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`Santen/Asahi Glass Exhibit 2059
`Micro Labs v. Santen Pharm. and Asahi Glass
`IPR2017-01434
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`

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`PhXA34 — a prostaglandin F2" analogue. Effect on intraocular pressure in patients with ocular hypertension
`
`215
`
`from each eye always starting with the right eye.
`The median value of the three readings was taken
`as the true IOP.
`
`HYPERAEMIA
`
`The degree of hyperaemia was determined from
`colour photographs and graded on a scale from 0
`to 3 with seven steps, by comparing with four
`standard photographs covering the range from
`none to pronounced hyperaemia. The average of
`four independent and masked gradings deter-
`mined the hyperaemia.
`
`CELLS AND FLARE
`
`The anterior chamber was examined by slit—lamp
`biomicroscopy. Flare was graded none, slight,
`moderate, or severe, and the number of cells, if
`any, were counted.
`
`SYMPTOMS
`
`Prior to IOP measurements the patients were
`asked in a standardised way about
`local and
`systemic Symptoms. Symptoms and discomfort
`were graded mild, moderate, or severe.
`
`DATA ANALYSIS
`
`All IOP values are presented as means with 95%
`confidence intervals. The IOP values used for
`the dose-response curve (Fig 1) are based on the
`IOP determinations at t8 and tn. These two IOP
`values were averaged and the difference between
`average IOP day 1 (before treatment) and day 2
`(after treatment) has been used as an estimate of
`drug effect for each patient. Also the differences
`in IOP for corresponding examination times on
`day 1 and day 2 have been calculated for all doses
`including placebo (see Table 2).
`To find statistically significant differences
`between placebo effect and drug effects non-
`
`IOPreduction
`
`mmHg
`
`... 0
`
`oh-NUAUImNWID
`
`Placzbo 0.3 ”9
`
`1.0 by
`
`3.0 Mg
`
`10.0 up
`
`etuasadln
`
`log (dose + 1)
`The effect an IOP and conjunctival hyperaemia of
`Figure I
`four single doses ofPhXA34 and placebo. The values used to
`express the 1OP reduction for each dose are based on the IOP
`determinations at ta and t; 2. These two values were averaged
`and the difference between average IOP day 1 (before
`treatment) and average IOP day 2 (after treatment) was used
`as an estimate ofdrug effectfor each patient. Hyperaemia was
`estimated for each patient as the difference between maximum
`score on day 2 (after treatment) and the registration at to day 2.
`Closed circles: mean I01’ reduction with 95% confidence
`interval; open circles: mean hyperaemia.
`
`Table I Forty patients were randomised to one offive
`different treatments with eight patients in each group. The
`baseline characteristics for the different treatment groups are
`shown
` Placebo 0'3 pg 1 pg 3 pg 10 pg
`
`
`
`
`Number
`8
`8
`8
`8
`8
`Females
`8
`S
`6
`6
`7
`Males
`0
`3
`2
`2
`1
`Mean age
`58-9
`64-4
`67-6
`58-4
`65-0
`STD
`10-4
`6-6
`5-6
`12-2
`8-0
`Range
`45—73
`56—75
`56—78
`41—72
`54—75
`IOP
`22-4
`22-8
`23-2
`22-8
`23-1
`STD
`2-54
`3-83
`4-40
`2-47
`2-95
`Exfoliations
`3
`4
`6
`0
`3
`Right eyes
`3
`6
`4
`3
`2
`
`Z 4 S5Left eyes 6
`
`
`
`
`
`,
`
`IOP is expressed as the mean of pretreaunent day to, 13, and 1.2.
`
`paired ttestS have been used. The effect on IOP
`expressed as the area under the curve for the
`differences in IOP day 1 and day 2 for each
`treatment group has been calculated using a
`Simple numerical estimation of area by the
`trapezoidal rule.7
`The contralateral eyes were a mixed group of
`normal eyes and eyes with ocular hypertension,
`and they have not been included in the analysis.
`The estimated hyperaemia is based on the
`difference between the maximum score on day 2
`and the score before examination and IOP
`measurement at to day 2.
`
`Results
`All patients completed the study. The results of
`randomisation are shown in Table 1. Figure 1
`shows the average IOP reductions (mean with
`95% confidence interval) for placebo and increas—
`ing doses of PhXA34 8 and 12 hours post-dose.
`
`IOP in the study eyes for the different treatment
`Table 2
`groups day l and day 2
`
`Time Day 1
`Placebo
`0
`24-9 (23-2-26‘6)
`0-5
`8
`20-8 (19-2—22-3)
`12
`21-6 (20-2—23-0)
`24
`25-8 (22-5—29-0)
`PhXA34 0-3 pg
`0
`24-9 (22-1—27-6)
`0-5
`8
`20-6 (17-7—23-5)
`12
`23-0 (19-8—26-2)
`24
`23-9 (20-1—27-7)
`PhXA34 1 pg
`0
`25-8 (20-5—31-0)
`0-5
`8
`22-0 (205-235)
`12
`21-9 (19-3—24-4)
`24
`24-5 (21-1—27-9)
`PhXA34 3 pg
`0
`24-5 (22-1—26-9)
`0-5
`8
`21-8 (20-6—22-9)
`12
`22-0 (20-2—23-8)
`24
`23-5 (20-8—26-2)
`PhXA34 10 pg
`0
`24-4 (21-2—27-6)
`0-5
`8
`22-5 (21-0—24-0)
`12
`22-4 (20-1—24-7)
`24
`24-0 (20-8—27-2)
`
`Day 2
`
`Change in IOP
`
`-0-9 (2-0— —3-8
`25-8 (22-5—29-0)
`26-8 (24-0—29-5) —1-0(—0-1——1-9)
`201(18-5—21-8)
`0-6 (1-6— —-0-4)
`20-6 (17-9-23-4)
`1-0 (2-9— -0-9)
`22-9 (20-2—25-5)
`2-9 (5-4— —-0-4)
`23-9 (20-1—27-7)
`1-0 (3-4— —1-4)
`25-1 (21-8—28-5) —1-3(1-2—-3-7)
`18-9 (16-9—20-8)
`1-8 (3-7— —0-0)
`19-9 (16-0—23-8)
`3-1 (5-1— 1-2)
`21-9 (19-3—24-5)
`2-0 (4-7— -0-7)
`24-5 (21-1—27-9)
`1-3 (4-3— —1-8
`23-4 (18-4—28-4)
`1-1(3-2— —1-0
`171 (14-8-19-4)
`4-9 (6-5—3-2)
`16-4 (13-1—19-7)
`5-5 (8-6—2-4)
`21-5 (17-4—25-6)
`3-0 (5-5—0-5)
`23-5 (20-8—26-2)
`1-0 (3-2— —1-2)
`24-0 (22-1-25-9) —-0-5 (2-1— —3-1)
`15-0 (13-0—17-0)
`6-8 (8-4—5-1)
`14-4 (11-8—16-9)
`7-6 (9-4—5-8)
`20-3 (17-7—22-8)
`3-3 (5-2—1-3)
`24-0 (20-8—27-2)
`0-4 (2-5— —l-8)
`24-9 (21-4—28-4) —0-9 (1-0— —2-8)
`15-5 (14-2—16-8)
`7-0 (8-1—5-9)
`14-5 (13-7—15-3)
`7-9 (10-5—5-2)
`18-6 (17-2-20-0)
`5'4 (8-1—2-7)
`
`The values are means in mm Hg with 95% confidence interval.
`The drug was given topically shortly after to (7 am) on day 2. The
`change in IOP is calculated as IOP day 1 minus IOP day 2 at the
`corresponding time of the day except for the 10., value which is
`compared with the IOP just before drug application (to on day 2).
`[OP values 11,. on day l are identical to the values to on day 2, but
`listed to make comparison easier. Negative values indicate an
`increase in IOP and positive values indicate a reduction in IOP.
`There were eight patients in each group.
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`216
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`Villumsen, Alm
`
`Table 3 The degree ofhyperaemia in the study eyes. The
`procedures usedfor the grading are described in the text
`
`in any treatment group before drug
`present
`application. No hyperaemia was observed for
`any dose 30 minutes after drug application, and
`hyperaemia was practically absent for doses
`lower than 10 pg. This dose however produced
`observable hyperaemia grade 15—2 in most
`patients
`(Table 3). Photographs were not
`achieved from three patients due to camera
`problems. These patients were treated with
`placebo,
`1 pg, and 3 pg PhXA34 respectively,
`and the 8—hour photograph from a patient treated
`with 03 pg PhXA34 was not possible to grade.
`No flare or cells were seen in the anterior
`chamber.
`
`Discussion
`The result of randomisation did not show any
`important differences except for an uneven dis-
`tribution of the 16 eyes with exfoliations. The
`high frequency of patients with exfoliations
`reflects the expected distribution in a group of
`patients with ocular hypertension in
`the
`northern part of Sweden.
`A prior study has shown a clear dose-related
`IOP reduction in normal eyes.6 A dose-related
`response was also found in this study with regard
`to IOP reduction; 3 and 10 pg PhXA34 seem to
`be almost equipotent with regard to IOP reduc-
`tion based on average IOP reduction 8 and 12
`hours post close, but 10 pg appears more potent
`if the IOP reduction 24 hours after the dose is
`included as in the values expressed as area under
`the curve. The 8 and 12 hours average IOP
`reduction was chosen as the primary variable for
`this dose-response study because it
`is known
`from prior studies that the maximal effect
`is
`observed within this period for most doses. In
`this study the maximal effect is seen 12 hours
`after the dose for all doses of PhXA34, and the
`inclusion of the 8-hour values therefore results in
`a slight underestimate of the peak IOP reduction.
`In the contralateral eyes we observed only
`minor fluctuations in IOP with a tendency
`towards a slight IOP reduction of normally less
`than 1 mm Hg on day 2, and these changes
`seemed to be completely unrelated to the dose
`given in the study eye. Hyperaemia was neg-
`ligible for doses lower
`than 10 pg PhXA34
`suggesting that
`the dose-response curve for
`hyperaemia is displaced to the right of the IOP
`dose-response curve. This is in contrast to the
`hyperaemia observed after PGFZn-IE where all
`effective doses caused some hyperaemia. There
`is also a difference in the timing of the hyperaemia
`since none was visible for any close of PhXA34 30
`minutes after application, while PGFZn-IE pro—
`duces maximal hyperaemia within the first hour.
`High doses of PGFZa-IE also caused an initial
`increase in IOP, probably due to intraocular
`vasodilation, something that was not observed
`even with 10 pg PhXA34.
`In summary PhXA34 is a potent ocular hypo—
`tensive agent also in patients with ocular hyper-
`tension, where one topical dose of 3 pg reduce
`IOP about 32% 8—12 hours after application
`without clinically significant side effects.
`
`PhXA34 eye drops and project support were supplied by Kabi
`Phan'nacia Ophthalmics AB, Uppsala, Sweden. The authors have
`no commercial or proprietary interest in PhXA34 eye drops.
`
`Grade of hyperaemia
`0
`0-5
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`Treatment
`time
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`12
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`The numbers in each column indicate the number ofeyes with the
`specific grade of hyperaemia,
`The drug was given shortly after to.
`'Notifies that the number of photographs in that row is 7.
`
`They were 0'8 (-0~7—2'3), 24 (04—45), 5-4
`(30—78),
`7-0 (53-8-7) and 7-8 (58-98)
`mm Hg.
`The
`corresponding ‘ reductions
`expressed as a percentage of IOP on day 1 were
`4%,11%, 25%, 32% and 35%.
`When compared with placebo l, 3, and 10 pg
`PhXA34 were significantly better in reducing the
`IOP whereas 0-3 pg was not
`significantly
`changed from placebo: 03 pg p<0-1,
`1 pg
`p<0-002, 3 pg p<0-001, 10 pg p<0-001; (t test
`for two independent means with pooled estimate
`of common variance).
`Table 2 presents the IOP values on day l and
`day 2 for the five different treatment groups
`including the differences in IOP between the 2
`days.
`The change in IOP for the different treatment
`groups can also be expressed as area under the
`curve and these values were for placebo and
`increasing doses of PhXA34: 24 (—15—65), 42
`(—12—96), 94 (38—153),
`118 (72—164),
`132
`(82—184). Values are means in mm Hg hours
`with upper and lower limits for the 95% confi-
`dence interval.
`IOP was measured 30 minutes after the drug
`application on day 2 and at that time no signifi-
`cant effect on IOP was found for any dose of
`PhXA34.
`No discomfort was felt by any patient before
`drug application, but mild discomfort was noted
`by a total of seven patients at some time during
`the remaining part of day 2. Symptoms in both
`eyes with no difference between the two eyes
`were felt by three patients. Discomfort in the
`treated eye only, mainly in the form of a mild
`foreign body sensation, was reported by four
`patients: one placebo treated, two treated with
`1 pg PhXA34, and one treated with 3 pg
`PhXA34. Additionally, headache was reported
`by one patient treated with placebo.
`No significant difference
`in hyperaemia
`between study eyes and contralateral eyes was
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`PhXA34 - a prastaglandin F2,, analogue. Effecl on inlraocularpressure in patients with ocular )1pr
`
`217
`
`1 Kerstetter JR, Brubaker RF, Wilson SE, :1 a1. Prostaglandin
`F2,,-l—isopropylester
`lowers intraocular pressure without
`decreasing aqueous flow. Am] Ophthalmol 1988; 105: 30-4.
`2 Villumsen J, Alm A. Prostaglandin Flu-isopropylester eye
`drops: effects in normal human eyes. Br] Ophthalmol 1989;
`73: 419—26.
`3 Villumsen I, Alm A, Soderstrom M. Prostaglandin Flu-impro-
`pylester eye drops: effect on intraocular pressure in open
`angle glaucoma. BI] Ophthalmol 1989; 73: 975—9.
`4 Camras CB, Siebold EC, Lustgarten IS, er a1. Maintained
`reduction of intraocular pressure by prostaglandin Fla-l-
`isopropylester applied in multiple doses in ocular hyperten-
`
`sives and glaucoma patients. Ophthalmology 1989; 96:
`1329—37.
`5 Villumsen J, Alm A. The effect of adding prostaglandin F1“-
`isopropylester
`to tirnolol
`in patients with open angle
`glaucoma. Arch Ophthalmol 1990; 108: ”02—5.
`6 Alm A, Villumscn I. PhXA34—a new potent ocular hypotensive
`drug. A study on dose-response relationship on aqueous
`humor dynamics in healthy volunteers. Arch Ophthalmol
`1991; 109: 1564—8.
`7 Rowland M, Tozer TN. In: Clinical pharmacolzinetic: concept:
`and applicatim. Philadelphia: Lea and Febiger, 1980: 288.
`
`FIFTY YEARS AGO
`
`Paper Salvage
`
`paper of every kind are badly needed. It has been
`rather a wrench to cast out copies of old text-books
`which we used in the days of our Studentship. Some
`of these were at least forty years out of date but had
`a sentimental interest to us.
`Those who were brought up in Victorian days will
`be aware of the hoarding propensities of parents in
`the matter of family and other letters. A great many,
`but not all, of these are very suitable for salvage.
`Young hopeful's reiterated appeals from school -for a
`hamper or a new cricket bat or even a modest half-
`a-crown are not worth keeping, but no one in his
`senses would destroy letters by eminent hands. If, in
`going through bundles of old correspondence, one
`fights upon a letter,
`for instance,
`from the poet
`Wordsworth to one’s own grandfather it will be wise
`to preserve it, for its value may appreciate in post-
`war times.
`Br] Ophthalmol 1942; 26: 225—6.
`
`
`
`Our readers will probably have noticed the slight
`
`difference in texture and tint of the paper used for
`printing the Journal since the beginning of this year.
`Our stock of paper came to an end in December last
`
`and like everybody else we have had to make do
`with what the controller allows us. In after years it
`
`may be of interest as dating some of the War years.
`Deterioration in quality of paper during war is no
`
`new thing. Exactly the same happened in the
`
`Napoleonic struggle. Much of the paper used in the
`
`earlier years of the last century was very poor in
`
`quality and no one now-a-days would dream of
`
`reading such a thing as the first edition of Waverley
`
`(published 1814), if he could get a later edition.
`
`It behoves us all to contribute as much as we can
`
`to the paper salvage campaign. For ourselves we
`
`almost tremble to think of the numbers of gallcys of
`
`
`back numbers which we have sent to the pulping
`machine. Old books, old letters, old receipts and
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