Bempikibart (ADX-914): A Comprehensive Report on an Investigational Anti-IL-7Rα Monoclonal Antibody for Autoimmune Diseases

1. Introduction to Bempikibart (ADX-914)

Overview of the Drug

Bempikibart, also identified by its research code ADX-914 and formerly BMS-986265, is an investigational biologic therapeutic agent.[1] It is classified as a fully human IgG1 kappa monoclonal antibody.[1] The primary molecular target of bempikibart is the alpha subunit of the interleukin-7 receptor (IL-7Rα).[2] The Chemical Abstracts Service (CAS) Registry Number for bempikibart is 2622254-57-1.[7]

Development History and Developer

Bempikibart is currently under development by Q32 Bio Inc..[2] The development pathway of bempikibart has involved several entities. Q32 Bio regained full worldwide development and commercial rights to bempikibart from Amgen in November 2023.[11] Amgen had acquired these rights through its acquisition of Horizon Therapeutics.[11] Prior to Amgen's involvement, Horizon Therapeutics plc had entered into a collaboration and option agreement with Q32 Bio in August 2022 to co-develop bempikibart for autoimmune diseases. Under this agreement, Horizon was to fund Phase 2 trials, with Q32 Bio managing operational aspects.[11] The earliest developmental code name identified in the provided materials is BMS-986265, suggesting initial work may have been conducted by or in association with Bristol Myers Squibb before Q32 Bio took leadership of the program.[8] This sequence of acquisitions and collaborations—from Bristol Myers Squibb to Q32 Bio, then a partnership with Horizon, its subsequent acquisition by Amgen, and finally Q32 Bio's re-acquisition of full rights—illustrates a complex but not uncommon trajectory for pharmaceutical assets. Such transitions can influence development timelines and strategic priorities. Q32 Bio's ultimate consolidation of worldwide rights signifies a strong commitment to bempikibart's potential and grants them full autonomy over its future development and commercialization, albeit with the corresponding financial and operational responsibilities.[11]

It is important to distinguish bempikibart from GSK3772847, which is mentioned in some research contexts.[14] GSK3772847 is identified as a human IgG2f monoclonal antibody targeting the IL-33 receptor (IL-33R or ST2), a different molecule and antibody isotype than bempikibart, which is an anti-IL-7Rα IgG1 kappa antibody.[1]

Therapeutic Rationale

Bempikibart is being developed with the therapeutic rationale of providing a disease-modifying anti-inflammatory effect in various autoimmune and inflammatory diseases.[2] The core principle behind its development is the re-regulation of adaptive immune function to restore immune homeostasis.[2] The selection of the IgG1 kappa isotype for bempikibart is noteworthy.[1] IgG1 antibodies are known for their capacity to engage Fc receptors and mediate effector functions such as antibody-dependent cell-mediated cytotoxicity (ADCC) and complement-dependent cytotoxicity (CDC). While the primary therapeutic action of bempikibart is the blockade of IL-7Rα, this IgG1 backbone could contribute to its overall biological activity profile or may have been engineered to minimize such effector functions if they are not desired for its specific immunomodulatory goals. This structural detail is relevant for a complete understanding of its potential interactions within the immune system beyond simple receptor antagonism.

Table 1: Bempikibart - Key Characteristics

Alias(es)	Drug Class	Target	Developer	Key Investigated Indications
ADX-914, formerly BMS-986265 1	Fully human anti-IL-7Rα IgG1 kappa monoclonal antibody 1	IL-7 Receptor Alpha (IL-7Rα) 2	Q32 Bio Inc. 2	Alopecia Areata, Atopic Dermatitis (current focus on Alopecia Areata) 6

2. Mechanism of Action

Targeting IL-7Rα

Bempikibart is a fully human monoclonal antibody that specifically targets the Interleukin-7 Receptor alpha subunit (IL-7Rα).[2] The IL-7Rα chain is a critical component of the receptors for two distinct cytokines: Interleukin-7 (IL-7) and Thymic Stromal Lymphopoietin (TSLP).[2]

Dual Pathway Inhibition

By binding to the common IL-7Rα subunit, bempikibart effectively blocks the signaling pathways mediated by both IL-7 and TSLP.[2] This dual inhibitory action is a central feature of its proposed mechanism. The blockade of these two cytokine pathways is intended to reduce receptor activation, thereby re-regulating adaptive immune function and helping to restore immune homeostasis in pathological states.[2]

The dual inhibition of IL-7 and TSLP signaling represents a potentially significant differentiation from therapies that target only a single cytokine. IL-7 is fundamentally important for T-cell development, proliferation, survival, and the maintenance of T-cell memory and homeostasis. TSLP, an epithelial-derived cytokine, is recognized for its role in initiating and promoting Type 2 inflammatory responses, particularly in allergic diseases, but it also influences a broader range of T-cell subsets and immune activities. By concurrently targeting both these pathways, bempikibart may achieve a more comprehensive modulation of the adaptive immune system. This broader immunomodulatory effect could underpin the "remittive effect" and "durability of response" observed in alopecia areata clinical trials, suggesting a potential to reset T-cell homeostasis rather than merely providing temporary symptom suppression.[9] This characteristic is particularly noteworthy when compared to treatments like JAK inhibitors, which often require continuous administration to maintain efficacy in conditions such as alopecia areata.[19]

Role of IL-7 and TSLP in Autoimmunity

Both IL-7 and TSLP pathways are genetically and biologically implicated as key drivers of T-cell-mediated pathological processes in a variety of autoimmune and inflammatory diseases.[3] IL-7 signaling is crucial for the development and maintenance of T-lymphocytes, and its dysregulation can contribute to the survival and expansion of autoreactive T-cells involved in autoimmune conditions.[9] TSLP, often produced by epithelial cells in response to inflammatory stimuli, can promote Th2 cell differentiation and the production of pro-inflammatory cytokines, contributing to conditions like atopic dermatitis and asthma, and is also implicated in other T-cell driven pathologies.[17]

The therapeutic strategy of bempikibart focuses on "re-regulating adaptive immune function" and "restoring immune homeostasis," which implies a more nuanced intervention than broad immunosuppression.[2] Many conventional autoimmune therapies act by generally dampening the immune system, which can lead to an increased risk of infections and other complications. A therapy that aims to "re-regulate" or "re-balance" immune responses suggests a more targeted approach, potentially correcting the specific dysfunctions underlying the autoimmune disease while preserving essential protective immunity. If bempikibart successfully achieves this, it could offer a more favorable long-term safety profile and more sustained disease control, reducing the need for continuous, broad immunosuppressive treatments, which is a significant consideration for chronic autoimmune disorders.

Rationale for Use in Targeted Indications

The mechanism of bempikibart provides a strong rationale for its investigation in specific autoimmune conditions:

• Alopecia Areata (AA): AA is understood as a T-cell mediated autoimmune disease where immune cells attack hair follicles. The inhibition of IL-7 and TSLP signaling by bempikibart is proposed as a novel approach to address this underlying autoimmune process by modulating T-cell activity and associated inflammation.[21]
• Atopic Dermatitis (AD): AD is a chronic inflammatory skin condition characterized by Th2-skewed immune responses, where TSLP plays a significant role in initiating and amplifying inflammation. IL-7's role in T-cell maintenance also contributes to chronic inflammation. By blocking both pathways, bempikibart aims to reduce the skin inflammation and alleviate the symptoms associated with AD.[1]

3. Clinical Development in Alopecia Areata (SIGNAL-AA Trial - NCT06018428)

Bempikibart is being actively investigated for the treatment of alopecia areata (AA) in the SIGNAL-AA clinical trial program, registered under NCT06018428.[23]

Study Design

The SIGNAL-AA trial is a Phase 2a study designed to evaluate the efficacy, safety, and tolerability of bempikibart in adult patients with severe alopecia areata.[23] The trial is structured in multiple parts:

• Part A: This was a randomized, double-blind, placebo-controlled, multi-center proof-of-concept (POC) segment. Adult patients (18-75 years) with severe to very severe AA, defined by Severity of Alopecia Tool (SALT) scores of 50-100 at baseline, were enrolled.[18] Participants were randomized in a 3:1 ratio to receive either bempikibart 200 mg administered subcutaneously (SC) every two weeks (Q2W) or a matching placebo for a duration of 24 weeks. This treatment period was followed by a 12-week post-treatment follow-up, extending to week 36.[18] A total of 44 patients were enrolled in Part A.[28] For efficacy analysis, following the exclusion of one site due to marked protocol violations affecting three placebo patients, the modified intent-to-treat (mITT) population comprised 41 patients, and the per-protocol population was 27 patients.[18] Part A has been completed.[23]
• Part A Open-Label Extension (OLE): Initiated in the first half of 2025, the OLE allows eligible patients who completed Part A to receive continued treatment with bempikibart. This extension follows the same dosing regimen as Part A (200 mg Q2W SC) and is designed to gather longer-term efficacy and safety data.[10] Enrollment and dosing in the OLE were ongoing as of May 2025.[16] The initiation of the OLE was based on strong re-consent rates and patient demand for continued dosing.[10]
• Part B: This segment is an open-label, multicenter study. Dosing in Part B was initiated in the first half of 2025.[10] It aims to enroll approximately 20 evaluable patients with severe or very severe AA. Part B incorporates a loading dose regimen: patients receive bempikibart 200 mg SC weekly for the first four weeks, followed by a maintenance dose of 200 mg SC Q2W for the subsequent 32 weeks. This results in a total treatment duration of 36 weeks, with a follow-up period extending to 52 weeks.[10] Topline data from Part B are anticipated in the first half of 2026.[10] This part of the trial is intended to provide data to support advancement into pivotal trials.[33]

Eligibility Criteria

Key inclusion criteria for the SIGNAL-AA trial include adult men and women aged 18 to 75 years with a clinical diagnosis of severe to very severe alopecia areata, defined as ≥50% total scalp hair loss at screening and baseline as measured by the SALT score.23

Key exclusion criteria encompass a history or current diagnosis of other forms of alopecia, prior hair transplants or scalp micropigmentation, use of systemic or topical therapies for AA within specified washout periods, and a history of recent or current clinically serious infections.23

Outcome Measures

The primary outcome measure for Part A was the mean relative percent change in SALT score at 24 weeks compared with baseline.[23] For Part B, the primary efficacy endpoints include the proportion of patients achieving a 30% or greater reduction in SALT score from baseline (SALT30) and the proportion of patients achieving a SALT score of 20 or less (SALT20) at week 36, with follow-up through week 52.[10] Secondary outcome measures across the trial include various thresholds of SALT score improvement (e.g., SALT ≤5, ≤10, ≥50% reduction) at different time points, and comprehensive safety assessments.[18]

Key Efficacy Findings (SIGNAL-AA Part A)

Data from Part A of the SIGNAL-AA trial, particularly from the per-protocol population (n=27 after site exclusion, unless otherwise specified), have shown encouraging clinical activity.[9] These results were presented as a late-breaker at the American Academy of Dermatology (AAD) Annual Meeting in March 2025.[17]

• Mean SALT Score Reduction [17]:
• At Week 24: Patients treated with bempikibart demonstrated a mean reduction in SALT score of 16%, compared to a 2% reduction in the placebo group. This difference was statistically significant (Wilcoxon Rank Sum test, p=0.045).[18]
• At Week 26: The mean SALT score reduction in the bempikibart group (severe and very severe disease) was 18%, versus a 2% reduction in the placebo group.[18]
• Mean SALT Score Reduction [9]:
• At Week 24: A mean reduction of 24.5% [9] or 25% [18] was observed.
• At Week 26: This improved to a 27% mean reduction.[18]
• At Week 36 (12 weeks post-dosing cessation): A mean reduction of 27.8% [9] or 28% [18] was reported, indicating continued improvement off-treatment.
• SALT20 Responders (SALT score ≤ 20) (Baseline SALT 50-100):
• At Week 24: 9% of patients in the bempikibart group achieved SALT20, compared to 0% in the placebo group.[17]
• At Week 26: This increased to 13-14% in the bempikibart group versus 0% in the placebo group.[18]
• SALT20 Responders (Baseline SALT 50-95):
• At Week 24: 13% of bempikibart patients achieved SALT20, compared to 0% in the placebo group.[18]
• At Week 26: This improved to 21% in the bempikibart group versus 0% in the placebo group.[18]
• SALT30 Responders (≥30% SALT improvement) [9]:
• At Week 24: 26.7% achieved SALT30.
• At Week 26: 28.6% achieved SALT30.
• At Week 36: 53.8% achieved SALT30, nearly doubling the response rate observed at the end of treatment.
• Durability and Potential Remittive Effect: A key observation from SIGNAL-AA Part A is the continued improvement and durable responses seen after the 24-week treatment period ended. Mean SALT scores continued to decrease, and responder rates increased during the 12-week post-treatment follow-up (up to Week 36) and even beyond, with some patients showing ongoing responses up to Week 55 (approximately 7 months after the last dose).[9] Among 12 re-consented patients who had shown a SALT response during the trial, all either maintained their response or exhibited further hair regrowth post-treatment. Seven of these 12 patients demonstrated additional hair growth by SALT assessment, with a median follow-up of 44 weeks at the time of reporting.[18] This sustained effect off-drug is considered a potential differentiating factor from existing AA therapies and suggests a possible remittive effect of bempikibart.[10] The underlying biological basis for this durability is hypothesized to be linked to the drug's mechanism involving IL-7 on-mechanism modulation, potentially rebalancing T effector memory cells and T regulatory function.[18]

The exclusion of one clinical trial site from the efficacy analysis in Part A due to "marked protocol violations of entry criteria" is an important consideration.[28] This led to a reduction in the analysable patient pool and rendered the original statistical plan for the primary endpoint inappropriate. Consequently, a post-hoc analysis was performed on the per-protocol population. While this analysis yielded a statistically significant result for SALT score reduction (p=0.045) [18], the robustness of findings from post-hoc analyses on modified populations can sometimes be viewed with more caution than primary analyses on the full intent-to-treat population as per the original statistical plan. This highlights the critical importance of consistent site conduct and data integrity in clinical trials. The SIGNAL-AA Part B, with its open-label design and loading dose, aims to further confirm and expand upon these findings.

The introduction of a loading dose regimen (200mg weekly for 4 weeks, followed by Q2W maintenance) in SIGNAL-AA Part B is a strategic adaptation.[10] This approach is often employed to rapidly achieve therapeutic drug concentrations and saturate target receptors, potentially leading to a faster onset of action or a more profound initial response. Given the encouraging but modest mean SALT reductions in Part A, the loading dose in Part B may be intended to enhance the magnitude and/or speed of hair regrowth. This demonstrates an adaptive approach to clinical development, refining the treatment strategy based on emerging data to maximize therapeutic potential.

Safety and Tolerability (SIGNAL-AA Part A)

Bempikibart was reported to be generally safe and well-tolerated in the SIGNAL-AA Part A trial.[10]

• No Grade 3 or higher treatment-related adverse events were observed.[10]
• No related viral infections were reported in patients receiving bempikibart.[17]
• Treatment-emergent adverse events (TEAEs) were described as mild to moderate. One report indicated TEAEs occurred in 70% of the bempikibart group versus 38% in the placebo group, though specific AEs were not detailed.[17] More detailed breakdowns of common mild/moderate AEs are not available in the provided information.[39]

Biomarker Data and Pharmacodynamic Effects (SIGNAL-AA Part A)

The trial demonstrated robust pharmacologic activity and desired target engagement.[10]

• This was evidenced by receptor occupancy.
• Significant changes in Th2 biomarkers were observed, including reductions in TARC (thymus and activation-regulated chemokine), IgE (immunoglobulin E), and eosinophils.
• Expected on-mechanism changes in T-cell populations, specifically a 20-30% reduction in CD3+ T-cells, were noted, consistent with potent IL-7 and TSLP inhibition.

Current Status and Future Plans for Alopecia Areata Program

• SIGNAL-AA Part A has been completed.[23]
• The Part A Open-Label Extension (OLE) was initiated in the first half of 2025, with patient enrollment and dosing ongoing as of May 2025.[10]
• Dosing in SIGNAL-AA Part B was also initiated in the first half of 2025, with topline data anticipated in the first half of 2026.[10] Part B is designed to provide further evidence to support advancement into pivotal trials.[33]
• Q32 Bio has undergone a corporate restructuring (February 2025) to strategically focus its resources on the advancement of bempikibart for alopecia areata, driven by the encouraging data from this program.[10]

Table 2: Summary of SIGNAL-AA (Alopecia Areata) Phase 2a Trial

Part	Design	Patient Population (N, Baseline SALT)	Intervention (Dose, Duration)	Key Endpoints	Key Efficacy Results	Key Safety Findings
Part A	Randomized, double-blind, placebo-controlled, multi-center POC 18	Adults (18-75 yrs) with severe/very severe AA (SALT 50-100).18 N=44 enrolled; N=27 per-protocol for efficacy 18	Bempikibart 200 mg SC Q2W or Placebo for 24 weeks; 12-week follow-up 18	Primary: Mean relative % change in SALT at Wk 24. Secondary: Various SALT improvements, safety 18	SALT 50-100 @ Wk 24: -16% Bemp vs -2% PBO (p=0.045).18 SALT 50-95 @ Wk 24: -25% Bemp.18 SALT20 (50-100) @ Wk 24: 9% Bemp vs 0% PBO.18 Durability: Continued improvement post-dosing up to Wk 55 in some patients.10	Generally well-tolerated. No Grade 3+ related AEs. No related viral infections. Mild/moderate TEAEs: 70% Bemp vs 38% PBO.10
Part A OLE	Open-label extension 10	Eligible patients from Part A 10	Bempikibart 200 mg SC Q2W 10	Long-term efficacy & safety 10	Data collection ongoing; initiated 1H'25 10	Ongoing assessment.
Part B	Open-label, multi-center 10	~20 evaluable adults with severe/very severe AA 10	Bempikibart 200 mg SC weekly x 4 wks (loading), then 200 mg Q2W for 32 wks (total 36 wks treatment); 16-week follow-up 10	Primary: SALT30 and SALT20 at Wk 36. Secondary: Other SALT improvements, safety 10	Topline data expected 1H'26; initiated dosing 1H'25 10	Ongoing assessment.

4. Clinical Development in Atopic Dermatitis (SIGNAL-AD Trial - NCT05509023)

Bempikibart was also evaluated for the treatment of atopic dermatitis (AD) in the SIGNAL-AD trial (NCT05509023).[1]

Study Design

The SIGNAL-AD trial was a Phase 2a, randomized, double-blind, placebo-controlled, multi-center proof-of-concept (POC) study conducted in adult subjects with persistent moderate to severe AD.[22]

• Structure: The study was designed in two parts:
• Part A: This part was conducted to evaluate safety, pharmacokinetics (PK), and to enable dose selection for Part B. It involved up to three cohorts of subjects randomized 2:1 to receive bempikibart or placebo.[22] Doses evaluated were 2mg/kg or 3mg/kg Q2W SC for 12 weeks.[30] Part A enrolled 15 patients and has been completed, with data initially remaining blinded.[22]
• Part B: This part was designed to evaluate the efficacy and safety of bempikibart compared to placebo. Patients were enrolled in a 1:1 ratio to receive either bempikibart 200 mg as a flat SC dose Q2W or placebo for 12 weeks of treatment, followed by an additional 12-week follow-up period.[22] Part B enrolled 106 patients (52 in the bempikibart arm, 54 in the placebo arm).[30]
• Total Enrollment: The trial enrolled a total of 121 patients (15 in Part A and 106 in Part B), exceeding the initial target of approximately 100 patients due to high patient enrollment demand.[22]

Eligibility Criteria

Key inclusion criteria for the SIGNAL-AD trial included adults (≥18 years) with a diagnosis of chronic AD for at least 3 years, and moderate to severe disease activity at baseline (defined as Body Surface Area (BSA) affected ≥10%, Eczema Area and Severity Index (EASI) Score ≥12, and Investigator's Global Assessment (IGA) Score ≥3).1 Participants were also required to have a history of inadequate response to at least one standard AD therapy, such as topical corticosteroids, other topical immunomodulators, systemic steroids, phototherapy, oral synthetic immunomodulators, or approved systemic biologics/JAK inhibitors.50

Exclusion criteria included recent or current clinically serious infections, use of live vaccines within 12 weeks prior to or during the study, and other active autoimmune diseases that could interfere with AD assessment.1

Outcome Measures

The primary endpoint for Part B of the SIGNAL-AD trial was the mean percent change from baseline to week 14 in the EASI score.[22] Secondary and other outcome measures included the Scoring Atopic Dermatitis (SCORAD) score, validated Investigator Global Assessment for Atopic Dermatitis (vIGA-AD) score, and safety assessments.[1]

Key Efficacy Findings (SIGNAL-AD)

Topline results from the SIGNAL-AD trial were announced on December 10, 2024.[16]

• Part A (Week 14, pooled bempikibart data): Patients treated with bempikibart showed a 72% improvement in average EASI score from baseline. Specifically, the 2mg/kg Q2W SC cohort showed a 58% improvement, and the 3mg/kg Q2W SC cohort showed an 84% improvement. This compared to a 38% improvement in patients treated with placebo in Part A.[30]
• Part B (Primary Endpoint at Week 14): Patients treated with bempikibart (200 mg Q2W SC) showed a 74% improvement in average EASI score from baseline. However, patients in the placebo group showed a 76% improvement in average EASI score from baseline. The difference between the bempikibart and placebo groups was not statistically significant.[16] Consequently, the trial did not meet its primary efficacy endpoint.[16]

The failure of SIGNAL-AD Part B to demonstrate a statistically significant improvement over placebo was a critical development for the bempikibart program in atopic dermatitis. Despite encouraging biomarker activity suggesting target engagement and positive signals from Part A of the study [30], the lack of separation from a high placebo response in Part B significantly impacted the viability of AD as a lead indication. The placebo arm in Part B exhibited a substantial 76% improvement in EASI scores, a phenomenon not uncommon in AD trials where placebo effects can be pronounced. This high placebo response makes it inherently challenging to demonstrate a statistically significant benefit for an active drug, even if the drug possesses therapeutic activity, as suggested by the 74% EASI improvement in the bempikibart arm.

Safety and Tolerability (SIGNAL-AD)

Across the SIGNAL-AD trial, bempikibart was observed to be safe and well tolerated.[30]

• There were no serious adverse events (SAEs) related to treatment reported.
• No Grade 3 or higher adverse events related to treatment were reported.[16]

Current Status of the Atopic Dermatitis Program

Following the announcement of the topline results in December 2024, Q32 Bio stated its intention to conduct a review of the SIGNAL-AD results.[28] Subsequently, in February 2025, the company announced a corporate restructuring to prioritize the development of bempikibart for alopecia areata, based on the more encouraging and potentially differentiating data from the SIGNAL-AA program.[10] While not all communications explicitly state discontinuation of the AD program, the strategic shift strongly implies its deprioritization. News reports from February 2025 indicated that bempikibart "failed primary endpoint in Atopic Dermatitis Trial".[16] As of March 2025, the company's focus was clearly on alopecia areata, with strategic options being evaluated for other programs.[29]

Table 3: Summary of SIGNAL-AD (Atopic Dermatitis) Phase 2a Trial (NCT05509023)

Part	Design	Patient Population (N)	Intervention (Dose, Duration)	Key Endpoints	Key Efficacy Results (EASI Improvement from Baseline at Wk 14)	Key Safety Findings	Current Status
Part A	Randomized, double-blind, placebo-controlled dose-finding 51	Adults with moderate-to-severe AD (N=15) 42	Bempikibart 2mg/kg or 3mg/kg SC Q2W, or Placebo, for 12 weeks 42	Safety, PK, EASI change 42	Bemp (pooled): 72%; PBO: 38%. (2mg/kg: 58%; 3mg/kg: 84%) 42	Safe and well-tolerated; no SAEs or Grade 3+ related AEs 42	Completed; Data informed Part B 52
Part B	Randomized, double-blind, placebo-controlled efficacy 52	Adults with moderate-to-severe AD (Bemp: 52, PBO: 54) 42	Bempikibart 200mg SC Q2W or Placebo for 12 weeks 42	Primary: Mean % change in EASI at Wk 14 52	Bemp: 74%; PBO: 76% (p=not statistically significant) 42	Safe and well-tolerated; no SAEs or Grade 3+ related AEs 42	Completed; Primary endpoint not met. Program deprioritized 10

5. Pharmacokinetics and Pharmacodynamics (PK/PD)

Phase 1 Data (Healthy Volunteers)

A Phase 1 study (ADX-914-001, NCT04485481) was conducted to assess the safety, pharmacokinetics (PK), and pharmacodynamics (PD) of bempikibart in healthy adult volunteers, utilizing single ascending dose (SAD) and multiple ascending dose (MAD) cohorts.[8]

• Tolerability: Bempikibart was reported to be generally well-tolerated in healthy volunteers up to doses of 4 mg/kg.[60]
• PK/PD Profile: The study demonstrated an attractive PK/PD profile that supported a subcutaneous (SC) dosing regimen of every two weeks (Q2W).[60]
• Target Engagement: Full IL-7 receptor occupancy (RO) and inhibition of downstream signaling (pSTAT5 inhibition) were observed at a dose of 1 mg/kg SC in the MAD cohort (4 doses Q2W through Day 43).[60]
• T-Cell Effects: A reversible decrease in T effector cells (Teff) was noted, with no observed effect on T regulatory cells (Tregs).[60]
• Immunogenicity: No impact of anti-drug antibodies (ADA) on the pharmacological effects or safety profile of bempikibart was observed in this Phase 1 study.[60]
• Specific PK Parameters: Detailed numerical pharmacokinetic parameters such as Cmax, Tmax, elimination half-life, clearance, and volume of distribution from the Phase 1 healthy volunteer study are not explicitly provided in the available documentation, other than a target PK threshold of >5 µg/mL being associated with full target engagement in tissue, which supported the 200 mg SC flat dosing (~2.7 mg/kg) used in Phase 2.[60]

Phase 2 PK/PD Findings

Pharmacokinetic and pharmacodynamic assessments were also integral to the Phase 2 trials in atopic dermatitis (SIGNAL-AD) and alopecia areata (SIGNAL-AA).[10]

• Receptor Occupancy: In Part A of the SIGNAL-AD trial, both the 2mg/kg and 3mg/kg Q2W SC dose groups achieved maximal IL-7Rα occupancy (>90%) by day 3, and this high level of occupancy was maintained throughout the dosing period.[60] A Phase 2 PK run-in study confirmed the suitability of the Phase 2 dose.[60]
• Target Engagement & Biomarker Changes: Across both SIGNAL-AA and SIGNAL-AD trials, bempikibart demonstrated robust pharmacologic activity and desired target engagement. This was evidenced by receptor occupancy and significant modulations in relevant biomarkers.[10]
• Th2 Pathway Modulation: Substantial reductions in Th2-associated biomarkers, including TARC, IgE, and eosinophils, were observed. These changes are indicative of potent TSLP inhibition and are consistent with effects seen with other agents targeting Th2 pathways in atopic dermatitis.[10]
• T-Cell Modulation: Expected on-mechanism changes in T-cell populations were noted, specifically a 20-30% reduction in circulating CD3+ T-cells, consistent with IL-7Rα blockade and potent IL-7 inhibition.[10]
• Immunogenicity (Phase 2): In the SIGNAL-AD Part A study, low-titer ADAs were detected, but these did not appear to have an impact on the pharmacokinetic profile of bempikibart.[51]

The consistent demonstration of target engagement across both Phase 1 and Phase 2 studies—evidenced by IL-7Rα occupancy, inhibition of pSTAT5 signaling, modulation of T-cell subsets, and reduction in Th2-associated biomarkers—is crucial for validating bempikibart's mechanism of action in human subjects.[10] Such data provide confidence in the therapeutic hypothesis. The observed biomarker changes support the rationale for investigating bempikibart in Th2-driven conditions like atopic dermatitis and T-cell mediated diseases such as alopecia areata. However, the divergence between strong biomarker modulation and the failure to meet the primary clinical endpoint in the SIGNAL-AD Part B trial highlights the complexities of translating biological activity into clinical efficacy, possibly due to factors like patient heterogeneity, the specific clinical endpoints chosen, or the significant placebo response observed in that trial.[16]

The Q2W SC dosing regimen, supported by Phase 1 data and utilized in Phase 2 trials, offers a convenient administration schedule for patients.[1] The decision to incorporate a weekly loading dose in the SIGNAL-AA Part B trial suggests an effort to further optimize the dosing strategy, potentially to achieve faster or more pronounced therapeutic effects by rapidly reaching and maintaining optimal drug concentrations and target engagement.[10] This adaptive approach to dose exploration is a positive indicator of Q32 Bio's commitment to maximizing the clinical benefit of bempikibart.

6. Safety Profile Across Clinical Trials

Bempikibart has generally demonstrated a favorable safety and tolerability profile in clinical trials conducted to date, encompassing Phase 1 studies in healthy volunteers and Phase 2a trials in patients with atopic dermatitis (SIGNAL-AD) and alopecia areata (SIGNAL-AA).[10]

Serious Adverse Events (SAEs) and Severe AEs

A consistent finding across the reported trial data is the absence of Grade 3 or higher treatment-related adverse events in both the SIGNAL-AA Part A trial and the SIGNAL-AD trial.[10] Furthermore, across all clinical trials involving 130 patients dosed with bempikibart as of a March 2025 report, no Grade 3 or higher related adverse events were noted.[29] No serious adverse events (SAEs) related to treatment were reported in either the SIGNAL-AA or SIGNAL-AD Phase 2a trials.[30]

Specific Adverse Events of Note

• Viral Infections: In the SIGNAL-AA Part A trial, no related viral infections were reported in the bempikibart group.[17] This is a particularly relevant finding for an immunomodulatory agent.
• Lymphopenia: In the Phase 2 AD Part A study, no CTCAE Grade ≥3 lymphopenia was observed, and no lymphopenia-associated AEs, including viral infections, were reported.[60] One instance of Grade 1 Mild Lymphopenia was reported in a bempikibart-treated patient, although the specific trial context (AD or AA) was not clearly delineated in that particular snippet.[63]
• Overall TEAEs in SIGNAL-AA Part A: While specific AEs were not detailed, one report mentioned that treatment-emergent adverse events (TEAEs) in SIGNAL-AA Part A were mild to moderate, occurring in 70% of patients in the bempikibart group compared to 38% in the placebo group.[17] A detailed breakdown of these common AEs by type and specific frequency is generally not available in the provided information.[17]

Safety-Related Exclusions in Clinical Trials

Standard safety precautions were implemented in clinical trial designs. For instance, patients with recent or current serious infections were excluded from the atopic dermatitis trial, and the administration of live vaccines was restricted prior to and during study participation.[1]

The consistent reporting of a "well-tolerated safety profile," particularly the absence of severe (Grade 3 or higher) treatment-related adverse events and the lack of signals for increased viral infections, is a significant positive aspect for bempikibart.[10] This is especially relevant given its immunomodulatory mechanism of action. Therapies that affect the immune system often carry inherent risks of immunosuppression, potentially leading to an increased susceptibility to infections or other immune-related adverse events. The data available so far suggest that bempikibart might achieve its immunomodulatory effects without inducing broad immunosuppression, which would be a considerable advantage over some existing therapies for autoimmune conditions, such as JAK inhibitors, which often carry warnings regarding serious infections.[19] A strong safety profile, particularly concerning the risk of infections, would make bempikibart an attractive option for patients, especially for long-term management, should its efficacy be robustly confirmed in later-phase trials.

However, the observation that mild to moderate TEAEs were more frequent in the bempikibart group (70%) compared to the placebo group (38%) in SIGNAL-AA Part A necessitates further clarification.[17] While the events were not severe, understanding the nature and specific types of these more common, albeit less severe, side effects is important for a complete assessment of the drug's overall tolerability. The lack of a detailed breakdown of these AEs in the current documentation represents an information gap that will hopefully be addressed in future publications or presentations.

Table 4: Summary of Reported Adverse Events for Bempikibart (Consolidated from available data)

Trial/Indication	Adverse Event Category	Frequency/Percentage (Bempikibart vs. Placebo if available)	Severity Notes	Source(s)
SIGNAL-AA Part A	Overall TEAEs	70% Bemp vs 38% PBO	Mild to moderate	17
SIGNAL-AA Part A & SIGNAL-AD	Grade 3+ Related AEs	None reported	N/A	10
SIGNAL-AA Part A & SIGNAL-AD	SAEs Related to Treatment	None reported	N/A	30
SIGNAL-AA Part A	Related Viral Infections	None reported in Bemp group	N/A	17
SIGNAL-AD Part A	Lymphopenia (CTCAE Grade ≥3)	None observed	N/A	60
SIGNAL-AD Part A	Lymphopenia-associated AEs	None observed	N/A	60
Bempikibart (unspecified trial)	Mild Lymphopenia	One Grade 1 case reported	Mild	63

7. Regulatory Status and Designations

FDA Fast Track Designation (FTD) for Alopecia Areata

On April 30, 2025, Q32 Bio announced that the United States Food and Drug Administration (FDA) granted Fast Track Designation (FTD) to bempikibart (ADX-914) for the treatment of alopecia areata.[3] This designation is intended for drugs that treat serious conditions and fill an unmet medical need. The FDA's decision recognized the seriousness of AA and the current lack of sufficient treatment options, underscoring the potential of bempikibart as a novel therapy.[3]

Implications of Fast Track Designation

The FTD facilitates more frequent communication between Q32 Bio and the FDA throughout the drug development and review process. It also allows for a rolling review of the marketing application, where the company can submit portions of its application before the complete application is ready. Furthermore, drugs with FTD may be eligible for Accelerated Approval and Priority Review if relevant criteria are met, potentially shortening the time to market.[3]

European Medicines Agency (EMA) and Pharmaceuticals and Medical Devices Agency (PMDA - Japan) Status

The available information indicates that alopecia areata was a topic of discussion at the March 2025 meeting of the EMA's Committee for Medicinal Products for Human Use (CHMP).[65] However, there is no specific information in the provided snippets regarding any regulatory filings, designations, or approvals for bempikibart for either alopecia areata or atopic dermatitis from the EMA or Japan's PMDA.[1] The EU Clinical Trials Register is mentioned as a source for clinical trial information generally, but no specific registration or status for bempikibart in the EU register is detailed for these indications.[1]

8. Corporate Strategy and Future Outlook (Q32 Bio)

Strategic Restructuring and Focus on Alopecia Areata

In February 2025, Q32 Bio Inc. announced a significant corporate restructuring plan. This strategic shift involves prioritizing the company's resources towards the advancement of bempikibart for the treatment of alopecia areata.[10] This decision was largely influenced by the continued emergence of encouraging clinical data from the SIGNAL-AA Part A trial, including strong patient re-consent rates for continued dosing and data suggesting potential for durable responses, coupled with the less favorable outcome in the atopic dermatitis program.[10] The restructuring included a reduction in workforce, expected to be substantially completed by the end of the second quarter of 2025, with associated severance charges.[29]

This strategic pivot to concentrate on alopecia areata, driven by the promising, albeit early, signals of durability and the contrasting outcome in the atopic dermatitis trial, represents a common and often necessary adaptive maneuver in the biotechnology industry. It reflects a prudent allocation of finite resources towards the asset and indication with the perceived highest probability of clinical success and market differentiation.

Status of Other Programs

As part of the restructuring, Q32 Bio announced the discontinuation of its Phase 2 renal basket clinical trial of ADX-097, its tissue-targeted complement inhibitor.[10] The company stated it would evaluate strategic options for its complement inhibitor platform.[16] The planned Phase 2 trial of ADX-097 in ANCA-Associated Vasculitis (AAV) was also deferred.[28]

Financial Position and Cash Runway

As of December 31, 2024, Q32 Bio reported cash and cash equivalents of $78.0 million.[29] Following the February 2025 restructuring, the company anticipated that its existing cash reserves would be sufficient to fund operations into the second half of 2026.[10] This financial runway is expected to support the company through key upcoming milestones for the bempikibart alopecia areata program, including the open-label extension of SIGNAL-AA Part A and the topline data readout from SIGNAL-AA Part B.[16] For the three months ended March 31, 2025, cash and cash equivalents were $65.5 million, with research and development expenses at $7.1 million for that quarter.[38] The company has indicated that its current cash is not expected to be sufficient to advance programs through regulatory approval without raising additional capital.[29]

The projected cash runway extending into the second half of 2026 is critically linked to the successful execution and positive outcomes of the ongoing and planned clinical activities for bempikibart in alopecia areata, particularly the topline results from SIGNAL-AA Part B. This timeline underscores the financial pressures inherent in biotechnology drug development and elevates the importance of the upcoming data readouts for the company's valuation and future financing capabilities.

Potential for Bempikibart in Other Autoimmune Conditions

While the immediate focus has narrowed to alopecia areata, Q32 Bio has noted the potential utility of bempikibart across additional autoimmune conditions, given that the IL-7 and TSLP pathways are implicated in numerous T-cell-mediated pathological processes.[3] The company has previously mentioned the potential applicability for conditions influenced by Th2 and Th1 signaling pathways, such as asthma, COPD, ulcerative colitis, rheumatoid arthritis, celiac disease, and multiple sclerosis.[42] However, active development in these areas appears to be on hold pending further progress in the lead indication.

9. Conclusion

Bempikibart (ADX-914) is an investigational fully human anti-IL-7Rα monoclonal antibody with a dual mechanism of action, inhibiting both IL-7 and TSLP signaling pathways. This approach aims to re-regulate adaptive immune function and restore immune homeostasis, offering a novel therapeutic strategy for T-cell-mediated autoimmune diseases.

Currently, Q32 Bio is prioritizing the development of bempikibart for severe alopecia areata. Phase 2a (SIGNAL-AA Part A) clinical trial results in this indication have shown encouraging signals of efficacy, particularly in terms of hair regrowth (SALT score reduction) and, most notably, a potential for durable responses and continued improvement even after treatment cessation. This observation of a possible remittive effect is a key point of differentiation and, if substantiated in further trials, could significantly alter the treatment landscape for alopecia areata. The ongoing SIGNAL-AA Part B, which includes a loading dose and extended treatment duration, along with the open-label extension of Part A, will be critical in confirming these findings and further characterizing the long-term efficacy and safety profile. Bempikibart has received FDA Fast Track Designation for alopecia areata, which may expedite its development and review.

The clinical development program for atopic dermatitis (SIGNAL-AD) did not meet its primary efficacy endpoint in Phase 2a Part B, leading to a strategic deprioritization of this indication as Q32 Bio focuses its resources on the more promising alopecia areata program.

Across the clinical trials conducted so far, bempikibart has demonstrated a generally favorable safety and tolerability profile, with no Grade 3 or higher treatment-related adverse events reported. Pharmacodynamic data have consistently shown target engagement and modulation of relevant immune biomarkers.

Key remaining questions revolve around the confirmation of the durability of response in alopecia areata in larger, longer-term studies, a more detailed characterization of the mild to moderate adverse event profile, and ultimately, comparative efficacy against existing and emerging therapies. The successful progression of the SIGNAL-AA Part B trial and subsequent pivotal studies will be crucial for establishing bempikibart as a novel, effective, and safe therapeutic option for patients with alopecia areata and potentially other autoimmune diseases in the future. The company's financial runway is closely tied to achieving these clinical milestones.

10. References

(References are implicitly included via snippet IDs throughout the text.)

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