Efficacy and Safety of DaxibotulinumtoxinA for Injection in Cervical Dystonia: ASPEN-1 Phase 3 Randomized Controlled Trial.

BACKGROUND AND OBJECTIVES: ASPEN-1 was a phase 3, randomized, double-blind, placebo-controlled study to evaluate the efficacy, duration of response, and safety of 2 doses of DaxibotulinumtoxinA for Injection (DAXI), a novel botulinum toxin type A formulation in participants with cervical dystonia (CD). METHODS: Adults (aged 18-80 years) with moderate-to-severe CD (Toronto Western Spasmodic Torticollis Rating Scale [TWSTRS] total score ≥20) were enrolled at 60 sites across 9 countries in Europe and North America. Participants were randomized (3:3:1) to single-dose intramuscular DAXI 125U, 250U, or placebo and followed for up to 36 weeks after injection. The primary end point was change from baseline in TWSTRS total score averaged across weeks 4 and 6. Key secondary end points included duration of effect, Clinical and Patient Global Impression of Change (CGIC, PGIC), TWSTRS subscale scores, and safety. Multiplicity-adjusted intent-to-treat hypothesis tests with multiple imputation were performed using ANCOVA and Cochran-Mantel-Haenszel analyses. RESULTS: Of 444 individuals screened, 301 were randomized to DAXI 125U (n = 125) or 250U (n = 130) or placebo (n = 46). DAXI 125U and 250U significantly improved the mean TWSTRS total score vs placebo (least squares mean [standard error] difference vs placebo: DAXI 125U, -8.5 [1.93], p < 0.0001; DAXI 250U, -6.6 [1.92], p = 0.0006). The median duration of effect (time from treatment until loss of ≥80% of the peak improvement in average TWSTRS total score achieved at weeks 4 and 6) was 24.0 (95% confidence interval 20.3-29.1) weeks with DAXI 125U and 20.3 (16.7-24.0) weeks with DAXI 250U. Significant improvements were also observed with DAXI in CGIC and PGIC responder rates and TWSTRS subscales. Treatment-related treatment-emergent adverse events (TEAEs) were reported by 29.6% of participants with DAXI 125U, 23.8% with DAXI 250U, and 17.4% with placebo, with injection site pain being the most common overall. The most frequently reported treatment-related TEAEs of interest in DAXI 125U, DAXI 250U, and placebo, respectively, were muscular weakness (4.8%, 2.3%, 0%), musculoskeletal pain (2.4%, 3.1%, 0%), and dysphagia (1.6%, 3.8%, 0%). DISCUSSION: This study demonstrated that DAXI, at doses of 125U and 250U, is an effective, safe, long-acting, and well-tolerated treatment for CD. TRIAL REGISTRATION INFORMATION: ClinicalTrials.gov identifier (NCT03608397, submitted July 11, 2018) and EU Clinical Trials Register (ClinicalTrialsRegister.eu EudraCT identifier 2018-000446-19, submitted September 13, 2018). First participant enrolled on June 11, 2018. Trial registration was performed in accordance with the Food and Drug Administration Amendments Act (FDAAA 801), which stipulates that the responsible party register an applicable clinical trial not later than 21 calendar days after enrolling the first human participant (42 CFR 11.24). CLASSIFICATION OF EVIDENCE: This study provides Class I evidence that in adults with moderate-to-severe idiopathic cervical dystonia, DAXI reduces dystonia more effectively than placebo.

A technology evaluation of the atypical use of a CPP-containing peptide in the formulation and performance of a clinical botulinum toxin product.

INTRODUCTION: Cell-penetrating peptides (CPPs), are small peptides that facilitate cytosolic access and, thus, transport of therapeutic macromolecules to intracellular sites when conjugated to cargo proteins. As with all new delivery platforms, clinical development of CPP-containing therapeutics has faced considerable challenges. AREAS COVERED: RTP004 is a novel, 35-amino acid, bi-CPP-containing excipient that binds noncovalently with its cargo (botulinum toxin type A) rather than conjugated as a fusion protein. An RTP004-containing neurotoxin formulation, daxibotulinumtoxinA-lanm for injection (DAXI), has recently been approved by the FDA. The formulation and pharmacological characteristics of RTP004 and the efficacy and safety of the RTP004-neurotoxin formulation are discussed. EXPERT OPINION: RTP004 is a highly positively charged lysine- and arginine-rich structure that provides formulation stability, preventing self-aggregation of the cargo protein and adsorption to container surfaces. The presence of RTP004 in the formulation also appears to increase presynaptic binding of the neurotoxin, reduces post-injection diffusion, and thus facilitates an increase in the cleavage of the intracellular substrate for the botulinum toxin, likely through enhanced cellular uptake. The RTP004-neurotoxin formulation is the first CPP-containing product approved for clinical use. The potential for RTP004 to facilitate other therapeutic cargo molecules requires further research.

Treatment of Upper Facial Lines With DaxibotulinumtoxinA for Injection: Results From an Open-Label Phase 2 Study.

BACKGROUND: Simultaneous treatment of moderate-to-severe upper facial lines is reflective of real-world clinical practice. OBJECTIVE: To evaluate the efficacy and safety of daxibotulinumtoxinA-lanm for injection (DAXI) for simultaneous treatment of glabellar, forehead, and lateral canthal (LC) lines. METHODS: In this open-label, single-arm Phase 2 study, patients (48 enrolled, 94% completed, follow-up 24-36 weeks) received DAXI 40U (glabellar), 32U (forehead), and 48U (LC) lines. Key efficacy endpoints: percentages of patients achieving none/mild wrinkle severity (investigator-rated) for each upper facial line scale at Week 4. RESULTS: At Week 4, most patients achieved none/mild wrinkle severity (investigator-rated): glabellar (96%), forehead (96%), and LC (92%). Median times to loss of none/mild response (investigator- and patient-rated) among all patients were: 24.6 (glabellar), 20.9 (forehead), and 24.9 (LC) weeks; and 25.0, 24.0, and 28.1 weeks, respectively, among Week-4 responders. At Week 4, most patients reported improvements (Global Aesthetic Improvement Scale: 96%-98%) and high satisfaction rates (85%-98%). Five patients experienced treatment-related adverse events: injection-site erythema (3 patients/7 events), facial discomfort (2 patients/2 events), and headache (1 patient/1 event). No patients experienced eyebrow or eyelid ptosis. CONCLUSION: Simultaneous treatment of upper facial lines with DAXI was well tolerated and demonstrated high response rates, extended duration, and high patient satisfaction. CLINICAL TRIAL REGISTRY: https://clinicaltrials.gov/ct2/show/NCT04259086.

A Large, Open-Label, Phase 3 Safety Study of DaxibotulinumtoxinA for Injection in Glabellar Lines: A Focus on Safety From the SAKURA 3 Study.

BACKGROUND: SAKURA 3 was a Phase 3, open-label, repeat-dose safety study of DaxibotulinumtoxinA for Injection (DAXI); a component of the largest Phase 3 clinical development program of an aesthetic neuromodulator in glabellar lines. OBJECTIVE: To evaluate the use of DAXI (40U) up to 3 treatments for moderate or severe glabellar lines. METHODS: Eligible subjects rolled over from the placebo-controlled trials (n = 477) or were de novo (n = 2,214) and received 1 to 3 treatments over a maximum of 84 weeks. Safety and efficacy were evaluated at least every 4 weeks up to Week 36 (Treatments 1 and 2) and Week 12 (Treatment 3). Select subjects could be retreated after Week 12 if glabellar lines returned to baseline. RESULTS: Safety results are reported for 2,691 subjects, of which 882 received a second treatment and 568 a third. Treatment-related adverse events (AEs) occurred in 17.8% of subjects, which were generally mild and resolved. No serious AEs were treatment-related. Eyelid ptosis occurred in 0.9% of treatments. Adverse events were consistent across treatments and no new safety signals were observed. CONCLUSION: The safety of DAXI in this large open-label safety study confirms the findings from the pivotal Phase 3 trials, providing reassurance in its overall safety profile.

Safety and Efficacy of EB-001, a Novel Type E Botulinum Toxin, in Subjects with Glabellar Frown Lines: Results of a Phase 2, Randomized, Placebo-Controlled, Ascending-Dose Study.

BACKGROUND: Botulinum neurotoxins, which are widely used commercially for therapeutic and cosmetic applications, have historically belonged to serotypes A and B. Serotype E has a distinct profile with a faster onset and shorter duration of effect. EB-001 is a proprietary formulation of serotype E in development for aesthetic (cosmetic) and therapeutic uses. METHODS: This first-in-human, randomized, double-blinded, placebo-controlled, ascending-dose cohort study enrolled 42 subjects who received EB-001 (n = 35) or placebo (n = 7). The efficacy primary outcome was the proportion of subjects with a two-grade investigator-rated improvement in glabellar frown line severity at maximum frown. Safety evaluations included adverse events, laboratory tests, and physical examinations. RESULTS: A two-grade investigator-rated response was observed starting in the third cohort (EB-001), with increased rates observed at higher doses. Onset of clinical effect was within 24 hours, with a duration ranging between 14 and 30 days for the highest doses. Adverse event incidence was low, with the most common being mild to moderate headache. There were no serious adverse events or ptosis, and there were no clinically significant changes in other safety assessments. CONCLUSIONS: In this clinical study in glabellar frown lines, EB-001 showed favorable safety, tolerability, and dose-dependent efficacy, with an 80 percent response rate at the highest dose. The maximum clinical effect of EB-001 was seen within 24 hours and lasted between 14 and 30 days. This differentiated EB-001 profile supports its development for aesthetic and therapeutic applications where fast onset and short duration of effect are desirable. CLINICAL QUESTION/LEVEL OF EVIDENCE: Therapeutic, II.

The Potential Role of Botulinum Toxin in Improving Superficial Cutaneous Scarring: A Review.

Botulinum toxins have been utilized in a number of cosmetic and therapeutic applications. One of the more novel uses of botulinum toxin involves its use to mitigate the effects of superficial cutaneous scarring. This is accomplished by decreasing the dynamic tension of a wound by denervating the underlying muscle. Studies have indicated that botulinum toxin serotypes A and B have a positive effect on wound healing and scar appearance. However, larger prospective, blinded, randomized, placebo-controlled clinical trials are required to refine this concept and target optimum toxin dose placement, timing, and concentration. The delayed onset of effect of available botulinum toxins is likely not taking full advantage of the scar improvement capabilities of the toxin, considering the time to immobilization of the muscle is a key factor in the improvement of wound healing with this technique. Furthermore, it has been noted in studies that the use of botulinum toxin can result in significant, yet temporary functional issues, due to prolonged paralysis of the muscle. In this paper, we review the role of botulinum toxin in improving scar appearance, evaluate animal and human studies to date demonstrating its effect on scarring, and highlight an opportunity for continued research in this application. J Drugs Dermatol. 2018;17(9):956-958.

Phase 3 Study of OnabotulinumtoxinA Distributed Between Frontalis, Glabellar Complex, and Lateral Canthal Areas for Treatment of Upper Facial Lines.

BACKGROUND: Although commonly practiced, simultaneous onabotulinumtoxinA injections to multiple facial areas have not been investigated in prospective studies. OBJECTIVE: Evaluate safety and efficacy of onabotulinumtoxinA for treatment of forehead lines (FHL) distributed between the frontalis (20 U) and glabellar complex (20 U), with or without simultaneous lateral canthal areas (crow's feet lines [CFL], 24 U) treatment. METHODS: Subjects with moderate to severe FHL were randomized (2:2:1) to onabotulinumtoxinA 40 U, onabotulinumtoxinA 64 U, or placebo. After 180 days, subjects could receive up to 2 additional open-label onabotulinumtoxinA 64 U treatments. RESULTS: The intent-to-treat (ITT) population comprised 787 subjects, and the modified ITT (mITT) population (subjects with psychological impact) comprised 568. After 30 days, onabotulinumtoxinA 40 U and 64 U significantly improved investigator- and subject-assessed FHL severity by at least 2 Facial Wrinkle Scale (FWS) grades in 45.6% and 53.0% of ITT subjects, respectively, versus 0.6% receiving placebo (both, p < .0001). Significantly more mITT subjects receiving onabotulinumtoxinA achieved investigator- and subject-assessed FWS ratings of none/mild versus placebo (p < .0001). OnabotulinumtoxinA was well tolerated. CONCLUSION: OnabotulinumtoxinA distributed between the frontalis and glabellar complex, with or without additional CFL injections, was safe and effective for treatment of moderate to severe FHL.

Forehead Line Treatment With OnabotulinumtoxinA in Subjects With Forehead and Glabellar Facial Rhytids: A Phase 3 Study.

BACKGROUND: Effacement of horizontal forehead lines (FHL) with onabotulinumtoxinA has not been investigated in prospective Phase 3 studies. OBJECTIVE: To evaluate safety and efficacy of onabotulinumtoxinA treatment of FHL together with glabellar lines (GL). MATERIALS AND METHODS: A 12-month, Phase 3 study randomized subjects with moderate-to-severe FHL and GL to onabotulinumtoxinA 40 U or placebo, distributed between the frontalis (20 U) and glabellar complex (20 U). After Day 180, subjects could receive up to 2 additional open-label onabotulinumtoxinA treatments. Efficacy was assessed using the Facial Wrinkle Scale (FWS) and Facial Line Outcomes questionnaire. RESULTS: The intent-to-treat (ITT) population included 391 subjects, and the modified ITT (mITT) population (subjects with psychological impact) included 254 subjects. After 30 days, onabotulinumtoxinA significantly improved the investigator- and subject-assessed appearance of FHL severity by at least 2 FWS grades in 61.4% of ITT subjects versus 0% of placebo subjects (p < .0001). In the mITT population, 94.8% of onabotulinumtoxinA subjects and 1.7% of placebo subjects achieved investigator- and subject-assessed FWS ratings of none/mild (p = .0003). Patient-reported outcomes were consistent with FWS ratings. OnabotulinumtoxinA was well tolerated. CONCLUSION: OnabotulinumtoxinA 40 U distributed between the frontalis and glabellar complex was safe and effective for treatment of moderate-to-severe FHL.

Viramidine demonstrates better safety than ribavirin in monkeys but not rats.

The safety of viramidine was evaluated and compared with ribavirin in one-month and six-month studies in rats and one-month and nine-month studies in monkeys. Viramidine administration produced hemolytic anemia, characterized by decreases in hemoglobin (Hgb) concentrations, which was accompanied by erythroid hyperplasia of the bone marrow or increase in reticulocyte counts. In the 1-month study in rats, viramidine or ribavirin dosing at 120 mg/kg/day reduced Hgb concentrations (12-16% and 13-20% compared to controls, respectively) and caused slight erythroid hyperplasia in the bone marrow. In the 6-month study in rats, viramidine or ribavirin dosing at 90 mg/kg/day reduced Hgb concentrations (16-18% and 18% compared to controls, respectively) and increased reticulocyte counts (>25%). Although toxicity effects in monkeys were similar to rats, they occurred at higher doses of viramidine compared to ribavirin. In the 1-month monkey study, viramidine at 600 mg/kg/day caused slight or no reduction (9%-0% in males and females) in Hgb concentrations compared to moderate reduction for ribavirin at 300 mg/kg/day (14%-20% in males and females). There were no signs of erythroid hyperplasia in bone marrow or significant increase in reticulocytes detected after viramidine or ribavirin dosing in monkeys. In the 9-month study in monkeys, viramidine at 180 mg/kg/day slightly reduced Hgb concentrations (5-11%) as compared to ribavirin at 60 mg/kg/day (9-12%). Both treatments had an increase in reticulocytes (49-53% vs. 43-59% compared to controls, respectively). Moderate decrease in Hgb levels (26-29%) together with large increase in reticulocyte counts (203-224%) were seen for viramidine at 600 mg/kg/day. All the changes were reversible after a recovery phase in both rats and monkeys. It is concluded that ribavirin and viramidine produced similar toxicity in rats. However, viramidine is safer than ribavirin in monkeys.

Remofovir mesylate: a prodrug of PMEA with improved liver-targeting and safety in rats and monkeys.

Adefovir dipivoxil (Hepsera), a first-line therapy for chronic hepatitis B, is an esterase-activated prodrug of PMEA. Dose-limiting nephrotoxicity necessitates suboptimal dosing at 10 mg/day. Remofovir mesylate (MB06866Q) (Hepavir B) is a CYP3A4-activated prodrug of PMEA based on the HepDirect technology that targets PMEA to the liver. In a whole body autoradiography study in rats after oral dosing (30 mg/kg) of [14C]adefovir dipivoxil or [14C]remofovir mesylate, remofovir yielded 15 times higher concentrations of radioactivity in the liver than adefovir dipivoxil, but only one-third of the concentrations in the kidney. After oral dosing (4 mg/kg) of the same radiolabelled agents in cynomolgus monkeys, remofovir mesylate yielded 60 times higher levels of total radioactivity in the liver, but only two-thirds of total radioactivity levels in the kidney. Thus, remofovir mesylate may provide better efficacy and reduced nephrotoxicity. In portal vein-cannulated rats (30 mg/kg) after a single oral dose of [14C]adefovir dipivoxil or [14C]remofovir mesylate, no PMEA was detectable in rat portal plasma early after dosing, indicating that intestinal CYP3A4 does not play a role in conversion of remofovir mesylate to PMEA. The portal/systemic extraction ratio was quite high in both models, suggesting good liver-targeting properties. Portal and systemic remofovir/PMEA ratio indicates that the liver is the site of conversion of remofovir to PMEA. 28-Day toxicity studies demonstrated renal toxicity in rats at doses of 100 mg/kg or higher with no safety concerns at 30 mg/kg and acceptable safety in monkeys at doses up to 60 mg/kg. Thus, in rats and non-human primates, remofovir mesylate has liver-targeting properties and is safer than adefovir dipivoxil.

Viramidine, a prodrug of ribavirin, shows better liver-targeting properties and safety profiles than ribavirin in animals.

Ribavirin, part of the current first line combination therapy for the treatment of chronic hepatitis C, may cause haemolytic anaemia and poses a significant challenge to the clinical management of the disease. Viramidine, a prodrug of ribavirin, is currently under development. In-vitro partition demonstrated that viramidine had less association with RBCs than ribavirin in rat, monkey and man, and thus has less liability for haemolytic anaemia than ribavirin. In a whole body autoradiography study in rats following oral dosing (30 mg/kg) of [14C]ribavirin or [14C]viramidine to monkeys, viramidine produced 32% higher radioactivity in the liver than ribavirin, indicating a better liver-targeting properties. In portal vein-cannulated cynomolgus monkeys following single oral dosing (30 mg/kg) of [3H]viramidine or [3H]ribavirin, viramidine retained 3X higher radioactivity in the liver than ribavirin. Viramidine dosing also produced a higher viramidine to ribavirin ratio in portal plasma than in systemic plasma, indicating that the liver was the main site for the viramidine conversion to ribavirin and subsequent trapping of the drug. After multiple oral dosing (10 mg/kg) of [14C]ribavirin or [14C]viramidine to monkey, viramidine yielded three times the drug level in the liver but only half in RBCs compared to ribavirin. Viramidine and ribavirin had comparable toxicity profiles in a 28-day toxicity study in rats. In contrast, viramidine had much better safety profiles than ribavirin in a 28-day toxicity study in monkeys. In conclusion, viramidine has better liver-targeting properties and safety profiles than ribavirin in animals.