582
`
`Treprostinil sodium Pharmacia
`Sarat C Chattaraj
`
`Address
`Mylan Pharmaceuticals Inc
`781 Chestnut Ridge Road
`PO Box 4310
`Morgantown
`WV 26504-4310
`USA
`Email: sarat_c82@hotmail.com
`
`Current Opinion in Investigational Drugs 2002 3(4):582-586
` PharmaPress ISSN 1472-4472
`
`United Therapeutics Corp (UTC) is developing treprostinil
`sodium (Remodulin, UT-15), a stable structural analog of
`prostacyclin, for the potential treatment of primary pulmonary
`(arterial) hypertension (PAH), peripheral vascular disease (PVD)
`and other cardiovascular conditions [327593], including critical
`limb ischemia (CLI) [412483].
`
`In August 2000, UTC submitted the initial, non-clinical sections
`of an NDA for the treatment of pulmonary hypertension [378906].
`Treprostinil, which had previously been designated as an Orphan
`Drug, was also awarded Priority Review status by the US FDA in
`October 2000 [385864], [386271]. In December 2000, UTC agreed
`with the FDA that the NDA for treprostinil did not need to be
`presented to the Cardiovascular and Renal Drugs Advisory
`Committee, which was expected to allow UTC and the FDA to
`work towards the 6-month Priority Review timeline [393888]. On
`August 9, 2001, the advisory committee recommended approval of
`treprostinil and UTC refiled the NDA on the same day [418682].
`In February 2002, the FDA issued an approvable letter for
`treprostinil injection for the treatment of PAH. The FDA proposed
`drug labeling for PAH consistent with the treatment of both
`primary and secondary pulmonary hypertension in patients with
`New York Heart Association (NYHA) Class II-IV symptoms. The
`approvable letter also stated that the FDA intended to approve
`treprostinil with a requirement that UTC subsequently conduct a
`post-marketing controlled clinical trial to verify and further
`describe the drug's clinical benefit [439278].
`
`In February 2001, UTC submitted a marketing authorization
`application (MAA) in France for approval of treprostinil for the
`treatment of PAH. Upon approval of the MAA, UTC planned to
`file for Mutual Recognition in other European countries and was
`also preparing similar submissions to non-European countries
`[391986], [397958].
`
`By early 2001, phase II trials of treprostinil for the treatment of
`CLI were underway [412483]. In March 2001, the company was
`planning a phase III pivotal study in late-stage PVD by the end of
`2001 [424180]. In April 2000, UTC was issued US-06054486 for
`the method of treating PVD with treprostinil [364130].
`
`In February 2000, UTC entered into an agreement with Paladin
`Labs for the exclusive Canadian distribution of treprostinil for the
`remainder of clinical trials and after regulatory approvals
`[357302]. In November 2000, UTC and Antigen Pharmaceuticals
`entered into a strategic alliance for the distribution of treprostinil
`in the UK and Ireland [390157].
`
`In November 2000, Deutsche Banc Alex Brown predicted a sales
`potential of US $250 million to US $350 million [418736]. In
`August 2001, Merril Lynch predicted sales of US $10 million to
`$20 million in 2002 [420652].
`
`Originator Pharmacia & Upjohn Co
`
`Licensee GlaxoSmithKline, United Therapeutics Corp
`
`Status Pre-registration
`
`Indication Peripheral vascular disease, Hypertension,
`Cardiovascular disease
`
`Action Vascular agent, Prostacyclin agonist
`
`Synonyms UT-15, Uniprost, Remodulin
`
`CAS Acetic acid, [[(1R,2R,3aS,9aS)-2,3,3a,4,9,9a-
`hexahydro-2-hydroxy-1-[(3S)-3-hydroxyoctyl]-1H-
`benz[f]inden-5-yl]oxy]-
`Registry No: 81846-19-7
`
`O
`
`OH
`
`O
`
`H
`
`OH
`
`H
`
`OH
`
`CH3
`
`Introduction
`Pulmonary arterial hypertension (PAH) is a potentially life-
`threatening heart and lung disease that results from the
`progressive occlusion of blood vessels in the lungs with
`several different manifestations,
`including primary
`pulmonary hypertension (PPH) [378906]. An approved drug
`treatment exists
`for PPH, consisting of continuous
`intravenous Flolan
`(epoprostenol; GlaxoSmithKline), a
`synthetic form of prostacyclin, and oral (tablet) bosentan, an
`endothelin
`antagonist developed by Actelion
`and
`Genentech. Other drugs, like the aerosolized inhaler iloprost
`(Ilomedin, Schering AG, approved in Europe), and oral
`beraprost (United Therapeutics Corp (UTC), approved in
`Japan) are currently at different stages of clinical
`development for PPH [443033], [443034]. This form of the
`disease, targeted by treprostinil sodium, is estimated to
`afflict 50,000 persons in North America and Europe [378906].
`UTC is seeking approval for treprostinil for the long-term
`treatment of PAH in New York Heart Association (NYHA)
`class II, III and IV patients.
`
`PGI2, the major prostanoid that is produced naturally by
`healthy blood vessel walls in the body, inhibits platelet
`aggregation [237635], [408374], [419929], relaxes vascular
`smooth muscle, suppresses smooth muscle proliferation
`[73171],
`[419930] and keeps blood vessels healthy.
`Continuous intravenous infusion of epoprostenol is an
`effective treatment for PPH, but epoprostenol is chemically
`unstable and its intravenous infusion requires the insertion
`of a permanent central venous catheter [365625], [390157].
`Treprostinil sodium, on the other hand, can be delivered
`subcutaneously.
`
`Liquidia's Exhibit 1035
`Page 1
`
`

`

`Anti-infective
`
`Anti-inflammatory
`
`Cardiovascular
`
`CPNS
`
`Oncological
`
`Peripheral arterial disease (PAD) is a disorder involving a
`reduction in natural prostacyclin in blood vessels of the
`lower legs. This results in intermittent claudication and
`critical lower limb ischemia, which occurs late in the course
`of the disease and is the most common cause of pain and
`disability in patients over the age of 40 [408374], [419929]. It
`is estimated to afflict more than 12 million people in North
`America. Severe peripheral vascular disease (PVD) leads to
`more than 100,000 amputations and 300,000 other surgical
`procedures per year in North America alone.
`
`Treprostinil is in development by UTC for the treatment of
`moderate PPH, severe PVD and other cardiovascular
`conditions [327593], [408374].
`
`Pentoxifylline, a blood viscosity-reducing agent and
`cilostazol, a platelet aggregation inhibitor and vasodilator,
`both launched by Otsuka, are the two drugs used for relief
`of claudication approved by the US FDA. Cilostazol is
`limited to patients without a history of congestive heart
`failure and currently there is no drug approved by the FDA
`to treat the symptoms of critical limb ischemia. Treprostinil
`could represent a novel method for the treatment of PVD,
`for which it is particularly suited as it is not degraded when
`it passes through the lungs, and also has a long half-life and
`potent peripheral vasodilatory properties.
`
`Synthesis and SAR
`Treprostinil is a synthetically designed and chemically stable
`tricyclic benzindene analog of
`the natural molecule,
`prostacyclin, but with a
`longer half-life. Structural
`modifications were made to enable the molecule to be
`delivered by subcutaneous infusion with a pager-sized
`MiniMed microinfusion device to patients with pulmonary
`hypertension, compared to a difficult 24-h-a-day, 365-days-
`a-year
`intravenous delivery system required
`for
`the
`currently approved synthetic prostacyclin, epoprostenol
`[378906]. The synthesis of treprostinil has been disclosed
`[419933]. Treprostinil
`is chemically stable at
`room
`temperature and neutral pH.
`
`Pharmacology
`Treprostinil inhibits platelet aggregation, reduces gastric
`secretion and bronchodilation. Treprostinil and related
`compounds are potentially useful as antithrombotics, anti-
`ulcer agents and anti-asthmatic agents. A novel method for
`the treatment of PPH and PVD comprising administration of
`an effective amount of treprostinil is claimed in US-04306075.
`
`Treprostinil (6 and 12 µg/kg iv bolus) administered to
`anesthetized newborn piglets abolished hypoxia-induced
`increases in pulmonary vascular resistance [419933]. A study of
`the effect of treprostinil (0.32 to 3.2 µg/kg iv bolus and 10-min
`infusions) on PVD in anesthetized dogs demonstrated dose-
`dependent decreases
`in mean arterial blood pressure.
`Intravenous infusions of treprostinil (0.1 to 3.0 µg/kg/min) for
`4 h in anesthetized dogs produced dose-dependent decreases in
`mean total peripheral vascular resistance [419933].
`
`The effects of treprostinil were also studied in experimental
`pulmonary hypertension models - an open-chest preparation
`of an anesthetized cat and a conscious spontaneously
`hypertensive rat model. Each animal was dosed by iv
`
`Treprostinil sodium Chattaraj 583
`
`infusions of treprostinil equivalent to 100 or 300 ng and 1 or 3
`µg/kg/min infused over a period of 20 min. Hypoxia was
`induced in the animal during the last 5 min of the infusion.
`Treprostinil
`reduced hypoxia-induced
`increases
`in
`pulmonary arterial pressure and pulmonary vascular
`resistance in a dose-related manner without appreciably
`affecting cardiac output or heart rate. At higher doses, the
`test compound reduced systemic arterial pressure and
`systemic vascular resistance. The study also reported that
`hypoxia-induced pulmonary vasoconstriction could be
`reduced without disturbing the systemic hemodynamics, by
`suitably adjusting the dose [419934].
`
`The usefulness of the nasal route of administration of
`treprostinil and treprostinil conjugated to polyethylene glycol
`(PEG) was tested in the male Wistar rat model. The effect of a
`single
`intratracheal
`instillation of
`treprostinil or PEG-
`treprostinil was compared to vehicle (phosphate buffer, saline
`or PEG) and papvarine. Treprostinil is an effective pulmonary
`vasodilator when delivered via the airways, and PEGylation
`extends the time course of this action [419931].
`
`is characterized by
`Primary pulmonary hypertension
`increased pulmonary vascular resistance and smooth muscle
`proliferation [443036]. The antiproliferative activity of several
`prostacyclin (PGI2) analogs on human pulmonary arterial
`smooth muscle cells showed a ranking in effectiveness:
`treprostinil > iloprost > cicaprost > beraprost [443036].
`
`Metabolism
`The bioavailability of treprostinil was tested in a crossover
`design study in 15 healthy volunteers. The mean half-life of
`treprostinil administered intravenously was 0.9 h and
`subcutaneously was 1.5 h [Wade M, United Therapeutics,
`unpublished data], [408374].
`
`Toxicity
`No data are currently available.
`
`Clinical Development
`In May 2001, UTC reported data based on 50 patients and
`showing
`that patients with pulmonary hypertension
`increased their baseline walking distance by an average of
`40 m after 12 months of treprostinil therapy [408490]. In May
`2000, UTC filed an IND with the US FDA to commence a
`clinical study to investigate the safety of transitioning PPH
`patients from epoprostenol to treprostinil [365625].
`
`Preliminary analysis of UTC's pivotal trial in March 2000
`demonstrated that patients who received treprostinil achieved a
`significant improvement in their ability to exercise, compared
`to those receiving placebo. In addition, patients treated with
`treprostinil
`achieved
`a
`significant
`improvement
`in
`cardiopulmonary hemodynamic parameters
`[360910]. A
`reduction in mean pulmonary arterial pressure of 3 mmHg, an
`increase in cardiac output of 0.35 l/min and a reduction in
`pulmonary vascular resistance of 5 Woods Units were reported.
`The drug was well tolerated and effective in the treatment of
`pulmonary hypertension and improved the quality of life of the
`patients using it [380399].
`
`Phase I/II
`Eight patients with moderate to severe PVD (Fontaine Stage
`IIb-III) were administered intravenously with placebo for a
`
`Liquidia's Exhibit 1035
`Page 2
`
`

`

`584 Current Opinion in Investigational Drugs 2002 Vol 3 No 4
`
`minimum of 30 min and then with increasing doses of
`treprostinil (1 h of dosing at each dose step) up to the
`maximum tolerated dose. Common side effects at peak dose
`were headache and nausea, but no serious adverse events
`were noted during hospitalization. The most common
`maintenance dosing level was 10 ng/kg/min. The study also
`showed that blood flow velocity in lower limb arteries in each
`patient was
`increased significantly. Acute
`intravenous
`treprostinil administration was well tolerated in patients with
`moderate-to-severe PVD [419933].
`
`A 26-patient study for PPH concluded that intravenous
`treprostinil is a safe treatment for PPH and favorably affects
`hemodynamics and exercise tolerance. It was well tolerated
`and worked similarly to epoprostenol [338441]. The safety
`and efficacy of long-term treprostinil therapy for PPH was
`studied in 14 patients (three males and 11 females). Baseline
`and follow-up 6 min distances, hemodynamics and NYHA
`functional class were evaluated. Six patients dropped out
`and the study was continued for approximately 13 months
`with eight patients. One patient was withdrawn due to
`inability to achieve a tolerable dose; two were withdrawn
`due to intolerable pain at the infusion site and three were
`withdrawn due to clinical deterioration. The study showed
`that treprostinil significantly improved exercise capacity
`during the first year of treatment [408373].
`
`The safety, efficacy and hemodynamic effects of treprostinil
`were studied in eight patients with stable severe intermittent
`claudication. A symptom-limited, dose-escalation protocol
`was followed, beginning with placebo and then with
`increasing doses at 60-min intervals, followed by a 2-h period
`of maintenance dose up to the maximum tolerated infusion.
`In most patients, the optimal infusion rate was 10 to 20
`ng/kg/min. Hemodynamics in lower extremity arteries were
`evaluated with a duplex ultrasound technique. Treprostinil
`was well tolerated and increased the blood flow in most of the
`peripheral arteries of the lower limb. The study reported an
`increase in blood flow in the femoral artery and increased
`blood velocity in downstream arteries of the lower extremities
`of patients with PAD [300147], [316467], [408374].
`
`Phase III
`The safety and efficacy of treprostinil was investigated in
`patients with PAH. A total of 470 patients were randomized
`in a parallel, placebo-controlled 12-week trial with the
`primary endpoint being exercise capacity assessed by a 6
`min walk. The results demonstrated the safety and efficacy
`of treprostinil for the use of primary and secondary
`pulmonary hypertension. The p value of the primary
`endpoint of the ability to exercise was 0.006, which was
`based on 232 patients randomized to treprostinil and 237
`patients randomized to placebo. The majority of patients
`(86% and 93%, respectively randomized to treprostinil and
`placebo), completed the 12-week study. The difference in
`completion rates was due to patients on treprostinil who
`discontinued their participation as a result of pain at the
`subcutaneous injection site [380399]. On average, patients on
`
`treprostinil walked 20 m further than control patients after 6
`min, and those who achieved doses in the highest quartile
`walked 35 m further than control patients [385864]. Exercise
`capacity was reduced more in patients receiving placebo
`than in those receiving treprostinil. In addition, treprostinil
`improved hemodynamic parameters, clinical signs and
`symptoms, was well tolerated and produced significant and
`sustained favorable effects in PAH, demonstrating its
`usefulness in the management of PAH [389245], [389663].
`Preliminary data from this trial demonstrated significant
`improvements in the patients' ability to exercise [363255].
`
`Side Effects and Contraindications
`Dose-limiting side effects reported during treatment were
`moderate and included headache and nausea [316467], jaw
`pain, diarrhea, edema, flushing and infusion site pain [300147].
`
`Current Opinion
`There is a therapeutic need for more effective PPH and PVD
`treatments. A few agents are currently being used in PPD
`and PVD management but, although their effectiveness has
`been proved,
`associated problems
`are numerous.
`Epoprostenol lasts only a few minutes, resulting in rapid
`dissipation of its hemodynamic effects, and any inadvertent
`interruption of
`the
`infusion can be potentially
`life-
`threatening. Also, as prostacyclin is a very fragile molecule,
`the infusion must be intravenous via a surgically implanted
`catheter, which is very inconvenient.
`
`Treprostinil is designed to be a non-intravenous treatment of
`PPH and has demonstrated positive preliminary results in a
`pivotal phase III trial. Like prostacyclin, it is a vasodilator with
`platelet anti-aggregatory action that may improve blood flow in
`the lower limbs of patients with PAD. A key benefit of
`treprostinil is that it remains biologically active for a much
`longer time than epoprostenol, and that intravenous delivery or
`a surgically-implanted catheter are not required. Subcutaneous
`delivery can be performed using the infusion pump that
`diabetics use for insulin, allowing for outpatient administration.
`In such circumstances a stable,
`long-acting molecule,
`administered via a convenient route, could be advantageous,
`and the pharmacodynamic and functional pharmacokinetic
`profile of treprostinil indicates that it could be used for the
`treatment of PPH. The current analysis suggests that the
`adverse effects are injection site pain, headaches, nausea,
`diarrhea,
`jaw pain and
`flushing. Unlike epoprostenol,
`treprostinil remains stable at room temperature, does not
`require reconstitution and is unlikely to cause serious infections
`due to its subcutaneous method of delivery [365625].
`
`According to leading pulmonary hypertension specialists,
`treprostinil is well tolerated by patients with pulmonary
`hypertension and significantly relieves their symptoms and
`increases their exercise capability. Further studies to
`investigate the effects of long-term use of treprostinil, the
`development of tolerance, any withdrawal effects and its
`metabolism in humans, are required.
`
`Licensing
`Glaxo Wellcome plc and United Therapeutics Corp
`Treprostinil was designed and tested by the Upjohn Co and Burroughs-Wellcome in the early 1990s, but after Pharmacia
`acquired Upjohn, and Glaxo (now GlaxoSmithKline; GSK) acquired Burroughs-Wellcome in the mid-1990s, Glaxo and
`Pharmacia agreed to license treprostinil exclusively to United Therapeutics in 1997 in exchange for royalties [316494].
`
`Liquidia's Exhibit 1035
`Page 3
`
`

`

`Treprostinil sodium Chattaraj 585
`
`Date
`12-FEB-02
`
`12-FEB-02
`
`07-FEB-01
`
`15-AUG-00
`
`01-DEC-99
`
`01-DEC-99
`
`01-DEC-99
`
`Anti-infective
`
`Reference
`439278
`
`439278
`
`397958
`
`378906
`
`346837
`
`346837
`
`346837
`
`300147
`
`365625
`
`316494
`
`Development history
`Developer
`United Therapeutics Corp
`
`Country
`Switzerland
`
`Status
`Pre-registration
`
`Indication
`Hypertension
`
`United Therapeutics Corp
`
`Canada
`
`Pre-registration
`
`Hypertension
`
`United Therapeutics Corp
`
`France
`
`Pre-registration
`
`Hypertension
`
`United Therapeutics Corp
`
`US
`
`Pre-registration
`
`Hypertension
`
`United Therapeutics Corp
`
`Western Europe
`
`Phase III
`
`Hypertension
`
`United Therapeutics Corp
`
`Israel
`
`United Therapeutics Corp
`
`Australia
`
`United Therapeutics Corp
`
`United Therapeutics Corp
`
`US
`
`US
`
`Phase III
`
`Phase III
`
`Phase II
`
`Hypertension
`
`Hypertension
`
`Peripheral vascular disease
`
`06-OCT-98
`
`Discovery
`
`Cardiovascular disease
`
`10-MAY-00
`
`Anti-inflammatory
`
`Cardiovascular
`
`CPNS
`
`Oncological
`
`Glaxo Wellcome plc
`
`Pharmacia & Upjohn Inc
`
`US
`
`US
`
`Discontinued
`
`Peripheral vascular disease
`
`01-DEC-97
`
`Discontinued
`
`Peripheral vascular disease
`
`01-DEC-97
`
`316494
`
`Literature classifications
`Chemistry
`Study Type
`Synthesis and SAR.
`
`Result
`Synthesis of tresprostinil, a chemically-stable tricyclic benzindene analog of the natural molecule
`prostacyclin, which is stable at room temperature.
`
`Biology
`Study Type
`In vivo
`
`Effect Studied
`Pulmonary vascular
`resistance.
`
`Experimental Model
`Anesthetized newborn piglets
`administered treprostinil (6 and 12
`µg/kg iv).
`
`Result
`Abolished hypoxia-induced
`increases in pulmonary vascular
`resistance.
`
`Reference
`419933
`
`Reference
`419933
`
`In vivo
`
`PVD.
`
`Anesthetized dogs administered
`treprostinil (0.32 to 3.2 µg/kg iv) in
`10-min infusions.
`
`Dose-dependent decreases in mean
`arterial blood pressure.
`
`419933
`
`In vivo
`
`In vivo
`
`Peripheral vascular
`resistance.
`
`Anesthetized dogs administered
`treprostinil (0.1 to 3.0 µg/kg iv) for 4 h.
`
`Dose-dependent decreases in mean
`total peripheral vascular resistance.
`
`Pulmonary
`hypertension.
`
`Anesthetized cat open-chest model
`and conscious spontaneously
`hypertensive rat, treprostinil (100 ng,
`300 ng, 1 µg and 3 µg/kg/min iv) for
`20 min. Hypoxia was induced in last
`5 min of infusion.
`
`Dose-dependently reduced hypoxia-
`induced increase in pulmonary
`arterial pressure and pulmonary
`vascular resistance. Higher doses
`caused reduction in systemic arterial
`pressure and systemic vascular
`resistance.
`
`419933
`
`419934
`
`In vivo
`
`Route of administration.
`
`Treprostinil and PEGylated
`treprostinil in male Wistar rats.
`
`Effective when delivered via the
`airways; PEGylation extends the
`time course of action.
`
`419931
`
`Metabolism
`Study Type
`In vivo
`
`Effect Studied
`Bioavailability.
`
`Model Used
`Phase I trial in 15 healthy
`volunteers.
`
`Result
`Mean t½ of treprostinil = 0.9 h (iv)
`and 1.5 h (sc).
`
`Reference
`408374
`
`Clinical
`Effect Studied
`Safety and efficacy.
`
`Model Used
`Phase II trial in patients with
`intermittent claudication.
`
`Result
`Optimal infusion rate was 10 to 20 ng/kg/min. The drug was
`well-tolerated and increased blood flow and velocity in
`femoral artery and downstream arteries was observed.
`Dose-limiting side effects were headache and nausea.
`
`Reference
`316467
`
`Safety and efficacy.
`
`Phase III trial in 470 patients with
`pulmonary arterial hypertension.
`
`Patients who received treprostinil walked 20 m further in 6 min
`than control patients. Treprostinil was well tolerated (p = 0.006).
`
`380399
`
`Liquidia's Exhibit 1035
`Page 4
`
`

`

`586 Current Opinion in Investigational Drugs 2002 Vol 3 No 4
`
`Associated patent
`
`Title Use of 9-deoxy-2',9-α-methano-3-oxa-4,5,6-trinor-3,7-(1',3'-interphenylene)-
`13,14-dihydro-prostaglandin F1 to treat peripheral vascular disease.
`
`Assignee United Therapeutics Corp
`
`Publication WO-09925357 27-MAY-99
`
`Priority US-00066049 14-NOV-97
`
`389245 Efficacy and safety of chronic subcutaneous infusion UT-15 in
`pulmonary arterial hypertension (PAH). Barst RJ, Simonneau G, Rich S,
`Blackburn SD, Naeije R, Rubin LJ CIRCULATION 2000 102 18 Abs 477
`
`-
`389663 American Heart Association 73rd Scientific Sessions
`OVERNIGHT REPORT (Part II), New Orleans, LA, USA. Ahmed T IDDB
`MEETING REPORT 2000 November 12-15
`
`390157 United Therapeutics and Antigen Phamaceuticals sign UT-15
`distribution agreement for the United Kingdom and Ireland. United
`Therapeutics Corp PRESS RELEASE 2000 November 16
`
`Inventors Crow JW, Blackburn SD, Roscigno R, Wade M, Cloutier G,
`Rothblatt M.
`
`391986 United Therapeutics plans expected transition to commercial
`operations. United Therapeutics Corp PRESS RELEASE 2000 December 01
`
`Associated references
`
`73171 Effects of prostacyclin and orally active stable mimetic agent RS-
`93427-007 on basic mechanisms of atherogenesis. Willis AL, Smith-DL,
`Vigo C, Kluge AF LANCET 1986 2 8508 682-683
`
`237635 Pharmacodynamic profile of prostacyclin. Vane JR, Botting RM
`AM J CARDIOL 1995 75 3 3A-10A
`
`300147 United Therapeutics Corporation completes successful pilot
`study in peripheral vascular disease. United Therapeutics Corp PRESS
`RELEASE 1998 October 01
`
`316467 Phase II trial of a novel prostacyclin analog, UT-15, in patients with
`severe intermittent claudication. Mohler ER, Klugherz B, Goldman R, Fishman
`AP, Wade M, Sehgal CM J AM COLL CARDIOL 1999 33 2 Abs 840-843
`
`316494 United Therapeutics home-page. United Therapeutics Corp
`COMPANY WORLD WIDE WEB SITE 1999 February 26
`
`to support pulmonary
`327593 United Therapeutics Telemedicine
`hypertension trial. FDC REPORTS PINK SHEET 1999 61 23 21-22
`
`338441 United Therapeutics Corp clinical trial data announced at
`European Society of Cardiology. United Therapeutics Corp PRESS
`RELEASE 1999 August 31
`
`346837 United Therapeutics completes patient enrollment in second of
`two phase III clinical trials of UT-15 in pulmonary hypertension. United
`Therapeutics Corp PRESS RELEASE 1999 November 08
`
`357302 United Therapeutics signs Canadian distribution agreement with
`Paladin Labs for Uniprost. Unigene Therapeutics Corp PRESS RELEASE
`2000 February 25
`
`360910 United Therapeutics announces positive results from pivotal
`pulmonary hypertension trial. United Therapeutics Corp PRESS RELEASE
`2000 March 27
`
`363255 Uniprost posts positive results from pivotal phase III study;
`Synsorb Cd commences phase III trial. Paladin Labs Inc PRESS RELEASE
`2000 April 14
`
`364130 United Therapeutics granted patent for treatment of peripheral
`vascular disease with Uniprost. United Therapeutics Corp PRESS
`RELEASE 2000 April 25
`• US-06054486 is equivalent to WO-09925357. The claims are to the use of
`treprostinil for PVD.
`
`365625 United Therapeutics announces commencement of Flolan-to-
`Uniprost transition study in pulmonary hypertension. United Therapeutics
`Corp PRESS RELEASE 2000 May 08
`
`378906 United Therapeutics submits initial sections of Uniprost NDA.
`United Therapeutics Corp PRESS RELEASE 2000 August 14
`
`380399 United Therapeutics Corporation: pulmonary hypertension
`clinical trial discussed at seminar associated with European Cardiology
`Conference. United Therapeutics Corp PRESS RELEASE 2000 August 28
`
`385864 United Therapeutics Corporation announces filing of NDA for
`pulmonary hypertension drug at Salomon Smith Barney Health Care
`Conference in New York. United Therapeutics Corp PRESS RELEASE 2000
`October 16
`
`386271 FDA grants Priority Review to United Therapeutics New Drug
`Application for pulmonary hypertension. United Therapeutics Corp
`PRESS RELEASE 2000 October 19
`
`393888 United Therapeutics announces UT-15 NDA will not require FDA
`Advisory Committee. United Therapeutics Corp PRESS RELEASE 2000
`December 14
`
`397958 United Therapeutics Corporation announces submission of MAA
`in France. United Therapeutics Corp PRESS RELEASE 2001 February 05
`
`408373 Efficacy of long-term subcutaneous infusion of UT-15 in primary
`pulmonary hypertension. Baarst RJ, Horn EM, Widlitz AC, Goudie SM, Kerstein
`D, Berman-Rosenzweig E, Blackburn SD EUR HEART J 2000 21 315
`
`408374 Trial of a novel prostacyclin analog, UT-15, in patients with
`severe intermittent claudication. Mohler III ER, Klugherz B, Goldman R,
`Kimmel SE, Wade M, Sehgal CM VASC MED 2000 5 4 231-237
`
`408490 United Therapeutics announces presentations of long-term
`follow-up data on Remodulin patients. United Therapeutics Corp PRESS
`RELEASE 2001 May 09
`
`412483 Annual Report 2000 - United Therapeutics Corp. United
`Therapeutics Corp ANNUAL REPORT 2000 December 31
`
`418682 FDA advisory committee recommends approval of Remodulin for
`pulmonary arterial hypertension. United Therapeutics Corp PRESS
`RELEASE 2001 August 09
`
`418736 United Therapeutics Corp - data presented provide further
`evidence supporting approvability and clinical utility of Uniprost.
`DEUTSCHE BANC ALEX BROWN 2000 November 14
`
`419929 The prevalence of peripheral arterial disease in a defined
`population. Criqui MH, Fronek A, Barrett-Conor E, Klauber MR, Gabriel S,
`Goodman D CIRCULATION 1985 71 510-515
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`419930 Prostaglandins and cyclic nucleotides. Hajjar DP BIOCHEM
`PHARMACOL 1985 34 295 - 300
`
`419931 Pulmonary vasodilation by airway delivered prostacyclin analogues,
`UT-15 & Pegylated UT-15. Emery CJ, Lal H, Marriott HM, Whittle BJR, Shorr R,
`Bentley M, Zhao X, Higenbottam TW THORAX 2000 55 Suppl 3 A35
`419933 US-06054486: Use of 9-deoxy-2',9-αααα-methano-3-oxa-4,5,6-trinor-
`to
`treat
`F1
`3,7-(1',3'-interphenylene)-13,14-dihydro-prostaglandin
`peripheral vascular disease. Crow JW, Blackburn J, Shelmer D, Roscigno
`R, Wade M, Cloutier G, Rothblatt M US PATENT 2000 April 25
`
`419934 US-05153222: Method of treating pulmonary hypertension with
`benzidine prostaglandins. Tadepalli AS, Long WA, Crow JW, Klein KB US
`PATENT 1992 October 6
`
`420652 Priority Healthcare Corp - The tide is turning. MERRILL LYNCH
`CAPITAL MARKETS 2001 August 10
`
`424180 United Therapeutics Corp: Form 10K. Unitech Pharmaceuticals Inc
`FORM 10-K 2001 March 30
`
`for
`letter
`439278 United Therapeutics receives FDA approvable
`Remodulin to treat pulmonary arterial hypertension. United Therapeutics
`Corp PRESS RELEASE 2002 February 11
`
`443033 Medical therapy of pulmonary hypertension. The prostacyclins.
`Galie N, Manes A, Branzi A CLIN CHEST MED 2001 22 3 529-537
`
`443034 Use of prostacyclin and its analogues in the treatment of
`cardiovascular disease. Fink AN, Frishman WH, Azizad M, Agarwal Y
`HEART DIS 1999 1 1 29-40
`
`443036 Differential effects of stable prostacyclin analogs on smooth
`muscle proliferation and cyclic AMP generation in human pulmonary
`artery. Clapp LH, Finney P, Turcato S, Tran S, Rubin LJ, Tinker A AM J
`RESPIR CEL MOL BIOL 2002 26 2 194-201
`
`Liquidia's Exhibit 1035
`Page 5
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