Federal Circuit Rules Against The Medicines Company in Angiomax® (bivalirudin) Patent Litigation

02 Jul 2015

The Medicines Company (NASDAQ:MDCO) announced the U.S. Court of Appeals for the Federal Circuit Court has ruled against the Company in its Angiomax® (bivalirudin) patent litigation with Hospira, Inc.

In its ruling today, the Federal Circuit held that U.S. Patent Nos. 7,582,727 (the ‘727 patent) and 7,598,343 (the ‘343 patent) are invalid.

On March 31, 2014, the U.S. District Court of Delaware found that all of the asserted claims of the ‘727 patent and the ‘343 patent covering Angiomax were valid but not infringed by Hospira’s ANDA products. The Medicines Company appealed the District Court’s claim construction and non-infringement rulings, while Hospira appealed the validity rulings.

“We are evaluating today’s Court ruling and considering our next steps,” said Clive Meanwell, MD, PhD, Chairman and Chief Executive Officer, The Medicines Company. “We remain committed to interventional cardiovascular medicine and will continue to support bivalirudin. We are focused on the current launch of KENGREALTM, our newly approved platelet inhibitor, which we anticipate will be used by many of our existing customers in cardiac catheterization laboratories. We also look forward to the release of important new data on our PCSK9 RNAi compound at the European Society of Cardiology meeting, August 31st to September 2nd. Meantime our launch and launch preparations for IONSYS®, ORBACTIV® and a new formulation of MINOCIN® for Injection are also underway.”

About ANGIOMAX® (bivalirudin)

Angiomax® is indicated in patients undergoing PCI with provisional use of GPI and in patients with, or at risk of, heparin-induced thrombocytopenia and thrombosis syndrome (HIT/HITTS) undergoing PCI. In addition, Angiomax is also indicated for use as an anticoagulant in patients with unstable angina undergoing percutaneous transluminal coronary angioplasty (PTCA). Angiomax is intended for use with aspirin. Angiomax is not approved for use in patients with acute coronary syndromes (ACS) not undergoing PCI or PTCA.

In clinical trials comparing Angiomax and heparin, the most common adverse reaction for Angiomax was bleeding (28%). Other common adverse reactions were headache, thrombocytopenia and fever. An unexplained fall in blood pressure or hematocrit, or any unexplained symptom, should lead to serious consideration of a hemorrhagic event and cessation of Angiomax administration. Angiomax should be used with caution in patients with disease states associated with an increased risk of bleeding.

In gamma brachytherapy, an increased risk of thrombus formation, including fatal outcomes, has been associated with the use of Angiomax. Angiomax is contraindicated in patients with active major bleeding or hypersensitivity to Angiomax or its components.

Please see full prescribing information for Angiomax, available at http://www.angiomax.com.

About KENGREAL™ (cangrelor)

KENGREAL, a synthetic, small molecule, is indicated as an adjunct to percutaneous coronary intervention (PCI) to reduce the risk of periprocedural myocardial infarction (MI), repeat coronary revascularization, and stent thrombosis (ST) in patients who have not been treated with a P2Y12 platelet inhibitor and are not being given a glycoprotein IIb/IIIa inhibitor.

Important Safety Information

KENGREAL is contraindicated in patients with significant active bleeding.

KENGREAL is contraindicated in patients with known hypersensitivity (e.g., anaphylaxis) to cangrelor or any component of the product.

Drugs that inhibit platelet P2Y12 function, including KENGREAL, increase the risk of bleeding. In CHAMPION PHOENIX, bleeding events of all severities were more common with KENGREAL than with clopidogrel. Bleeding complications with KENGREAL™ were consistent across a variety of clinically important subgroups. Once KENGREAL is discontinued, there is no antiplatelet effect after an hour.

The most common adverse reaction is bleeding.

Please see full prescribing information for KENGREAL, available at http://www.kengreal.com.

About IONSYS® (fentanyl iontophoretic transdermal system), CII

IONSYS® contains the opioid fentanyl and is a compact, needle-free, pre-programmed system that is indicated for the short-term management of acute postoperative pain in adult patients requiring opioid analgesia in the hospital. IONSYS is only for use in patients who are alert enough and have adequate cognitive ability to understand the directions for use. IONSYS is not for home use and is intended for use only in patients in the hospital. Discontinue treatment with IONSYS before patients leave the hospital. IONSYS is for use after patients have been titrated to an acceptable level of analgesia using alternate opioid analgesics.

IONSYS will only be administered to patients in hospitals enrolled in the IONSYS REMS program, the goal of which is to decrease the risk of respiratory depression resulting from accidental exposure to persons for whom it is not prescribed by ensuring it is only dispensed to patients in certified hospitals and informing health care providers of the serious risk of respiratory depression resulting from accidental exposure to fentanyl.

Important Safety Information

WARNING: HOSPITAL USE ONLY; LIFE-THREATENING RESPIRATORY DEPRESSION; IONSYS REMS; ADDICTION, ABUSE, AND MISUSE; and CYTOCHROME P450 3A4 INTERACTION

Life Threatening Respiratory Depression

  • Use of IONSYS may result in potentially life-threatening respiratory depression and death as a result of the active drug, fentanyl. Only the patient should activate IONSYS dosing.
  • Accidental exposure to an intact IONSYS or to the hydrogel component, especially by children, through contact with skin or contact with mucous membranes, can result in a fatal overdose of fentanyl.
  • Keep out of reach of children.
  • IONSYS is for use only in patients in the hospital. Discontinue treatment with IONSYS before patients leave the hospital.

IONSYS Risk Evaluation and Mitigation Strategy (REMS) Program

  • Because of the of potentially life-threatening respiratory depression resulting from accidental exposure, IONSYS is available only through a restricted program required by the Food and Drug Administration, called a Risk Evaluation and Mitigation Strategy (REMS). Hospitals must enroll in the program before they can dispense IONSYS. Further information is available at www.ionsysrems.com, or by calling 1-877-488-6835.

Addiction, Abuse, and Misuse

  • IONSYS contains fentanyl, a Schedule II controlled substance with abuse liability similar to other opioid analgesics.
  • IONSYS exposes users to risks of addiction, abuse, and misuse, which can lead to overdose and death. Assess each patient’s risk before prescribing, and monitor regularly for development of these behaviors or conditions.

Cytochrome P450 3A4 Interaction

  • The concomitant use of IONSYS with all cytochrome P450 3A4 inhibitors may result in an increase in fentanyl plasma concentrations, which could increase or prolong adverse drug effects and may cause potentially fatal respiratory depression. In addition, discontinuation of a concomitantly used cytochrome P450 3A4 inducer may result in an increase in fentanyl plasma concentration. Monitor patients receiving IONSYS and any CYP3A4 inhibitor or inducer.

Contraindications

  • Significant respiratory depression
  • Acute or severe bronchial asthma
  • Known or suspected paralytic ileus and GI obstruction
  • Hypersensitivity to fentanyl or cetylpyridinium chloride (e.g., Cepacol®) or any component of IONSYS

Warnings and Precautions

Interactions with CNS depressants: Concomitant use with alcohol or other central nervous system (CNS) depressants (e.g., sedatives, anxiolytics, hypnotics, neuroleptics, otheropioids) may cause hypotension, profound sedation, respiratory depression, coma and death. Monitor patients closely if co-administration is required.

Risk of Injury During MRI Procedure: IONSYS contains metal parts and must be removed and properly disposed of before an MRI procedure.

Radiographic Imaging, Cardioversion, Defibrillation, Pacemakers: IONSYS contains metal parts and must be removed and properly disposed of before cardioversion or defibrillation to avoid damage to IONSYS from the strong electromagnetic fields set up by these procedures. IONSYS contains radio-opaque components and may interfere with an X-ray image or CAT scan.

Topical Skin Reactions: Topical skin reactions may occur with use of IONSYS and are typically limited to the site application area. Reactions generally resolve without treatment. If a severe skin reaction is observed, remove IONSYS and discontinue further use.

Use in Elderly, Cachectic, and Debilitated Patients: Life-threatening respiratory depression is more likely to occur in elderly, cachectic, or debilitated patients. Monitor such patients closely when IONSYS is used concomitantly with other drugs that depress respiration.

Use in Patients with Chronic Pulmonary Disease: Monitor patients with significant chronic obstructive pulmonary disease or cor pulmonale, and patients having a substantially decreased respiratory reserve, hypoxia, hypercapnia, or pre-existing respiratory depression for respiratory depression, particularly when initiating therapy with IONSYS. Consider the use of alternative non-opioid analgesics in these patients if possible.

Hypotensive Effect: IONSYS may cause severe hypotension including orthostatic hypotension and syncope in ambulatory patients. There is increased risk in patients whose ability to maintain blood pressure has already been compromised by a reduced blood volume, or concurrent administration of certain CNS depressant drugs (e.g., phenothiazines or general anesthetics). Monitor these patients after initiating IONSYS. In patients with circulatory shock, IONSYS may cause vasodilation that can further reduce cardiac output and blood pressure. Avoid the use of IONSYS in patients with circulatory shock.

Patients with Head Injury or Increased Intracranial Pressure: IONSYS is not suitable for use in patients who are not alert and able to follow directions. Monitor for sedation and respiratory depression. Avoid use of IONSYS in patients with impaired consciousness or coma susceptible to intracranial effects of CO2 retention. IONSYS may reduce respiratory drive, and the resultant CO2 retention can further increase intracranial pressure. Opioids may obscure the clinical course of patients with head injury. Use IONSYS with caution in patients with brain tumors.

Use in Patients with Gastrointestinal Conditions: IONSYS is contraindicated in patients with gastrointestinal obstruction, including paralytic ileus. Fentanyl may cause spasm of the sphincter of Oddi. Monitor patients with biliary tract disease, including acute pancreatitis for worsening symptoms. Opioids may cause increases in serum amylase.

Use in Patients with Convulsive or Seizure Disorders: IONSYS may aggravate convulsions in patients with convulsive disorders, and may induce or aggravate seizures in some clinical settings. Monitor patients with a history of seizure disorders for worsened seizure control during IONSYS therapy.

Cardiac Disease: IONSYS may produce bradycardia in some patients. Monitor patients with bradyarrhythmias closely for changes in heart rate, particularly when initiating therapy with IONSYS.

Hepatic Impairment: Insufficient data are available on the use of IONSYS in patients with impaired hepatic function. Monitor for signs of sedation and respiratory depression in patients with hepatic impairment.

Renal Impairment: A clinical pharmacology study with intravenous fentanyl in patients undergoing kidney transplantation has shown that patients with high blood urea nitrogen level had low fentanyl clearance. Monitor for signs of sedation and respiratory depression in patients with renal impairment.

Adverse Reactions

Most common (frequency ? 2%) headache, hypotension, nausea, vomiting, anemia, dizziness, application site reaction-erythema, pruritus, and urinary retention.

Please see full prescribing information for IONSYS, available at http://www.ionsys.com.

About ORBACTIV® (oritavancin)

ORBACTIV® (oritavancin) for injection received FDA approval in the U.S. in August 2014. ORBACTIV is the first and only FDA-approved single-dose IV antibiotic for the treatment of adult patients with acute bacterial skin and skin structure infections (ABSSSI) caused or suspected to be caused by susceptible isolates of the following gram-positive microorganisms: Staphylococcus aureus (including methicillin-susceptible and methicillin–resistant isolates),Streptococcus pyogenesStreptococcus agalactiaeStreptococcus dysgalactiae, Streptococcus anginosus group (includes S. anginosusS. intermedius, and S. constellatus), and Enterococcus faecalis (vancomycin-susceptible isolates only).

IMPORTANT SAFETY INFORMATION

Contraindications

Use of intravenous unfractionated heparin sodium is contraindicated for 48 hours after ORBACTIV administration because the activated partial thromboplastin time (aPTT) test results are expected to remain falsely elevated for approximately 48 hours after ORBACTIV administration.

ORBACTIV is contraindicated in patients with known hypersensitivity to ORBACTIV.

Warnings and Precautions

Concomitant warfarin use: Co-administration of ORBACTIV and warfarin may result in higher exposure of warfarin, which may increase the risk of bleeding. Use ORBACTIV in patients on chronic warfarin therapy only when the benefits can be expected to outweigh the risk of bleeding.

Coagulation test interference: ORBACTIV has been shown to artificially prolong aPTT for up to 48 hours, and may prolong PT and INR for up to 24 hours.

Hypersensitivity reactions have been reported with the use of antibacterial agents including ORBACTIV. Discontinue infusion if signs of acute hypersensitivity occur. Monitor closely patients with known hypersensitivity to glycopeptides.

Infusion-related reactions have been reported. Slow the rate or interrupt infusion if infusion reaction develops.

Clostridium difficile-associated colitis: Evaluate patients if diarrhea occurs.

Osteomyelitis: Institute appropriate alternate antibacterial therapy in patients with confirmed or suspected osteomyelitis.

Prescribing ORBACTIV in the absence of a proven or strongly suspected bacterial infection is unlikely to provide benefit to the patient and increases the risk of the development of drug-resistant bacteria.

Adverse Reactions

The most common adverse reactions (? 3%) in patients treated with ORBACTIV were headache, nausea, vomiting, limb and subcutaneous abscesses, and diarrhea.

Please see www.orbactiv.com for the full prescribing information.

About MINOCIN® (minocycline) for Injection

Indication

MINOCIN® (minocycline) for Injection is indicated for the treatment of infections due to susceptible strains of designated microorganisms, including Acinetobacter species bacteria. For additional full list of indications and designated susceptible pathogens, please see the full prescribing information available at www.minociniv.com.

IMPORTANT SAFETY INFORMATION

Contraindications

MINOCIN® (minocycline) for Injection is contraindicated in persons who have shown hypersensitivity to any of the tetracyclines or to any of the components of the product formulation.

Warnings

Tooth Development

MINOCIN, like other tetracycline-class antibacterials, can cause fetal harm when administered to a pregnant woman. If any tetracycline is used during pregnancy, or if the patient becomes pregnant while taking these drugs, the patient should be apprised of the potential hazard to the fetus. The use of drugs of the tetracycline class during tooth development (last half of pregnancy, infancy, and childhood to the age of 8 years) may cause permanent discoloration of the teeth (yellow-gray-brown).

This adverse reaction is more common during long-term use of the drugs but has been observed following repeated short-term courses. Enamel hypoplasia has also been reported. Tetracycline drugs, therefore, should not be used during tooth development unless other drugs are not likely to be effective or are contraindicated.

Skeletal Development

All tetracyclines form a stable calcium complex in any bone-forming tissue. A decrease in the fibula growth rate has been observed in premature human infants given oral tetracycline in doses of 25 mg/kg every six hours. This reaction was shown to be reversible when the drug was discontinued.

Results of animal studies indicate that tetracyclines cross the placenta, are found in fetal tissues, and can have toxic effects on the developing fetus (often related to retardation of skeletal development). Evidence of embryotoxicity has been noted in animals treated early in pregnancy.

Dermatologic Reaction

Drug Rash with Eosinophilia and Systemic Symptoms (DRESS) including fatal cases have been reported with minocycline use. If this syndrome is recognized, the drug should be discontinued immediately.

Anti-anabolic Action

The anti-anabolic action of the tetracyclines may cause an increase in BUN. While this is not a problem in those with normal renal function, in patients with significantly impaired function, higher serum levels of tetracycline may lead to azotemia, hyperphosphatemia, and acidosis. Under such conditions, monitoring of creatinine and BUN is recommended, and the total daily dosage should not exceed 200 mg in 24 hours. If renal impairment exists, even usual oral or parenteral doses may lead to systemic accumulation of the drug and possible liver toxicity.

Photosensitivity

Photosensitivity manifested by an exaggerated sunburn reaction has been observed in some individuals taking tetracyclines. This has been reported with minocycline.

Central Nervous System Effects

Central nervous system side effects including light-headedness, dizziness or vertigo have been reported. Patients who experience these symptoms should be cautioned about driving vehicles or using hazardous machinery while on minocycline therapy. These symptoms may disappear during therapy and usually disappear rapidly when the drug is discontinued.

Clostridium difficile Associated Diarrhea

Clostridium difficile associated diarrhea (CDAD) has been reported with use of nearly all antibacterial agents, including MINOCIN®, and may range in severity from mild diarrhea to fatal colitis. If CDAD is suspected or confirmed, ongoing antibacterial use not directed against C. difficile may need to be discontinued.

Intracranial Hypertension

Intracranial hypertension (IH, pseudotumor cerebri) has been associated with the use of tetracyclines including Minocin. Clinical manifestations of IH include headache, blurred vision, diplopia, and vision loss; papilledema can be found on fundoscopy. Women of childbearing age who are overweight or have a history of IH are at greater risk for developing tetracycline associated IH. Concomitant use of isotretinoin and Minocin should be avoided because isotretinoin is also known to cause pseudotumor cerebri.

Although IH typically resolves after discontinuation of treatment, the possibility for permanent visual loss exists. If visual disturbance occurs during treatment, prompt ophthalmologic evaluation is warranted. Since intracranial pressure can remain elevated for weeks after drug cessation patients should be monitored until they stabilize.

PRECAUTIONS

As with other antibacterial preparations, use of this drug may result in overgrowth of nonsusceptible organisms, including fungi. If superinfection occurs, the antibacterial should be discontinued and appropriate therapy instituted.

Hepatotoxicity has been reported with minocycline; therefore, minocycline should be used with caution in patients with hepatic dysfunction and in conjunction with other hepatotoxic drugs.

Incision and drainage or other surgical procedures should be performed in conjunction with antibiotic antibacterial therapy when indicated.

MINOCIN (minocycline) Injection contains magnesium sulphate heptahydrate. Because magnesium is excreted primarily by the kidney, serum levels of magnesium should be monitored in patients with renal impairment.

Because MINOCIN (minocycline) Injection contains magnesium, close monitoring is recommended in patients with heart block or myocardial damage.

Prescribing MINOCIN (minocycline) Injection in the absence of a proven or strongly suspected bacterial infection or a prophylactic indication is unlikely to provide benefit to the patient and increases the risk of the development of drug-resistant bacteria.

Adverse Reactions

For a complete list of adverse reactions that have been observed in patients receiving tetracyclines, consult the full prescribing information for MINOCIN® (minocycline) for injection available at www.minociniv.com.

About The Medicines Company

The Medicines Company's purpose is to save lives, alleviate suffering and contribute to the economics of healthcare by focusing on 3000 leading acute/intensive care hospitals worldwide. Its vision is to be a leading provider of solutions in three areas: serious infectious disease care, acute cardiovascular care and surgery and perioperative care. The company operates in the Americas, Europe and the Middle East, and Asia Pacific regions with global centers today in Parsippany, NJ, USA and Zurich, Switzerland.

Forward-Looking Statements

Statements contained in this press release about The Medicines Company that are not purely historical, and all other statements that are not purely historical, may be deemed to be forward-looking statements for purposes of the safe harbor provisions under The Private Securities Litigation Reform Act of 1995. Without limiting the foregoing, the words "believes," "anticipates," "expects," “hopes” and “potential” and similar expressions, are intended to identify forward-looking statements. These forward-looking statements involve known and unknown risks and uncertainties that may cause the Company's actual results, levels of activity, performance or achievements to be materially different from those expressed or implied by these forward-looking statements. Important factors that may cause or contribute to such differences include whether physicians, patients and other key decision makers will accept clinical trial results, the Company’s ability to successfully compete with potential competitors which may discover, develop or commercialize competing products more successfully than we do, whether third parties on whom the Company relies to manufacture and support the development and commercialization of our products are able to fulfill their obligations or the Company is able to establish or maintain such arrangements; and such other factors as are set forth in the risk factors detailed from time to time in the Company's periodic reports and registration statements filed with the Securities and Exchange Commission including, without limitation, the risk factors detailed in the Company's Quarterly Report on Form 10-Q filed with the SEC on May 5, 2015, which are incorporated herein by reference. The Company specifically disclaims any obligation to update these forward-looking statements.


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