Selective Inhibition of NaV1.8 with VX-548 for Acute Pain.

BACKGROUND: The NaV1.8 voltage-gated sodium channel, expressed in peripheral nociceptive neurons, plays a role in transmitting nociceptive signals. The effect of VX-548, an oral, highly selective inhibitor of NaV1.8, on control of acute pain is being studied. METHODS: After establishing the selectivity of VX-548 for NaV1.8 inhibition in vitro, we conducted two phase 2 trials involving participants with acute pain after abdominoplasty or bunionectomy. In the abdominoplasty trial, participants were randomly assigned in a 1:1:1:1 ratio to receive one of the following over a 48-hour period: a 100-mg oral loading dose of VX-548, followed by a 50-mg maintenance dose every 12 hours (the high-dose group); a 60-mg loading dose of VX-548, followed by a 30-mg maintenance dose every 12 hours (the middle-dose group); hydrocodone bitartrate-acetaminophen (5 mg of hydrocodone bitartrate and 325 mg of acetaminophen every 6 hours); or oral placebo every 6 hours. In the bunionectomy trial, participants were randomly assigned in a 2:2:1:2:2 ratio to receive one of the following over a 48-hour treatment period: oral high-dose VX-548; middle-dose VX-548; low-dose VX-548 (a 20-mg loading dose, followed by a 10-mg maintenance dose every 12 hours); oral hydrocodone bitartrate-acetaminophen (5 mg of hydrocodone bitartrate and 325 mg of acetaminophen every 6 hours); or oral placebo every 6 hours. The primary end point was the time-weighted sum of the pain-intensity difference (SPID) over the 48-hour period (SPID48), a measure derived from the score on the Numeric Pain Rating Scale (range, 0 to 10; higher scores indicate greater pain) at 19 time points after the first dose of VX-548 or placebo. The main analysis compared each dose of VX-548 with placebo. RESULTS: A total of 303 participants were enrolled in the abdominoplasty trial and 274 in the bunionectomy trial. The least-squares mean difference between the high-dose VX-548 and placebo groups in the time-weighted SPID48 was 37.8 (95% confidence interval [CI], 9.2 to 66.4) after abdominoplasty and 36.8 (95% CI, 4.6 to 69.0) after bunionectomy. In both trials, participants who received lower doses of VX-548 had results similar to those with placebo. Headache and constipation were common adverse events with VX-548. CONCLUSIONS: As compared with placebo, VX-548 at the highest dose, but not at lower doses, reduced acute pain over a period of 48 hours after abdominoplasty or bunionectomy. VX-548 was associated with adverse events that were mild to moderate in severity. (Funded by Vertex Pharmaceuticals; VX21-548-101 and VX21-548-102 ClinicalTrials.gov numbers, NCT04977336 and NCT05034952.).

HTX-011 Reduced Pain and Opioid Use After Primary Total Knee Arthroplasty: Results of a Randomized Phase 2b Trial.

BACKGROUND: HTX-011 is an extended-release, dual-acting local anesthetic consisting of bupivacaine and low-dose meloxicam in a novel polymer that is administered by needle-free application during surgery. The active ingredients are released from the polymer by controlled diffusion over 72 hours. METHODS: This phase 2b, double-blind, placebo-controlled and active-controlled trial enrolled patients undergoing primary unilateral total knee arthroplasty under general anesthesia. Two hundred thirty-two patients were randomized into 4 groups: HTX-011 400 mg bupivacaine/12 mg meloxicam, applied without a needle into the surgical site, the same dose of HTX-011 with a separate 50 mg ropivacaine injection into the posterior capsule, bupivacaine hydrochloride (HCl) 125 mg injection, and saline placebo injection. Only opioids were permitted for postoperative pain rescue. Primary and key secondary endpoints were mean area under the curve of pain intensity scores over 48 hours and 72 hours, respectively, for HTX-011 groups vs placebo. RESULTS: Both HTX-011 groups had significantly reduced mean pain intensity vs placebo through 48 and 72 hours (both P < .001). Ropivacaine added a small initial benefit in the first 12 hours. Both HTX-011 groups also had decreased mean pain intensity vs bupivacaine HCl alone through 48 and 72 hours (P < .05). The HTX-011 groups had significantly earlier discharge readiness along with lower opioid consumption through 72 hours. HTX-011 alone or with ropivacaine was well-tolerated with a safety profile similar to controls. CONCLUSION: Needle-free application of HTX-011 400 mg bupivacaine/12 mg meloxicam provided superior pain reduction through 72 hours after total knee arthroplasty compared with placebo and bupivacaine HCl alone.

Long-Term Follow-up of Onychomycosis Patients Treated With Efinaconazole

BACKGROUND: Onychomycosis is a common disease that remains difficult to treat despite the introduction of new topical agents. Clinical trials on efinaconazole and tavaborole included 48 weeks' daily treatment regimens with a 4-week follow-up. It has been suggested that either a longer treatment regimen or longer follow-up would lead to even better results, primarily due to the time taken for the diseased nail to grow out, especially in those patients with more severe disease. OBJECTIVE: To investigate the impact of a longer follow-up period on the efficacy of efinaconazole 10% topical solution in patients with moderate-to-severe onychomycosis. METHODS: &Single center, open-labeled study in 23 subjects aged 18-80 years with a clinical and mycological diagnosis of moderate-to-severe dermatophyte toenail onychomycosis (40-75% clinical involvement). Subjects were treated with efinaconazole 10% solution, once-daily for 48 weeks, with two 12-week post-treatment follow-ups (at week 60 and 72). Primary efficacy endpoint was complete cure rate (0% clinical involvement of target toenail, and both negative potassium hydroxide examination and fungal culture). Secondary endpoints included mycologic cure rates and treatment success (defined as those patients who had at least a 50% improvement in affected toenail from baseline). RESULTS: Twenty-two subjects completed the study. Mean baseline age 59.4 years (range, 37-77), predominance of male subjects (73.9%). Median baseline severity 50% affected target toenail. At week 72, two subjects were complete cures and 56.5% of subjects achieved treatment success. There were no complete cures at week 48, but 39.1% achieved treatment success. Mycologic cure rates were 91.3% at week 48. Median percent affected target toenail reduced to 40%, and further to 25% (week 48 and 72, respectively). Treatment was well tolerated, with no adverse events related to medication. CONCLUSIONS: This single-center phase 4 study supports previous data showing good efficacy and tolerability of efinaconazole in moderately severe onychomycosis. Continued reduction in disease severity post-treatment suggest that a longer follow-up of patients treated with efinaconazole would afford better efficacy results, as indicated by greater treatment success, and increase in number of subjects who became complete cures.

Access of efinaconazole topical solution, 10%, to the infection site by spreading through the subungual space.

OBJECTIVE: To evaluate the ability of efinaconazole vehicle to reach the site of toenail onychomycosis by spreading through the subungual space between the nail plate and nail bed. Lacquer-based vehicles are primarily limited to application on the nail plate and dependent on nail plate permeation. METHODS: 11 patients (mean age 48.5 years) were entered with clinically determined onychomycosis. Presence of fungal infection was confirmed by KOH testing in eight patients. Two separate applications of vehicle (with fluorescein incorporated for better visualization) were applied at the hyponychium, avoiding application to the exterior nail plate surface. Affected nails were later clipped to allow examination of the nail bed and further examination of the underside of the nail. Spread of formulation was assessed under visible and UV light conditions by photographing target toenails after vehicle application, and after nail clipping. RESULTS: Assessments under both visible and UV light indicated that the vehicle had spread into the subungual space, with deposition of flourescein wherever vehicle had reached, including in the nail bed. Nail clippings also indicated deposition to the underside of the nail plate. LIMITATIONS: The relative contributions of spreading into the subungual space, or permeation through the nail plate to the efficacy of efinaconazole topical solution, 10% in treating onychomycosis were not assessed. CONCLUSIONS: This study suggests that the vehicle developed for efinaconazole topical solution, 10%, when applied at the hyponychium, spreads into the subungual space between the nail plate and nail bed, reaching the site of infection.

The efficacy and safety of tavaborole, a novel, boron-based pharmaceutical agent: phase 2 studies conducted for the topical treatment of toenail onychomycosis.

OBJECTIVE: To assess the potential efficacy, safety, and optimal dosing concentration of tavaborole, a novel, boron-based pharmaceutical agent with broad-spectrum antifungal activity, for the treatment of onychomycosis of the toenail due to dermatophytes. METHODS: One double-blind, randomized, vehicle-controlled study (study 1) and two open-label studies (studies 2 and 3) examined the efficacy, safety, and optimal dosing concentration of tavaborole topical solution applied once daily or three times weekly for 180 days at concentrations of 1.0%, 2.5%, 5.0%, or 7.5%. Patient cohort 3 of study 2 received open-label tavaborole 5.0% once daily for 360 days. All three studies assessed day 180 treatment success, defined as complete or partial clinical evidence of clear nail growth plus negative fungal culture. RESULTS: A total of 336 patients were included in the intent-to-treat (ITT) or modified ITT populations and efficacy analyses across the 3 studies. In study 1, treatment success rates at day 180 were higher with tavaborole 2.5%, 5.0%, and 7.5% vs vehicle (27%, 26%, and 32% vs 14%, respectively; slope P=0.030). In cohort 3 of study 2, 7% of patients achieved treatment success with tavaborole 5.0% at day 360. Negative culture rates at day 180 in study 1 were numerically higher for tavaborole 2.5%, 5.0%, and 7.5% vs vehicle (slope P=0.046). Application-site reactions of general irritation, erythema, scaling, and stinging/burning were most common with tavaborole 7.5%, were generally mild to moderate, and resolved with treatment discontinuation and/or a reduction in dosing frequency. No systemic safety concerns were observed. CONCLUSION: Tavaborole solution demonstrated favorable efficacy and safety in phase 2 clinical studies. Based on these findings, tavaborole topical solution, 5% was further investigated in larger, more definitive phase 3 studies. Results from these completed phase 3 studies will provide additional evidence regarding the safety and efficacy of tavaborole in the treatment of toenail onychomycosis.

Mechanism of action of HTX-011: a novel, extended-release, dual-acting local anesthetic formulation for postoperative pain.

BACKGROUND AND OBJECTIVES: Obtaining consistent efficacy beyond 12-24 hours with local anesthetics, including extended-release formulations, has been a challenging goal. Inflammation resulting from surgery lowers the pH of affected tissues, reducing neuronal penetration of local anesthetics. HTX-011, an investigational, nonopioid, extended-release dual-acting local anesthetic combining bupivacaine and low-dose meloxicam, was developed to reduce postsurgical pain through 72 hours using novel extended-release polymer technology. Preclinical studies and a phase II clinical trial were conducted to confirm the mechanism of action of HTX-011. METHODS: In a validated postoperative pain pig model and a phase II bunionectomy trial, the analgesic effects of HTX-011, oral meloxicam (preclinical only), liposomal bupivacaine (preclinical only) and saline placebo were evaluated. The optimal meloxicam:bupivacaine ratio for HTX-011 and the effect of HTX-011 on incisional tissue pH were also evaluated preclinically. RESULTS: Preclinical data demonstrate the ability of HTX-011 to address local tissue inflammation as demonstrated by a less acidic tissue pH, which was associated with potentiated and prolonged analgesic activity. In the phase II bunionectomy study, HTX-011 achieved superior and sustained pain relief through 72 hours after surgery compared with each component in the polymer. CONCLUSIONS: Preclinical animal and clinical results confirm that the low-dose meloxicam in HTX-011 normalizes the local pH in the incision, resulting in superior and synergistic analgesic activity compared with extended-release bupivacaine. HTX-011 represents an extended-release local anesthetic with a dual-acting mechanism of action that may provide an important advancement in the treatment of postoperative pain. TRIAL REGISTRATION NUMBER: NCT02762929.

Efficacy and Safety of Intravenous Meloxicam in Patients With Moderate-to-Severe Pain Following Bunionectomy: A Randomized, Double-Blind, Placebo-controlled Trial.

OBJECTIVE: To evaluate the analgesic efficacy and safety of a novel intravenous (IV) formulation of meloxicam (30 mg) in patients with moderate-to-severe pain following a standardized, unilateral bunionectomy with first metatarsal osteotomy and internal fixation. MATERIALS AND METHODS: Patients who met the criteria for moderate-to-severe postoperative pain were randomized to receive bolus injections of meloxicam IV 30 mg (n=100) or placebo (n=101) administered once daily. The primary efficacy endpoint was the Summed Pain Intensity Difference over 48 hours (SPID48). Secondary efficacy endpoints included sum of time-weighted pain intensity differences (SPID) values at other timepoints/intervals, time to first use of rescue analgesia, and number of rescue doses taken. Safety assessments included the incidence of adverse events (AEs), physical examinations, laboratory tests, 12-lead electrocardiography, and wound healing. RESULTS: Patients randomized to meloxicam IV 30 mg exhibited a statistically significant difference in SPID48 versus the placebo group (P=0.0034). Statistically significant differences favoring meloxicam IV over placebo were also observed for secondary efficacy endpoints, including SPID at other times/intervals (SPID6: P=0.0153; SPID12: P=0.0053; SPID24: P=0.0084; and SPID24-48: P=0.0050) and first use of rescue medication (P=0.0076). Safety findings indicated that meloxicam IV 30 mg was generally well tolerated; no serious AEs or bleeding events were observed. Most AEs were assessed by the investigator to be mild in intensity, and no patients discontinued due to AEs. There were no meaningful differences between the study groups in vital signs, electrocardiographic findings, or laboratory assessments. In most cases, investigators found that wound healing followed a normal course and mean wound-healing satisfaction scores were similar for meloxicam IV 30 mg and placebo. DISCUSSION: Meloxicam IV doses of 30 mg provided effective pain relief when administered once daily by bolus injection to patients with moderate-to-severe pain following bunionectomy, and had an acceptable safety profile.

Efinaconazole Topical Solution, 10%: Factors Contributing to Onychomycosis Success.

To provide an adequate therapeutic effect against onychomycosis, it has been suggested that topical drugs should have two properties: drug permeability through the nail plate and into the nail bed, and retention of their antifungal activity in the disease-affected areas. Only recently has the importance of other delivery routes (such as subungual) been discussed. Efinaconazole has been shown to have a more potent antifungal activity in vitro than the most commonly used onychomycosis treatments. The low keratin affinity of efinaconazole contributes to its effective delivery through the nail plate and retention of its antifungal activity. Its unique low surface tension formulation provides good wetting properties affording drug delivery both through and under the nail. High antifungal drug concentrations have been demonstrated in the nail of onychomycosis patients, and effectiveness of efinaconazole topical solution, 10% confirmed in two large well-controlled multicenter Phase 3 clinical studies in patients with mild-to-moderate disease.

Efinaconazole topical solution, 10%: the development of a new topical treatment for toenail onychomycosis.

BACKGROUND: Toenail onychomycosis is a common disease with limited treatment options; treatment failure and relapse are frequently encountered. Many patients experience long-standing disease affecting multiple toenails, with substantial discomfort and pain. Although some patients might prefer a topical therapy, efficacy with ciclopirox nail lacquer has been disappointing. METHODS: Efinaconazole topical solution, 10% is the first topical triazole antifungal agent specifically developed for the treatment of onychomycosis. This paper reviews the preclinical and clinical data on efinaconazole topical solution, 10%. RESULTS: Efinaconazole has a broad spectrum of antifungal activity in vitro and is more potent than ciclopirox against common onychomycosis pathogens. It has a more optimal keratin affinity than ciclopirox, and it exhibits significantly greater in vivo activity owing to its superior nail penetration. Mycologic cure rates at week 52 were 55.2% (study 1) and 53.4% (study 2) with efinaconazole topical solution, 10% compared with 16.8% and 16.9%, respectively, with vehicle (P<.001 for both). In addition, efinaconazole is well tolerated. CONCLUSIONS: Efinaconazole topical solution, 10% may likely become a preferred topical agent for the management of mild-to-moderate onychomycosis.