LNA043: A Comprehensive Report on its Development and Discontinuation for Osteoarthritis

1. Introduction to LNA043

LNA043, a novel investigational biologic, was developed by Novartis as a potential disease-modifying osteoarthritis drug (DMOAD).[1] Osteoarthritis (OA) is a prevalent and debilitating chronic joint disease characterized by cartilage degradation, leading to pain, stiffness, and impaired mobility, with limited treatment options beyond symptomatic relief.[3] LNA043 was envisioned as a therapy capable of regenerating damaged cartilage and potentially altering the disease's progression.[2] This report provides a comprehensive overview of LNA043, detailing its scientific rationale, mechanism of action, preclinical and clinical development, regulatory status, intellectual property, and the factors leading to its eventual discontinuation. The journey of LNA043 offers valuable perspectives on the complexities and challenges inherent in developing DMOADs for osteoarthritis.

2. Scientific Rationale and Mechanism of Action

2.1. Discovery and Nature of LNA043

LNA043 is a modified, recombinant protein derived from the C-terminal domain of human angiopoietin-like 3 (ANGPTL3).[3] It was identified through a phenotypic screen of approximately 6,300 candidate proteins for its potent ability to induce chondrogenesis in human mesenchymal stem cells (MSCs).[3] This discovery positioned LNA043 as a potential first-in-class DMOAD, distinct from existing OA treatments that primarily address symptoms.[6] The development of LNA043 as a peptide/protein modality administered via intra-articular injection was aimed at direct delivery to the affected joint.[3]

2.2. Proposed Mechanism of Action

LNA043 was designed to stimulate joint-resident MSCs to differentiate along the chondrocyte lineage, thereby promoting the repair of damaged cartilage and reducing inflammation in patients with primary knee OA.[3] The proposed mechanism involves several key interactions:

• ANGPTL3 Agonism/Stimulation: LNA043 acts as an ANGPTL3 stimulant or agonist, leveraging the chondrogenic properties identified in its parent molecule.[5]
• Integrin α5​β1​ Binding: A crucial aspect of LNA043's mechanism is its binding to the fibronectin receptor, integrin α5​β1​, on MSCs and chondrocytes.[3] This interaction is thought to mimic some of the cartilage repair effects of fibronectin.
• Modulation of Signaling Pathways: Through integrin α5​β1​ engagement, LNA043 was shown to mediate the secretion of the WNT signaling inhibitor DKK1. It also upregulated the expression of DKK1 and FRZB (another WNT inhibitor) in human OA cartilage. Furthermore, LNA043 upregulated BMP inhibitors (e.g., GREM1, CHRDL2) and downregulated BMP6 expression.[3] These modulations are significant as WNT and BMP pathways are critically involved in cartilage homeostasis and OA pathogenesis.
• Reversal of OA Transcriptome: Transcriptomic profiling from the Phase 1 trial indicated that LNA043 could reverse the OA transcriptome signature, inducing the expression of hyaline cartilage matrix components and anabolic signaling pathways while suppressing mediators of OA progression, such as FN1, SPP1/OPN, and DNER.[3] The downregulation of specific FN1 splice variants by LNA043 was considered potentially beneficial, as these variants can exacerbate OA.[3]

The ability of LNA043 to target damaged cartilage and modulate multiple biological pathways involved in cartilage regeneration formed the core of its therapeutic hypothesis.[2] Unlike the native ANGPTL3, LNA043 was engineered to avoid inducing angiogenesis, a potentially undesirable effect in the joint.[3] This selective biological activity, coupled with its chondrogenic potential, underscored its novelty.

3. Preclinical Development

Preclinical studies provided foundational evidence for LNA043's potential as a cartilage-regenerating agent. In vitro experiments demonstrated that LNA043 stimulated chondrogenic differentiation of human MSCs, leading to increased expression of cartilage anabolic markers such as aggrecan and collagen type II, and secretion of DKK1.[3] It also exhibited chondroanabolic effects on mature chondrocytes in human OA cartilage explants, increasing proteoglycan (PRG4) and collagen type II levels.[3] Importantly, LNA043 was shown to partially preserve chondrogenesis under inflammatory conditions and restore PRG4 secretion in primary human OA chondrocytes after stimulation with inflammatory cytokines, suggesting its potential efficacy even in an inflamed joint environment.[3]

In vivo studies in animal models of OA and cartilage injury further supported these findings:

• In a rat meniscal tear (RMT) model of early post-traumatic OA, a single intra-articular injection of LNA043 significantly decreased cartilage degeneration and increased the hyaline cartilage marker collagen type II.[3]
• In a therapeutic rat OA model (initiated after OA establishment), weekly intra-articular LNA043 treatment improved cartilage integrity and proteoglycan content, leading to a reduction in the overall cartilage degeneration score.[3]
• In a minipig full-thickness cartilage injury model, two cycles of LNA043 treatment (each cycle consisting of four weekly injections) resulted in improved macroscopic cartilage defect filling and increased amounts of healthy hyaline cartilage compared to placebo.[3]

These preclinical data collectively indicated that LNA043 could promote chondrogenesis and regenerate hyaline articular cartilage, providing a strong rationale for advancing to clinical trials.[3] No adverse events specifically associated with LNA043 treatment, such as cartilage overgrowth or ectopic cartilage formation, were observed in these preclinical models or in subsequent toxicology studies.[3]

4. Clinical Development Program

Novartis advanced LNA043 through a clinical development program primarily focused on knee osteoarthritis, involving multiple clinical trials to assess its safety, tolerability, and efficacy.

4.1. Overview of Clinical Trials

LNA043 was investigated in at least six clinical trials.[1] As of early 2024, three trials were reported as completed, one as ongoing, and two as terminated.[1] However, later reports in 2024 and early 2025 indicated the discontinuation of the LNA043 program.[12]

Key clinical trials included:

• NCT02491281 (CLNA043X2101): A Phase 1, first-in-human (FIH), single ascending dose study in patients with knee OA scheduled for total knee replacement (TKR).[3]
• NCT03275064 (CLNA043X2202): A Phase 2a/b, proof-of-concept (PoC) study evaluating multiple intra-articular injections in patients with articular cartilage lesions (Part A) and knee OA (Part B).[9]
• NCT04864392 (CLNA043A12202, ONWARDS): A Phase 2b, 5-year, multicenter study assessing various dosing regimens in patients with symptomatic knee OA.[3]
• NCT04814368: A Phase 2 study investigating LNA043 following canakinumab in patients with knee OA, which was later terminated.[5]

4.2. Phase 1 Studies (NCT02491281)

The FIH trial (NCT02491281) was a randomized, double-blind, placebo-controlled, single ascending dose study involving 28 patients with knee OA awaiting TKR.[3] Participants received a single intra-articular injection of LNA043 (doses ranging from 0.2 mg to 40 mg) or placebo at 2 hours, 7 days, or 21 days before surgery.[3]

• Primary Objective (Safety and Tolerability): LNA043 met its primary safety endpoint and was generally well-tolerated.[3] The overall incidence of adverse events (AEs) was similar between LNA043 (66.7%) and placebo (71.4%) groups, with most AEs attributed to the TKR surgery.[3] One patient receiving 40 mg LNA043 reported mild, transient dry mouth and altered taste, suspected to be drug-related but resolved.[3] No clinically relevant drug-related serious AEs or anti-LNA043 antibodies were detected.[3]
• Pharmacokinetics (PK): LNA043 exhibited short serum pharmacokinetics, with dose-dependent detection in serum for up to 4-8 hours post-injection, indicating rapid distribution from the joint into systemic circulation.[3] It was not detectable in serum for most patients at lower doses (0.2 mg) or after 3 days for higher doses.[3]
• Cartilage Penetration: LNA043 was detected in superficial articular cartilage and soft tissues 2 hours post-injection, particularly in damaged cartilage areas (diffusing four times deeper into damaged vs. undamaged cartilage).[3] It was not detectable in cartilage or synovial fluid 7 or 21 days post-injection.[3] This rapid but transient local exposure was a key finding.
• Pharmacodynamics (Transcriptomics): Post-hoc transcriptomic analysis of cartilage biopsies revealed that a single LNA043 injection induced a dose-dependent reversal of the OA transcriptome signature for at least 21 days. This included upregulation of hyaline cartilage matrix components and anabolic signaling pathways (e.g., WNT and BMP inhibitors) and suppression of OA progression mediators (e.g., FN1, SPP1, DNER).[3] These molecular changes suggested a chondroanabolic effect.

The successful outcome of this FIH trial, demonstrating safety and target engagement at a molecular level, supported progression to Phase 2 studies.

4.3. Phase 2 Studies

Several Phase 2 studies were initiated to evaluate the efficacy and further characterize the safety of LNA043.

NCT03275064 (Proof-of-Concept): This was a two-part, randomized, placebo-controlled, proof-of-concept study.16 Part A focused on patients with articular cartilage lesions, and Part B on knee OA patients.15 Results from Part A, involving 58 patients with partial-thickness cartilage lesions receiving 4 weekly intra-articular injections of 20 mg LNA043 or placebo, were presented.9

* Primary Endpoint (T2 Relaxation Time): No significant change in T2 relaxation time (an MRI marker of collagen network integrity) was detected between LNA043 and placebo groups.17

* Secondary/Exploratory Endpoints (Cartilage Volume/Filling):

* Manual MRI segmentation showed a trend towards continuous filling of femoral cartilage lesions up to week 28 in LNA043-treated patients (p=0.08 vs placebo), but no effect on patellar lesions.9

* An exploratory analysis using automated MRI segmentation software (MRCH) indicated a statistically significant refilling of cartilage in the medial femoral weight-bearing region over time in the LNA043 group (Δ=123 mm³ at week 28, p=0.05).17 This automated method was deemed more sensitive than manual segmentation for these lesions.

* No cartilage overgrowth was observed in healthy femoral regions.17

* Safety: The safety profile remained favorable, with mild/moderate local reactions like joint swelling (9.3% LNA043 vs 0% placebo) and arthralgia (11.6% LNA043 vs 6.7% placebo) being more common in the LNA043 group, resolving spontaneously or with simple analgesia. No anti-drug antibodies were detected.17

The mixed results, with the primary endpoint not being met despite some positive signals on exploratory imaging endpoints, highlighted the challenges in demonstrating efficacy.

NCT04864392 (ONWARDS): This was a large, 5-year, Phase 2b, randomized, double-blind, placebo-controlled, multicenter study designed to determine the optimal dosing regimen of LNA043 in patients with symptomatic knee OA.3 The study planned a 2-year core period followed by a 3-year extension.21

* Primary Objective: To assess efficacy compared to placebo at Week 104, measured by the mean change from baseline in cartilage thickness using quantitative MRI (qMRI) of the target knee.21

* Secondary Objectives: Included changes in WOMAC pain and function scores, performance on physical tests (e.g., 40-meter walk test), and proportion of patients with structural improvement.25

* Status: Initially listed as "active, not recruiting" 21, this trial was part of the program that was eventually discontinued by Novartis.12 The trial was registered with a start date of July 21, 2021.25

NCT04814368: This Phase 2 trial was designed to evaluate the safety and efficacy of LNA043 following an anti-inflammatory (canakinumab) injection in participants with knee OA.[5] This trial was terminated by Novartis on August 9, 2024, due to a sponsor decision.[5]

The discontinuation of the LNA043 program, announced in Novartis's 2024 annual report (covering 2023 activities) and further detailed by AdisInsight, suggests that the outcomes from these later Phase 2 studies, particularly the readout from the ONWARDS trial or an interim analysis, did not meet the predefined efficacy criteria or strategic imperatives for continued development.[5]

5. Regulatory Status

5.1. FDA Fast Track Designation

LNA043 received Fast Track designation from the U.S. Food and Drug Administration (FDA) on September 3, 2021, for the treatment of osteoarthritis of the knee.[6] This designation is intended to facilitate the development and expedite the review of drugs that treat serious conditions and fill an unmet medical need. The granting of Fast Track status for LNA043 was based on its potential as a first-in-class disease-modifying therapy for OA, supported by proof-of-concept data suggesting it could regenerate damaged cartilage.[6] This regulatory milestone underscored the perceived potential of LNA043 at that stage of development.

5.2. EMA PRIME Designation

There is no information in the provided materials to indicate that LNA043 received PRIME (Priority Medicines) designation from the European Medicines Agency (EMA). The PRIME scheme, similar to FDA's Fast Track, supports the development of medicines targeting unmet medical needs.[27] While LNA043 addressed an unmet need, its progression or application for PRIME is not documented.

6. Intellectual Property

The development of LNA043 and related technologies is covered by patent applications.

• WO2014138687A1: Titled "Peptides and compositions for treatment of joint damage," this patent application, with a priority date of March 8, 2013, and assigned to Irm Llc (a company subsequently associated with Novartis's research activities), describes new protease-resistant polypeptides derived from ANGPTL3.[29] These variants, including modifications such as at position 423 of the ANGPTL3 sequence, were designed for improved stability and reduced susceptibility to proteolysis, while retaining chondrogenic activity. The patent covers these modified ANGPTL3 polypeptides, pharmaceutical compositions containing them, and their methods of use for treating joint damage, arthritis, and inducing chondrocyte differentiation.[29] While LNA043 is not explicitly named, the descriptions of modified ANGPTL3 polypeptides for cartilage repair align closely with the known characteristics of LNA043. This patent highlights the early inventive steps to create a more drug-like ANGPTL3 derivative for joint diseases.
• WO2017079765A1: This patent application, assigned to Samumed, Llc, with a priority date of November 6, 2015, is titled "Compositions and methods for treating osteoarthritis" and pertains to compounds of a specific Formula (I) for intra-articular administration.[30] This patent does not appear to be directly related to LNA043 or ANGPTL3, based on the provided abstract and assignee information.

The core intellectual property for LNA043 likely resides in patents similar to WO2014138687A1, which cover the specific modified ANGPTL3 sequence (the LNA043 molecule itself) and its use in treating cartilage damage and osteoarthritis. Such patents are crucial for protecting the investment in research and development and securing market exclusivity if the drug were to be approved.

7. Discontinuation of LNA043

Despite early promise and FDA Fast Track designation, Novartis discontinued the development of LNA043 for osteoarthritis.

7.1. Announcement and Timeline

The discontinuation was noted in Novartis's 2024 Annual Report (pipeline update as of year-end 2023), which listed LNA043 under "Projects removed from the development table since 2023" with the reason "Development discontinued".[13] AdisInsight further reported that Phase 2 development for osteoarthritis was discontinued in the UK and USA effective December 31, 2024, and that the Phase 2 trial NCT04814368 was terminated on August 9, 2024, due to a "sponsor decision".[12] Synapse by Patsnap also noted the program's discontinuation following a Phase 2 readout.[5]

7.2. Reasons for Discontinuation

While Novartis's annual report did not provide specific reasons beyond "Development discontinued" [13], the timing, coupled with reports of a "Phase 2 readout" [5] and the termination of NCT04814368 due to "sponsor decision" [12], strongly suggests that the decision was driven by efficacy data from the Phase 2 program. It is highly probable that LNA043 did not demonstrate a sufficiently robust and clinically meaningful benefit in these later-stage trials to warrant further investment, particularly in a challenging therapeutic area like OA DMOAD development. The failure to meet the primary endpoint in the NCT03275064 PoC study for cartilage lesions, despite some positive exploratory imaging signals, may have been an early indicator of the challenges in translating the biological hypothesis into clear clinical efficacy.[17] The complex nature of OA, the difficulty in achieving significant cartilage regeneration that translates to symptomatic improvement, and the high bar for DMOAD approval likely contributed to this outcome.

8. Scientific Dissemination

Findings from the LNA043 development program were shared with the scientific community through presentations at major rheumatology conferences and publications.

• American College of Rheumatology (ACR) Meetings:
• ACR Convergence 2020: Results from the first-in-human trial (NCT02491281) were presented (Abstract #1483, Scotti et al.), highlighting LNA043's favorable safety profile, transient cartilage penetration, rapid clearance, and chondroanabolic response at the RNA level.[17]
• An abstract (POS0277) detailed results from the imaging-based proof-of-concept trial (NCT03275064, Part A) in patients with focal articular cartilage lesions. This presentation reported regeneration of damaged cartilage in femoral lesions with 4 weekly intra-articular injections of 20 mg LNA043, although the primary endpoint (T2 relaxation time) was not met. Automated MRI analysis showed a treatment effect on cartilage volume in the femoral index region.[17]
• EULAR (European Alliance of Associations for Rheumatology) Congress:
• EULAR 2022 Congress: LNA043 was mentioned by Prof. Tonia Vincent as an "interesting candidate" among future pro-regenerative therapies for OA, with two clinical trials noted as ongoing at that time.[31]
• Publications:
• A key publication by Gerwin et al. in Nature Medicine (December 2022) detailed LNA043's chondroprotective and cartilage-regenerative properties, including molecular data from the Phase 1 experimental medicine study (NCT02491281), suggesting potential efficacy in humans.[3]

The dissemination of LNA043 research at prominent international conferences and in a high-impact journal like Nature Medicine indicates that it was considered a scientifically significant development in the OA field. These presentations and publications allowed for peer scrutiny and tracked the evolving understanding of LNA043 from initial safety and molecular effects to early efficacy signals and challenges.

9. Expert Assessment and Concluding Remarks

9.1. Synthesis of LNA043's Trajectory

LNA043 embarked on its development journey as a scientifically compelling candidate for osteoarthritis treatment. Derived from ANGPTL3 and engineered for enhanced chondrogenic activity and stability, its mechanism of action, centered on stimulating cartilage regeneration via integrin α5​β1​ binding and modulation of key signaling pathways, offered a novel approach to a disease with high unmet medical need. Preclinical studies robustly supported its potential, demonstrating cartilage repair in various animal models.[3] The Phase 1 first-in-human trial (NCT02491281) further bolstered confidence, showing a favorable safety profile, evidence of target engagement through cartilage penetration, and promising pharmacodynamic effects at the molecular level, including reversal of the OA transcriptome signature.[3] However, the transition to Phase 2, aimed at demonstrating clinical efficacy, proved challenging. The proof-of-concept study in focal cartilage lesions (NCT03275064) yielded mixed results: while some imaging endpoints suggested cartilage regeneration in specific femoral regions, the primary endpoint was not met.[17] Ultimately, following a subsequent Phase 2 readout, likely from the larger ONWARDS trial (NCT04864392) or related studies, Novartis made the decision to discontinue the LNA043 program.[5]

9.2. Critical Analysis of Development and Discontinuation

The development of Disease-Modifying Osteoarthritis Drugs (DMOADs) is notoriously difficult, a fact underscored by the trajectory of LNA043. Osteoarthritis is a complex, multifactorial disease characterized by slow progression, making it challenging to demonstrate significant structural modification and corresponding clinical benefit within typical clinical trial timelines.[3] The high placebo response often observed in OA pain and function trials further complicates the assessment of true drug efficacy.

For LNA043, the failure to meet the primary endpoint in the NCT03275064 study, even with some encouraging secondary or exploratory imaging signals, represented a significant hurdle.[17] While innovative imaging techniques, such as automated MRI segmentation, showed promise in detecting subtle changes, the lack of a clear win on a predefined primary outcome measure likely tempered enthusiasm. The FDA Fast Track designation, while a positive regulatory signal, does not guarantee success and is contingent on the drug ultimately demonstrating a favorable benefit-risk profile in adequate and well-controlled studies.[6] The eventual discontinuation, explicitly linked to a "Phase 2 readout" and "sponsor decision," strongly implies that the later-stage efficacy data did not provide a compelling enough signal to justify the substantial investment required for Phase 3 development and pursuit of regulatory approval in such a high-risk therapeutic area.[5] Novartis's simultaneous discontinuation of other pipeline assets around the same period might also suggest a broader strategic portfolio prioritization, but the specific mention of a Phase 2 readout for LNA043 points to a data-driven decision for this particular compound.

9.3. Lessons Learned and Implications for Osteoarthritis Drug Development

The LNA043 story offers several important lessons for the field of osteoarthritis drug development:

1. Endpoint Sensitivity and Clinical Relevance: The experience with LNA043, particularly the discrepancy between different imaging analysis methods in NCT03275064 [17], highlights the critical need for robust, sensitive, and clinically relevant endpoints for both structural modification and symptomatic improvement in OA trials. Measuring cartilage regeneration is complex, and correlating these structural changes with meaningful patient-reported outcomes remains a key challenge.
2. Translating Biological Rationale to Clinical Efficacy: Despite a strong biological rationale, promising preclinical data, and positive early human pharmacodynamic signals, translating these into definitive clinical efficacy for a chronic, slowly progressive disease like OA is a formidable task. The disconnect observed for LNA043 is not uncommon in DMOAD development.
3. The High Bar for DMOADs: The discontinuation of LNA043, a candidate with a novel mechanism and initial positive signals, adds to a long list of DMOADs that have not reached the market.[3] This underscores the exceptionally high bar for success in this field and the need for continued innovation in identifying targets, designing molecules, and conducting clinical trials.
4. Strategic Decision-Making in Pharma: The decision to discontinue, even after significant investment and positive early indicators like FDA Fast Track, reflects the rigorous data-driven and strategic decision-making processes within pharmaceutical companies when balancing potential benefits, risks, and the likelihood of ultimate regulatory and commercial success.

In conclusion, LNA043 represented a scientifically innovative attempt to address the unmet need for a DMOAD in osteoarthritis. Its journey from a promising preclinical candidate to a discontinued Phase 2 asset illustrates the profound challenges in this therapeutic area. While LNA043 itself will not reach patients, the research conducted has contributed valuable knowledge regarding ANGPTL3 biology, cartilage regeneration, and the intricacies of OA clinical trial design, which may inform future efforts to develop effective treatments for this debilitating condition.

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