Vixarelimab (KPL-716/RO7622888): A Dual Inhibitor of IL-31 and OSM Signaling via OSMRβ – Profile, Clinical Development, and Therapeutic Potential

1. Executive Summary

Vixarelimab, an investigational fully human monoclonal antibody also identified by the development codes KPL-716 and RO7622888/RG6536, is engineered to target the oncostatin M receptor beta (OSMRβ). This specific binding allows Vixarelimab to concurrently inhibit the signaling pathways of two pivotal cytokines: interleukin-31 (IL-31), a principal mediator of pruritus, and oncostatin M (OSM), which is significantly implicated in inflammatory processes, tissue remodeling, and fibrosis.[1] This dual inhibitory mechanism forms the core of its therapeutic rationale across a range of conditions characterized by these pathological features.

Under the initial development by Kiniksa Pharmaceuticals, Vixarelimab (then KPL-716) demonstrated considerable promise in early and mid-stage clinical investigations. A key highlight was the Phase 2a study (NCT03816891) in prurigo nodularis (PN), a chronic and profoundly debilitating skin disorder marked by severe itch and the formation of nodular lesions. In this trial, Vixarelimab achieved its primary efficacy endpoints, delivering statistically significant and clinically meaningful reductions in pruritus intensity and notable improvements in skin lesion appearance.[4] These compelling findings were instrumental in the U.S. Food and Drug Administration (FDA) granting Breakthrough Therapy designation to Vixarelimab for the treatment of pruritus associated with PN.[6]

A significant transition in Vixarelimab's development occurred in August 2022, when Kiniksa Pharmaceuticals licensed the global development and commercialization rights to Genentech, a member of the Roche Group.[3] This event precipitated a strategic realignment in the drug's developmental trajectory. Genentech is currently prioritizing the investigation of Vixarelimab in severe fibrotic conditions, including idiopathic pulmonary fibrosis (IPF) and systemic sclerosis-associated interstitial lung disease (SSc-ILD), as well as in systemic inflammatory disorders such as ulcerative colitis (UC).[3] Consequently, while Kiniksa had progressed plans for a Phase 2b trial in PN, this indication has been deprioritized under Genentech's stewardship.[1]

At present, Vixarelimab is under evaluation in several ongoing clinical trials led by Genentech. These include Phase 2 studies in UC (NCT06137183) [8], IPF, and SSc-ILD (NCT05785624) [10], alongside a Phase 1c/2 study in UC (NCT06693908) designed to yield deeper mechanistic understanding.[12] These studies are critical for further delineating the efficacy, safety profile, and pharmacokinetics of Vixarelimab in these complex and often refractory diseases. The strategic shift in focus by Genentech towards fibrotic and systemic inflammatory diseases, despite early successes in pruritic dermatological conditions, suggests a calculated assessment of Vixarelimab's dual mechanism. The inhibition of OSM, in particular, offers a robust rationale for addressing the inflammation and fibrosis central to conditions like IPF and UC, potentially representing larger markets or areas of higher unmet medical need than prurigo nodularis alone.

The unique capacity of Vixarelimab to concurrently modulate both IL-31 and OSM signaling by targeting the shared OSMRβ subunit is consistently presented as its primary differentiating attribute.[2] This dual action is hypothesized to confer a broader therapeutic impact than agents targeting only IL-31 or other individual inflammatory mediators, addressing not only symptomatic pruritus but also the underlying inflammatory and fibrotic processes. This forms the scientific basis for its investigation across such a diverse spectrum of pathologies.

2. Vixarelimab: Profile and Mechanism of Action

2.1. Introduction to Vixarelimab (KPL-716 / RO7622888)

Vixarelimab is an investigational biologic therapeutic, specifically a fully human monoclonal antibody of the IgG4 lambda isotype.[3] As a biotech product, its development has been marked by several identifiers corresponding to its different developmental stages and sponsoring entities. The fundamental characteristics and nomenclature of Vixarelimab are summarized in Table 1.

Table 1: Vixarelimab - Key Identifiers and Properties

Feature	Details	References
DrugBank Accession No.	DB16350	User Query, 16
CAS Number	2243320-83-2	User Query, 15
Type	Biotech, Fully Human Monoclonal Antibody, Human IgG4 lambda	10
Key Synonyms	KPL-716, RO7622888, RG6536, BIIB069, BIIB-069, Immunoglobulin g (234-proline,303-glutamine), anti-(human oncostatin m receptor subunit.beta.) (human monoclonal kpl-716.gamma.-chain), disulfide with human monoclonal kpl-716.lambda.-chain, dimer, 30C6 (N73D) IGG4P.AGLY/IGG1	7
Molecular Target	Oncostatin M Receptor Beta (OSMRβ)	1
Original Developer	Kiniksa Pharmaceuticals	3
Current Developer/Licensee	Genentech (a member of the Roche Group)	3

Vixarelimab was originated and its initial clinical development was conducted by Kiniksa Pharmaceuticals under the designation KPL-716.[14] In August 2022, Kiniksa entered into a global license agreement with Genentech, a subsidiary of Roche, granting Genentech the rights for the continued development and future commercialization of Vixarelimab.[1] Consequently, the drug is also identified by Roche/Genentech codes RO7622888 and RG6536.[7] The existence of multiple identifiers such as KPL-716, RO7622888, RG6536, and BIIB069 is a common occurrence in the pharmaceutical industry, reflecting the drug's journey through different stages of research, development, and corporate partnerships. Each code typically corresponds to the internal tracking system or nomenclature of the entity responsible for that phase of development. The transition from KPL-716 (Kiniksa) to RO7622888/RG6536 (Genentech/Roche) clearly marks the shift in primary developmental stewardship.

2.2. Molecular Target and Dual Inhibitory Mechanism

Vixarelimab exerts its pharmacological effects by specifically binding to the Oncostatin M Receptor Beta (OSMRβ), a transmembrane protein subunit that plays a crucial role in the signaling of two distinct cytokines: Interleukin-31 (IL-31) and Oncostatin M (OSM).[1]

IL-31 is a cytokine predominantly recognized for its role in mediating pruritus (itch). It signals through a heterodimeric receptor complex formed by the IL-31 receptor alpha (IL-31RA) subunit and OSMRβ.[1] By binding to OSMRβ, Vixarelimab interferes with the formation or functional signaling of this IL-31 receptor complex, thereby attenuating IL-31-driven itch signals.

Oncostatin M is a pleiotropic cytokine belonging to the IL-6 family, implicated in a wide array of biological processes including inflammation, hematopoiesis, and tissue remodeling, such as fibrosis and hyperkeratosis.[1] OSM can signal via two distinct receptor complexes:

1. Type I OSM Receptor: Composed of the leukemia inhibitory factor receptor (LIFR) and the common signaling subunit gp130.
2. Type II OSM Receptor: Composed of OSMRβ and gp130. Vixarelimab's interaction with OSMRβ specifically inhibits OSM signaling through the Type II receptor pathway.[2]

This targeted engagement with OSMRβ confers Vixarelimab with a dual inhibitory mechanism, allowing it to simultaneously block the signaling pathways of both IL-31 and OSM.[2] This dual action is considered a unique attribute of Vixarelimab. Kiniksa Pharmaceuticals has suggested that KPL-716 was the only monoclonal antibody in development designed to target both these pathways concurrently through a single receptor interaction.[6]

The therapeutic rationale for this dual inhibition stems from the distinct but often overlapping roles of IL-31 and OSM in various pathologies:

• Attenuation of Pruritus: Primarily achieved through the blockade of the IL-31/OSMRβ/IL-31RA pathway.[1]
• Modulation of Inflammation and Fibrosis: Largely mediated by the inhibition of OSM signaling via the OSMRβ/gp130 complex. This aspect is particularly relevant for the drug's development in inflammatory and fibrotic diseases.[1]

A critical aspect of Vixarelimab's mechanism is its selectivity. Preclinical evidence suggests that Vixarelimab does not bind to or inhibit the LIFR component of the Type I OSM receptor complex.[2] This is significant because the Type I receptor is utilized by OSM and LIF for other physiological functions, including aspects of hematopoiesis. By selectively targeting OSMRβ-mediated signaling, Vixarelimab may avoid interfering with these essential LIFR-dependent processes, potentially contributing to a more favorable safety and tolerability profile. This selective inhibition of the OSM Type II receptor pathway, while sparing Type I signaling, represents a nuanced pharmacological approach. It allows for the disruption of pathological OSM activities (inflammation and fibrosis) while potentially minimizing off-target effects associated with broader cytokine receptor blockade.

The combined inhibition of IL-31 (a key driver of itch) and OSM (a mediator of inflammation, fibrosis, and hyperkeratosis) provides a strong and unified mechanistic basis for Vixarelimab's investigation across a diverse array of clinical conditions. These range from dermatological disorders where itch and skin inflammation are prominent (such as prurigo nodularis and atopic dermatitis) to severe systemic inflammatory and fibrotic diseases like ulcerative colitis, idiopathic pulmonary fibrosis, and systemic sclerosis-associated interstitial lung disease. The OSMRβ subunit serves as a common molecular nexus for these pathological processes, making it a highly strategic target for therapeutic intervention.

3. Clinical Development and Therapeutic Applications

Vixarelimab has been investigated, or is currently under investigation, for a range of conditions where IL-31 and/or OSM signaling are believed to play significant pathophysiological roles. The clinical development program has evolved, with an initial focus on pruritic dermatoses by Kiniksa Pharmaceuticals, followed by a strategic shift towards fibrotic and systemic inflammatory diseases under Genentech. A summary of key clinical trials is presented in Table 2.

Table 2: Summary of Key Clinical Trials for Vixarelimab

NCT ID	Indication(s)	Phase	Sponsor(s)	Current Status	Key Efficacy Endpoints/Brief Results Summary (if available)	Key Safety Notes/Tolerability (if available)	References
NCT03816891	Prurigo Nodularis, Pruritus	2a	Kiniksa Pharmaceuticals, Ltd.	Completed	Primary: LS-mean PCFB WI-NRS @ Wk 8 (-50.6% Vixarelimab vs -29.4% Placebo; p=0.03). Secondary: PN-IGA 0/1 @ Wk 8 (30.4% Vixarelimab vs 7.7% Placebo; p=0.03).	Generally well-tolerated; TEAEs comparable to placebo. No serious TEAEs or discontinuations due to AEs in Vixarelimab arm.	4
Phase 1b AD Trial (No NCT ID specified in snippets)	Atopic Dermatitis (moderate-to-severe with moderate-to-severe pruritus)	1b	Kiniksa Pharmaceuticals, Ltd.	Completed	Reduction in WI-NRS (-40.4% Vixarelimab vs -17.6% Placebo @ Day 28, no TCS). Improved sleep. Reduction in EASI scores.	Single IV and SC doses well-tolerated in healthy volunteers and AD patients.	19
NCT06137183 (MOONGLOW)	Ulcerative Colitis (moderate to severe)	2	Genentech, Inc.	Active, not recruiting	Efficacy, safety, PK of Vixarelimab vs placebo.	Under evaluation.	7
NCT06693908	Ulcerative Colitis (moderate to severe, active)	1c/2	Genentech, Inc.	Recruiting	PD effects (change in inflammatory fibroblast products in colonic tissue), receptor occupancy, PK, safety.	Under evaluation.	7
CTR20241947	Ulcerative Colitis (moderate to severe)	2	Not specified (likely Genentech or partner)	Active, not recruiting	Efficacy, safety, PK in Chinese patients.	Under evaluation.	25
NCT05785624	Idiopathic Pulmonary Fibrosis (IPF), Systemic Sclerosis-associated Interstitial Lung Disease (SSc-ILD)	2	Genentech, Inc.	Recruiting	Efficacy (lung function, e.g., FVC), safety vs placebo.	Under evaluation.	1
NCT03858634	Chronic Pruritic Diseases (exploratory cohorts)	2	Kiniksa Pharmaceuticals, Ltd.	Completed	Efficacy, safety, tolerability in reducing pruritus across various conditions.	Generally well-tolerated across cohorts.	14

PCFB: Percent Change From Baseline; WI-NRS: Worst Itch-Numeric Rating Scale; PN-IGA: Prurigo Nodularis-Investigator's Global Assessment; TEAE: Treatment-Emergent Adverse Event; AD: Atopic Dermatitis; TCS: Topical Corticosteroids; EASI: Eczema Area and Severity Index; UC: Ulcerative Colitis; PK: Pharmacokinetics; PD: Pharmacodynamics; IPF: Idiopathic Pulmonary Fibrosis; SSc-ILD: Systemic Sclerosis-associated Interstitial Lung Disease; FVC: Forced Vital Capacity.

3.1. Prurigo Nodularis (PN)

Prurigo nodularis is a chronic inflammatory skin disorder characterized by intensely pruritic, firm, hyperkeratotic nodules, leading to a significant burden on patients' quality of life.[1] The severe itch often results in a persistent itch-scratch cycle, further exacerbating the lesions. At the time of Vixarelimab's early development for PN, there was a substantial unmet need due to the lack of FDA-approved therapies and the often inadequate relief provided by existing treatments.[1]

The cornerstone of Vixarelimab's investigation in PN was the NCT03816891 trial, a Phase 2a, randomized, double-blind, placebo-controlled study sponsored by Kiniksa Pharmaceuticals.[4] This multicenter trial, conducted in the US and Canada, enrolled 50 adult patients (18-75 years) with a confirmed diagnosis of PN for at least six months, at least 10 pruritic nodules, and moderate-to-severe pruritus (WI-NRS ≥7 at screening).[4] Participants received either weekly subcutaneous Vixarelimab (720 mg loading dose, then 360 mg) or placebo for an 8-week treatment period.[1]

The primary efficacy endpoint was the least squares (LS)-mean percent change from baseline (PCFB) at Week 8 in the weekly average WI-NRS score. Key results from this trial, as detailed in Table 3, demonstrated statistically significant and clinically meaningful improvements with Vixarelimab compared to placebo.

Table 3: Detailed Efficacy and Safety Results from NCT03816891 (Prurigo Nodularis at Week 8)

Outcome Measure	Vixarelimab Group (N=23)	Placebo Group (N=26)	LS-Mean Difference (95% CI) / Comparison	P-value	Reference(s)
LS-Mean PCFB WI-NRS	-50.6%	-29.4%	-21.2% (-40.82, -1.60)	0.03	4
Proportion with ≥4-point WI-NRS Reduction	52.2% (12/23)	30.8% (8/26)		0.11	4
Proportion with PN-IGA Score 0/1	30.4% (7/23)	7.7% (2/26)		0.03	4
LS-Mean PCFB Pruritus VAS	-54.4%	-32.6%	-21.8% (Difference not explicitly CI reported, but p-value given)	0.03	5
LS-Mean PCFB Sleep Loss VAS	-56.3%	-30.0%	-26.3% (Difference not explicitly CI reported, but p-value given)	0.02	5
Safety Summary
Any TEAE	91.3% (21/23)	76.9% (20/26)			4
Drug-Related TEAEs	43.5% (10/23)	38.5% (10/26)			4
Serious TEAEs / Discontinuations due to AEs	0%	0%			4

WI-NRS: Worst Itch-Numeric Rating Scale; PCFB: Percent Change From Baseline; PN-IGA: Prurigo Nodularis-Investigator's Global Assessment; VAS: Visual Analog Scale; TEAE: Treatment-Emergent Adverse Event.

The robust efficacy data, particularly the significant reduction in itch (the primary symptom) and the improvement in skin lesions (PN-IGA), alongside a favorable safety profile, were pivotal. These results demonstrated Vixarelimab's potential to address both the severe pruritus and the physical manifestations of PN rapidly, within an 8-week timeframe. This strong performance directly led to the FDA granting Breakthrough Therapy designation to Vixarelimab in November 2020 for the treatment of pruritus associated with PN.[6]

Despite this early success and regulatory recognition, the development trajectory for Vixarelimab in PN shifted following the licensing agreement with Genentech in 2022. Kiniksa had been preparing for a Phase 2b study in PN.[6] However, Genentech's strategic focus moved towards fibrotic and other inflammatory diseases, leading to the deprioritization of the PN indication.[1] Kiniksa subsequently announced they would not disclose data from the planned Phase 2b PN trial.[1] This change in direction highlights how corporate strategy and portfolio management can influence a drug's development path, even when early clinical data for a specific indication are promising.

3.2. Atopic Dermatitis (AD)

Kiniksa Pharmaceuticals also investigated KPL-716 (Vixarelimab) in atopic dermatitis, another chronic inflammatory skin condition characterized by intense pruritus. A Phase 1a/1b clinical trial included cohorts of adult healthy volunteers and adult subjects with moderate-to-severe AD who were also experiencing moderate-to-severe pruritus.[19]

In this early-phase study, single intravenous (IV) and subcutaneous (SC) doses of KPL-716 were found to be well-tolerated by both healthy individuals and AD patients.[20] More significantly, KPL-716 demonstrated an anti-pruritic effect in the AD patient cohort. During the initial 28-day period where concomitant topical corticosteroids (TCS) were not permitted, KPL-716 recipients experienced a mean percentage decrease in weekly-average WI-NRS of 40.4%, compared to a 17.6% decrease in placebo recipients. Similarly, the mean percentage change in Pruritus VAS was a reduction of 55.4% for KPL-716 versus 10.4% for placebo.[20] A clinically meaningful response, defined as a ≥4-point reduction in weekly-average WI-NRS, was achieved by 50% of KPL-716 recipients, in contrast to only 10% of those on placebo at Day 28.[20]

Beyond itch relief, KPL-716 treatment was associated with improved sleep, as indicated by a 59.5% decrease in sleep-loss VAS scores compared to a 2.3% decrease in the placebo group at Day 28 (without TCS).[20] The anti-pruritic effects appeared to be durable, persisting through Day 56, a period during which concomitant TCS use was allowed.[20] Furthermore, an encouraging reduction in Eczema Area and Severity Index (EASI) scores was noted after only a single dose of KPL-716, suggesting a potential impact on the overall severity of AD.[20]

These positive results from the Phase 1b AD study, demonstrating both safety and early signals of efficacy in reducing pruritus and improving disease parameters, provided crucial human proof-of-concept for the OSMRβ inhibition strategy in pruritic skin diseases. This supported Kiniksa's decision to advance KPL-716 into broader Phase 2 development for conditions like prurigo nodularis and other chronic pruritic diseases.[19] The findings were disseminated through presentations at medical conferences such as the American Academy of Dermatology (AAD) and the European Academy of Dermatology and Venereology (EADV).[2]

3.3. Development by Genentech (as RO7622888 / RG6536)

Following the global license agreement executed in August 2022, Genentech (a member of the Roche Group) assumed the primary responsibility for the development and commercialization of Vixarelimab.[3] This transition heralded a significant shift in the drug's clinical development focus, with Genentech prioritizing investigations into fibrotic and other severe inflammatory diseases, leveraging the anti-OSM arm of Vixarelimab's dual mechanism.[3]

3.3.1. Ulcerative Colitis (UC)

The rationale for investigating Vixarelimab in ulcerative colitis stems from the hypothesis that OSM signaling plays a role in the inflammatory fibroblast-myeloid axis implicated in UC pathogenesis.13

Several clinical trials are underway:

• NCT06137183 (MOONGLOW Study): This is a Phase 2, multicenter induction study with an optional active treatment extension period. It is designed to evaluate the efficacy, safety, and pharmacokinetics of Vixarelimab compared with placebo in adult participants with moderate to severe active UC who have had an inadequate response to, loss of response to, or intolerance to prior conventional or advanced therapies.[7] As of early 2025, this trial was reported as active but not recruiting.[8]
• NCT06693908: This is a Phase 1c/2, open-label, single-arm study designed to provide deeper mechanistic insights into Vixarelimab's action in UC. The primary objectives include evaluating pharmacodynamic effects in the gut (specifically, changes in inflammatory fibroblast products from colonic tissue), receptor occupancy, pharmacokinetics, and safety in approximately 24 patients with moderate to severe active UC.[7] This study aims to gather mechanistic data at earlier time points than feasible in the larger Phase 2 study, thereby informing the broader development program.[13] This trial is currently recruiting participants.[12]
• CTR20241947: A Phase 2 study is also listed in China for moderate to severe UC, which is active but not recruiting.[25]

The design of the Phase 1c UC study (NCT06693908), with its focus on direct tissue-based pharmacodynamic markers and receptor occupancy, illustrates a commitment to thoroughly understanding the drug's biological activity within the target organ early in the development for this new indication. Such an approach can help confirm the therapeutic hypothesis and de-risk later, more extensive clinical trials.

3.3.2. Idiopathic Pulmonary Fibrosis (IPF) and Systemic Sclerosis-associated Interstitial Lung Disease (SSc-ILD)

The involvement of OSM as a mediator of fibrosis provides a strong rationale for evaluating Vixarelimab in IPF and SSc-ILD, both of which are severe and progressive fibrotic lung diseases with high unmet medical needs.[1]

• NCT05785624: This is a Phase 2 study designed to evaluate the efficacy (primarily changes in lung function, such as Forced Vital Capacity - FVC) and safety of Vixarelimab compared with placebo in participants with IPF and in participants with SSc-ILD.[1] The study, which includes an optional open-label extension period where all participants can receive Vixarelimab, has an estimated enrollment of 320 participants and is currently recruiting.[10]

Genentech's strategic selection of IPF, SSc-ILD, and UC for Vixarelimab's continued development signals an intent to address severe conditions where the dual inhibition of inflammation (via IL-31 and OSM) and fibrosis (primarily via OSM) by OSMRβ blockade may offer a significant therapeutic advantage. Regulatory submissions for Vixarelimab in IPF and SSc-ILD in the US and EU are anticipated by Genentech in 2028 and beyond.[30]

3.4. Other Investigated Conditions (by Kiniksa)

Prior to the licensing agreement with Genentech, Kiniksa Pharmaceuticals conducted broader exploratory investigations of KPL-716 (Vixarelimab). An exploratory Phase 2 clinical trial, NCT03858634, was initiated to evaluate KPL-716 in a range of diseases characterized by chronic pruritus.[14] The objective of this trial was to identify specific chronic pruritic conditions where signaling through OSMRβ might play a pathogenic role and to assess the efficacy, safety, and tolerability of KPL-716 in reducing moderate-to-severe pruritus in these patient populations.[18] Kiniksa had planned to release interim data from this study on a cohort-by-cohort basis.[14]

According to DrugBank and other sources, completed trial cohorts under this or related investigational programs by Kiniksa included patients with Chronic Idiopathic Pruritus, Chronic Idiopathic Urticaria, Lichen Planopilaris, Lichen Simplex Chronicus, and Psoriasis Vulgaris (Plaque Psoriasis).[16] Specific, detailed results for these individual cohorts are not extensively available in the provided documentation. This broad exploratory approach is characteristic of early to mid-stage development for novel mechanisms, aiming to uncover the full therapeutic potential of an asset before committing to more focused, larger-scale trials.

4. Pharmacokinetics and Pharmacodynamics (PK/PD)

The pharmacokinetic (PK) and pharmacodynamic (PD) properties of Vixarelimab have been investigated in both preclinical models and human clinical trials.

Human Clinical Pharmacokinetics (Phase 1a/1b - KPL-716):

Data from the Phase 1a/1b study, which included healthy volunteers and patients with atopic dermatitis (AD), indicated that single intravenous (IV) and subcutaneous (SC) doses of KPL-716 were well-tolerated.20 The pharmacokinetic profile showed dose-dependent elimination, consistent with a target-mediated drug disposition (TMDD) profile.20 This observation suggests that Vixarelimab's clearance is, at least in part, influenced by its binding to its target, OSMRβ. At lower concentrations, receptor binding significantly contributes to drug elimination, potentially leading to non-linear pharmacokinetics. As doses increase and receptor sites approach saturation, other, typically slower, linear clearance mechanisms may become more dominant. This TMDD characteristic can influence dosing strategies and often indicates high-affinity target engagement. Notably, KPL-716 was detectable in circulation for at least eight weeks following a single high dose of 7.5 mg/kg IV in subjects with AD, suggesting a prolonged presence in the body, which could be indicative of a long terminal half-life or sustained tissue distribution and binding.20 However, specific quantitative human PK parameters such as maximum concentration (Cmax​), area under the curve (AUC), elimination half-life (t1/2​), detailed metabolism pathways, and excretion routes are not extensively detailed in the provided human trial summaries beyond these general observations.19

Human Clinical Pharmacodynamics (Phase 1a/1b - KPL-716 in AD):

The Phase 1a/1b study in AD patients provided early evidence of Vixarelimab's pharmacodynamic activity. Treatment with KPL-716 led to a reduction in pruritus, as measured by both the Worst-Itch Numeric Rating Scale (WI-NRS) and Pruritus Visual Analog Scale (VAS), and also resulted in improved sleep, assessed by a sleep-loss VAS.20 Specifically, 50% of KPL-716 recipients achieved a clinically meaningful ≥4-point reduction in weekly-average WI-NRS compared to 10% of placebo recipients at Day 28 (in the absence of concomitant topical corticosteroids).20 This anti-pruritic effect appeared to be sustained through Day 56, a period during which concomitant topical corticosteroid use was permitted.20 Furthermore, an encouraging reduction in Eczema Area and Severity Index (EASI) scores was observed after only a single dose, suggesting an impact on overall AD severity.20

Preclinical Pharmacodynamics (Cynomolgus Monkeys):

Preclinical PK/PD studies in cynomolgus monkeys using an IL-31 challenge model were instrumental in establishing an efficacious concentration range for KPL-716. These studies identified a target concentration of 5 – 8.5 µg/mL, at or above which KPL-716 provided protection from IL-31-induced pruritus (scratching behavior).21 Importantly, these preclinical PK/PD findings were reported to be predictive of the pruritus reduction observed in the human Phase 1a/1b AD clinical trial, validating the animal model for this specific pharmacological effect and providing a basis for dose selection in early human studies.21

Ongoing PK/PD Evaluation by Genentech:

Current clinical trials sponsored by Genentech continue to evaluate the PK and PD of Vixarelimab in its newer target indications:

• NCT06693908 (Phase 1c UC): Key objectives include the evaluation of receptor occupancy in colonic tissue and detailed pharmacokinetics.[13]
• NCT06137183 (Phase 2 UC): This study also includes pharmacokinetic evaluations as part of its design.[8]
• NCT05785624 (Phase 2 IPF/SSc-ILD): Standard Phase 2 trial designs typically incorporate PK and PD assessments to understand drug exposure and response relationships in the target patient population.

The results from these ongoing studies will be crucial for further characterizing Vixarelimab's PK/PD profile in these specific disease contexts and for optimizing dosing regimens.

5. Preclinical Evidence

Preclinical studies, encompassing both in vitro and in vivo models, have provided foundational support for Vixarelimab's mechanism of action and therapeutic potential.

Mechanism of Action Support (in vitro):

Vixarelimab (KPL-716) has been demonstrated to inhibit IL-31 and OSM signaling by targeting the OSMRβ subunit.10 A key piece of in vitro evidence comes from studies on human epidermal keratinocytes (HEK) and human dermal fibroblasts (HDF). In these cell types, KPL-716, at concentrations of 0.001 µg/mL or higher, significantly decreased the levels of Monocyte Chemoattractant Protein-1 (MCP-1/CCL2), both basally and when MCP-1 production was induced by OSM or a combination of OSM and IL-4.10 The maximum inhibitory effect on MCP-1/CCL2 was observed at KPL-716 concentrations of 0.01 µg/mL and 0.1 µg/mL.10 MCP-1/CCL2 is a potent chemokine responsible for the recruitment of monocytes, which are precursors to macrophages and play significant roles in inflammatory and fibrotic processes. The ability of Vixarelimab to reduce MCP-1/CCL2 production in skin-relevant cells provides a tangible cellular mechanism underpinning its anti-inflammatory effects, extending beyond simple receptor blockade. This finding is relevant not only for skin inflammation but also potentially for inflammatory processes in other tissues targeted by Vixarelimab, such as the gut in ulcerative colitis or the lungs in IPF and SSc-ILD.

Efficacy in Animal Models (in vivo):

• Pruritus Model (Cynomolgus Monkeys): In a non-human primate model, KPL-716 effectively reduced IL-31-induced scratching behavior. Pharmacokinetic/pharmacodynamic (PK/PD) modeling in these studies established an efficacious plasma concentration range of 5 – 8.5 µg/mL. This concentration range was subsequently found to be predictive of the anti-pruritic effects observed in human subjects with atopic dermatitis in the Phase 1a/1b clinical trial, lending strong translational validity to the animal model for this specific endpoint.[21]

General Support for OSMRβ Inhibition Strategy:

Preclinical data presented by Kiniksa Pharmaceuticals, for instance at the European Society of Dermatological Research (ESDR) meeting in 2019, further reinforced the scientific rationale for targeting OSMRβ for the treatment of chronic pruritic diseases. These presentations highlighted KPL-716's potential to treat such conditions by dually inhibiting both IL-31 and OSM pathways, thereby addressing both itch and underlying inflammation/fibrosis.18

Collectively, the preclinical evidence package for Vixarelimab established its mode of action, demonstrated relevant biological activity in vitro by modulating key inflammatory mediators like MCP-1, and showed in vivo efficacy in a relevant animal model of pruritus with translational PK/PD correlations to human responses. These findings were instrumental in supporting the progression of Vixarelimab into clinical development.

6. Developmental History and Corporate Licensing

Vixarelimab's journey from an early-stage investigational compound to its current status reflects a common trajectory in biopharmaceutical development, involving initial discovery and de-risking by a smaller biotech company followed by licensing to a larger pharmaceutical entity for broader and later-stage development.

Initial Development by Kiniksa Pharmaceuticals:

Vixarelimab, originally designated KPL-716, was discovered and developed by Kiniksa Pharmaceuticals.3 Kiniksa spearheaded the compound's advancement through comprehensive preclinical studies and into early to mid-stage clinical trials. This included a Phase 1a/1b program in healthy volunteers and patients with atopic dermatitis, which established initial safety, tolerability, and early signals of anti-pruritic efficacy.19 Building on these findings, Kiniksa initiated a pivotal Phase 2a trial (NCT03816891) in patients with prurigo nodularis, which successfully met its primary and key secondary endpoints, demonstrating significant reductions in itch and improvements in skin lesions.4 Kiniksa also conducted an exploratory Phase 2 trial (NCT03858634) to evaluate KPL-716 across a basket of other chronic pruritic conditions.14 A significant milestone during Kiniksa's stewardship was the granting of Breakthrough Therapy designation by the U.S. FDA in November 2020 for KPL-716 for the treatment of pruritus associated with prurigo nodularis, underscoring its potential to address a serious unmet medical need.6

Global Licensing Agreement with Genentech (Roche):

In August 2022, a significant strategic development occurred when Kiniksa Pharmaceuticals announced a global license agreement with Genentech, a member of the Roche Group. Under this agreement, Genentech acquired the exclusive rights to develop and commercialize Vixarelimab worldwide.1 The financial terms of the deal were substantial, with Kiniksa receiving $100 million in upfront and near-term payments, and eligibility for up to approximately $600 million in future clinical, regulatory, and sales-based milestones, in addition to royalties on net sales.3

This licensing agreement precipitated a notable shift in the primary development focus for Vixarelimab. Genentech articulated its intention to concentrate development efforts on fibrotic diseases, where OSM-mediated pathogenesis is considered a key therapeutic target.[3] Consequently, while Kiniksa had been advancing plans for a Phase 2b trial of Vixarelimab in prurigo nodularis, this indication was deprioritized by Genentech. Kiniksa subsequently stated it would no longer disclose data for the PN Phase 2b trial.[1] Post-licensing, Vixarelimab is also identified within the Roche/Genentech pipeline by the codes RO7622888 or RG6536.[7]

The decision by Kiniksa to license Vixarelimab, despite its promising results in PN, likely reflects the significant financial resources required for late-stage development and commercialization, particularly for multiple indications. The substantial upfront and milestone payments from Genentech provided Kiniksa with non-dilutive capital to allocate to other assets in its portfolio.[3] For Genentech, a larger organization with extensive experience in complex diseases, the acquisition of Vixarelimab represents an opportunity to leverage its dual mechanism, particularly the anti-OSM effects, in challenging areas like idiopathic pulmonary fibrosis, systemic sclerosis-associated interstitial lung disease, and ulcerative colitis. This strategic realignment underscores how the developmental path of a drug can be shaped by the differing priorities, resources, and strategic assessments of successive developing entities.

7. Conclusion and Future Perspectives

Vixarelimab (KPL-716/RO7622888) has emerged as an investigational monoclonal antibody with a distinct and compelling mechanism of action, characterized by its dual inhibition of IL-31 and OSM signaling through the specific targeting of OSMRβ. This unique pharmacological profile provides a strong scientific rationale for its therapeutic potential in a variety of conditions driven by pruritus, inflammation, and fibrosis.

The initial development by Kiniksa Pharmaceuticals yielded significant achievements, most notably the positive Phase 2a results in prurigo nodularis (NCT03816891). This study demonstrated Vixarelimab's ability to rapidly and meaningfully reduce itch and improve skin lesions, leading to an FDA Breakthrough Therapy designation for pruritus associated with PN.[4] Early Phase 1b data in atopic dermatitis also showed promising anti-pruritic signals and good tolerability.[20]

The current development landscape for Vixarelimab is spearheaded by Genentech, following a global licensing agreement. Genentech's strategy has pivoted towards addressing high unmet medical needs in severe systemic inflammatory and fibrotic diseases, specifically ulcerative colitis, idiopathic pulmonary fibrosis, and systemic sclerosis-associated interstitial lung disease.[3] Multiple Phase 2 and Phase 1c clinical trials are actively evaluating Vixarelimab's efficacy, safety, and pharmacokinetics in these challenging patient populations. While this strategic shift has deprioritized the prurigo nodularis indication, it opens avenues for Vixarelimab to potentially address diseases with profound systemic impact.

Future research will be critical in several areas. The outcomes of the ongoing Phase 2 trials in UC, IPF, and SSc-ILD will be paramount in defining Vixarelimab's clinical utility and therapeutic positioning in these conditions. Comprehensive characterization of its pharmacokinetic and pharmacodynamic profile in these diverse patient populations, along with long-term safety and efficacy data, will be essential for regulatory consideration. There may also be potential for Vixarelimab in other OSM or IL-31-mediated diseases that have not yet been extensively explored. Comparative efficacy studies against existing or other emerging therapies within these indications will further clarify its relative value.

If Vixarelimab proves successful in its current Genentech-led clinical programs, it could establish OSMRβ as a validated and important therapeutic target for a new class of drugs in severe fibrotic and inflammatory diseases, potentially extending beyond its initial promise in dermatology. This would represent a significant advancement, particularly for conditions like IPF and SSc-ILD where therapeutic options remain limited and the need for effective anti-fibrotic and anti-inflammatory agents is acute.

However, the deprioritization of prurigo nodularis by Genentech, despite the strong early clinical data and FDA designation, leaves an unresolved question regarding the future availability of Vixarelimab for this specific debilitating skin condition. Unless development for PN is revisited or pursued by another entity, patients with this condition may not benefit from this particular therapeutic agent. This situation underscores the complex interplay of scientific discovery, clinical evidence, market dynamics, and corporate strategy that ultimately shapes the journey of an investigational drug from bench to bedside. The ongoing and future studies will ultimately determine the full therapeutic impact of Vixarelimab's novel dual-inhibitory mechanism.

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