Ophthalmology Management
`Ophthalmology Management (cid:9)
`
`Page 2 of 7
`Page 2 of 7
`
`Part of the problem might reside with the regulatory process
`itself. The process for
`Part of the problem might reside with the regulatory process itself. The process for
`clearance of a new drug is complex and as the knowledge base concerning dry eye disease
`clearance of a new drug is complex and as the knowledge base concerning dry eye disease
`expands,
`the
`
`scientific basis for drug
`
`testing changes. According to Michael A. Lemp, MD,
`expands, the scientific basis for drug testing changes. According to Michael A. Lemp, MD,
`clinical professor at
`
`Georgetown and George Washington universities,
`
`"it was anticipated
`clinical professor at Georgetown and George Washington universities, "it was anticipated
`that the FDA would issue new guidelines
`for clinical trials in dry eye disease
`
`several years
`that the FDA would issue new guidelines for clinical trials in dry eye disease several years
`ago, but
`these have not been made public. The delay may rest with senior management
`ago, but these have not been made public. The delay may rest with senior management
`within the Agency."
`within the Agency."
`
`The result is that
`there is no "one-stop
`shopping"
`
`source would-be sponsors where
`
`
`can learn
`The result is that there is no "one-stop shopping" source where would-be sponsors can learn
`the guidelines
`for
`
`clinical trial endpoints. Instead,
`sponsors
`
`must go to the
`
`FDA and make a
`the guidelines for clinical trial endpoints. Instead, sponsors must go to the FDA and make a
`proposal as
`
`to how they would perform a clinical trial; the FDA reviews the proposal and
`proposal as to how they would perform a clinical trial; the FDA reviews the proposal and
`informs the
`
`if sponsor it is acceptable,
`
`or
`
`which portions are
`acceptable
`or
`informs the sponsor if it is acceptable, or which portions are acceptable or unacceptable.
`"While the FDA is quite open to these
`inquires
`
`and willing to listen to novel ap proaches,
`"While the FDA is quite open to these inquires and willing to listen to novel ap proaches,
`many times
`companies new to
`this
`
`field feel as if they are
`guessing what the FDA wants,"
`many times companies new to this field feel as if they are guessing what the FDA wants,"
`Dr. Lemp explains.
`"They wonder
`if the FDA has changed what is acceptable
`since
`the
`Dr. Lemp explains. "They wonder if the FDA has changed what is acceptable since the last
`time they heard. It's
`
`like trying to read the tea
`leaves."
`time they heard. It's like trying to read the tea leaves."
`
`unacceptable.
`
`last
`
`Chugging Along
`Chugging Along
`
`Despite the
`
`regulatory hurdles, some
`dry
`eye
`drugs making slow but steady are
`
`
`progress
`Despite the regulatory hurdles, some dry eye drugs are making slow but steady progress
`toward beleaguered physicians and
`their patients. Most are
`anti-inflammatories,
`so
`toward beleaguered physicians and their patients. Most are anti-inflammatories, so their
`approval would fulfill a wish of Dr. Trattler's.
`"I use pulses of topical steroids
`frequently
`approval would fulfill a wish of Dr. Trattler's. "I use pulses of topical steroids frequently for
`dry eye patients, and if there were
`additional anti-inflammatory
`drugs
`
`that work in
`dry eye patients, and if there were additional anti-inflammatory drugs that could work in
`this area,
`that
`would be very helpful for patients, since
`
`
`dry is an inflammatory eye
`
`this area, that would be very helpful for patients, since dry eye is an inflammatory
`condition."
`condition."
`• EGP-437. The
`
`closest to the goal is EyeGate's EGP-437. Currently in a phase 3 drug
`
`• EGP-437. The closest drug to the goal is EyeGate's EGP-437. Currently in a phase 3
`via
`efficacy study, it's a dexamethasonederived
`
`corticosteroid solution delivered to the eye
`efficacy study, it's a dexamethasonederived corticosteroid solution delivered to the eye via
`an iontophoretic drug delivery system that enables
`the
`drug
`
`to problem of low overcome
`
`an iontophoretic drug delivery system that enables the drug to overcome the problem of low
`bioavailability
`that limits other
`topical agents.
`"You have to
`
`try bypass natural barriers to
`
`bioavailability that limits other topical agents. "You have to try to bypass natural barriers
`a
`that are
`in place: the tear film and cornea," Mr. From says.
`"It's
`
`very difficult to
`
`get large
`that are in place: the tear film and cornea," Mr. From says. "It's very difficult to get a large
`quantity of drug into the
`
`front the eye, or of
`
`
`any to the posterior pole of the eye drug
`
`for
`quantity of drug into the front of the eye, or any drug to the posterior pole of the eye for
`retinal diseases."
`
`Iontophoresis also allows EGP-437 to
`
`bypass the method physicians have
`retinal diseases." Iontophoresis also allows EGP-437 to bypass the method physicians have
`had to resort
`to
`
`deliver large quantities
`
`of drug into the
`eye: needles.
`had to resort to deliver large quantities of drug into the eye: needles.
`
`for
`could
`
`The doughnut-shaped applicator holds a sponge saturated
`
`with drug; the
`
`applicator is
`The doughnut-shaped applicator holds a sponge saturated with drug; the applicator is
`placed on the sclera after a topical anesthetic
`
`is applied to prevent the patient's blinking. An
`placed on the sclera after a topical anesthetic is applied to prevent the patient's blinking. An
`electrode at
`
`the base of the applicator
`is connected to a small, handheld generator
`that
`electrode at the base of the applicator is connected to a small, handheld generator that
`supplies a charge. A negatively charged drug in the foam portion gets
`a negative charge
`supplies a charge. A negatively charged drug in the foam portion gets a negative charge to
`the electrode,
`thus
`
`using the principle of electrorepulsion
`to push the drug at
`a high velocity
`the electrode, thus using the principle of electrorepulsion to push the drug at a high velocity
`into the
`eye.
`into the eye.
`
`to
`
`their
`
`the
`
`The process, Mr. From says, requires only a couple of minutes. "Depending on how high the
`The process, Mr. From says, requires only a couple of minutes. "Depending on how high the
`current
`is, or how long we leave this on the eye, will dictate how much drug goes into
`the
`current is, or how long we leave this on the eye, will dictate how much drug goes into the
`eye and how deep
`it penetrates
`into
`the
`eye."
`eye and how deep it penetrates into the eye."
`
`EGP-437 is a small molecule.
`In its recently-completed phase 2 study, it was able to
`treat
`EGP-437 is a small molecule. In its recently-completed phase 2 study, it was able to treat
`multiple signs
`
`and symptoms
`of dry eye, rather
`than just one in each category, Mr. From
`multiple signs and symptoms of dry eye, rather than just one in each category, Mr. From
`says, "So we
`
`actually had the lucky advantage of being able
`to
`
`choose the best
`sign and the
`says, "So we actually had the lucky advantage of being able to choose the best sign and the
`best symptom for our phase 3
`trial."
`
`Even better, he says, was its onset of action, which
`best symptom for our phase 3 trial." Even better, he says, was its onset of action, which
`begins within hours. "If you're a Sjogren's patient and you have severe
`dry
`
`eye, you are in a
`begins within hours. "If you're a Sj6gren's patient and you have severe dry eye, you are in a
`lot of discomfort and pain" and at risk for
`scarring, Mr. From explains. Such patients would
`lot of discomfort and pain" and at risk for scarring, Mr. From explains. Such patients would
`welcome a therapy with rapid onset of action. "No other drug that I'm aware of works as
`welcome a therapy with rapid onset of action. "No other drug that I'm aware of works as
`quickly as
`our
`
`drug is working," he says.
`quickly as our drug is working," he says.
`
`Although data from EyeGate's 83-patient
`
`phase trial are not yet available, 2
`
`
`the company
`Although data from EyeGate's 83-patient phase 2 trial are not yet available, the company
`did say that
`staining
`
`decreased in both fluorescein and lissamine green
`
`dyes, that
`did say that staining decreased in both fluorescein and lissamine green dyes, that
`conjunctival redness was reduced and that
`tear
`
`film breakup
`time increased.
`conjunctival redness was reduced and that tear film breakup time increased.
`
`As for dosage, the drug would be administered in a physician's office, probably on a
`As for dosage, the drug would be administered in a physician's office, probably on a
`quarterly basis, according to Mr. From, depending on severity. The company has begun
`quarterly basis, according to Mr. From, depending on severity. The company has begun
`
`0418
`
`MYLAN - EXHIBIT 1004 (Part 4 of 4)
`
`

`
`Ophthalmology Management
`Ophthalmology Management (cid:9)
`
`Page 3 of 7
`Page 3 of 7
`
`enrolling patients
`for
`the phase 3
`clinical
`
`trial of approximately 180 planned. Mr. From
`enrolling patients for the phase 3 clinical trial of approximately 180 planned. Mr. From
`anticipates
`that
`the
`should trial be completed during the
`
`
`first
`
`quarter 2011, with top-line of
`
`anticipates that the trial should be completed during the first quarter of 2011, with top-line
`data available at the
`end of that period.
`data available at the end of that period.
`
`He describes EyeGate's approach
`as
`
`acute for a chronic problem. "We are able therapy
`
`He describes EyeGate's approach as acute therapy for a chronic problem. "We are able to
`put so much drug in so quickly to
`the
`
`tissues the eye
`
`that
`of knocking down the we're
`
`put so much drug in so quickly to the tissues of the eye that we're knocking down the
`inflammatory cascade
`
`very rapidly. The drug doesn't stay
`
`
`in the eye very long, but the
`inflammatory cascade very rapidly. The drug doesn't stay in the eye very long, but the
`pharmacological
`effect lasts for a long time."
`pharmacological effect lasts for a long time."
`
`to
`
`• CF101. Can-Fite
`
`BioPharma Ltd. recently opened an Investigational New Drug application
`• CF101. Can-Fite BioPharma Ltd. recently opened an Investigational New Drug application
`(IND) with the FDA for a phase 3
`
`study its lead drug, CF101, of
`
`for treatment
`of moderate
`(IND) with the FDA for a phase 3 study of its lead drug, CF101, for treatment of moderate
`to severe
`dry
`eye
`
`disease. Dr. Pnina Fishman, Can-Fite's
`
`CEO, says that
`CF101
`exerts
`to severe dry eye disease. Dr. Pnina Fishman, Can-Fite's CEO, says that CF101 exerts an
`anti-inflammatory
`effect and also an immunomodulatory
`one.
`The
`study be initiated in
`
`anti-inflammatory effect and also an immunomodulatory one. The study will be initiated in
`few months.
`few months.
`
`an
`will
`
`weeks,
`
`An earlier phase 2 study,
`in which CF101 was
`taken orally as
`a monotherapy
`for
`12
`An earlier phase 2 study, in which CF101 was taken orally as a monotherapy for 12 weeks,
`showed a statistically
`significant benefit
`in the clearing
`
`of fluorescein staining in the nasal,
`showed a statistically significant benefit in the clearing of fluorescein staining in the nasal,
`temporal, pupillary and inferior cornea,
`the
`
`company reports. CF101 also
`
`was to be
`temporal, pupillary and inferior cornea, the company reports. CF101 also was found to be
`safe and well tolerated in the Phase 2. Further, the study
`showed a decrease in intraocular
`safe and well tolerated in the Phase 2. Further, the study showed a decrease in intraocular
`pressure
`in patients with dry eye,
`findings
`
`that have prompted Can-Fite to initiate a phase 2
`pressure in patients with dry eye, findings that have prompted Can-Fite to initiate a phase 2
`clinical study
`for
`
`the drug's
`treatment
`
`of glaucoma.
`clinical study for the drug's treatment of glaucoma.
`
`found
`
`discontinuing
`
`The randomized, double-masked phase 3
`
`trial will compare
`two
`oral doses of CF101 to
`The randomized, double-masked phase 3 trial will compare two oral doses of CF101 to
`placebo. Approximately 240 patients
`will be enrolled at multiple centers,
`to be treated
`
`for 24
`placebo. Approximately 240 patients will be enrolled at multiple centers, to be treated for 24
`weeks. The clinical endpoints are
`
`improvement corneal fluorescein staining, of
`
`tear
`weeks. The clinical endpoints are improvement of corneal fluorescein staining, tear
`production and dry eye symptom score.
`production and dry eye symptom score.
`
`bromfenac.
`• Low-dose
`
`Ista Pharmaceuticals' phase 2
`trial of low-dose bromfenac
`• Low-dose bromfenac. Ista Pharmaceuticals' phase 2 trial of low-dose bromfenac
`(Remura) demonstrated improvement
`in both a key sign (lissamine green staining) and in
`(Remura) demonstrated improvement in both a key sign (lissamine green staining) and in
`symptoms
`(as measured by the Ocular Surface
`Disease Index) of dry eye in 38 patients
`
`symptoms (as measured by the Ocular Surface Disease Index) of dry eye in 38 patients
`over a six-week period. Further, patients
`treated with low-dose bromfenac maintained
`the
`over a six-week period. Further, patients treated with low-dose bromfenac maintained the
`improvement
`in signs and
`symptoms
`for
`10
`
`days treatment.
`after
`The
`improvement in signs and symptoms for 10 days after discontinuing treatment. The
`company
`is currently
`in the process of initiating the efficacy portion of the phase 3 program,
`company is currently in the process of initiating the efficacy portion of the phase 3 program,
`which will entail two studies with a total of approximately
`1,000 patients
`followed over a six-
`which will entail two studies with a total of approximately 1,000 patients followed over a six-
`week period, according to Dr. Chandler. The
`
`safety portion of the phase 3 trial Is tentatively
`week period, according to Dr. Chandler. The safety portion of the phase 3 trial is tentatively
`scheduled
`to begin later this year
`
`and will comprise a six-month and a 12-month
`trial, with
`scheduled to begin later this year and will comprise a six-month and a 12-month trial, with
`a total of approximately
`4,000 patients.
`a total of approximately 4,000 patients.
`
`Dr. Chandler notes that
`
`low-dose bromfenac
`could address
`the
`
`impact of inflammation on
`Dr. Chandler notes that low-dose bromfenac could address the impact of inflammation on
`
`the ocular surface, central feature a
`
`
`of dry eye.
`
`"Controlling inflammation could both quiet
`the ocular surface, a central feature of dry eye. "Controlling inflammation could both quiet
`
`the symptoms — that is, irritation, dryness, gritty, sandy
`
`feeling, burning in some cases
`the symptoms — that is, irritation, dryness, gritty, sandy feeling, burning in some cases —
`and improve the
`signs,
`such
`
`as of ocular surface
`
`staining, disease," he explains. The
`and improve the signs, such as staining, of ocular surface disease," he explains. The
`approach yields a dual benefit, Dr. Chandler contends, because of bromfenac's
`efficacy in
`approach yields a dual benefit, Dr. Chandler contends, because of bromfenac's efficacy in
`dealing with pain as well as its ability to interrupt
`the
`
`inflammatory cycle, thereby
`allowing
`dealing with pain as well as its ability to interrupt the inflammatory cycle, thereby allowing
`the ocular surface
`to
`heal.
`
`"There medications
`that
`
`are truly
`address
`very
`the ocular surface to heal. "There are very few medications that truly address the
`inflammatory cascade
`
`that is central to the disease
`
`while improving patient comfort," he
`inflammatory cascade that is central to the disease while improving patient comfort," he
`says.
`says.
`
`—
`
`the
`
`Although the inflammatory etiology of dry eye remains
`theoretical.
`
`Dr. Chandler says
`it does
`
`Although the inflammatory etiology of dry eye remains theoretical, Dr. Chandler says it does
`explain the results
`
`seen in the phase 2 open-label
`trial. Dr. Chandler contends that low-dose
`explain the results seen in the phase 2 open-label trial. Dr. Chandler contends that low-dose
`bromfenac has
`
`an onset of action that
`is "much faster"
`than
`the
`
`approximately eight weeks
`bromfenac has an onset of action that is "much faster" than the approximately eight weeks
`required for
`topical cydosporine.
`In studies completed to date, he
`
`says, the drug produced a
`required for topical cyclosporine. In studies completed to date, he says, the drug produced a
`response rate that hovers around 70%.
`response rate that hovers around 70%.
`
`Regarding safety.
`Dr. Chandler points out that higher-dose
`
`bromfenac
`
`studied in more than
`Regarding safety, Dr. Chandler points out that higher-dose bromfenac studied in more than
`1,600 patients did not result in any serious
`corneal
`adverse
`
`events; ocular adverse
`events
`1,600 patients did not result in any serious corneal adverse events; ocular adverse events
`observed in these studies
`resolved with no sequelae. From the perspective
`of global clinical
`observed in these studies resolved with no sequelae. From the perspective of global clinical
`experience with bromfenac,
`in about 19 million ophthalmic uses
`of the currently marketed
`
`experience with bromfenac, in about 19 million ophthalmic uses of the currently marketed
`higher concentration,
`
`there been 22 serious have
`
`corneal adverse events
`
`reported overall.
`higher concentration, there have been 22 serious corneal adverse events reported overall.
`Not all were considered drug related. Dr. Chandler points out,
`and most were in subjects
`Not all were considered drug related, Dr. Chandler points out, and most were in subjects
`who had undergone cataract
`surgery.
`
`"Lowering the concentration of bromfenac as
`we have
`
`who had undergone cataract surgery. "Lowering the concentration of bromfenac as we have
`done could further
`reduce the likelihood of severe corneal adverse events,"
`
`
`says. he As part
`done could further reduce the likelihood of severe corneal adverse events," he says. As part
`
`0419
`
`

`
`Ophthalmology Management
`Ophthalmology Management (cid:9)
`
`Page 4 of 7
`Page 4 of 7
`
`of its commitment
`to patient safety,
`
`Ista has incorporated frequent monitoring of the cornea
`of its commitment to patient safety, Ista has incorporated frequent monitoring of the cornea
`into the protocols for
`the
`large
`safety being planned.
`
`trials
`into the protocols for the large safety trials being planned.
`• SAR 1118.
`phase 2 results for SAR-118,
`Sarcode
`
`says Corp. that the
`
`a
`
`topical small-
`• SAR 1118. Sarcode Corp. says that the phase 2 results for SAR-118, a topical small-
`molecule
`lymphocyte
`
`function-associated antigen-1
`antagonist,
`
`showed clear improvements
`molecule lymphocyte function-associated antigen-1 antagonist, showed clear improvements
`in signs and symptoms
`of dry eye at
`12
`
`weeks. The trial was a randomized, multisite,
`in signs and symptoms of dry eye at 12 weeks. The trial was a randomized, multisite,
`doublemasked
`study involving 230 subjects.
`Various
`
`dose levels (0.1,
`1.0
`and 5.0%) were
`
`doublemasked study involving 230 subjects. Various dose levels (0.1, 1.0 and 5.0%) were
`compared to placebo, with subjects receiving the
`drops BID for 12 weeks.
`
`The primary
`compared to placebo, with subjects receiving the drops BID for 12 weeks. The primary
`objective measure was inferior corneal staining; major secondary measures were OSDI
`objective measure was inferior corneal staining; major secondary measures were OSDI
`symptom score
`
`and tear production by Schirmer
`test.
`The
`
`company will present
`full details
`symptom score and tear production by Schirmer test. The company will present full details
`
`of the phase 2 study in spring 2011. Sarcode
`is
`
`currently preparing for
`a phase 3
`trial
`to
`of the phase 2 study in spring 2011. Sarcode is currently preparing for a phase 3 trial to
`begin in mid-2011.
`begin in mid-2011.
`• Mapracorat. Bausch + Lomb is addressing the issue of tear hyperosmolarity in dry eye
`• Mapracorat. Bausch + Lomb is addressing the issue of tear hyperosmolarity in dry eye
`disease, which research suggests
`
`is a mechanism involved in ocular surface
`inflammation,
`disease, which research suggests is a mechanism involved in ocular surface inflammation,
`with its selective
`glucocorticoid receptor agonist
`(mapracorat), currently
`in phase 2 trials. In
`with its selective glucocorticoid receptor agonist (mapracorat), currently in phase 2 trials. In
`vitro studies
`suggest
`
`mapracorat inhibits hyperosmolar-induced cytokine release and
`vitro studies suggest mapracorat inhibits hyperosmolar-induced cytokine release and
`mitogenactivated protein kinase pathways
`in human corneal epithelial cells. Development of
`mitogenactivated protein kinase pathways in human corneal epithelial cells. Development of
`the compound continues
`to progress as
`a novel product with a new mechanism of action for
`
`the compound continues to progress as a novel product with a new mechanism of action for
`the treatment
`
`of dry eye,
`according to B+L.
`the treatment of dry eye, according to B+L.
`
`A study in the September
`
`2010 issue of Molecular Vision showed it to have comparable
`A study in the September 2010 issue of Molecular Vision showed it to have comparable
`
`activity to dexamethasone in combating inflammation. The
`investigators
`evaluated
`activity to dexamethasone in combating inflammation. The investigators evaluated
`mapracorat's
`anti-inflammatory
`
`effects in an in vitro osmotic
`stress
`
`model that induced
`mapracorat's anti-inflammatory effects in an in vitro osmotic stress model that induced
`hyperosmolar
`conditions
`
`In cultured human corneal cells. The model stimulated
`
`the release
`hyperosmolar conditions in cultured human corneal cells. The model stimulated the release
`of pro-inflammatory
`cytokines
`
`interieukin-6, interleukin-8
`and monocyte chemotactic
`of pro-inflammatory cytokines interleukin-6, interleukin-8 and monocyte chemotactic
`protein-1, and also altered the phosphorylation state of p38 and c-Jun N-terminal kinase
`protein-1, and also altered the phosphorylation state of p38 and c-Jun N-terminal kinase
`(JNK), and the transcriptional
`
`activity of NFkappaB and AP-1. The researchers
`found
`that
`(JNK), and the transcriptional activity of NFkappaB and AP-1. The researchers found that
`the incubation of cells with mapracorat
`inhibited hyperosmolarinduced cytokine release with
`the incubation of cells with mapracorat inhibited hyperosmolarinduced cytokine release with
`potency comparable
`to the dexamethasone
`
`
`control group. Additionally, increased
`potency comparable to the dexamethasone control group. Additionally, increased
`phosphorylation of p38 and JNK caused by hyperosmolarity was inhibited by mapracorat,
`phosphorylation of p38 and JNK caused by hyperosmolarity was inhibited by mapracorat,
`and the
`compound caused a significant decrease in the hyperosmolar-induced rise in
`and the compound caused a significant decrease in the hyperosmolar-induced rise in
`NFkappaB and AP-1 transcriptional
`activity.
`NFkappaB and AP-1 transcriptional activity.
`• RX-10045. One
`of a class of medicines called resolvins, RX-10045
`
`is a small-molecule
`• RX-10045. One of a class of medicines called resolvins, RX-10045 is a small-molecule
`lipid mediator
`that
`
`Resolvyx Pharmaceuticals
`says
`activates
`the mechanisms
`
`for
`lipid mediator that Resolvyx Pharmaceuticals says activates the body's own mechanisms for
`shutting off inflammation.
`It is administered as a topical eye drop. Resolvyx completed a
`shutting off inflammation. It is administered as a topical eye drop. Resolvyx completed a
`phase 2
`trial last year
`for
`chronic
`
`eye. dry In the randomized, placebo-controlled,
`
`232-
`phase 2 trial last year for chronic dry eye. In the randomized, placebo-controlled, 232-
`patient
`trial, RX-10045 produced dose-dependent,
`statistically
`
`significant improvement
`on
`patient trial, RX-10045 produced dose-dependent, statistically significant improvement on
`the primary endpoints
`for
`
`both the signs
`and
`
`symptoms dry eye,
`
`of and was generally
`the primary endpoints for both the signs and symptoms of dry eye, and was generally
`shown to be safe and well tolerated,
`the
`company
`says.
`shown to be safe and well tolerated, the company says.
`
`The phase 2 study examined three doses
`of RX-10045 and used a controlled adverse
`The phase 2 study examined three doses of RX-10045 and used a controlled adverse
`environment
`(CAE) simulator
`to
`measure
`
`
`
`corneal in a stressful staining drying environment,
`environment (CAE) simulator to measure corneal staining in a stressful drying environment,
`as well as daily patient diaries
`
`using a standard visual analog scale to assess
`symptom
`as well as daily patient diaries using a standard visual analog scale to assess symptom
`improvement
`over
`the
`course the 28-day
`
`
`of study.
`
`The produced a significant drug
`
`improvement over the course of the 28-day study. The drug produced a significant
`dosedependent
`improvement
`
`from baseline
`in symptoms
`recorded in daily patient diaries.
`dosedependent improvement from baseline in symptoms recorded in daily patient diaries. It
`also reduced staining of the central
`cornea by 75% (P<0.00001)
`versus placebo, the
`also reduced staining of the central cornea by 75% (P<0.00001) versus placebo, the
`difference approaching
`
`statistical significance
`(P=0.11).
`
`Additionally, the drug showed a
`difference approaching statistical significance (P=0.11). Additionally, the drug showed a
`significant
`improvement in CAE-induced staining
`in the inferior cornea and in the composite
`significant improvement in CAE-induced staining in the inferior cornea and in the composite
`of central and inferior cornea,
`
`which also approached statistical
`significance
`
`over placebo
`of central and inferior cornea, which also approached statistical significance over placebo
`(P=0.09).
`(P=0.09).
`
`It
`
`Resolvyx says
`
`the phase 3
`trial
`
`should begin by the end of the year.
`Resolvyx says the phase 3 trial should begin by the end of the year.
`• AzaSlte. Currently
`
`there is no prescription product Indicated for blepharitis, a void Inspire
`• AzaSite. Currently there is no prescription product indicated for blepharitis, a void Inspire
`
`Pharmaceuticals would like to
`fill with AzaSite (azithromycin).
`
`
`drug The is already approved
`Pharmaceuticals would like to fill with AzaSite (azithromycin). The drug is already approved
`as a treatment
`
`for bacterial conjunctivitis, but it did not meet statistically
`significant
`as a treatment for bacterial conjunctivitis, but it did not meet statistically significant
`endpoints
`in two phase 2 trials for
`anterior blepharitis
`last
`spring.
`
`Though a four-week
`trial
`endpoints in two phase 2 trials for anterior blepharitis last spring. Though a four-week trial
`did demonstrate
`
`improvement in measured
`signs
`
`and symptoms
`compared
`to placebo,
`
`did demonstrate improvement in measured signs and symptoms compared to placebo,
`statistical
`significance
`
`was not achieved for the primary endpoint of mean lid margin
`statistical significance was not achieved for the primary endpoint of mean lid margin
`hyperemia.
`hyperemia.
`
`body's
`
`0420
`
`

`
`Ophthalmology Management
`Ophthalmology Management (cid:9)
`
`Page 5 of 7
`Page 5 of 7
`
`On the secondary
`endpoints, however, Inspire president and chief executive officer Adrian
`On the secondary endpoints, however, Inspire president and chief executive officer Adrian
`Adams reports
`
`seeing some statistical
`
`significance in the areas
`
`of signs and
`symptoms. In
`Adams reports seeing some statistical significance in the areas of signs and symptoms. In
`the two-week
`trial,
`
`there no statistically were
`
`significant improvements
`for AzaSite
`the two-week trial, there were no statistically significant improvements for AzaSite
`compared
`to vehicle;
`this included the primary endpoint of clearing of lid debris.
`compared to vehicle; this included the primary endpoint of clearing of lid debris.
`The company
`
`says will use the data obtained it
`
`from these studies
`to
`continue
`The company says it will use the data obtained from these studies to continue to develop
`trial parameters
`using AzaSite as
`
`a treatment
`for
`
`both anterior and posterior blepharitis,
`trial parameters using AzaSite as a treatment for both anterior and posterior blepharitis,
`and expects
`
`to refine the
`trial design through the end of this year. The
`
`refinement will
`and expects to refine the trial design through the end of this year. The refinement will
`include study populations and "seeking improved mappability
`for
`
`assessing and measuring
`include study populations and "seeking improved mappability for assessing and measuring
`signs and symptoms,"
`
`says Mr. Adams. "With that, we are
`looking to utilize the
`signs and symptoms," says Mr. Adams. "With that, we are looking to utilize the
`photographic
`reading centers
`
`to maximize the trial."
`photographic reading centers to maximize the trial."
`
`to
`
`develop
`
`Inspire anticipates
`
`completing the additional phase 2 AzaSite clinical work in 2011. The
`Inspire anticipates completing the additional phase 2 AzaSite clinical work in 2011. The
`initiation of the phase 3
`
`
`should trial begin sometime later next year.
`initiation of the phase 3 trial should begin sometime later next year.
`• LX-214. Lux Biosciences' dose-ascending phase 1 trial showed that LX-214, a novel
`• LX-214. Lux Biosciences' dose-ascending phase 1 trial showed that LX-214, a novel
`topical formulation of voclosporin, was
`
`well tolerated by healthy volunteers.
`There was no
`topical formulation of voclosporin, was well tolerated by healthy volunteers. There was no
`difference in tolerability between
`the vehicle control and the concentrations
`of drug tested
`
`difference in tolerability between the vehicle control and the concentrations of drug tested
`(0.2% and 0.02%).
`In five subjects
`diagnosed with dry eye syndrome,
`the
`cohort
`(0.2% and 0.02%). In five subjects diagnosed with dry eye syndrome, the cohort "showed
`some
`improvement in their signs
`(measured by Schirmer's
`tear test)
`and symptoms
`
`some improvement in their signs (measured by Schirmer's tear test) and symptoms
`(measured by the OSDI); most notably, the
`changes
`
`observed occurred in the relatively
`(measured by the OSDI); most notably, the changes observed occurred in the relatively
`brief timeframe
`of the study,
`two weeks compared
`to what has been reported previously
`brief timeframe of the study, two weeks compared to what has been reported previously
`with cyclosporine emulsion,"
`
`according to Dr. Anglade.
`with cyclosporine emulsion," according to Dr. Anglade.
`
`Voclosporin affects the
`
`immune response at
`the
`
`of surface the eye, he explains.
`
`
`"We think
`Voclosporin affects the immune response at the surface of the eye, he explains. "We think
`by controlling the local inflam matory response,
`it will allow the
`
`tear-producing lacrimal
`by controlling the local inflam matory response, it will allow the tear-producing lacrimal
`gland and the
`surface of the eye
`to
`
`heal and improve tear production.
`gland and the surface of the eye to heal and improve tear production.
`LX-214 belongs to
`a class of agents known as calcineurin phosphatase
`inhibitors, developed
`LX-214 belongs to a class of agents known as calcineurin phosphatase inhibitors, developed
`by the company
`into
`a nanomicellar
`formulation.
`
`"This renders LX214, a highly insoluble
`by the company into a nanomicellar formulation. "This renders LX214, a highly insoluble
`compound,
`a solution as
`
`opposed to an emulsion," Dr. Anglade explains. He believes the
`compound, a solution as opposed to an emulsion," Dr. Anglade explains. He believes the
`drug's solution
`formulation will help make it better
`tolerated
`
`than cyclosporine emulsion.
`drug's solution formulation will help make it better tolerated than cyclosporine emulsion.
`
`Another advantage,
`
`says Anglade,
`
`Dr. is voclosporin's higher concentration.
`
`"A limitation of
`Another advantage, says Dr. Anglade, is voclosporin's higher concentration. "A limitation of
`other forms
`
`of topical cyclosporine is that
`sufficiently high concentrations may not be
`other forms of topical cyclosporine is that sufficiently high concentrations may not be
`
`achieved locally. The ability to achieve high local concentrations may translate into
`achieved locally. The ability to achieve high local concentrations may translate into