Key words inflammation - biomarkers - pharmacokinetics
Introduction
Aging is tightly linked to chronic diseases such as neoplastic, cardiovascular,
neurodegenerative, metabolic, or autoimmune diseases, frailty, and death [1 ]
[2 ].
Preclinical studies have shown that lifespan and health span can be extended by
nutritional and pharmacological interventions. The first group includes fasting,
overall caloric restraint, restriction of specific nutrients such as the recent
branched amino acid [2 ]
[3 ], or supplementation of micronutrients. A
pharmacological approach is, however, desirable considering the low compliance of
the general population to dietary changes and the ever-expanding knowledge of the
pathways underlying aging [2 ]. Several drugs
have been researched for this indication, such as SIRT activators, polyphenols,
metformin, rapamycin, and senolytics, capable of inducing apoptosis in senescent
cells, and blockers of telomere shortening [2 ].
Isomyosamine, an isomer of myosmine, is a synthetic alkaloid derived from tobacco
plant, which has been shown to inhibit the production and release of cytokines,
including IFN-γ, IL-2, IL-10, and TNF-α, from human peripheral blood
mononuclear cells in a dose-dependent manner [4 ]. TNF-α is the protein in the body that causes inflammation and
helps activate the process of aging. In preclinical studies and recently published
reports, Isomyosamine could suppress in vitro the release of TNF-α from
splenic CD4 T cells and reducing disease incidence and severity in mouse models of
autoimmune thyroiditis and multiple sclerosis [2 ]
[4 ], in the absence of measurable
toxicity. These models, based on a relatively short administration (12 weeks for
thyroiditis and 3 weeks for experimental autoimmune encephalomyelitis; EAE),
included the mechanism of reducing the number of infiltrating Th1 CD4 T cells and
follicular B cells [4 ]
[5 ]
Isomyosamine also holds significant promise in other autoimmune conditions such as
Rheumatoid Arthritis. Aging brings about a diminished capacity of the tissues to
remodel, predisposing to fibrotic diseases like pulmonary, cardiac, and renal
fibrosis [6 ]. Therapies endowed with both
anti-inflammatory and anti-fibrotic actions, thus, represent a compelling,
synergistic strategy to ameliorate age-related conditions. Aging and age-related
diseases represent a therapeutic goal for senolytics and drugs targeting
inflammatory or metabolic pathways. In vitro BioMAP profile analysis of Isomyosamine
with reference benchmarks has shown that Isomyosamine exhibits similar biological
activities to mTOR inhibitors everolimus and sirolimus owing to their largely
overlapping mechanisms of action [7 ].
The ease of Isomyosamine oral dosing is a groundbreaking differentiator compared to
currently available TNF-α blockers, all of which require delivery by
injection or infusion. No approved TNF inhibitor has ever been dosed orally. The
second and third key differentiators are selectivity and low toxicity. Unlike other
therapies, Isomyosamine is designed to selectively block TNF-α when it
becomes overactivated in autoimmune diseases and cytokine storms, but not to block
it from doing its normal job of being a first responder to any routine type of
moderate infection. In addition, the drug is not immunosuppressive and has not been
shown to cause serious side effects common with traditional therapies that treat
inflammation [8 ]. The current phase 1 study
was conducted to further evaluate the safety, tolerability, and pharmacokinetic (PK)
of Isomyosamine over the single and multiple dose ranges in healthy male and female
adult subjects. The exploratory aims included the quantification of the relationship
between plasma concentrations of Isomyosamine and change-from-baseline QTcF,
corrected QT interval by Frederica, and to assess the biomarkers, pyridyloxobutyl
(POB) adducts in hemoglobin and TNF-α after oral dose of Isomyosamine.
Materials and Methods
This phase 1, double-blind, placebo-controlled, randomized single ascending, and
multiple dose study was conducted in healthy adult subjects at a single center.
Institutional review board approval was received by ADVARRA, and this trial was
performed under IND#138161. The study consisted of 2 parts: single ascending dose
(SAD) and multiple ascending dose (MAD). Dosing levels for SAD were 150 mg
(Cohort 1), 300 mg (Cohort 2), and 450 mg (Cohort 3) and for MAD was
600 mg (Cohort 4). In each cohort, a total of 8 subjects were randomized to
receive either Isomyosamine (N=6) or placebo (N=2) for a total of 32
subjects for the entire study. The SAD cohorts consisted of 17 (70.8%) males
and 7 (29.2%) females) whereas the MAD cohort consisted of 3 (37.5%)
males and 5 (63.5%) females. The SAD cohorts ages ranged from 22–64
years of age whereas the MAD cohort consisted of ages ranging from 28–50
years of age ([Tables 1 ] and [2 ]). Each subject participated in the study
for approximately 8 weeks, including a screening period of up to 30 days, a
confinement period in the clinic (3- or 6-days post administration), SAD and MAD
respectively, end of study (EOS) on Day 8 or 11, and a telephone follow-up 5 days
after EOS. The subjects were administered a single dose or multiple doses of either
Isomyosamine or placebo, each subject participated in only one of the four cohorts
during the study ([Figs. 1 ] and [2 ]). Measurements of QTC intervals
were derived from overread ECGs measured in triplicates by the Investigator at the
respective clinical site. Concentrations of Isomyosamine in plasma and urine were
determined by validated liquid chromatography with tandem mass spectrometry
(LC-MS/MS) analytical methods (Keystone Bioanalytical, Inc., North Wales,
PA). An LC-MS/MS procedure (M190307.00) has been developed for the
quantification of Myridine in K2 EDTA human plasma using Turbo Ionspray
LC-MS/MS. In summary, myridine and the internal standard (amphetamine-d5)
are isolated from human K2 EDTA plasma by protein precipitation (methanol
is used as solvent). After shaking and centrifuging, 20 μL of the
supernatant is transferred into a plastic injection vial containing
100 μL of water. The vial is capped and vortexed for
60 seconds. A total of 5–20 μL injection volume is
used for LC-MS/MS analysis. The stability parameters include reinjection
stability of extracted samples for up to 51.5 hours at 10°C;
refrigeration stability of extracted samples for up to 53.5 hours at
2–8°C; bench-top stability of unextracted samples for up to
6.9 hours in ice-water; and freeze-thaw stability for up to four freeze-thaw
cycles at −70°C, and long-term storage stability for up to 98 days
at −70°C, which is enough to cover the maximum sample storage period
(92 days) [9 ].
Fig. 1 Study Schema – Single Dose.
Fig. 2 Study Schema – Multiple Dose.
Table 1 Demographics and Baseline Characteristics –
Single Ascending Dose (Safety Analysis Set)
Isomyosamine
Variable/ Category
Statistic
Placebo (N=6)
150 mg (N=6)
300 mg (N= 6)
450 mg (N=6)
All Subjects (N=24)
Sex
Male
n (%)
3 (50.0)
5 (83.3)
4 (66.7)
5 (83.3)
17 (70.8)
Female
n (%)
3 (50.0)
1 (16.7)
2 (33.3)
1 (16.7)
7 (29.2)
Race
White
n (%)
3 (50.0)
5 (83.3)
6 (100.0)
2 (33.3)
16 (66.7)
Black or African American
n (%)
3 (50.0)
1 (16.7)
0
4 (66.7)
8 (33.3)
Age (years)
n
6
6
6
6
24
Mean
39.5
48.8
50.7
38.0
44.3
SD
15.4
10.5
8.6
13.3
12.8
CV%
39.1
21.4
17.1
35.1
28.8
Minimum
22
34
34
24
22
Median
41
53
53
38
46
Maximum
64
59
58
57
64
WOCBP
No
n (%)
0
1 (100.0)
2 (100.0)
1 (100.0)
4 (57.1)
Yes
n (%)
3 (100.0)
0
0
0
3 (42.9)
Ethnicity
Hispanic or Latino
n (%)
3 (50.0)
2 (33.3)
2 (33.3)
1 (16.7)
8 (33.3)
Not Hispanic or Latino
n (%)
3 (50.0)
4 (66.7)
4 (66.7)
5 (83.3)
16 (66.7)
Height (cm)
n
6
6
6
6
24
Mean
168.98
177.68
174.18
170.18
172.76
SD
7.91
14.31
6.61
6.22
9.40
CV%
4.7
8.1
3.8
3.7
5.4
Minimum
162.6
162.6
162.6
165.1
162.6
Median
165.1
171.1
174.6
167.7
171.1
Maximum
180.3
198.1
180.3
177.8
198.1
Weight (kg)
n
6
6
6
6
24
Mean
81.57
83.43
83.47
74.87
80.83
SD
12.74
20.46
10.90
9.59
13.60
CV%
15.6
24.5
13.1
12.8
16.8
Minimum
63.1
54.1
71.3
64.9
54.1
Median
78.9
79.6
81.4
74.8
77.8
Maximum
99.8
114.8
95.8
91.9
114.8
BMI(kg/m **2)
n
6
6
6
6
24
Mean
28.35
26.17
27.63
25.48
26.91
SD
2.53
3.43
2.81
2.21
2.84
CV%
8.9
13.1
10.2
8.7
10.6
Minimum
23.7
20.6
23.3
23.0
20.6
Median
28.7
26.6
28.2
25.2
27.1
Maximum
30.7
31.1
30.8
28.7
31.1
Note(s): BMI=body mass index; CV%=coefficient of
variation; SD=standard deviation; WOCBP=woman of
childbearing potential. Percentage of woman of childbearing potential are
based on the number of female subjects.
Table 2 Demographics and Baseline Characteristics –
Multiple Dose (Safety Analysis Set)
Isomyosamine
Variable/ Category
Statistic
Placebo(N=2)
600 mg (N=6)
All Subjects (N=8)
Sex
Male
n (%)
0
3 (50.0)
3 (37.5)
Female
n (%)
2 (100.0)
3 (50.0)
5 (62.5)
Race
White
n (%)
1 (50.0)
4 (66.7)
5 (62.5)
Black or African American
n (%)
1 (50.0)
2 (33.3)
3 (37.5)
Age (years)
n
2
6
8
Mean
ND
39.2
38.4
SD
ND
10.2
8.7
CV%
ND
26.0
22.8
Minimum
36
28
28
Median
ND
39
36
Maximum
36
50
50
WOCBP
No
n (%)
0
0
0
Yes
n (%)
2 (100.0)
3 (100.0)
5 (100.0)
Ethnicity
Hispanic or Latino
n (%)
0
3 (50.0)
3 (37.5)
Not Hispanic or Latino
n (%)
2 (100.0)
3 (50.0)
5 (62.5)
Height (cm)
n
2
6
8
Mean
ND
169.50
169.99
SD
ND
8.53
7.30
CV%
ND
5.0
4.3
Minimum
170.2
160.0
160.0
Median
ND
168.1
170.2
Maximum
172.7
182.9
182.9
Weight (kg)
n
2
6
8
Mean
ND
67.98
70.43
SD
ND
8.65
10.58
CV%
ND
12.7
15.0
Minimum
66.2
56.5
56.5
Median
ND
66.2
67.3
Maximum
89.3
80.6
89.3
BMI(kg/m**2)
n
2
6
8
Mean
ND
23.77
24.36
SD
ND
4.63
4.47
CV%
ND
19.5
18.3
Minimum
22.7
18.2
18.2
Median
ND
23.6
24.0
Maximum
29.6
30.4
30.4
Note(s): BMI=body mass index; CV%=coefficient of
variation; SD=standard deviation; WOCBP=woman of
childbearing potential; ND=not determined. Percentage of woman of
childbearing potential are based on the number of female subjects.
Summary Statistics and Treatment Summarization
Approximately 32 subjects were to be enrolled in this study ([Figs. 1 ] and [2 ]). A total of 4 cohorts with size of 8
(6 active:2 placebo) were explored and considered adequate for characterizing
the endpoints planned in this study. No formal sample size calculation was
performed for exploratory outcomes as described in the protocol. The sample size
is typical for this type of study and was approved by the regulatory agency
(FDA) to serve the primary objective of this clinical study (safety and
tolerability). Qualitative variables, population size (N for sample size and n
for available data) and percentages (of available data for each class of the
variable) were presented ([Tables 1 ] and
[2 ]). Quantitative non-PK variables
were summarized using descriptive statistics, including N, n, mean, standard
deviation (SD), coefficient of variation (CV%), median, minimum, and
maximum values [Table 3 ]).
Pharmacokinetic concentrations (plasma only) and parameters (plasma and urine)
were summarized using descriptive statistics, including N, n, arithmetic mean,
SD, CV%, median, minimum, and maximum. In general, the tables, figures,
and listings were presented separately by study part (SAD/MAD), if not
otherwise specified. Non-PK data were presented for each treatment group with
placebo subjects from all treatment groups combined into a single, overall
placebo group. Non-PK data for all active-treated or all subjects combined were
also presented when appropriate. Pharmacokinetic data were presented for active
treatment groups. Geometric mean and geometric CV% were additionally
included for PK parameters, where applicable. In contrast, tmax was
only summarized using N, n, median, minimum, and maximum.
Table 3 Descriptive Statistics for Isomyosamine Plasma
Pharmacokinetic Parameters by Cohort and Dose – SAD and MAD
(Pharmacokinetic Analysis Set)
Cohort/Dose Statistic
AUC(0-inf) (ng·h/mL)
AUC(0-last) (ng·h/mL)
AUC(0–24) (ng·h/mL)
Cmax (ng/mL)
tmax
a (h)
t1/2 (h)
CL/F (L/h)
Vz /F (L)
Cavg (ng/mL)
FI (%)
RAUC
RCmax
LI
SAD Cohorts Cohort 1/150 mg
n
0
5
5
5
5
0
0
0
–
–
–
–
–
Geo Mean
NC
5.213
6.491
2.9019
1.02
NC
NC
NC
–
–
–
–
–
Geo CV%
NC
160.3
183.1
45.0
(0.48, 8.00)
NC
NC
NC
–
–
–
–
–
Cohort 2/300 mg
n
3
6
6
6
6
3
3
3
–
–
–
–
–
Geo Mean
7.175
6.246
6.521
13.3595
0.25
0.3971
41810
23960
–
–
–
–
–
Geo CV%
14.2
21.4
20.5
32.7
(0.25, 0.50)
61.9
14.2
81.0
–
–
–
–
–
Cohort 3/450 mg
n
5
6
6
6
6
5
5
5
–
–
–
–
–
Geo Mean
20.04
14.49
15.19
26.0582
0.25
0.2226
22450
7211
–
–
–
–
–
Geo CV%
358.0
362.4
342.5
486.3
(0.25, 0.55)
24.0
358.0
445.0
–
–
–
–
–
MAD Cohort
Cohort 4/600 mg (Day 1)
n
5
6
6
6
6
5
5
5
–
–
–
–
–
Geo Mean
19.74
15.50
17.60
26.7205
0.26
0.7145
30390
31320
–
–
–
–
–
Geo CV%
83.7
90.5
81.7
142.4
(0.25, 0.52)
60.5
83.7
179.0
–
–
–
–
–
Cohort 4/600 mg (Day 5)
n
0
6
6
6
6
4
6
4
6
6
6
6
5
Geo Mean
NC
25.32
27.12
32.0875
0.50
0.5485
22130
18110
1.130
2840
1.541
1.201
1.272
Geo CV%
NC
50.1
48.3
64.4
(0.25, 0.50)
89.2
48.3
98.2
48.3
40.1
97.5
225.0
92.7
a Median (minimum, maximum) are displayed for tmax .
Note(s): CV%=coefficient of variation;
Geo=geometric; NC=not calculated; SD=standard
deviation.
Pharmacokinetic Analyses: Plasma PK parameters were calculated for Isomyosamine
for each treatment using noncompartmental methods. Isomyosamine plasma
concentrations and PK parameters were listed and summarized using descriptive
statistics ([Figs. 3 ] and [4 ]). Area under the plasma
concentration-time curve (AUC) was quantified from time zero extrapolated to
infinity, last, and 24 hours (ng*h/mL). AUC was
calculated by linear up/log down trapezoidal summation for zero to last
timepoint. AUC for zero to infinity was calculated by linear up/log down
trapezoidal summation and extrapolated to infinity by addition of the last
quantifiable observed concentration divvied by the elimination rate constant.
AUC for zero to 24 hours was calculated by linear up/log down
trapezoidal summation and extrapolated/interpolated to the nominal time
of 24 hours. Concentration-QTc Analysis: The relationship between plasma
concentration of Isomyosamine and change-from-baseline QT interval corrected
using Fridericia’s formula (QTcF) was investigated by mixed-effects
modeling ([Fig 5 ]). The software use to
the complete the mixed modeling for Concentration-QTc analysis (as well as all
summaries, listings, and graphs) for this study us SAS Version 9 (SAS Institute,
Cary NC).
Fig. 3 Mean (±SD) Single-dose Isomyosamine Plasma
Concentrations versus Scheduled Time by Dose – (SAD and MAD Day
1) (Pharmacokinetic Analysis Set).
Fig. 4 Mean (±SD) Single-dose and Multiple-dose
Isomyosamine Plasma Concentrations versus Scheduled Time (MAD Day 1 and
Day 5) (Pharmacokinetic Analysis Set).
Fig. 5 Change-from-baseline QTcF versus MYMD1 Plasma Concentration
with Population Regression Line and 90% Confidence Band - Day 1
(Concentration- QTc and Pharmacokinetic Analysis Set).
Safety Analysis: All safety data were listed by subject. Treatment-emergent
adverse events (AEs) were summarized for each treatment by system organ class,
preferred term, maximum intensity, and relationship to test article ([Tables 4 ] and [5 ]). There were no statistical comparisons
between the treatment groups for safety data.
Table 4 Overall Summary of All Treatment-emergent Adverse
Events – Single Ascending Dose (Safety Analysis
Set)
Isomyosamine
Placebo (N=6)
150 mg (N=6)
350 mg (N=6)
450 mg (N=6)
All Active (N=18)
TEAS
0
1 (16.7%)
0
0
1 (5.6%)
Related TEAs
0
0
0
0
0
Severe TEAs
0
0
0
0
0
Serious TEAs
0
0
0
0
0
TEAEs leading to discontinuation
0
0
0
0
0
TEAEs leading to death
0
0
0
0
0
Note(s): TEAE=treatment-emergent adverse event. A subject
experiencing multiple occurrences of an adverse event in a category was
counted, at most, once for that category for each treatment and once for
“All Active”.
Table 5 Overall Summary of All Treatment-emergent Adverse
Events – Multiple Ascending Dose (Safety Analysis
Set)
Isomyosamine
Placebo (N=2)
600 mg (N=6)
TEAS
1 (50%)
3 (50%)
Related TEAs
0
3 (50%)
Severe TEAs
0
0
Serious TEAs
0
0
TEAEs leading to discontinuation
0
0
TEAEs leading to death
0
0
Note(s): TEAE=treatment-emergent adverse event. A subject
experiencing multiple occurrences of an adverse event in a category was
counted, at most, once for that category for each treatment and once for
“All Active”.
Analysis Sets
All Subjects Enrolled Analysis Set: All subjects signed the informed consent
form; this set was used primarily for subject accounting purposes. Safety
Analysis Set: The safety analysis set contained all subjects randomly assigned
to study treatment and who took at least 1 dose of study treatment and were
analyzed according to the actual treatment received. Subjects in this population
were used for all demographics, safety, and dosing summaries. Biomarker, PK
listings, PK parameter derivations, and plots of individual concentration-time
data were also based on the Safety Analysis Set. Pharmacokinetic Analysis Set:
This set consisted of all subjects who took at least one dose of active drug
(Isomyosamine) and had at least 1 quantifiable concentration collected post dose
without events (protocol deviations) thought to significantly affect the PK
sample. Subjects were analyzed according to actual treatment received. The PK
summaries were based on this set. All the protocol deviations reported in SAD
part were either study procedures criteria or laboratory assessment criteria and
all were minor and were not expected to have any impact on the study outcome. No
protocol deviations were reported in MAD part. There was no COVID-19 impact on
the protocol deviations. Biomarker Analysis Set: This set consisted of all
subjects who had at least 1 quantifiable concentration collected post dose
without deviations or events that significantly affect the biomarker endpoint.
Subjects were analyzed according to actual treatment received. Concentration-QTc
(C-QTc) Analysis Set: This set consisted of all subjects who took at least one
dose of active drug (Isomyosamine) and had at least 1 evaluable baseline and 1
evaluable post dose electrocardiogram (ECG) endpoint (QTc) without protocol
deviations or events that would affect the C-QTc analysis. The C-QTc analyses
were based on this set.
Results
Disposition and Demography
A total of 32 subjects were enrolled across four cohorts. Twenty-four subjects on
Isomyosamine (six per cohort) and eight subjects on placebo (2 per cohort) were
randomized in the SAD (Cohorts 1–3) and MAD (Cohort 4). Of the 24
subjects randomized in SAD part, 23 (95.8%) completed the study. One
subject was unable to complete the follow-up phone call. All the 8 subjects
randomized in the MAD part completed the study.
In SAD part, most of the subjects were white and not Hispanic or Latino (16
[66.7%]) and males (17 [70.8%]). In MAD part, most of the
subjects were white and not Hispanic or Latino (5 [62.5%]) and females
(5 [62.5%]; ([Tables 1 ] and [2 ]).
Pharmacokinetic Results
Absorption of Isomyosamine was rapid following a single dose administered in both
the SAD and MAD portions of the study. Following a single 150 mg dose of
Isomyosamine, median tmax was approximately 1 hour. Median
tmax following single doses of 300 mg to 600 mg,
was approximately 15 minutes. Over the SAD Isomyosamine dose range of
150 mg to MAD 600 mg (4-fold increase in dose), geometric mean
AUC(0-last) and Cmax values increased approximately
3-fold and 9-fold, respectively. A 2-fold increase in dose from 300 mg
to 600 mg resulted in an approximate 2.5-fold and 2-fold increase in
geometric AUC(0-last) and Cmax , respectively. Isomyosamine
geometric mean half-life following a single dose in both the SAD and MAD
portions of the study ranged from approximately 15 minutes to
45 minutes following doses from 300 mg to 600 mg. In the
MAD portion of the study, 600 mg administered once daily for 5 days
resulted in an approximate 20% to 50% rate of accumulation
relative to exposure following a single 600 mg dose (based on geometric
mean accumulation ratios for Cmax and AUC, respectively). Following
Isomyosamine 600 mg administered once daily for 5 days, the half-life
was approximately 30 minutes. The linearity index (LI) was just slightly
larger than unity providing evidence. Isomyosamine PK is time independent. In
the SAD portion of the study, less than 0.02% of a Isomyosamine dose was
excreted in urine following a single dose of 150 mg to 450 mg.
No subject receiving a single dose of Isomyosamine of 150 mg to
450 mg had N-nitrosonornicotine detected in urine and only three
subjects had 4-(Methylnitrosamino)-1-(3-pyridyl)-1-butanol (NNAL)
nicotine-derived nitrosamine ketone detected in urine following a single dose of
Ismoyosamine. These quantifiable levels of NNAL nicotine-derived nitrosamine
ketone were observed from 32 hours to 48 hours post dose only.
Placebo subjects were not part of this analysis. In the MAD portion of the
study, less than 0.03% of the 600 mg Isomyosamine single dose
was excreted in the urine on Day 1 and less than 0.02% of the
600 mg Isomyosamine daily dose was excreted on Day 5. No subject had
N-nitrosonornicotine detected in urine on Day 1 or Day 5. Only one subject had
NNAL nicotine-derived nitrosamine ketone detected in urine following a single
dose on Day 1 and no subjects had detectable levels on Day 5.
Concentration-QTcF Results
A non-significant exposure-response relationship was observed between
Isomyosamine concentration (p value for slope=0.3523 and the
corresponding 90% CI included zero) over the Isomyosamine dose range
evaluated and change-from-baseline QTcF. The magnitude of the slope combined
with its direction (slope estimate=0.008469) would not be indicative of
a cause for concern. Changes predicted in QTcF at geometric mean Cmax
values (range of −1.54 msec to -−1.34 msec) were small and
negative for all Isomyosamine doses; upper 90% confidence limits ranged
from 0.07 msec to 0.26 msec.
Safety Results
Isomyosamine single doses each of 150 mg, 300 mg, and
450 mg and multiple doses of 600 mg were safe and well tolerated
in healthy subjects. There were no new or unexpected safety findings reported in
this study.
No AE leading to discontinuation, severe AEs, serious AEs, or deaths were
reported during the study.
One subject in 150 mg group (SAD) had mild headache, 1 subject in
the placebo group (MAD) had moderate vulvovaginal mycotic infection and
3 subjects in 600 mg group (MAD) had mild AEs of dysgeusia.
Analyses of laboratory parameters, vital sign, ECG, and physical findings
did not reveal any clinically relevant effect of Isomyosamine.
In one dose group (150 mg), there was a decrease in TNF-α
levels found in Isomyosamine treated subjects, but no change in the
levels in subjects given placebo (p=0.05).
Biomarker Results
In both SAD and MAD parts, minor fluctuations were reported in cytosine, guanine,
deoxyguanosine, thymidine, butanone, and TNF-α values, but due to the
small sample size, there are no conclusions that can be ascertained. One dose
group treated with Isomyosamine had a decrease in TNF- α, with no change
reported in levels in subjects receiving placebo.
Discussion and Conclusion
Discussion and Conclusion
This report details the phase 1 clinical trial as part of the clinical development
program of Isomyosamine to evaluate the safety, tolerability, and pharmacokinetic
(PK) profile over the single and multiple dose ranges in healthy male and female
adult subjects. Isomyosamine single doses each of 150 mg, 300 mg,
and 450 mg and multiple doses of 600 mg were safe and well tolerated
in healthy subjects. The increase in Isomyosamine exposure was proportional to dose
across the dose range of 300 mg to 600 mg when administered as a
single dose. There was minimal accumulation of Isomyosamine following 5 days of once
daily dosing of Isomyosamine 600 mg. Isomyosamine half-life ranged from
approximately 15 minutes to 45 minutes across all doses in the SAD
and MAD portion of the study and the renal pathway is a minor route of elimination
for Isomyosamine. A non-significant exposure-response relationship was observed
between Isomyosamine concentration (p value for slope=0.3523 and the
corresponding 90% CI included zero) over the Isomyosamine dose range
evaluated and change-from-baseline QTcF. The magnitude of the slope combined with
its direction (slope estimate=−0.008469) would not be indicative of
a cause for concern. Changes predicted in QTcF at geometric mean Cmax values (range
of −1.54 msec to −1.34 msec) were small and negative for all
Isomyosamine doses; upper 90% confidence limits ranged from 0.07 msec to
0.26 msec. There was no significant relationship between Isomyosamine concentration
and change-from-baseline QTcF. Changes predicted in QTcF at geometric mean
Cmax values (range of −1.54 msec to −1.34 msec) were
small and negative for all Isomyosamine doses.
Limitations and Future Research
Common in Phase 1 clinical trials and per protocol, this study included a small
sample size limiting the ability to have adequate power to analyze exploratory
endpoints. Additionally, the population consisted of more white and male
subjects, however, these characteristics were well-balanced across cohorts. The
sample size was adequate for the purpose of determining safety and tolerability
in humans to permit continuation by regulatory authorities for the clinical
development of the novel therapeutic compound.
Isomyosamine has been investigated in vitro and in animal models suggesting
various mechanisms and potential indications for development. A study utilizing
a mice model of spontaneous thyroiditis suggests that Isomyosamine ameliorates
thyroiditis acting on specific lymphoid subsets via the reduction of Th1
responses and TNF-a release [4 ]. Another
study in mice and in vitro showed improvement of the course of experimental
autoimmune encephalomyelitis (EAE) induced by immunization with myelin
oligodendrocyte glycoprotein and suppressed activation of effector T cells
without causing global immunosuppression or toxicity [5 ]. Lastly, most recently, a researchers in
vitro and in vivo concluded that Isomysoamine possessed anti-proliferative,
anti-inflammatory, and anti-fibrotic properties that were more inhibitive than
rapamycin and resulted in improved mice health span characteristics (milder body
weight loss, greater muscle strength, and slower progression to frailty) [7 ]. The prior in vitro and in vivo research
in combination with the current trial in humans lays the foundation for future
support and testing of Isomyosamine as a potential treatment for autoimmune
diseases. Isomyosamine is now under investigation in a phase 2 trial targeting
the sarcopenia/frailty as the indication with future plans to perform
clinical trials for other indications, specifically treatment of
hashimoto’s thyroiditis and rheumatoid arthritis.
In conclusion, Isomysoamine single doses each of 150 mg, 300 mg,
and 450 mg, and multiple doses of 600 mg were safe and well
tolerated in a healthy population supporting the advancement of clinical
development of this compound for various autoimmune diseases.
