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The following is an excerpt from a 10-K SEC Filing, filed by UNITED THERAPEUTICS CORP on 2/26/2009.
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UNITED THERAPEUTICS CORP - 10-K - 20090226 - BUSINESS

ITEM 1.    BUSINESS

        We are a biotechnology company focused on the development and commercialization of unique products to address the unmet medical needs of patients with chronic and life-threatening cardiovascular and infectious diseases and cancer.

        Our key therapeutic platforms are:

    Prostacyclin Analogues , which are stable synthetic forms of prostacyclin, an important molecule produced by the body that has powerful effects on blood vessel health and function. Our lead prostacyclin analogue is Remodulin®, a treprostinil-based compound for the treatment of cardiovascular disease. Remodulin (treprostinil sodium) Injection has been approved by the U.S. Food and Drug Administration (FDA) for the treatment of pulmonary arterial hypertension (PAH) in patients with New York Heart Association (NYHA) Class II-IV (moderate to severe) symptoms to diminish symptoms associated with exercise. Remodulin has been approved in most of Europe for the treatment of NYHA Class III patients with idiopathic (familial) PAH and in other countries for use similar to that for which it is approved in the United States. Our inhaled and oral formulations of treprostinil are in the later stages of development. A New Drug Application (NDA) for our inhaled formulation is currently under review by the FDA and a Marketing Authorization Application (MAA) is currently under review by the European Medicines Agency (EMEA). We are also developing modified release beraprost (beraprost-MR), another prostacyclin analogue, for the treatment of PAH;

    Phosphodiesterase 5 (PDE5) inhibitors , which act to inhibit the degradation of cyclic guanosine monophosphate (cGMP) in cells. CGMP is activated by nitric oxide (NO) to signal relaxation of vascular smooth muscle. Our investigational therapy in this platform is tadalafil, a product developed by Eli Lilly and Company (Lilly). Lilly's NDA for tadalafil for the treatment of PAH is currently under review by the FDA. We entered into a license agreement with Lilly to obtain certain rights to tadalafil for PAH, effective December 18, 2008;

    Monoclonal Antibodies , which are antibodies that activate patients' immune systems to treat cancer. Our platform includes the 3F8 and 8H9 murine antibodies, which we are developing for the treatment of neuroblastoma and metastatic brain cancer, respectively. We expect to begin a Phase II clinical trial in the second quarter of 2009 of the 3F8 antibody in patients with neuroblastoma; and

    Glycobiology Antiviral Agents , which are a novel class of small, sugar-like molecules that have shown pre-clinical indications of efficacy against a broad range of viruses, such as hepatitis C.

        We devote most of our resources to developing products within our key therapeutic platforms. We also devote resources to the commercialization and further development of telemedicine products and services, principally for the detection of cardiac arrhythmias (abnormal heart rhythms).

        We generate revenues from the sale of Remodulin and telemedicine products and services. Our sales and marketing staff for Remodulin, which is supplemented by our specialty pharmaceutical distributors, supports the commercial availability of Remodulin in the United States, Canada, Europe and other countries.

        United Therapeutics was incorporated in Delaware in June 1996. Our principal executive offices are located at 1110 Spring Street, Silver Spring, Maryland 20910. We also maintain executive offices at 55 T.W. Alexander Drive, Research Triangle Park, North Carolina 27709.

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        Unless the context requires otherwise or unless otherwise noted, all references in this Annual Report on Form 10-K to "United Therapeutics" and to the "company", "we", "us" or "our" are to United Therapeutics Corporation and its subsidiaries.

Our Products

        Our product portfolio includes the following as of December 31, 2008:

Product
  Mode of
Delivery
  Indication/Market   Current Status   Our Territory

Remodulin

  Continuous subcutaneous     Pulmonary arterial hypertension   Commercial in the U.S., most of Europe*, Canada, Israel, Australia, Mexico, Argentina and Peru;
MAA filed with EMEA
  Worldwide

Remodulin

 

Continuous intravenous

   

Pulmonary arterial hypertension

 

Commercial in the U.S., Canada, Israel, Mexico, Argentina and Peru;
MAA filed with EMEA

 

Worldwide

CardioPAL® SAVI and Decipher Cardiac Monitors

 

Telemedicine

   

Cardiac arrhythmias and ischemic heart disease

 

Commercial

 

Worldwide

Inhaled Treprostinil

 

Inhaled

   

Pulmonary arterial hypertension

 

NDA filed with FDA;
MAA filed with EMEA

 

Worldwide

Oral Tadalafil

 

Oral

   

Pulmonary hypertension

 

NDA filed with FDA

 

United States

Oral Treprostinil

 

Oral

   

Pulmonary arterial hypertension

 

Phase III

 

Worldwide

Beraprost-MR

 

Oral

   

Pulmonary arterial hypertension

 

Phase II

 

North America/Europe

3F8 MAb

 

Intravenous

   

Neuroblastoma

 

Phase II

 

Worldwide

Oral Treprostinil

 

Oral

   

Peripheral vascular disease

 

Phase II

 

Worldwide

CardioPAL SAVI Wireless Cardiac Event Monitors

 

Telemedicine

   

Cardiac arrhythmias and ischemic heart disease

 

Phase II

 

Worldwide

Inhaled Treprostinil

 

Inhaled

   

Pulmonary arterial hypertension associated with Idiopathic pulmonary fibrosis

 

Phase I

 

Worldwide

Inhaled Treprostinil with AERx Essence®

 

Inhaled

   

Pulmonary hypertension

 

Phase I

 

Worldwide

8H9 MAb

 

Intravenous

   

Metastatic brain cancer

 

Phase I

 

Worldwide

Celgosivir

 

Oral

   

Hepatitis C

 

Phase I

 

Worldwide

Miglustat

 

Oral

   

Hepatitis C

 

Pre-Clinical

 

Worldwide

Glycobiology Antiviral Agents

 

Oral

   

Hepatitis C and other infectious diseases

 

Pre-Clinical

 

Worldwide


*
We have obtained approval in 23 member countries of the European Union (EU), as well as European countries that are not members of the EU. We have received formal approval letters and pricing approval in most of these countries.

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Remodulin

        Our lead product for treating PAH is Remodulin (treprostinil sodium) Injection, the main ingredient of which is treprostinil sodium, a prostacyclin analogue. We sell Remodulin to our specialty pharmaceutical distributors in the United States at a discount from an average wholesale price recommended by us, and to our international distributors at a transfer price set by us. We recognized approximately $269.7 million, $200.9 million and $152.5 million in Remodulin revenues, representing 96%, 95% and 96% of our net revenues in 2008, 2007 and 2006, respectively. We obtained worldwide rights for all indications to Remodulin from GlaxoSmithKline PLC (formerly Glaxo Wellcome, Inc.) (Glaxo) in January 1997 and from Pfizer, Inc. (formerly Pharmacia & Upjohn Company)(Pfizer) in December 1996. In May 2002, Remodulin was approved by the FDA as a continuous subcutaneous (under the skin) infusion for the treatment of PAH in patients with NYHA Class II-IV (moderate to severe) symptoms. In November 2004, the FDA expanded its approval to permit continuous intravenous (through a vein) infusion for patients who cannot tolerate subcutaneous infusion. In March 2006, the FDA expanded its approval to include transition of patients to Remodulin from Flolan® (epoprostenol), the first FDA-approved prostacyclin for PAH. Remodulin is also approved as a continuous subcutaneous infusion treatment for various forms of PAH in 33 countries throughout the world, and as a continuous intravenous infusion treatment for various forms of PAH in Canada, Israel, Mexico, Peru and Argentina. Applications for approval for both subcutaneous and intravenous Remodulin infusion are under review in many other countries. We continue to work on expanding Remodulin commercialization to other new territories, including Japan.

        PAH is a life-threatening disease that affects the blood vessels in the lungs and is characterized by increased blood pressure in the blood vessels leading from the heart to the lungs, known as the pulmonary arteries. The elevated pressure in the pulmonary arteries strains the right side of the heart as it pumps blood to the lungs leading to right heart failure and death. PAH is characterized by the disruption of blood vessel walls, the aggregation of platelets and the alteration of smooth muscle function. It is estimated that PAH affects between 100,000 and 200,000 individuals worldwide. In recent years, as awareness of PAH has grown, we have seen an increase in the number of people diagnosed with the disease. However, because of the rarity of PAH and the complexity of diagnosing it, only a small fraction of patients with PAH are being treated. There is scientific interest in identifying easier, less invasive methods of diagnosing PAH. If this research is successful, more patients could be diagnosed at an earlier stage of the disease.

        The complexity of diagnosing PAH reflects in part the current uncertainties surrounding the etiology and pathophysiology of the condition. Currently, treatment of PAH focuses on three distinct molecular pathways that have been implicated in the disease process. These are the endothelin pathway, the NO pathway, and the prostacyclin pathway. Patients with PAH have been shown to have elevated levels of endothelin, a naturally occurring substance in the body that causes constriction of the pulmonary blood vessels. Therefore, one established therapeutic approach has been to block the action of endothelin with drugs that are known as endothelin receptor antagonists (ERAs). Patients with PAH have also been shown to have reduced levels of the enzyme responsible for producing NO, a naturally occurring substance in the body that has the effect of relaxing pulmonary blood vessels. NO produces this effect by increasing intracellular levels of an intermediary known as cGMP. Therefore, another established therapeutic approach has been to inhibit the degradation of cGMP, using drugs that are termed Phosphodiesterase 5 (PDE5) inhibitors. Finally, patients with PAH have been shown to have reduced levels of prostacyclin, a naturally occurring substance that has the effect of relaxing the pulmonary blood vessels, preventing platelet aggregation, and inhibiting the proliferation of smooth muscle cells in pulmonary vessels. Therefore, drugs that mimic the action of prostacyclin, termed prostacyclin analogues, are also established PAH treatments. Because any or all of these three pathways may be operative in a patient, these three classes of drugs are used alone or in combination to treat patients with PAH. We currently market Remodulin, a prostacyclin analogue, and are awaiting FDA approval to market tadalafil, a PDE5 inhibitor, for the treatment of pulmonary hypertension.

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        A long-term outcome study published in the European Respiratory Journal (vol. 28, Number 6; December 2006) demonstrated improved survival with Remodulin therapy when compared to predicted survival (NIH registry formula) over a four-year period. One-, two-, three- and four-year survival was 87%, 78%, 71%, and 68%, respectively, for all 860 patients in the study (including 130 patients who received Remodulin in combination with other PAH therapies) and 88%, 79%, 73%, and 70%, respectively, for 730 of the patients in the study who received only Remodulin. In patients with idiopathic PAH for whom baseline hemodynamics (measurement of bloodflow and pressures) were available (332 patients), survival was 91%, 82%, 76%, and 72% at years one through four, respectively. This compares to respective predicted survival estimates of 69%, 56%, 46%, and 38% over the four-year period based on the NIH registry formula.

        Flolan, the first FDA-approved prostacyclin analogue for PAH, is delivered continuously through a surgically implanted intravenous catheter connected to an external pump. Flolan is approved for the treatment of patients with certain subsets of late-stage PAH. We believe Remodulin provides patients with a less invasive alternative to Flolan. In contrast to Flolan, Remodulin is stable at room temperature and lasts significantly longer inside the human body. These attributes allow for safer and more convenient drug delivery to patients. Unlike Flolan, Remodulin can be delivered by subcutaneous infusion with a pager-sized miniature pump device. Subcutaneous delivery of Remodulin also eliminates the risk of central venous catheter infection and the hospitalization required to begin intravenous infusion. Remodulin's extended presence in the body may also reduce the risk of rebound PAH, and possibly death, if treatment is abruptly interrupted. The stability of Remodulin also allows it to be packaged as an aqueous solution, so patients do not have to mix the drug, as they do with Flolan. Remodulin can be continuously infused for up to 48 hours before refilling the infusion pump, unlike Flolan, which must be mixed and refilled every 24 hours. Treprostinil sodium, the active ingredient in Remodulin, is highly soluble in an aqueous solution and therefore Remodulin can be manufactured at highly concentrated solutions. This allows therapeutic concentrations of Remodulin to be delivered at low flow rates via miniaturized infusion pumps for both subcutaneous and intravenous infusion. Lastly, Remodulin does not require the patient to continuously keep the drug cool even during infusion. This eliminates the need for cooling packs or refrigeration to keep it stable, as is required with Flolan due to Flolan's chemical instability at room temperature. In June 2008, the FDA approved a generic version of Flolan, developed by GeneraMedix, Inc., that is stable at room temperature, but still shares all of Flolan's other inconvenient attributes including, but not limited to, risk of central venous catheter infection, required hospitalization at the start of treatment, shorter half-life increasing risk of rebound PAH, mixing, greater frequency of pump refills and larger pump size.

        There are noteworthy adverse events associated with Remodulin infusion. When infused subcutaneously, Remodulin causes infusion site pain and reaction (redness and swelling) in most patients to varying degrees. Patients who cannot tolerate subcutaneous Remodulin may instead use it intravenously. Intravenous Remodulin is delivered continuously by an external pump through a surgically implanted central venous catheter, similar to Flolan. When delivered intravenously, Remodulin bears the risk of a serious bloodstream infection known as sepsis, as does Flolan.

    FDA Review of Subcutaneous Remodulin

        In March 2000, we completed an international, randomized, placebo-controlled, double-blind study of subcutaneous Remodulin involving a total of 470 patients with PAH. Half of the patients received Remodulin subcutaneously for 12 weeks, while the other half received a placebo. The study data showed that patients who received Remodulin had significant improvement in important clinical endpoints. These clinical endpoints included a composite index that measured exercise capacity and shortness of breath, cardiopulmonary hemodynamics and the signs and symptoms of the disease. Based on the favorable results of this study, we filed an NDA with the FDA in late 2000. In May 2002, the FDA approved Remodulin, under Subpart H regulations, as a continuous subcutaneous infusion for the treatment of PAH in patients with NYHA class II-IV symptoms to diminish symptoms associated with

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exercise. Remodulin may be prescribed for all types of PAH and is the only PAH treatment approved for patients with NYHA class II-IV symptoms.

    FDA Review of Intravenous Remodulin

        In July 2003, the FDA accepted our Investigational NDA for the development of Remodulin by intravenous delivery for the treatment of PAH. A study in volunteers was performed in late 2003, which established that intravenous and subcutaneous Remodulin are bioequivalent (meaning that both routes of infusion result in comparable levels of Remodulin in the blood). In addition, animal toxicology studies were completed and indicated that there were no additional safety concerns associated with chronic intravenous infusion.

        On January 30, 2004, we filed a supplemental NDA with the FDA to request approval for intravenous use of Remodulin for PAH. On November 24, 2004, based on data establishing intravenous Remodulin's bioequivalence with the previously approved subcutaneous administration of Remodulin, the FDA approved the intravenous use of Remodulin for those not able to tolerate subcutaneous infusion.

        On March 20, 2006, the FDA approved a supplemental NDA that we filed to satisfy of our Subpart H commitment from our original May 2002 approval for subcutaneous Remodulin. This approval added language to Remodulin's package insert indicating patients can be transitioned from Flolan to Remodulin.

        In January 2007, the results of a prospective, open-label study demonstrated that rapid transition from intravenous Flolan to intravenous Remodulin was achieved in 12 PAH patients with no serious adverse events and baseline clinical status was maintained over 12 weeks. The patients were transitioned from Flolan to intravenous Remodulin by a direct switch from a Flolan medication cassette to a Remodulin medication cassette. All patients reported fewer prostacyclin-related side effects with Remodulin and remained on Remodulin after study completion. The study demonstrated that stable patients with PAH can be safely transitioned from Flolan to intravenous Remodulin using a rapid switch protocol.

        Although intravenous Remodulin does not possess all the safety and convenience benefits of subcutaneous Remodulin, it has one important advantage: it eliminates infusion site pain and reaction, a common side effect of subcutaneous Remodulin. Many patients are unsuccessful in managing their infusion site pain even when using available pain management techniques or medication. Intravenous Remodulin has many beneficial characteristics that differentiate it from intravenous Flolan. Intravenous Remodulin does not require refrigeration whereas Flolan must be refrigerated. Furthermore, Remodulin persists in the blood for a few hours, whereas Flolan is highly unstable and only remains active in the body for a few minutes. Because Remodulin persists in the body longer, it may reduce the risk of rebound PAH, a severe recurrence of the disease that can occur when therapy is abruptly interrupted. Intravenous Remodulin can be infused continuously for up to 48 hours once the administering pump has been filled, while Flolan can only be infused for 24 hours once the drug has been mixed and the administering pump filled. This allows patients to fill their pumps with medication every other day as opposed to daily. Also, because Remodulin can be made in highly concentrated solutions, a wide variety of pump options, including miniaturized pumps, is available to patients.

        In February 2007, the Scientific Leadership Committee (SLC) of the Pulmonary Hypertension Association announced new guidelines related to the treatment of PAH patients on long-term intravenous therapy. The SLC guidelines were issued in response to the release of a slide presentation prepared by researchers with the U.S. Centers for Disease Control and Prevention (CDC) entitled, Bloodstream infections among patients treated with intravenous epoprostenol and intravenous treprostinil for pulmonary arterial hypertension, United States 2004—2006 . These slides accompanied a presentation to the SLC and were subsequently published in the March 2, 2007, issue of the CDC's Morbidity and Mortality Weekly Report . The slides and report were prepared in connection with a CDC retrospective

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inquiry at seven centers into a report of increased blood stream infections (sepsis), particularly gram-negative blood stream infections, among PAH patients treated with intravenous Remodulin as compared to intravenous Flolan. The SLC guidelines noted that the CDC observations were hypothesis-generating and did not permit definitive or specific conclusions. The SLC reminded physicians of the need to be aware of the range of possible gram-negative and gram-positive infectious organisms in patients with long-term central venous catheters and to treat them appropriately. The risk of sepsis was already noted in the Remodulin package insert. In February 2008, the FDA approved a revised package insert for Remodulin that more fully described the associated infection risk and appropriate techniques to be practiced when preparing and administering Remodulin for intravenous infusion.

    International Regulatory Review of Subcutaneous and Intravenous Remodulin

        Remodulin for subcutaneous use is approved in countries throughout the world. We used the mutual recognition process to obtain approval of subcutaneous Remodulin in the EU. The mutual recognition process is described more fully in the section entitled Governmental Regulation below. The mutual recognition process for subcutaneous Remodulin was completed in August 2005, with positive decisions received from most EU member countries. We withdrew our applications in Ireland, Spain and the United Kingdom following a request for additional documentation from these countries. We anticipate resubmitting these applications following approval of intravenous Remodulin in the EU. Licenses and pricing approvals have been received in most EU member countries. In addition, we have submitted a variation of the license for approval of intravenous Remodulin in the EU through the mutual recognition process, as we are required to follow the same approval process used for the approval of subcutaneous Remodulin. The license variation for intravenous Remodulin is currently under review by the host nation, France, which has notified us that it is not currently satisfied with our application. We are working to address their concerns and believe that we will eventually receive commercial approval for intravenous Remodulin in at least some EU member countries. In the meantime, we will continue to sell (but not market) Remodulin under the named-patient system in EU member countries where we are not approved. Under the named-patient system, we are permitted to import Remodulin into EU member countries for sale to hospitals for use in treating specifically identified patients.

    Sales and Marketing

        Our marketing strategy for Remodulin is to use our sales and marketing teams to educate the prescriber community to increase PAH awareness and awareness of our products. The sales and marketing team consisted of approximately 80 employees as of December 31, 2008, up from approximately 65 employees as of December 31, 2007. We anticipate continued growth in our sales force in the near-term as we position our business for further expansion. We divide our domestic sales force into two teams. One sales team is primarily responsible for medical practice accounts that are historical Remodulin prescribers. The other sales team is primarily responsible for medical practice accounts that have not historically prescribed Remodulin. The efforts of our sales and marketing teams are supplemented by our specialty pharmaceutical distributors. For additional information about our agreements with our distributors, see the next section entitled Domestic Distribution of Remodulin . Our distributors are experienced in all aspects of using and administering chronic therapies, as well as patient care, the sale and distribution of these medicines and reimbursement from insurance companies and other payers. Outside of the United States, we have entered into exclusive distribution agreements covering most of Europe, South America, Israel, and parts of Asia. Sales in Canada are currently conducted under the management of our wholly-owned subsidiary, Unither Biotech Inc., through a national specialty pharmaceutical wholesaler. We are working with our current distributors to expand Remodulin sales into other countries in which they have distribution rights.

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    Domestic Distribution of Remodulin

        To market, promote and distribute subcutaneous and intravenous Remodulin through specialty pharmaceutical distributors in the United States, we entered into non-exclusive distribution agreements with CuraScript, Inc. (a wholly-owned subsidiary of Express Scripts, Inc., formerly Priority Healthcare Corporation) (CuraScript), Accredo Therapeutics, Inc. (a wholly-owned subsidiary of Medco Health Solutions, Inc.) (Accredo) and CVS Caremark Corporation (Caremark). Effective January 1, 2007, Accredo also became the exclusive U.S. distributor for Flolan. Our distributors are responsible for assisting patients with obtaining reimbursement for the cost of Remodulin therapy and providing other support services. Under our distribution agreements, we sell Remodulin to our distributors at a discount from an average wholesale price recommended by us. Our distribution agreements with Accredo and Caremark include automatic term renewals for additional one-year periods subject to notice of termination. Our distribution agreement with Curascript contains two-year term renewal periods. We update our distribution agreements from time to time to reflect changes in the regulatory environment. These changes have not had a significant impact on our operations or our relationships with our distributors, and tend to occur in the ordinary course of business. If our distribution agreements expire or terminate, we may, under certain circumstances, be required to repurchase any unsold Remodulin inventory held by our distributors. We have also established a patient assistance program in the United States, which provides qualified uninsured or underinsured patients with Remodulin at no charge. None of our current agreements grants our distributors the distribution rights for inhaled or oral treprostinil in the United States.

    International Distribution of Remodulin

        We currently sell Remodulin to six distributors who have certain exclusive distribution rights for subcutaneous and intravenous Remodulin in EU member countries, and other non-EU countries, such as South America, Israel and parts of Asia. In the European markets where we are not licensed, we sell (but do not market) Remodulin under the named-patient system in which patients typically are approved for therapy on a case by case review by a national medical review board. We are working on expanding our sales of subcutaneous and intravenous Remodulin into new territories outside of the United States through our existing distributors and by creating relationships with new distributors. In March 2007, we entered into a distribution agreement with Mochida Pharmaceutical Co., Ltd. (Mochida) to obtain approval and exclusively distribute subcutaneous and intravenous Remodulin in Japan. In addition, Grupo Ferrer Internacional, S.A. (Grupo Ferrer) has been actively working toward commencing commercial sales of Remodulin in Taiwan and South Korea. However, certain countries, like Japan, may require that new clinical trials, called bridging studies, be conducted in order to demonstrate the efficacy and safety of a drug in their patient population. Commercial sales in such countries could therefore be several years from realization.

    Inhaled Treprostinil

        We are working to gain approval of an inhaled formulation of treprostinil for the treatment of PAH. During 2004 and 2005, independent clinical investigators in Europe and the United States performed small uncontrolled trials of inhaled formulations of treprostinil in patients with PAH. In April 2004, the EMEA granted orphan designation for inhaled treprostinil for the treatment of both PAH and chronic thromboembolic pulmonary hypertension. We also plan to seek orphan drug designation for inhaled treprostinil in the United States. If successful, we will be granted a seven-year period of orphan drug exclusivity for inhaled treprostinil that will begin upon the approval of our NDA.

        In June 2005, we commenced a 12-week, randomized, double-blind, placebo-controlled Phase III trial of inhaled treprostinil in patients with PAH who were optimized (therapeutically well-maintained) on Tracleer®, an oral ERA marketed by Actelion Ltd (Actelion). In May 2006, the FDA agreed that we could also include in the trial PAH patients who were optimized on Revatio®, an oral PDE5 inhibitor marketed by Pfizer. During the 12-week trial, patients were administered inhaled treprostinil or placebo

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in four daily inhalation sessions with a maximum dose of approximately 54 micrograms per session. The primary endpoint of the trial was the peak six-minute walk distance (6MWD) improvement test, which is a typical benchmark test of cardiovascular health. The 6MWD test measures the distance a patient walks in six minutes on a treadmill at the start of the trial as compared to additional pre-specified points in time during the trial in order to detect any improvement in the distance the patient is able to walk. This trial, TRIUMPH-1 ( TR eprostinil Sodium I nhalation U sed in the M anagement of P ulmonary Arterial H ypertension), was conducted at approximately 36 centers in the United States and Europe.

        In November 2007, we announced the completion of our TRIUMPH-1 trial. The study population consisted of 235 patients. Ninety-eight percent of patients were classified as New York Heart Association (NYHA) Class III. Patients in the trial were affected by PAH of varied etiologies, including idiopathic or familial PAH (~55%), collagen vascular disease associated PAH (~35%), and PAH associated with HIV, anorexigens (appetite suppressants) or other associated conditions (~10%). Mean baseline 6MWD was approximately 350 meters.

        The primary efficacy endpoint of the trial was the 6MWD at 12 weeks measured at peak exposure, defined by the trial protocol as 10-60 minutes after inhalation of treprostinil, relative to baseline. Analysis of the TRIUMPH-1 results demonstrated an improvement in median 6MWD of approximately 20 meters (p<0.0005, using the Hodges-Lehmann estimate and non-parametric analysis of covariance in accordance with the trial's pre-specified statistical analysis plan), in patients receiving inhaled treprostinil as compared to patients receiving placebo.

        At trough exposure, which was defined by the trial protocol as a minimum of four hours after inhalation of treprostinil, the treatment-related change in 6MWD at week 12 relative to baseline was also significantly improved, with an increase in median 6MWD of approximately 14 meters (p<0.01). Additionally, the 6MWD at week six measured at peak exposure relative to baseline was significantly improved, with an increase in median 6MWD of approximately 18 meters (p<0.0005). Quality of life was assessed using the Minnesota Living with Heart Failure Questionnaire. Both the Global Score (p<0.03) and the physical score (p<0.04) were significantly improved. NT-Pro BNP, a biomarker correlated with right ventricular function, also improved significantly at week 12 (p<0.002).

        Analysis of other secondary endpoints, including change in Borg Dyspnea Scale rating (shortness of breath test), NYHA functional class, time to clinical worsening (as defined by death, transplant, the need for atrial septostomy (surgical opening of the septum), hospitalization due to PAH, or initiation of another approved PAH therapy, and the 6MWD at treatment day one, did not differ significantly between the inhaled treprostinil and placebo groups (p>0.05).

        Inhaled treprostinil was generally well tolerated in the trial and adverse events appeared to be similar to those previously reported for treprostinil or due to administration by inhalation. The most common adverse events seen in the trial were transient cough, headache, nausea, dizziness and flushing. All patients in the trial had the option to continue receiving inhaled treprostinil in an open-label continuation study after completion of the 12-week study period. Of the 212 patients who completed the 12-week study period, approximately 200 patients entered the open-label continuation study. Approximately 125 patients continue to be treated with inhaled treprostinil, with the longest duration of treatment exceeding two years.

        In June 2008, we submitted an NDA to obtain FDA approval to market inhaled treprostinil for the treatment of PAH in the United States with an expected action date of April 30, 2009. The Optineb® nebulizer (the ultra-sonic nebulizer that was exclusively used for administration of inhaled treprostinil in the TRIUMPH-1 trial) was submitted for approval as part of this filing. The Optineb is manufactured by NEBU-TEC International Med Products Eike Kern GmbH (NEBU-TEC), a German company. The Optineb is CE-marked in Europe, which means that NEBU-TEC asserts that the device conforms to EU health and safety requirements. In December 2008 we filed an MAA for inhaled treprostinil in the EU using the centralized filing process. The standard time for review of an NDA by the FDA and of an MAA by the EMEA is generally 10 to 12 months. See the section entitled Governmental Regulation below for further discussion on the centralized filing process for the EU.

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        This is the first time we have submitted a device to the FDA for approval. Since we do not manufacture the Optineb device, we relied on NEBU-TEC for certain design, mechanical, operational and study information needed for the filing. In December 2008, we entered into an Agreement of Sale and Transfer with NEBU-TEC under which NEBU-TEC will sell to us its Optineb business and all associated assets and rights. Closing and transfer of all the associated assets and rights is expected to occur within 30 days of receiving FDA approval for our inhaled treprostinil therapy and its use with the Optineb nebulizer. In the interim period prior to the closing of the Agreement of Sale and Transfer, both NEBU-TEC and we remain subject to an existing Clinical and Commercial Supply Agreement, as amended, pursuant to which NEBU-TEC is required to maintain all aspects of the FDA's required current good manufacturing practices. Refer to the section entitled NEBU-TEC Agreement of Sale and Transfer below for further details related to our asset acquisition.

        We were recently notified that the FDA Office of Safety and Epidemiology has preliminarily approved the tradename Tyvaso for our inhaled treprostinil therapy. The FDA Division of Cardiorenal Drug Products will conduct the final review and approval of the tradename, which usually occurs simultaneously with NDA approval.

        Currently, the only FDA approved inhaled prostacyclin analogue is Ventavis®. Ventavis is marketed by Actelion in the United States and by Schering AG in Europe. The active ingredient in Ventavis, iloprost, has a half-life of approximately 20 to 30 minutes and lacks selectivity to the lungs. The lack of selectivity to the lungs can cause a decrease in patient blood pressure if the drug is administered at too high a dose. As a result, Ventavis is inhaled via a nebulizer six to nine times per day at a low dose. Per its label, each 15 minute session on the nebulizer must be continuously inhaled. Due to the longer half-life of treprostinil and its greater selectivity to the lungs, treprostinil is administered four times a day, in six to nine breaths over an approximately one-minute session. We are currently conducting an open-label study in the United States to investigate the clinical effects of switching patients from Ventavis to inhaled treprostinil. This study began enrollment in December 2008.

        The inhalation device market is ever-changing, with new technologies being discovered and improved devices being developed constantly. We are interested in new technologies that would enable a more efficient and convenient means of administering inhaled treprostinil to patients. For this reason, in August 2007, our subsidiary, Lung Rx, Inc. (Lung Rx), entered into an exclusive license, development and commercialization agreement with Aradigm Corporation (Aradigm) for the rights to manufacture, develop and commercialize its AERx Essence® device, a pulmonary drug delivery system, for use as a next-generation metered-dose inhaler with inhaled treprostinil.

    UT-15C Sustained Release (Oral Treprostinil)

        Pulmonary Arterial Hypertension.     We are developing an oral formulation of treprostinil, treprostinil diethanolamine, which is a novel salt form of treprostinil. During 2004, we completed studies of various formulations of treprostinil diethanolamine in healthy volunteers. Based on these studies, a formulation was selected that uses technology licensed from Supernus Pharmaceuticals, Inc. (Supernus), to provide for sustained release of treprostinil in tablets. The coating technology, which is resistant to being broken down by the body's digestive system, allows for treprostinil to be released into the body through an extremely small hole that is laser-drilled into the coating of each tablet. This technology releases treprostinil at a relatively even rate in the gastrointestinal tract. In 2005, a Phase I study of normal volunteers not diagnosed with PAH demonstrated that the formulation and coating provided sustained blood concentrations of treprostinil for 8 to 10 hours following a single oral dose. This duration may allow for twice daily dosing. In July 2005, the EMEA announced that oral treprostinil had been granted orphan product status in the EU. If we obtain a separate orphan drug designation in the United States for oral treprostinil for the treatment of PAH, then we may obtain a seven-year period of orphan drug exclusivity for oral treprostinil that will begin upon the approval of our NDA.

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        In October 2006, we commenced two Phase III multi-national, placebo-controlled clinical trials of oral treprostinil in patients with PAH to study both dosing and efficacy. The FREEDOM-C trial was a 16-week study of patients on approved background therapy using a PDE5 inhibitor, such as Revatio, or an ERA, such as Tracleer, or a combination of both. The FREEDOM-M trial is a 12-week study of patients who are not on any background therapy. Both trials have been conducted at approximately 60 centers throughout the United States and the rest of the world. During these trials, patients are administered oral treprostinil or placebo twice a day. The dosage initially began at 1 mg twice daily for both trials but during the trial, 0.5 mg and 0.25 mg tablet doses became available. The maximum dose is set at 16 mg twice daily for the FREEDOM-C trial and 12 mg twice daily for the FREEDOM-M trial, based on symptomatic benefit and tolerability. The primary study endpoint of the trials is 6MWD.

        We commenced both trials using a 1 mg tablet, but during the open-label extension trial (and associated pharmacokinetic substudy) we discovered that the treprostinil concentrations were higher in PAH patients than in healthy individuals due to the difference in absorption rate between these two populations. This difference in absorption rate led to a number of discontinuations by patients randomized to receive drug due to tolerability-related side effects, including nausea, jaw-pain and headaches. As a result, we introduced a 0.5 mg tablet in July 2007 to enable more gradual dose titration (increase). The 0.25 mg tablet was introduced into the trials in April 2008.

        In mid-November 2008, we announced that the FREEDOM-C trial did not meet statistical significance for its primary endpoint. The study population consisted of 354 patients. The majority (~75%) of patients were World Health Organization (WHO) Class III of varied etiologies, including idiopathic or familial PAH (~65%), collagen vascular disease associated PAH (~25%), and PAH associated with HIV or other associated conditions (~10%). Mean baseline 6MWD was approximately 345 meters.

        The placebo-corrected median change in 6MWD at week 16 was 11 meters (p=0.072). A statistically significant treatment effect was observed at week 12, with a placebo-corrected median change in 6MWD of 13 meters (p=0.015).

        Exploratory analyses suggest that the inability to dose titrate was a limiting issue that suppressed the overall treatment effect. Of the 174 patients who received active drug, 25 patients discontinued due to an adverse event and 33 patients completed the trial but were unable to titrate their doses above 1 mg twice daily. Accordingly, 58 (33%) of the patients in the active treatment group were only able to maintain a suboptimal dose of below 1 mg twice daily. Adverse events that led to discontinuation or inability to dose-escalate included headache, nausea and vomiting. Dropouts were most common in patients who only had access to the 1 mg tablets during the study, which was the only size tablet available when the trial began. There were no discontinuations among patients who had access to the 0.25 mg tablet.

        Preliminary analysis of other secondary efficacy measures, including change in combined 6MWD, Borg dyspnea score and Dyspnea-Fatigue index demonstrated statistically significant improvements (p<0.05) compared to placebo. Other secondary efficacy measures including change in WHO functional class, time to clinical worsening, and PAH signs and symptoms, did not differ significantly between patients administered oral treprostinil versus placebo (p>0.05).

        Enrollment in FREEDOM-M was closed on October 31, 2008, with 171 patients enrolled in the trial. However, based on what we learned from the FREEDOM-C trial relating to patient tolerability of our three different tablet strengths of oral treprostinil, we submitted a protocol amendment to the FDA on February 20, 2009, seeking to increase the number of patients enrolled in FREEDOM-M by approximately 140 patients. These new patients will start the study on the 0.25 mg tablet, which we know from the FREEDOM-C trial is the best-tolerated tablet strength.

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        We believe that this protocol amendment will allow us to more accurately assess the effectiveness of oral treprostinil for many reasons. First, by starting patients on the 0.25 mg tablets and titrating up to reach an effective maintenance dose, we expect there will be a reduced rate of premature discontinuation due to adverse events. Second, the study will be statistically powered using a reduced effect size (from a 50 to 45 meter change in 6MWD) and a change in statistical significance level (from 0.05 to 0.01). Finally, the primary endpoint of change in 6MWD will be tested only in patients who had access to the 0.25 mg tablets at the start of the study, which reflects the expected dosing regimen for oral treprostinil. Due to the anticipated time required to receive FDA consent to the protocol amendment and to package and ship new clinical trial supplies to study sites, we expect to begin enrolling additional patients in the second quarter of 2009.

        We are also in the planning stages of designing a new FREEDOM-C clinical trial of patients with PAH who are on an approved background therapy, FREEDOM-C 2 . This clinical trail is expected to enroll 300 patients, all using the 0.25 mg tablet. The FREEDOM-C 2 clinical trial is expected to commence in late 2009. Currently, we do not anticipate filing an NDA for oral treprostinil before 2012.

        There are currently no approved oral prostacyclin therapies available to patients in the United States or Europe. If we are successful in developing oral treprostinil, patients and physicians may be encouraged to use prostacyclin earlier in the PAH disease continuum and for the treatment of other diseases.

        Peripheral Arterial Disease/Critical Limb Ischemia.     We are also developing oral treprostinil for a subset of late-stage peripheral arterial disease (PAD) known as critical limb ischemia (CLI). PAD is a narrowing of the blood vessels that carry blood to the upper or lower extremities, especially the legs. While the precise causes of PAD are unknown, diabetes, high blood pressure, smoking, eating a high fat diet and lack of exercise are associated with the disease. Blood vessels affected by PAD often have a reduced level of natural prostacyclin similar to those affected by PAH.

        Severe PAD can often lead to CLI, which is characterized by extreme leg pain, non-healing ulcers or gangrene in the legs, severely reduced exercise capacity and blood flow in the legs. In the United States, it is estimated that 2 million people suffer from CLI but there are currently no drugs approved to treat it. Physicians often suggest surgical interventions, such as balloon angioplasty, stents and by-pass, to restore or improve blood flow in the limbs. These procedures can provide temporary relief to patients, but do not address the underlying causes of the disease. Due to the lack of adequate pharmaceutical treatment, approximately 160,000 leg amputations are performed each year on patients with CLI.

        In September 1998, we completed a Phase II study assessing the safety and blood flow effects of intravenous Remodulin on patients with CLI. The study demonstrated that Remodulin can be administered safely to patients with CLI and that Remodulin substantially increases blood flow in the affected areas of the legs. We commenced a 30 patient placebo-controlled, pre-pivotal clinical study of Remodulin for CLI in 2002. Approximately 19 patients were enrolled but we ended the study early due to difficulty recruiting patients. We believe that more convenient formulations of treprostinil, such as our oral formulation, may be more appropriate for patients with CLI. Accordingly, we have commenced Phase I studies of oral treprostinil for patients with CLI.

        We have also initiated a Phase II Study in 2009 to investigate the effectiveness of oral treprostinil in reducing the frequency and severity of ulcers located on the fingers and toes of scleroderma patients.

    Tadalafil

        Tadalafil is a PDE5 inhibitor and is also the active pharmaceutical ingredient in Cialis®, which is marketed by Lilly for the treatment of erectile dysfunction. Patients with PAH have been shown to have reduced levels of the enzyme responsible for producing NO, a naturally occurring substance in the body

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that has the effect of relaxing pulmonary blood vessels, which is also a cause of erectile dysfunction. NO works to relax pulmonary blood vessels by increasing intracellular levels of an intermediary known as cGMP. An established therapeutic approach in the treatment of PAH is to use PDE5 inhibitors to increase levels of NO in patients to inhibit the degradation of cGMP.

        Revatio is the only currently approved PDE5 inhibitor for the treatment of PAH, and is marketed by Pfizer. Sildenafil, the active ingredient in Revatio, is also the active ingredient in Viagra®, which is also marketed by Pfizer for erectile dysfunction. Revatio has a three times daily dosing regimen. We expect tadalafil to have a once daily dosing regimen.

        The PHIRST Study, which was conducted by Lilly, was a Phase III 16-week, double-blind, placebo-controlled efficacy and safety study of once-daily tadalafil in PAH patients. 405 patients with idiopathic PAH or PAH associated with connective tissue disease, anorexigen use, HIV, atrial septal defect, or surgical repair of congenital left-to-right shunt were randomized to placebo or tadalafil (2.5, 10, 20 or 40 mg) orally once daily as monotherapy or as add on therapy to bosentan, the active ingredient in Tracleer. Demographics, clinical data, and health related quality of life (HRQoL) data were collected at baseline. Clinical and HRQoL data were again collected at weeks 4, 8, 12 and 16. Cardiopulmonary hemodynamics were conducted in a subset of patients (n=93).

        The 40mg dose of tadalafil was shown to increase 6MWD compared to placebo (p<0.001 +41.1m versus +9.2m). Changes in WHO functional class and Borg dyspnea score did not differ significantly compared to placebo. The 40 mg dose also delayed the time to clinical worsening compared to placebo (p<0.05, relative risk reduction 68% less than placebo). Compared with placebo, improvements were observed in patients treated with 40 mg tadalafil-treated patients in six out of the eight SF-36 domains (p<001), the EuroQol (EQ-5D) U.S. and U.K. index scores, and for the visual analog scale (VAS) (all p<0.05). It was also shown to increase cardiac output (0.6 L/min) and reduced pulmonary artery pressures (-4.3mmHg) and pulmonary vascular resistance (-209dyn.s/cm 5 ) compared to baseline (p<0.05). The most common treatment-related adverse event reported with tadalafil was headache (32% versus 15% with placebo). Discontinuation due to adverse events was low (tadalafil 11% versus placebo 16%). Of the 405 patients in the trial, 189 (47%) were not taking concomitant bosentan (the ERA marketed as Tracleer). In these patients, tadalafil 40mg dose increased 6MWD compared to placebo (p<0.10+42.2m versus -2.9m).

        Lilly submitted an NDA to the FDA based on these significant trial results with an expected action date of May 24, 2009.

        On December 18, 2008, we completed the transactions contemplated by several agreements we entered into with Lilly and one of its subsidiaries on November 14, 2008, including a license agreement, a manufacturing and supply agreement and a stock purchase agreement. Pursuant to the license agreement, Lilly granted us an exclusive license for the right to develop, market, promote and commercialize tadalafil for the treatment of pulmonary hypertension in the United States and Puerto Rico. In connection with the license agreement, we also entered into a stock purchase agreement and a manufacturing and supply agreement. Pursuant to the manufacturing and supply agreement, Lilly agreed to manufacture tadalafil and distribute it via its wholesaler network, in the same manner that it distributes its own pharmaceutical products. In December 2008, upon closing, we made a one-time payment of $125.0 million under the manufacturing and supply agreement and a one-time payment of $25.0 million under the license agreement. Pursuant to the stock purchase agreement, we issued 3,150,837 shares of our common stock to Lilly from treasury for an aggregate purchase price of $150.0 million. See the section entitled Strategic Licenses and Relationships below for more details on these agreements.

        We intend to use our existing sales and marketing team to promote and sell tadalafil. We expect that the prescribers of tadalafil will include most of the same health care practitioners upon whom our sales force currently focuses on with respect to marketing our other PAH therapies.

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    Beraprost-MR

        In June 2000, we entered into an agreement with Toray Industries, Inc. (Toray) for the exclusive right to develop and market a sustained release formulation of beraprost (beraprost-SR), an oral prostacyclin, in the United States and Canada for the treatment of cardiovascular indications. Beraprost is a chemically stable, orally bioavailable prostacyclin analogue. Like natural prostacyclin and Remodulin, beraprost is believed to dilate blood vessels, prevent platelet aggregation and prevent proliferation of smooth muscle cells surrounding blood vessels.

        In March 2007, Lung Rx entered into an amended agreement with Toray to assume and amend the rights and obligations of our June 2000 agreement with Toray concerning the commercialization of a modified release formulation of beraprost (beraprost-MR). The amended agreement grants us additional exclusive rights to commercialize beraprost-MR in Europe and broadens the treatment indication to include vascular disease (excluding renal disease), among other revisions. Although earlier clinical trials of an immediate release formulation of beraprost sodium did not provide conclusive evidence of efficacy, these trials did provide encouraging results suggesting that beraprost-MR could prove to be safe and effective for PAH. Since individual PAH patients may have varied responses to different molecules within the same general class, we believe that the development of multiple molecules within the same family is a good strategy to treat PAH. In addition, we are in the early stages of exploring the use of beraprost-MR for the treatment of other cardiovascular and cardiopulmonary indications.

        In October 2007, Toray announced that beraprost-MR received regulatory approval in Japan for use in the treatment of PAH. In July 2008, beraprost-MR was granted Orphan Medicinal Product Designation by the EMEA.

Products to Treat Cancer

    3F8 and 8H9 Antibodies

        In December 2007, we entered into two agreements with Memorial Sloan-Kettering Cancer Center (MSKCC) to license certain exclusive rights to two investigational monoclonal antibodies, 3F8 and 8H9, for the treatment of neuroblastoma and metastatic brain cancer. The monoclonal antibody 3F8 is a mouse IgG3 MAb, which is currently used in an investigational setting for the treatment of neuroblastoma, a rare cancer of the sympathetic nervous system mainly affecting children. It is the most common extracranial solid cancer in children and the most common cancer in infants. More than 400 patients have been treated with the 3F8 antibody since 1986 under investigator-initiated Investigational New Drug Applications. There are fewer than 1,000 new cases of neuroblastoma diagnosed each year. We expect to begin a patient trial in the second quarter of 2009 using the 3F8 antibody in patients with neuroblastoma.

        The monoclonal antibody 8H9 is an IgG1 antibody that is also a mouse antibody. The 8H9 antibody is highly reactive with a range of human solid tumors, including human brain cancers. The 8H9 antibody is in early investigational development for metastases that develop in the brain from the spread of cancers from other tissues in the body. Metastatic brain cancers are ten times more common than cancers that originate in the brain, and prognosis is very poor. In the United States, more than 100,000 cases of metastatic brain cancer are diagnosed each year.

    OvaRex

        In April 2002, we entered into a license agreement with AltaRex Corp. which later became AltaRex Medical Corp., a wholly-owned subsidiary of ViRexx Medical Corp. (AltaRex). The license agreement with AltaRex provided us with certain exclusive rights to a platform of five investigational immunotherapeutic monoclonal antibodies: OvaRex, BrevaRex, OncoRex, ProstaRex and GivaRex.

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These products were being developed by AltaRex to treat various forms of cancer, including ovarian, prostate, lung, breast, multiple myeloma and gastrointestinal cancers. The lead product, OvaRex® MAb for the treatment of advanced ovarian cancer, had completed Phase II studies when we entered into the license agreement.

        Ovarian cancer is the deadliest form of women's reproductive cancer and is the fifth leading cause of cancer death among women in the United States. Over 25,000 cases of ovarian cancer are diagnosed in the United States every year, with over 16,000 women dying of the disease annually.

        In December 2007, we announced the completion of our two pivotal trials of OvaRex. Analysis of the results demonstrated that the studies failed to reach statistical significance.

        The identical studies, known as IMPACT I and II ( IM munotherapy P ivotal ov A rian C ancer T rial), were randomized, double-blind, placebo-controlled trials conducted at over 60 centers across the United States. The studies enrolled 367 ovarian cancer patients and assessed the efficacy of OvaRex mono-immunotherapy during the so-called "watchful waiting" period following front-line carboplatin-paclitaxel based chemotherapy. The program sought to confirm data observed in a subset analysis of a prior randomized Phase II study, which suggested the potential of OvaRex to extend the time to disease relapse among patients who had successfully completed front-line therapy. The studies were well balanced in terms of patient demographics and the safety profile and quality of life were similar between active and control populations. The studies demonstrated no difference between active (standard of care followed by OvaRex) and control (standard of care followed by placebo) populations. The results of IMPACT I and II were consistent with each other.

        Based on the results of the IMPACT I and II trials, we decided to terminate our license agreement with AltaRex and cease further development of the entire platform of antibodies licensed thereunder. We have incurred approximately $2.0 million in total closeout costs for this program and do not anticipate significant additional future costs related to this program.

Products to Treat Infectious Diseases—Glycobiology Antiviral Agents

        In March 2000, we entered into a license agreement with Synergy Pharmaceuticals, Inc. (Synergy), to obtain the exclusive worldwide rights to certain patents relating to novel antiviral compounds. Synergy was working with the Glycobiology Department at the University of Oxford to develop antiviral compounds, such as miglustat. We have the exclusive right to commercialize miglustat for certain infectious diseases and viruses. In 2003, by mutual consent, we terminated our license agreement with Synergy. We are now working directly with Oxford University on the development of new antiviral compounds. These glycobiology antiviral agents are small molecules that may be effective as oral therapies for the treatment of hepatitis B and C infections, as well as dengue fever, Japanese encephalitis and other infectious diseases. Currently, many of these agents are undergoing laboratory testing, and new agents are also being synthesized.

        In January 2009, we entered into a license agreement with MIGENIX, Inc. (MIGENIX), a Canadian company, to obtain the exclusive worldwide rights to develop and commercialize celgosivir for hepatitis C and other viral diseases. Celgosivir is a novel antiviral agent that appears to be a potent inhibitor of alpha-glucosidase I, a host enzyme that is critical to the folding of viral proteins. Inhibition of alpha-glucosidase I leads to improper viral folding, which, in turn, prevents viral replication. This effect has many potential therapeutic applications. The rights to develop and commercialize celgosivir are contingent upon our acceptance of further preclinical studies to be performed by MIGENIX to assess celgosivir's utility in combating the hepatitis C virus. If the results of the studies are acceptable to us, MIGENIX will be entitled to milestone payments based upon the achievement of certain clinical and regulatory events and royalties based on net sales of celgosivir, if commercialized.

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Products to Provide Telemedicine Services for Cardiac Arrhythmias and Ischemic Heart Disease

    CardioPAL SAVI and Decipher Recorders

        We provide telemedicine services to detect cardiac arrhythmias and ischemic heart disease through our wholly-owned subsidiary Medicomp, Inc. (Medicomp), which we acquired in December 2000. Cardiac arrhythmias and ischemic heart disease affect an estimated 20 million Americans, and possibly ten times that number worldwide. If left undetected and untreated, these conditions can result in heart attacks and death. Medicomp provides cardiac Holter monitoring (a 24-hour continuous test of heart rhythms), event monitoring (a test that typically extends to 30 days and looks for more elusive, intermittent arrhythmias), analysis, and pacemaker monitoring remotely via telephone and the Internet for hospitals, clinicians and other providers. Medicomp's services are delivered through its proprietary, miniaturized, digital Decipher Holter recorder/analyzer and its CardioPAL family of event monitors. In March 2005, Medicomp received FDA market clearance for a p-wave analysis in addition to its artificial intelligence algorithm that runs on all of its newly manufactured CardioPAL devices. The p-wave is a diminutive but important portion of the electrocardiograph that helps determine if an arrhythmia was generated from the top chambers of the heart, the atria, or from the bottom chambers of the heart, the ventricles. This level of analysis leads to more reliable, automatic detection of arrhythmias, like atrial fibrillation.

        Holter, event and pacemaker services and systems are marketed to physicians, hospitals, and managed care providers directly by Medicomp's internal sales force. We recognized revenues of approximately $9.5 million, $7.7 million and $6.6 million from the sales of telemedicine products and services in 2008, 2007 and 2006, respectively.

Arginine Products for Vascular Function

        In December 2000, we expanded our cardiovascular focus when we acquired the assets and certain liabilities of Cooke Pharma, Inc., the exclusive maker of the HeartBar® line of arginine-enriched products, which was then operated as Unither Pharma, Inc., our wholly-owned subsidiary. Arginine is required by the body to produce NO. Unither Pharma Inc. is the exclusive licensee of patents entitling it to claim that arginine is critical for maintaining vascular function and certain other natural functions.

        The HeartBar® and a related line of products were marketed directly to consumers by us, by independent distributors and through the Internet. In January 2006, we discontinued sales of the HeartBar line of products, after evaluating recent clinical trial results and market potential, among other factors.

        In November 2006, we settled litigation with three companies that we believed were infringing our arginine patents. We received a settlement payment and will receive additional royalties from sales of products containing arginine from one of the parties.

        In September 2007, we discontinued all sales of our remaining arginine products and we reevaluated our assumptions used in determining the value of our arginine patents, based on a then recent publication discounting the benefits of arginine supplementation and a June 2007 United States Supreme Court decision concerning the enforceability of patents. This decision had no effect on the terms of our settlement agreements with companies selling arginine products.

        Approximately $41,000, $123,000 and $100,000 of revenues were earned from the sales and royalties of arginine-related products in 2008, 2007 and 2006, respectively.

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Strategic Licenses and Relationships

    Northern Therapeutics, Inc.

        In December 2000, we formed a new company in Canada, Northern Therapeutics, Inc. (Northern), in conjunction with the inventor of a new form of autologous gene therapy (gene transfer using materials derived from a patient's own body instead of foreign materials such as viruses) for the treatment of PAH and other diseases. Northern is currently conducting a Phase I gene therapy trial in Canada and, until February 2006, was distributing Remodulin in Canada.

        In October 2006, Northern agreed to grant us an exclusive license to develop and commercialize the autologous gene therapy in the United States for PAH. Under this license, we are required to make incremental milestone payments to Northern depending on patient enrollment. If the planned 18 patient Phase I trial is successfully enrolled, such payments will total $1.5 million. We did not incur any expenses associated with this agreement during 2008. For the twelve months ended December 31, 2007, we incurred approximately $150,000 of expenses related to Northern. If the Phase I trial is successfully completed, we will assume the development program and related costs for the United States market. Northern will receive royalty payments following commercialization. As part of this agreement, we terminated the Remodulin distribution agreement with Northern for Canada. Our Canadian wholly-owned subsidiary, Unither Biotech Inc., contracts with a specialty distributor to distribute Remodulin in Canada. See the section entitled Sales and Marketing above for more information on our distribution arrangements in Canada.

        Due to our $5.0 million investment, we currently own approximately 68% of Northern, but only 49% of the voting rights of its common stock. Because minority shareholders possess substantive participating rights as defined under EITF Issue No. 96-16, Investors Accounting for an Investee when the Investor Has a Majority of the Voting Interest but the Minority Shareholders or Shareholders Have Certain Approval or Veto Rights , we are precluded from controlling Northern and thus do not consolidate Northern's financial statements with our own.

    NEBU-TEC Supply Agreement

        In June 2004 and September 2006, we entered into Clinical and Commercial Supply Agreements with NEBU-TEC to provide for the availability of Optineb nebulizers and related supplies for use in our TRIUMPH-1 clinical trial of inhaled treprostinil and for commercial use following regulatory approval. These non-exclusive agreements require NEBU-TEC to sell us Optineb devices and supplies for clinical and commercial use at specified prices and payment terms. These agreements also specify each party's obligations with respect to regulatory approvals. In February and April 2008, we entered into amendments to the September 2006 Clinical and Commercial Supply Agreement under which the term of the agreement was extended to the earlier of the first anniversary of the date of regulatory approval of inhaled treprostinil in the United States or EU. We also agreed to an advance order of Optineb devices and related supplies following satisfactory completion of a testing program in support of our NDA filing. The amendments also clarified certain regulatory obligations of the parties and provided NEBU-TEC with the first opportunity to sell devices in Europe for so long as NEBU-TEC was able to meet market demand.

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    NEBU-TEC Agreement of Sale and Transfer

        In December 2008, we entered into an Agreement of Sale and Transfer with NEBU-TEC, under which NEBU-TEC agreed to sell us its Optineb line of business and all its related assets and rights. Upon signing the agreement, we paid NEBU-TEC €2.5 million. Closing and transfer of the related assets and rights is expected to occur within 30 days of receiving FDA approval for our inhaled treprostinil therapy and its use with the Optineb nebulizer. In the interim period prior to the closing of the Agreement of Sale and Transfer, both NEBU-TEC and we remain subject to an existing Clinical and Commercial Supply Agreement, as amended, pursuant to which NEBU-TEC is required to maintain all aspects of the FDA's current good manufacturing practices. At closing, we will pay NEBU-TEC an additional €2.5 million. In addition, we agreed to pay future consideration of up to €10.0 million depending on the occurrence of specific events and the attainment of a certain number of patients administering inhaled treprostinil using the Optineb or NEBU-TEC's next generation inhalation device currently under development. Furthermore, if we do not receive FDA approval for inhaled treprostinil under certain circumstances, we may cancel the Agreement of Sale and Transfer in which event NEBU-TEC will be required to refund the €2.5 million paid at signing.

    Aradigm License Agreement

        In August 2007, Lung Rx entered into an exclusive license, development and commercialization agreement with Aradigm for the rights to manufacture, develop and commercialize its AERx Essence pulmonary drug delivery system, for use as a next-generation metered-dose inhaler with our investigational inhaled treprostinil product in patients with PAH and other conditions. Under the terms of the agreement, Aradigm conducted and funded laboratory tests and a proof-of-concept clinical trial comparing the inhalation delivery of treprostinil using the AERx Essence technology to delivery using the Optineb nebulizer used in the TRIUMPH-1 trial.

        The bridging clinical trial was completed in November 2008, and failed to prove that the drug dispersed with the AERx Essence was bioequivalent to that dispersed by the Optineb nebulizer. However, the clinical trial results revealed that the AERx Essence device delivered inhaled treprostinil with deeper lung penetration than the Optineb nebulizer. We believe that these results merit further clinical studies. Therefore, we agreed to pay the first milestone payment of $2.0 million required under the terms of our agreement with Aradigm in the fourth quarter of 2008.

        Our agreement with Aradigm specifies that second and third milestone payments are due no later than the second and third anniversaries of the effective date of the agreement, such payments increasing incrementally by $1.0 million each year. The agreement allows for the extension of payment deadlines by the amount of time equal to the duration of any delay caused by a regulatory agency. In addition, we agreed to pay Aradigm royalty fees on a sliding scale based on net sales of the AERx Essence device once it is approved.

    Toray Amended License Agreement

        In June 2000, we licensed from Toray the exclusive right to develop and market beraprost-SR, a chemically stable oral prostacyclin analogue, in a sustained release formulation in the United States and Canada for the treatment of cardiovascular indications. In March 2007, Lung Rx entered into an amended agreement with Toray to assume and amend the rights and obligations of our June 2000 agreement with Toray concerning the commercialization of beraprost-MR. The amended agreement grants us additional exclusive rights to commercialize beraprost-MR in Europe and broadens the indication to vascular disease (excluding renal disease), among other revisions.

        In accordance with the terms of the amended agreement, in March 2007 we issued 200,000 shares of our common stock to Toray in exchange for the cancellation of Toray's existing right to receive an option grant to purchase 500,000 shares of our common stock (the Option Grant). Under the June

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2000 Agreement, Toray's right to receive the Option Grant was conditioned upon Toray's delivery to us of adequate documentation regarding the use of beraprost-SR in humans and its transfer of clinical trial material to us, neither of which had occurred as of the effective date of the amended agreement. Had the Option Grant been made, the exercise price of the options would have been set at the average closing price of our common stock for the period one month prior to the delivery date. Under the terms of the amended agreement, Toray has the right to request that we repurchase the newly issued 200,000 shares of our common stock upon 30 days prior written notice at the price of $54.41 per share, which was the average closing price of our common stock between January 11, 2007, and February 23, 2007. Based on the average closing price of our common stock for the two trading days prior to and the two trading days after the effective date of the amended agreement (March 16, 2007), we recognized a research and development expense of approximately $11.0 million relating to the issuance of the 200,000 shares, because beraprost-MR had not yet obtained regulatory approval for commercial sales. In accordance with the provisions of SFAS No. 133, Accounting for Derivative Instruments and Hedging Activities , EITF 00-19 and EITF Topic No. D-98, Classification and Measurement of Redeemable Securities , these shares of our common stock are reflected in mezzanine equity as common stock subject to repurchase valued at the repurchase price. If Toray requests that we repurchase these shares, then an amount equal to the repurchase price will be transferred to a liability account until the repurchase is completed.

        The amended agreement also specifies that we make certain milestone payments to Toray during the development period and upon U.S. or EU regulatory approval. Upon execution of the amended agreement, we made a $3.0 million payment to Toray in addition to the issuance of the 200,000 shares of our common stock discussed above. Additional annual milestone payments of $2.0 million are specified in the amended agreement and commenced in the first quarter of 2008, increasing annually in $1.0 million increments through 2011. These payments will be expensed when incurred. These payments are contingent upon the receipt of clinical trial material and commercial drug from Toray that meet all regulatory standards and requirements, including those relating to chemistry, manufacturing and controls, and are documented to the satisfaction of U.S. and EU regulatory authorities. In addition, if Toray elects to terminate production of beraprost-MR, no further payments would be due under the amended agreement. Conversely, if we elect to terminate development of beraprost-MR, then all remaining milestone payments would be due to Toray, unless certain regulatory standards and requirements have not been met, or if material problems have been identified with respect to manufacturing and regulatory compliance.

    Lilly Agreements Related to Tadalafil

        On December 18, 2008, we completed the transactions contemplated by several agreements we entered into on November 14, 2008 with Lilly, including a license agreement, a manufacturing and supply agreement, and a stock purchase agreement.

        License Agreement.     Under the terms of the license agreement, Lilly granted us an exclusive license for the right to develop, market, promote and commercialize tadalafil for the treatment of pulmonary hypertension in the United States and Puerto Rico. Tadalafil is also the active pharmaceutical ingredient in Cialis, which is developed and marketed by Lilly for the treatment of erectile dysfunction.

        In exchange for the license, we agreed to pay Lilly a one-time fee of $25.0 million, which was expensed upon the effective date of the agreement, December 18, 2008, since tadalafil has not yet received regulatory approval for commercial sales. We also agreed to pay Lilly royalties equal to 5% of our net sales of tadalafil in the United States and Puerto Rico, as a pass through of Lilly's third-party royalty obligations, for so long as Lilly is required to make such payments.

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        Lilly retained the exclusive rights to develop, manufacture and commercialize pharmaceutical products containing tadalafil for the treatment of pulmonary hypertension outside of the United States and Puerto Rico and for the treatment of other diseases worldwide. Lilly will retain authority for all regulatory activities with respect to tadalafil, including retail pricing, which is expected to be at price parity with Cialis.

        Early in the third quarter of 2008, Lilly filed an NDA with the FDA for tadalafil for the treatment of PAH. Pursuant to our license agreement, we may conduct additional trials for tadalafil related to the treatment of pulmonary hypertension with Lilly's prior consent. Upon approval of tadalafil by the FDA, Lilly will be responsible for manufacturing tadalafil, pursuant to a separate manufacturing and supply agreement with us, which is discussed below.

        If in the future Lilly seeks to grant rights to a third party to develop or commercialize tadalafil for the treatment of pulmonary hypertension in any other country (excluding Japan), the license agreement provides that we will have a right of first negotiation to acquire those rights.

        The license agreement will continue in effect until the later of: (i) expiration, lapse, cancellation, abandonment or invalidation of the last to expire claim within a Lilly patent covering the commercialization of tadalafil for the treatment of pulmonary hypertension in the United States and Puerto Rico; or (ii) expiration of any government-conferred exclusivity rights to use tadalafil for the treatment of pulmonary hypertension in the United States and Puerto Rico.

        We have the right to terminate the license agreement upon six months written notice to Lilly. Lilly has the right to terminate the license agreement if a separate brand name for tadalafil is not approved by the FDA for the treatment of PAH (in which event Lilly will refund the $25.0 million license fee), or if we experience a change of control. Either party may terminate the license agreement upon a material breach by the other party of it or the manufacturing and supply agreement, described below.

        Manufacturing and Supply Agreement.     Under the terms of the manufacturing and supply agreement, Lilly has agreed to manufacture tadalafil and distribute it via its wholesaler network, in the same manner that it distributes its own pharmaceutical products. Under the terms of this agreement, we will take title to tadalafil upon its manufacture by Lilly. Tadalafil will be shipped to customers, generally pharmaceutical wholesalers, in accordance with customers' purchase orders received by Lilly. Upon receipt of tadalafil by the wholesaler, Lilly will invoice and collect the invoice amount due from the customer subject to customary discounts and rebates, if any. Although Lilly is providing these services on our behalf, we maintain the risk of loss as it pertains to inventory and nonpayment of sales invoices. The manufacturing and supply agreement will continue in effect until expiration or termination of the license agreement.

        As consideration for Lilly's agreement to manufacture and supply tadalafil, we agreed to make a one-time payment to Lilly of $125.0 million, which was expensed upon the effective date of the manufacturing and supply agreement. Lilly will refund this payment in the event that the FDA does not approve a separate brand name for tadalafil for the treatment of PAH. We also agreed to purchase tadalafil at a fixed cost, which may be adjusted by Lilly.

        Stock Purchase Agreement.     Under the terms of the stock purchase agreement, on December 18, 2008, we issued 3,150,837 shares of our common stock to Lilly from treasury for an aggregate purchase price of $150.0 million, representing approximately 13.6% of the then-current outstanding shares of our common stock. The shares were issued at a price of $47.61 per share, representing 90% of the average closing price of our common stock for the five trading days commencing on and including November 17, 2008. The weighted average acquisition price of the treasury stock issued was $52.12 per share. The excess of the acquisition cost of the treasury stock above the price paid by Lilly for the shares was approximately $14.2 million and has been included in our accumulated deficit.

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Patents and Proprietary Rights

        Our success depends in part on our ability to obtain and maintain patent protection for our products, preserve trade secrets, prevent third parties from infringing upon our proprietary rights and operate without infringing upon the proprietary rights of others in the United States and worldwide.

    Glaxo Assignment

        In January 1997, Glaxo assigned to us all rights to the use of the stable prostacyclin analogue now known as Remodulin. The patent covering the use of Remodulin for PAH expires in the United States in October 2014 (as extended—see Patent Term Extensions below) and on various dates from September 2009 to August 2013 in nine other countries.

    Pfizer License

        In December 1996, Pharmacia & Upjohn Company (now Pfizer) exclusively licensed to us certain patents, a patent application and know-how for the composition and production of the stable prostacyclin analogue now known as Remodulin. We filed our own United States patent application for a new synthesis and production method for Remodulin in October 1997, and the patent was granted in August 2002. Two additional patents covering this synthesis and production method were granted in March 2003 and August 2004. We believe that our method of synthesis is a substantial improvement over the Pharmacia method and we are using our unique synthesis method rather than the licensed Pharmacia method for the production of Remodulin. We have also registered two patents and have one pending patent application with respect to additional Remodulin synthesis improvements.

    Lilly

        In November 2008, we entered into a license agreement with Lilly pursuant to which Lilly granted us an exclusive right to develop, market, promote and commercialize tadalafil for the treatment of pulmonary hypertension in the United States and Puerto Rico. In connection with these license rights, we made a one-time, upfront payment to Lilly of $25.0 million. Additionally, we agreed to pay Lilly royalties of 5% of our net sales of tadalafil as a pass through of Lilly's third-party royalty obligations for as long as Lilly is required to make such royalty payments. The term of the license agreement will continue generally until the later of: (1) the expiration or lapse of the last to expire claim within a Lilly patent covering commercialization of tadalafil, or (2) expiration of any government conferred exclusivity rights to tadalafil. In addition, the license agreement may be terminated in the event that a separate brand name for tadalafil is not approved by the FDA, in which case Lilly will refund our $25.0 million payment.

    Stanford University and New York Medical College Licenses

        In 2000, we acquired the exclusive license to patents from Stanford University and New York Medical College related to arginine-based dietary supplements that work to enhance the level of naturally occurring NO in the vascular system. The licenses cover worldwide territories and are valid for the life of the patents (expiration dates ranging from 2010 to 2018). We will own all rights to any new products derived from these patents.

    Supernus Pharmaceutical License

        In June 2006, we entered into an exclusive license agreement with Supernus to use certain of its technologies in our sustained release oral treprostinil formulation. Under the agreement, in return for the license, we will pay Supernus certain amounts upon the achievement of specified milestones based on the development of oral treprostinil and its commercial launch. In addition, the agreement provides that we will pay a royalty to Supernus based on net worldwide sales of the initial product. Any such

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royalty will be paid for approximately twelve years commencing with the first product sale and is subject to adjustments as specified in the agreement. Additional milestone payments and royalty payments may be due for the development and commercialization of other products developed using the technology granted under this license.

    Aradigm Corporation

        In August 2007, we entered into an exclusive license, development and commercialization agreement with Aradigm for the rights to manufacture, develop and commercialize the AERx Essence pulmonary drug delivery system, for use as a next-generation metered-dose inhaler with our investigational inhaled treprostinil product for patients with PAH and other conditions. The terms of the agreement include various payments to be made to Aradigm including those related to the completion of certain milestones and license fees over the course of the development period. In addition, we will fund the costs to develop, commercialize and manufacture inhaled treprostinil for use with AERx Essence.

    TransMIT License

        In March 2007, TransMIT Gesellschaft fur Technologletransfer GmbH (TransMIT), an affiliate of the University of Giessen in Germany, assigned to Lung Rx its entire interest in the German patent rights to a portable ultrasonic nebulizer and related technology in order to make, have made, use and sell products based on such patent rights. As consideration for the assignment, Lung Rx paid to TransMIT approximately $779,000 and agreed to pay a 5% running royalty on net sales of nebulizers using the technology in Germany. However, no royalty payments are due to TransMIT until royalties on net sales of products in Germany exceed the original payment of approximately $779,000.

    Memorial Sloan Kettering

        In December 2007, we entered into two agreements with MSKCC to exclusively license certain rights to two investigational monoclonal antibodies, 3F8 and 8H9, for the treatment of neuroblastoma and metastatic brain cancer. The monoclonal antibody 3F8 is a mouse IgG3 MAb, which is currently used in an investigational setting for the treatment of neuroblastoma, a rare cancer of the sympathetic nervous system mainly affecting children. 8H9 is also a mouse monoclonal antibody, but of the IgG1 subclass. The 8H9 antibody is highly reactive with a range of human solid tumors, including brain cancers. The 8H9 antibody is in early investigational development for metastatic brain cancer.

        Under the terms of the agreements, MSKCC granted us an exclusive license for the development and commercialization of the 3F8 and 8H9 antibodies for cancer throughout the universe. In exchange for these exclusive licenses, we agreed to pay a royalty fee on net sales, with an annual minimum royalty payment for each antibody. Milestone payments may also be due for the development and commercialization of these antibodies under our licenses.

    Patent Term Extensions

        In February 2005, we were granted a five-year patent term extension by the United States Patent and Trademark Office for a patent covering the method of treating PAH using Remodulin. U.S. Patent Number 5,153,222, entitled "Method of Treating Pulmonary Hypertension with Benzidine Prostaglandins", was originally scheduled to expire on October 6, 2009. It will now expire on October 6, 2014. The five-year Hatch-Waxman Act extension is the maximum extension allowed under 35 U.S.C. §156. Additional patents covering other products to which we have rights may also be eligible for extensions of up to five years based upon patent term restoration procedures under the Hatch-Waxman Act in the United States, and under similar procedures in Europe.

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Research & Development Expenditures

        We are engaged in research and development and have incurred substantial expenses for these activities. These expenses generally include the cost of acquiring or inventing new technologies and products, as well as new product development. Research and development expenses during 2008, 2007 and 2006 totaled approximately $239.2 million, $83.4 million and $57.6 million, respectively. See Item 7—Management's Discussion and Analysis of Financial Condition and Results of Operations—Major Research and Development Projects for additional information regarding expenditures related to major research and development projects.

Manufacturing and Supply

        We made treprostinil sodium, the active ingredient for Remodulin and inhaled treprostinil, and treprostinil diethanolamine, the active ingredient for oral treprostinil, at our manufacturing facility in Chicago, Illinois, until March 2007 at which time we transitioned these activities to our new laboratory facility in Silver Spring, Maryland. In July 2008, we submitted an application to the FDA for approval of the new facility for commercial manufacturing, and we expect to receive approval in the first half of 2009. Until we receive FDA approval, we cannot use or sell commercially any products manufactured in our Silver Spring facility. We currently maintain an inventory of formulated Remodulin that will meet over two years of expected demand.

        With the transfer of our manufacturing operations to our Silver Spring facility, we have also changed our internal manufacturing process. When we began, we produced treprostinil sodium starting with basic chemicals and completed the full manufacturing process. Over the last several years, we have been modifying the manufacturing process to begin with advanced intermediate compounds made by outside vendors. We anticipate that, upon commercialization of oral treprostinil, the need for treprostinil diethanolamine will be greater than the need for treprostinil sodium. By beginning the manufacturing process with the advanced intermediate compound, we are able to make treprostinil diethanolamine and then convert that compound to treprostinil sodium as needed. We believe this process will give us the most flexibility and efficiency in meeting future demands for both forms of treprostinil. We have approved three vendors to supply the advanced intermediate compounds in order to reduce the risk of supply shortages.

        Baxter Healthcare Corporation (Baxter) formulates the active ingredient we manufacture into Remodulin for us. The term of our initial agreement with Baxter ended in October 2004. The agreement is renewable for successive eighteen-month terms and has been continuously renewed since October 2004. In late 2008, Baxter gave us verbal notice that it does not intend to renew our agreement upon the expiration of its current term in late October 2010. We eventually intend to formulate Remodulin ourselves in the combination office and laboratory facility that we are currently constructing adjacent to our Silver Spring laboratory facility. In the meantime, we intend to engage another third party to formulate Remodulin prior to the termination of our agreement with Baxter to serve as a secondary manufacturer. Also, although we maintain a two-year inventory of Remodulin, we believe that engaging a third-party formulator will mitigate the risk that we might not be able to formulate sufficient quantities of Remodulin to meet patient demand. In addition, we expect to increase contingent inventory levels of formulated Remodulin from an approximate two-year supply to a three-year supply based on projected demand.

        We rely on Catalent Pharma Solutions, Inc. (formerly Cardinal Health, Inc.) (Catalent) to conduct stability studies on Remodulin, formulate inhaled treprostinil, formulate oral treprostinil for clinical trials and to analyze other products we develop. We expect to begin manufacturing oral treprostinil in our new manufacturing facility in Research Triangle Park, North Carolina, during the second half of 2009.

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        In 2009, we anticipate commencing commercial development of the 3F8 and 8H9 antibodies licensed from MSKCC at our Silver Spring, Maryland, facility. We expect that we will be able to utilize much of the equipment that we obtained for the OvaRex manufacturing process for 3F8 and 8H9 antibody development.

        Our telemedicine products are currently manufactured by Winland Electronics, Inc. Prior to 2008, our telemedicine products were made by MSI of Florida, Inc.

        Although we believe that other manufacturers and suppliers could provide similar products, services and materials, there are few companies that could replace these manufacturers and suppliers. A change in supplier or manufacturer could cause a delay in the manufacture, distribution and research efforts associated with our respective products or result in increased costs. See also Item 1A—Risk Factors included elsewhere in this Annual Report on Form 10-K.

Competition

        Many drug companies engage in research and development to commercialize products to treat cardiovascular and infectious diseases and cancer. For the treatment of PAH, we compete with many approved products in the United States and the rest of the world, including the following:

    Flolan. The first product approved by the FDA for treating PAH, Flolan is a prostacyclin analogue that is delivered by intravenous infusion. Glaxo began marketing Flolan in the United States in 1996. In 2006, Myogen, Inc. (Myogen) acquired the marketing rights from Glaxo for Flolan in the United States. In November 2006, Myogen was acquired by Gilead Sciences, Inc. (Gilead). The generic exclusivity period for Flolan expired in April 2007;

    Generic epoprostenol. In April 2008, Teva Pharmaceuticals Industries Ltd. (Teva) announced that the FDA approved its version of generic epoprostenol for the treatment of PAH. This is the first approved generic version of Flolan. In June 2008, GeneraMedix Inc. (GeneraMedix) received FDA approval for its version of generic epoprostenol, which is stable at room temperature. In February 2009, Actelion announced that it had entered into an agreement with GeneraMedix to acquire its generic epoprostenol product;

    Ventavis. Approved in December 2004 in the United States and in September 2003 in Europe, Ventavis is the only prostacyclin analogue that has been approved for inhalation. Ventavis was initially marketed by CoTherix, Inc. (CoTherix) in the United States and is marketed by Schering AG in Europe as Iloprost. In January 2007, CoTherix was acquired by Actelion, the manufacturer and distributor of Tracleer;

    Tracleer. The first oral drug to be approved for PAH, Tracleer is also the first drug in its class, known as ERAs. Tracleer was approved in December 2001 in the United States and in May 2002 in Europe. Tracleer is marketed worldwide by Actelion;

    Revatio. Approved in June 2005 in the United States, Revatio is also an oral therapy and is marketed by Pfizer Inc. Revatio contains sildenafil, the same active ingredient as Viagra, and is the first PDE5 inhibitor, to be approved for PAH;

    Letairis™. Approved in June 2007 in the United States, Letairis is an oral therapy marketed by Gilead for the treatment of PAH. Like Tracleer, Letairis is an ERA. In April 2008, Glaxo received marketing authorization from the EMEA for Letairis in Europe where it is known as Volibris®; and

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    Thelin®. Approved in August 2006 in the EU, Thelin is an oral therapy, which was developed and initially marketed in Europe by Encysive Pharmaceuticals Inc. (Encysive), for the treatment of PAH. Like Tracleer and Letairis, Thelin is an ERA. In June 2008, Pfizer completed its acquisition of Encysive. Pfizer has stated that it plans to conduct a pivotal Phase III clinical trial to support registration of Thelin in the United States and eventually seek FDA approval.

        Due to their ease of use, oral therapies, such as Tracleer and Revatio, are generally considered front-line therapies for newly diagnosed PAH patients. Flolan and Remodulin, more complex infusion therapies, are generally considered later-stage therapies for sicker patients. The use of the available oral therapies and Ventavis, either alone or in combination, will delay the need for infusion therapy for many patients. As a result, while we may not currently compete head-to-head with these drugs as front-line therapy, the success of their use affects our commercial operations. As we develop both inhaled and oral treprostinil therapies, we will be expanding our range of therapeutics to include front line and mid-range treatment options. Furthermore, the commercialization of generic forms of other approved PAH therapies may exert downward pressure on the pricing of our products. For further discussion on this risk, see Item 1A—Risk Factors—We may not successfully compete with established drugs, products and the companies that develop and market them

        Holter and event monitoring analysis services and systems are provided by many local and regional competitors and a few national competitors.

        We compete with all of these companies for customers, funding, access to licenses, personnel, third-party collaborators, product development and commercialization. Almost all of these companies have substantially greater financial, marketing, sales, distribution and technical resources, and more experience in research and development, product development and marketing, clinical trials and regulatory matters, than we have.

Governmental Regulation

        The research, development, testing, manufacture, promotion, marketing and distribution of pharmaceutical products are extensively regulated by governmental agencies in the United States and in other countries. Drugs are subject to rigorous regulation by the FDA in the United States, the EMEA in the EU and similar regulatory authorities in other countries. The steps ordinarily required before a new drug may be marketed in the United States, which are similar to steps required in most other countries, include:

    Preclinical laboratory tests, preclinical studies in animals, formulation studies and the submission to the FDA of an Investigational New Drug Application (IND) for a new drug;

    Clinical studies in healthy volunteers;

    Adequate and well-controlled clinical trials to establish the safety and efficacy of the drug for each indication;

    The submission of an NDA to the FDA; and

    FDA review and approval of the NDA prior to any commercial sale or shipment of the drug.

        Preclinical tests include laboratory evaluation of product chemistry, toxicity and formulation, as well as animal studies. The results of preclinical testing are submitted to the FDA as part of an IND. A 30-day waiting period after the filing of each IND is required prior to the commencement of clinical testing in humans. At any time during this 30-day period or at any time thereafter, the FDA may halt proposed or ongoing clinical trials until it authorizes trials under specified terms. The IND process may be extremely costly and may substantially delay development of our products. Moreover, positive results of preclinical tests will not necessarily indicate positive results in clinical trials.

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        Clinical trials in support of an NDA are typically conducted in three sequential phases, but the phases may overlap. During Phase I, the initial introduction of the drug into healthy human subjects or patients, the drug is tested to assess its effects on bodily functions and safety, including side effects associated with increasing doses. Phase II usually involves studies in a limited patient population to:

    assess the efficacy of the drug in specific, targeted indications;

    assess dosage tolerance and optimal dosage; and

    identify possible adverse effects and safety risks.

        If a compound is found to be potentially effective and to have an acceptable safety profile in Phase II evaluations, then Phase III trials, also called pivotal studies, major studies or advanced clinical trials, are undertaken to further demonstrate clinical efficacy and to further test for safety within an expanded patient population at geographically diverse clinical study sites.

        After successful completion of the required clinical testing, an NDA or a Biologics License Application is typically submitted to the FDA in the United States, and an MAA is typically submitted to the EMEA in the EU. The regulatory authorities may request additional information before accepting an application, in which case the application must be resubmitted with the additional information. Once the application has been accepted, the regulatory authority reviews the application and responds to the applicant. The review process is often significantly extended by requests from regulatory authorities for additional information or clarification. In the United States, the FDA may refer the application to an appropriate advisory committee for review, evaluation and recommendation as to whether it should be approved. The FDA is not bound by the recommendation of an advisory committee. The regulatory authorities may also inspect the manufacturing facility before approving an application.

        In the United States, if FDA evaluations of the application and the manufacturing facilities are favorable, the FDA may issue either an approval letter or a complete response letter. A complete response letter will usually contain a number of conditions that must be met in order to secure final approval of the application and authorization of commercial marketing of the drug for certain indications.

        At the request of an applicant, the FDA may designate a product as an "orphan drug" in the United States if the drug is intended to treat a rare disease or condition. A disease or condition is considered rare if it affects fewer than 200,000 people in the United States. If an applicant obtains the first FDA marketing approval for a certain orphan drug, the applicant will have a seven-year exclusive right as against generic versions to market the drug for the orphan indication. The FDA has approved the orphan designation for treprostinil for the treatment of PAH without regard to drug product formulation. We believe that the orphan designation of treprostinil includes all types of PAH, regardless of etiology. However, such designation does not preclude us from seeking orphan drug designation for other formulations of treprostinil or for other etiologies of PAH or medically plausible subsets of PAH, and does not preclude the FDA from granting a new seven-year period of orphan drug exclusivity upon the approval of an NDA for a new formulation of treprostinil for the designated new indication, provided we demonstrate that such new formulation is clinically superior to the older formulation of parenteral Remodulin.

        Subcutaneous Remodulin was approved by the FDA for the treatment of PAH in patients with NYHA Class II-IV symptoms to diminish symptoms associated with exercise, and intravenous Remodulin was approved for those patients not able to tolerate subcutaneous infusion. If regulatory approval of our other products is granted, such approvals will similarly be limited to certain disease states or conditions. The manufacturers of approved products and their manufacturing facilities will be subject to continual review and periodic inspections. Furthermore, identification of certain side effects or the occurrence of manufacturing problems after a drug is on the market could cause subsequent

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withdrawal of approval, reformulation of the drug, additional preclinical testing or clinical trials, and changes in labeling of the product.

        The Hatch-Waxman Act provides that patent terms may be extended to compensate for some of the patent life that is lost during the FDA regulatory review period for the product. This extension period would generally be one-half the time between the effective date of an IND and the submission date of an NDA, plus all of the time between the submission date of an NDA and its approval, subject to a maximum extension of five years. Similar patent term extensions are available under European laws. Following FDA approval, we filed a patent term extension application with the United States Patent and Trademark Office for our patent covering the method of treating PAH using Remodulin. The application was approved in February 2005, and the patent for Remodulin is currently set to expire on October 6, 2014.

        Outside of the United States, our ability to market our products will also be contingent upon receiving marketing authorizations from the appropriate regulatory authorities. The foreign regulatory approval process may include some or all of the risks associated with FDA approval set forth above. The requirements governing the conduct of clinical trials and marketing authorization vary widely from country to country. At present, foreign marketing authorizations are applied for at a national level, although, within Europe, procedures are available to companies wishing to market a product in more than one EU member state.

        In the EU, marketing authorizations may be submitted through a centralized body or through a decentralized or a national level process. The centralized procedure is mandatory for the approval of biotechnology products and high technology products and is available at the applicant's option for other products. The centralized procedure provides for the grant of a single marketing authorization that is valid in all EU member countries. The decentralized procedure is available for all medicinal products that are not subject to the centralized procedure. The decentralized procedure provides for mutual recognition of national approval decisions, changes existing procedures for national approvals and establishes procedures for coordinated EU actions on products, suspensions and withdrawals. Under this procedure, the holder of a national marketing authorization for which mutual recognition is sought may submit an application to one or more EU member countries, certify that the dossier is identical to that on which the first approval was based, or explain any differences and certify that identical dossiers are being submitted to all EU member countries for which recognition is sought. Within 90 days of receiving the application and assessment report, each EU member country must decide whether to recognize approval. The procedure encourages member states to work with applicants and other regulatory authorities to resolve disputes concerning mutual recognition. Lack of objection of a given country within 90 days automatically results in approval in that country. Following receipt of marketing authorization in an EU member country, the applicant is then required to engage in pricing discussions and negotiations with a separate prescription pricing authority in that country. Commercial sales are only able to commence in a country once pricing approval has been received.

        To secure European regulatory approvals for subcutaneous Remodulin for PAH, we used the mutual recognition process. Under the rules then applicable, centralized filing was not required and we perceived the decentralized procedure to be the most effective means for approval. We filed our first MAA in France in February 2001. Review of our application was completed in 2005. As a result, Remodulin was approved in 23 member countries of the EU under the mutual recognition process described above. We withdrew applications in Spain, the United Kingdom and Ireland with the intent of resubmitting the applications when we file for approval for intravenous Remodulin since these countries required additional information not required by the other European countries. We had to file for approval for intravenous Remodulin using the mutual recognition process since intravenous use of Remodulin is considered a variation to the original license. We filed our application with our reference member state, France, which has notified us that it is not satisfied with our filing. We are working to address France's concerns and believe that we will eventually receive commercial approval for

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intravenous Remodulin in at least some European countries. We have regulatory applications pending in other countries as well.

        To secure European regulatory approval for inhaled treprostinil, we are using the centralized process. Regulations in Europe have changed since we made our initial filing for Remodulin and all therapies for orphan diseases must use the centralized process. We submitted our application for European approval of inhaled treprostinil in December 2008.

        To secure approval of the Optineb nebulizer in the United States, applicable regulations require a quality system for the design, manufacture, packaging, labeling, storage, installation and servicing of devices intended for commercial distribution. These quality system regulations require that various specifications and controls be established for devices, devices be designed under a quality system to meet these specifications, devices be manufactured under a quality system, finished devices meet these specifications, devices be correctly installed, checked and serviced, quality data be analyzed to identify and correct quality problems, and complaints be processed. Regulatory authorities may also require additional patient data to support approval for these devices. We are also subject to inspections by regulatory agencies and ensuring that NEBU-TEC and we meet all requirements during inspections.

        To continue marketing our products after approval, applicable regulations require us to maintain a positive risk-benefit profile, maintaining regulatory applications through periodic reports to regulatory authorities, fulfilling pharmacovigilance requirements, maintaining manufacturing facilities to Good Manufacturing Practices requirements, and successfully completing regulatory agency inspections, among other requirements.

        Our telemedicine products are manufactured at contract facilities that are regulated by the FDA under different laws and regulations that apply to medical devices. The telemedicine devices designed and sold by Medicomp have received marketing clearance from the FDA under Section 510(k) of the Food, Drug and Cosmetic Act. Medical devices are required to be manufactured in conformance with the FDA's Quality System Regulations.

        In the United States, many independent third-party payers, as well as the Medicare and Medicaid programs, reimburse Remodulin. Medicare is the federal program that provides health care benefits to senior citizens and certain disabled and chronically ill persons. Medicaid is the federal program administered by the states to provide health care benefits to certain indigent persons. The Medicare contractors who administer the program provide reimbursement for Remodulin at a rate generally equal to 95% of the published average wholesale price, as recommended by us. The state Medicaid programs also generally provide reimbursement for Remodulin at a price that is below the published average wholesale price. Beginning in 2007, the Medicare Modernization Act requires that we and the Centers for Medicare and Medicaid Services negotiate a new price for Remodulin. We anticipate that the new rules will not have an impact on Remodulin reimbursement rates in 2009. In return for including Remodulin in the Medicare and Medicaid programs, we have agreed to pay a rebate to state Medicaid agencies that provide reimbursement for Remodulin. We have also agreed to sell Remodulin under contracts with the Veterans Administration, Department of Defense, Public Health Service and numerous other federal agencies as well as certain hospitals that are designated as 340B entities (entities designated by federal programs to receive drugs at discounted prices) at prices that are significantly below the price we charge to our specialty pharmaceutical distributors. These programs and contracts are highly regulated and impose restrictions on our business. Failure to comply with these regulations and restrictions could result in a loss of our ability to continue receiving reimbursement for Remodulin. We estimate that between 35-50% of Remodulin sales in the United States are reimbursed under the Medicare and Medicaid programs.

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Employees

        We had approximately 360 employees as of January 29, 2009. We also maintain active independent contractor relationships with various individuals, most of whom have month-to-month or annual consulting agreements. We believe our employee relations are excellent.

Industry Segments and Geographic Areas

        We operate two business segments: pharmaceuticals and telemedicine. We sell our products in the United States and throughout the rest of the world. The information required by Item 101(b) and 101(d) of Regulation S-K relating to financial information about industry segments and geographical areas, respectively, is contained in Note 19 of the consolidated financial statements included in this Annual Report on Form 10-K.

Corporate Website

        Our Internet website address is http://www.unither.com . Our filings on Form 10-K, Form 10-Q, Form 3, Form 4, Form 5, Form 8-K and any and all amendments thereto are available free of charge through this internet website as soon as reasonably practicable after they are filed or furnished to the Securities and Exchange Commission (SEC). They are also available through the SEC's EDGAR portal at http://www.sec.gov/edgar/searchedgar/companysearch.html .

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EXECUTIVE OFFICERS OF THE REGISTRANT

        The following is a list, as of February 21, 2009, setting forth certain information regarding our executive officers. Each executive officer holds office until the first meeting of the Board of Directors after the annual meeting of stockholders, and until his or her successor is elected and qualified or until his or her earlier resignation or removal. Each executive officer's employment will end pursuant to the terms of his or her employment contract. Each of the employment contracts generally provides for an initial term of service of five years, which five-year term may be renewed after each year for additional one-year periods.

Name
  Age  
Position

Martine A. Rothblatt, Ph.D., J.D., M.B.A. 

    54   Chairman, Chief Executive Officer and Director

Roger Jeffs, Ph.D. 

   

47

 

President, Chief Operating Officer and Director

John M. Ferrari

   

54

 

Chief Financial Officer and Treasurer

Paul A. Mahon, J.D. 

   

45

 

Executive Vice President for Strategic Planning, General Counsel and Corporate Secretary

         Martine A. Rothblatt, Ph.D., J.D., M.B.A ., started United Therapeutics in 1996 and has served as Chairman and Chief Executive Officer since its inception. Prior to founding United Therapeutics, she launched several satellite communications companies. She also represented the radio astronomy interests of the National Academy of Sciences' Committee on Radio Frequencies before the FCC and led the International Bar Association's efforts to present the United Nations with a draft Human Genome Treaty. Her book, Y OUR L IFE OR M INE: H OW G EOETHICS C AN R ESOLVE THE C ONFLICT B ETWEEN P UBLIC AND P RIVATE I NTERESTS I N X ENOTRANSPLANTATION , was published by Ashgate in 2004. She is a co-inventor on three of our patents pertaining to treprostinil.

         Roger Jeffs, Ph.D., joined United Therapeutics in September 1998 as Director of Research, Development and Medical. Dr. Jeffs was promoted to Vice President of Research, Development and Medical in July 2000 and to President and Chief Operating Officer in January 2001. Prior to 1998, Dr. Jeffs worked at Amgen, Inc. as Manager of Clinical Affairs and Associate Director of Clinical Research from 1995 to 1998, where he served as the worldwide clinical leader of the Infectious Disease Program.

         John M. Ferrari joined United Therapeutics in May 2001 as Controller. Mr. Ferrari was promoted to Vice President of Finance in December 2003 and to Vice President of Finance and Treasurer in June 2004. In August 2006 Mr. Ferrari was promoted to Chief Financial Officer and Treasurer. Prior to joining United Therapeutics, Mr. Ferrari served as Controller for Blackboard, Inc., from 1998 to 2001. Prior to his employment with Blackboard, Inc., Mr. Ferrari served in various senior financial management positions since beginning his accounting career in 1984.

         Paul A. Mahon, J.D., has served as General Counsel and Corporate Secretary of United Therapeutics since its inception in 1996. In June 2001, Mr. Mahon joined United Therapeutics full-time as Senior Vice President, General Counsel and Corporate Secretary. In November 2003, Mr. Mahon was promoted to Executive Vice President for Strategic Planning, General Counsel and Corporate Secretary. Prior to June 2001, he served United Therapeutics, beginning with its formation in 1996, in his capacity as principal and managing partner of a law firm specializing in technology and media law.

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