has involved at least 8 clinical trials, encompassing completed, ongoing, and terminated studies.[11] Indications investigated include Atopic Dermatitis (AD), Crohn's Disease (CD), Delayed Graft Function (DGF) after renal transplantation, Type 2 Diabetes Mellitus (T2DM), Inflammatory Bowel Diseases (IBD) more broadly, and Behcet's Disease.[2]

The current active development focus is primarily on Atopic Dermatitis, where GSK-1070806 is in Phase 2 clinical trials.[1] Development for Crohn's Disease also reached Phase 2, although recent reports on its current status are conflicting.[3] Trials for DGF and T2DM were discontinued following Phase 2a studies that failed to demonstrate efficacy.[3] The status for IBD and Behcet's Disease is less clear, with some databases listing Phase 1 or 2 activity but potentially reflecting earlier stages or related indications like CD.[3]

Administration routes have varied depending on the trial and indication. Early studies and those in acute settings (like DGF) utilized intravenous (IV) infusion [5], while development for chronic conditions like AD has transitioned to subcutaneous (SC) injection, which is more suitable for long-term patient use.[1]

Table 2: Clinical Trial Overview for GSK-1070806 (Aletekitug)

Indication	Phase	Trial Identifier(s)	Status (as reported)	Key Objective(s)	Administration Route	References
Healthy Volunteers / Obesity	Phase 1	NCT01035645 / GSK Study ID 110040	Completed	Safety, tolerability, PK, PD (FTIH)	IV	6
Atopic Dermatitis (Moderate-to-Severe)	Phase 1b	NCT04975438	Completed	Safety, tolerability, PK, PD, clinical activity, PROs	IV	7
Atopic Dermatitis (Moderate-to-Severe)	Phase 2b	NCT05999799 / EU CT 2023-505414-15-00 / GSK ID 219538	Recruitment Complete (Apr 2025)	Efficacy (dose-finding), safety, PK, PD	SC	1
Atopic Dermatitis (Moderate-to-Severe)	Phase 2	NCT06447506 / GSK Study ID 220723 (LTE Study)	Recruiting (Jan 2025)	Long-term safety and efficacy	SC	1
Crohn's Disease (Moderate-to-Severe)	Phase 1b/2b	ISRCTN11093445 / EUCTR2018-002001-65-GB	Recruiting (reported 2018)	Safety, tolerability, clinical activity, PK, PD	IV	33
Crohn's Disease	Phase 2	11	Status Unclear/Conflicting	Efficacy, safety	IV/SC?	3
Delayed Graft Function (Renal Transplant)	Phase 2a	NCT02723786	Terminated	Evaluate effect on DGF occurrence, safety, PK, PD	IV	3
Type 2 Diabetes Mellitus (Obese)	Phase 2a	NCT01648153 / GSK Study ID 116378	Completed	Efficacy (glucose control), safety, tolerability, PK, PD	IV	3
Inflammatory Bowel Diseases	Phase 1	3	No recent reports	Safety, tolerability	IV?	3
Behcet's Disease	Phase 2	7	No recent reports	Efficacy, safety	IV/SC?	7

Note: Status information reflects the latest available data in the provided sources and may be subject to change. Conflicting reports exist for Crohn's Disease status.

5. Clinical Evidence in Atopic Dermatitis (AD)

The rationale for investigating GSK-1070806 in Atopic Dermatitis (AD) stems from the understanding that IL-18 contributes to the overactive immune response and cutaneous inflammation characteristic of this chronic skin condition.[1] By neutralizing IL-18, GSK-1070806 aims to reduce this inflammation and alleviate AD symptoms like redness, itch, and skin lesions.[1]

• Phase 1b Study (NCT04975438) This initial study in patients was a multicenter, randomized, double-blind, parallel-group, placebo-controlled trial designed to evaluate a single intravenous (IV) infusion of GSK-1070806.14 It enrolled 34 adults (≥18 years) with a confirmed AD diagnosis for at least 6 months and moderate-to-severe disease, defined by an Eczema Area and Severity Index (EASI) score ≥16 and an Investigator's Global Assessment (IGA) score ≥3.14 Participants received either GSK1070806 at 2 mg/kg (n=23) or placebo (n=11) via a one-hour IV infusion.14 The study's objectives were to assess the safety, tolerability, pharmacokinetics (PK), pharmacodynamics (PD), and preliminary clinical activity of GSK1070806, including its impact on patient-reported outcomes (PROs).14 The results indicated significant clinical improvements with GSK1070806 compared to placebo after 12 weeks.[14] Key PROs were assessed using validated instruments: Peak Pruritis Numerical Rating Scale (PP-NRS) for itch severity, Dermatology Life Quality Index (DLQI) for quality of life impact, Patient-Reported Outcomes Measurement Information System Sleep Disturbance Short Form 8b (PROMIS-SD 8b), Brief Fatigue Inventory Item 3 (BFI-Item 3), and Functional Assessment of Chronic Illness Therapy-Fatigue (FACIT-F).[14] Assessments were performed at baseline and followed over 24 weeks, with PP-NRS and BFI-Item 3 collected daily, and others weekly or biweekly.[14] At Week 12, analysis using a Bayesian repeated measures model showed substantial improvements in the GSK1070806 group versus placebo.[14] The posterior median difference in change from baseline (CFB) for PP-NRS was -4.6 (95% credible interval [CrI]: -5.5, -3.7) for GSK1070806, compared to -0.5 (95% CrI: -1.7, 0.7) for placebo. For DLQI, the CFB was -6.1 (95% CrI: -8.8, -3.4) for GSK1070806 versus -0.01 (95% CrI: -4.3, 4.1) for placebo.[14] These results signify clinically meaningful reductions in itch and improvements in quality of life for patients receiving the active drug. Additionally, observed mean scores for PROMIS-SD 8b, BFI-Item 3, and FACIT-F indicated improvements in sleep disturbance and fatigue among patients treated with GSK1070806 compared to placebo, although specific numerical results and statistical analyses for these secondary PROs were not detailed in the available abstract.[14] The study concluded that GSK1070806 provided positive benefits across multiple clinical and patient-reported outcome domains in moderate-to-severe AD.[14] The consistent positive findings across various relevant endpoints in this Phase 1b study provided a strong foundation for advancing GSK-1070806 into larger, dose-ranging Phase 2b trials. Achieving significant improvements in core AD symptoms like itch (PP-NRS) and overall impact on life (DLQI), alongside positive signals in sleep and fatigue, suggests a potentially broad therapeutic effect relevant to patient needs.
• Phase 2b Dose-Finding Study (NCT05999799 / EU CT 2023-505414-15-00) Following the promising Phase 1b results, GSK initiated a Phase 2b study (GSK Study ID: 219538).16 This is a randomized, double-blind, parallel-group, placebo-controlled dose-finding trial designed to evaluate the efficacy, safety, PK, and PD of GSK1070806 administered via subcutaneous (SC) injection in adult participants with moderate-to-severe AD.13 The study includes four different dose arms of GSK1070806 compared against a placebo arm.16 A total of 163 participants were enrolled across multiple countries, including Germany, Bulgaria, Spain, Czech Republic, Italy, France, Poland, and others.3 As of April 2025, recruitment for this study was reported as complete.16 The primary purpose is treatment evaluation, focusing on identifying an optimal dose regimen.[13] Key efficacy endpoints include the Percent Change from Baseline (PCFB) in EASI score at various time points, with Week 16 being a primary timepoint.[13] The trial commenced in Q4 2023, and initial data readouts are anticipated in 2025.[13] The shift from IV administration in Phase 1b to SC administration in Phase 2b represents a critical step in the development pathway. For a chronic condition like AD requiring long-term treatment, SC injection offers significantly greater patient convenience and facilitates potential self-administration compared to IV infusions, making it the preferred route for eventual commercialization. This transition is standard practice for developing monoclonal antibodies for chronic dermatological or immunological diseases.
• Phase 2 Long-Term Extension (LTE) Study (AtDvance - NCT06447506) To assess the durability of effect and long-term safety profile, an open-label, long-term extension (LTE) study (GSK Study ID: 220723), named AtDvance, was initiated.1 This non-randomized, parallel assignment study aims to enroll approximately 159 participants with moderate-to-severe AD who have successfully completed the parent Phase 2b study (NCT05999799).15 Participants will continue to receive GSK1070806 via SC injection, although the masking 15 requires confirmation.15 The primary purpose is to evaluate long-term safety, assessed through the incidence of adverse events (AEs), serious adverse events (SAEs), AEs of special interest (AESIs), and discontinuations due to AEs, monitored for up to 280 weeks (End of Study, EoS).[15] Secondary objectives focus on long-term efficacy, including the proportion of participants achieving EASI ≥75% reduction (EASI-75), IGA score of 0 (clear) or 1 (almost clear), and ≥4-point improvement in PP-NRS, as well as maintained responses for these endpoints, assessed at multiple time points up to Week 280.[15] The study began in June 2024 and is projected to conclude in November 2029.[15] As of January 2025, the LTE study was actively recruiting participants in various locations across the US, Canada, Argentina, and potentially other regions involved in the parent study.[1] Evaluating long-term outcomes is essential for therapies intended for chronic diseases like AD, providing crucial data on sustained efficacy and any potential cumulative or late-onset safety issues.

Table 3: Key Efficacy Outcomes in Atopic Dermatitis Studies (GSK-1070806 vs Placebo)

Trial ID	Phase	Endpoint	Timepoint	GSK-1070806 Result (CFB / Response)	Placebo Result (CFB / Response)	Notes	References
NCT04975438	1b	PP-NRS CFB (Posterior Median)	Week 12	-4.6 (95% CrI: -5.5, -3.7)	-0.5 (95% CrI: -1.7, 0.7)	Significant improvement vs placebo	14
NCT04975438	1b	DLQI CFB (Posterior Median)	Week 12	-6.1 (95% CrI: -8.8, -3.4)	-0.01 (95% CrI: -4.3, 4.1)	Significant improvement vs placebo	14
NCT04975438	1b	PROMIS-SD 8b, BFI-Item 3, FACIT-F CFB	Week 12+	Observed mean improvements vs placebo	Observed mean improvements vs placebo	Specific means/statistical significance not reported in source	14
NCT05999799	2b	PCFB EASI Score	Week 16	Results Pending (Anticipated 2025)	Results Pending (Anticipated 2025)	Primary endpoint for dose-finding	13
NCT06447506	2 LTE	EASI-75 Response Rate	Week 16+	Results Pending	N/A (Open-label extension)	Secondary endpoint	15
NCT06447506	2 LTE	IGA 0/1 Response Rate	Week 16+	Results Pending	N/A (Open-label extension)	Secondary endpoint	15
NCT06447506	2 LTE	PP-NRS ≥4-point Improvement Rate	Week 16+	Results Pending	N/A (Open-label extension)	Secondary endpoint	15

CFB = Change From Baseline; CrI = Credible Interval; DLQI = Dermatology Life Quality Index; EASI = Eczema Area and Severity Index; FACIT-F = Functional Assessment of Chronic Illness Therapy-Fatigue; IGA = Investigator's Global Assessment; LTE = Long-Term Extension; PCFB = Percent Change From Baseline; PP-NRS = Peak Pruritis Numerical Rating Scale; PROMIS-SD = Patient-Reported Outcomes Measurement Information System Sleep Disturbance.

6. Clinical Evidence in Crohn's Disease (CD)

Crohn's Disease (CD) is a chronic inflammatory bowel disease characterized by inflammation of the gastrointestinal tract.[33] IL-18 is considered a key cytokine involved in this gut inflammation, providing a rationale for investigating IL-18 inhibition as a therapeutic strategy.[33] There remains an unmet medical need for effective treatments, particularly for patients with moderate-to-severe CD.[33]

• Phase 1b/2b Study (ISRCTN11093445 / EUCTR2018-002001-65-GB) A clinical trial investigating GSK1070806 in CD was initiated, identified as ISRCTN11093445 and EUCTR2018-002001-65-GB.33 This study was designed as a Phase 1b/2b, randomized, double-blind, placebo-controlled trial.33 It aimed to enroll approximately 30 patients aged 16 years or older with active, moderate-to-severe CD, defined by a Crohn's Disease Activity Index (CDAI) score between 220-450 and endoscopic evidence of active disease (Simple Endoscopic Score for Crohn's Disease ≥6, or ≥4 for isolated ileal disease) confirmed at baseline.33 Eligible participants were required to have had a CD diagnosis for at least 3 months prior to screening.33 Patients were permitted to continue stable doses of certain protocol-defined maintenance medications for CD.33 Key exclusion criteria included significant liver function abnormalities (AST/ALT >2x ULN, alkaline phosphatase/bilirubin >1.5x ULN) and requirements related to contraception for participants of childbearing potential.33 The study protocol involved administering a single intravenous (IV) infusion of either GSK1070806 or placebo on Day 1.[33] The primary objective was to assess the safety and tolerability of this single IV dose.[33] Secondary objectives likely included evaluation of clinical activity, pharmacokinetics, and pharmacodynamics.[33] The trial was sponsored by the University of Birmingham and GSK, with University Hospital Birmingham also involved.[38] Recruitment was reported as active in the United Kingdom as of late 2018.[38] However, the current status of development for GSK-1070806 in Crohn's Disease is unclear due to conflicting information in the available sources. While the initiation of the Phase 1b/2b trial is documented [33], and some sources refer to a "leading Phase II program" in CD [11], another source with a more recent timestamp (December 2024) indicates "No development reported" for Crohn's disease.[3] This discrepancy could imply that the program was paused, deprioritized, or terminated after the initial Phase 1b/2b study, or that reporting timelines differ between sources. Without definitive results or updated status reports from the Phase 1b/2b trial or subsequent Phase 2 activities, the viability of GSK-1070806 in Crohn's Disease remains uncertain. Further clarification from the developer or updated trial registries is needed to resolve this ambiguity.

7. Investigations in Discontinued Indications

GSK-1070806 was evaluated in Phase 2a trials for two other indications, Delayed Graft Function (DGF) and Type 2 Diabetes Mellitus (T2DM), but development in these areas was subsequently discontinued due to lack of efficacy.[3]

• Delayed Graft Function (DGF) in Renal Transplant (NCT02723786) DGF is a manifestation of acute kidney injury (AKI) occurring after kidney transplantation, particularly common following donation after circulatory death (DCD). It is associated with poor long-term graft outcomes, and effective preventative treatments are limited.17 IL-18 is recognized as a biomarker of AKI, released from damaged renal cells, and contributes to inflammation and immune activation.17 The rationale for trial NCT02723786 was to test whether neutralizing IL-18 with GSK1070806 immediately prior to graft reperfusion could prevent DGF.5 The study was designed as a Phase 2a, multicenter, single-arm pilot trial employing a Bayesian sequential design to enable efficacy assessment with a small sample size.[5] It enrolled seven adult, dialysis-dependent recipients of a first or second single DCD kidney transplant across the UK and Spain.[5] Participants received a single 3 mg/kg IV dose of GSK1070806 administered just before kidney allograft reperfusion.[5] The dose was selected based on extensive physiologically based pharmacokinetic (PBPK) modeling, which predicted rapid and high (>90%) IL-18 target engagement in both plasma and the kidney interstitium.[5] The primary endpoint was the frequency of DGF, defined as the requirement for dialysis (excluding for hyperkalemia within 24 hours) within the first 7 days post-transplantation.[5] The trial was terminated early due to futility. The primary endpoint analysis revealed that DGF occurred in 4 out of 7 enrolled patients (57%), a rate numerically higher than the background standard-of-care DGF rate of 50% used in the Bayesian design.[5] Furthermore, two additional patients, while not meeting the strict DGF definition, exhibited poor graft function. Only one of the seven patients avoided dialysis and had a serum creatinine level <400 μmol/L within the first four days post-transplant.[5] Safety assessment in this acutely ill population revealed 17 SAEs among 6 patients, with two SAEs (pneumonia and respiratory arrest in a single patient) considered potentially related to GSK1070806 treatment; all SAEs resolved.[5] Pharmacodynamic assessments confirmed target engagement: IL18-GSK1070806 complex was detected, total serum IL-18 levels increased (due to prolonged half-life from antibody binding), and serum IL-18 binding protein (IL18-BP) levels decreased.[5] However, levels of downstream IFN-γ-induced chemokines, IP-10 and MIG, generally declined or remained unchanged post-treatment, suggesting limited impact on this specific inflammatory pathway in the context of DGF.[5] Based on these findings, the study concluded it was unlikely that GSK1070806 at the tested dose and timing would be efficacious in preventing DGF in the DCD transplant population.[5] The clear demonstration of target engagement coupled with the failure to improve clinical outcomes strongly suggests that IL-18 neutralization, at least via this specific intervention strategy (single pre-reperfusion dose), is insufficient to overcome the complex multifactorial pathophysiology driving DGF. Development for this indication was subsequently discontinued.[3]
• Type 2 Diabetes Mellitus (T2DM) (NCT01648153) Evidence linking chronic subclinical inflammation to the pathogenesis of T2DM and its associated micro- and macrovascular complications provided the rationale for investigating IL-18 inhibition in this disease.18 Circulating IL-18 levels have been associated with obesity and T2DM comorbidities.20 Trial NCT01648153 aimed to assess the preliminary efficacy and safety of GSK1070806 in improving glycemic control in patients with T2DM.18 This was a Phase 2a, multicenter, randomized, single-blind (sponsor-unblinded), placebo-controlled, parallel-group study conducted in obese patients (aged 18-70 years) with T2DM inadequately controlled on metformin monotherapy.[18] Thirty-seven patients were randomized to receive two IV doses (on Day 1 and Day 29) of either placebo (n=12), GSK1070806 0.25 mg/kg (n=13), or GSK1070806 5 mg/kg (n=12).[18] The primary endpoints were the change from baseline in fasting plasma glucose (FPG) and the weighted mean glucose area under the curve from 0-4 hours (AUC[0-4h]) following a mixed meal tolerance test (MMT), assessed on Days 29, 57, and 85.[18] The study failed to meet its primary endpoints. There were no statistically significant effects of either GSK1070806 dose on FPG levels or weighted mean glucose AUC(0-4h) post-MMT compared with placebo at any assessment time point.[6] While individual patient glucose values fluctuated, no consistent trends favoring the active treatment groups were observed.[32] Analysis of HbA1c showed some reduction from baseline up to Day 85 in the 5 mg/kg group compared to placebo, but the data were highly variable.[32] No notable differences were found in derived measures of insulin sensitivity (HOMA-%S) or beta-cell function (HOMA-%B), nor in body mass index or waist circumference.[32] GSK1070806 was reported to be well tolerated in this patient population.[6] The study concluded that inhibition of IL-18 with GSK1070806 did not lead to improvements in glucose control in obese patients with T2DM, although the authors noted that smaller, potentially clinically meaningful effects could not be entirely excluded due to study limitations.[6] Consequently, development for T2DM was discontinued.[3]

The failure of GSK-1070806 in both DGF and T2DM underscores the significant challenge in selecting appropriate indications for targeted cytokine therapies. While IL-18 is implicated in numerous inflammatory processes, its role may not be sufficiently central or dominant in all conditions to make its inhibition clinically impactful. These results suggest that future success for anti-IL-18 therapies like GSK-1070806 might depend more heavily on identifying diseases where IL-18 plays a demonstrably critical role in pathophysiology, potentially guided by strong biological rationale or patient stratification using biomarkers.

8. Pharmacokinetics (PK) and Pharmacodynamics (PD) Profile

The pharmacokinetic (PK) and pharmacodynamic (PD) properties of GSK-1070806 have been characterized in several clinical studies involving healthy volunteers and patient populations.

• Pharmacokinetics (PK) The first-time-in-human (FTIH) study (NCT01035645) evaluated single IV doses ranging from 0.008 mg/kg to 10 mg/kg in healthy subjects and obese subjects.6 The plasma PK profiles were found to be comparable between healthy and obese individuals.6 Analysis of dose proportionality for key PK parameters, area under the concentration-time curve extrapolated to infinity (AUC∞​) and maximum observed concentration (Cmax​), showed no major deviations, although a trend towards a dose-dependent increase in terminal half-life (t1/2​) was observed.6 This behavior is typical for monoclonal antibodies where target-mediated drug disposition can influence clearance at lower doses. In the Phase 2a DGF study (NCT02723786), a single 3 mg/kg IV dose resulted in a mean Cmax​ of 53.14 μg/mL and a mean serum t1/2​ of 37.96 days.[5] This long half-life is consistent with that expected for an IgG1 monoclonal antibody. The Phase 2a T2DM study (NCT01648153) assessed PK parameters (Cmax​, Tmax​, t1/2​) following two IV doses (0.25 or 5 mg/kg), although specific values were not detailed in the provided sources.[34] PK was also assessed in the Phase 1b AD study (NCT04975438), but results were not reported in the available abstract.[14]
• Pharmacodynamics (PD) Evidence of target engagement has been consistently observed across studies. A hallmark PD effect following GSK1070806 administration is a rapid and sustained increase in total serum IL-18 levels, accompanied by the detection of IL18-GSK1070806 complexes in serum.5 This phenomenon is attributed to the antibody binding to IL-18, thereby prolonging its circulatory half-life.5 Consequently, levels of free, unbound IL-18 were generally found to be below the limit of quantification after treatment.5 Target engagement was formally assessed using assays specifically detecting drug-bound IL-18.9 Additionally, in the DGF study, serum levels of the natural IL-18 inhibitor, IL-18 binding protein (IL18-BP), were reduced by up to two-fold following GSK1070806 treatment.5 Regarding downstream biological effects, ex vivo whole blood assays performed in the FTIH study demonstrated prolonged pharmacological activity, specifically the inhibition of IL-18-induced IFN-γ production.[6] This confirms the drug's ability to block the key intended biological pathway. However, in vivo assessment of downstream markers in the DGF study showed that serum levels of IFN-γ itself were generally low, and levels of IFN-γ-induced chemokines (IP-10 and MIG) mostly declined or remained unchanged in most patients, suggesting limited impact on this axis in the clinical setting of DGF.[5] The T2DM study included assessment of changes in other inflammatory markers (IL-6, IP-10, MMP-9, ICAM-1, PAI-1) as secondary PD endpoints, but results were not detailed.[34] The observed PK/PD profile, characterized by a long pharmacokinetic half-life typical of monoclonal antibodies and sustained pharmacodynamic evidence of target engagement (IL-18 binding) and biological activity (inhibition of IFN-γ induction ex vivo), supports the feasibility of less frequent dosing regimens. This relationship likely underpins the exploration of dosing schedules such as every two weeks or potentially longer intervals in the ongoing Phase 2 trials for the chronic indication of Atopic Dermatitis, facilitating practical subcutaneous administration.[15]

9. Safety and Tolerability Assessment

The safety and tolerability profile of GSK-1070806 has been evaluated across multiple clinical trials in diverse populations.

Overall, GSK-1070806 was generally reported as well tolerated in studies involving healthy volunteers, obese subjects, patients with T2DM, and patients with Atopic Dermatitis.[6] In the FTIH study (NCT01035645), the most frequently reported adverse events (AEs) were nasopharyngitis and headache.[6] These occurred with similar frequency in both the placebo and active drug groups, and most AEs were considered mild to moderate in severity and unrelated to the dose level administered.[6]

However, the safety profile observed in the Phase 2a DGF trial (NCT02723786), which enrolled a small cohort of critically ill patients undergoing DCD kidney transplantation, presented more concerns.[5] In this study, 6 out of 7 participants experienced a total of 17 serious adverse events (SAEs). Two SAEs occurring in one patient—pneumonia and respiratory arrest—were considered by the investigators to be possibly related to the study treatment.[5] All SAEs were eventually resolved, and no fatal SAEs were reported during the study.[5] This finding highlights that the safety profile can be significantly influenced by the underlying health status of the patient population and the clinical context (e.g., major surgery, concomitant immunosuppression). While the drug appeared well-tolerated in relatively healthier populations, its use in acutely ill, high-risk patients warrants caution and careful monitoring.

Regarding immunogenicity, the incidence was reported as low in the FTIH study.[6] No allergic reactions or delayed-type hypersensitivity reactions related to GSK1070806 infusion were reported in that study.[6] General potential safety considerations mentioned for monoclonal antibodies like GSK1070806 include the risk of allergic reactions and potentially an increased risk of infections due to immune modulation.[1] Reflecting these concerns, clinical trial protocols typically incorporate stringent exclusion criteria, often prohibiting enrollment of individuals with a history of malignancy, significant organ dysfunction, active or chronic/recurrent infections (including tuberculosis, serious bacterial infections, or opportunistic infections), or recent use of other potent immunosuppressants or anti-inflammatory biologics.[15] Due to unknown risks to a developing fetus, participation is contraindicated during pregnancy, and strict contraception measures are required for participants of childbearing potential.[15]

Table 4: Summary of Safety Findings Across Key GSK-1070806 Trials

Trial ID / Indication	Phase	Population	Key Safety Findings	References
NCT01035645 / Healthy & Obese	Phase 1	Healthy & Obese Males	Generally well tolerated. Common AEs: nasopharyngitis, headache (similar to placebo), mostly mild/moderate, dose-unrelated. No allergic/hypersensitivity reactions. Low immunogenicity.	6
NCT04975438 / Atopic Dermatitis	Phase 1b	Adults with Moderate-to-Severe AD	Generally well tolerated (implied by focus on positive efficacy/PRO results). Specific AE details not provided in source abstract.	14
NCT02723786 / DGF (Renal Transplant)	Phase 2a	Adult DCD Kidney Transplant Recipients	High rate of SAEs (17 in 6/7 pts). 2 SAEs (pneumonia, respiratory arrest in 1 pt) considered treatment-related. All SAEs resolved, no fatalities.	5
NCT01648153 / Type 2 Diabetes Mellitus	Phase 2a	Obese Adults with T2DM on Metformin	Well tolerated. Specific AE details not provided, but conclusion emphasizes tolerability alongside lack of efficacy.	6
NCT06447506 / Atopic Dermatitis (LTE)	Phase 2	Adults with Moderate-to-Severe AD (rollover)	Ongoing. Primary outcomes include incidence of AEs, SAEs, AESIs, and discontinuations due to AEs over long-term (up to 280 weeks).	15

AD = Atopic Dermatitis; AE = Adverse Event; AESI = Adverse Event of Special Interest; DCD = Donation after Circulatory Death; DGF = Delayed Graft Function; FTIH = First-Time-In-Human; LTE = Long-Term Extension; SAE = Serious Adverse Event; T2DM = Type 2 Diabetes Mellitus.

10. Compassionate Use in Very Early-Onset Inflammatory Bowel Disease (VEOIBD)

A compelling case study provides significant evidence for the potential efficacy of GSK-1070806 in a specific, rare disease context driven by IL-18 dysregulation.[21] The study detailed the treatment of a four-year-old girl suffering from Very Early-Onset Inflammatory Bowel Disease (VEOIBD) since the age of six weeks.[21] Her disease was exceptionally severe and recalcitrant, characterized by recurrent fevers, skin rash, extensive oral and perianal ulceration, and severe ulceration throughout her upper and lower gastrointestinal tract, necessitating total parenteral nutrition (TPN).[21] She had failed to achieve sustained remission despite treatment with high-dose corticosteroids and sequential trials of various immunosuppressants and biologics (including cyclosporine, sirolimus, colchicine, etanercept, infliximab, and anakinra).[21] Even a hematopoietic stem cell transplant (HSCT) at 20 months old provided only temporary remission, with relapse occurring six months post-transplant alongside declining donor chimerism.[21]

Upon relapse, detailed cytokine profiling revealed markedly elevated serum concentrations of total IL-18 compared to both healthy controls and age-matched children with sepsis-associated fevers.[21] Crucially, other pro-inflammatory cytokines typically elevated during sepsis (like TNF-α and IL-6) were not significantly raised in the patient, pointing towards a specific dysregulation of the IL-18 pathway, termed an "IL-18opathy," as the likely driver of her VEOIBD.[21]

Given the failure of all conventional therapies and the strong evidence implicating IL-18, compassionate use of GSK1070806 was initiated.[21] Treatment commenced with 0.25 mg/kg IV every two weeks, incrementally increasing to a dose of 5 mg/kg every two weeks over several months.[21] The response to treatment was remarkable and sustained over the 18-month observation period reported.[21] Clinical improvements included the resolution of fevers and gastrointestinal symptoms, significant decreases in inflammatory markers (C-reactive protein and fecal calprotectin), and restoration of the ability to tolerate a normal oral diet, allowing discontinuation of TPN and eventual hospital discharge.[21] Endoscopic biopsies confirmed histological improvement, with restoration of normal esophageal and colonic mucosa.[21] Pharmacodynamically, total serum IL-18 levels became undetectable at the 5 mg/kg dose.[21] Importantly, the treatment was well-tolerated with no drug-related adverse effects observed during this period.[21]

The authors concluded that VEOIBD can be associated with an underlying IL-18opathy and demonstrated that such cases can respond effectively to targeted anti-IL-18 antibody therapy.[21] This case provides strong proof-of-concept for the efficacy of GSK-1070806 when IL-18 is clearly identified as the primary pathological driver. The stark contrast between this success and the failures in the broader DGF and T2DM populations strongly suggests that a biomarker-driven approach may be key to unlocking the therapeutic potential of GSK-1070806. Identifying patients whose disease is fundamentally mediated by IL-18, perhaps through measuring IL-18 levels or identifying specific genetic markers associated with IL-18opathies, could define a niche indication or allow for patient stratification within broader disease areas like AD or IBD. This case highlights the potential value of precision medicine strategies in guiding the development of targeted cytokine inhibitors.

11. Concluding Remarks and Future Directions

GSK-1070806 (Aletekitug) is a humanized anti-IL-18 monoclonal antibody that has demonstrated clear target engagement and downstream biological effects (inhibition of IFN-γ induction ex vivo) in clinical studies.[5] However, its clinical development journey has been marked by variable success across different indications.

Currently, the primary focus of development is Atopic Dermatitis, where GSK-1070806 is advancing through Phase 2 trials.[1] Promising results from a Phase 1b study showed significant improvements in both clinical signs and patient-reported outcomes (itch, quality of life, sleep, fatigue) compared to placebo.[14] The ongoing Phase 2b dose-finding study (NCT05999799), utilizing subcutaneous administration, and its long-term extension (NCT06447506) are crucial for confirming these initial signals, establishing an optimal dose, and assessing long-term safety and efficacy.[13] Development in Crohn's Disease reached Phase 2, but conflicting reports make its current status uncertain.[3]

Significant challenges were encountered in earlier programs. Phase 2a trials in Delayed Graft Function prevention (NCT02723786) and Type 2 Diabetes Mellitus (NCT01648153) were discontinued due to lack of efficacy, despite evidence of target engagement.[3] These setbacks underscore the difficulty in translating IL-18 inhibition into broad clinical benefit and highlight the critical importance of appropriate indication selection and potentially patient stratification.

In stark contrast, the remarkable success of GSK-1070806 in inducing sustained remission in a compassionate use case of severe, refractory VEOIBD driven by a confirmed IL-18opathy provides compelling proof-of-concept for its efficacy in a precisely defined, biomarker-selected population.[21] This suggests a potential path forward focusing on rare diseases mediated by IL-18 or employing biomarker strategies (e.g., baseline IL-18 levels) to identify responders within broader indications.

The future of GSK-1070806 hinges significantly on the outcomes of the ongoing Phase 2b trial in Atopic Dermatitis, with data anticipated in 2025.[13] Positive results would validate the potential in this indication and likely lead to Phase 3 investigation. Negative or marginal results would necessitate a re-evaluation of the program's direction, potentially shifting focus towards biomarker-defined populations or niche indications informed by the VEOIBD experience. Financial projections, such as an estimated $19 million annual revenue by 2040 in the US, are highly dependent on successful clinical development, regulatory approval, and market adoption, and carry significant risk as reflected in risk-adjusted Net Present Value (rNPV) models.[11]

Close monitoring of data releases from the Phase 2b AD trial (NCT05999799) and clarification regarding the status of the Crohn's Disease program are warranted to fully assess the future prospects of Aletekitug.

Works cited

1. Humanised Igg1 Kappa Monoclonal Antibody Against Interleukin 18 – Application in Therapy and Current Clinical Research, accessed May 2, 2025, https://clinicaltrials.eu/inn/humanised-igg1-kappa-monoclonal-antibody-against-interleukin-18/
2. GSK-1070806 by GSK for Atopic Dermatitis (Atopic Eczema): Likelihood of Approval, accessed May 2, 2025, https://www.pharmaceutical-technology.com/data-insights/gsk-1070806-gsk-atopic-dermatitis-atopic-eczema-likelihood-of-approval/
3. GSK 1070806 - AdisInsight - Springer, accessed May 2, 2025, https://adisinsight.springer.com/drugs/800031499
4. GSK-1070806 (Aletekitug) | IL-18 Antibody - MedchemExpress.com, accessed May 2, 2025, https://www.medchemexpress.com/gsk-1070806.html?locale=ko-KR
5. A pilot study evaluating GSK1070806 inhibition of interleukin-18 in ..., accessed May 2, 2025, https://pmc.ncbi.nlm.nih.gov/articles/PMC7939287/
6. Aletekitug - Drug Targets, Indications, Patents - Synapse, accessed May 2, 2025, https://synapse.patsnap.com/drug/72502164999248b7b3cf0498fe6bea71
7. Compound: GSK-1070806 (CHEMBL2109606) - ChEMBL - EMBL-EBI, accessed May 2, 2025, https://www.ebi.ac.uk/chembl/explore/compound/CHEMBL2109606
8. Cytokines of the IL-1 family: recognized targets in chronic inflammation underrated in organ transplantations - PubMed, accessed May 2, 2025, https://pubmed.ncbi.nlm.nih.gov/28798075/
9. Safety, tolerability, pharmacokinetics, and pharmacodynamics of single-dose anti-interleukin-18 mAb GSK1070806 in healthy and obese subjects | Request PDF - ResearchGate, accessed May 2, 2025, https://www.researchgate.net/publication/264628850_Safety_tolerability_pharmacokinetics_and_pharmacodynamics_of_single-dose_anti-interleukin-18_mAb_GSK1070806_in_healthy_and_obese_subjects
10. Safety, tolerability, pharmacokinetics, and pharmacodynamics of single-dose antiinterleukin- 18 mAb GSK1070806 in healthy and obese subjects - PubMed, accessed May 2, 2025, https://pubmed.ncbi.nlm.nih.gov/25109413/
11. Risk Adjusted Net Present Value: What is the current valuation of GSK's GSK-1070806, accessed May 2, 2025, https://www.pharmaceutical-technology.com/data-insights/gsk-1070806-gsk-net-present-value/
12. Pipeline | GSK, accessed May 2, 2025, https://www.gsk.com/en-gb/innovation/pipeline/
13. Pipeline assets and clinical trials appendix - Q1 2024 - GSK, accessed May 2, 2025, https://www.gsk.com/media/11102/q1-2024-pipeline-assets-and-clinical-trials-report.pdf
14. 678 - Patient-reported outcomes for GSK1070806, an anti-IL-18 ..., accessed May 2, 2025, https://academic.oup.com/bjd/article/191/Supplement_2/ljae266.052/7728590
15. Long-Term Study (AtDvance) to Evaluate GSK1070806 in Atopic Dermatitis., accessed May 2, 2025, https://www.gsk-studyregister.com/en/trial-details/?id=220723
16. A Dose Finding Study to Investigate the Safety and Effectiveness of GSK1070806 in Adult Participants with Moderate to Severe Atopic Dermatitis, accessed May 2, 2025, https://www.gsk-studyregister.com/en/trial-details/?id=219538
17. A pilot study evaluating GSK1070806 inhibition of interleukin-18 in renal transplant delayed graft function - PubMed, accessed May 2, 2025, https://pubmed.ncbi.nlm.nih.gov/33684160/
18. A Study to Investigate the Efficacy and Safety of an Anti-Interleukin-18 Monoclonal Antibody in the Treatment of Type 2 Diabetes Mellitus | PLOS One, accessed May 2, 2025, https://journals.plos.org/plosone/article?id=10.1371/journal.pone.0150018
19. (PDF) A pilot study evaluating GSK1070806 inhibition of interleukin-18 in renal transplant delayed graft function - ResearchGate, accessed May 2, 2025, https://www.researchgate.net/publication/349910039_A_pilot_study_evaluating_GSK1070806_inhibition_of_interleukin-18_in_renal_transplant_delayed_graft_function
20. A Study to Investigate the Efficacy and Safety of an Anti-Interleukin-18 Monoclonal Antibody in the Treatment of Type 2 Diabetes Mellitus - PubMed, accessed May 2, 2025, https://pubmed.ncbi.nlm.nih.gov/26930607/
21. Very Early-Onset IBD-Associated IL-18opathy Treated with an Anti ..., accessed May 2, 2025, https://pmc.ncbi.nlm.nih.gov/articles/PMC11508724/
22. Very Early-Onset IBD-Associated IL-18opathy Treated with an Anti-IL-18 Antibody - MDPI, accessed May 2, 2025, https://www.mdpi.com/2077-0383/13/20/6058
23. Anti-IL-18 Interleukins antibody | Read Reviews & Product Use Citations - Selleck Chemicals, accessed May 2, 2025, https://www.selleckchem.com/products/anti-il-18.html
24. ALETEKITUG - GSRS, accessed May 2, 2025, https://gsrs.ncats.nih.gov/ginas/app/beta/substances/YJ4XZ74SWG
25. GSK 1070806|CAS - DC Chemicals, accessed May 2, 2025, https://www.dcchemicals.com/product_show-gsk-1070806.html
26. International nonproprietary name - Wikipedia, accessed May 2, 2025, https://en.wikipedia.org/wiki/International_nonproprietary_name
27. International non-proprietary name | European Medicines Agency (EMA), accessed May 2, 2025, https://www.ema.europa.eu/en/glossary-terms/international-non-proprietary-name
28. International Nonproprietary Names Programme and Classification of Medical Products - World Health Organization (WHO), accessed May 2, 2025, https://www.who.int/teams/health-product-and-policy-standards/inn
29. Trademarks INN (International Non-proprietary Names) Search - SSRANA, accessed May 2, 2025, https://ssrana.in/ip-laws/trademarks-in-india/trademarks-inn-search/
30. International Nonproprietary Names for Pharmaceutical Substances (INN) - World Health Organization (WHO), accessed May 2, 2025, https://cdn.who.int/media/docs/default-source/international-nonproprietary-names-(inn)/pl131.pdf?sfvrsn=ba04dc1b_5&download=true
31. Nonproprietary Naming of Biological Products Guidance for Industry | FDA, accessed May 2, 2025, https://www.fda.gov/files/drugs/published/Nonproprietary-Naming-of-Biological-Products-Guidance-for-Industry.pdf
32. A Study to Investigate the Efficacy and Safety of an Anti-Interleukin-18 Monoclonal Antibody in the Treatment of Type 2 Diabetes Mellitus, accessed May 2, 2025, https://pmc.ncbi.nlm.nih.gov/articles/PMC4773233/
33. ISRCTN11093445: A clinical trial of antibody ... - ISRCTN, accessed May 2, 2025, https://www.isrctn.com/ISRCTN11093445
34. Investigate the Efficacy and Safety of GSK1070806 in Obese Subjects with T2DM, accessed May 2, 2025, https://www.gsk-studyregister.com/en/trial-details/?id=116378
35. GSK-A18110040 - Clinical Study Data Request, accessed May 2, 2025, https://clinicalstudydatarequest.com/Posting.aspx?ID=3543
36. First Time in Human Study of Intravenous Interleukin-18 Antibody, accessed May 2, 2025, https://www.gsk-studyregister.com/en/trial-details/?id=110040
37. Study on the Effects of GSK1070806 Injection in Adults with Moderate to Severe Atopic Dermatitis - Clinical trials, accessed May 2, 2025, https://clinicaltrials.eu/trial/study-on-the-effects-of-gsk1070806-injection-in-adults-with-moderate-to-severe-atopic-dermatitis/
38. Database of Drug Development for Rare Diseases - DDrare, accessed May 2, 2025, https://ddrare.nibn.go.jp/ddrare_Mar2022/ddrare_Mar2021/cgi-bin/drug_who_e.cgi?query=gsk1070806&disease_id=56%2C%2096