CNS Drugs https://doi.org/10.1007/s40263-021-00797-x ORIGINAL RESEARCH ARTICLE First‑in‑Human Randomized Trial to Assess Safety, Tolerability, Pharmacokinetics and Pharmacodynamics of the KDM1A Inhibitor Vafidemstat Rosa María Antonijoan1,2 · Juan Manuel Ferrero‑Cafiero1 · Jimena Coimbra1 · Montse Puntes1 · Joan Martínez‑Colomer1 · María Isabel Arévalo3 · Cristina Mascaró3 · Cesar Molinero3 · Carlos Buesa3 · Tamara Maes3 Accepted: 12 February 2021 © The Author(s) 2021 Abstract Background Vafidemstat, an inhibitor of the histone lysine-specific demethylase KDM1A, corrects cognition deficits and behavior alterations in rodent models. Here, we report the results from the first-in-human trial of vafidemstat in healthy young and older adult volunteers. A total of 110 volunteers participated: 87 were treated with vafidemstat and 23 with placebo. Objectives The study aimed to determine the safety and tolerability of vafidemstat, to characterize its pharmacokinetic and pharmacodynamic profiles, to assess its central nervous system (CNS) exposure, and to acquire the necessary data to select the appropriate doses for long-term treatment of patients with CNS disease in phase II trials. Methods This single-center, randomized, double-blind, placebo-controlled phase I trial included a single and 5-day repeated dose-escalation and open-label CNS penetration substudy. Primary outcomes were safety and tolerability; secondary out- comes included analysis of the pharmacokinetics and pharmacodynamics, including chemoprobe-based immune analysis of KDM1A target engagement (TE) in peripheral blood mononuclear cells (PBMCs) and platelet monoamine oxidase B (MAOB) inhibition. CNS and cognitive function were also evaluated. Results No severe adverse events (AEs) were reported in the dose-escalation stage. AEs were reported at all dose levels; none were dose dependent, and no significant differences were observed between active treatment and placebo. Biochemistry, urinalysis, vital signs, electrocardiogram, and hematology did not change significantly with dose escalation, with the excep- tion of a transient reduction of platelet counts in an extra dose level incorporated for that purpose. Vafidemstat exhibits rapid oral absorption, approximate dose-proportional exposures, and moderate systemic accumulation after 5 days of treatment. The cerebrospinal fluid-to-plasma unbound ratio demonstrated CNS penetration. Vafidemstat bound KDM1A in PBMCs in a dose-dependent manner. No MAOB inhibition was detected. Vafidemstat did not affect the CNS or cognitive function. Conclusions Vafidemstat displayed good safety and tolerability. This phase I trial confirmed KDM1A TE and CNS penetra- tion and permitted characterization of platelet dynamics and selection of phase IIa doses. Trial registration EUDRACT No. 2015-003721-33, filed 30 October 2015. Key Points Vafidemstat displays good safety and tolerability in the * Tamara Maes dose range 0.2–2.5 mg/day. tmaes@oryzon.com 1 A chemoprobe-based assay revealed that vafidemstat Centre d’Investigació del Medicament, Institut de Recerca effectively bound the KDM1A target in humans. de l’Hospital de la Santa Creu i Sant Pau (IIB-Sant Pau), Barcelona, Spain Vafidemstat displays central nervous system penetration. 2 Pharmacology and Therapeutics Department, Universitat Autònoma de Barcelona (UAB), Bellaterra, Spain 3 Oryzon Genomics S.A. Carrer Sant Ferran 74, Cornellà de Llobregat, 08940 Barcelona, Spain Vol.:(0123456789) R. M. Antonijoan et al. 1 Introduction hydroxypropyl methylcellulose capsules) were manufactured in accordance with good manufacturing practices (GMP) The etiology of sporadic neurodegenerative disorders such as guidelines and labeled according to Annex 13 of the EU Alzheimer’s or Parkinson’s disease is currently unknown. Epi- GMP guidelines. The chemical structure of the compound genetics plays an important role in brain development and the is shown in Fig. 1a. The maximum recommended starting establishment and loss of memory and cognition [1–4]; modu- dose (MRSD) was 0.2 mg, as calculated in the most sensitive lation of epigenetic factors may present a unique opportunity species (rat). The dose-escalation regimens were 0.2, 0.6, for treatment of central nervous system (CNS) diseases [5]. 1.5, 2.5, and 4 mg for the single ascending dose (SAD) study KDM1A is a histone demethylase that has been proposed and 0.2, 0.6, 1, 1.5, 2.5 mg, and an additional dose level of as a target for the treatment of neurodegenerative or neurode- 4.0 mg for the multiple ascending dose (MAD) study. In the velopmental diseases [6–8]. cerebrospinal fluid (CSF) substudy, the doses were 2 and 4 Vafidemstat (ORY-2001) is an orally bioavailable and mg (Fig. 1c, d). Blinding, randomization, and dose-escala- brain penetrant compound that was originally identified as tion procedures are available in Supplemental Materials and a dual inhibitor of the flavin adenine dinucleotide (FAD)- Methods in Online Resource. dependent amine oxidases KDM1A (EC 1.14.99.66) and monoamine oxidase B (MAOB; EC 1.4.3.4) [10]. KDM1A 2.2 Study Design is a histone demethylase that acts in the nucleus and is involved in transcription regulation [9]. MAOB is structur- This study was designed as a single-center, randomized, ally related but involved in dopamine metabolism and is a double-blind, placebo-controlled phase I trial to assess the validated drug target in Parkinson’s disease. safety, tolerability, pharmacokinetics, and pharmacody- In vitro, vafidemstat inhibits the catalytic activity of namics of vafidemstat. It consisted of a SAD study in male KDM1A and MAOB through irreversible binding to their volunteers, a MAD study in healthy young and older adult FAD cofactors. Vafidemstat also interferes with the capacity populations, and a substudy of CSF. of KDM1A to interact with part of its recruiting transcription The primary objectives of the study were to assess the factors. In vivo, it primarily inhibits KDM1A, and MAOB safety and tolerability of vafidemstat; the secondary objec- inhibition is not significant in the therapeutic dose range. Vafi- tives were to assess the pharmacokinetic and pharmacody- demstat restored cognition and behavior alterations in several namic profiles of vafidemstat after (1) single ascending oral rodent models [10]. Comparison of vafidemstat with selective dose administration in healthy young male volunteers, (2) KDM1A or MAOB inhibitors revealed that KDM1A inhibi- repeated (5 days) ascending daily oral dose administration in tion is key to the efficacy of vafidemstat. In the brain, KDM1A young male and female healthy subjects, and (3) repeated (5 is recruited by transcription factors, including serum response days) daily oral dose administration in older adults. factor, and is involved in behavior alterations; vafidemstat pro- The MRSD was determined according to US FDA and motes the response of immediate early genes [10]. Vafidem- European Medicines Agency guidelines [14, 15] based on stat also has anti-inflammatory activity in the CNS, evidenced available preclinical data. The no observed adverse effect by its efficacy in mouse models for multiple sclerosis (MS) level (NOAEL) in nonclinical good laboratory practices [11]. In rodents, the therapeutic effects of vafidemstat can be achieved in the absence of an impact on hematopoiesis, a known on-target effect of KDM1A inhibition [12, 13]. ◂ Fig. 1  Clinical trial design. a Chemical structure of vafidemstat. Here, we report the results of a first-in-human phase I clini- b Impact of vafidemstat on platelet levels in nonclinical species, rep- cal trial in healthy young and older adult volunteers. The study resented as % inhibition compared with control animals. All values aimed to determine the safety and tolerability of vafidemstat, to are expressed as mg/m2/day to allow for direct comparison. Differ- ences in administration (once daily by oral gavage in rats and dogs vs. characterize its pharmacokinetic and pharmacodynamic param- drinking water in mice) were accounted for. Doses in mg/kg/day were eters, and to assess its CNS exposure. The data obtained from converted to mg/m2/day by multiplication with the Km factor for each this study were used to select the appropriate doses for long- species (3, 6, 20, 37 for mouse, rat, dog, human, respectively). Black term treatment of patients with CNS disease in phase II trials. triangles indicate the SAMP8 efficacy studies in mouse; gray circles indicate the 28-day toxicity in rats; white squares indicate the 28-day toxicity in dogs; black arrows represent the doses chosen for the SAD and MAD cohorts; gray arrows represent those for the CSF cohorts 2 Materials and Methods in the phase I trial. The maximum recommended starting dose was 0.2 mg. c Clinical trial doses per cohort. d Study design of the SAD, MAD, and CSF cohorts. Dark gray rectangle indicates the sentinel 2.1 Study Drug and Treatment subject, light gray rectangles indicate subjects in active treatment; white rectangles indicate subjects receiving placebo. CSF cerebrospi- The investigational medicinal drug substance and drug nal fluid, MAD multiple ascending dose, p.o. oral administration, PLT product (placebo or vafidemstat 0.2, 1, 1.5, or 4 mg in platelet, QD once daily, SAD single ascending dose First-in-Human Trial of KDM1A Inhibitor Vafidemstat R. M. Antonijoan et al. (GLP) toxicology studies in rats and dogs was established engagement (TE) and platelet MAOB activity in the SAD at 0.200 and 0.075 mg/kg, respectively. The MRSD was cal- and MAD studies. An open-label CSF pharmacokinetics culated based on the NOAEL in a 28-day GLP toxicity study study was included to assess the pharmacokinetic profile in rats, the most sensitive species: in the CNS after a single oral dose of vafidemstat. Details MRSD = 1/safety factor × Km, rat/Km, human × about the assessments, analytical methods, and statistics are NOAELrat × human body weight = 0.2 mg, where the safety available in ESM-1. factor = 10; Km, rat = 6; Km, human = 37; NOAELrat = 0.2 mg/kg; and human body weight = 60 kg. 2.4 Analytical Methods The dose escalation was designed to commence from the MRSD and continue to the minimum intolerable dose 2.4.1 Pharmacokinetics (MID). The MID was defined as the dose at which a serious adverse event (SAE) occurs in one or more subjects and the Plasma and CSF samples for pharmacokinetic analysis were causality is established as certainly, probably, or possibly obtained predose and at preestablished timepoints. Vafidem- related to the study drug; when > 50% of subjects experi- stat concentrations were determined in human plasma and ence a limiting grade 2 or higher AE after active treatment CSF using a highly sensitive GLP-validated liquid chroma- but not placebo; when > 50% of AEs occur in subjects under tography–tandem mass spectrometry method (lower limit active treatment but not placebo; or (in view of the role of of quantification 10 pg/mL for plasma and 50 pg/mL for KDM1A in hematopoiesis) when a > 50% decrease in plate- CSF) with electron spray ionization in positive ion mode let levels from baseline or grade 1 or higher thrombocyto- and deuterated vafidemstat as internal standard, developed penia platelet values are found in at least > 50% of subjects at Laboratorios Echevarne, S.A, Spain. Liquid–liquid extrac- under active treatment but not placebo. tion with ethyl acetate was used for sample processing, and The original dose escalation regimens designed were 0.2, chromatography was run on a Venusil XBP C18 column, 0.6, 1.5, 2.5, and 4 mg for the SAD and 0.2, 0.6, 1, 1.5, and with 0.1% formic acid in water and acetonitrile as mobile 2.5 mg for the MAD. This dose range was based on the phases A and B, respectively. Intra- and interday precision nonclinical toxicology and efficacy data, was equivalent to in the validation ranged between 0.57 and 9.75% for plasma the therapeutic dose in preclinical species, and was designed and between 1.18 and 5.63% for CSF. Intra- and interday to identify the onset of hematological engagement (Fig. 1b). accuracy (bias) in the validation ranged between − 4.74 and An extra cohort at 4 mg was incorporated into the MAD 9.50% of the nominal values for plasma and between − 8.39 study after protocol modification. In the CSF pharmacoki- and 10.25% of the nominal values for CSF. Incurred sample netic substudy, the doses were 2 and 4 mg (Fig. 1d). reanalysis was conducted on study samples to confirm the The eligibility criteria and programmed interventions reproducibility of the bioanalytic method. All the repeat and are presented in Tables S1 and Tables S2–S4 in ESM-2, original samples (n = 244 distributed into six independent respectively. bioanalytical batches for plasma and n = 10 into two batches for CSF) were within 20% of the mean of the two values, 2.3 Study Population and Assessments meeting the preestablished acceptance criteria of 67% and therefore confirming the reproducibility of the assay. Sample Healthy adult male (SAD) and male or female subjects analysis was GLP compliant, and pharmacokinetic param- (MAD) complying with the eligibility criteria as shown in eters—including the dose normalized maximum (peak) Table S1 in ESM-2 were randomized and included in the concentration (Cmax), time to reach Cmax (tmax), and area study and dosed in the SAD, MAD, and CSF studies. Vafi- under the plasma concentration–time curve (AUC)—were demstat or placebo were administered as a single oral dose calculated by means of noncompartmental analysis using (SAD and CSF pharmacokinetics) or as a daily oral dose for ­WinNonlin® 2.1 software. Plasma-concentration-versus-time 5 consecutive days (MAD). profiles are presented on linear or log-linear scale mean pro- Physical examination included vital signs, AE checklist, files ± standard error of the mean for each treatment. electrocardiograph (ECG), and neurological evaluations: visual analogue scale (VAS), Leeds Sleep Evaluation Ques- 2.4.2 Plasma Unbound Concentrations tionnaire (LSEQ), Wisconsin Card Sorting Test (WCST), and Sternberg test. Blood samples were obtained for safety Plasma unbound concentrations were calculated by cor- laboratory tests (hematology, biochemistry, and urinalysis) recting the measured total concentrations with the plasma and at baseline and preestablished timepoints (see Tables fraction unbound value of 0.029, which had been sepa- S2–S4 in ESM-2) after the first drug administration for rately assessed in vitro by equilibrium dialysis using the pharmacokinetic analysis using a GMP-validated method ­HTDialysis® system at Advinus Therapeutics Ltd., India. and for pharmacodynamic analysis to assess KDM1A target First-in-Human Trial of KDM1A Inhibitor Vafidemstat 2.4.3 KDM1A Target Engagement TEx (%) = 100 − 100 × Rx (%)∕RTo (%), For the evaluation of KDM1A TE (% of KDM1 bound to where vafidemstat), a proprietary chemoprobe-based assay [16, 17] RLUfree ( ) was used at Oryzon Genomics S.A., Spain. Briefly, blood R (%) = × 100. RLUtotal samples were collected in EDTA (ethylenediaminetetraacetic acid) K2 tubes from healthy volunteers at baseline and pre- specified timepoints. Peripheral blood mononuclear cells (PBMCs) were obtained by density gradient centrifugation 3 Results in LeucoSep™ tubes. Cells were lysed in 1X cell lysis buffer (Cell Signaling; #9803) containing 1X Complete Mini, pro- The first subject was enrolled on 4 April 2016, and the last tease inhibitor cocktail tablets (ROCHE; # 11836153001) subject completed the study on 2 June 2017. Subjects were in the presence of 25 nM biotinylated KDM1A chemoprobe screened during the 28 days prior to dosing. OG-881. The chemoprobe binds the free KDM1A (i.e., not A total of 40 healthy young male subjects were enrolled occupied by vafidemstat) in the sample. This lysate was then in the SAD study and treated with placebo or vafidemstat used to perform a chemiluminescent KDM1A sandwich (randomization ratio 2:6) at doses ranging from 0.2 to 4 mg. enzyme-linked immunosorbent assay (ELISA) (using anti- Eight subjects were enrolled per dose level. KDM1A-coated ELISA plates) and a chemoprobe ELISA In the MAD study, 40 healthy young male and female (using streptavidin-coated ELISA plates) to determine both subjects were enrolled and treated for 5 days with placebo total and free KDM1A in the sample. Streptavidin (Promega or vafidemstat (randomization ratio 2:6) at doses ranging Biotech Ibérica; #Z7041) at 10 µg/mL in phosphate buff- from 0.2 to 2.5 mg per day. Eight subjects were enrolled per ered saline (PBS) or mouse monoclonal anti-KDM1A anti- each of the dose levels. After a protocol modification, four body (Abcam; #ab53269) at 2 µg/mL in PBS were used to additional young subjects were enrolled in a sixth cohort coat LumiNunc Plates MaxiSorp (NUNC; #436110) plates. and treated for 5 days with placebo or vafidemstat (rand- Rabbit monoclonal anti-KDM1A antibody (Cell Signal- omization ratio 1:3) at 4 mg per day. Finally, four older adult ing; #2184) at 0.125 µg/mL in PBS was used for primary subjects were enrolled and treated for 5 days with placebo detection, and the peroxidase-conjugated secondary anti- or vafidemstat at 2.5 mg per day (randomization ratio 1:3). rabbit immunoglobulin G antibody (Jackson ImmunoRe- The demographics and baseline characteristics of the search; #711-035-152) at 1:5000 dilution in PBS was used subjects are summarized in Table S5 in ESM-2. In the SAD for secondary detection in combination with 100 µL/well and MAD studies, the distribution of demographics was of chemiluminescent substrate (Invitrogen; #37074). Anti- similar in the treated and placebo arms. All subjects were body #2184 recognizes the N-terminal and #ab53269 the Caucasian. C-terminal region of KDM1A in the native complex. The KDM1A antibodies used were KDM1A knockout validated, 3.1 Safety and Tolerability and we confirmed that coincubation with synthetic peptides corresponding to the respective target epitopes eliminated A total of 120 AEs were reported during the three study the KDM1A signal. Intraday precision of the validation stages (SAD, MAD, and older adult population): 90 AEs in human PBMC ranged between 0.31 and 5.08% for total by subjects receiving vafidemstat and 30 AEs by subjects KDM1A and between 1.03 and 8.02% for free KDM1A. receiving placebo, i.e., the same proportion as the treatment Interday precision was 11.9 and 19.7% for total and free to placebo randomization (3:1). Of these, 108 AEs were KDM1A, respectively. classified as treatment-emergent AEs (TEAEs) possibly or All ELISA and chemoprobe ELISA assays were run probably related to the study drug: 79 TEAEs were reported as technical triplicates. After raw data processing (robust in volunteers treated with vafidemstat and 29 in volunteers elimination of outliers according to Grubbs criteria and sub- treated with placebo. No differences in the proportion of traction of blank signal), the TE or percentage of KDM1A subjects reporting AEs or differences between the AEs bound by vafidemstat was calculated relative to the predose reported were observed between the active treatment and sample (T0) from the same subject as follows: placebo. No SAEs were reported during the study. During the SAD stage in healthy young male volunteers (N = 40), 15 AEs were reported; 13 were considered to be treatment related (12 in subjects receiving vafidemstat and one in the placebo arm). Nine subjects experienced at least one AE. In the vafidemstat treatment group, the most R. M. Antonijoan et al. common AEs were headache, followed by euphoric mood. 50% of baseline levels in two of three vafidemstat-treated None of the AEs were dose dependent. subjects by 216 h after the first treatment administration and During the MAD stage in healthy young male/female in all subjects at 240 h and 264 h and recovered during the volunteers (N = 44), a total of 69 AEs were reported (51 follow-up visits (Fig. 2c). Based on these data, the MID AEs with vafidemstat and 18 with placebo). The most com- as defined per protocol was met at dose 4 mg/day, and the mon AEs were headache, followed by dry mouth, asthenia, maximum tolerated dose was established at 2.5 mg/day. postural dizziness, and somnolence. In total, 61 AEs were In summary, no SAEs or AEs leading to treatment discon- related to the study treatment (44 with vafidemstat and 17 tinuation were reported in the SAD or MAD cohorts. With with placebo). The data from a subcohort (N = 4) subject exception of the effect on platelets observed in the extra to a dosing error are represented separately in Table S6 in cohort (4 mg/day) as described, all hematology, biochemis- ESM-2. None of the AEs were considered severe. Moder- try, and urinalysis parameters, as well as vital signs and ECG ate AEs (all headaches experienced with vafidemstat) were assessments in SAD and MAD, were within normal ranges reported in dose levels I (0.2 mg/day), III (1.0 mg/day), and in the vafidemstat treatment arms and revealed no significant IV (1.5 mg/day) but not in the highest dose levels (V and VI, differences between treatment arms. 2.5 and 4 mg/day, respectively). The rest of the AEs were considered mild. Regarding the AEs reported in the highest 3.2 Pharmacokinetics dose levels, the proportion of subjects who experienced the most common AEs was similar in the active treatment and In the SAD and MAD cohorts, the plasma pharmacokinetic placebo arms. profiles of vafidemstat after single (Fig. 3a) and multiple Safety and tolerability results from the MAD stage in (Fig. 3b) dosing reflected rapid oral absorption, with a tmax young male and female volunteers supported the initiation of ~ 0.5–2 h, moderate variability (overall coefficient of of the MAD stage in older adult volunteers at dose level VI variation ≤ 30%), a relatively long half-life (~ 20–30 h), (4.0 mg/day, N = 4; three active and one placebo). A total and approximately dose-proportional exposures (based on of 23 AEs were reported: 12 with vafidemstat and 11 with dose normalized Cmax and AUC). A tendency for more than placebo. Three subjects reported at least one AE. The most proportional increases was found starting from the dose of common AEs were postural dizziness (in a subject in the 2.5 mg/day in the MAD cohort, which could result from a placebo arm) followed by headache, blunted affect, and ver- saturation of drug absorption and/or elimination at higher tigo. Most reported AEs were mild. A total of 21 treatment- dose levels, among other causes. Apparent clearance was related TEAEs were reported (10 with vafidemstat and 11 low (6 L/h). A moderate systemic accumulation (mean accu- with placebo). TEAEs possibly or probably related to the mulation ratios [AUC​0–t Day5/AUC​0–t Day1] ~ 2) was observed study drug in the SAD, MAD, and older adult cohort are after 5 days of administration, and pharmacokinetic mod- presented in Table 1. eling indicated that a stationary state would be reached No significant changes were observed over time in hema- between approximately days 5 and 7 (data not shown). tological, biochemical, or urinalysis parameters or in vital Pharmacokinetic profiles at 2.5 mg/day did not differ sig- signs or ECG values in the planned SAD or MAD (including nificantly between the young and older adult populations older adult) cohorts. Platelet levels showed no variations at (Fig. 3b). The mean apparent volume of distribution was any of the SAD dose levels or up to MAD dose III (1.0 mg/ 150 L, indicating potentially low to moderate distribution day). At MAD dose levels IV (1.5 mg/day) and V (2.5 mg/ to tissues (Table 2). day), platelet counts were within the normal range, but a ten- In the CSF cohort, vafidemstat was shown to cross the dency for lower counts was emerging in the active treatment human blood–brain barrier, with quantifiable concentra- arm compared with the placebo arm. At 1.5 and 2.5 mg/ tions found from 2 h post-dose, the first timepoint analyzed. day, a slight reduction (− 11 and − 21%) of the mean was Additionally, CSF/plasma (unbound) ratios observed in this observed by 192 h after the first administration and a small study (mean of 0.81) suggested that no or minor CNS-to- rebound (+ 15 and + 18%) was observed in the follow-up blood efflux transport of vafidemstat is expected in humans visit (Fig. 2a, b). Although the differences between placebo (Fig. 3c and Table 2). and active treatment arms were not significant, these changes were thought to reflect the first indication of hematopoietic 3.3 Pharmacodynamics engagement. A protocol amendment was issued to incor- porate an additional MAD dose (level VI; N = 4; placebo Failure to efficiently inhibit the target is a factor that con- or 4 mg/day) to characterize the hematopoietic impact. At tributes to the low success rate of clinical drug development this dose level, a transient reduction of platelet levels was and underscores the relevance of demonstrating target occu- observed by 192 h, and platelet evolution was monitored to pancy in early-stage clinical trials. To evaluate the pharma- characterize the nadir and rebound. Platelets dropped below codynamics of vafidemstat, we used a chemoprobe-based First-in-Human Trial of KDM1A Inhibitor Vafidemstat Table 1  Number of TEAEs (and percentage of total TEAEs) possibly or probably related to the study drug by preferred term and dose levels/(n = subjects) in the SAD, MAD, and older adult cohorts Cohort and MedDRA AE term Placebo I (0.2 mg/day) II (0.6 mg/day) III (1.0 mg/day) III (1.5 mg/day) IV (2.5 mg/day) V (4.0 mg/day) SAD cohort n = 10 n=6 n=6 n=0 n=6 n=6 n=6 Diarrhea 1 (7.7) Headache 1 (7.7) 1 (7.7) 1 (7.7) Feeling hot 1 (7.7) Euphoric mood 1 (7.7) 1 (7.7) Musculoskeletal stiffness 1 (7.7) Paresthesia 1 (7.7) Abdominal discomfort 1 (7.7) Dry mouth 1 (7.7) Asthenia 1 (7.7) Blunted affect 1 (7.7) Total 13 (100) 1 (7.7) 1 (7.7) 3 (23.1) 2 (15.4) 3 (23.1) 3 (23.1) MAD cohort n = 11 n=6 n=6 n=6 n=6 n=6 n=3 Palpitations 1 (1.6) Dry mouth 5 (8.2) 4 (6.5) 3 (4.9) 1 (1.6) Asthenia 2 (3.3) 2 (3.3) 1 (1.6) 1 (1.6) Feeling hot 1 (1.6) 1(1.6) Muscle spasms 1(1.6) Dizziness postural 2 (3.3) 1(1.6) 1 (1.6) Headache 3 (4.9) 3 (4.9) 1 (1.6) 2 (3.3) 2 (3.3) 2 (3.3) Dyspepsia 1 (1.6) Salivary hypersecretion 1 (1.6) 1 (1.6) Feeling drunk 1 (1.6) Somnolence 2 (3.3) 1 (1.6) Apathy 1 (1.6) Blunted affect 2 (3.3) Euphoric mood 1 (1.6) Daydreaming 1 (1.6) Diplopia 1 (1.6) Vision blurred 1 (1.6) Constipation 1 (1.6) 1 (1.6) Feeling cold 3 (4.9) Nasopharyngitis 1 (1.6) Hematoma 1 (1.6) Total 61 (100) 17 (27.9) 10 (16.4) 11 (18.0) 13 (21.3) 7 (11.5) 1 (1.6) 2 (3.3) Elderly cohort n=1 n=3 Palpitations 1 (4.8) Vertigo 1 (4.8) 1 (4.8) Diarrhea 2 (9.5) Asthenia 1 (4.8) Feeling cold 1 (4.8) Gait disturbance 1 (4.8) Musculoskeletal stiffness 1 (4.8) Postural dizziness 4 (19.0) Headache 3 (14.3) Somnolence 1 (4.8) Blunted effect 2 (9.5) 1 (4.8) Euphoric mood 1 (4.8) Total 21 (100) 11 (52.4) 10 (47.6) Data are presented as n (%). AEs occurring on the same day are only counted once AE adverse event, MAD multiple ascending dose, MedDRA Medical Dictionary for Regulatory Activities, SAD single ascending dose, TEAE treatment-emergent adverse event R. M. Antonijoan et al. Fig. 2  Hematological impact of vafidemstat. Impact of vafidemstat on platelet levels at a 1.5 mg/day, b 2.5 mg/day, and (c) the extra dose level of 4 mg/ day, represented as % change from baseline levels. Black dots indicate vafidemstat (volunteers analyzed n = 6 in [a/b] or n = 3 in [c]); open circles indicate placebo treatment (volunteers analyzed n = 2 in [a/b] or n = 1 in [c]); black arrows represent dosing occasions. Data are pre- sented as means and standard error of the mean. CFB change from baseline immunoassay [16, 17]. The assay was validated for use in a clear relationship was evidenced between the Cmax/AUC clinical trials and used to calculate the TE from the amount parameters and the amount of vafidemstat bound to KDM1A of free (uninhibited) and total KDM1A protein in PBMC in the tested dose range (Fig. 4e, f). Similarly, the impact samples obtained predose and at different timepoints after on platelets increased with exposure, reaching level drops administration (Fig. 4a, b). Vafidemstat bound KDM1A in (from baseline) of ~ 50% at Cmax,ss of ~ 100 ng/mL and PBMCs in a dose-dependent manner. In the SAD cohorts, a AUC​ss of ~ 1000 ng·h/mL (Fig. 4g, h). KDM1A TE was maximum KDM1A TE of around 80% was observed at 12 h 85.6% in the older adult population (evaluable sample from (4 mg), and substantial binding remained 72 h after dosing a single individual), comparable with that observed in young (Fig. 4c). KDM1A TE values observed 12 h after the last volunteers at the same dose level. As far as we can tell, this dose in the MAD study (108 h after first dose) were similar is the first time a chemoprobe-based method has been used to those found in the SAD study. Maximum TE values of to effectively monitor the dynamics of TE in a clinical trial. up to 90% were reached at 108 h. KDM1A TE turnover was KDM1A TE in the brain could not be tested in this study slow, with 40–60% TE remaining at 192 h (96 h after last because no KDM1A positron emission tomography tracer dose, Fig. 4d). KDM1A TE increased with plasma expo- was available. However, since vafidemstat binds KDM1A in sure, reaching a peak of ~ 90% at Cmax,ss (where ss is steady the human brain and PBMC samples ex vivo with compa- state) of ~ 30 ng/mL and AUCss of ~ 500 ng·h/mL. Thus, rable efficacy (data not shown), and the calculated plasma First-in-Human Trial of KDM1A Inhibitor Vafidemstat Fig. 3  Vafidemstat pharmacokinetics. (a) Plasma concentrations as mean and standard error of the mean. Volunteers analyzed at each after single and (b) multiple ascending doses in healthy young (full datapoint, n = 6 except for MAD 4 mg, n = 3. (c) Cerebrospinal fluid lines) and older adult (dotted line) subjects. Light blue circles 0.2 mg; (full lines) and plasma (unbound, dotted lines) concentrations after a white squares 0.6 mg; light blue triangles 1 mg; white triangles 1.5 single dose of 2 mg (diamonds) or 4 mg (circles) mg; blue diamonds 2.5 mg; white circles 4 mg. Data are presented unbound vafidemstat levels were similar to those in CSF, cohorts, as assessed using a VAS. Subjects reported feel- the available pharmacokinetic and pharmacodynamic data ing “partially calm” throughout the study, a feeling shared anticipate proper brain KDM1A TE. by those receiving placebo or vafidemstat regardless of the Finally, vafidemstat did not significantly inhibit platelet dose level administered and attributed to participation in MAOB levels in vivo in the dose range used (Fig. S1 in the study. Vafidemstat did not disrupt sleeping or awaken- ESM-3). ing patterns, as assessed by the LSEQ in the SAD, MAD, or CSF cohorts. A few spurious individual VAS values com- 3.4 Neuropsychological Assessments posing the global score reached statistical significance, but no dose response was observed. No significant differences Treatment with vafidemstat did not provoke somnolence were observed at any dose level or parameter in the WCST or reveal a potential for abuse in the SAD, MAD, or CSF or Sternberg test in the SAD, MAD, or CSF cohorts. R. M. Antonijoan et al. Table 2  Pharmacokinetics and central nervous system penetrance of vafidemstat Cohort and param- Dose level and results eter SADa I: 0.2 mg II: 0.6 mg III: 1.5 mg IV: 2.5 mg V: 4.0 mg (n = 6) (n = 6) (n = 6) (n = 6) (n = 3) tmax (h) 2.75 (59) 1.83 (36) 0.92 (56) 1.58 (83) 1.71 (73) Cmax (ng/mL) 1.11 (24) 3.21 (12) 11.95 (29) 18.78 (30) 38.05 (33) AUC​0–t (ng·h/mL) 28.03 (12) 83.32 (13) 297.12 (50) 402.09 (20) 550.01 (17) AUC​0–inf (ng·h/ 30.93 (16) 90.67 (13) 427.58 (80) 438.11 (25) 568.46 (18) mL) Vd/F (L) 260 (20) 256 (14) 213 (9.7) 203 (9.5) 204 (17) CL/F (L/h) 6.59 (14) 6.72 (14) 5.34 (52) 6.03 (26) 7.20 (15) t½ (h) 28 (28) 27 (6.6) 41 (76) 25 (28) 20 (17) a MAD I: 0.2 mg/day II: 0.6 mg/day III: 1.0 mg/day IV: 1.5 mg/day V: 2.5 mg/day Older adult: 2.5 VI: 4.0 mg/day (n = 6) (n = 6) (n = 6) (n = 6) (n = 6) mg/day (n = 6) (n = 3) tmax, ss (h after 5.1 (1.7) 2.25 (1.4) 1.83 (1.7) 1.17 (0.4) 2.17 (1.7) 2.33 (1.6) 1.33 (1.1) last dosing) Cmax (ng/mL) 1.28 (23) 3.69 (22) 6.83 (56) 11.35 (30) 26.64 (54) 24.28 (12) 55.97 (27) (D1) Cmax,ss (ng/mL) 2.32 (17) 7.65 (39) 14.11 (43) 23.61 (18) 49.92 (59) 41.00 (42) 109.73 (50) (D5) AUC​0–t (ng·h/mL) 18.73 (21) 50.57 (28) 95.08 (35) 137.96 (17) 292.25 (45) 257.53 (33) 563.85 (28) (D1) AUC​0–t,ss (ng·h/ 37.69 (18) 113.68 (49) 198.74 (38) 298.69 (17) 634.21 (65) 442.23 (39) 994.50 (49) mL) (D5) RAC​ 1.91 (17) 1.90 (22) 1.92 (9.2) 1.87 (7.0) 1.86 (7.2) 1.92 (6.7) 1.79 (15) t½ (h) 22 (25) 22 (33) 23 (14) 22 (11) 22 (11) 23 (10) 20 (23) b CSF 2.0 mg 4.0 mg ( n = 3) ( n = 3) CSF (pg/mL) 239.42 (56) 387.34 (41) @2h CSF (pg/mL) 181.47 (11) 733.75 (27) @6h CSF (pg/mL) @ 169.68 (14) 549.93 (5.3) 12 h ­Plasmau (pg/mL) 315.68 (56) 589.71 (56) @2h ­Plasmau (pg/mL) 248.31 (17) 870.66 (13) @6h ­Plasmau (pg/mL) 186.35 (23) 609.11 (12) @ 12 h CSF/plasmau 0.78 (15) 0.69 (18) @2h CSF/plasmau 0.74 (7.8) 0.83 (14) @6h CSF/plasmau @ 0.92 (8.9) 0.91 (15) 12 h Data are presented as mean (coefficient of variation, %) a Plasma pharmacokinetic parameters of the SAD and MAD (after single [D1] and 5-day repeated [D5] dose) cohorts. n = 6 healthy young vol- unteers per cohort (0.2–4 mg SAD and 0.2–2.5 mg/day MAD), n = 3 healthy young volunteers in the 4 mg/day MAD cohort, and n = 3 older healthy adult volunteers in the 2.5 mg/day cohort. MAD AUC​inf (D1) not reported as extrapolated AUC was > 20% b Pharmacokinetic parameters in the CSF cohort after administration of a single dose. CSF and ­plasmau concentrations, and CSF-to-plasmau ratios after a single dose of vafidemstat 2 or 4 mg. n = 3 subjects per timepoint AUC​0–inf area under the concentration–time curve within time 0 to infinity, AUC​0–t area under the concentration–time curve within time 0–24 h, CL/F apparent clearance, Cmax maximum (peak) concentration, CSF cerebrospinal fluid, D1 day 1, D5 day 5, MAD multiple ascending dose, plasmau plasma unbound, RAC​ratio of accumulation (calculated from t½/Ke; Ke elimination rate constant), SAD single ascending dose, ss steady state, t½ terminal half-life, tmax time to reach Cmax, Vd/F apparent volume of distribution First-in-Human Trial of KDM1A Inhibitor Vafidemstat 4 Discussion provided a 30-fold window between the therapeutic effect and hematopoietic impact. Importantly, in rodents, efficacy Inhibitors of KDM1A have attracted attention for their could be obtained at doses with no or negligible hematopoi- potential use in the treatment of oncological diseases such etic engagement. Based on the data obtained in this study as acute myeloid leukemia and small-cell lung cancer. Com- and the characterization of platelet dynamics, phase II doses pounds currently undergoing clinical testing in oncology and were established at 0.6 and 1.2 mg/day. These doses were hematology include iadademstat (ORY-1001) [18], bome- estimated to be sufficient to reach ~ 60–80% KDM1A TE demstat (IMG-7289) [19], CC-90011 [20], and INCB059872 (efficacious in preclinical species) while avoiding a clinically [21]. relevant platelet impact, based on the exposure–response Vafidemstat (ORY-2001) is the first KDM1A inhibitor relationships (half and 80% maximal effective concentra- envisaged for CNS disease and evaluated in healthy vol- tion). Evaluation of long-term data in phase IIa trials will unteers. This study reports the results of a first-in-human permit vafidemstat dose selection for future pivotal phase phase I clinical trial of vafidemstat in healthy young and III studies. older adult volunteers to determine its safety and tolerabil- ity, to characterize its pharmacokinetics and pharmacody- namics, and to assess its CNS exposure. Vafidemstat was 5 Conclusion well-tolerated and did not produce any SAEs in the SAD or MAD studies. AEs were mild to moderate, and none were The 5-day treatment with vafidemstat was safe in the origi- dose related, and the total frequency of AEs was similar in nally designed dose range. The pharmacodynamic results subjects receiving vafidemstat or placebo. confirmed dose-dependent KDM1A TE but the absence The pharmacokinetic data from this phase I trial indi- of any significant MAOB inhibition at the doses used and cate that vafidemstat is suitable for daily administration. confirmed the CNS penetration of vafidemstat. This phase I The compound presents moderate accumulation after 5-day trial permitted the characterization of platelet dynamics and treatment, reaches steady state by day 5, and is CNS pen- selection of phase IIa doses. etrant. Whereas in vitro biochemical assays indicated near Vafidemstat has been tested in several phase IIa trials in equipotency for KDM1A TE and MAOB inhibition, phar- patients with relapsing–remitting and secondary-progressive macodynamic analyses on ex vivo samples from healthy vol- MS, in patients with mild to moderate Alzheimer’s disease, unteers revealed dose-dependent KDM1A TE in PBMCs but and in patients displaying aggression in different psychi- no platelet MAOB inhibition. These data correspond with atric diseases and moderate to severe Alzheimer’s disease previous ex vivo findings obtained in preclinical species (EUDRACT 2017-002838-23; 2017-004893-32; 2018- that show vafidemstat acts primarily as a selective KDM1A 002140-88; 2019-001436-54; NCT03867253). Based on the inhibitor in vivo, with no significant pharmacological good safety profile in older adults in long-term treatments, MAOB activity at the therapeutic doses used. No signifi- and on the rapid and potent anti-inflammatory properties cant effects were detected on hematology in the SAD and observed in models for MS, a randomized, open-label phase MAD studies at the initially planned doses, and escalation II study is ongoing to evaluate the ability of vafidemstat in the MAD was continued until the expected hematological to prevent acute respiratory distress syndrome in severely impact emerged. Platelet level was the only parameter that ill adult patients with severe acute respiratory syndrome was significantly altered in this study, as expected and previ- coronavirus 2 (SARS-CoV-2; coronavirus disease 2019) ously observed for other KDM1A inhibitors. (EUDRACT Nº 2020-001618-39). Recent phase IIa efficacy The obvious limitations of this first-in-human trial are data support vafidemstat as an emerging therapeutic option the small number of subjects included in each dose level for treatment of agitation/aggression in psychiatric disor- (especially in the older adult population), which may not ders such as attention-deficit/hyperactivity disorder, border- reveal less frequent AEs, and the short treatment duration, line personality disorder (BPD), autism spectrum disorder, which does not permit evaluation of long-term effects. Dif- and moderate-severe Alzheimer’s disease [22, 23]. Based ferent phase IIa trials (see below) have indicated a good on these results, a multicenter, double-blind, randomized, safety profile for vafidemstat even after long-term exposure placebo-controlled phase IIb trial to evaluate the efficacy and (up to 18 months). safety of vafidemstat in patients with BPD with agitation/ The dose range chosen in this clinical trial was the aggressiveness has been initiated (PORTICO; EUDRACT human equivalent of the dose range used in efficacy stud- Nº 2020-003469-20), and an additional phase IIb trial to ies in rodent models. In rodents, vafidemstat showed good address cognitive impairment and negative symptoms in brain penetration and TE in brain and peripheric tissues and patients with schizophrenia is planned to launch in 2021. R. M. Antonijoan et al. First-in-Human Trial of KDM1A Inhibitor Vafidemstat ◂Fig. 4  Vafidemstat pharmacodynamics. a The KDM1A chemoprobe ics. TM has received other compensation from the Alzheimer’s Drug OG-881 used to capture uninhibited protein. b Graphical representa- Discovery Foundation, outside the submitted work; is listed as inventor tion of the chemoprobe and sandwich ELISA used to determine free in WO2017/158136 (pending), WO2017/212061 (issued in multiple and total KDM1A. c KDM1A TE after SAD and d MAD in healthy countries), and WO2019/025588 (pending) and further reports patent young subjects. Light blue dots 12 h; medium blue dots 108 h; dark WO2012/013728 (issued in multiple countries), all assigned to Oryzon blue dots 72 h (SAD) or 192 h (MAD) after the first dose. Data are Genomics; is executive director and shareholder of Oryzon Genomics; presented as mean and standard error of the mean. Volunteers sam- and is a member of the Scientific Review Board of the Alzheimer’s pled at each dose: n = 6 except MAD 4 mg, n = 3. e, f Pharmacoki- Drug Discovery Foundation, for which no compensation is received. netic/pharmacodynamic relationship between exposure, as reflected by Cmax,ss or AUCss, and KDM1A TE. g, h Pharmacokinetic/phar- Ethics approval This study was registered under EUDRACT No. macodynamic relationship between exposure, as reflected by Cmax,ss 2015-003721-33 and carried out in accordance with the protocol or AUCss, and platelet dynamics (represented as % CFB levels). All CL01-ORY-2001 and good clinical practices (Declaration of Helsinki, values correspond to independent subjects. Calculated E ­ C50/EC80 guideline ICH CPMP/ICH/135/95, European Directive 2001/20/EC, values are also shown in the respective graphs. Light blue circles 0.2 and Spanish RD 561/1993 and RD 223/2004). The study protocol and mg; white squares 0.6 mg; light blue triangles 1 mg; white triangles informed consent forms were approved by the Spanish Agency for 1.5 mg; blue diamonds 2.5 mg; white circles 4 mg; full lines nonlin- Medicines and Health Products and the institutional review board. ear fit; dotted lines 95% confidence interval. Volunteers sampled at each dose: n = 6 except MAD 4 mg, n = 3. Samples that did not pass Consent to participate Written informed consent was obtained from quality control were omitted. AUC,ss area under the plasma concen- all candidate subjects participating in this study before any clinical tration–time curve at steady state, CFB change from baseline, Cmax,ss procedures were undertaken. maximum concentration at steady state, EC50 half maximal effective concentration, EC80 80% maximal effective concentration, ELISA Consent for publication The written informed consent allows publica- enzyme-linked immunosorbent assay, HRP horseradish peroxidase, tion of the data included in this manuscript. MAD multiple ascending dose, PBMCs peripheral blood mononuclear cells, SAD single ascending dose, SS steady state, TE target engage- Availability of data and material Materials can be obtained through ment a material transfer agreement upon reasonable request. The KDM1A Target Engagement Method validation protocol and report are available upon request. Access to the full trial protocol and clinical trial data can be obtained through a data-sharing agreement upon reasonable request Supplementary Information The online version contains supplemen- and in compliance with applicable laws. Contact the corresponding tary material available at https://d​ oi.o​ rg/1​ 0.1​ 007/s​ 40263-0​ 21-0​ 0797-x. author or email info@oryzon.com. Acknowledgements The authors are grateful to the volunteers who Code availability Not applicable. participated in this clinical trial. Open Access This article is licensed under a Creative Commons Attri- Declarations bution-NonCommercial 4.0 International License, which permits any non-commercial use, sharing, adaptation, distribution and reproduction Author contributions Conceptualization: RMA, TM, CMo, CB. For- in any medium or format, as long as you give appropriate credit to the mal analysis: MIA, RMA, JMF-C, JM-C, JC. Funding acquisition: CB, original author(s) and the source, provide a link to the Creative Com- TM. Investigation: RMA, JMF-C, JMC, JC, CMa, MIA. Methodology: mons licence, and indicate if changes were made. The images or other TM. Project Administration: CMo, RMA. Resources: RMA, JMF-C, third party material in this article are included in the article’s Creative JM-C, JC. Supervision: RMA, CMo. Visualization: MIA. Original Commons licence, unless indicated otherwise in a credit line to the draft preparation: RMA, TM, MIA. All authors contributed to the material. If material is not included in the article’s Creative Commons review and editing of this article. All authors approved the content of licence and your intended use is not permitted by statutory regula- the manuscript and take responsibility for the content of the article. tion or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this licence, visit Funding The open access fee was paid by Oryzon Genomics, S.A. This http://​creat​iveco​mmons.​org/​licen​ses/​by-​nc/4.​0/. study was funded by Oryzon Genomics, S.A. (the sponsor), and grant CIIP-20152001/E9683, EUROSTARS-2/CDTI, Spanish Ministry of Science, Innovation and Universities. References Conflict of interest RMA has received personal fees from Centre 1. Barter JD, Foster TC. Aging in the brain: new roles of epigenetics d’Investigació del Medicament, Institut de Recerca de l’Hospital de la in cognitive decline. Neuroscientist. 2018;24(5):516–25. Santa Creu© Sant Pau (IIB-Sant Pau) and Hospital de la Santa Creu i 2. Wood IC. The contribution and therapeutic potential of epi- Sant Pau, Barcelona, Spain. JMF-C, JC, MP, and JM-C have received genetic modifications in Alzheime’s disease. Front Neurosci. personal fees from Centre d’Investigació del Medicament, Institut de 2018;12:649. 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