Raylumis (tanezumab) / Eli Lilly, Pfizer - LARVOL DELTA

Re: Re: Laboratory safety evaluation of bedinvetmab, a canine anti-nerve growth factor monoclonal antibody, in dogs. (PubMed, Vet J) - "Their questions appear to have stemmed from an anti-NGF mAb developed for the treatment of osteoarthritis in humans (tanezumab; FDA, 2021) which in 2021 failed to achieve marketing approval due to an unfavorable benefit: risk profile, primarily due to a syndrome called Rapidly Progressive Osteoarthritis (RPOA) which occurred more commonly in treatment groups when compared to controls...These findings have previously been determined to be incidental and not bedinvetmab-associated. To address the questions posed, it is important to briefly define RPOA and summarize the syndrome in humans, review why the bone/joint findings in bedinvetmab safety studies in dogs are not indicative of RPOA or an RPOA-like condition, provide an update on joint health after use of bedinvetmab since market approval (>3 years in some markets), and summarize why Zoetis, the manufacturer of Librela, has confidence in joint safety after use of bedinvetmab in dogs."

Journal • Immunology • Osteoarthritis • Pain • Rheumatology

Effect size varies based on calculation method and may affect interpretation of treatment effect: an illustration using randomised clinical trials in osteoarthritis. (PubMed, Adv Rheumatol) - P3 | "Differences in ES affect interpretation of treatment effect. Therefore, we advocate clearly reporting individual elements of ES in addition to its overall calculation. This is particularly important when ES estimates are used to determine sample sizes for clinical trials, as larger ES will lead to smaller sample sizes and potentially underpowered studies."

Journal • Immunology • Musculoskeletal Pain • Osteoarthritis • Pain • Rheumatology

Phase 2 Randomized, Double-blind, Placebo-controlled Study of the Anti-nerve Growth Factor (NGF) Antibody Tanezumab in Subjects with Moderate to Severe Pain Due to Schwannomatosis (AAN 2024) - "Among schwannomatosis patients with moderate-to-severe pain, tanezumab reduced pain intensity; although these changes reflect clinically meaningful differences (2 points), they lacked statistical significance. Limited enrollment during the pandemic resulted in an underpowered study. A larger trial is needed to assess tanezumab's potential for treating SWN-related pain."

Clinical • P2 data • Brain Cancer • Immunology • Neuralgia • Osteoarthritis • Pain • Rheumatology • Solid Tumor • NGF

Phase 2 Study of Tanezumab in Subjects With Moderate to Severe Pain Due to Schwannomatosis (clinicaltrials.gov) - P2 | N=9 | Active, not recruiting | Sponsor: Massachusetts General Hospital | Trial completion date: Mar 2024 ➔ Sep 2024

Trial completion date • Brain Cancer • Pain • Solid Tumor

Characterization of adverse joint outcomes in patients with osteoarthritis treated with subcutaneous tanezumab. (PubMed, Osteoarthritis Cartilage) - P3 | "In placebo- and NSAID controlled studies of SC tanezumab for OA, adjudicated CJSE, RPOA, and TJR most commonly occurred in patients treated with tanezumab and with more severe radiographic or symptomatic OA. NCT02697773; NCT02709486; NCT02528188."

Adverse events • Journal • Immunology • Musculoskeletal Diseases • Musculoskeletal Pain • Orthopedics • Osteoarthritis • Pain • Rheumatology

Various Doses of Tanezumab in the Management of Chronic Low Back Pain (CLBP): A Pooled Analysis of 4,514 Patients. (PubMed, Cureus) - "However, tanezumab 5 mg showed significantly less reduction of LBPI compared to 10 mg at two, four, eight, and 12 weeks (MD ranging from 0.19 to 0.32). These findings suggest that tanezumab is an effective treatment for CLBP, with 5 mg and 10 mg doses providing clinically meaningful reductions in LBPI."

Journal • Retrospective data • Review • Back Pain • Lumbar Back Pain • Musculoskeletal Pain • Pain

Phase 2 Randomized, Double-blind, Placebo-Controlled Study of the Anti-Nerve Growth Factor (NGF) Antibody Tanezumab in Subjects with Moderate to Severe Pain Due to Schwannomatosis (SNO 2023) - "Nine subjects were enrolled (median age 44 years, 7 females). At baseline, mean NRS-11 score was 7.6 (SD 2.1) and mean PROMIS-PI T-score was 63.2 (SD 6.6). During double-blind treatment, four participants were randomized to receive tanezumab (early group) and five were randomized to placebo (delayed group)."

Clinical • P2 data • Brain Cancer • Immunology • Osteoarthritis • Pain • Rheumatology • Solid Tumor • NGF

Prediction of relative change in free nerve growth factor (NGF) following subcutaneous administration of tanezumab, a novel monoclonal antibody to NGF. (PubMed, CPT Pharmacometrics Syst Pharmacol) - P3 | "Free NGF concentration was predicted to return to baseline level at ~8 weeks (95% prediction interval: 5-16 weeks) after the last tanezumab dose. This model adequately described plasma tanezumab and serum total NGF concentrations following subcutaneous administration of tanezumab 2.5 or 5 mg Q8W, allowed prediction of relative change in systemic free NGF following subcutaneous (SC) administration of tanezumab."

Journal • Immunology • Osteoarthritis • Pain • Rheumatology

Peripheral Nerve Safety of Nerve Growth Factor Inhibition by Tanezumab: Pooled Analyses of Phase III Clinical Studies in Over 5000 Patients with Osteoarthritis. (PubMed, Clin Drug Investig) - P3 | "Tanezumab IV or SC had an increased incidence of AEs of APS, such as paresthesia and hypoesthesia, and diagnoses of mononeuropathy compared with placebo. However, tanezumab was not associated with generalized peripheral neuropathy."

Journal • P3 data • Immunology • Osteoarthritis • Pain • Peripheral Neuropathic Pain • Rheumatology

A Randomized Placebo-Controlled Trial of the Anti-Nerve Growth Factor Antibody Tanezumab in Subjects With Cancer Pain Due to Bone Metastasis. (PubMed, Oncologist) - P3 | "Tanezumab 20 mg met the primary efficacy endpoint at week 8. Conclusions on longer-term efficacy are limited since the study was not designed to evaluate the durability of the effect beyond 8 weeks. Safety findings were consistent with adverse events expected in subjects with cancer pain due to bone metastasis and the known safety profile of tanezumab. Clinicaltrials.gov identifier: NCT02609828."

Clinical • Journal • Musculoskeletal Diseases • Musculoskeletal Pain • Neuralgia • Oncology • Pain • Solid Tumor

Role of imaging for eligibility and safety of a-NGF clinical trials. (PubMed, Ther Adv Musculoskelet Dis) - "In 2021, an FDA advisory committee voted against approving tanezumab (one of the a-NGF compounds being evaluated) and declared that the risk evaluation and mitigation strategy was not sufficient to mitigate potential safety risks...In OA efficacy trials image acquisition and evaluation aims at maximizing sensitivity in order to capture structural effects between treated and non-treated participants in longitudinal fashion. In contrast, the aim of imaging in a-NGF trials is to enable detection of structural tissue alterations that either increase the risk of a negative outcome (eligibility) or may result in termination of treatment (safety)."

Journal • Review • Immunology • Osteoarthritis • Pain • Rheumatology

Barriers to participation in a prospective clinical trial for schwannomatosis-related pain (AAN 2023) - P2 | "A clinical trial of tanezumab, an anti-nerve growth factor antibody, was initiated for SWN-related pain (NCT04163419)...Importantly, participants did not cite the double-blind design as a reason for non-participation. These results will inform design of future prospective clinical trials for SWN-related pain."

Clinical • Brain Cancer • Immunology • Oncology • Osteoarthritis • Pain • Rheumatology • Solid Tumor

The Current Role of Disease-modifying Osteoarthritis Drugs. (PubMed, Arch Bone Jt Surg) - "It was encountered that many publications have analyzed the impact of several DMOAD methods, including anti-cytokine therapy (tanezumab, AMG 108, adalimumab, etanercept, anakinra), enzyme inhibitors (M6495, doxycycline, cindunistat, PG-116800), growth factors (bone morphogenetic protein-7, sprifermin), gene therapy (micro ribonucleic acids, antisense oligonucleotides), peptides (calcitonin) and others (SM04690, senolitic, transient receptor potential vanilloid 4, neural EGFL-like 1, TPCA-1, tofacitinib, lorecivivint and quercitrin). In conclusion, even though DMOADs seem promising, their clinical effectiveness has not yet been demonstrated for managing OA. Until forthcoming studies can proved the medications' capacity to repair and regenerate tissues affected by OA, physicians should keep using treatments that only intend to alleviate pain."

Journal • Review • Gene Therapies • Immunology • Musculoskeletal Pain • Orthopedics • Osteoarthritis • Pain • Rheumatology • NELL1

Examining the Relationships Among Treatment, Pain, and Physical Function in Patients with Osteoarthritis: A Mediation-Modeling Approach. (PubMed, Clin J Pain) - P3 | "At least 75% of the treatment effect of tanezumab on physical functioning can be explained by the improvements in pain. However, tanezumab had an additional effect on physical functioning (~25%), which was independent of improvements in pain. Such independent effects are of considerable interest and require further research to determine their mechanisms."

Journal • Immunology • Osteoarthritis • Pain • Rheumatology

Predicting Treatment Responses in Patients with Osteoarthritis: Results from Two Phase 3 Tanezumab Randomized Clinical Trials. (PubMed, Clin Pharmacol Ther) - P3 | "These secondary-data analyses identified distinct and common patient-based variables to predict response to placebo or tanezumab. These findings will inform the design of future clinical trials helping to move forward clinical pharmacology and translational science."

Clinical • Journal • P3 data • Immunology • Osteoarthritis • Pain • Rheumatology

Clinical characteristics of immune checkpoint inhibitor-related type 1 diabetes mellitus (PubMed, Zhonghua Yi Xue Za Zhi) - "The drugs used in 10 patients were all programmed cell death receptor 1 (PD-1) inhibitors, including 5 cases of pembrolizumab, 3 cases of sintilimab, 1 case of tanezumab, and 1 case of toripalimab. All the 10 patients were successfully treated and depended on insulin therapy. Immune checkpoint inhibitors can cause type 1 diabetes, including fulminant type 1 diabetes, which mostly begins with DKA, requiring early identification and aggressive insulin therapy."

Checkpoint inhibition • Journal • Diabetes • Esophageal Cancer • Gastric Cancer • Gastrointestinal Cancer • Genito-urinary Cancer • Head and Neck Cancer • Immune Modulation • Inflammation • Lung Cancer • Metabolic Disorders • Nasopharyngeal Carcinoma • Oncology • Renal Cell Carcinoma • Solid Tumor • Type 1 Diabetes Mellitus

Different Dosage Regimens of Tanezumab for the Treatment of Chronic Low Back Pain: A Meta-analysis of Randomized Controlled Trials. (PubMed, Clin Neuropharmacol) - "Intravenous and subcutaneous tanezumab injections as treatment for improving CLBP have promising clinical application as its great improvement on all efficacy and its controllable safety issues. Furthermore, intravenous and subcutaneous tanezumab injections were proved to achieve excellent and long-term curative effect on CLBP through our subgroup analysis and comparison."

Journal • Retrospective data • Back Pain • Lumbar Back Pain • Musculoskeletal Pain • Pain

Time to first and sustained improvement in WOMAC domains among patients with osteoarthritis receiving tanezumab. (PubMed, Osteoarthr Cartil Open) - P3 | "Time to improvement of 50% was more variable, with first and sustained events expected within 4-16 and 8-24 weeks, respectively. NCT02697773; NCT02709486; NCT02528188."

Journal • Immunology • Osteoarthritis • Pain • Rheumatology

"Pain treatment in #osteoarthritis 👉🏾POC efficacy of tanezumab in 56wk NSAIDcontrolled study, BUT-- +toxicity o DC'd (great work @Tuhina_Neogi!) #ACR22 #ACRAmbassador #osteoarthritis" (@vksandhumd)

Clinical • Immunology • Osteoarthritis • Pain • Rheumatology

A Two-Step, Trajectory-Focused, Analytics Approach to Attempt Prediction of Analgesic Response in Patients with Moderate-to-Severe Osteoarthritis. (PubMed, Adv Ther) - P3 | "Analyzing initial 8-week analgesic responses using a two-step, trajectory-based approach can predict future response in patients with moderate-to-severe osteoarthritis treated with NSAIDs or 2.5 mg tanezumab. These findings demonstrate that prediction of treatment response based on a single dose of a novel therapeutic is possible and that predicting future outcomes based on initial response offers a way to potentially advance the approach to clinical management of patients with osteoarthritis."

Journal • Immunology • Musculoskeletal Pain • Osteoarthritis • Pain • Rheumatology

Nerve Growth Factor (NGF) Encourages the Neuroinvasive Potential of Pancreatic Cancer Cells by Activating the Warburg Effect and Promoting Tumor Derived Exosomal miRNA-21 Expression. (PubMed, Oxid Med Cell Longev) - "In vivo tumorigenesis experiments, Tanezumab markedly alleviated nerve invasion of PC cells as well as relieved nociceptive conduction in animal models. These findings displayed that NGF/TrkA encouraged the neuroinvasive potential of PC cells by activating the Warburg effect in DRG cells through upregulation of TDE-miR-21-5p expression."

Journal • Gastrointestinal Cancer • Hepatology • Oncology • Pancreatic Cancer • Solid Tumor • MIR21 • NGF

Phase 2 Study of Tanezumab in Subjects With Moderate to Severe Pain Due to Schwannomatosis (clinicaltrials.gov) - P2 | N=9 | Active, not recruiting | Sponsor: Massachusetts General Hospital | Recruiting ➔ Active, not recruiting | N=46 ➔ 9 | Trial primary completion date: Jun 2023 ➔ Sep 2022

Enrollment change • Enrollment closed • Trial primary completion date • Brain Cancer • Pain • Solid Tumor

Design of a randomized, placebo-controlled, phase 2 study evaluating the safety and efficacy of tanezumab for treatment of schwannomatosis-related pain. (PubMed, Contemp Clin Trials) - P2 | "This study is the first therapeutic trial for SWN patients and targets a biological driver of SWN-related pain. It aims to establish a model for future pain studies in SWN and other rare diseases."

Clinical • Journal • P2 data • Brain Cancer • Meningioma • Oncology • Pain • Rare Diseases • Solid Tumor

Efficacy and safety of tanezumab, NSAIDs, and placebo in patients with moderate to severe hip or knee osteoarthritis and a history of depression, anxiety, or insomnia: post-hoc analysis of phase 3 trials. (PubMed, Curr Med Res Opin) - P3 | " Patients with OA and a history of depression, anxiety, or insomnia did not appear to experience reduced efficacy outcomes or an altered safety profile in response to tanezumab or NSAID treatment as compared with those without. NCT02697773; NCT02709486; NCT02528188."

Journal • P3 data • Retrospective data • CNS Disorders • Depression • Immunology • Insomnia • Mood Disorders • Osteoarthritis • Pain • Psychiatry • Rheumatology • Sleep Disorder

Clinical Meaningfulness of Response to Tanezumab in Patients with Chronic Low Back Pain: Analysis From a 56-Week, Randomized, Placebo- and Tramadol-Controlled, Phase 3 Trial. (PubMed, Pain Ther) - P3 | "The totality of the evidence as captured by measures of pain, interference with daily function, patient overall assessment of disease status, and satisfaction with treatment demonstrates the clinically meaningful benefit of tanezumab for some patients with CLBP compared with placebo."

Journal • P3 data • Back Pain • Lumbar Back Pain • Musculoskeletal Pain • Pain