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APL-105
(Trademarked as FRESHKOTE® in the USA and UK)
A New Artificial Tear that treats all 3 Layers of the Human Tear Film,
has the Highest Oncotic Pressure (65mm/Hg) for ocular surface
healing, enhances wettability, is preserved with a proprietary &
non-irritating preservative, and is globally patent pending.
Developed by the esteemed Dr. Frank J. Holly of the Dry Eye
Institute (www.dry-eye-institute.org) and formerly Professor of
Ophthalmology and Biochemistry at Harvard University/Schepens
Eye Institute and Texas Tech University Medical School.
PRODUCT PROFILE
SUMMARY
OF
CLINICAL STUDIES
 William Trattler, M.D. – Miami, Florida USA
o Corneal specialist ophthalmologist/refractive surgeon in
large group practice
 Grant Mason, O.D. – Melbourne, Australia
o Optometrist in large private practice
 David Lamberts, M.D. – Lubbock, Texas USA
o Corneal specialist ophthalmologist/lacrimologist and
President of Contact Lens Association of
Ophthalmologists
 TLC Vision Toronto, Canada – Dr. Sondra Black – Open evaluation
for 6 months in post-refractive dry eye patients
 Linda Butler, O.D. – Oakhurst, New Jersey USA
o Optometrist in large private practice
 Kazuo Tsubota, M.D. – Tokyo, Japan
o Leading Corneal specialist ophthalmologist and Chairman
of the largest ophthalmology department in Japanese
university setting
 Post-LASIK Dry Eye Cyber Study – Dry Eye Institute
1
APL-105
Tear Breakup Time, Patient Questionnaire Results &
General Observations
Bill Trattler, MD
Results through October 18th, 2002
APL-105 observations:
I have had the opportunity to work with both Dakrina and APL-105 during
2002. I have been even more impressed by the response to this new medication
(APL-105) by my patients. In particular, many of my patients had previously used
commercially available artificial tears, and noted significant symptom improvement
after using APL-105. On my clinical exam, I noticed an improvement in my patient’s
corneal surface. As well, the tear break up time improved in almost all of the patients
(please see the results on next page).
The patient responses on the dry eye questionnaire show that APL-105
provided improvement in their symptoms. Question 1 asked about the severity of
burning symptoms. Pre APL-105, the average score was 2.2 – which improved to 1.0
(scale of 1 to 4, with 1 being “My eyes do not feel this way at all” and 4 being “I
notice these symptoms all of the time, and it does interfere with my normal
activities”).
Question 2 asked about a “gritty sensation” of the eye, and the score improved
from an average of 2.6 to 1.25
Question 3 asked about the eyes feeling “tired or dry”, and the score improved
from an average of 3.0 to 1.25.
In summary, patients with significant dry eye problems related to poor tear film
quality had significant improvements both subjectively and objectively. I personally
feel that this product has been a great treatment for my patients.
I am happy to answer any further questions. Objective results on next page.
William Trattler, MD
Cornea & External Diseases
Miami, FL
305-598-2020 ext 1200
http://www.AskLasikDocs.com
2
Tear Breakup Times* for APL-105
Patient #
Eye
111
OD
OS
OD
OS
OD
OS
OD
OS
OD
OS
113
114
115
116
First visit
(seconds)
9
5
10
8
10
7
4
8
6
8
Second visit
(seconds)
10
11
12
11
12
13
11
14
8
12
Third visit
(seconds)
12
14
12
14
11
12
12
14
12
12
*TBUT of 10 seconds or lower indicates Dry Eye Syndrome; with 1 being the most severe
All of the patients feel better with this new formulation (APL-105), and my
overall impression is that this formulation is working well at treating the
symptoms of the patients. I have not had any patients have any problems
with the medication.
The tear breakup times have improved with all of the
patients. After checking the first time, I did reapply the product, wait 5
minutes, and recheck the tear break up time. Interestingly, this did not
improve the tear-break up time. This suggests that therapeutically this
product is helping improve the entire ocular surface, so that perhaps this
is a treatment of poor tear film quality rather than just a temporizing
measure.
Bill
Bill Trattler, MD
Miami FL
http://www.AskPhysicians.com
http://www.AskLasikDocs.com
305-598-2020 ext 1200
3
Grant Mason
BScOptom MOptom FACBO FCOVD(USA)
OPTOMETRIST
CONTACT LENS PRACTITIONER
PAEDIATRIC OPTOMETRY
SPORTS VISION
LILYDALE MARKETPLACE
33 HUTCHINSON ST, LILYDALE 3140
PH. 9735 3433
Provider 815523Y AUSTRALIA
22 GLYNNE RD
NORTH RINGWOOD, 3134
PH. 9735 3433
Provider 815521B
12th October 2002
Mr J Echols and Dr F Holly
Aqueous Pharma
USA
In ref to: Clinical Trial of APL-105
Dear Joe and Frank,
I have had 3 patients complete the 2 week trial to date.
Two found that they were better than their prior drop (Bion Tears) and needed to use the drops with
reduced frequency. One patient was using the Bion Tears about every 10 minutes (timed by her
husband). The APL-105 was only being used every 30-40 minutes and although she was still
having some discomfort problems, she felt much better with the APL-105.
Both these patients showed an improvement in FBUT from 4 and 7 seconds to 6 and 10 seconds
after the 2 weeks. There was also reduced stain with the Lissamine Green.
One patient was discontinued after 10 days. She was doing fine for 8 days, but suddenly began to
have other, unrelated ocular problems. Her FBUT improved from 2s to 4s and staining was reduced
somewhat (she had particularly bad KCS with heavy staining of both corneas and conjunctivae). In
light of this being a trial it was decided to resume her prior tear supplement, Polygel, which gave
her smeary vision for 20 minutes, but her vision was adequate for 10 minutes until the next
instillation of the gel. Her vision for the 10 days of the APL-105 was clear and she reported that she
was disappointed that she became symptomatic with other problems after the 8 days, as her vision
had not been this clear for over 4 years.
At this stage, my impression is that APL-105 is at least as good as Bion Tears, which is the most
prescribed drop for dry eye in Australia now; but most likely much better. I have found that the
frequency of use is much less than Bion Tears and the tear film appears to be closer to the
physiological tears due to the reduction in staining. Comfort and vision certainly are better than
with the Bion Tears. As for advanced cases of KCS, my one candidate was fine initially and
reported much better vision.
4
Grant Mason
BScOptom MOptom FACBO FCOVD(USA)
OPTOMETRIST
CONTACT LENS PRACTITIONER
PAEDIATRIC OPTOMETRY
SPORTS VISION
LILYDALE MARKETPLACE
33 HUTCHINSON ST, LILYDALE 3140
PH. 9735 3433
Provider 815523Y
AUSTRALIA
18th October 2002
Dr F Holly & Mr J Echols
Aqueous Pharma
USA
Dear Frank and Joe,
I have just completed my trial study of APL-105. The results have been very good and I have seen
noticeable improvement with advanced dry eye patients.
11 patients in total were placed on APL-105, to be used as required. 2 patients discontinued the
drops due to discomfort and stinging, but I believe this was due to chemically induced keratitis, as
both had severe corneal damage prior to commencement of the study.
The 9 remaining patients all reported improved comfort and reduced need to lubricate than with
their prior drops or gel. One patient, a moderate KCS sufferer went from drops every ½ to 1 hour to
2-3 drops daily.
All 9 patients also showed reduced corneal staining with fluorescein and Lissamine Green; some (3
patients) had total regeneration of the corneal epithelium.
Tear break-up time measured both non-invasively and with fluorescein was the same in 4 patients,
and improved with 5 patients, although only by 1-3 seconds (which I thought was pretty
impressive, especially for a 2 week study).
Overall, I was impressed by the results and especially with the improvement in clarity among those
using gels for control of the dry eye problems.
I would like to thank you for allowing me to be a part of this trial.
Yours sincerely,
Dr. Grant Mason
BScOptom MOptom FACBO FCOVD
Melbourne, Australia
5
Clinical Study of a New, Lipid-Containing Artificial Tear, APL-105
The study was designed by and conducted in the Lubbock, Texas clinic of David W. Lamberts,
M.D., a corneal specialist ophthalmologist and a well known lacrimologist. The data was tabulated
and formatted by Frank J. Holly, Ph.D. of the Dry Eye Institute in Yantis, Texas.
Eleven patients are included in the study which lasted four weeks during the fall of 2002. At the
end of the second week, the eye drops are crossed over, i.e. the contra-lateral eye then received the
test drop between 2 and 4 weeks. APL-105 was furnished by Aqueous Pharma. The control eye
drop was Tears Naturale, Alcon Laboratories. Drs. Lamberts and Holly were not compensated for
their involvement in this study. This report was written by Dr. Frank J. Holly.
The following clinical signs are measured in each eye of each patient at each visit starting on the
initial visit:
1. The degree of vital staining by Lissamine green estimated on a scale from 0 – 9.
2. Width of tear meniscus in millimeters.
3. Degree of redness on a scale 0 to 4.
4. Degree of mucus precipitation in the eye on a scale from 0 to 4.
The following subjective symptoms are also determined at each visit starting on the initial visit:
1. Degree of burning on a scale between 0 – 4.
2. Degree of dryness on a scale between 0 - 4.
3. Degree of blurred vision on a scale between 0 - 4.
4. Degree of foreign body sensation on a scale between 0 - 4.
The frequency of instillation per day is recorded.
The following patients were included in the study:
Patient #01 61 year old female diagnosed with Sjögren’s syndrome.
Patient #02 52 year old female diagnosed with Sjögren’s syndrome.
Patient #03 60 year old female diagnosed with Sjögren’s syndrome.
Patient #04 66 year old female diagnosed with Sjögren’s syndrome.
Patient #05 52 year old female diagnosed with Severe KCS.
Patient #06 65 year old female diagnosed with Sjögren’s syndrome.
Patient #07 68 year old female diagnosed with Moderately-Severe KCS.
Patient #08 54 year old female diagnosed with Severe KCS
Patient #09 57 year old female diagnosed with Moderately-Severe KCS.
Patient #10 53 year old female diagnosed with Sjögren’s syndrome.
Patient #11 50 year old female diagnosed with Sjögren’s syndrome.
Results:
Eight patients completed the study which means that the test drop was tried in
sixteen eyes and the control was also used in sixteen due to the cross-over at two weeks. In half of
these eyes, the test drop was used first and after two weeks, the control was used. In the other half
of the eyes, the order was reversed. Three more patients partially completed the study. These
yielded three more eyes to the study in which the test drops were used, and three eyes in which the
control drop was used. Nineteen eyes total for each drop.
6
The ranking shows that in 7 out of 8 parameters APL-105 was superior to Tears Naturale. Only in
one parameter (tear meniscus) was APL-105 equal to Tears Naturale. The better performance by
APL-105 was shown in the most important clinical parameter: the degree of healing of the corneal
epithelium as shown by the decrease in vital staining. 90% of the eyes showed better healing with
the test solution and none showed better healing with the control solution.
CONCLUSION: Based on this double-blinded, crossover, controlled clinical study it appears that
APL-105 is a very effective and long-lasting therapy for the most severe form of KCS, as 8 of the
11 patients were diagnosed with Sjögren’s syndrome and the remaining 3 patients were diagnosed
with moderately-severe to severe KCS, thereby substantiating results from 2 previous clinical
studies; one by Dr. William Trattler of Miami, Florida and the second by Dr. Grant Mason of
Melbourne, Australia. APL-105 is in full compliance with the FDA Ophthalmic Monograph
21CFR§349.12., so is considered as FDA approved. It will be marketed under the brand:
FRESHKOTE™ in the US.
David W. Lamberts, M.D., Lubbock, Texas
Frank J. Holly, Ph.D., Dry Eye Institute, Yantis, Texas
February 1, 2003
7
OPEN EVALUATION OF FRESHKOTE™ (APL-105)
Linda Butler, O.D.
780 West Park Avenue
Oakhurst, NJ 07727
Phone: 732-531-6300
[email protected]
Patient #1 30 y/o female KCS - Moderate
Patient #2 40 y/o female KCS - Moderate
Patient #3 19 y/o female KCS – Mild to Moderate
Baseline: #1 TBUT 3 sec. OU, 1+ SPK, 1+ FL stain
#2 TBUT 4 sec. OU, 1+ SPK, 1+ FL stain
#3 TBUT 6 sec. OU, 1+SPK, 1 + FL stain.
Week #1: #1 TBUT 5 sec. OD, 4 sec. OS, 1+ SPK and stain
#2 TBUT 6 sec. OU, Trace SPK and stain
#3 TBUT 6 sec. OU, 1+SPK and stain
Week #2: #1 TBUT 6 sec. OU, no SPK or stain
#2 TBUT 8 sec. OU, no SPK or stain
#3 TBUT 6 sec. OU, no SPK or stain
No adverse effects reported. Patient’s subjective comments were not solicited but all 3 patients felt that the
drops were very comfortable and preferred over all previous artificial tears used.
TBUT continued to improve in Patients #1 and #2 but remained the same in Patient #3.
All 3 patients had no SPK or staining at the end of 2 weeks.
Dr. Linda Butler
April 18, 2003
8
EVALUATION IN JAPAN
In July/August of 2003, FreshKote™ (APL-105) was evaluated by the leading
corneal specialist ophthalmologist in Japan, as follows:
Kazuo Tsubota, M.D.
Professor & Chairman
Department of Ophthalmology
Tokyo Dental College
5-11-13 Sugano
Ichikawa, Chiba 272-8513
JAPAN
 tel: +81-47-322-0151
 fax: +81-47-322-6786
Aqueous Pharma sent 24 bottles of FreshKote to Dr. Tsubota for evaluation in his
large corneal clinic and research centre in Tokyo; especially for use in his most
difficult dry eye patients.
Dr. Tsubota reported back to Aqueous Pharma on 19th August 2003:
“I wish to take this opportunity to thank you for you supplying me with the
FreshKote dry eye drop treatment. My colleagues and I tried the drops and it seems
to be very wonderful”.
(specific details of the evaluation have not yet been published by Dr. Tsubota)
9
OPEN CLINICAL TRIAL IN CYBER SPACE ON POST-LASIK PATIENTS WITH
REGARD TO DRY EYE MANAGEMENT
An unusual clinical study was conducted through cyberspace via the participation of leaders and members of Surgical
Eyes Foundation, a web-based organization with the co-operation of the Dry Eye Institute, including the eye care
professionals in charge of the recuperating patients, and Aqueous Pharma which made the eye drops available through a
sterile compounding pharmacy.
This approach excluded haphazard and harmful treatment modalities that they are in vogue in the treatment of post-lasik patients,
such as use of ointments, use of antibiotics for sterile inflammation, use of steroids when the inflammation was from the direct
result of poor tear film stability, and the too frequent use (flooding the ocular surface) of otherwise benign eye drops, and the
discontinuation of highly viscous drops and gels. Depending on the diagnosis of the patients and her symptoms, the proper Aqueous
Pharma drop or a combination of such drops was recommended, with APL-105 (FreshKote) the most preferred. Feedback from the
patients was solicited and considered in deciding the type of drops suggested and their regimen.
After six months of this open study in which more than 200 patients participated, a polling of these patients took place. The
participants were asked whether the following statement was “TRUE” or “FALSE” or they were “UNCERTAIN” whether it was true or
false. The statement was:
“At least some of these (Aqueous Pharma) drops helped my conditions more than other regimen(s) I have tried.”
The results are shown on this bar chart.
Presented at the Tear Film & Ocular Surface Society
Annual Conference 17-19 November 2004, Fajardo,
Puerto Rico; by Dr. Frank J. Holly.
80
Percentage of Patients
Most of the patients had previously tried every
commonly available artificial tear.
Efficacy of Aqueous Pharma Drops
76
70
60
50
40
30
20
14
10
10
0
TRUE
FALSE
UNCERTAIN
10