A first-in-human study to investigate the safety, tolerability, pharmacokinetics, and pharmacodynamics of KM-819 (FAS-associated factor 1 inhibitor), a drug for Parkinson’s disease, in healthy volunteers

Figures & data

Figure 1 Study Design of the single ascending dose (SAD) study (A), and multiple ascending dose (MAD) study (B).

Notes: ^aBaseline; ^bRandomization and study drug administration; ^cStudy drug administration.

Table 1 Demographic characteristics of the study subjects

SAD study
Parameter (unit)	Placeboa (N=12)	KM-819
		10 mg (N=6)	30 mg (N=6)	100 mg (N=6)	200 mg (N=6)	400 mg (N=6)	200 mgb (N=6)
Age (years)	35.6 (19.8)	23.7 (6.3)	25.2 (7.6)	26.2 (5.0)	27.5 (6.4)	26.3 (4.1)	75.0 (5.8)
Height (cm)	172.0 (7.1)	175.5 (2.1)	175.2 (7.3)	175.3 (6.3)	176.8 (4.9)	177.2 (5.9)	167.5 (5.2)
Weight (kg)	69.5 (9.5)	70.5 (5.9)	68.3 (9.2)	70.8 (8.3)	77.1 (5.6)	71.4 (9.5)	70.6 (11.1)
BMI (kg/m^2)	23.6 (3.3)	22.9 (1.4)	22.3 (2.8)	23.0 (2.2)	24.7 (1.8)	22.7 (2.6)	25.1 (3.2)
MAD study
Parameter (unit)	Placeboa (N=12)	KM-819
		30 mg (N=6)	100 mg (N=6)	200 mg (N=6)	400 mg (N=6)	200 mgb (N=6)
Age (years)	38.5 (19.7)	27.5 (7.6)	30.2 (6.9)	28.7 (5.7)	22.5 (1.4)	72.8 (6.6)
Height (cm)	173.1 (7.6)	176.3 (2.3)	169.2 (10.9)	175.3 (5.3)	171.3 (3.9)	165.5 (4.8)
Weight (kg)	72.6 (14.2)	74.0 (8.9)	66.6 (6.3)	71.9 (8.6)	69.3 (6.6)	64.5 (1.7)
BMI (kg/m^2)	24.1 (3.5)	23.8 (3.2)	23.4 (2.8)	23.4 (2.7)	23.7 (2.9)	23.6 (1.7)

Notes: Data are shown as mean (SD).

a Subjects who received placebo within each cohort were pooled.

b Elderly male subjects.

Abbreviations: SAD, single ascending dose; MAD, multiple ascending dose; BMI, body mass index.

Table 2 Pharmacokinetic parameters of KM-819 in the SAD study

Parameter (unit)	KM-819 dose
	10 mg (n=6)	30 mg (n=6)	100 mg (n=6)	200 mg (n=6)	400 mg (n=6)	200 mga (n=6)
Cmax (ng/mL)	244.1 (31.4)	503.6 (28.0)	1,152 (36.7)	1,879 (55.3)	2,767 (43.4)	1,766 (26.0)
Tmax (h)	1.50 (0.50–2.00)	1.00 (0.50–2.00)	2.00 (1.00–4.00)	2.00 (1.00–4.00)	4.00 (2.00–4.00)	2.00 (1.0–4.00)
AUClast (ng·h/mL)	583.4 (24.5)	1,705 (17.1)	4,306 (31.1)	7,637 (47.7)	12,210 (33.3)	10,840 (10.3)
AUCinf (ng·h/mL)	594.2 (24.4)	1,731 (17.3)	4,872 (30.8)	7,338 (51.9)	12,640 (36.1)	10,970 (9.8)
t1/2 (h)	1.786 (28.3)	4.791 (25.0)	9.159 (41.2)	9.010 (71.6)	8.527 (63.2)	10.55 (28.5)
tlag (h)	0.00 (0.00–0.25)	0.00 (0.00–0.00)	0.00 (0.00–0.00)	0.00 (0.00–0.25)	0.00 (0.00–0.00)	0.00 (0.00–0.00)
CL/F (mL/h)	16,830 (24.4)	17,340 (17.3)	20,530 (30.8)	27,260 (51.9)	31,650 (36.1)	18,230 (9.8)

Notes: Data are shown as geometric mean (coefficient of variation%), except T_max and t_lag which are as median (min–max). The terminal phase rate-constant (λ_z) related pharmacokinetics parameters such as t_1/2 and AUC_inf were not estimated for 2 subjects in the 100 mg cohort, 1 subject in the 200 mg cohort and 1 subject in the 400 mg cohort, due to either the duration of time over which λ_z was estimated being less than 1.5-fold the subsequently estimated t_1/2 and/or the adjusted regression coefficient (R² adjusted) being less than 0.8.

a Elderly male subjects.

Abbreviations: SAD, single ascending dose; C_max, maximum plasma concentration; T_max, time to achieve C_max; AUC_last, area under the concentration-time curve (AUC) from time zero to the last quantifiable concentration; AUC_inf, AUC from time zero extrapolated to infinity; t_1/2, terminal elimination half-life; t_lag, lag time; CL/F, apparent oral clearance.

Figure 2 Mean plasma concentration-time profile of KM-819 in the single ascending dose (SAD) (A) and multiple ascending dose (MAD) (B) studies.

Note: ^aElderly subjects cohort.

Table 3 Pharmacokinetic parameters of KM-819 in the MAD study

Parameter (unit)	KM-819 dose (QD for 7 days)
	30 mg (n=6)	100 mg (n=6)	200 mg (n=6)	400 mg (n=6)	200 mga (n=6)
Day 1
Cmax (ng/mL)	512.0 (30.9)	1,009 (33.0)	1,465 (77.2)	3,163 (50.7)	3,542 (76.4)
Tmax (h)	2.00 (1.00–6.00)	2.00 (1.00–4.00)	3.00 (2.00–6.00)	2.00 (1.00–6.00)	2.00 (1.00–6.00)
AUC0–24 (ng·h/mL)	1,761 (21.3)	3,735 (38.5)	6,485 (62.2)	11,260 (37.1)	17,590 (53.3)
Day 7
Cmax,ss (ng/mL)	418.5 (51.7)	1,012 (39.5)	1,111 (64.3)	3,172 (37.9)	3,231 (52.5)
Cmin,ss (ng/mL)	NC	9.983 (31.1)	32.44 (19.4)	75.14 (28.4)	44.82 (48.3)
Tmax,ss (h)	2.00 (1.00–6.00)	3.00 (1.00–4.00)	4.00 (4.00–4.00)	2.00 (0.50–4.00)	2.00 (1.00–4.00)
AUCtau (ng·h/mL)	1,572 (24.8)	3,477 (17.9)	8,023 (7.7)	19,530 (96.4)	16,250 (34.1)
Rac (AUC)	0.8923 (0.70–1.13)	0.9727 (0.69–1.37)	0.7568 (0.57–1.00)	1.485 (0.86–2.56)	0.9241 (0.67–1.28)
Rac (Cmax)	0.8173 (0.53–1.26)	1.003 (0.73–1.39)	0.6227 (0.55–0.71)	1.117 (1.00–1.25)	0.9122 (0.53–1.58)

Notes: Data are shown as geometric mean (Coefficient of variation%), except T_max which is as median (min–max) and R_ac which is as geometric mean (95% confidence interval). The AUC_tau was not estimated for 1 subjects in the 100 mg cohort, 2 subject in the 200 mg cohort and 3 subject in the 400 mg cohort, due to either the duration of time over which terminal phase rate-constant (λ_z) being estimated was less than 1.5-fold the subsequently estimated t_1/2 and/or the adjusted regression coefficient (R² adjusted) being less than 0.8 and/or %AUCex (percentage of AUC_inf that is due to extrapolation beyond last sampling time point) was >40%.

a Elderly male subjects.

Abbreviations: MAD, multiple ascending dose; C_max, maximum plasma concentration; T_max, time to achieve C_max; AUC_0–24, area under the concentration-time curve (AUC) from time zero to 24 hours postdose; Cmax,ss, maximum plasma concentration at steady state; Cmin,ss, minimum plasma concentration at steady state; T_max,ss, time to achieve C_max,ss; AUC_tau, AUC over the dosing interval at steady state; R_ac (AUC), observed accumulation by AUC; R_ac (C_max), observed accumulation by C_max; QD, once daily; NC, not calculated.

Table 4 Assessment of dose proportionality of KM-819 pharmacokinetic parameters (power model)

Part	Day	Parameter	N	Estimated mean slope	95% CI
SAD	1	Cmax (ng/mL)	30	0.667	0.5644–0.7697
		AUClast (ng·h/mL)	30	0.8027	0.7166–0.8888
		AUCinf (ng·h/mL)	26	0.8233	0.7307–0.9158
MAD	1	Cmax (ng/mL)	24	0.6764	0.4702–0.8827
		AUC0–24 (ng·h/mL)	24	0.7157	0.5458–0.8856
	7	Cmax,ss (ng/mL)	22	0.7158	0.4918–0.9397
		Cmin,ss (ng/mL)	21	1.1852	1.0233–1.3471
		AUCtau (ng·h/mL)	16	0.9124	0.7227–1.1021

Abbreviations: SAD, single ascending dose; MAD, multiple ascending dose; C_max, maximum plasma concentration; AUC_last, area under the concentration-time curve (AUC) from time zero to the last quantifiable concentration; AUC_inf, AUC from time zero extrapolated to infinity; AUC_0–24, AUC from time zero to 24 hours postdose; _Cmax,ss, maximum plasma concentration at steady state; C_min,ss, minimum plasma concentration at steady state; AUC_tau, AUC over the dosing interval at steady state.

Table 5 Treatment emergent adverse events in the SAD and MAD studies

SAD study
Parameter (unit)	Placeboa (N=12)	KM-819
		10 mg (N=6)	30 mg (N=6)	100 mg (N=6)	200 mg (N=6)	400 mg (N=6)	200 mgb (N=6)
Subjects with any TEAEs	3 (25.0)	2 (33.3)	2 (33.3)	2 (33.3)	1 (16.7)	0	2 (33.3)
Eye swelling	1 (8.3)	0	0	0	0	0	0
Abdominal discomfort	0	0	0	0	1 (16.7)	0	0
Hyperbilirubinemia	0	2 (33.3)	0	1 (16.7)	0	0	0
Influenza	1 (8.3)	0	0	0	0	0	0
Face injury	0	0	0	0	0	0	1 (16.7)
Pain in extremity	0	0	1 (16.7)	0	0	0	0
Headache	1 (8.3)	0	0	0	0	0	2 (33.3)
Hypoesthesia	0	0	0	1 (16.7)	0	0	0
Syncope	0	0	1 (16.7)	0	0	0	0
Proteinuria	0	0	0	1 (16.7)	0	0	0
Cough	1 (8.3)	0	0	0	0	0	0
Hot flush	0	0	0	0	0	0	1 (16.7)
MAD study
Parameter (unit)	Placeboa (N=12)	KM-819
		30 mg (N=6)	100 mg (N=6)	200 mg (N=6)	400 mg (N=6)	200 mgb (N=6)
Subjects with any TEAEs	5 (50.0)	2 (33.3)	4 (66.7)	5 (83.3)	5 (83.3)	3 (50.0)
Erythema of eyelid	0	0	0	0	1 (16.7)	0
Abdominal discomfort	1 (10.0)	0	0	1 (16.7)	0	0
Abdominal pain	0	0	0	0	0	1 (16.7)
Diarrhea	1 (10.0)	0	0	0	0	1 (16.7)
Nausea	0	2 (33.3)	1 (16.7)	4 (66.7)	0	0
Vomiting	0	2 (33.3)	0	4 (66.7)	0	0
Hyperbilirubinemia	1 (10.0)	0	0	1 (16.7)	0	0
Back pain	3 (30.0)	0	2 (33.3)	1 (16.7)	1 (16.7)	2 (33.3)
Muscle hemorrhage	0	0	0	0	0	1 (16.7)
Musculoskeletal stiffness	0	0	0	1 (16.7)	1 (16.7)	0
Neck pain	0	0	0	0	0	1 (16.7)
Dizziness	2 (20.0)	1 (16.7)	1 (16.7)	2 (33.3)	0	0
Headache	2 (20.0)	2 (33.3)	1 (16.7)	5 (83.3)	4 (66.7)	1 (16.7)
Hypoesthesia	1 (10.0)	0	0	2 (33.3)	0	0
Anxiety	1 (10.0)	0	0	0	0	0
Insomnia	0	0	0	0	0	1 (16.7)
Epistaxis	0	0	0	0	1 (16.7)	0
Oropharyngeal pain	0	0	0	1 (16.7)	0	0
Erythema	1 (10.0)	0	0	0	0	0
Hyperhidrosis	1 (10.0)	0	0	0	1 (16.7)	0

Notes: Data are shown as number of subjects with adverse events (percentage calculated using the number of subjects in the safety population as denominator).

a Subjects who received placebo within each cohort were pooled.

b Elderly male subjects.

Abbreviations: SAD, single ascending dose; MAD, multiple ascending dose; TEAE, treatment-emergent adverse event.

Table S1 Inclusion and exclusion criteria for KM-819 first-in-human study

Inclusion criteria
1	Institutional Review Board (IRB)/Independent Ethics Committee (IEC) approved written informed consent and privacy language as per national regulations must be obtained from the subject prior to any study-related procedures (including withdrawal of prohibited medication, if applicable).
2	Male subjects should be between 19 and 45 years old (for young adult cohorts) or over 60 years old (for elderly cohorts).
3	Subject should have a body mass index (BMI) range of 18.5–30 kg/m^2 inclusive at screening.
4	Male subject and his female spouse/partner who is of childbearing potential must be using highly effective contraception consisting of 2 forms of birth control (at least one of which must be a barrier method) starting at screening and continuing throughout the study period and for 90 days after final study drug administration. Highly effective contraception is defined as: • Established use of oral, injected, or implanted hormonal methods of contraception • Placement of an intrauterine device or intrauterine system • Barrier methods of contraception: condom with spermicidal foam, gel, film, cream, suppository or occlusive cap (diaphragm or cervical/vault caps) with spermicidal foam, gel, film, cream, or suppository.
5	Male subjects must not donate sperm starting at screening, throughout the study period and for at least 90 days after final study drug administration.
6	Female subjects with child bearing age were excluded.
7	Subject agrees not to participate in another investigational study while on study treatment.
Exclusion criteria
1	Subject has a known or suspected hypersensitivity to KM-819, or any components of the formulation(s) used.
2	Subject has previously participated in a clinical study with KM-819.
3	Subject has any of the liver enzymes (aspartate aminotransferase, AST; alanine transaminase, ALT; alkaline phosphatase, γ-glutamyl transferase) or total bilirubin (TBIL) above the ULN. If any liver enzyme is >1 × ULN but <1.5 × ULN, the assessment may be repeated once during the screening period or on check-in. If the repeated assessment is above the ULN, it is exclusionary. If the initial value is >1.5 × ULN, it cannot be repeated and is exclusionary.
4	Subject has any clinically significant history of allergic conditions (including drug allergies, asthma, eczema, or anaphylactic reactions, but excluding untreated, allergic rhinitis or rhinoconjunctivitis, or house dust mite allergy at time of dosing).
5	Subject with a history of a suicide attempt or suicidal behavior. Any recent suicidal ideation (a level of 4 or 5) within the last 3 months, or having a positive C-SSRS at check-in (day −1), or who is at significant risk to commit suicide, as judged by the investigator using the C-SSRS at screening.
6	Subject has/had febrile illness or symptomatic viral, bacterial (including upper respiratory infection) or fungal (noncutaneous) infection within 1 week before site check-in.
7	Subject has any clinically significant abnormality following the investigator’s review of the physical examination, ECG, and protocol-defined clinical laboratory tests at screening or site check-in.
8	Subject has a mean pulse <40 or >90 beats per minute (bpm); mean SBP >140 mmHg; or mean DBP >90 mmHg (measurements taken in triplicate after subject has been resting in the supine position for 5 minutes; pulse will be measured automatically) at screening or check-in. If the mean pulse, mean SBP, or mean DBP is out of the range specified above, one additional triplicate measurement may be taken at screening and check-in.
9	Subject has a mean QTcF interval of >430 ms (for males) and >450 ms (for females) at screening or check-in. If the mean QTcF exceeds the limits above, one additional ECG can be taken. If this also gives an abnormal result, the subject should be excluded.
10	Subject has a history of unexplained syncope, cardiac arrest, unexplained cardiac arrhythmias or torsade de pointes, structural heart disease, or a family history of Long QT Syndrome.
11	Subject has use of any prescribed or non-prescribed drugs (including vitamins, hormone replacement therapy, natural and herbal remedies, eg, St John’s Wort) in the 2 weeks before study drug administration. Acetaminophen up to 2,000 mg/day is allowed.
12	Subject has had any use of tobacco- or nicotine-containing products within 6 months prior to screening.
13	Subject has history of consuming more than 14 units of alcoholic beverages per week within 6 months prior to screening or has a history of alcoholism or abuse of amphetamines, barbiturates, benzodiazepines, cannabinoids, cocaine, and opiates (drugs-of-abuse) within the past 2 years prior to screening (Note: 1 unit=355 mL of beer, 118 mL of wine, or 29 mL of spirits/hard liquor) or the subject tests positive at screening or site admission for alcohol or drugs-of-abuse.
14	Subject has used any drugs-of-abuse within 3 months before check-in.
15	Subject has used any inducers of metabolism (eg, barbiturates, rifampin) in the 3 months prior to check-in.
16	Subject has any significant blood loss, donated 1 unit (450 mL) of blood or more, or received a transfusion of any blood, or blood products within 60 days or donated plasma within 7 days before check-in.
17	Subject has a positive serology test for hepatitis B surface antigen (HbsAg), anti-hepatitis A virus Immunoglobulin M (HAV IgM), anti-hepatitis C virus (HCV Ab), or anti-human immunodeficiency virus (HIV Ab).
18	Subject has participated in any interventional clinical study or has been treated with any investigational drugs within 3 months or 5 half-lives, whichever is longer, before the initiation of screening.
19	Subject has (recent history of) any other condition which, in the opinion of the investigator, precludes the subject’s participation in the trial.
20	Subject is an employee of the Kainos Medicine, Inc. or vendors involved in the study.
21	Subject has any history or evidence of any clinically significant cardiovascular, gastrointestinal, endocrinologic, hematologic, hepatic, immunologic, metabolic, urologic, pulmonary, neurologic, dermatologic, psychiatric, renal, and/or other major disease or malignancy, as judged by the investigator or designee.
22	Elderly subject is excluded if the glomerular filtration rate (calculated based on Cockcroft–Gault formula) is <60 mL/min/1.73 m^2.
23	Clinically significant abnormal findings in the lumbar X-ray examination (only for elder subjects for MAD study).

Abbreviations: ULN, upper limit of normal; C-SSRS, Columbia Suicide Severity Rating Scale; ECG, electrocardiogram; MAD, multiple ascending dose.

Table S2 Summary of change from baseline (day 1 predose) to day 7 for PD parameters

Parameter (unit)	Placeboa (N=10)	KM-819
		30 mg (N=6)	100 mg (N=6)	200 mg (N=6)	400 mg (N=6)	200 mgb (N=6)
Alpha-synuclein oligomer, CSF (pg/mL)	20.30 (58.53)	49.94 (72.09)	−252.56 (643.49)	0.60 (18.22)	18.21 (103.83)	34.87 (51.42)
Alpha-synuclein oligomer,	−4,464.91	3,884.41	575.46 (18,379.46)	3,809.51	−64,843.29	−11,712.09
plasma (pg/mL)	(15,002.05)	(30,559.28)		(14,003.04)	(130,397.59)	(17,679.68)
Total tau, CSF (pg/mL)	20.82 (29.73)	60.30 (64.42)	9.23 (15.82)	−3.16 (15.01)	27.86 (66.07)	29.30 (100.07)
Phosphor-tau, CSF (pg/mL)	5.31 (7.89)	6.41 (19.04)	0.21 (1.13)	4.47 (7.88)	6.70 (11.82)	5.16 (10.88)

Notes: Data are shown as mean SD.

a Subjects who received placebo within each cohort were pooled.

b Elderly male subjects.

Abbreviation: CSF, cerebrospinal fluid.

Data availability

The raw data of this study will not be shared because of confidentiality.