Panna Sanga

Efficacy, safety, and tolerability of fulranumab, an anti-nerve growth factor antibody, in the treatment of patients with moderate to severe osteoarthritis pain

Summary Fulranumab, a new class of analgesic therapy, was safe and efficacious in a randomized, double‐blind, placebo‐controlled trial in patients with moderate to severe osteoarthritis pain. Abstract Nerve growth factor (NGF) is increased in chronic pain conditions. This study examined analgesic efficacy and safety of fulranumab, a fully human monoclonal anti‐NGF antibody, in adults with chronic osteoarthritis pain. Patients (n = 466, intent‐to‐treat) were randomized to receive, in addition to their current pain therapy, subcutaneous injections in 1 of 6 parallel treatment groups: placebo (n = 78), fulranumab 1 mg (n = 77) or 3 mg (n = 79) every 4 weeks (Q4wk), 3 mg (n = 76), 6 mg (n = 78), or 10 mg (n = 78) every 8 weeks (Q8wk). Primary efficacy results showed that fulranumab significantly reduced the average pain intensity score (P ≤ 0.030) from baseline to week 12 compared with placebo in the 3mgQ4wk, 6mgQ8wk, and 10mgQ8wk groups. Secondary efficacy outcomes indicated that significant improvement occurred compared with placebo at week 12 on the Western Ontario and McMaster Universities Osteoarthritis Index subscales of pain, stiffness, and physical function (P < 0.040) across all fulranumab groups except 1mgQ4wk, on the Brief Pain Inventory–Short Form subscales of pain intensity (P ≤ 0.016) and pain interference (P ≤ 0.030) in the 3mgQ4wk and 10mgQ8wk groups, and on the Patient Global Assessment score (P ≤ 0.040) in the 3mgQ4wk, 6mgQ8wk, and 10mgQ8wk groups. The most common (≥5% of patients) treatment‐emergent adverse events in overall fulranumab groups during the first 12 weeks included paresthesia (7%), headache (5%), and nasopharyngitis (5%). Most neurologic‐related treatment‐emergent adverse events were mild or moderate and resolved at the end of week 12. Serious adverse events occurred in 3 patients, but they were not neurologically related and resolved before study completion. Fulranumab treatment resulted in statistically significant efficacy in pain measures and physical function versus placebo and was generally well tolerated.

Fulranumab for treatment of diabetic peripheral neuropathic pain: A randomized controlled trial

Objective: To assess efficacy and safety of fulranumab, a fully human monoclonal antibody against nerve growth factor, in patients with diabetic peripheral neuropathic pain (DPNP). Methods: In this phase II, double-blind, placebo-controlled trial, patients with moderate to severe DPNP were randomized to treatments with fulranumab (1, 3, or 10 mg) or placebo administered subcutaneously every 4 weeks. Results: Because of early study termination (clinical hold) by the US Food and Drug Administration, 77 (intent-to-treat) of the planned 200 patients were enrolled. The primary endpoint, the mean reduction of average daily pain at week 12 compared with baseline, showed a positive dose-response relationship (p = 0.014, 1-sided); the pair-wise comparison between the 10-mg group and placebo was significant (unadjusted p = 0.040, 2-sided). An exploratory responder analysis revealed that a greater proportion of patients in the 10-mg group reported ≥30% reduction in the average DPNP intensity compared with placebo at week 12 (p = 0.006). Although not statistically significant, several secondary endpoints showed directionally similar results to the primary efficacy dose-response relationship. During the combined efficacy and safety extension phases, the top 3 treatment-emergent adverse events in the combined fulranumab group were arthralgia (11%), edema peripheral (11%), and diarrhea (9%). No cases of joint replacement or death were reported. Conclusion: Despite early study termination, fulranumab treatment resulted in dose-dependent efficacy and was generally well tolerated. Classification of evidence: This study provides Class I evidence that in patients with DPNP, fulranumab 10 mg reduces pain by 1.2 points on an 11-point scale compared with placebo.

Efficacy, Safety, and Tolerability of Fulranumab as an Adjunctive Therapy in Patients With Inadequately Controlled, Moderate-to-Severe Chronic Low Back Pain: A Randomized, Double-blind, Placebo-controlled, Dose-ranging, Dose-loading Phase II Study

PURPOSE Fulranumab is an investigational, fully human recombinant monoclonal antibody (IgG2) that neutralizes the biological actions of human nerve growth factor. Low back pain is a common cause of noncancer chronic pain and represents one of the most significant socioeconomic health-related problems in developed countries. This randomized, double-blind, placebo-controlled study was conducted to evaluate the analgesic effect of fulranumab in patients with moderate-to-severe chronic low back pain. METHODS Patients (aged 18-80 years) were randomized to receive subcutaneous injections every 4 weeks in 1 of 5 parallel treatment groups: placebo or fulranumab 1mg (1mgQ4wk), 3mg (3mgQ4wk), 3mg after a 6mg loading dose (6mgLD+3mgQ4wk), or 10mg (10mgQ4wk) every 4 weeks. FINDINGS A total of 385 patients (median age, 53 years; women, 54%) received at least 1 injection of study medication. No statistically significant differences were observed in improvement of pain intensity scores between the fulranumab treatment regimens and the placebo group at week 12 (primary end point; mean [SD], placebo: -2.0 [2.17], 1mgQ4wk: -1.9 [2.14], 3mgQ4wk: -2.2 [1.89], 6mgLD+3mgQ4wk: -2.0 [1.72] and 10mgQ4wk: -2.1 [2.18]). Results for secondary efficacy parameters (change in the Oswestry Disability Index, Brief Pain Inventory-Short Form, and Patient Global Assessment scales) were consistent with the primary outcome. A placebo effect was observed; the overall percentage of patients with treatment-emergent adverse events (TEAEs) was similar between the placebo (76%) and fulranumab treatment groups (77%-90%). Across all phases, the most common TEAEs in at least 10% of patients (combined fulranumab group vs placebo) were arthralgia (15% vs 12%), back pain (15% vs 18%), upper respiratory tract infection (15% vs 8%), paresthesia (14% vs 8%), diarrhea (12% vs 4%), headache (12% vs 8%), hypoesthesia (11% vs 5%), pain in extremity (11% vs 8%), sinusitis (10% vs 5%), and nasopharyngitis (10% vs 9%). Across all phases, neurologic TEAEs were less frequent in the placebo group (14%) versus the fulranumab treatment groups (25%). In the posttreatment phase, 8 patients had joint replacement operations, which were considered a result of normal progression of osteoarthritis. One case in the 10-mg group was determined to be rapid progession of osteoarthritis and was considered to be possibly related to study drug. IMPLICATIONS Fulranumab did not demonstrate efficacy compared with placebo in patients with chronic low back pain but was generally well-tolerated. ClinicalTrials.gov identifier: NCT00973024.

Fulranumab in Patients with Pain Associated with Postherpetic Neuralgia and Postraumatic Neuropathy: Efficacy, Safety and Tolerability Results from a Randomized, Double-blind, Placebo-controlled, Phase-2 Study.

Objective: Fulranumab is an antibody that specifically neutralizes the biological activity of human nerve growth factor. This multicenter, phase-2, randomized, double-blind (DB), placebo-controlled study evaluated the analgesic efficacy and safety of fulranumab in postherpetic neuralgia (PHN) and posttraumatic neuropathy (PTN) patients. Methods: Patients (18 to 80 y) with inadequately controlled moderate-to-severe pain received study medication (subcutaneous injection) every 4 weeks. PHN patients were randomized (3:2:2:3) to receive either placebo or one of 3 doses of fulranumab: 1 mg (1 mgQ4 wk), 3 mg (3 mgQ4 wk), or 10 mg (10 mgQ4 wk). PTN patients were randomized (1:1) to receive either placebo or fulranumab 10 mgQ4 wk. Results: The US Food and Drug Administration placed a clinical hold (December 23, 2010) on all trials of antinerve growth factor drugs, including fulranumab, due to identified risks of osteonecrosis or rapidly progressing osteoarthritis; therefore, only 49 (of 150 planned) PHN patients and 34 (of 50 planned) PTN patients completed the DB efficacy evaluation. There was no significant difference (P>0.05, fulranumab vs. placebo) for change in 7-day average of daily pain intensity scores from DB baseline to end of 12-week DB efficacy phase in PHN or PTN patients (primary endpoint). No significant difference was found with fulranumab versus placebo (P>0.05) in other efficacy measures in either PHN or PTN patients. The most common treatment-emergent adverse events (>10% incidence) in PTN patients were sinusitis, carpal tunnel syndrome, and headache, whereas in PHN patients it was arthralgia. Discussion: Fulranumab did not demonstrate efficacy in either PHN or PTN patients, but was generally well-tolerated in this small underpowered and abbreviated study.

Analgesic efficacy of fulranumab in patients with painful diabetic peripheral neuropathy in a randomized, placebo-controlled, double-blind study

OBJECTIVE: To evaluate analgesic efficacy of fulranumab, a human recombinant investigational anti-nerve growth factor (NGF) monoclonal antibody, in patients with painful diabetic peripheral neuropathy (DPN). BACKGROUND: NGF antibodies offer a potential treatment option in DPN. DESIGN/METHODS: Multicenter, phase 2, placebo-controlled study (initiated Oct. 2009) with a 12-week double-blind (DB) efficacy-, 40-week DB safety extension-, and 52-week open-label safety extension phase. Patients with moderate to severe pain, stratified by concomitant treatment for neuropathic pain (yes/no), were randomized (3:2:2:3) to receive either placebo or fulranumab (1 mg-, 3 mg-, or 10 mg fulranumab; every 4 weeks [Q4wk] subcutaneously). RESULTS: Due to US FDA clinical hold, only 77 of planned 200 patients were enrolled: 62 (81%) patients (55.8% men; 81.8% white; mean [SD] age 58.7 [9.48] years) completed the DB efficacy phase. Change in 7-day average of daily pain intensity score from baseline to end of 12 week DB efficacy phase (primary endpoint) showed a positive dose response (p=0.014, one-sided). At DB efficacy endpoint, the pair-wise comparison between 10 mgQ4wk dose to placebo was significant (nominal p=0.04, two-sided). Least square (LS) means differences (95% CI) in change from baseline in average pain intensity scores vs placebo were: fulranumab 1mgQ4wk, 0.1 (-1.26; 1.36); 3mgQ4wk, -0.6 (-1.98; 0.74); and 10 mgQ4wk, -1.2 (-2.44; -0.06). 30% responder rates (≥30% improvement in average pain intensity score) at DB efficacy endpoint were: placebo, 21%; 1mgQ4wk, 44%; 3mgQ4wk, 43%; and 10 mgQ4wk, 61%. Multiple secondary efficacy endpoints showed dose-related improvement trends. Most common (≥5 patients) adverse events for total fulranumab-treated patients (n=53) vs placebo (n=24) were: peripheral oedema (11% vs 0%), arthralgia (11% vs 13%), and diarrhoea (9% vs 8%). No cases of joint replacement or deaths were reported during the study. CONCLUSIONS: Despite early study termination, fulranumab treatment resulted in dose-dependent efficacy and was generally well tolerated in this study. Supported by: Janssen Research & Development, LLC (previously known as Johnson & Johnson Pharmaceutical Research & Development, L.L.C), New Jersey, USA. Disclosure: Dr. Wang has received personal compensation for activities with Janssen Pharmaceutical as an employee. Dr. Wang has received (royalty or license fee or contractual rights) payments from Netrin3. Dr. Romano has received personal compensation for activities with Janssen Research & Development as an employee. Dr. Romano holds stock in Janssen Research & Development. Dr. Frustaci has received personal compensation for activities with Johnson & Johnson as an employee. Dr. Frustaci holds stock and/or stock options in Johnson & Johnson. Dr. Sanga has received personal compensation for activities with Janssen Research & Development as an employee. Dr. Ness has received personal compensation for activities with Janssen Research and Development LLC as an employee. Dr. Ness holds stock and/or stock options in Janssen Research and Development LLC. Dr. Russell has received personal compensation for activities with Janssen Pharmaceuticals as an employee. Dr. Russell holds stock and/or stock options in Janssen Pharmaceuticals. Dr. Fedgchin has received personal compensation for activities with Janssen Research & Development as an employee. Dr. Kelly has received personal compensatino for activities with Janssen Research and Development LLC as an employee. Dr. Kelly holds stock and/or stock options in Johnson & Johnson. Dr. Thipphawong has received personal compensation for activities with Janssen Pharmaceuticals as an employee. Dr. Thipphawong holds stock and/or stock options in Janssen Pharmaceuticals.

Long‐Term Safety and Efficacy of Fulranumab in Patients With Moderate‐to‐Severe Osteoarthritis Pain: A Phase II Randomized, Double‐Blind, Placebo‐Controlled Extension Study

To evaluate the long‐term safety and efficacy of fulranumab in patients with knee or hip pain caused by moderate‐to‐severe chronic osteoarthritis (OA).

Long-term Safety and Efficacy of Fulranumab in Patients with Moderate-to-Severe Osteoarthritis Pain: A Randomized, Double-blind, Placebo-controlled Study.

To evaluate the long‐term safety and efficacy of fulranumab in patients with knee or hip pain caused by moderate‐to‐severe chronic osteoarthritis (OA).

Bioavailability and Pharmacokinetics of TRPV1 Antagonist Mavatrep (JNJ‐39439335) Tablet and Capsule Formulations in Healthy Men: Two Open‐Label, Crossover, Single‐Dose Phase 1 Studies

To improve room temperature stability and oral bioavailability of mavatrep (JNJ‐39439335, a transient receptor potential vanilloid subtype‐1 antagonist), various formulations were initially developed and evaluated in 2 phase 1 open‐label, randomized, 3‐way crossover studies in healthy participants. Study 1 evaluated 2 new overencapsulated tablet formulations (formulations B and C) relative to an overencapsulated early tablet formulation (formulation A), using mavatrep HCl salt form. Because these tablets were still not room‐temperature stable, in study 2: two free‐base solid dispersion amorphous formulations (formulations D and E) were evaluated relative to the best encapsulated formulation from study 1 (formulation C) and also food effect. Both studies had screening (∼4 weeks), treatment (study 1: n = 18, 6‐sequenced; formulations B and C [2 × 25 mg] versus A [2 × 25 mg]; study 2, part 1: n = 24, formulations D and E [2 × 12.5 mg] versus C [1 × 25 mg]; study 2, part 2: n = 16, best formulation from part 1 fed versus fasted, 2 × 12.5 mg) with a 21‐day washout period and a follow‐up. Mavatrep exhibited consistent pharmacokinetics across formulations. Following rapid absorption (median tmax, 1.5–6.5 hours), plasma concentrations declined multiexponentially (mean t1/2, 67–104 hours). The new encapsulated tablet formulation (formulation C, capsule filler: poloxamer 407) was the best formulation (Cmax and AUC values 2‐3‐fold > than the other 2) from study 1. Using this as a reference in study 2, part 1, only small (<20%) differences in mean Cmax and AUC were observed between the 3 formulations (C, D, and E). Formulation E (gelatin capsule with amorphous solid dispersion [12.5 mg free base], hydroxypropyl methylcellulose, vitamin E polyethylene glycol succinate, silicified microcrystalline cellulose, magnesium stearate, colloidal silicon dioxide) showed improved room‐temperature stability and provided the best overall bioavailability with small variability. Small effects of a high‐fat meal on oral bioavailability were observed for formulation E, but were not clinically meaningful. Mavatrep safety profiles were similar across formulations and under fasted and fed conditions. No new safety concerns were reported.

Pharmacokinetics and Safety of Mavatrep (JNJ-39439335), a TRPV1 Antagonist in Healthy Japanese and Caucasian Men: A Double-Blind, Randomized, Placebo-Controlled, Sequential-Group Phase 1 Study

This single‐center, double‐blind, placebo‐controlled, sequential‐group phase 1 study evaluated the safety, tolerability, and pharmacokinetics (PK) of mavatrep (JNJ‐39439335), a transient receptor potential vanilloid 1 antagonist, in healthy Japanese and caucasian subjects. In part 1, a single‐ascending‐dose study, 50 subjects (25 each healthy Japanese and caucasians) were enrolled and received a single oral dose of 10, 25, or 50 mg mavatrep. Caucasian subjects were matched to Japanese subjects with respect to age (±5 years) and body mass index (±5 kg/m2). In part 2, a multiple‐ascending‐dose study, 36 Japanese subjects were enrolled and received once‐daily oral doses of 10, 25, or 50 mg of mavatrep for 21 days. The single‐dose PK of mavatrep and its metabolites was similar in the Japanese and caucasian subjects after adjustment of body weight. Following multiple dosing in Japanese subjects, a steady‐state condition was reached in approximately 14 days. M2 and M3 are major circulating metabolites with mean exposure > 10% of mavatrep. Nonrenal clearance was the major route of elimination for mavatrep, M2, and M3. Mavatrep exhibited a long half‐life, ranging from 68 to 101 and 82–130 hours for Japanese and caucasian subjects, respectively. After single and multiple dosing, mavatrep was well tolerated. The most common adverse events observed were thermohypoesthesia, feeling cold, chills, and feeling hot. Mavatrep and its metabolites exhibited similar PK profiles after single ascending doses in healthy Japanese and caucasian men.