ABBV-CLS-628: An Investigational Therapeutic for Kidney Diseases

1. Executive Summary

ABBV-CLS-628 is an investigational therapeutic agent emerging from a collaborative effort between AbbVie and Calico Life Sciences LLC.[1] The primary clinical focus for ABBV-CLS-628 is kidney diseases, with Autosomal Dominant Polycystic Kidney Disease (ADPKD) being the lead indication for its later-stage clinical development.[3] While the precise mechanism of action for ABBV-CLS-628 is not officially disclosed in all public databases, which often list it as "undefined" [1], a significant body of evidence from patent filings and preclinical research by the developing entities strongly indicates that ABBV-CLS-628 is likely an inhibitor of Pregnancy-Associated Plasma Protein A (PAPP-A). This proteinase plays a crucial role in modulating the local bioavailability of Insulin-like Growth Factor 1 (IGF-1).[6]

The development of ABBV-CLS-628 follows a structured path, characteristic of pharmaceutical collaborations. Calico Life Sciences LLC sponsored and completed a Phase 1 first-in-human clinical trial (ACTRN12622001550796) in healthy adult volunteers, assessing the safety, tolerability, and pharmacokinetics of single and multiple ascending doses administered intravenously and subcutaneously.[8] Initial safety and tolerability data from this Phase 1 study were slated for presentation at the ERA Congress in 2025.[10] Building on these early findings, AbbVie is planning to initiate a global Phase 2 clinical trial (NCT06902558; M25-147) in May 2025. This trial will evaluate the safety and efficacy of ABBV-CLS-628 in adult patients with ADPKD over an extended treatment period.[3]

The strategic partnership between Calico, with its deep expertise in the biology of aging, and AbbVie, with its extensive clinical development and commercialization capabilities, underpins the advancement of ABBV-CLS-628.[2] Calico's research into fundamental aging processes, where PAPP-A has been identified as a longevity regulator, provides a unique scientific foundation for targeting this pathway in age-related diseases like ADPKD, which often sees progression and worsening with age.[6] If ABBV-CLS-628 proves effective in modulating the PAPP-A/IGF-1 axis to slow ADPKD progression, it could represent a novel, disease-modifying therapeutic approach for a condition with significant unmet medical need.

2. Introduction to ABBV-CLS-628

2.1. Identification

The investigational therapeutic agent is primarily identified as ABBV-CLS-628. This designation is consistently used across various pharmaceutical development databases and clinical trial registries.[1] Alternative, less formal designations include ABBVCLS-628 and ABBVCLS 628, which appear to be variations in hyphenation or spacing rather than distinct entities.[1] The prefix "ABBV-CLS" in its designation strongly signifies its origin from the collaborative efforts of AbbVie and Calico Life Sciences, a naming convention often employed for co-developed assets.

2.2. Development Partnership: AbbVie and Calico Life Sciences LLC

ABBV-CLS-628 is a product of a strategic research and development collaboration between AbbVie (NYSE: ABBV) and Calico Life Sciences LLC. This partnership was formally announced on September 3, 2014, with the ambitious goal of discovering, developing, and commercializing new therapies for patients afflicted with age-related diseases, initially highlighting neurodegeneration and cancer as key focus areas.[2]

Calico Life Sciences, a company founded by Alphabet and led by prominent figures such as Arthur D. Levinson, Ph.D., is dedicated to unraveling the fundamental biology of aging and leveraging these insights for therapeutic innovation.[2] AbbVie, a global biopharmaceutical company, brings to the collaboration its extensive expertise in late-stage clinical development, regulatory processes, and worldwide commercialization.[2]

The operational framework of the collaboration designates Calico with the responsibility for research and early-stage development, typically through Phase 2a clinical trials, over an initial ten-year period. AbbVie provides scientific and clinical development support during these early phases and retains the option to manage late-stage development and subsequent commercial activities. The agreement involves substantial co-investment, with each company initially committing up to $250 million, and the potential for each to contribute an additional $500 million. Profits and costs arising from the collaboration are to be shared equally.[2]

ABBV-CLS-628 is explicitly identified as an asset developed under this joint venture.[1] The selection of kidney disease, and specifically ADPKD—a condition whose progression and severity are often exacerbated with age—as a therapeutic target for ABBV-CLS-628 aligns congruently with the collaboration's overarching mission to address age-related diseases. Other known clinical candidates from this partnership include ABBV-CLS-484, a PTPN2/N1 inhibitor for cancer immunotherapy [18], and fosigotifator (ABBV-CLS-7262), an eIF2B activator being investigated for Vanishing White Matter disease and Amyotrophic Lateral Sclerosis (ALS).[13]

The long-standing nature of this collaboration, active since 2014, suggests a mature and well-established partnership with refined workflows, which can be advantageous for the efficient progression of therapeutic candidates like ABBV-CLS-628. The clearly defined roles, with Calico managing early (Phase 1) development of ABBV-CLS-628 and AbbVie taking the helm for later-stage (Phase 2) studies, exemplifies the structured approach intended by the collaboration agreement. This transition implies that the compound has met critical early milestones to warrant advancement within the partnered pipeline.

3. Pharmacological Profile and (Potential) Mechanism of Action

3.1. Drug Class and Modality

Information regarding the specific drug class and modality of ABBV-CLS-628 is limited in publicly accessible drug databases. Platforms such as Ozmosi and AdisInsight frequently list its modality as "N/A" or its mechanism as "Undefined".[1] GlobalData places it within the "Genito Urinary System And Sex Hormones" therapeutic area but does not assign a specific pharmacological class.[12] AdisInsight does, however, categorize ABBV-CLS-628 as a "New Molecular Entity".[5]

Despite this lack of explicit classification for ABBV-CLS-628 itself, a strong inference regarding its modality can be drawn from the intellectual property portfolio of its developers. Patent US12157776, titled "Anti-PAPP-A antibodies and methods of use thereof," co-assigned to Calico Life Sciences LLC and AbbVie Inc., describes isolated human antibodies targeting human Pregnancy-Associated Plasma Protein A (PAPP-A). These antibodies are claimed for the treatment of PAPP-A associated disorders, explicitly including kidney disease. The patent provides details of specific heavy chain (VH) and light chain (VL) sequences, such as VH SEQ ID NO: 2 and VL SEQ ID NO: 7, and full heavy and light chain sequences (e.g., SEQ ID NO: 1 and SEQ ID NO: 6 respectively).[19] International patent application WO2024107728A1, also from Calico and AbbVie, further elaborates on anti-PAPP-A antibodies, including specific Complementarity Determining Regions (CDRs) and the use of a human IgG1 Fc region.[21] Given that ABBV-CLS-628 is being developed by these same entities for kidney disease, it is highly plausible that ABBV-CLS-628 is one of these patented anti-PAPP-A monoclonal antibodies or a closely related biologic derivative.

3.2. Mechanism of Action (MoA)

The precise mechanism of action for ABBV-CLS-628 is officially designated as "Unknown" or "Undefined mechanism" in several pharmaceutical development databases.[1] However, based on the aforementioned patent landscape and preclinical research conducted by the developers, the most probable MoA involves the inhibition of Pregnancy-Associated Plasma Protein A (PAPP-A).

PAPP-A is a secreted metalloproteinase that plays a critical role in regulating the local bioavailability of Insulin-like Growth Factor 1 (IGF-1). It achieves this by cleaving specific Insulin-like Growth Factor Binding Proteins (IGFBPs), primarily IGFBP-2, IGFBP-4, and IGFBP-5. This cleavage releases IGF-1 from its bound, inactive state, allowing it to interact with its receptor and stimulate downstream signaling pathways.[6] Thus, PAPP-A activity is a key determinant of local IGF-1 pathway activation.

In the context of Autosomal Dominant Polycystic Kidney Disease (ADPKD), research has shown that PAPP-A expression is significantly upregulated. Elevated levels of PAPP-A mRNA and protein have been observed in the kidneys of ADPKD mouse models (such as the Pkd1RC/RC model) and, crucially, in the cystic fluid and kidney tissues obtained from human ADPKD patients.[6] The transcriptional regulation of PAPP-A in ADPKD appears to involve the cAMP/CREB/CBP/p300 signaling pathway.[6] The overactive PAPP-A/IGF-1 axis is believed to contribute to the proliferation of cyst-lining epithelial cells and the overall growth and expansion of renal cysts, which are the pathological hallmarks of ADPKD.[6]

The therapeutic rationale for PAPP-A inhibition in ADPKD is supported by compelling preclinical evidence. Studies involving genetic deletion of the Pappa gene or pharmacological inhibition of PAPP-A (e.g., through the administration of neutralizing antibodies) in ADPKD mouse models have demonstrated significant therapeutic benefits. These include a marked reduction in the renal cystic burden, attenuation of kidney inflammation and fibrosis, improvements in kidney function (as indicated by markers like cystatin C and glomerular filtration rate), and a notable extension of lifespan in these disease models.[6]

Furthermore, PAPP-A is also recognized as a modulator of aging and longevity. PAPP-A knockout mice not only display a dwarf phenotype due to reduced systemic IGF-1 signaling during development but also exhibit an extended lifespan and a delay in the onset of various age-related pathologies across multiple tissues.[6] This broader biological role of PAPP-A aligns with the core research mission of Calico Life Sciences, which focuses on understanding the biology of aging to develop interventions for age-related diseases.[2]

The convergence of ABBV-CLS-628's developers, its primary clinical indication in kidney disease (specifically ADPKD), and the extensive patenting and publication record by Calico/AbbVie on anti-PAPP-A antibodies for kidney disorders strongly supports the hypothesis that PAPP-A inhibition is the intended MoA. The "unknown" status in public databases is typical for early-stage investigational drugs where detailed mechanistic information may be proprietary or pending further clinical validation.

Targeting PAPP-A offers a potentially disease-modifying approach for ADPKD. By inhibiting PAPP-A, ABBV-CLS-628 would be expected to reduce local IGF-1 activity within the kidney. This, in turn, could directly attenuate key pathological processes such as cyst cell proliferation and fluid secretion, which drive cyst enlargement and progressive kidney damage in ADPKD. This mechanism is distinct from existing ADPKD treatments, like tolvaptan, which primarily targets the vasopressin V2 receptor to reduce cyst fluid accumulation. The potential to modulate a fundamental growth pathway like PAPP-A/IGF-1, which is also implicated in aging, suggests that while promising, the long-term systemic effects and safety profile of such an intervention will require thorough evaluation in clinical trials.

4. Therapeutic Indications and Rationale

The primary therapeutic area for ABBV-CLS-628 is kidney disease, with a specific and well-documented focus on Autosomal Dominant Polycystic Kidney Disease (ADPKD).

4.1. Autosomal Dominant Polycystic Kidney Disease (ADPKD)

ADPKD is the most common monogenic kidney disorder, characterized by the bilateral development and progressive enlargement of numerous fluid-filled cysts in the kidneys. This relentless cyst growth ultimately distorts renal architecture, leading to a gradual decline in kidney function and, in many cases, end-stage renal disease (ESRD) necessitating dialysis or kidney transplantation.[3] The unmet medical need for effective therapies that can slow or halt ADPKD progression remains substantial.

The rationale for investigating ABBV-CLS-628 in ADPKD is strongly rooted in the (potential) PAPP-A inhibitory mechanism of action. As previously detailed, PAPP-A is significantly upregulated in both experimental models and human cases of ADPKD, where it is believed to promote cyst growth by enhancing local IGF-1 signaling.[6] Therefore, inhibiting PAPP-A activity presents a targeted therapeutic strategy to counteract a key driver of cystogenesis and disease progression.

The clinical development program for ABBV-CLS-628 clearly prioritizes ADPKD. A Phase 2 clinical trial (NCT06902558 / M25-147) is specifically designed to evaluate the safety and efficacy of ABBV-CLS-628 in adult participants with ADPKD.[1] The target patient population for this trial includes adults aged 18-55 [3] diagnosed with ADPKD according to the Mayo Clinic Imaging Classification (MCIC) classes 1C, 1D, or 1E, and who have an estimated glomerular filtration rate (eGFR) between ≥ 30 and < 90 mL/min/1.73 m².[3] This selection criteria targets individuals with established ADPKD who are at risk of progression but have not yet reached ESRD, representing a therapeutic window where intervention might be most beneficial. AdisInsight also lists ADPKD as an indication for which ABBV-CLS-628 was in preclinical development prior to the announcement of the Phase 2 trial.[5]

4.2. General Kidney Disease (Nephropathy)

In earlier stages of development, ABBV-CLS-628 was associated with the broader indication of "Kidney disease" or "Nephropathy." The Phase 1 first-in-human study (ACTRN12622001550796) lists "Kidney disease" as the specific health condition being investigated, although the trial was conducted in healthy volunteers.[8] Databases such as Clival [15] and GlobalData [12] also use this general terminology. Patent applications from Calico and AbbVie for anti-PAPP-A antibodies often claim utility for "kidney disease" in a broader sense, not exclusively limited to ADPKD.[19] This broader initial scope is typical in early drug development, allowing for potential exploration in various nephropathies before focusing on a lead indication based on accumulating preclinical and clinical data.

4.3. Other Mentioned Indications

Ozmosi, a pharmaceutical intelligence database, lists "Arthrogryposis" and "Kidney Diseases, Cystic" as Phase 2 indications for ABBV-CLS-628 under the trial identifier M25-147 (NCT06902558).[1] "Kidney Diseases, Cystic" is a general term consistent with the ADPKD focus. However, the indication of "Arthrogryposis" warrants critical evaluation. Arthrogryposis Multiplex Congenita (AMC) is a descriptive term for multiple congenital joint contractures resulting from various underlying causes, most commonly related to impaired fetal movement due to neurogenic or myogenic disorders.[29] The provided research material does not offer any scientific rationale or corroborating evidence linking PAPP-A biology or the mechanism of ABBV-CLS-628 to arthrogryposis. Furthermore, primary clinical trial registries for NCT06902558 explicitly state ADPKD as the sole indication under investigation.[3] Therefore, the mention of arthrogryposis by Ozmosi is likely an error or refers to an unconfirmed, extremely early exploratory concept not pursued in the current development plan for ABBV-CLS-628.

The consistent and well-supported evidence from preclinical studies, patent filings, and clinical trial registrations firmly establishes ADPKD as the primary and lead indication for ABBV-CLS-628.

Table 1: Investigational Indications for ABBV-CLS-628

Indication	Rationale/Supporting Evidence (Key Sources)	Current Highest Development Phase for ABBV-CLS-628	Key Patient Population Characteristics (Clinical Trials)
Autosomal Dominant Polycystic Kidney Disease (ADPKD)	PAPP-A upregulation in ADPKD; PAPP-A inhibition reduces cyst burden and improves kidney function in preclinical ADPKD models 6; Specific patent claims.19	Phase 2 (Planned)	Adults (18-55 or 18-75 years) with ADPKD (Mayo Clinic Imaging Classification 1C, 1D, or 1E); eGFR ≥ 30 and < 90 mL/min/1.73 m².3
General Kidney Disease/Nephropathy	Broader indication in Phase 1 trial title and some databases 8; General patent claims for PAPP-A inhibitors in kidney disease.19	Phase 1 (Completed)	Healthy adult volunteers in Phase 1.9
Arthrogryposis	Listed by Ozmosi for Phase 2 trial M25-147.1	Phase 2 (Disputed/Low Confidence)	Not applicable as this indication is not corroborated by primary trial registries or scientific rationale for ABBV-CLS-628. Likely a database error.

5. Preclinical Development

The preclinical development of ABBV-CLS-628, particularly for ADPKD, is substantiated by direct mentions in industry databases and strongly supported by foundational research on PAPP-A inhibition conducted by Calico Life Sciences and AbbVie.

AdisInsight indicates that ABBV-CLS-628 underwent preclinical trials for Autosomal Dominant Polycystic Kidney Disease in the USA, utilizing an intravenous (IV) formulation, with these activities occurring prior to March 2025.[5] Similarly, GlobalData lists ABBV-CLS-628 in preclinical development for "Kidney Disease (Nephropathy)," noting Calico Life Sciences LLC as a developer and mentioning activity in Japan.[12] These entries refer to specific studies conducted with the ABBV-CLS-628 compound itself.

The scientific underpinning for these ABBV-CLS-628-specific preclinical studies is largely derived from extensive research into the role of PAPP-A in kidney disease, particularly ADPKD, by scientists affiliated with Calico and AbbVie. A key publication in JCI Insight [6], authored by individuals also listed as inventors on pertinent PAPP-A antibody patents (e.g., Adam Freund, Yuliya Kutskova [19]), details critical preclinical findings:

• PAPP-A Upregulation in ADPKD: The research confirmed significantly elevated levels of PAPP-A mRNA and protein in the kidneys of ADPKD mouse models (specifically the Pkd1RC/RC orthologous model) and, importantly, in cystic fluid and kidney tissues from human ADPKD patients.
• Therapeutic Benefit of PAPP-A Deficiency/Inhibition: In the Pkd1RC/RC mouse model, genetic deletion of Pappa resulted in a remarkable amelioration of the disease phenotype. This included a significant reduction in kidney size and cystic area, preservation of kidney architecture, decreased markers of kidney inflammation and fibrosis, and improved renal function as measured by serum cystatin C levels and glomerular filtration rate (GFR). Crucially, PAPP-A deficiency extended the median survival of these ADPKD mice from 18 months to 28 months.

While the JCI Insight paper primarily focused on genetic deletion models to establish PAPP-A's role, other research from the Calico/AbbVie collaboration describes the development and in vivo effects of PAPP-A neutralizing antibodies.[6] These antibody studies, though perhaps not exclusively focused on kidney outcomes in all publications, demonstrated the feasibility of pharmacologically inhibiting PAPP-A and modulating IGF signaling and ECM gene expression systemically.

The progression from this foundational research on PAPP-A's role in ADPKD and the efficacy of its inhibition in animal models to the specific preclinical trials for ABBV-CLS-628 (as noted by AdisInsight and GlobalData) represents a logical and scientifically driven drug development pathway. These compound-specific preclinical studies would have been essential for Investigational New Drug (IND) application-enabling activities, including formal safety, toxicology, and pharmacology assessments of ABBV-CLS-628 before its advancement into human clinical trials. The mention of preclinical activities in both the USA and Japan [5] suggests an early consideration for global development, potentially addressing regional regulatory requirements or exploring ethnic sensitivities, which aligns with the inclusion of a dedicated Asian cohort in the subsequent Phase 1 clinical trial.[9]

6. Clinical Development Program

The clinical development of ABBV-CLS-628 has progressed from a first-in-human Phase 1 study in healthy volunteers to a planned Phase 2 study in patients with Autosomal Dominant Polycystic Kidney Disease (ADPKD).

6.1. Phase 1 Clinical Trial (ACTRN12622001550796 / M23-892)

The initial clinical evaluation of ABBV-CLS-628 was conducted under the ANZCTR registration ACTRN12622001550796, also identified by the secondary ID M23-892.[9]

• Title: "A Randomized, Double-blind, Placebo-controlled, Phase 1 First-in-Human Study to Evaluate the Safety, Tolerability and Pharmacokinetics of ABBV-CLS-628 in Healthy Adult Volunteers." [9]
• Sponsorship: The primary sponsor for this Phase 1 trial was Calico Life Sciences LLC. IQVIA RDS Pty. Limited served as a secondary sponsor in Australia.[9] This aligns with the AbbVie-Calico collaboration model where Calico handles early-stage development.[2]
• Regulatory Status and Timeline: The trial received ethics approval from the Alfred Health Human Research Ethics Committee (Approval: 8/23, HREC/92175Alfred-2023).[9] It was prospectively registered on December 15, 2022. Actual first participant enrolment occurred on May 3, 2023, and the actual last participant enrolment was on February 14, 2024. The anticipated date for the last data collection is July 11, 2024.[9] The trial status is currently "Active, not recruiting".[8] Ozmosi also lists the primary completion date as February 14, 2024.[1]
• Study Design: This was a randomized, double-blind, placebo-controlled, first-in-human study involving single and multiple ascending doses of ABBV-CLS-628. It was structured in three parts:
• Part A: Single ascending doses (ranging from 30mg up to a potential 900mg IV, and up to 100mg or 300mg SC, with an optional SC dose) in approximately 59 healthy volunteers. Each cohort included sentinel dosing.[9]
• Part B: Multiple ascending doses (administered subcutaneously or intravenously every two weeks for up to four doses, with doses determined based on Part A results) in approximately 42 healthy volunteers.[9]
• Part C: Single ascending doses (SC or IV, doses determined from Parts A & B) in approximately 34 healthy adult volunteers of Asian descent (specifically first- or second-generation Han Chinese or Japanese).[9]
• Target Population: Healthy adult volunteers, both male and female, aged 18 to 65 years, with a Body Mass Index (BMI) between 18.0 and 32.0 kg/m² and a minimum weight of 45 kg. Female participants were required to be of non-childbearing potential. Part C had specific ethnicity requirements as noted above.[9] A total of 138 participants were enrolled against a target of 135.[9]
• Primary Outcome Measures: The primary objective was to evaluate the safety and tolerability of escalating single and multiple doses of ABBV-CLS-628 administered via IV infusion or SC injection. Adverse events (AEs) were assessed and graded according to the NIH DAIDS scale. Monitoring included potential effects on blood cell counts, blood clotting parameters, and injection site reactions. AE collection extended up to Day 106-149 post-dose, depending on the study part.[9]
• Secondary Outcome Measures:
• Pharmacokinetics (PK): Key PK parameters such as maximum observed serum concentration (Cmax​), time to Cmax​ (Tmax​), area under the serum concentration-time curve from time 0 to the time of last measurable concentration (AUCt​) and to infinity (AUCinf​), terminal phase elimination rate constant (ß), and elimination half-life (t1/2​) were assessed in blood following single (Parts A & C) and multiple (Part B) doses. Extensive PK blood sampling schedules were implemented.[9]
• Immunogenicity: Prevalence of anti-drug antibodies (ADA) to ABBV-CLS-628 was measured in serum at baseline, and the incidence of ADA development was monitored throughout the study at multiple timepoints.[9]
• Pharmacodynamics (PD): Exploratory biomarkers were measured in blood, urine, and hair samples collected at various timepoints to assess the pharmacodynamic effects of ABBV-CLS-628.[9]
• Location: The trial was conducted in Victoria, Australia, with Nucleus Network in Melbourne serving as a key investigational site.[8]
• Reported Data/Updates: Larvol Delta has noted an abstract for the ERA Congress 2025 titled: "Safety and Tolerability of ABBV-CLS-628: Results From a Phase 1 First-in-Human Study".[10] This indicates that initial findings from this Phase 1 trial are expected to be publicly presented.

6.2. Phase 2 Clinical Trial (NCT06902558 / M25-147 / EudraCT 2024-517143-31-00)

Following the Phase 1 study, ABBV-CLS-628 is planned to advance into a Phase 2 clinical trial targeting ADPKD patients.[1]

• Title: "A Study to Assess Adverse Events and Effectiveness of IntraVenous Infusions of ABBV-CLS-628 in Adult Participants With Autosomal Dominant Polycystic Kidney Disease (ADPKD)" or "A Phase 2, Multicenter, Randomized, Double-blind, Placebo-controlled Study to Evaluate the Safety and Efficacy of ABBV-CLS-628 in Adult Subjects With Autosomal Dominant Polycystic Kidney Disease (ADPKD)." [3]
• Sponsorship: AbbVie is the sponsor for this Phase 2 trial.[3] This reflects the planned transition of development leadership within the AbbVie-Calico collaboration.[2]
• Regulatory Status and Timeline: The trial is registered on ClinicalTrials.gov (NCT06902558) and EudraCT (2024-517143-31-00).[3] It is currently listed as "Not yet recruiting".[1] The estimated study start date is May 2025, with an anticipated primary completion date of September 2029.[1]
• Study Design: This will be a multicenter, randomized, double-blind, placebo-controlled study. Participants will be assigned to one of four treatment arms, which include three different dose levels of ABBV-CLS-628 and one placebo arm.[3]
• Target Population: Approximately 240 adult participants diagnosed with ADPKD are planned for enrolment.[3]
• Age criteria vary slightly between sources: 18 to 55 years [3] or 18 to 75 years.[4]
• Participants must have ADPKD Class 1C, 1D, or 1E based on the Mayo Clinic Imaging Classification.
• Kidney function must meet an eGFR ≥ 30 mL/min/1.73 m² and < 90 mL/min/1.73 m² (calculated using the CKD-EPI equation) at screening.[3]
• Exclusion criteria include current interventions for ADPKD with non-approved medications or specific lifestyle modifications, and other exclusionary medical conditions as defined in the protocol.[3]
• Intervention: Participants will receive intravenous (IV) infusions of ABBV-CLS-628 (at Dose A, Dose B, or Dose C) or a matching placebo every 4 weeks for a total duration of 92 weeks.[3]
• Follow-up: Participants will be followed for up to 15 weeks after the completion of the treatment period.[3]
• Primary Objectives: The study aims to assess the safety (adverse events) and efficacy of ABBV-CLS-628 in the treatment of ADPKD. Specific primary efficacy endpoints are not explicitly detailed in the provided snippets but are implied by the study's focus on "effectiveness".[3]
• Locations: The trial is planned to be conducted at approximately 100 sites worldwide.[3]

The progression from a Calico-sponsored Phase 1 trial in healthy volunteers to an AbbVie-sponsored Phase 2 trial in ADPKD patients is a pivotal step. It suggests that the Phase 1 data on safety, tolerability, and pharmacokinetics were sufficiently favorable to support advancement. The design of the Phase 2 trial, with its long duration and multiple dose arms, is well-suited for evaluating a potential disease-modifying therapy in a chronic condition like ADPKD. The inclusion of specific Mayo Clinic Imaging Classifications and eGFR criteria will help enroll a patient population where the impact of the intervention on disease progression can be meaningfully assessed. The global nature of this trial, combined with early PK data from an Asian cohort in Phase 1, underscores a comprehensive strategy for worldwide development and potential registration.

Table 2: Overview of ABBV-CLS-628 Clinical Trials

Feature	ACTRN12622001550796 (Phase 1)	NCT06902558 (Phase 2)
Full Title	A Randomized, Double-blind, Placebo-controlled, Phase 1 First-in-Human Study to Evaluate the Safety, Tolerability and Pharmacokinetics of ABBV-CLS-628 in Healthy Adult Volunteers 9	A Phase 2, Multicenter, Randomized, Double-blind, Placebo-controlled Study to Evaluate the Safety and Efficacy of ABBV-CLS-628 in Adult Subjects With Autosomal Dominant Polycystic Kidney Disease (ADPKD) 3
Primary Sponsor	Calico Life Sciences LLC 9	AbbVie 3
Current Status	Active, not recruiting (Last participant enrolled Feb 2024) 9	Not yet recruiting (Est. start May 2025) 4
Study Design	Randomized, double-blind, placebo-controlled, single & multiple ascending dose 9	Randomized, double-blind, placebo-controlled, multicenter 3
Target Population (N)	Healthy adult volunteers (18-65 years); N=138 (Actual) 9	Adult ADPKD patients (18-55 or 18-75 years); N≈240 (Target) 3
Key Inclusion Criteria	Healthy, BMI 18-32 kg/m², specific ethnicity for Part C 9	ADPKD (MCIC 1C, 1D, or 1E), eGFR ≥30 & <90 mL/min/1.73m² 3
Intervention Arms & Dosing	ABBV-CLS-628 (IV & SC, single & multiple ascending doses) vs. Placebo 9	ABBV-CLS-628 (3 dose levels, IV) vs. Placebo, q4w for 92 weeks 3
Primary Outcome(s)	Safety and tolerability (AEs) 9	Safety (AEs) and Efficacy (specifics not detailed) 3
Key Secondary Outcome(s)	Pharmacokinetics (Cmax, AUC, t1/2 etc.), Immunogenicity (ADA), Pharmacodynamics (exploratory biomarkers) 9	Not detailed in snippets
Duration of Treatment/Follow-up	Varied by part, AE collection up to Day 106-149 9	92 weeks treatment, up to 15 weeks follow-up 3
Geographic Scope	Australia (VIC) 8	Approx. 100 sites worldwide 3
Anticipated/Reported Results	Initial results anticipated at ERA 2025 (abstract) 10	Primary completion estimated Sep 2029 1

7. Discussion and Future Outlook

ABBV-CLS-628 emerges as a significant investigational agent from the strategic collaboration between AbbVie and Calico Life Sciences. The development program is primarily focused on addressing Autosomal Dominant Polycystic Kidney Disease (ADPKD), a condition with considerable unmet medical need. While its precise mechanism of action remains officially undisclosed in some public databases, a compelling body of evidence from patent filings and preclinical research by the developers strongly points towards ABBV-CLS-628 functioning as an inhibitor of Pregnancy-Associated Plasma Protein A (PAPP-A). This enzyme is a key modulator of local Insulin-like Growth Factor 1 (IGF-1) activity, a pathway implicated in cyst proliferation and progression in ADPKD.[6]

The clinical journey of ABBV-CLS-628 has advanced through a successfully completed Phase 1 first-in-human trial (ACTRN12622001550796) conducted in healthy volunteers.[8] This study, sponsored by Calico, evaluated the safety, tolerability, pharmacokinetics, and pharmacodynamics of both intravenous and subcutaneous administrations across single and multiple ascending doses, including a dedicated cohort of Asian participants. The anticipation of initial results from this Phase 1 study, potentially at the ERA Congress in 2025 [10], is a key upcoming milestone. The successful completion of this phase and positive preliminary data are implied by the planned progression to a more extensive Phase 2 trial.

AbbVie is set to sponsor a global Phase 2 trial (NCT06902558 / M25-147), anticipated to commence in May 2025. This trial will assess the efficacy and further confirm the safety of ABBV-CLS-628 in adult ADPKD patients over a 92-week treatment period.[1] The design of this trial, targeting patients with specific Mayo Clinic Imaging Classifications and eGFR criteria, indicates a focus on individuals at a clear risk of disease progression, where a therapeutic intervention could yield meaningful clinical benefits.

The potential significance of ABBV-CLS-628 is substantial. If the PAPP-A inhibitory mechanism is validated in humans and the drug demonstrates robust efficacy in slowing ADPKD progression with an acceptable safety profile, it could offer a novel, targeted, and potentially disease-modifying therapy. This would be a considerable advancement over current ADPKD treatments, which are limited. Moreover, PAPP-A's established role as a longevity regulator and its involvement in fundamental aging processes [6] positions this therapeutic approach at an interesting intersection of disease-specific treatment and aging biology research, a core tenet of Calico's mission.[2] Success in ADPKD might therefore open avenues for investigating PAPP-A modulation in other age-related renal conditions or even systemic aspects of aging.

However, the development path is not without challenges. Definitive confirmation of ABBV-CLS-628's MoA as a PAPP-A inhibitor in humans and its ability to effectively modulate the PAPP-A/IGF-1 pathway are critical. The upcoming Phase 1 data, particularly any pharmacodynamic marker results, will be instrumental in this regard. Demonstrating a clinically significant impact on ADPKD progression markers, such as eGFR slope or total kidney volume (TKV) growth, in a large and diverse patient population over the extended duration of the Phase 2 trial, will be a key determinant of its future. The long-term safety of modulating a pathway with diverse physiological roles like PAPP-A/IGF-1 will also require meticulous evaluation.

Future development steps will hinge on the outcomes of these clinical trials. Full disclosure of the Phase 1 results will provide the first comprehensive look at the drug's human pharmacology. Successful execution and positive results from the Phase 2 ADPKD trial would pave the way for Phase 3 studies and potential regulatory submissions. Further research may also explore the utility of the subcutaneous formulation developed in Phase 1 for ADPKD and investigate the potential of ABBV-CLS-628 in other PAPP-A-relevant conditions.

7.1. Conclusions

ABBV-CLS-628 represents a scientifically intriguing investigational therapeutic, born from a strategic collaboration focused on leveraging insights into aging biology for treating complex diseases. Its development for ADPKD, likely via PAPP-A inhibition, is supported by a strong preclinical rationale. The progression to a global Phase 2 trial under AbbVie's stewardship indicates positive early signals and a commitment to advancing this novel agent. The forthcoming Phase 1 data and the subsequent outcomes of the Phase 2 ADPKD study will be critical in determining the ultimate therapeutic value and future trajectory of ABBV-CLS-628.

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