United Therapeutics Receives a Rare Pediatric Disease Priority Review Voucher following the Approval of Unituxin™ for Pediatric High-Risk Neuroblastoma

SILVER SPRING, Md. and RESEARCH TRIANGLE PARK, N.C., March 10, 2015 /PRNewswire/ -- United Therapeutics Corporation (UTHR) announced today that the United States Food and Drug Administration (FDA), as part of the Biologics License Application approval for Unituxin, awarded United Therapeutics a Rare Pediatric Priority Review Voucher (PPRV) for neuroblastoma, a rare pediatric disease.

The voucher can be sold (without limitation), and the holder of the voucher can redeem it with a subsequently filed New Drug Application or Biologics License Application, requiring FDA to meet the review goals for a priority review, as opposed to a standard review.

"We are thrilled to be the recipient of this pediatric priority review voucher, and are grateful to the Creating Hope Act for its instrumental role in making this voucher program available to encourage development of therapies, like Unituxin, for children with rare conditions and high unmet need," said Roger Jeffs, Ph.D., United Therapeutics' President and Co-CEO.

The PPRV was created in 2012 by the Food and Drug Administration Safety and Innovation Act (FDASIA) to encourage development of treatments for rare pediatric diseases. 

To qualify to receive a PPRV, a sponsor must submit an application for a drug or biologic intended to prevent or treat a rare pediatric disease.  The rare pediatric disease application also must be eligible for priority review and rely on clinical data derived from studies examining a pediatric population and dosages of the drug intended for that population.

About Unituxin

Unituxin (dinutuximab) is a disialoganglioside, GD2-binding chimeric monoclonal antibody (formerly called ch14.18) indicated, in combination with granulocyte-macrophage colony-stimulating factor (GM-CSF), interleukin-2 (IL-2), and 13-cis-retinoic acid (RA), for the treatment of pediatric patients with high-risk neuroblastoma who achieve at least a partial response to prior first-line multiagent, multimodality therapy.  The safety and effectiveness of Unituxin was evaluated in a randomized, open-label, multicenter trial conducted in pediatric patients with high-risk neuroblastoma.  All patients had received prior therapy consisting of induction combination chemotherapy, maximum feasible surgical resection, myeloablative consolidation chemotherapy followed by autologous stem cell transplant, and radiation therapy to residual soft tissue disease.

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Important Safety Information for Unituxin

Boxed WARNING

Serious Infusion Reactions
Serious and potentially life threatening infusion reactions (facial and upper airway edema, dyspnea, bronchospasm, stridor, urticaria, and hypotension) occurred in 26% of patients treated with Unituxin
Administer required prehydration and premedication including antihistamines prior to each Unituxin infusion
Monitor patients closely for signs and symptoms of an infusion reaction during and for at least four hours following completion of each Unituxin infusion
Immediately interrupt Unituxin for severe infusion reactions and permanently discontinue Unituxin for anaphylaxis
Neuropathy
Unituxin causes severe neuropathic pain in the majority of patients
Administer intravenous opioid prior to, during, and for 2 hours following completion of the Unituxin infusion
Severe (Grade 3) peripheral sensory neuropathy ranged from 2% to 9% in patients with neuroblastoma
In clinical studies of Unituxin and related GD2-binding antibodies, severe motor neuropathy was observed in adults.  Resolution of motor neuropathy was not documented in all cases
Discontinue Unituxin for severe unresponsive pain, severe sensory neuropathy, or moderate to severe peripheral motor neuropathy
CONTRAINDICATIONS
Unituxin is contraindicated in patients with a history of anaphylaxis to dinutuximab.

WARNINGS AND PRECAUTIONS

Serious Infusion Reactions
Serious infusion reactions requiring urgent intervention including blood pressure support, bronchodilator therapy, corticosteroids, infusion rate reduction, infusion interruption, or permanent discontinuation of Unituxin included facial and upper airway edema, dyspnea, bronchospasm, stridor, urticaria, and hypotension.  Infusion reactions generally occurred during or within 24 hours of completing the Unituxin infusion.  Due to overlapping signs and symptoms, it was not possible to distinguish between infusion reactions and hypersensitivity reactions in some cases.
Severe (Grade 3 or 4) infusion reactions occurred in 35 (26%) patients in the Unituxin/13-cis-retinoic acid (RA) group compared to 1 (1%) patient receiving RA alone
Pain and Peripheral Neuropathy
Pain:  114 (85%) patients treated in the Unituxin/RA group experienced pain despite pre-treatment with analgesics including morphine sulfate infusion.  Severe (Grade 3) pain occurred in 68 (51%) patients in the Unituxin/RA group compared to 5 (5%) patients in the RA group.
Peripheral Neuropathy:  Severe (Grade 3) peripheral sensory neuropathy occurred in 2 (1%) patients and severe peripheral motor neuropathy occurred in 2 (1%) patients in the Unituxin/RA group
Capillary Leak Syndrome
Severe (Grade 3 to 5) capillary leak syndrome occurred in 31 (23%) patients in the Unituxin/RA group and in no patients treated with RA alone
Depending on severity, manage by immediate interruption, infusion rate reduction or permanent discontinuation of Unituxin
Hypotension
Severe (Grade 3 or 4) hypotension occurred in 22 (16%) patients in the Unituxin/RA group compared to no patients in the RA group
Prior to each Unituxin infusion, administer required intravenous hydration
Closely monitor blood pressure during Unituxin treatment
Depending on severity, manage by immediate interruption, infusion rate reduction or permanent discontinuation of Unituxin
Infection
Severe (Grade 3 or 4) bacteremia requiring intravenous antibiotics or other urgent intervention occurred in 17 (13%) patients in the Unituxin/RA group compared to 5 (5%) patients treated with RA alone.  Sepsis occurred in 24 (18%) of patients in the Unituxin/RA group and in 10 (9%) patients in the RA group
Monitor patients closely for signs and symptoms of systemic infection and temporarily discontinue Unituxin in patients who develop systemic infection until resolution of the infection
Neurological Disorders of the Eye
Neurological disorders of the eye experienced by two or more patients treated with Unituxin included blurred vision, photophobia, mydriasis, fixed or unequal pupils, optic nerve disorder, eyelid ptosis, and papilledema
Interrupt Unituxin in patients experiencing dilated pupil with sluggish light reflex or other visual disturbances that do not cause visual loss
Upon resolution and if continued treatment with Unituxin is warranted, decrease the Unituxin dose by 50%
Permanently discontinue Unituxin in patients with recurrent eye disorder following dose reduction and in patients who experience loss of vision
Bone Marrow Suppression
Severe (Grade 3 or 4) thrombocytopenia (39% vs. 25%), anemia (34% vs. 16%), neutropenia (34% vs. 13%) and febrile neutropenia (4% vs. 0 patients) occurred more commonly in patients in the Unituxin/RA group compared to patients treated with RA alone
Monitor peripheral blood counts closely during Unituxin therapy
Electrolyte Abnormalities
Severe (Grade 3 or 4) hypokalemia and hyponatremia occurred in 37% and 23% of patients in the Unituxin/RA group, respectively, compared to 2% and 4% of patients in the RA group
Monitor serum electrolytes daily during therapy with Unituxin
Atypical Hemolytic Uremic Syndrome
Hemolytic uremic syndrome in the absence of documented infection and resulting in renal insufficiency, electrolyte abnormalities, anemia, and hypertension occurred in two patients following receipt of the first cycle of Unituxin
Permanently discontinue Unituxin and institute supportive management
Embryo-Fetal Toxicity
Unituxin may cause fetal harm
Advise pregnant women of the potential risk to a fetus
Advise females of reproductive potential to use effective contraception during treatment, and for two months after the last dose of Unituxin
ADVERSE REACTIONS
The most common adverse drug reactions (greater than or equal to 25%) in Unituxin/RA compared with RA alone are pain (85% vs. 16%), pyrexia (72% vs. 27%), thrombocytopenia (66% vs. 43%), lymphopenia (62% vs. 36%), infusion reactions (60% vs. 9%), hypotension (60% vs. 3%), hyponatremia (58% vs. 12%), increased alanine aminotransferase (56% vs. 31%), anemia (51% vs. 22%), vomiting (46% vs. 19%), diarrhea (43% vs. 15%), hypokalemia (43% vs. 4%), capillary leak syndrome (40% vs. 1%), neutropenia (39% vs. 16%), urticaria (37% vs. 3%), hypoalbuminemia (33% vs. 3%), increased aspartate aminotransferase (28% vs. 7%), and hypocalcemia (27% vs. 0%).

The most common serious adverse reactions (greater than or equal to 5%) are infections, infusion reactions, hypokalemia, hypotension, pain, fever, and capillary leak syndrome.

Please see Full Prescribing Information including Boxed WARNING for Unituxin, available at http://www.unither.com/UFullPrescribingInformation.PDF.

About United Therapeutics

United Therapeutics Corporation is a biotechnology company focused on the development and commercialization of innovative products to address the unmet medical needs of patients with chronic and life-threatening conditions.

Forward-looking Statements

Statements included in this press release that are not historical in nature are "forward-looking statements" within the meaning of the Private Securities Litigation Reform Act of 1995.  Forward-looking statements include, among others, statements regarding the use or sale of the Rare Pediatric Priority Review Voucher received from FDA.  These forward-looking statements are subject to certain risks and uncertainties, such as those described in our periodic reports filed with the Securities and Exchange Commission, that could cause actual results to differ materially from anticipated results.  Consequently, such forward-looking statements are qualified by the cautionary statements, cautionary language and risk factors set forth in our periodic reports and documents filed with the Securities and Exchange Commission, including our most recent Annual Report on Form 10-K, Quarterly Reports on Form 10-Q, and Current Reports on Form 8-K.  We claim the protection of the safe harbor contained in the Private Securities Litigation Reform Act of 1995 for forward-looking statements.  We are providing this information as of March 10, 2015, and assume no obligation to update or revise the information contained in this press release whether as a result of new information, future events or any other reason. [uthr-g]

UNITUXIN is a trademark of United Therapeutics Corporation. 

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