EFFECT OF RETINAL THICKNESS VARIABILITY ON VISUAL OUTCOMES AND FLUID PERSISTENCE IN NEOVASCULAR AGE-RELATED MACULAR DEGENERATION: A Post Hoc Analysis of the HAWK and HARRIER Studies.

PURPOSE: To determine the association between central subfield thickness (CST) variability and visual outcomes in eyes with neovascular age-related macular degeneration treated with anti-vascular endothelial growth factor therapies. METHODS: In this post hoc, treatment-agnostic analysis, patients (N = 1,752) were grouped into quartiles of increasing CST variation. The association between CST variability and best-corrected visual acuity was measured from baseline, or from the end of the loading phase, until the end of the study using a multilevel modeling for repeated-measures model. The association between CST variability and the presence of retinal fluid was also assessed. RESULTS: Increased CST variability was associated with worse best-corrected visual acuity outcomes at the end of study, with a least-square mean difference in best-corrected visual acuity of 8.9 Early Treatment Diabetic Retinopathy Study letters between the quartiles with the lowest and highest CST variability at the final visit. Increased variability was also associated with a higher mean fraction of visits with the presence of fluid. CONCLUSION: More stable CST was associated with better visual outcomes at the end of treatment suggesting that CST variability may provide a more reliable prognostic marker of visual outcomes than the presence of fluid alone, with the potential to enhance the clinical care of neovascular age-related macular degeneration patients.

HAWK and HARRIER: Ninety-Six-Week Outcomes from the Phase 3 Trials of Brolucizumab for Neovascular Age-Related Macular Degeneration.

PURPOSE: To report the 96-week outcomes from HAWK and HARRIER. DESIGN: Phase 3, prospective, randomized, double-masked, multicenter studies comparing efficacy and safety of brolucizumab 3 mg (HAWK only) and 6 mg with aflibercept 2 mg in eyes with neovascular age-related macular degeneration (nAMD). PARTICIPANTS: Treatment-naïve eyes with nAMD were randomized 1:1:1 to brolucizumab 3 mg (n = 358), brolucizumab 6 mg (n = 360), aflibercept 2 mg (n = 360; HAWK) or 1:1 to brolucizumab 6 mg (n = 370), aflibercept 2 mg (n = 369; HARRIER). METHODS: After 3 monthly loading doses, brolucizumab patients received every (q)-12-week (w) dosing, possibly adjusting to q8w dosing if disease activity was present at predefined disease activity assessment (DAA) visits. Aflibercept was dosed in a fixed q8w regimen. Visual and anatomic parameters were assessed throughout. Primary end point was at week 48 (48w), confirmed at 96w. MAIN OUTCOME MEASURES: Mean best-corrected visual acuity (BCVA) change from baseline, proportion of patients on an q12w regimen, retinal thickness, retinal fluid changes, and safety, all to 96w. RESULTS: Mean change (least squares [LS] mean ± standard error) in BCVA from baseline to 96w in HAWK was 5.6±0.79 Early Treatment Diabetic Retinopathy Study (ETDRS) letters for brolucizumab 3 mg, 5.90±0.78 letters for brolucizumab 6 mg, and 5.3±0.78 letters for aflibercept and in HARRIER was 6.1±0.73 letters for brolucizumab 6 mg and 6.6 ± 0.73 letters for aflibercept. Greater central subfield thickness reductions were observed with brolucizumab 6 mg versus aflibercept in HAWK (LS mean, -174.8 µm vs. -148.7 µm; 95% confidence interval for treatment difference, -46.2 to -5.9 µm; P = 0.0115) and HARRIER (LS mean, -197.7 µm vs. -155.1 µm; 95% confidence interval for treatment difference, -62.0 to -23.3 µm; P < 0.0001). The proportions of eyes with intraretinal fluid and/or subretinal fluid (IRF/SRF) at 96w in HAWK were 31% (P = 0.0688) and 24% (P = 0.0002) for brolucizumab 3 mg and 6 mg and 37% for aflibercept, whereas in HARRIER, they were 24% for brolucizumab 6 mg (P < 0.0001) and 39% for aflibercept. At 92w (last DAA), a 45.4% and 38.6% probability was observed for brolucizumab 6 mg patients of maintaining an q12w treatment regimen in HAWK and HARRIER, respectively. Brolucizumab exhibited an overall well-tolerated safety profile. CONCLUSIONS: Visual outcomes from 48w to 96w confirm the efficacy achieved at 48w. Brolucizumab demonstrated greater fluid resolution compared with aflibercept. The q12w potential for brolucizumab observed at 48w was maintained to 96w.

Brolucizumab: A Newly Developed Anti-VEGF Molecule for the Treatment of Neovascular Age-Related Macular Degeneration.

BACKGROUND: Despite the success of anti-vascular endothelial growth factors (anti-VEGFs), currently, there is a need for highly effective compounds that can alleviate the burden of managing neovascular age-related macular degeneration (nAMD). PURPOSE: To review the milestones in the molecular and clinical development of brolucizumab, the first single-chain antibody fragment (scFv) designed specifically for intraocular use in humans. METHODS: In this article, we summarize the preclinical and current clinical evidence of brolucizumab administration with an overview of the other treatment regimens and additional indications under investigation. RESULTS: The unique molecular design of brolucizumab led to a low molecular weight of only 26 kDa, allowing for a concentrated molar dose of 1 intravitreal injection compared with other anti-VEGF agents. Phase I and II clinical trial outcomes validated the efficacy of brolucizumab in the treatment of nAMD with signals of a more durable treatment effect. The pivotal phase III trials, HAWK and HARRIER, which included a total of 1,817 patients, established that brolucizumab can be administered every 3 months while maintaining disease control. CONCLUSIONS: The preclinical and clinical data on brolucizumab provide evidence of sustained disease control with longer injection intervals, thus potentially reducing the treatment burden in patients with nAMD.

Use of Composite End Points in Early and Intermediate Age-Related Macular Degeneration Clinical Trials: State-of-the-Art and Future Directions.

The slow progression of early age-related macular degeneration (AMD) stages to advanced AMD requires the use of surrogate end points in clinical trials. The use of combined end points may allow for shorter and smaller trials due to increased precision. We performed a literature search for the use of composite end points as primary outcome measures in clinical studies of early AMD stages. PubMed was searched for composite end points used in early/intermediate AMD studies published during the last 10 years. A total of 673 articles of interest were identified. After reviewing abstracts and applicable full-text articles, 33 articles were eligible and thus included in the qualitative synthesis. The main composite end point categories were: combined structural and functional end points, combined structural end points, combined functional end points and combined multicategorical end points. The majority of the studies included binary composite end points. There was a lack of sensitivity analyses of different end points against accepted outcomes (i.e., progression) in the literature. Various composite outcome measures have been used but there is a lack of standardization. To date no agreement on the optimal approach to implement combined end points in clinical studies of early stages of AMD exists, and no surrogate end points have been accepted for AMD progression.

Single-Chain Antibody Fragment VEGF Inhibitor RTH258 for Neovascular Age-Related Macular Degeneration: A Randomized Controlled Study.

PURPOSE: To assess the safety and efficacy of different doses of RTH258 applied as single intravitreal administration compared with ranibizumab 0.5 mg in patients with neovascular age-related macular degeneration (AMD). DESIGN: Six-month, phase 1/2, prospective, multicenter, double-masked, randomized, ascending single-dose, active-controlled, parallel-group study. PARTICIPANTS: A total of 194 treatment-naive patients, aged ≥50 years, with primary subfoveal choroidal neovascularization secondary to AMD. METHODS: Patients received a single intravitreal injection of RTH258 0.5 mg (n = 11), 3.0 mg (n = 31), 4.5 mg (n = 47), or 6.0 mg (n = 44), or ranibizumab 0.5 mg (n = 61). MAIN OUTCOME MEASURES: The primary efficacy end point was the change from baseline to month 1 in central subfield thickness (CSFT) measured by spectral-domain optical coherence tomography. The secondary efficacy end point was the duration of treatment effect measured as time from the initial injection to receipt of post-baseline therapy (PBT) guided by protocol-defined criteria. Adverse events (AEs) were recorded throughout the study. RESULTS: RTH258 demonstrated noninferiority compared with ranibizumab in mean change in CSFT from baseline to month 1 for the 4.5- and 6.0-mg dose groups (margin: 40 µm, 1-sided alpha 0.05). The difference in CSFT change at month 1 comparison with ranibizumab was 22.86 µm (90% confidence interval [CI], -9.28 to 54.99) and 19.40 µm (95% CI, -9.00 to 47.80) for RTH258 4.5 and 6 mg, respectively. The median time to PBT after baseline therapy was 60 and 75 days for patients in the RTH258 4.5- and 6.0-mg groups, respectively, compared with 45 days for ranibizumab. Changes in best-corrected visual acuity with RTH258 were comparable to those observed with ranibizumab. The most frequent AEs reported for the RTH258 groups were conjunctival hemorrhage, eye pain, and conjunctival hyperemia; the majority of these events were mild in intensity. CONCLUSIONS: This first-in-human study of RTH258 demonstrated noninferiority in the change in CSFT at 1 month for the 4.5- and 6.0-mg doses compared with ranibizumab and an increase of 30 days in the median time to PBT for the 6.0-mg dose. There were no unexpected safety concerns, and the results support the continued development of RTH258 for the treatment of neovascular AMD.

Therapeutic response in the HAWK and HARRIER trials using deep learning in retinal fluid volume and compartment analysis.

OBJECTIVES: To assess the therapeutic response to brolucizumab and aflibercept by deep learning/OCT-based analysis of macular fluid volumes in neovascular age-related macular degeneration. METHODS: In this post-hoc analysis of two phase III, randomised, multi-centre studies (HAWK/HARRIER), 1078 and 739 treatment-naive eyes receiving brolucizumab or aflibercept according to protocol-specified criteria in HAWK and HARRIER, respectively, were included. Macular fluid on 41,840 OCT scans was localised and quantified using a validated deep learning-based algorithm. Volumes of intraretinal fluid (IRF), subretinal fluid (SRF), pigment epithelial detachment (PED) for all central macular areas (1, 3 and 6 mm) in nanolitres (nL) and best corrected visual acuity (BCVA) change in ETDRS letters were associated using mixed models for repeated measures. RESULTS: Baseline IRF volumes decreased by >92% following the first intravitreal injection and consistently remained low during follow-up. Baseline SRF volumes decreased by >74% following the first injection, while PED volume resolved by 68-79% of its baseline volume. Resolution of SRF and PED was dependent on the substance and regimen used. Larger residual post-loading IRF, SRF and PED volumes were all independently associated with progressive vision loss during maintenance, where the differences in mean BCVA change between high and low fluid volume subgroups for IRF, SRF and PED were 3.4 letters (p < 0.0001), 1.7 letters (p < 0.001) and 2.5 letters (p < 0.0001), respectively. CONCLUSIONS: Deep-learning methods allow an accurate assessment of substance and regimen efficacy. Irrespectively, all fluid compartments were found to be important markers of disease activity and were relevant for visual outcomes.

Effects of ketoconazole and valproic acid on the pharmacokinetics of the next generation NNRTI, lersivirine (UK-453,061), in healthy adult subjects.

AIMS: To investigate the effect of inhibitors of cytochrome P450 (CYP) 3A4 and glucuronidation (UGT2B7) on the pharmacokinetics of lersivirine (UK-453,061), a next generation non-nucleoside reverse transcriptase inhibitor with a unique resistance profile, and to investigate the safety and tolerability of co-administration of lersivirine with these inhibitors. METHODS: Two open-label, randomized, placebo-controlled, crossover studies were conducted in healthy subjects. Study 1 investigated the effect of ketoconazole (400 mg once daily) on the pharmacokinetics of lersivirine (250 mg once daily). Subjects received ketoconazole 400 mg once daily or placebo on days 1-2 and received lersivirine 250 mg once daily and ketoconazole 400 mg once daily or placebo on days 3-9. Study 2 investigated the effect of valproic acid (VPA, sodium valproate, 1000 mg once daily) on the PK of lersivirine (500 mg once daily). On days 1-7, subjects received lersivirine 500 mg once daily plus either VPA 1000 mg or placebo. RESULTS: Compared with lersivirine alone, co-administration with ketoconazole increased the lersivirine mean area under the curve (AUC(0,24 h)) and maximum plasma concentration (C(max) ) by 82% (90% CI 74%, 91%) and 61% (90% CI 41%, 83%), respectively. VPA increased the mean lersivirine AUC(0,24 h) by 25% (90% CI 16%, 35%), with little effect on C(max) (2.5%, 90% CI -9%, 16%). There were no serious adverse events and no treatment-related discontinuations from either study. CONCLUSIONS: Inhibition of CYP3A4 and UGT2B7 by ketoconazole increased lersivirine exposure. Inhibition of UGT2B7-mediated glucuronidation by VPA had a modest effect on lersivirine exposure. Co-administration of lersivirine with either ketoconazole or VPA appeared to be well tolerated.

Topical Anti-TNFα Agent Licaminlimab (OCS-02) Relieves Persistent Ocular Discomfort in Severe Dry Eye Disease: A Randomized Phase II Study.

Purpose: To assess the efficacy, safety, and pharmacokinetics of new topical ocular anti-TNFα antibody fragment licaminlimab in the relief of persistent ocular discomfort in severe dry eye disease (DED). Patients and Methods: Patients with ≥6-month history of DED, regular use of artificial tears, and best-corrected visual acuity (BCVA) of ≥55 letters in each eye (Early Treatment Diabetic Retinopathy Score) at baseline were included in this multicenter, randomized, vehicle-controlled, double masked study. A total of 514 patients were screened. After a 2-week run-in with Vehicle, all qualifying patients received Vehicle eye drops for 4 weeks. Patients with global ocular discomfort score ≥50 at the end of this 4-week period were randomized to receive licaminlimab (60 mg/mL ophthalmic solution) (69 patients) or Vehicle (65 patients) for 6 weeks. The primary efficacy endpoint was change from baseline in global ocular discomfort score at Day 29. Safety assessments included adverse events and ophthalmology examination including intraocular pressure (IOP). Serum licaminlimab levels were also determined. Results: Change from baseline to Day 29 in global ocular discomfort score was statistically significantly greater for licaminlimab than for Vehicle (p = 0.041). No safety issues were identified. Serum licaminlimab was undetectable in most patients; the maximum concentration observed was 8.47 ng/mL. Conclusion: Topical ocular licaminlimab demonstrated statistically significant improvement in global ocular discomfort score compared to Vehicle in patients with severe DED, with good tolerability, no increase in IOP, and minimal systemic drug exposure.

Topical Ocular Anti-TNFα Agent Licaminlimab in the Treatment of Acute Anterior Uveitis: A Randomized Phase II Pilot Study.

Purpose: Licaminlimab is a new anti-TNFα antibody fragment for topical ocular application. This phase II study assessed the tolerability, treatment effect, and pharmacokinetics of licaminlimab in acute anterior uveitis (AAU). Methods: In this multicenter, randomized, parallel-group, double-masked study, 43 adult patients with non-infectious AAU and Standardization of Uveitis Nomenclature (SUN) anterior chamber (AC) cell score of 2+ or 3+ were randomized (3:1 ratio) to licaminlimab (60 mg/mL, 8 drops/day for 15 days, 4 drops/day for 7 days, then matching vehicle for 7 days) or dexamethasone eye drops (8 drops/day for 15 days, tapering to 1 drop/day over 14 days). The primary efficacy end point was clinical response (≥2-step decrease in AC cell grade at day 15). A treatment effect was considered as established if the lower limit of the 95% posterior interval of the responder rate was >30%. Serum levels of licaminlimab were determined. Results: The day 15 response rate for licaminlimab was 56%; the lower bound of the 95% credible interval was 40% (i.e. >30%), demonstrating a treatment effect according to prespecified criteria. By day 4, 36% of licaminlimab-treated patients were responders; 76% had an AC cell grade of 0 on ≥1 post-treatment visit. The day 15 dexamethasone response rate was 90% (no inferential between-arm comparison was planned). Both treatments were well-tolerated. Intraocular pressure increased from baseline with dexamethasone but not licaminlimab. Licaminlimab was undetectable in serum in most patients. Conclusions: Licaminlimab is the first biologic demonstrated to have a treatment effect on an intraocular condition with topical ocular application. The trial met its primary objective and the observed responder rate for licaminlimab was 56.0%. Ocular administration of licaminlimab was well-tolerated in adult subjects with AAU for up to 35 days.

Efficacy and safety of brolucizumab versus aflibercept in eyes with polypoidal choroidal vasculopathy in Japanese participants of HAWK.

PURPOSE: To compare the efficacy and safety of brolucizumab versus aflibercept in eyes with polypoidal choroidal vasculopathy (PCV) over 96 weeks in the HAWK study. DESIGN: HAWK was a global, 2-year, randomised, double-masked, multicentre phase III trial in participants with neovascular age-related macular degeneration. METHODS: Of the Japanese participants with PCV, 39 received brolucizumab 6 mg and 30 received aflibercept 2 mg. After 3 monthly loading doses, brolucizumab-treated eyes received an injection every 12 weeks (q12w) but were adjusted to q8w if disease activity was detected. Aflibercept-treated eyes received fixed q8w dosing. Mean change in best-corrected visual acuity (BCVA), the proportion of participants on q12w, retinal thickness, retinal fluid changes and safety were assessed to Week 96. RESULTS: Mean change in BCVA (early treatment diabetic retinopathy study (ETDRS) letters) from baseline to week 48/week 96 was+10.4/+11.4 for brolucizumab and +11.6/+11.1 for aflibercept. For brolucizumab-treated eyes, the probability of only q12w dosing after loading through week 48 was 76%, and 68% through week 96. Fluid resolution was greater with brolucizumab than aflibercept: respective proportions of eyes with intraretinal fluid and/or subretinal fluid were 7.7% and 30% at week 48% and 12.8% and 16.7% at week 96. Brolucizumab exhibited an overall well-tolerated safety profile despite a higher rate of intraocular inflammation compared with aflibercept. CONCLUSION: In Japanese eyes with PCV, brolucizumab q12w/q8w monotherapy resulted in robust and consistent BCVA gains that were comparable to q8w aflibercept dosing. Anatomical outcomes favoured brolucizumab over aflibercept, with 76% of brolucizumab participants maintained on q12w dosing after loading to week 48.

A Randomized, Double-Masked, Multicenter Trial of Topical Acrizanib (LHA510), a Tyrosine Kinase VEGF-Receptor Inhibitor, in Treatment-Experienced Subjects With Neovascular Age-Related Macular Degeneration.

PURPOSE: To evaluate whether topical acrizanib (LHA510), a small-molecule vascular endothelial growth factor receptor inhibitor, could suppress the need for anti-vascular endothelial growth factor therapy over a 12-week period in patients with neovascular age-related macular degeneration. DESIGN: A phase 2 multicenter randomized double-masked, vehicle-controlled proof-of-concept study. METHODS: Trial includes n = 90 patients with active choroidal neovascularization due to neovascular age-related macular degeneration and under anti-vascular endothelial growth factor treatment. All patients received an intravitreal injection of ranibizumab at baseline and were retreated when there was evidence of disease recurrence (rescue). Patients were randomized 1:1 to receive topical LHA510 or vehicle for 12 weeks. Drops were administered twice a day for 8 weeks and then 3 times a day for the last 4 weeks. MAIN OUTCOME MEASURE: The primary outcome was the number of patients requiring rescue over 84 days of topical dosing. Key secondary outcome measures were time to first rescue, total number of ranibizumab injections, changes in central subfield thickness, and changes of visual acuity from baseline to day 84. RESULTS: The extended per protocol set included 70 patients of whom 25 of 33 patients in the LHA510 group (75.8%) and 25 of 37 patients in the placebo group (67.6%) required rescue by day 84 (P = .8466). Secondary and subgroup analysis did not support evidence of efficacy. Twenty-one of 46 patients administered LHA510 developed a reversible corneal haze that resolved with cessation of treatment and did not recur in patients restarted at once daily frequency. CONCLUSION: In spite of extensive optimization for topical efficacy, LHA510 failed to demonstrate clinical efficacy.

Effect of single doses of maraviroc on the QT/QTc interval in healthy subjects.

AIMS: To assess the effect of a single dose of maraviroc on the QTc interval in healthy subjects and to evaluate the QTc interval-concentration relationship. METHODS: A single-dose, placebo- and active-controlled, five-way crossover study was conducted to investigate the effects of maraviroc (100, 300, 900 mg) on QTc in healthy subjects. Moxifloxacin (400 mg) was used as the active comparator. The study was double-blind with respect to maraviroc/placebo and open label for moxifloxacin. There was a 7-day wash-out period between each dose. QT interval measurements obtained directly from the electrocardiogram (ECG) recorder were corrected for heart rate using Fridericia's correction (QTcF). A placebo run-in day was conducted before period 3, when ECGs were collected at intervals while subjects were resting or during exercise. These ECGs plus other predose ECGs were used to evaluate the QT/RR relationship for each subject to enable calculation of an individual's heart rate correction for their QT measurements (QTcI). ECGs were taken at various intervals pre- and postdose in each study period. Pharmacokinetic parameters were determined for each maraviroc dose. The end-points that were evaluated were QTcF at median time to maximum concentration (T(max)) based on the machine readings and QTcI at median T(max) based on manual over-reads of the QT/RR data. A separate analysis of variance was used for each of the pair-wise comparisons for each end-point. The relationship between QTc interval and plasma concentration was also investigated using a mixed-effects modelling approach, as implemented by the NONMEM software system. A one-stage model was employed in which the relationship between QT and RR and the effects of maraviroc plasma concentration on QT were estimated simultaneously. RESULTS: The mean difference from placebo in machine-read QTcF at median T(max) for maraviroc 900 mg was 3.6 ms [90% confidence interval (CI) 1.5, 5.8]. For the active comparator, moxifloxacin, the mean difference from placebo in machine-read QTcF was 13.7 ms. The changes from placebo for each of the end-points were similar for men and women. No subjects receiving maraviroc or placebo had a QTcF > or = 450 ms (men) or QTcF > or = 470 ms (women), nor did any subject experience a QTcF increase > or = 60 ms from baseline at any time point. Analysis based on the QTcI data obtained from the manual over-readings of the ECGs gave numerically very similar results. The QT:RR relationship was similar pre- and postdose and was not related to maraviroc concentration. The population estimate of the QT:RR correction factor was 0.324 (95% CI 0.309, 0.338). The population estimate of the slope describing the QT-concentration relationship was 0.97 micros ml ng(-1) (95% CI -0.571, 2.48), equivalent to an increase of 0.97 ms in QT per 1000 ng maraviroc plasma concentration. Most adverse events were mild to moderate in severity. CONCLUSIONS: Single doses of maraviroc, up to and including 900 mg, had no clinically relevant effect on QTcF or QTcI. At all maraviroc doses and for both end-points, the mean difference from placebo for QTc was < 4 ms. There was no apparent relationship between QT interval and maraviroc plasma concentration up to 2363 ng ml(-1). This conclusion held in both male and female subjects, and there was no evidence of a change in the QT/RR relationship with concentration.

Cognitive testing in early-phase clinical trials: development of a rapid computerized test battery and application in a simulated Phase I study.

BACKGROUND: Inclusion of cognitive assessment in Phase I trials of novel pharmaceutical agents may help identify subtle yet meaningful CNS effects early in clinical development, and lead to a greater understanding of the pharmacokinetic/pharmacodynamic relationship prior to entering pivotal late-phase trials. AIMS: To examine issues surrounding the inclusion of a computerised cognitive test battery in Phase I clinical trials. METHODS: A 12-minute battery of five computerized cognitive tasks was administered to 28 healthy males in a double-blind, single ascending dose study using three doses of midazolam (0.6 mg, 1.75 mg and 5.25 mg) with placebo insertion. Subjects were enrolled and assessed at two Phase I units. Statistical analyses sought to determine the sensitivity of the test battery to sedation-related cognitive dysfunction, any between-site differences in outcome, and also the effects of repeated test administration (i.e., practice or learning effects). RESULTS: There were no significant differences in data collected between sites. All standard safety measurements were completed. No substantial technical issues were noted. No learning effects were observed on four of the five cognitive tasks. ANOVA comparing baseline to post-baseline results revealed significant cognitive deterioration on all five cognitive tasks 1 h following administration of 5.25 mg midazolam. The magnitude of these changes were very large according to conventional statistical criteria. Smaller but significant changes were observed on a subset of memory and learning tasks at 1 h post-dosing in 1.75 mg condition, and at 2 h post-dosing in the 5.25 mg condition. CONCLUSIONS: The cognitive test battery was well tolerated by subjects and research unit staff. The tests demonstrated minimal learning effects, were unaffected by language and cultural differences between sites, and were sensitive to the sedative effects of midazolam. Inclusion of this cognitive test battery in future studies may allow identification of cognitive impairment or enhancement early in the clinical development cycle.

The safety, tolerability, pharmacokinetics, and pharmacodynamics of single oral doses of RO5068760, an MEK inhibitor, in healthy volunteers: assessment of target suppression.

RO5068760, a substituted hydantoin, represents a new class of potent, highly selective, non-adenosine triphosphate (ATP)-competitive MEK1/2 inhibitors. The study aimed to determine the safety/tolerability, pharmacokinetics, and pharmacodynamics of single ascending doses of RO5068760 in human healthy volunteers. All participants received a single dose followed by 48 hours of pharmacokinetics, pharmacodynamics, and safety/tolerability assessments. The pharmacodynamics were measured by changes in ERK phosphorylation (pERK) in peripheral blood mononuclear cells, ex vivo stimulated by phorbol 12-myristate 13-acetate (PMA). Forty-eight participants received 6 doses (50, 100, 200, 400, 600, 800 mg). RO5068760 was well tolerated up to 800 mg. There were no clinically significant safety findings, including laboratory, electrocardiogram, ophthalmological assessment, and fecal occult blood tests. Of the total 13 adverse events (n = 12), 11 were mild, 2 were moderate, and none were severe, and only 5 were considered by the investigator as possibly related to treatment. RO5068760 was absorbed with a t(max), of 2 hours. Disposition appeared to be biphasic with a terminal elimination t(1/2) of 5 to 9 hours. The variability was moderate to high, ranging from 38% to 62% for C(max) and 41% to 69% AUC. Within the dose range tested, pERK inhibition was relatively modest with a mean maximal pERK suppression of 55%.

The safety, tolerability, pharmacokinetics, and pharmacodynamics of single oral doses of CH4987655 in healthy volunteers: target suppression using a biomarker.

PURPOSE: CH4987655 (RO4987655) is an orally active and highly selective small-molecule MEK inhibitor. It potently inhibits mitogen-activated protein kinase signaling pathway activation and tumor cell growth, with an in vitro IC(50) of 5.2 nmol/L for inhibition of MEK1/2. Single-agent oral administration of CH4987655 resulted in complete tumor regressions in xenograft models. EXPERIMENTAL DESIGN: All 40 subjects received a single oral dose followed by 72 hrs of pharmacokinetic, pharmacodynamic, and safety/tolerability assessments. The pharmacodynamics were measured by changes in phosphorylated extracellular signal-regulated kinase (pERK) levels in a surrogate tissue peripheral blood mononuclear cells ex vivo stimulated by PMA. RESULTS: Doses of 0.5, 1, 2, 3, and 4 mg were safe and well tolerated. No clinically significant safety event was observed. A total of 26 adverse events (n = 15) were reported: 21 mild, 5 moderate, and none severe. Moderate adverse events were experienced by one subject at 1 mg (autonomic nervous system imbalance) and three subjects at 4 mg (diarrhea, abdominal pain, autonomic nervous system and acne). CH4987655 was rapidly absorbed with a t(max) of approximately 1 h. Exposures were dose proportional from 0.5 to 4 mg. The disposition was biphasic with a terminal t(1/2) of approximately 25 hr. Intersubject variability was low, 9% to 23% for C(max) and 14% to 25% for area-under-the-curve (AUC). pERK inhibition was exposure dependent and was greater than 80% inhibition at higher doses. The pharmacokinetic-pharmacodynamic relationship was characterized by an inhibitory E(max) model (E(max) approximately 100%; IC(50) 40.6 ng/mL) using nonlinear mixed-effect modeling. CONCLUSIONS: A significant extent of pERK inhibition was achieved for a single dose that was considered to be safe and well tolerated in healthy volunteers.