INTRODUCTION

Voltage-gated sodium channels (Navs)–and inhibition of these channels specifically–have been a main area of interest for pharmacological pain research in the last decades. Currently, Nav inhibitors are among the most investigated drugs classes in early phases of the trajectory (i.e., up to clinical trial phase IIa)—only surpassed by the opioid, and non-steroidal anti-inflammatory drug classes.1 Pain relief by Nav inhibitors has been indicated through blocking of the Nav1.3, Nav1.7, Nav1.8, and Nav1.9 subtypes, whereas blocking of other Nav subtypes (e.g., Nav1.5, which is predominantly present in cardiac muscle) leads to unwanted (cardiac) side effects. For example, the first-generation nonselective Nav inhibitor lidocaine is effective in reducing pain and widely used as a topical agent; however, its systemic use is limited given the high risk of cardiac adverse effects (AEs) at doses required for alleviating pain.2-4

To reduce side effects associated with broad inhibition of Nav subtypes while increasing long-term efficacy, pharmacological research shifted to selectively inhibiting pain-facilitating channels, such as Nav1.8: a sensory neuron-specific channel preferentially expressed on the dorsal root ganglion (DRG) and trigeminal ganglion neurons that has been found to play a critical role in pain signaling.5, 6 Specifically, gain-of-function mutations in the Nav1.8 gene—which alter Nav1.8 channel properties in a proexcitatory manner and so increase DRG neuron excitability—have been reported to cause chronic pain in patients with painful small fiber neuropathy.7-9 Furthermore, Nav1.8 contributes to repetitive firing and neuronal excitability, as Nav1.8 rapidly recovers from inactivation and has a more depolarized voltage-dependency of (in)activation when compared with other Navs. Evidence from in vitro studies indicate excitation of Nav1.8 is therefore involved in the development of peripheral sensitization, eventually leading to central sensitization and pain chronification,6, 10 whereas inhibition of Nav1.8 was shown to block this activity leading to analgesia in vitro.11, 12 These findings combined demonstrate the potential of Nav1.8 as a pharmacological target for the treatment of pain, specifically when related to nociceptor hyperexcitability.

Based on the above, VX-128, an orally bioavailable, highly potent, and selective Nav1.8 inhibitor was developed. We evaluated the safety, tolerability, and pharmacokinetics (PKs) of VX-128 in healthy subjects in a single- and multiple-ascending-dose (SAD, MAD) first-in-human (FIH) study. Pharmacodynamics (PDs) were additionally evaluated in the MAD part using an integrated battery of evoked pain tests.13-16

MATERIALS AND METHODS Overall study design

This was a two-part FIH study to evaluate the safety and tolerability, PKs, and PDs of VX-128 in healthy adults. Both parts (A and B) had a randomized, double-blind, placebo-controlled parallel-group design; part A evaluated VX-128 in SADs, and part B in MADs. Dose escalation was based on a review of the available safety, tolerability, and PK data from (the) preceding cohort(s).

The study was performed at the Centre For Human Drug Research (CHDR, Leiden, The Netherlands), in accordance with the Declaration of Helsinki of 1975, its amendments, and the Guideline for Good Clinical Practice. Approval was received from Medical Review and Ethics Committee Stichting Beoordeling Ethiek Biomedisch Onderzoek (Stichting BEBO, Assen, The Netherlands) before study start. The study was registered under ToetsingOnline number NL63609.056.17 and EudraCT 2017-003557-42.

Design part A–SAD

Four cohorts of eight subjects each were randomized in a 3:1 ratio to receive VX-128 or placebo as oral suspension under fasted conditions on day 1. Subjects were admitted to the clinical research unit (CRU) on day–1, received a single dose of VX-128 or placebo on day 1, and were discharged on day 5. Safety assessments (12-lead and continuous electrocardiograms [ECGs], vital signs, safety laboratory testing, and physical examinations [Pes]) and PK blood sampling were conducted throughout the study. Each subject completed his or her study participation with a safety follow-up visit 7–10 days after study drug dosing.

Design part B–MAD

Three cohorts (B1–B3) of 12 subjects, each randomized in a 5:1 ratio to receive VX-128 or placebo as an oral suspension, were admitted to the CRU on day –1, dosed with VX-128 or placebo on days 1 up to and including day 10, and discharged from the clinic on day 14. Pain thresholds were measured using a panel of evoked pain tests (section Study procedures–pharmacodynamic) on day 1 (all cohorts) and on day 10 (only cohort B2). Safety assessments (12-lead ECG, safety laboratory testing, PE, and vital signs), and the Columbia-Suicide Severity Rating Scale (C-SSRS) were carried out throughout the study and evaluated for any trends or abnormalities. Plasma PKs was sampled throughout the study (section Study procedures-PK). Subjects completed study participation with a safety follow-up visit 7–10 days after the last study drug administration.

Participants

Healthy men (parts A and B) and women of non-childbearing potential (only part A) aged 18–55 years, inclusive, underwent screening procedures prior to enrollment. Key criteria that were evaluated for eligibility were overt healthiness and that subjects had no present or past medical conditions that could put the subject’s safety in jeopardy, or influence study outcomes (e.g., history of or current cardiovascular, mental or neurological disorders, [chronic] pain, significant allergies, malignancies, or any conditions affecting drug absorption). Written informed consent was obtained from all study participants prior to any assessment taking place. Subjects were allowed to participate in only one cohort of one study part.

A training session with the pain test battery (section Study procedures–pharmacodynamic) was part of screening procedures, to minimize learning effects, as well as to exclude any subjects indicating to be too sensitive or tolerable to the included tests. The latter was defined as being tolerant to more than 80% of the maximum input intensity for the pressure, electrical, or cold pressor pain test.

Study drug VX-128 and study drug administration procedures

VX-128 is a potent and selective orally bioavailable molecule that targets the Nav1.8 sodium channel (details on the potency and selectivity of VX-128 undisclosed by sponsor request).

In the morning of dosing days, a single dose of VX-128 was administered as an oral suspension with 240 ml of water in the fasted state. A taste-masking agent was provided prior and after dosing. Doses administered in part A were 10, 40, 120, or 300 mg; and in part B were 10, 30, or 100 mg based on the maximum recommended starting dose determined from preclinical toxicity studies performed in monkeys, being the most sensitive species (not published). No dose above 100 mg once daily (q.d.) was tested in part B due to the study being terminated prematurely (section Multiple-ascending dose).

Study procedures–safety

Subject safety was evaluated on an ongoing basis by AE monitoring, clinical laboratory assessments, clinical evaluation of vital signs, standard 12-lead ECGs, and physical examinations.

Study procedures–PKs

Blood plasma was sampled to evaluate VX-128 concentration time profiles. Samples in part A (SAD) were collected predose on day 1 (0 h), and at 0.5, 1, 1.5, 2, 3, 4, 5, 6, 8, 12, and 24 (day 2), 36 (day 2), 48 (day 3), 72 (day 4), and 96 h (day 5) postdose. Samples in part B (MAD) were collected predose on day 1, (0 h), and at 0.5, 1, 1.5, 2, 3, 4, 5, 6, 8, and 12 h postdose. Samples were collected before the next administered dose on days 2, 5, 6, 7, 8, and 9. On day 10, samples were collected predose and at 0.5, 1, 1.5, 2, 3, 4, 5, 6, 8, 12, and 24 (day 11), 36 (day 11), 48 (day 12), 72 (day 13), and 96 h (day 14) after the final dose (that was given on day 10).

Study procedures–PDs Pain test procedures

A detailed description of all pain test procedures is provided in a related article.17

In brief, analgesic effects were measured twice predose, at baseline, and at 1, 2, 4, 7, and 10 h postdose using an evoked pain tests battery in a fixed sequence: electrical stair pain test,1 pressure pain test, cold pressor pain test, electrical stair pain test,2 heat pain test on untreated skin, and heat pain test on capsaicin-treated skin. The latter two tests (heat pain on capsaicin and heat pain on untreated skin) were switched predose, ensuring that the predose heat pain test on capsaicin-treated skin was performed 30 min after application of the capsaicin, and whereas keeping the remainder of the test sequence intact (details on the capsaicin application hereunder, section Application of capsaicin 1% cream [MAD part only]).

For all assessments except the heat pain tests, subjects were asked to hold an electronic visual analogue scale slider (eVAS slider), to indicate their current perceived pain intensity. The eVAS ranged from 0–100. The eVAS at 0 was defined as “no pain,” eVAS greater than 0 as the pain detection threshold (PDT), and eVAS = 100 as the pain tolerance threshold (PTT): “worst pain tolerable.” When PTT was reached, the test automatically stopped, thereby immediately relieving the subject from their pain.

Heat PDTs were determined on the capsaicin-treated skin (on the dominant volar forearm), as well as on normal (nonstimulated) skin (on the nondominant volar forearm), and recorded by the subject pushing a button on the handheld feedback control. The average of a triplicate measurement was used for further analysis of heat PDTs.

Application of capsaicin 1% cream (MAD part only)

Capsaicin 1% cream was used to evoke thermal allodynia, by selectively sensitizing the transient receptor potential cation channel subfamily V member 1 channel.18, 19 Capsaicin 1% cream was applied during screening to confirm subjects were not hyper-responsive to the cream, and was applied for 30 min, starting 60 min prior to study drug administration on a 3 × 3 cm area on the dominant volar arm. The nondominant volar forearm served as a nonstimulated control. Further details of the capsaicin model used may be found in our related article.17

Statistical considerations and analysis Randomization

Both study parts were double-blind; subjects were randomly assigned to treatments. The randomization code was produced by a qualified randomization vendor (Cytel), and approved by a designated unblinded biostatistician who was not part of the study execution team.

Sample size

No formal sample size calculations were performed. Parts A and B enrolled eight and 12 subjects per ascending dose, respectively. This is a typical sample size for an FIH study in healthy subjects.

PK and PD analysis

Safety, demographic, and PK data are presented as mean ± SD unless stated otherwise. PK parameters for VX-128 were determined using standard noncompartmental methods.

For PD results, the baseline value was defined as (the average of) the non-missing pretreatment measurements for all pain tests. Only descriptive statistics were reported. Numbers represent mean (±SD), unless stated otherwise.

RESULTS Baseline characteristics

In part A, 80 individuals were screened so that 32 male subjects were randomized. Eight subjects received placebo; and six subjects per dose level received VX-128 10, 40, 120, or 300 mg. Subjects not enrolled were mostly excluded based on hypertension, illicit drug use, abnormal clinical chemistry results, or logistical or personal reasons (e.g., change in personal or clinical planning). In Part B, 93 individuals were screened resulting in 31 male subjects that were randomized. Five subjects received placebo, 10 subjects received VX-128 10 mg q.d., 10 subjects 30 mg q.d., and six subjects received VX-128 100 mg q.d. Primary reasons for exclusion of subjects in part B were reporting to have too high tolerance to pain tasks at screening, hypertension, abnormal clinical chemistry results, illicit drug use, or logistical reasons.

Demographics and other subject characteristics were generally similar in both parts (i.e., SAD and MAD) and in the study cohorts (Table 1). Mean subject age for SAD and MAD was 28.6 (±8.9) years and 32.1 (±10.5) years, respectively. In both study parts, ~87% were White.

TABLE 1. Subject baseline characteristics, both study parts

SAD

Placebo

N = 8

SAD

10 mg

N = 6

SAD

40 mg

N = 6

SAD

120 mg

N = 6

SAD

300 mg

N = 6

MAD

Placebo

N = 5

MAD

10 mg q.d.

N = 10

MAD

30 mg q.d.

N = 10

MAD

100 mg q.d.

N = 6

Sex, n (%) Male 8 (100) 6 (100) 6 (100) 6 (100) 6 (100) 5 (100) 10 (100) 10 (100) 6 (100) Age, years Mean (SD) 32.1 (11.4) 25.7 (2.3) 31.7 (9.8) 29.8 (10.6) 22.7 (2.4) 30.2 (8.7) 30.7 (9.9) 33.7 (11.7) 33.3 (12.7) Race, n, % White 7 (87.5) 5 (83.3) 5 (83.3) 5 (83.3) 6 (100.0) 5 (100.0) 8 (80.0) 9 (90.0) 5 (83.3) Black or African American 1 (12.5) 0 0 1 (16.7) 0 0 2 (20.0) 0 0 Asian 0 1 (16.7) 0 0 0 0 0 0 1 (16.7) Other 0 0 1 (16.7) 0 0 0 0 1 (10.0) 0 Weight, kg Mean (SD) 73.3 (10.2) 84.8 (16.6) 85.5 (8.8) 77.7 (4.9) 85.3 (14.6) 76.5 (16.5) 77.8 (14.6) 76.7 (13.3) 77.0 (13.4) Height, cm Mean (SD) 180.5 (8.4) 184.3 (9.7) 180.4 (8.0) 179.8 (4.2) 180.5 (9.8) 175.1 (6.4) 178.1 (8.3) 177.7 (5.6) 180.5 (9.0) BMI, kg/m2 Mean (SD) 22.42 (2.34) 24.91 (3.97) 26.43 (3.74) 24.03 (1.26) 26.11 (3.91) 24.98 (5.32) 24.39 (3.27) 24.46 (5.29) 23.65 (3.97) Abbreviations: BMI, body mass index; MAD, multiple-ascending dose; n, number of subjects; SAD, single-ascending dose; SD, standard deviation. Safety and tolerability Single-ascending dose

VX-128 administered as a single dose was generally well-tolerated up to the highest evaluated dose (300 mg). AEs in subjects who received VX-128 were generally mild; mild AEs occurred in eight subjects (33.3% of those dosed with VX-128). Moderate AEs occurred in two subjects (8.3%). The most common AE was headache and only occurred in subjects who received VX-128 (37.5%; Table 2). AE incidence was higher in subjects receiving VX-128 compared with those receiving placebo (n = 10, 41.7% vs. n = 2, 25%, respectively). One subject had a minimally prolonged QT interval 4.5 h post-VX-128 300 mg administration (447 to 460 ms), which was mild in severity and resolved without intervention or sequelae. Overall, there were no clinically meaningful changes in laboratory results, vital signs, or ECGs.

TABLE 2. AEs in at least two subjects, part A (SAD)

Placeboa

N = 8

n (%)

10 mg

N = 6

n (%)

40 mg

N = 6

n (%)

120 mg

N = 6

n (%)

300 mg

N = 6

n (%)

VX−128 total

N = 24

n (%)

Total

N = 32

n (%)

Number of AEs, total 3 19 4 8 3 34 37 Subjects with any AEs 2 (25.0) 4 (66.7) 2 (33.3) 2 (33.3) 2 (33.3) 10 (41.7) 12 (37.5) Subjects with AEs by relationship Not related 1 (12.5) 0 0 1 (16.7) 0 1 (4.2) 2 (6.3) Unlikely related 1 (12.5) 0 0 0 1 (16.7) 1 (4.2) 2 (6.3) Possibly related 0 4 (66.7) 2 (33.3) 1 (16.7) 1 (16.7) 8 (33.3) 8 (25.0) Related 0 0 0 0 0 0 0 Subjects with AEs by severity Mild 2 (25.0) 3 (50.0) 1 (16.7) 2 (33.3) 2 (33.3) 8 (33.3) 10 (31.3) Moderate 0 1 (16.7) 1 (16.7) 0 0 2 (8.3) 2 (6.3) Severe 0 0 0 0 0 0 0 Life threatening 0 0 0 0 0 0 0 Subjects with SAEs 0 0 0 0 0 0 0 Subjects with AEs leading to death 0 0 0 0 0 0 0 System organ classb preferred term Nervous system disorders 0 4 (66.7) 2 (33.3) 1 (16.7) 2 (33.3) 9 (37.5) 9 (28.1) Headache 0 2 (33.3) 0 1 (16.7) 2 (33.3) 5 (20.8) 5 (15.6) Tension headache 0 2 (33.3) 2 (33.3) 0 0 4 (16.7) 4 (12.5) General disorders and administration site conditions 1 (12.5) 3 (50.0) 1 (16.7) 0 0 4 (16.7) 5 (15.6) Fatigue 0 2 (33.3) 0 0 0 2 (8.3) 2 (6.3) Musculoskeletal and connective tissue disorder 1 (12.5) 0 1 (16.7) 1 (16.7) 0 2 (8.3) 3 (9.4) Myalgia 1 (12.5) 0 1 (16.7) 0 0 1 (4.2) 2 (6.3) Note When summarizing number of events, a subject with multiple events within a category was counted multiple times in that category. When summarizing number and percentage of subjects, a subject with multiple events within a category was counted only once in that category. Abbreviations: AE, adverse event; N, number of subjects in the analysis set; n, number of subjects with data; PT, preferred term; SAD, single-ascending dose; SAE, serious adverse event.

Of the subjects that were administered VX-128, three received paracetamol orally post-study drug administration to treat malaise (~36 h post-VX-128 10 mg administration), myalgia (~87 h post-VX-128 40 mg administration), or influenza (~152 h post-VX-128 40 mg administration). These AEs occurred in one individual each.

Multiple-ascending dose

VX-128 administered as multiple doses was generally well-tolerated, with the exception of the occurrence of rash events in 5 of 26 (19%) subjects who received VX-128. The occurrence of rash led to treatment discontinuation in two subjects who received 100 mg q.d. of VX-128. The clinical study was subsequently terminated early due to tolerability issues. AEs in subjects that received VX-128 were generally mild and occurred in 18 subjects (69.2% of those receiving VX-128; Table 3). The most common AEs reported were headache (in n = 9 subjects, 34.6%), and somnolence and dizziness (n = 4, 15.4% each). AE incidence in the VX-128 group was lower than in the placebo group (VX-128: n = 18, 69.2%, placebo: n = 4, 80%). There were no clinically meaningful changes in laboratory results, vital signs, ECGs, or evidence of suicidal thoughts based on the C-SSRS.

TABLE 3. AEs in at least twp subjects, part B (MAD)

Placeboa

N = 5

n (%)

10 mg q.d.

N = 10

n (%)

30 mg q.d.

N = 10

n (%)

100 mg q.d.

N = 6

n (%)

VX−128 total

N = 26

n (%)

Total

N = 31

n (%)

Number of AEs, total 21 22 12 40 74 95 Subjects with any AEs 4 (80.0) 6 (60.0) 6 (60.0) 6 (100.0) 18 (69.2) 22 (71.0 ) Subjects with AEs by relationship Not related 2 (40.0) 1 (10.0) 0 0 1 (3.8) 3 (9.7) Unlikely related 0 0 5 (50.0) 2 (33.3) 7 (26.9) 7 (22.6)