Drug-Exposure Limitations of Oral Methotrexate at Doses Greater
`Than or Equal to 15 Mg May Be Overcome with Subcutaneous
`Administration
`
`Antares Pharma Announces the Publication of a Head-to-Head, Randomized,
`Crossover Study of Oral versus Subcutaneous Methotrexate in Patients with
`Rheumatoid Arthritis
`
`April 17, 2014 07:00 AM Eastern Daylight Time
`
`EWING, N.J.--(BUSINESS WIRE)--Antares Pharma, Inc. (NASDAQ: ATRS) today announced that the Annals of
`the Rheumatic Diseases has published results from an open-label, head-to-head randomized, crossover study
`comparing the relative bioavailability, safety and tolerability of OTREXUP to oral methotrexate (MTX) in adult
`patients with rheumatoid arthritis (RA).
`
`In this multicenter, three-way crossover study, patients greater than or equal to 18 years old with adult RA
`undergoing treatment with MTX for three months or more were assigned to receive one of four dose levels of
`OTREXUP, 10 mg, 15 mg, 20 mg, and 25 mg weekly in a random sequence of three treatments: oral,
`subcutaneous into the abdomen and subcutaneous into the thigh. For 24 hours after the administration of each
`treatment, blood samples were collected to measure drug levels and injection sites were assessed. Forty-seven
`patients completed the study and the results showed that the systemic availability of methotrexate following oral
`dosing plateaus at 15 mg and greater. Following administration of OTREXUP, the systemic availability
`increased proportionally at every dose, which extended the range of exposure compared to patients receiving
`oral therapy. No unexpected adverse events were noted for either formulation in this short term study and
`higher systemic MTX exposure was not associated with increases in adverse events.
`
`“The study results show for the first time that plasma levels of oral dosed MTX are no greater for 20 mg or 25 mg
`doses than for 15 mg doses,” said Michael H. Schiff, M.D., Clinical Professor of Medicine in the Rheumatology
`Division at the University of Colorado School Of Medicine in Denver. “If a patient fails to respond to 15 mg of
`MTX orally, it may be more effective to switch to a subcutaneous regimen rather than continue to raise the oral
`dose. These findings may have implications on future prescribing habits of specialists.”
`
`Medac Exhibit 2017
`Frontier Therapeutics v. Medac
`IPR2016-00649
`Page 00001
`
`

`
`Historically, parenteral MTX use has been limited in clinical practice for several reasons including the
`inconvenience of weekly injections by a healthcare professional, and/or the challenges associated with
`teaching patients with impaired hand function, safe, sterile and precise self-injection techniques. To address
`these issues, an easy to use, single-use MTX auto injector (OTREXUP) was developed to optimize the clinical
`benefit of MTX, potentially leading to cost effective treatment outcomes.
`
`Paul K. Wotton, Ph.D., President and Chief Executive Officer, stated, “The publication of this data by the Annals
`of the Rheumatic Diseases adds further validation to the value proposition of OTREXUP.” He continued, “The
`parenteral administration of methotrexate is an accepted treatment method for extending the use to higher
`doses. We believe OTREXUP provides not only greater bioavailability, but more precise, hygienic and greater
`dosing flexibility for RA patients.”
`
`The article can be accessed using the following link: http://ard.bmj.com/cgi/content/full/annrheumdis-2014-
`205228
`
`IMPORTANT SAFETY INFORMATION (ABBREVIATED)
`
`Otrexup (methotrexate) injection, for subcutaneous use
`
`Otrexup can cause serious side effects that can lead to death, including:
`
`An increased risk of death from organ toxicity. Types of organ toxicity can
`include: gastrointestinal, bone marrow, liver, immune system, nerve, lung,
`kidneys and skin.
`
`Women who are pregnant are at increased risk for death of the baby and
`birth defects. Women who are pregnant or who plan to become pregnant must
`not take Otrexup. Contraception should be used by both females and males
`while taking Otrexup. For males, pregnancy should be avoided for a minimum of
`3 months after treatment with Otrexup, and for females, for at least 1 menstrual
`cycle after treatment.
`
`Do not take Otrexup if you:
`
`Are pregnant or planning to become pregnant
`
`Are breastfeeding
`
`Have alcohol problems
`
`Have liver problems
`
`Have problems fighting infection
`
`Have a blood disorder
`
`Have an allergy to methotrexate
`
`Possible side effects of Otrexup
`
`Page 00002
`
`

`
`Fertility problems
`
`Certain cancers
`
`Tissue and bone problems
`
`Common side effects of Otrexup include: nausea, stomach pain, indigestion, mouth sores, and rash.
`
`You are encouraged to report negative side effects of prescription drugs to the FDA. Visit
`www.fda.gov/medwatch, or call 1-800-FDA-1088. For more information, go to www.Otrexup.com or call 1-855-
`OTREXUP (1-855-687-3987).
`
`
`About Vibex Auto Injectors
`
`
`The Vibex Auto Injector is a single-dose, disposable pressure assisted auto injector designed to provide a fast,
`
`safe and time-efficient method of self-injection. The Vibex system features a triggering collar that shields the
`needle from view. The patented retracting collar springs back and locks in place as a protective needle guard
`after the injection, making the device safe for general disposal. Encompassing a wide variety of sizes and
`designs, this technology operates by using pressure to force the drug, solution or suspension through the skin
`
`and deposit the drug into the subcutaneous tissue. Our proprietary Vibex disposable auto injector systems
`combine a low-energy, spring-based power source with a shielded needle designed to deliver the needed drug
`®
`solution. Vibex Auto Injectors are designed, developed and manufactured in America.
`
`About Antares Pharma
`
`Antares Pharma focuses on self-administered parenteral pharmaceutical products. The Company has received
`marketing approval from the U.S. Food and Drug Administration for OTREXUP (methotrexate) injection for the
`treatment of adults with severe active rheumatoid arthritis, children with active polyarticular juvenile idiopathic
`arthritis and adults with severe recalcitrant psoriasis. Antares Pharma is also developing VIBEX QS T for
`testosterone replacement therapy. The Company's technology platforms include VIBEX disposable Medi-Jet,
`disposable multi-use pen injectors and reusable needle-free injectors marketed as Tjet and Zomajet by Teva
`Pharmaceutical Industries, Ltd (Teva) and Ferring Pharmaceuticals (Ferring), respectively. Antares Pharma has
`a multi-product deal with Teva that includes Tev-Tropin [somatropin (rDNA origin) for injection] human growth
`hormone (hGH), VIBEX epinephrine and several other products. Antares Pharma’s partnership with Ferring
`includes Zomacton hGH (somatropin) injection. In the U.S. Antares has received FDA approval for Gelnique 3%
`(oxybutynin) gel, a treatment for overactive bladder that is marketed by Actavis. Elestrin (estradiol gel) is FDA
`approved for the treatment of moderate-to-severe vasomotor symptoms associated with menopause, and is
`marketed in the U.S. by Meda Pharma. Antares Pharma has two facilities in the U.S. The Parenteral Products
`Group located in Minneapolis, Minnesota directs the manufacturing and marketing of the Company’s reusable
`needle-free injection devices and related disposables, and develops its disposable pressure-assisted Medi-Jet
`and pen injector systems. The Company’s corporate office and Product Development and Commercial Groups
`are located in Ewing, New Jersey.
`
`Safe Harbor Statement
`
`This press release contains forward-looking statements within the meaning of the safe harbor provisions of the
`Private Securities Litigation Reform Act of 1995. These statements are indicated by the words “may,” “will,”
`“plans,” “intends,” “believes,” “expects,” “anticipates,” “potential,” “could,” “would,” “should,” and similar
`expressions. Such forward-looking statements are not guarantees of future performance and are subject to risks
`and uncertainties that may cause actual results to differ materially from those anticipated by the forward-looking
`statements. These risks and uncertainties include, among others, changes in revenue growth and difficulties or
`delays in the initiation, progress, or completion of product development. Additional information concerning
`
`Page 00003
`
`

`
`these and other factors that may cause actual results to differ materially from those anticipated in the forward-
`looking statements is contained in the "Risk Factors" section of the Company's Annual Report on Form 10-K for
`the year ended December 31, 2013, and in the Company's other periodic reports and filings with the Securities
`and Exchange Commission. The Company cautions investors not to place undue reliance on the forward-
`looking statements contained in this press release. All forward-looking statements are based on information
`currently available to the Company on the date hereof, and the Company undertakes no obligation to revise or
`update these forward-looking statements to reflect events or circumstances after the date of this press release,
`except as required by law.
`
`Contacts
`Antares Pharma, Inc.
`Jack Howarth
`Vice President, Corporate Affairs
`609-359-3016
`jhowarth@antarespharma.com
`
`Page 00004