Peripheral Nerve Safety of Nerve Growth Factor Inhibition by Tanezumab: Pooled Analyses of Phase III Clinical Studies in Over 5000 Patients with Osteoarthritis.

Background: Tanezumab, a humanized anti-nerve growth factor antibody, was developed for the treatment of pain associated with osteoarthritis. Due to its mechanism of action, peripheral nerve safety was assessed in all clinical studies.

Objectives: To summarize the neurological safety of intravenous (IV) and subcutaneous (SC) tanezumab versus placebo in patients with osteoarthritis.

A Randomized Placebo-Controlled Trial of the Anti-Nerve Growth Factor Antibody Tanezumab in Subjects With Cancer Pain Due to Bone Metastasis.

Background: This phase III, randomized, double-blind, placebo-controlled, parallel-group study assessed the efficacy and safety of tanezumab in subjects with cancer pain predominantly due to bone metastasis receiving background opioid therapy.

Methods: Subjects were randomized (stratified by (1) tumor aggressiveness and (2) presence/absence of concomitant anticancer treatment) to placebo or tanezumab 20 mg. Treatment was administered by subcutaneous injection every 8 weeks for 24 weeks (3 doses) followed by a 24-week safety follow-up period.

Predicting Treatment Responses in Patients With Osteoarthritis: Results From Two Phase III Tanezumab Randomized Clinical Trials.

Prediction of treatment responses is essential to move forward translational science. Our question was to identify patient-based variables that predicted responses to treatments. We conducted secondary analyses on pooled data from two randomized phase III clinical trials (NCT02697773 and NCT02709486) conducted in participants with moderate to severe osteoarthritis randomized to subcutaneous placebo (n = 514) or tanezumab 2.

Patient characteristics, pain treatment patterns, and incidence of total joint replacement in a US population with osteoarthritis.

Background: Currently available medications for chronic osteoarthritis pain are only moderately effective, and their use is limited in many patients because of serious adverse effects and contraindications. The primary surgical option for osteoarthritis is total joint replacement (TJR). The objectives of this study were to describe the treatment history of patients with osteoarthritis receiving prescription pain medications and/or intra-articular corticosteroid injections, and to estimate the incidence of TJR in these patients.

Inter-Reader Consistency and Exclusionary Findings During Radiographic Screening for Phase 3 Trials of Tanezumab in Patients With Osteoarthritis.

Objective: Describe the radiograph-based screening program and frequencies of ineligibility in 3 large, international, randomized, double-blind, phase 3 studies of subcutaneous tanezumab in patients with osteoarthritis (OA).

Design: Standardized bilateral shoulder, hip, and knee screening radiographs were obtained by trained imaging technologists and centrally read by 1 of 5 musculoskeletal radiology experts trained using a program-specific imaging atlas. Inter-reader consistency was tracked with test cases blindly inserted into the reader queue.

Design of a randomized, placebo-controlled, phase 2 study evaluating the safety and efficacy of tanezumab for treatment of schwannomatosis-related pain.

Background: Schwannomatosis (SWN) is a rare tumor suppressor syndrome that predisposes affected individuals to develop multiple schwannomas and, less often, meningiomas. The most common symptom is chronic, severe pain. No medications are broadly effective in treating SWN-associated pain.

Observed efficacy and clinically important improvements in participants with osteoarthritis treated with subcutaneous tanezumab: results from a 56-week randomized NSAID-controlled study.

Background: A recent phase 3 study demonstrated that treatment with tanezumab, a nerve growth factor inhibitor, or nonsteroidal anti-inflammatory drugs (NSAIDs) improves pain and physical function in participants with moderate-to-severe osteoarthritis (OA) of the hip or knee. Here, we evaluated the time course and clinical importance of these initial efficacy findings using a mixture of primary, secondary, and post hoc endpoints.

Methods: Participants on stable NSAID therapy and with a history of inadequate response to other standard OA analgesics were enrolled in an 80-week (56-week treatment/24-week safety follow-up), randomized, NSAID-controlled, phase 3 study primarily designed to assess the safety of tanezumab for moderate-to-severe OA of the knee or hip.

Tanezumab for chronic low back pain: a long-term, randomized, celecoxib-controlled Japanese Phase III safety study.

This trial investigated long-term (56-week treatment/24-week follow-up) use of subcutaneous tanezumab (5 or 10 mg every 8 weeks) or oral celecoxib (200 mg/day) in Japanese patients with chronic low back pain. Tanezumab safety was consistent with previous studies, except overall adverse events (tanezumab 5 mg = 63.0%, tanezumab 10 mg = 54.

Energy constrains to increasing complexity in the biosphere.

Thirty years ago, the systems ecologist Howard T. Odum introduced the concept of transformity, which is a thermodynamic measure of quality within the trial and error evolutionary dynamics of ecosystems, namely an indicator of rank in the hierarchical system structure of the biosphere. Based on a global database of individual processes and whole economies, this paper extends, refines, and updates Odum's idea, demonstrating the strength of the postulated relation.

General Safety and Tolerability of Subcutaneous Tanezumab for Osteoarthritis: A Pooled Analysis of Three Randomized, Placebo-Controlled Trials.

Objective: This pooled analysis of 3 randomized, placebo-controlled trials (16-24 week treatment and 8-24 week follow-up) assessed safety of subcutaneous tanezumab (2.5-10 mg every 8 weeks) in 1,840 patients with hip or knee osteoarthritis.

Methods: Overall treatment-emergent adverse events (TEAEs) and TEAEs of abnormal peripheral sensation (APS) were prospectively assessed in 3 trials.

Subcutaneous tanezumab for osteoarthritis: Is the early improvement in pain and function meaningful and sustained?

Background: To evaluate if early improvements in pain and function with subcutaneous tanezumab are meaningful and sustained over 24 weeks.

Methods: Patients with moderate-to-severe osteoarthritis (hip or knee) in Europe and Japan were randomized to placebo, tanezumab 2.5 mg or tanezumab 5 mg (baseline, Week 8 and Week 16).

Long-Term Safety and Efficacy of Subcutaneous Tanezumab Versus Nonsteroidal Antiinflammatory Drugs for Hip or Knee Osteoarthritis: A Randomized Trial.

Objective: To assess the long-term safety and 16-week efficacy of subcutaneous tanezumab in patients with hip or knee osteoarthritis (OA).

Methods: This was a phase III randomized, double-blind, active treatment-controlled (using nonsteroidal antiinflammatory drugs [NSAIDs] as the active treatment control) safety trial of tanezumab (56-week treatment/24-week posttreatment follow-up) in adults who were receiving stable-dose NSAID therapy at the time of screening and who had Western Ontario and McMaster Universities Osteoarthritis Index (WOMAC) pain and physical function scores of ≥5; patient global assessment (PtGA) of OA of fair, poor, or very poor; history of inadequate pain relief with standard analgesics; and no history or radiographic evidence of prespecified bone/joint conditions beyond OA. Patients received oral naproxen, celecoxib, or diclofenac twice daily (NSAID group; n = 996) or tanezumab 2.

The moral status of the fetus: Implications of the somatic integration definition of human life.

This account of the moral status of the human fetus makes four interlocking claims, which together comprise the Fetal Life Moral Status Thesis: (1) life as a human organism begins at the fetal stage of development; (2) the non-organismal life of the human embryo begins at fertilization; (3) the human fetus has intrinsic moral status as a human being; and (4) the human embryo has extrinsic moral status as a non-organismal human individual. The somatic integration definition of human life functions as a premise in two supporting arguments: the Fetal Life Argument and the Fetal Moral Status Argument. These arguments are articulated, objections are considered, and the resulting account of the moral status of the human fetus is applied to the problem of abortion.

Onset and maintenance of efficacy of subcutaneous tanezumab in patients with moderate to severe osteoarthritis of the knee or hip: A 16-week dose-titration study.

Objective: To examine the onset and maintenance of efficacy of subcutaneous tanezumab for pain relief and functional improvement in difficult-to-treat patients with moderate-to-severe osteoarthritis (OA) in a 16-week dose-titration study (NCT02697773).

Methods: Patients were randomized to placebo (placebo group) or tanezumab 2.5 mg at baseline and week 8 (tanezumab 2.

Subcutaneous tanezumab for osteoarthritis of the hip or knee: efficacy and safety results from a 24-week randomised phase III study with a 24-week follow-up period.

Objective: Tanezumab, a nerve growth factor inhibitor, was investigated for osteoarthritis (OA) of the hip or knee in a study with 24-week treatment and 24-week safety follow-up.

Methods: This double-blind, randomised, phase III study enrolled adults in Europe and Japan with moderate-to-severe OA who had not responded to or could not tolerate standard-of-care analgesics. Patients were randomised to tanezumab 2.

The somatic integration definition of the beginning of life.

The somatic integration definition of life is familiar from the debate on the determination of death, with some bioethicists arguing that it supports brain death while others argue that some brain-dead bodies exhibit sufficient somatic integration for biological life. I argue that on either interpretation, the somatic integration definition of life implies that neither the preimplantation embryo nor the postimplantation embryo meet the somatic integration threshold condition for organismal human life. The earliest point at which a somatic integration determination of life could be made would be the beginning of the fetal stage, 9 weeks postfertilization.

Effect of Tanezumab on Joint Pain, Physical Function, and Patient Global Assessment of Osteoarthritis Among Patients With Osteoarthritis of the Hip or Knee: A Randomized Clinical Trial.

Importance: Patients with osteoarthritis (OA) may remain symptomatic with traditional OA treatments.

Objective: To assess 2 subcutaneous tanezumab dosing regimens for OA.

Design, Setting, And Participants: A randomized, double-blind, multicenter trial from January 2016 to May 14, 2018 (last patient visit).

Pooled analysis of tanezumab efficacy and safety with subgroup analyses of phase III clinical trials in patients with osteoarthritis pain of the knee or hip.

Purpose: A pooled analysis was conducted to evaluate tanezumab efficacy and safety in patients with osteoarthritis (OA), including subgroup analyses of at-risk patients with diabetes, severe OA symptoms, and those aged ≥65 years.

Patients And Methods: Data from phase III placebo-controlled clinical trials of patients with moderate-to-severe OA of the knee or hip were pooled to evaluate tanezumab efficacy (four trials) and safety (nine trials). Patients received intravenous tanezumab, tanezumab plus an oral NSAID (naproxen, celecoxib, or diclofenac), active comparator (naproxen, celecoxib, diclofenac, or oxycodone), or placebo.

First-in-human randomized clinical trials of the safety and efficacy of tanezumab for treatment of chronic knee osteoarthritis pain or acute bunionectomy pain.

Introduction: The neurotrophin nerve growth factor has a demonstrated role in pain transduction and pathophysiology.

Objectives: Two randomized, double-blind, placebo-controlled, phase 1 studies were conducted to evaluate safety, tolerability, and analgesic efficacy of single doses of tanezumab, a humanized anti-nerve growth factor monoclonal antibody, in chronic or acute pain.

Methods: In the first study (CL001), patients with moderate to severe pain from osteoarthritis (OA) of the knee received a single intravenous infusion of tanezumab (3-1000 μg/kg) or placebo in a dose-escalation (part 1; N = 42) or parallel-arm (part 2; N = 79) study design.