Lorecivivint: A potential treatment for knee osteoarthritis

Highlights

• Knee osteoarthritis is an inflammatory condition affecting millions worldwide
• Mechanical stress, inflammation, biochemical reactions, and metabolic disorders are among the driving forces for knee osteoarthritis
• Lorecivivint is an intra-articular treatment aimed at treating moderate to severe knee osteoarthritis
• Lorecivivint works by modulating the Wnt pathway, enhancing chondrogenesis, chondrocyte function, and anti-inflammation effect
• Over the years, intra-articular injection of Lorecivivint proved its safety and efficacy across many preclinical and clinical studies
• The optimal dose (0.07 mg) of Lorecivivint in clinical settings improved pain and function in patients with moderate-to-severe knee osteoarthritis

Introduction

Knee osteoarthritis (KOA), or degenerative joint disease, is an inflammatory condition resulting from joint wear and tear with progressive loss of articular cartilage. A recent study that assessed population-based trials estimated that in 2020, 654.1 million individuals worldwide (40 years and older) were suffering from KOA. The literature indicates that risk factors for the condition include obesity, female gender, and old age. KOA can be subdivided into primary and secondary based on etiology. The primary KOA is idiopathic articular degeneration, while secondary KOA is due to trauma or conditions like rheumatoid arthritis.‍

‍

‍

Driving forces behind knee osteoarthritis

The literature indicates that about 85% of the osteoarthritis burden worldwide is linked to KOA (1). KOA is a multifactorial condition driven by several causative factors, like mechanical stress, inflammation, biochemical reactions, and metabolic disorders (2). Currently, research is trying to determine whether inflammatory reactions are the drivers of osteoarthritic changes or whether inflammation is secondary to them. Chronic pain is one of the KOA outcomes, and people having it are more likely to develop depression (1).

Type II collagen, proteoglycans, chondrocytes, and water are the primary components of articular cartilage (3). Under normal circumstances, equilibrium between the mentioned components ensures the health of articular cartilage. In other words, any degradation is matched by synthesis (3). In pathological conditions like KOA, degradative enzymes, like metalloproteases, are overexpressed, disrupting the set equilibrium and resulting in the loss of proteoglycans and other vital components. During early osteoarthritis stages, chondrocytes try to increase their synthesis of proteoglycans to compensate for the loss, but eventually, their capacity to produce is overtaken by degradative processes (3). It is important to understand that although KOA is related to aging, it is not a consequence but a disease on its own.

Lorecivivint and Biosplice Therapeutics overview

Lorecivivint (SM04690) is an injectable medication with a molecular formula of C₂₉H₂₄FN₇O and is indicated for treating osteoarthritis (intraarticularly). It is also being investigated for its potential in intervertebral disc degeneration, hip osteoarthritis, and shoulder osteoarthritis (4, 5). Preclinical studies suggested that Lorecivivint has a dual mechanism of action that produces three outcomes, including generating new articular cartilage, slowing cartilage degradation, and reducing joint inflammation (4).

The molecule is developed by Biosplice Therapeutics, formerly Samumed (4). The company is currently investigating other products covering neurology and oncology areas across different clinical phases (5).

Lorecivivint: Understanding the mechanism of action

Lorecivivint is an inhibitor of enzymes: CDC-like kinase 2 (CLK2) and dual-specificity tyrosine phosphorylation-regulated kinase 1A (DYRK1A) (4). The kinases family regulates splicing by phosphorylation of SR-proteins (serine and arginine-rich proteins) and other splicing factors (6). The splicing process is responsible for modulating the process of translating genetic information into protein structure (7).

Inhibition of the CLK2 and DYRK1A pathways downregulates the Wnt pathway, leading to enhanced chondrogenesis, chondrocyte function, and anti-inflammation (4). The Wnt pathway is essential for tissue regeneration and homeostasis and a key regulator of progenitor cell differentiation in the knee joint (8). Aberrant activity of this pathway during osteoarthritis drives progenitor cell differentiation into osteoblasts instead of chondrocytes.

‍

‍

Historical milestones for Lorecivivint

• In March 2014, Biosplice Therapeutics (Samumed at the time) initiated a phase I dose-escalation clinical study to test the safety and efficacy of Lorecivivint against placebo in patients with moderate to severe KOA (4). The study's efficacy and adverse events outcomes were shared during the 17th Annual Congress of the European League Against Rheumatism (EULAR) in 2016 (4).
• In 2015, Biosplice Therapeutics initiated phase II clinical studies involving elderly patients in the United States. The same year, the company released pharmacodynamics data from preclinical trials at the 79th American College of Rheumatology (ACR) Annual Meeting (4). In addition, it finalized a phase I trial investigating the potential of the therapeutic agent in KOA.
• In 2016, the company released several scientific updates about their studies' efficacy and safety outcomes (4). Also, Biosplice Therapeutics initiated phase III clinical studies in the United States for the indication of osteoarthritis. The same year, the company planned a phase I clinical trial to investigate the molecule in intervertebral disc degeneration. Moreover, it filed for an investigational new drug application with the Food and Drug Administration.
• In 2017, the company initiated another phase II trial for osteoarthritis in the United States. Also, results from previous studies have been presented at scientific congresses, like  EULAR and ACR (4). Phase I clinical studies for intervertebral disc degeneration were initiated in the same year.
• The year 2018 was similar to the previous years, where updates of earlier trials were released, new phase II studies were initiated, and plans for phase III pivotal trial (STRIDES I) were prepared (4). The years 2019 and 2020 followed the same pace as the previous years for the company. In 2021, Samumed changed its name to Biosplice Therapeutics.

‍

Lorecivivint in clinical studies

The first clinical publication dates back to 2017 (according to the PubMed database). It was a 24-week, randomized, phase I clinical trial aimed at assessing the safety, pharmacokinetics, and exploratory efficacy of Lorecivivint (9). The study included 61 subjects randomized to Lorecivivint (n=50) and placebo (n=11). Those receiving the medication were divided into three cohorts with intraarticular injections of 0.03 mg, 0.07 mg, and 0.23 mg of the drug. The study reported 72 adverse events (AEs), sixteen of which were considered to be related to the drug (occurred in eight cases) (9). Also, three subjects discontinued the medication (one case due to AEs). In the 0.07 mg cohort, two dose-limiting toxicities; increased pain following injection and paroxysmal tachycardia (a serious AE) were reported (9). The study concluded that Lorecivivint appeared to be safe, well tolerated, and with no evidence of systemic exposure. Exploratory efficacy analysis suggests that Lorecivivint is effective against KOA based on osteoarthritis pain and function measurements (9).

Another study was a phase IIa, randomized trial to assess the safety and efficacy of Lorecivivint in treating pain and preventing structural damage progression in moderate to severe symptomatic KOA (8). The study stretched over 52 weeks and involved multiple centers. It included 455 subjects who received either Lorecivivint (dose of 0.03 mg, 0.07 mg, or 0.23 mg) or placebo (8). Results of the study revealed that all treatment groups, including placebo, had improved pain and function scores from baseline at week 13. There were no significant differences in the incidence of AEs between the medication groups and placebo. In addition, no serious AEs were attributed to the study treatment (8). The authors concluded that despite the study not meeting its primary endpoint (significant improvement in pain and function score in treatment groups versus placebo at week 13), it identified the target population to evaluate the potential efficacy of Lorecivivint (8).

In addition to the above, PubMed included a phase IIb, randomized study to identify effective Lorecivivint doses. This 24-week, multicenter study included 695 patients aged between 40 and 80 (10). Subjects were randomized to receive 0.03, 0.07, 0.15, or 0.23 mg of treatment, placebo, or a dry-needle sham. The primary efficacy endpoints included changes in pain, function, and radiographic medial joint space width from baseline. Results revealed significant improvements in pain with 0.07 mg and 0.23 mg treatment groups versus placebo at weeks 12 and 24 (10). In addition, the 0.07 mg dose significantly improved Western Ontario and McMaster Universities Osteoarthritis Index pain and function scores versus placebo at week 12. No radiographic progression was observed in any group at week 24. The authors concluded that the optimal dose of Lorecivivint is 0.07 mg (10).

In 2020, Biosplice Therapeutics initiated the STRIDES-1 trial, a phase III, randomized, multicenter interventional study (11). The primary outcome measure was to evaluate change from baseline osteoarthritis pain in the target knee as assessed by the weekly average of daily pain numeric rating scale at week 12. This rating scale is an 11-point scale for self-reporting of average knee pain in the last 24 hours; 0 indicates no pain, and 10 represents the worst possible pain. Subjects were between the ages of 40 to 80 years. Until the date of article writing, no data concerning study results were published.

‍

‍

Lorecivivint: A new hope for patients with KOA

Current KOA treatments, like opioids and non-steroidal anti-inflammatory drugs, temporarily relieve signs and symptoms of the condition. At the same time, they come with many side effects. Treatments like Lorecivivint represent a new class of therapeutics known as disease-modifying osteoarthritis drugs. This kind of medication brings hope to many patients suffering from the condition, as these medications address cartilage loss and could potentially regenerate it.

‍

References:

1. Primorac D, Molnar V, Rod E, Jeleč Ž, Čukelj F, Matišić V, et al. Knee Osteoarthritis: A Review of Pathogenesis and State-Of-The-Art Non-Operative Therapeutic Considerations. Genes (Basel). 2020;11(8).
2. Mora JC, Przkora R, Cruz-Almeida Y. Knee osteoarthritis: pathophysiology and current treatment modalities. J Pain Res. 2018;11:2189-96.
3. Hsu H, Siwiec RM. Knee Osteoarthritis.  StatPearls. Treasure Island (FL): StatPearls Publishing Copyright © 2022, StatPearls Publishing LLC.; 2022.
4. Lorecivivint - Biosplice Therapeutics adisinsight.springer.com: Springer; 2022 [updated 01-18-2022; cited 2022 09-01]. Available from: https://adisinsight.springer.com/drugs/800040429.
5. Pipeline | Biosplice Biosplice.com: Biosplice Therapeutics; 2022 [cited 2022 09-02]. Available from: https://www.biosplice.com/clinical-development/default.aspx.
6. Walter A, Chaikuad A, Helmer R, Loaëc N, Preu L, Ott I, et al. Molecular structures of cdc2-like kinases in complex with a new inhibitor chemotype. PLOS ONE. 2018;13(5):e0196761.
7. Martín Moyano P, Němec V, Paruch K. Cdc-Like Kinases (CLKs): Biology, Chemical Probes, and Therapeutic Potential. Int J Mol Sci. 2020;21(20).
8. Yazici Y, McAlindon TE, Gibofsky A, Lane NE, Clauw D, Jones M, et al. Lorecivivint, a Novel Intraarticular CDC-like Kinase 2 and Dual-Specificity Tyrosine Phosphorylation-Regulated Kinase 1A Inhibitor and Wnt Pathway Modulator for the Treatment of Knee Osteoarthritis: A Phase II Randomized Trial. Arthritis Rheumatol. 2020;72(10):1694-706.
9. Yazici Y, McAlindon TE, Fleischmann R, Gibofsky A, Lane NE, Kivitz AJ, et al. A novel Wnt pathway inhibitor, SM04690, for the treatment of moderate to severe osteoarthritis of the knee: results of a 24-week, randomized, controlled, phase 1 study. Osteoarthritis Cartilage. 2017;25(10):1598-606.
10. Yazici Y, McAlindon TE, Gibofsky A, Lane NE, Lattermann C, Skrepnik N, et al. A Phase 2b randomized trial of lorecivivint, a novel intra-articular CLK2/DYRK1A inhibitor and Wnt pathway modulator for knee osteoarthritis. Osteoarthritis Cartilage. 2021;29(5):654-66.
11. A Study Utilizing Patient-Reported Outcomes to Evaluate the Safety and Efficacy of Lorecivivint (SM04690) for the Treatment of Moderately to Severely Symptomatic Knee Osteoarthritis Clinicaltrials.gov: US National Library of Medicine; 2022 [updated March 3, 2022; cited 2022 09-05]. Available from: https://clinicaltrials.gov/ct2/show/NCT04385303.

‍