Ladarixin (DB16212): A Comprehensive Review of a Dual CXCR1/2 Allosteric Inhibitor from Preclinical Promise to Clinical Crossroads

Executive Summary

Ladarixin (DB16212) is an orally bioavailable, investigational small molecule that functions as a potent, non-competitive, dual allosteric inhibitor of the C-X-C motif chemokine receptors 1 (CXCR1) and 2 (CXCR2). Its mechanism of action centers on blocking the pro-inflammatory signaling cascade initiated by Interleukin-8 (IL-8), thereby modulating the recruitment and activity of neutrophils and other myeloid cells. This report provides a comprehensive analysis of Ladarixin, from its fundamental pharmacology and extensive preclinical evaluation to its complex clinical development history and current regulatory standing.

Preclinical studies have established a robust and broad therapeutic rationale for Ladarixin. In animal models of Type 1 Diabetes (T1D), it demonstrated the ability to both prevent and reverse autoimmune-driven hyperglycemia by inhibiting insulitis. Furthermore, it showed potential to mitigate long-term diabetic complications independently of glycemic control. In oncology, Ladarixin exhibited multifactorial antineoplastic activity, including direct effects on tumor cells and, more significantly, the ability to remodel the tumor microenvironment. Its capacity to convert immunologically "cold" tumors to "hot" by disrupting myeloid-derived immunosuppression positions it as a promising candidate for combination therapy with checkpoint inhibitors. Its anti-inflammatory effects were also confirmed in various models of respiratory disease, including corticosteroid-resistant asthma.

The clinical development program, led by Dompé Farmaceutici S.p.A., has primarily focused on new-onset T1D. A pivotal Phase 2 trial (NCT02814838) failed to meet its primary endpoint in the overall patient population but revealed a significant therapeutic signal in a prespecified subgroup of patients with more severe disease at baseline. This finding prompted a strategic pivot, with the entire T1D program now hinging on the results of the GLADIATOR study (NCT04628481), a larger trial designed specifically for this responder population. In parallel, the sponsor has diversified its clinical strategy by initiating trials in oncology, notably a study combining Ladarixin with a KRAS inhibitor for non-small cell lung cancer.

Ladarixin remains an unapproved investigational agent globally. However, significant regulatory engagement with the European Medicines Agency (EMA), evidenced by a detailed Paediatric Investigation Plan (PIP), signals a clear intent to pursue marketing authorization in Europe for T1D, contingent on positive pivotal trial data. The future of Ladarixin is at a critical inflection point, awaiting the results of the GLADIATOR study, which will either validate its potential as a first-in-class treatment for a subset of T1D patients or necessitate a full strategic pivot towards its promising applications in oncology and other inflammatory diseases.

1.0 Molecular Profile and Pharmacology

This section details the fundamental scientific identity of Ladarixin, including its chemical structure, physicochemical properties, and the molecular interactions that define its pharmacological activity.

1.1 Chemical Identity and Physicochemical Properties

Ladarixin is a small molecule drug currently classified as an investigational agent.[1] From a chemical standpoint, it belongs to the classes of amides, sulfones, and sulfur compounds.[1] Its formal IUPAC name isphenyl] trifluoromethanesulfonate.[3] It is also known by several synonyms, including DF-2156A and Meraxin, and exists in both a free base and a sodium salt form.[4] The development of a sodium salt (CAS 865625-56-5) represents a common pharmaceutical strategy to improve the biopharmaceutical properties of an acidic parent drug.[4]

The molecule's low aqueous solubility of 0.121 mg/mL is a key characteristic that has influenced its formulation development.[1] Research-grade preparations often require dissolution in organic solvents like dimethyl sulfoxide (DMSO) or suspension in vehicles containing polyethylene glycol (PEG) for in vivo administration.[8] This inherent property underscores the importance of formulation science for the compound's clinical viability and is reflected in regulatory plans, such as the European Medicines Agency's Paediatric Investigation Plan, which mandates the development of an "age-appropriate oral liquid dosage form" to ensure proper delivery in younger populations.[3] Despite its solubility challenges, Ladarixin possesses favorable drug-like properties, adhering to both Lipinski's Rule of Five and the Ghose Filter, which are computational filters that predict if a compound has characteristics that would make it a likely orally active drug in humans.[1]

A consolidated summary of Ladarixin's key identifiers and physicochemical properties is provided in Table 1.

Table 1: Key Identifiers and Physicochemical Properties of Ladarixin

Parameter	Value	Source(s)
Generic Name	Ladarixin	1
DrugBank ID	DB16212	1
Type	Small Molecule	1
CAS Number	849776-05-2	1
IUPAC Name	phenyl] trifluoromethanesulfonate	3
Molecular Formula	$C_{11}H_{12}F_{3}NO_{6}S_{2}$	1
Molecular Weight	375.33 g/mol	1
InChIKey	DDLPYOCJHQSVSZ-SSDOTTSWSA-N	1
SMILES	CC@HC(=O)NS(=O)(=O)C
Water Solubility	0.121 mg/mL
LogP	2.51
pKa (Strongest Acidic)	4
Rule of Five	Yes
Ghose Filter	Yes

1.2 Mechanism of Action: Dual Allosteric Inhibition of CXCR1/2

Ladarixin is a potent, orally bioavailable, dual inhibitor of the G protein-coupled chemokine receptors CXCR1 and CXCR2. Its inhibitory activity is distinguished by its specific mode of action; it functions as a non-competitive, allosteric inhibitor. Rather than competing with the natural ligand at the primary binding site, Ladarixin binds to a distinct allosteric pocket located within the transmembrane region of the receptors. This binding event induces a conformational change in the receptor that prevents it from activating downstream signaling pathways, even when the natural ligand, Interleukin-8 (IL-8 or CXCL8), is bound.

This allosteric mechanism confers a significant potential therapeutic advantage. Competitive antagonists must be present at high enough concentrations to outcompete the high local concentrations of IL-8 found at sites of inflammation or within a tumor. In contrast, the efficacy of an allosteric modulator like Ladarixin is not overcome by high ligand concentrations, potentially leading to more consistent and durable target inhibition. Furthermore, this modulatory approach appears to offer a superior safety profile. Preclinical data indicate that Ladarixin effectively decreases localized neutrophil infiltration in animal models without causing a significant dose-related reduction in systemic neutrophil counts. The ability to dampen the pathogenic recruitment of neutrophils to specific tissues without inducing systemic neutropenia—a major toxicity concern that can leave a patient vulnerable to infection—is a key differentiating feature that likely contributes to the favorable tolerability observed in early clinical trials.

The inhibition of CXCR1/2-mediated signaling has profound and multifaceted downstream consequences, forming the basis for Ladarixin's investigation across multiple therapeutic areas:

• Anti-inflammatory Effects: The primary function of the IL-8/CXCR1/2 axis is to direct the migration of neutrophils to sites of injury or infection. By blocking this pathway, Ladarixin potently inhibits neutrophil recruitment, a key event in the pathogenesis of many inflammatory and autoimmune diseases. This provides the core rationale for its development in conditions such as Type 1 Diabetes, asthma, and chronic obstructive pulmonary disease (COPD). In vitro, Ladarixin has been shown to inhibit human neutrophil migration towards CXCL8 with a half-maximal inhibitory concentration ($IC_{50}$) of 0.7 nM.
• Antineoplastic Effects: In oncology, the CXCR1/2 pathway plays a critical role in shaping an immunosuppressive tumor microenvironment (TME). By blocking this axis, Ladarixin exerts several anti-cancer effects. It reduces the recruitment of immunosuppressive myeloid-derived suppressor cells (MDSCs) and tumor-associated neutrophils into the TME. This action helps to dismantle the immunosuppressive shield around the tumor, thereby "unleashing" effector immune cells like natural killer (NK) cells and cytotoxic T-lymphocytes (CTLs) to recognize and attack cancer cells. Additionally, CXCR1/2 signaling on cancer cells themselves can promote proliferation, angiogenesis, and metastasis; by inhibiting these signals through pathways like AKT and NF-κB, Ladarixin can exert direct anti-tumor effects.

1.3 Pharmacokinetics and Metabolism

Ladarixin is described as an orally bioavailable drug with an optimal pharmacokinetic (PK) profile that makes it suitable for chronic oral administration. Early-phase (Phase 1) clinical trials conducted in healthy volunteers confirmed its tolerability and established a foundational understanding of its human pharmacokinetics, which enabled the design of subsequent efficacy studies.

A dedicated Phase 1 trial, NCT04854642, was conducted to formally evaluate the effect of food on the absorption and PK of Ladarixin. In this study, a single 400 mg oral dose was administered to healthy volunteers under both fed and fasting conditions, with plasma concentrations of the drug and its metabolites measured over 72 hours to determine key PK parameters like maximum plasma concentration ($C_{max}$) and area under the concentration-time curve ($AUC_{0-t}$). While the specific numerical results of this study are not publicly available, its completion provided the necessary data to guide dosing recommendations in later-phase trials.

Data from clinical trial protocols reveal that Ladarixin is likely a pro-drug. A PK sub-study planned within the GLADIATOR trial (NCT04628481) specifies the measurement of plasma levels of "2156Y (acidic form of ladarixin)" and its metabolites, indicating that the administered compound is converted in vivo to an active acidic form.

The dosing regimen used consistently across Phase 2 and 3 trials for T1D is 400 mg administered orally twice daily (b.i.d.). Notably, this regimen is often administered in cycles of 14 days on treatment followed by 14 days off treatment. This intermittent dosing schedule is not arbitrary but appears to be a deliberate strategy to achieve immunomodulation rather than continuous immunosuppression. For a chronic autoimmune disease like T1D, which involves episodic flares of immune attack, this cyclical approach may be intended to interrupt the inflammatory cascade during the "on" periods while allowing the innate immune system to recover during the "off" periods. This strategy aims to maximize the therapeutic window by balancing efficacy against the potential long-term risks of chronic immune suppression, a critical consideration for a disease that often affects younger patients.

2.0 Preclinical Efficacy and Rationale for Development

The clinical development of Ladarixin is underpinned by a substantial body of preclinical research demonstrating its therapeutic potential across a spectrum of diseases, from autoimmunity to oncology. This section evaluates the key animal model data that provide the mechanistic rationale for its investigation in humans.

2.1 Foundational Research in Autoimmunity: Type 1 Diabetes

The primary impetus for developing Ladarixin for Type 1 Diabetes (T1D) originates from the established role of the CXCL8-CXCR1/2 signaling axis in amplifying inflammation and orchestrating the recruitment of neutrophils to pancreatic islets. This process, known as insulitis, is a key pathogenic event leading to the autoimmune destruction of insulin-producing beta cells.

Studies in the non-obese diabetic (NOD) mouse, a gold-standard model that spontaneously develops autoimmune diabetes mirroring the human disease, provided compelling proof-of-concept for Ladarixin's efficacy. When administered as a preventative measure, Ladarixin significantly delayed or completely prevented the onset of hyperglycemia. Even more impressively, when given to mice that had already developed recent-onset diabetes, Ladarixin was able to reverse hyperglycemia and induce disease remission. Histological analysis of the pancreas from treated mice confirmed that these functional benefits were associated with a marked reduction in immune cell infiltration into the islets (insulitis), directly demonstrating the drug's ability to quell the local autoimmune attack.

These findings were further corroborated in a chemically induced rat model of T1D using streptozotocin (STZ). In this model, early treatment with Ladarixin not only mitigated the primary metabolic dysfunction (elevated blood glucose, reduced insulin) but also prevented the development of signs associated with long-term diabetic complications, including diabetic peripheral neuropathy (DPN) and diabetic retinopathy (DR). This research yielded a particularly important finding: when Ladarixin administration was delayed until after diabetes was well-established, it failed to reverse the metabolic abnormalities, yet it still significantly mitigated the signs of DPN and DR. This suggests that the CXCR1/2 pathway is implicated not only in the initial autoimmune assault on the pancreas but also in the chronic, low-grade inflammatory processes that drive microvascular complications in established disease. This observation supports a dual therapeutic hypothesis for Ladarixin in diabetes: first, as a disease-modifying agent to preserve beta-cell function in new-onset T1D, and second, as a potential therapy to prevent or treat debilitating long-term complications, a major area of unmet need, even in patients with established disease.

2.2 Antineoplastic Potential: Modulating the Tumor Microenvironment

In parallel with its development in autoimmunity, Ladarixin has been investigated for its antineoplastic activities. The rationale in oncology is based on the critical role of CXCR1/2 signaling in creating an immunosuppressive tumor microenvironment (TME) that fosters tumor growth, metastasis, and resistance to therapy.

In preclinical models of cutaneous and uveal melanoma, Ladarixin demonstrated a multifactorial anti-tumor effect. It exerted direct effects on cancer cells, inhibiting their motility and inducing programmed cell death (apoptosis) by blocking pro-survival signaling pathways such as AKT and NF-κB. Concurrently, systemic treatment of melanoma-bearing mice led to a profound remodeling of the TME. Ladarixin treatment polarized tumor-associated macrophages toward a pro-inflammatory, anti-tumor M1 phenotype, inhibited the formation of new blood vessels (angiogenesis), and reduced the population of cancer stem cells responsible for tumor self-renewal.

The most compelling preclinical oncology data emerged from studies in pancreatic ductal adenocarcinoma (PDAC), a notoriously difficult-to-treat cancer known for its dense, immunosuppressive TME. While Ladarixin showed modest activity as a single agent, its true potential was revealed when combined with anti-PD-1 immunotherapy. Many tumors, including PDAC, are considered immunologically "cold" because they lack the T-cell infiltration required for checkpoint inhibitors like anti-PD-1 to be effective. The preclinical studies showed that Ladarixin's primary effect in the TME is to disrupt the myeloid-driven "shield" by inhibiting the recruitment and pro-tumor polarization of MDSCs and macrophages. By removing this immunosuppressive barrier, Ladarixin effectively converted the TME from "cold" to "hot," enabling an influx of effector T-cells. Once the TME was primed in this way, the subsequent administration of an anti-PD-1 antibody was highly effective, leading to significant tumor regression and improved survival in mouse models that were otherwise completely resistant to checkpoint inhibition alone. This positions Ladarixin not necessarily as a standalone cancer drug, but as a crucial immuno-oncology "sensitizer" capable of overcoming primary resistance to immunotherapy, a major challenge in modern oncology. This rationale directly supports its current clinical investigation in combination with other anti-cancer agents.

2.3 Broad Anti-Inflammatory Activity: Respiratory and Other Diseases

The therapeutic potential of Ladarixin extends to a range of non-autoimmune inflammatory conditions, particularly neutrophil-driven respiratory diseases. In mouse models of allergic asthma, Ladarixin treatment reduced the influx of both neutrophils and eosinophils into the airways, attenuated airway tissue remodeling, and decreased airway hyperresponsiveness. In a model of pulmonary fibrosis, it diminished both neutrophilic inflammation and the deposition of collagen, a hallmark of fibrotic disease. Furthermore, in a model mimicking acute exacerbations of COPD triggered by influenza infection in the context of cigarette smoke exposure, Ladarixin reduced airway inflammation, improved lung function, and significantly increased survival rates.

A critical finding across these respiratory models was the efficacy of Ladarixin in contexts where standard-of-care corticosteroids are ineffective. In a Th17-driven asthma model designed to be refractory to glucocorticoids, Ladarixin not only reduced the underlying neutrophilic inflammation but also appeared to restore the animal's sensitivity to corticosteroid treatment. This suggests a potential role for Ladarixin in treating severe, steroid-resistant inflammatory diseases, a significant unmet clinical need.

3.0 Clinical Development and Trial Analysis

This section provides a comprehensive analysis of Ladarixin's clinical trial program, synthesizing results, trial statuses, and strategic shifts to construct a complete narrative of its progression from early-phase studies to its current state.

3.1 Overview of the Clinical Program

Ladarixin has been evaluated in a portfolio of at least eight clinical trials sponsored primarily by Dompé Farmaceutici S.p.A.. The program has spanned multiple therapeutic areas, including autoimmune disease, oncology, and other inflammatory conditions, with the most advanced development being a Phase 3 program for Type 1 Diabetes. The full scope of this clinical investigation is summarized in Table 2.

Table 2: Summary of Ladarixin Clinical Trials

Trial ID	Phase	Indication	Status (as of latest data)	Sponsor	Source(s)
NCT04628481 (GLADIATOR)	Phase 2/3	New-Onset Type 1 Diabetes (low residual function)	Active, Not Recruiting	Dompé Farmaceutici S.p.A.
NCT02814838 (MEX0114)	Phase 2	New-Onset Type 1 Diabetes	Completed	Dompé Farmaceutici S.p.A.
NCT05815173	Phase 1/2	Advanced NSCLC (KRAS G12C) w/ Sotorasib	Recruiting	NYU Langone Health
NCT05368402 (CONSERVA)	Phase 2	Type 1 Diabetes (overweight, insulin-resistant)	Terminated (low recruitment)	Dompé Farmaceutici S.p.A.
NCT05035368	Phase 2	Type 1 Diabetes (overweight, insulin-resistant)	Withdrawn	Dompé Farmaceutici S.p.A.
NCT04899271	Phase 2	New-Onset Type 1 Diabetes (preserved function)	Terminated	Dompé Farmaceutici S.p.A.
NCT04854642	Phase 1	Healthy Volunteers (Food-effect study)	Completed	Dompé Farmaceutici S.p.A.
NCT01571895	Phase 2	Bullous Pemphigoid	Discontinued	Dompé Farmaceutici S.p.A.
N/A	Discontinued	Malignant Melanoma, Spinal Cord Injuries	Discontinued	Dompé Farmaceutici S.p.A.

3.2 The Type 1 Diabetes Program: A Critical Assessment

The most mature component of Ladarixin's clinical development is its program in new-onset T1D, which aims to preserve endogenous insulin production by targeting the autoimmune inflammatory process.

3.2.1 The MEX0114 (NCT02814838) Phase 2 Trial

The foundational efficacy study in this indication was MEX0114, a multicenter, randomized, double-blind, placebo-controlled trial involving 76 adult patients with new-onset T1D. Participants received either Ladarixin (400 mg b.i.d.) or a placebo, administered in three cycles of 14 days on treatment followed by 14 days off. The primary endpoint was the change in C-peptide production (a marker of beta-cell function) in response to a mixed-meal tolerance test (MMTT) at 13 weeks.

The trial did not meet its primary endpoint; there was no statistically significant difference in C-peptide preservation between the Ladarixin and placebo groups in the overall study population at either 13 or 26 weeks. However, analysis of secondary and subgroup endpoints revealed promising signals. At 26 weeks, a significantly greater proportion of patients treated with Ladarixin achieved better overall metabolic control, defined as a composite of maintaining an HbA1c below 7% and having a daily insulin requirement of less than 0.50 IU/kg, compared to the placebo group (76.6% vs. 45.8%, $p=0.0095$).

Most importantly, a prespecified subgroup analysis of patients who presented with more severe disease at baseline (defined by having a fasting C-peptide level below the median value for the trial population) showed a statistically significant benefit. In these patients, Ladarixin treatment led to significantly better C-peptide preservation compared to placebo at the 26-week timepoint ($p=0.041$). A subsequent post-hoc analysis further supported this finding, identifying a similar benefit in patients who had high daily insulin requirements at baseline. Ladarixin was well-tolerated, with the most common adverse events being dyspepsia (16% vs. 0% for placebo) and headache (16% vs. 15.4%).

3.2.2 The GLADIATOR (NCT04628481) Pivotal Study

The promising signal in the high-risk subgroup of the MEX0114 trial prompted a significant strategic pivot. Rather than abandoning the T1D indication, the sponsor launched the GLADIATOR study, a larger pivotal trial designed specifically to confirm the efficacy of Ladarixin in this targeted patient population. This Phase 2/3 study is a multicenter, randomized, double-blind, placebo-controlled trial designed to enroll approximately 130 to 327 adolescents and adults (ages 14-45) with new-onset T1D and documented low residual beta-cell function at baseline. The treatment regimen involves a longer duration of therapy: 400 mg b.i.d. for 13 cycles (one year) of 14 days on/14 days off, with a subsequent 12-month follow-up.

As of November 2024, the trial's status is listed as "Active, not recruiting". The primary completion date was recorded as April 5, 2024, and according to the FDA Amendments Act (FDAAA) tracker, the trial is overdue for reporting its results. The estimated final study completion date is April 2026. This trial represents a high-risk, high-reward strategy, concentrating the future of the T1D program on validating the subgroup finding from the initial Phase 2 study. The entire T1D franchise for Ladarixin now hinges on the outcome of this pivotal study.

3.2.3 Discontinued and Terminated Studies

The strategic consolidation around the GLADIATOR study is further evidenced by the discontinuation of other planned T1D trials. Study NCT05035368, a Phase 2 trial in overweight, insulin-resistant T1D patients, was withdrawn by Dompé prior to enrollment, citing "internal re-planning and an extensive review of the study design". A similar study, NCT05368402 (CONSERVA), was terminated early due to low recruitment rates after enrolling only three patients, making any efficacy evaluation impossible. Another Phase 2 trial, NCT04899271, which targeted T1D patients with preserved beta-cell function, was also terminated. Collectively, these actions demonstrate a clear and decisive shift away from exploring Ladarixin in broader or different T1D populations to focus all resources on the single most promising patient subgroup.

3.3 Strategic Diversification into Oncology

Leveraging the compelling preclinical data on TME modulation, a clinical program in oncology has been initiated. A Phase I/II trial (NCT05815173) is currently recruiting patients with advanced non-small cell lung cancer (NSCLC) harboring a KRAS G12C mutation. This study is evaluating Ladarixin in combination with Sotorasib, a targeted KRAS G12C inhibitor. This trial represents a strategically astute move to diversify Ladarixin's clinical portfolio, creating a parallel path to value and serving as a hedge against potential setbacks in the T1D program.

3.4 Consolidated Safety and Tolerability Profile

Across its clinical program, Ladarixin has demonstrated a favorable safety profile. Phase 1 studies in healthy volunteers and Phase 2 studies in patients have consistently shown the drug to be well-tolerated. As noted, the most frequent adverse events reported in the T1D program were mild-to-moderate dyspepsia and headache. The absence of reports of significant systemic neutropenia in clinical settings appears to support the preclinical observation that its allosteric mechanism may spare systemic neutrophil counts, a key safety advantage. Exclusion criteria in ongoing oncology trials, which preclude patients with significant pre-existing autoimmune, cardiac, or gastrointestinal conditions, provide insight into populations where caution may be warranted.

4.0 Regulatory Status and Strategic Outlook

This section synthesizes the global regulatory landscape for Ladarixin, analyzes key interactions with regulatory bodies, and provides an expert-level, forward-looking perspective on the drug's potential future, challenges, and critical milestones.

4.1 Global Regulatory Position

Ladarixin remains an investigational drug and has not received marketing approval in any country. Its regulatory status with key global agencies is as follows:

• U.S. Food and Drug Administration (FDA): Ladarixin is not approved by the FDA. All clinical trials conducted in the United States operate under an Investigational New Drug (IND) application. In line with FDA regulations, the contents of IND applications are confidential and not publicly disclosable until after a drug is approved. The molecule is registered within the FDA's Global Substance Registration System (GSRS) under the Unique Ingredient Identifier (UNII) DEH7Q6472O.
• Australia's Therapeutic Goods Administration (TGA): Ladarixin is not listed on the Australian Register of Therapeutic Goods (ARTG) and is therefore not approved for supply in Australia. Access for Australian patients would be limited to participation in a clinical trial or through special access pathways for unapproved medicines.
• European Medicines Agency (EMA): Ladarixin does not currently hold a Marketing Authorisation in the European Union. However, there has been significant and ongoing engagement between the sponsor, Dompé Farmaceutici S.p.A., and the EMA, particularly regarding pediatric development.

4.2 European Paediatric Investigation Plan (PIP)

A crucial indicator of the sponsor's regulatory strategy is the existence of an agreed and subsequently modified Paediatric Investigation Plan (PIP) with the EMA. An agreed PIP is a mandatory prerequisite for filing a Marketing Authorisation Application (MAA) for any new medicine in Europe. The process of negotiating and agreeing to a PIP is resource-intensive and legally binding, signaling a serious commitment to seek approval.

The PIP for Ladarixin is for the indication "Treatment of new-onset type 1 diabetes mellitus with residual beta cell function" and covers the pediatric population from 1 to less than 18 years of age. It includes a waiver for infants under one year old. The plan, which must be completed by July 2028, contractually obligates the sponsor to conduct a comprehensive series of studies, including:

• The development of a pediatric-appropriate oral liquid formulation.
• A definitive juvenile animal toxicity study.
• Three separate clinical trials to assess PK, efficacy, and safety across different pediatric age groups (1-6 years, 6-14 years, and 14-18 years).
• Pharmacokinetic modeling and simulation studies to support dose selection in children.

The existence of such a detailed and long-range development plan is a strong positive signal. It demonstrates the sponsor's confidence in the T1D program and their clear intent to pursue commercialization in the European Union, pending a successful outcome from the pivotal GLADIATOR study.

4.3 Expert Synthesis and Future Directions

Ladarixin represents a compelling case study of a drug with a broad and robust preclinical rationale that has encountered the complexities of clinical translation. Its elegant mechanism of action and strong performance in animal models of diabetes, cancer, and respiratory disease have set high expectations that have been only partially met in its lead clinical indication.

The entire T1D program is currently at a critical inflection point. The decision to pivot from a broad-population approach to a targeted strategy based on a subgroup signal from the initial Phase 2 trial was a bold one. The future of Ladarixin in T1D now rests entirely on the forthcoming results of the GLADIATOR study (NCT04628481). The fact that this trial's results are overdue for public reporting creates significant uncertainty and anticipation.

• A positive outcome from GLADIATOR would validate the subgroup strategy, providing a clear path toward regulatory submissions with the FDA and EMA for a defined T1D patient population. This would represent a major breakthrough, potentially establishing Ladarixin as a first-in-class, disease-modifying therapy for a subset of patients with new-onset T1D.
• A negative outcome would likely lead to the discontinuation of the T1D program. In this scenario, the company's focus would be expected to pivot entirely to its other areas of preclinical strength.

The initiation of a clinical program in oncology, investigating Ladarixin as a sensitizer for KRAS-targeted therapy in NSCLC, is a strategically sound move. It diversifies the asset's risk profile and leverages the strong preclinical data supporting its role in TME remodeling. This program provides a valuable secondary path to market that is independent of the T1D program's success.

In the long term, the therapeutic story of Ladarixin may extend beyond T1D and oncology. The extensive preclinical data in respiratory diseases, particularly in corticosteroid-resistant inflammation, highlights a significant area of unmet need where a novel, neutrophil-modulating agent could have a major impact. The ultimate success of Ladarixin will depend on successfully navigating the upcoming pivotal data readout and, if necessary, leveraging its unique mechanism to identify the specific patient populations and disease contexts where inhibition of the CXCR1/2 axis can provide a definitive clinical benefit.

Works cited

1. Ladarixin: Uses, Interactions, Mechanism of Action | DrugBank Online, accessed October 26, 2025, https://go.drugbank.com/drugs/DB16212
2. Dompe Farmaceutici - Ladarixin - AdisInsight - Springer, accessed October 26, 2025, https://adisinsight.springer.com/drugs/800021925
3. Ladarixin | C11H12F3NO6S2 | CID 11372270 - PubChem - NIH, accessed October 26, 2025, https://pubchem.ncbi.nlm.nih.gov/compound/Ladarixin
4. Ladarixin | CAS#849776-05-2 - MedKoo Biosciences, accessed October 26, 2025, https://www.medkoo.com/products/7958
5. Ladarixin Sodium - Drug Targets, Indications, Patents - Patsnap Synapse, accessed October 26, 2025, https://synapse.patsnap.com/drug/29bbc53c161e44c098e59407459394e3
6. Ladarixin Sodium | 849776-05-2 - ChemicalBook, accessed October 26, 2025, https://www.chemicalbook.com/ChemicalProductProperty_EN_CB53054553.htm
7. Ladarixin sodium | CAS NO.:865625-56-5 - GlpBio, accessed October 26, 2025, https://www.glpbio.com/ladarixin-sodium.html
8. Ladarixin | CAS NO.:849776-05-2 - GlpBio, accessed October 26, 2025, https://www.glpbio.com/ladarixin.html
9. Ladarixin (DF 2156A free base) | Dual CXCR1/2 Antagonist | MedChemExpress, accessed October 26, 2025, https://www.medchemexpress.com/ladarixin.html
10. European Medicines Agency decision P/0284/2020 of 12 August 2020 on the acceptance of a modification of an agreed paediatric inv, accessed October 26, 2025, https://www.ema.europa.eu/en/documents/pip-decision/p-0284-2020-ema-decision-12-august-2020-acceptance-modification-agreed-paediatric-investigation-plan-ladarixin-emea-002642-pip01-19-m01_en.pdf
11. Ladarixin (DF-2156A) | inhibitor/agonist | CAS 849776-05-2 - InvivoChem, accessed October 26, 2025, https://www.invivochem.com/ladarixin.html
12. Ladarixin, a dual CXCR1/2 inhibitor, attenuates experimental melanomas harboring different molecular defects by affecting malignant cells and tumor microenvironment - PMC - NIH, accessed October 26, 2025, https://pmc.ncbi.nlm.nih.gov/articles/PMC5362416/
13. Effects of CXCR1/2 Blockade with Ladarixin on Streptozotocin-Induced Type 1 Diabetes Mellitus and Peripheral Neuropathy and Retinopathy in Rat - Diabetes & Metabolism Journal, accessed October 26, 2025, https://www.e-dmj.org/journal/view.php?number=2934
14. CXCR1 and CXCR2 Inhibition by Ladarixin Improves Neutrophil-Dependent Airway Inflammation in Mice - Frontiers, accessed October 26, 2025, https://www.frontiersin.org/journals/immunology/articles/10.3389/fimmu.2020.566953/full
15. www.cancer.gov, accessed October 26, 2025, https://www.cancer.gov/research/participate/clinical-trials-search/v?id=NCI-2023-06210#:~:text=Ladarixin%20works%20by%20blocking%20certain,immune%20response%20against%20tumor%20cells.
16. CXCR1/2 Inhibitor Ladarixin Ameliorates the Insulin Resistance of 3T3-L1 Adipocytes by Inhibiting Inflammation and Improving Insulin Signaling - MDPI, accessed October 26, 2025, https://www.mdpi.com/2073-4409/10/9/2324
17. Ladarixin patents and clinical trials: Drug pipeline profiles for drugs in development, accessed October 26, 2025, https://www.drugpatentwatch.com/p/drugs-in-development/drugname/Ladarixin
18. Study Details | NCT04854642 | A Single Dose Study About the ..., accessed October 26, 2025, https://www.clinicaltrials.gov/study/NCT04854642
19. EU Clinical Trials Register, accessed October 26, 2025, https://www.clinicaltrialsregister.eu/ctr-search/trial/2020-001926-71/BE
20. Ladarixin, an inhibitor of the interleukin‐8 receptors CXCR1 and CXCR2, in new‐onset type 1 diabetes: A multicentre, randomized, double‐blind, placebo‐controlled trial - PMC, accessed October 26, 2025, https://pmc.ncbi.nlm.nih.gov/articles/PMC9540558/
21. Study Details | NCT05368402 | Clinical Trial on Ladarixin Adjunctive Therapy to Improve Glycemic Control in Type 1 Diabetes. | ClinicalTrials.gov, accessed October 26, 2025, https://clinicaltrials.gov/study/NCT05368402
22. Paolo Pozzilli, MD: Ladarixin in Patients with Type 1 Diabetes | HCPLive, accessed October 26, 2025, https://www.hcplive.com/view/paolo-pozzilli-md-ladarixin-a-cxcr1-2-inhibitor-in-type-1-diabetes
23. Dompé Announces First Patient Enrolled in Phase 3 trial of Ladarixin, an Oral Investigational CXCR1/2 Inhibitor, in New-Onset Type 1 Diabetes (T1D), accessed October 26, 2025, https://www.dompe.com/us/media/press-releases/dompe-announces-first-patient-enrolled-in-phase-3-trial-of-ladarixin-an-oral-investigational-cxcr1-2-inhibitor-in-new-onset-type-1-diabetes-t1d/
24. CXCR1/2 Inhibition Blocks and Reverses Type 1 Diabetes in Mice ..., accessed October 26, 2025, https://diabetesjournals.org/diabetes/article/64/4/1329/34861/CXCR1-2-Inhibition-Blocks-and-Reverses-Type-1
25. Ladarixin, a dual CXCR1/2 inhibitor, attenuates experimental melanomas harboring different molecular defects by affecting malignant cells and tumor microenvironment - PubMed, accessed October 26, 2025, https://pubmed.ncbi.nlm.nih.gov/28129639/
26. Ladarixin, a dual CXCR1/2 inhibitor, attenuates experimental ..., accessed October 26, 2025, https://www.oncotarget.com/article/14803/text/
27. CXCR1/2 dual-inhibitor ladarixin reduces tumour burden and ... - NIH, accessed October 26, 2025, https://pmc.ncbi.nlm.nih.gov/articles/PMC9902528/
28. CXCR1/2 dual-inhibitor ladarixin reduces tumour burden and promotes immunotherapy response in pancreatic cancer - PubliRES - Publications, Research, Expertise and Skills, accessed October 26, 2025, https://publires.unicatt.it/en/publications/cxcr12-dual-inhibitor-ladarixin-reduces-tumour-burden-and-promote/
29. CXCR1/2 dual-inhibitor ladarixin reduces tumour burden and promotes immunotherapy response in pancreatic cancer - PubMed, accessed October 26, 2025, https://pubmed.ncbi.nlm.nih.gov/36385556/
30. The role of CXCR1/2 dual inhibitor ladarixin on tumor burden and immunotherapy response in pancreatic cancer. | Journal of Clinical Oncology - ASCO Publications, accessed October 26, 2025, https://ascopubs.org/doi/10.1200/JCO.2022.40.16_suppl.e16304
31. Ladarixin and Sotorasib for the Treatment of Advanced KRAS G12C Mutant Non-Small Cell Lung Cancer - NCI, accessed October 26, 2025, https://www.cancer.gov/research/participate/clinical-trials-search/v?id=NCI-2023-06210
32. CXCR1 and CXCR2 Inhibition by Ladarixin Improves Neutrophil ..., accessed October 26, 2025, https://pmc.ncbi.nlm.nih.gov/articles/PMC7566412/
33. CXCR1 and CXCR2 Inhibition by Ladarixin Improves Neutrophil-Dependent Airway Inflammation in Mice - ResearchGate, accessed October 26, 2025, https://www.researchgate.net/publication/344330272_CXCR1_and_CXCR2_Inhibition_by_Ladarixin_Improves_Neutrophil-Dependent_Airway_Inflammation_in_Mice
34. NCT04628481 | A Study of Oral Ladarixin in Recent Onset Type 1 Diabetes and a Low Residual β-cell Function | ClinicalTrials.gov, accessed October 26, 2025, https://www.clinicaltrials.gov/study/NCT04628481
35. A Study of Oral Ladarixin in Recent Onset Type 1 Diabetes and a Low Residual β-cell Function - UCSD Clinical Trials, accessed October 26, 2025, https://clinicaltrials.ucsd.edu/trial/NCT04628481
36. Ladarixin Completed Phase 2 Trials for Diabetes Mellitus, Insulin Dependent Treatment, accessed October 26, 2025, https://go.drugbank.com/drugs/DB16212/clinical_trials?conditions=DBCOND0035532&phase=2&purpose=treatment&status=completed
37. Ladarixin With Sotorasib in Advanced NSCLC (NCT05815173), accessed October 26, 2025, https://www.ancora.ai/en/details/NCT05815173
38. Study Details | NCT05368402 | Clinical Trial on Ladarixin Adjunctive Therapy to Improve Glycemic Control in Type 1 Diabetes. | ClinicalTrials.gov, accessed October 26, 2025, https://www.clinicaltrials.gov/study/NCT05368402
39. Ladarixin Withdrawn Phase 2 Trials for Type 1 Diabetes Mellitus Treatment - DrugBank, accessed October 26, 2025, https://go.drugbank.com/drugs/DB16212/clinical_trials?conditions=DBCOND0029465&phase=2&purpose=treatment&status=withdrawn
40. Study Details | NCT05035368 | Ladarixin as Adjunctive Therapy to Improve Insulin Sensitivity and Glucometabolic Outcomes in Type 1 Diabetes | ClinicalTrials.gov, accessed October 26, 2025, https://www.clinicaltrials.gov/study/NCT05035368
41. Ladarixin Terminated Phase 2 Trials for New Onset Type 1 Diabetes Mellitus Treatment, accessed October 26, 2025, https://go.drugbank.com/drugs/DB16212/clinical_trials?conditions=DBCOND0032747&phase=2&purpose=treatment&status=terminated
42. Ladarixin, an inhibitor of the interleukin-8 receptors CXCR1 and CXCR2, in new-onset type 1 diabetes: A multicentre, randomized, double-blind, placebo-controlled trial - PubMed, accessed October 26, 2025, https://pubmed.ncbi.nlm.nih.gov/35589610/
43. 249-OR: A Randomized, Double-Blind Phase 2 Trial of the CXCR1/2 Inhibitor Ladarixin in Adult Patients with New-Onset Type 1 Diabetes, accessed October 26, 2025, https://diabetesjournals.org/diabetes/article/69/Supplement_1/249-OR/56830/249-OR-A-Randomized-Double-Blind-Phase-2-Trial-of
44. Post hoc analysis of a randomized, double-blind, prospective trial evaluating a CXCR1/2 inhibitor in new-onset type 1 diabetes: endo-metabolic features at baseline identify a subgroup of responders - PMC - PubMed Central, accessed October 26, 2025, https://pmc.ncbi.nlm.nih.gov/articles/PMC10319139/
45. A Study of Oral Ladarixin in Recent Onset Type 1 Diabetes... - Clinical Trial Discovery, accessed October 26, 2025, https://clinicaltrial.be/en/details/50732?per_page=20&only_recruiting=0&enrolling_by_invitation=1&active_not_recruiting=1¬_yet_recruiting=0&completed=0&only_eligible=0&only_active=0
46. NCT04628481 | A Study of Oral Ladarixin in Recent Onset Type 1 Diabetes and a Low Residual β-cell Function | ClinicalTrials.gov, accessed October 26, 2025, https://www.clinicaltrials.gov/study/NCT04628481?intr=NCT04628481&rank=1
47. NCT04628481: An overdue trial by Dompé Farmaceutici S.p.A, accessed October 26, 2025, https://staging-fdaaa.ebmdatalab.net/trial/NCT04628481/
48. Dompé Announces First Patient Enrolled in Phase 3 trial of Ladarixin, an Oral Investigational CXCR1/2 Inhibitor, in New-Onset Type 1 Diabetes (T1D), accessed October 26, 2025, https://www.dompe.com/it/media/comunicati-stampa/2-inhibitor-in-new-onset-type-1-diabetes-t1d/
49. Investigational New Drug Applications (INDs) for CBER-Regulated Products | FDA, accessed October 26, 2025, https://www.fda.gov/vaccines-blood-biologics/development-approval-process-cber/investigational-new-drug-applications-inds-cber-regulated-products
50. 21 CFR 312.130 -- Availability for public disclosure of data and information in an IND. - eCFR, accessed October 26, 2025, https://www.ecfr.gov/current/title-21/chapter-I/subchapter-D/part-312/subpart-F/section-312.130
51. Australian Register of Therapeutic Goods (ARTG), accessed October 26, 2025, https://www.tga.gov.au/products/australian-register-therapeutic-goods-artg
52. Therapeutic Goods Administration (TGA) | Australian Government Department of Health, Disability and Ageing, accessed October 26, 2025, https://www.tga.gov.au/
53. Access to unregistered drugs in Australia - Australian Prescriber - Therapeutic Guidelines, accessed October 26, 2025, https://australianprescriber.tg.org.au/articles/access-to-unregistered-drugs-in-australia.html