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Real world evidence for the efficacy of deuterium
depletion and the possibilities of its integration to
conventional therapies
Gábor Somlyai PhD
HYD LLC. & HYD Pharma Inc.
Budapest, Hungary
Challenges in the pharmaceutical industry
If pharma industry will continue anticancer drug
development focusing on targeted drug therapy, the
challenge of cancer treatment will remain with us for
decades.
Deuterium depletion is a completely different
approach to treat and prevent cancer
There are two ways of collecting data to prove the efficacy and safety:
➢Double blind, randomized phase 2-3 clinical trials (prospective study)
➢Observational data/real world data/real world evidence (retrospective
study)
•The US Food and Drug Administration defines RWE as “data regarding the usage, or
the potential benefits or risks, of a drug derived from sources other than traditional
clinical trials.”
•real-world data (RWD) as “data relating to patient health status and/or the delivery
of health care routinely collected from a variety of sources.”
(https://jamanetwork.com/journals/jamaoncology/article-
abstract/2733797https://jamanetwork.com/journals/jamaoncology/article-abstract/2733797)
DDW –Prospective clinical trial –
Prostate cancer
Human phase 2, double blind, randomized clinical
trial on prostate cancer ‒Prospective study)
44 evaluated patients (22 treated, 22 control)
Duration of treatment: 4 months
Treated group:
conventional treatment + DDW 85 ppm D
Placebo group:
conventional treatment + placebo 150 ppm D
0
100
200
300
400
500
600
406.4
521
80.3
277.4
PSA (ng/mL)
treated group control group
Cumulative PSA decreased by 80% in treated
vs. 47% in placebo group
Before
treatment
After
treatment
A. Kovacs et al., (2011) Journal of Cancer Therapy 2, 548-556
DDW-treated group had a significant decrease in prostate
volume from baseline to the last treatment visit compared to
placebo
Before treatment
After treatment
-160 cm3
-54 cm3
p= 0.0019
Treated group Control group
A. Kovacs et al., (2011) Journal of Cancer Therapy 2, 548-556 8
Survival was longer, death rate was lower in the DDW-
treated group (one-year survival)
Alive Death
Cumulated efficacy Alive Dead
Treated group 20 (91%) 2 (9%)
Control group 13 (59%) 9 (41%)
Death rate p=0.034
Survival p=0.029
A. Kovacs et al., (2011) Journal of Cancer Therapy 2, 548-556
9
DDW –Retrospective human clinical studies
Definition of median survival time (MST)
The
length of time from either the diagnosis or
the
treatment
of a disease, such as cancer, to the point
at
which
half of the patients diagnosed with the
disease
are
still alive.
In
a clinical trial, measuring the median survival time
is
one
way to see how well a new treatment works.
DDW –Retrospective study –
Prostate cancer
91 patients
46 patients
had distant
metastasis
during the
follow-up
33 patients:
the
metastasis
was limited to
the bone
32 patients had
adenocarcinoma
20 patients: the
bone metastasis
appeared within
1 year from the
diagnosis (DDW
started after the
diagnosis of the
bone metastasis)
12 patients: the
bone metastasis
appeared later
than 1 year from
the diagnosis
1patient had
anaplastic
adenocarcinoma
10 patients had
metastasis in other
organ (liver, lung,
bladder, etc.)
3patients had secondary tumor
45 patients
were free of
metastasis
Subgroups of prostatic cancer patients
in the retrospective study
A. Kovacs et al., (2011) Journal of Cancer Therapy 2, 548-556
Kaplan Meier survival curve in the subgroup of DDW-treated
patients (20), who developed bone metastasis within 1 year
from the diagnosis of prostate cancer
DDW
MST: 64.8 months
Three-fold increase
Historical control
MST: 15-20 months
A. Kovacs et al., (2011) Journal of Cancer Therapy2, 548-556
91 patients
46 patients
had distant
metastasis
during the
follow-up
33 patients:
the
metastasis
was limited to
the bone
32 patients had
adenocarcinoma
20 patients: the
bone metastasis
appeared within
1 year from the
diagnosis (DDW
started after the
diagnosis of the
bone metastasis)
12 patients: the
bone metastasis
appeared later
than 1 year from
the diagnosis
1patient had
anaplastic
adenocarcinoma
10 patients had
metastasis in other
organ (liver, lung,
bladder, etc.)
3patients had secondary tumor
45 patients
were free of
metastasis
Subgroups of prostatic cancer patients
in the retrospective study
A. Kovacs et al., (2011) Journal of Cancer Therapy 2, 548-556
Kaplan Meier survival curve in the subgroup of DDW-treated
patients (12), who developed bone metastasis later than one
year from the diagnosis of prostate cancer
MST: not calculable
Cumulative follow-up period
was 103 years, 2 patients
died out of 12
(1 death case/51.5 years)
A. Kovacs et al., (2011) Journal of Cancer Therapy2, 548-556
91 patients
46 patients
had distant
metastasis
during the
follow-up
33 patients:
the
metastasis
was limited to
the bone
32 patients had
adenocarcinoma
20 patients: the
bone metastasis
appeared within
1 year from the
diagnosis (DDW
started after the
diagnosis of the
bone metastasis)
12 patients: the
bone metastasis
appeared later
than 1 year from
the diagnosis
1patient had
anaplastic
adenocarcinoma
10 patients had
metastasis in other
organ (liver, lung,
bladder, etc.)
3patients had secondary tumor
45 patients
were free of
metastasis
Subgroups of prostatic cancer patients
in the retrospective study
A. Kovacs et al., (2011) Journal of Cancer Therapy2, 548-556
Kaplan Meier survival curve in the subgroup of DDW-
treated patients (45), having no metastasis during the
follow-up period
MST: not calculable
Cumulative follow-up
was 157 years, 4 patients
died out of 45
A. Kovacs et al., (2011) Journal of Cancer Therapy 2, 548-556
DDW –Retrospective study –Breast cancer
Design for the retrospective evaluation
of breast cancer patients
•232 breast cancer patients enrolled between
February 1993 and April 2011
•Patients ingested DDW (105 to 25 ppm D
concentration) longer than 90 days
•DDW treatment supplemented and not
substituted conventional therapies
Survival in breast cancer
(historical control)
Median survival time:
•80 to 98 months (6.6-8.1 years) in early
stage (15-20%) breast cancer, but 30%of
them have recurrent disease
•12 to 24 months (1-2 years) in advanced
disease
Kaplan Meier survival curve of 232 DDW-treated
breast cancer patients
L/E
0100 200 300 400
10
20
30
40
50
60
70
80
90
100
Time (months)
Survival probability (%)
MST: 12.3 years
55.6% of the
patients were in
advanced stage
K. Krempels, et al. (2013) Journal of Cancer Research & Therapy, 1(8):194–200
Survival from the start of DDW treatment in the
subgroups of breast cancer patients defined on
restaging at the involvement
L/E
050 100 150 200 250
0
20
40
60
80
100
Time (months)
Survival probability (%)
restaging at the DDWstart
A
P
R
R: 48 patients
DG_to_Flwup: 288.4 years
DDWstart_to_Flwup: 221.1 years
1 death / 48 patients
P < 0.0001
K. Krempels, et al. (2013) Journal of Cancer Research & Therapy, 1(8):194–200
Survival from the diagnosis in subgroups of breast
cancer patients undergoing single and continous or
repeated DDW treatment
L/E
0100 200 300 400
0
20
40
60
80
100
Time (months)
Survival probability (%)
Time pattern of the DDW treatment
Y (repeated)
N (single and continuous)
p < 0,0001
MST:
Repeated DDW consumption:
24 years / 53 pts
4 fold increase!
Single DDW consumption:
9 years / 179 pts
1.5 fold increase!
K. Krempels, et al. (2013) Journal of Cancer Research & Therapy, 1(8):194–200
DDW –Retrospective study –Lung cancer
Kaplan Meier survival curve of 366 DDW-treated lung cancer patients
(retrospective study, 190 male, 176 female patients)
MST: 5.2 years
7 fold incease
compared to
historical control
Kaplan Meier survival curve of 304 DDW-treated lung cancer patients
(retrospective study, 157 male, 147 female patients)
050 100 150 200
0
20
40
60
80
100
Time (months)
Survival probability (%)
MST: 4 years
6 fold incease
compared to
historical control
MR scan of a patient with brain metastasis from SCLC, at
diagnosis and in the course of the application of deuterium-
depleted water (DDW)
At diagnosis, 07.29.2001, after 3 months, after 23 months, after 43 months
K. Krempels, et al. (2008) Integrative Cancer Therapies 7(3):172-81.
The patient died 12 years after diagnosis.
Retrospective study of 2,222 DDW- treated
cancer patients
Percent distribution of major types of cancer in the follow-up
population (2,222 patients)
Tumor type Patient number/%
Digestive system 428/19.3
Breast 400/18.0
Lung, and pleura 366/16.5
Urological 284/12.8
Hematopoietic 193/8.7
Brain 160/7.2
Gynecological 155/7.0
Head and neck 84/3.8
Bone and soft parts 63/2,8
Skin 53/2.4
Other 22/1.0
Juvenile 14/0.6
Breast, lung, colorectal and prostate cancer
represent 54.1% of total 2,222 patient
population.
Incidence and mortality of cancer in Hungary
between 2003-2013
To estimate the MST of the Hungarian cancer population we took
data from the following paper:
Kásler, M., Ottó, Sz., Kenessey, I. The current situation of cancer morbidity and mortality in
the light of the National Cancer Registry, Hungary. Orv. Hetil., 2017, 158(3), 84–89.
Incidence of cancer Mortality of cancer
Cancer incidence and mortality in 2013 (Hungary)
Cancer incidence: 78,613/year
Mortality: 32,748/year
The deaths are 41.6% of the newly diagnosed cancer
patients
What is the MST for the whole Hungarian cancer
population?
Nine tumor types make up the 64.5% of the total
incidence and 75.2% of deaths in Hungary (2013)
Cancer
Type Incidence/year Deaths/year Death rate of new cases
Lung
11,304 8,591 75.9%
Colorectal
10,664 5,017 47.0 %
Breast
7,919 2,194 27.7 %
Pancreas
2,409 1,976 82.0 %
Lymphoma
and Hematopoetic 4,287 1,700 39.6 %
Stomach
2,433 1,619 66.5 %
Oral
3,759 1,431 38.0 %
Prostate
4,648 1,211 26.0 %
Bladder
3,300 899 27.0 %
Tumor types representing the highest death ratio
Cancer type Deaths/year Deaths % of
incidence/year % proportion of total
death cases/year
Lung
8,591 75.9% 26.0 %
Colorectal
5,017 47.0 % 15.0 %
Pancreas
1,976 82.0 % 6.1 %
Stomach
1,619 66.5 % 4.9 %
17.203 52.0 %
The above four tumor types are responsible for 52% of the death cases every year, their MST is shorter than 1 year!
MST for the whole Hungarian cancer population does not exceed 2.5 years!
Basic parameters of the data evaluation
•Gender, age, bodyweight
•Tumor type
•Date of diagnosis
•Date of the start of DDW consumption, start of follow-up
•End of DDW consumption
•End of follow-up
•Status at the end of follow-up: dead/alive
Main parameters in the statistical evaluation of the
follow-up population (2,222 patients) using DDW
date of diagnosis
start of DDW end of DDW administration
end of follow-up
3,517 years
8,338 years
4,821 years
2,415 years
Kaplan Meier survival curve in the retrospectively evaluated
population of 2,222 cancer patients treated with DDW
Means and Medians for Survival Time
MeanaMedian
Estimate
Std. Error
95% Confidence Interval
Estimate
Std. Error
95% Confidence Interval
Lower Bound
Upper Bound
Lower Bound
Upper
Bound
186,889
9,274
168,711
205,067
134,000
13,475
107,589
160,411
MST: 11.1 years
Stage of
illness in the
follow-up
population of
2,222 patients
at the start of
DDW-
treatment
2,018 patients started to
consume DDW with tumor
204 patients started to
consume DDW in remission
(tumor-free status)
Kaplan Meier survival curve in the retrospectively evaluated
population of 2,018 cancer patients (excluding tumor-free group)
Means and Medians for Survival Time
MeanaMedian
Estimate
Std. Error
95% Confidence Interval
Estimate
Std. Error
95% Confidence Interval
Lower Bound
Upper Bound
Lower Bound
Upper
Bound
172,631
9,187
154,625
190,638
114,000
9,512
95,357
132,643
MST: 9.5 years
Kaplan Meier survival curve in the retrospectively evaluated
tumor-free group of 204 cancer patients
Means and Medians for Survival Time
MeanaMedian
Estimate
Std. Error
95% Confidence Interval
Estimate
Std. Error
95% Confidence Interval
Lower Bound
Upper Bound
Lower Bound
Upper
Bound
273,144
17,308
239,221
307,068
.
.
.
.
MST was not calculable
(13 death cases/1,024 years cumulative
follow up time)
MST for women was almost double of that of
men’s MST in the whole DDW-population
Women (1,255), MST: 180 months/15 years
Average length of DDW consumption:
420 days
Men (967), MST: 101 months/8.4 years
Average length of DDW consumption:
365 days
Three determinative parameters affect MST:
- length of DDW-consumption
- staging at the start of DDW
- dosage
MST increases at 120 days of continuous DDW
consumption
134/11.16 134/11.16 133/11.08 133/11.08
142/11.83
147/12.25
157/13.08
120
125
130
135
140
145
150
155
160
1- 31- 61- 91- 121- 151- 181-
MST (months/years)
Length of DDW consumption (days)
2,222 2,155 (-67) 2,064 (-91) 1,962 (-102) 1,706 (-256) 1,525 (-181) 1,356 (-169)
number of patients
Calculation of Pearson correlation between the
length of DDW-consumption and the survival time
•The r-value varies between 0 and +1, the value closer to +1 means
stronger correlation
•r value 0.7 or higher very strong positive correlation
•r value between 0.4 and 0.69 strong positive correlation
•r value between 0.3 and 0.39 moderate positive correlation
Correlations
Survival time in
days
DDW treatment in
days
Survival time in days
Pearson Correlation
1
,480
**
Sig. (2
-tailed)
,000
N
2222
2222
DDW treatment in days
Pearson Correlation
,480
**
1
Sig. (2
-tailed)
,000
N
2222
2222
**. Correlation is significant at the 0.01 level (2
-tailed).
Correlation between MST and DDW treatment
in the full dataset
There was a strong, statistically significant correlation between survival time and length of
DDW treatment. (r=0.480, p<0.001)
2,222 patients’ MST: 134 months, 11.1 years
167 prostate cancer patients
(MST: 157 months, 13 years)
366 lung cancer patients
(MST: 62 months, 5.1 years)
400 breast cancer patients
(MST: 204 months, 17 years)
270 colorectal cancer patients
(MST: 84 months, 7 years)
71 pancreatic cancer patients
(MST: 19 months, 1.6 years)
Correlation between MST and DDW-treatment in five tumor types
Pearson correlation between lenght of DDW
consumption and survival time for different tumors
•2,222 patients r value = 0.480
•167 prostate cancer patients r value = 0.479
•366 lung cancer patients r value = 0.632
•400 breast cancer patients r value = 0.420
•270 colon cancer patients r value = 0.415
•71 pancreas cancer patients r value = 0.517
„r” value proved strong positive relationship between the lenght of
DDW consumption and the survival time for each tumor types
r value between 0.4 and 0.69
strong positive correlation
Exclusion of patients, died within 1-150 days from
the start of DDW-consumption, increased MST
134/11.1 135/11.2 135/11.2 136/11.3
153/12.7
159/13.2
120
125
130
135
140
145
150
155
160
165
1- 31- 61- 91- 121- 151-
MST (months/years)
Lenght of DDW consumption (days)
2,222 2,217(-5) 2,211(-6) 2,205(-6) 2,163(-42) 2,125(-38) number of patients
Total 97 deaths
within the first 6
months, which is 17%
of total death cases
Cumulative follow-up
time is 100,056
months
The first 6 months is
0.006% of cumulative
follow-up time
The expression of DDW dose
Deuterium depletion unit (DdU)
Main variable factors: - body weight (kgs)
- D-concentration of DDW (ppm)
- daily volume of DDW (L)
Examples for the calculation of DdU
Bodyweight: 60 kgs
Daily volume of DDW (L): 1.66 L
D-concentration of DDW: 65 ppm
Dose: 2.36 DdU
Body weight : 80 kg
Daily volume of DDW (L): 1.33 L
D-concentration of DDW: 105 ppm
Dose: 0.75 DdU
Relation between DDW-dose and response to
DDW-treatment in advanced breast cancer
(DdU> 1 or ≤1)
DdU CR
Complete response
PR
Partial response
NC
No change
PD
Progression of disease
> 1 12
(30%)
16
(40%)
3
(7%)
9
(23%)
≤13
(7%)
10
(24%)
10
(24%)
19
(45%)
p=0.0028
Journal of Cancer Research & Therapy 2013, 1(8):194–200
MST calculation of 1,405 DDW-treated patients with bodyweight less
than 75 kgs and 817 patients with bodyweight more than 75 kgs
Body weight under 75 kgs
MST 147 months (12.5 year)
Body weight over 75 kgs
MST 116 months (9.6 year)
MST of 851 patients, started DDW within 120 days after diagnosis, consumed
DDW longer than 120 days, excluding those who died within 120 days after start
DDW consumption
(MST 134 months, 95% CI: 100.130 –167.870)
Means and Medians for Survival Time
MeanaMedian
Estimate Std. Error 95% Confidence Interval Estimate Std. Error 95% Confidence Interval
Lower Bound Upper Bound Lower Bound
Upper Bound
156,754
7,857
141,354
172,155
134,000
17,281
100,130
167,870
a. Estimation is limited to the largest survival time if it is censored.
MST 134 month/11.1 years
4-5 fold increase of MST
comparing to existing data
Comparing data of 22 year- and 26 year-long
follow-up periods
Follow-up period
1993–2015 Follow-up period
1993–2019
1,656 tumorous patients 2,018 tumorous patients
Cumulative
time from diagnosis to the
end of
follow-up 6,079 years 7,296 years
MST
9.1 years 9.5 years
Average
time between diagnosis and
start of DDW
646 days !!! 602 days !!!
Average
length of DDW consumption 440 days 385 days
Number
of patients died 476 (28.7%) 543 (26.9%)
Cumulative
follow-up period/death 12.7 years 13.4 years
Comparing data of 22 year- and 26 year-long
follow-up periods
1993–2015 1993–2019
171 tumor
-free patients
204 tumor
-free patients
Cumulative
time from diagnosis
to
the
end of follow-up
801
years
1024
years
MST
Not
calculable
Not
calculable
Average
time between diagnosis
and start of DDW
374
days !!!
325
days !!!
Average
length of DDW
consumption
571
days
508
days
Number
of patients died
11 (6.4%)
13 (6.3%)
Cumulative
follow-up
period
/Death
72.8
years
78.7
years
What these numbers promise for the
Hungarian cancer population?
Facts
•78,613 new cases/year (2013)
•MST: 2.4 years; 78,613/32,748
•32,748 deaths/year (2013)
Opportunity
•MST: 11.1 years: 78,613/7,146
•7,146 deaths/year
We could save 25,000 lives in Hungary, every year!
Conclusions of real world data analysis
•Start DDW as close to the diagnosis as possible!
•Consume the proper dose!
•Continue DDW consumption even after achieving
remission!
•Have a break (not longer than 2-3 months) but start
again DDW even if there is no sign of cancer!
•Repeat DDW cures for several years even in remission!
•DDW consumption can prevent relapse
THANK YOU FOR YOUR ATTENTION!
www.deuteriumdepletion.com