Rapivab™ - peramivir injection Manufacturer: BioCryst Pharmaceuticals FDA Approval Date: 12/19/2014

Rapivab™ - peramivir injection Clinical Application Indications: Acute, uncomplicated influenza in patients 18 years and older who have been symptomatic for less than 2 days Place in therapy: Rapivab should be used in patients who: test positive for the influenza virus have symptoms for less than 48 hours AND are unable to tolerate inhaled or PO medication

Rapivab™ - peramivir injection Clinical Application Contraindications: NONE Warnings/ Precautions: Serious skin and hypersensitivity reactions Neuropsychiatric events Risk of bacterial infections

Rapivab™ - peramivir injection Clinical Application Pregnancy: Category C Lactation: Not known if the drug is excreted in human breast milk

Rapivab™ - peramivir injection Drug Facts Pharmacology: An injectable neuraminidase inhibitor for the influenza virus. Through inhibition of the neuraminidase enzyme, peramivir prevents infected cells from releasing viral particles.

Rapivab™ - peramivir injection Drug Facts Pharmacokinetics: A 100% bioavailability D Vd: 12.56 L < 30% protein binding M Not significantly metabolized E T1/2: ~20 hours eliminated via the kidney with 90% unchanged

Rapivab™ - peramivir injection Drug Interactions Drug Interactions – Object Drugs: Influenza Virus Vaccine  (variable %)

Rapivab™ - peramivir injection Drug Interactions Drug Interactions – Precipitant Drugs: NONE

Rapivab™ - peramivir injection Adverse Effects Placebo Diarrhea 8% 6% Alanine Aminotransferase (> 2.5 x ULN) 3% 2% Serum Glucose (> 160 mg/dL) 5% Creatine Phosphokinase (≥ 6.0 x ULN) 4% Neutrophils (< 1.000 x109 /L)

Rapivab™ - peramivir injection Monitoring Parameters Efficacy Monitoring: Resolution of influenza symptoms (headache, aches/pains, fatigue, cough, sore throat, nasal congestion) Toxicity Monitoring: Neurological abnormalities/abnormal behavior Rash after administration

Rapivab™ - peramivir injection Prescription Information Dosing: 600mg IV infusion over 15 minutes Cost: No information at this time

Rapivab™ - peramivir injection Literature Review Efficacy and Safety of Intravenous Peramivir for Treatment of Seasonal Influenza Virus Infection Purpose: To determine the safety and efficacy of a single administration of peramivir in patients with the influenza virus in the outpatient setting Design: Randomized, double-blind, placebo controlled trial Kohno S et al. AAC. 2010 Nov, 54(11): 4568-4574

Rapivab™ - peramivir injection Literature Review Inclusion Exclusion 20 – 64 year old, previously healthy Respiratory dysfunction/ chronic respiratory disorder Onset of influenza symptoms < 48 H Convulsions or other neurological symptoms Positive rapid antigen test HIV Fever > 38o C Renal impairment requiring hemodialysis Presence of at least 2 flu symptoms Treatment with steroids/ other immunosuppressants or anti-influenza drugs within the previous 7 days Women who are pregnant Kohno S et al. AAC. 2010 Nov, 54(11): 4568-4574

Rapivab™ - peramivir injection Literature Review Peramivir 300mg Peramivir 600mg Placebo Male 46 [46.5%] 53 [54.6%] 51 [51%] Age 34.2 33.9 34.4 Symptom Onset 0 – 24 hours 59 [59.6%] 51 [52.6%] 48 [48%] 24 – 48 hours 40 [40.6%] 46 [47.4%] 52 [52%] Composite symptom score 11.5 11.8 12.0 Body temperature 38.44 38.64 38.50 Influenza virus A/H1 74 [74.7%] 69 [71.1%] 72 [72%] A/H3 21 [21.2%] 25 [25.8%] 24 [24%] A/- 2 [2.0%] 2 [2.1%] 4 [4%] B 2 [1.0%] 0 [0%] Kohno S et al. AAC. 2010 Nov, 54(11): 4568-4574

Rapivab™ - peramivir injection Literature Review Primary Endpoint: time from start of treatment to recovery (all influenza symptoms scores had been 0 or 1 for 21.5 hours) Other Endpoints: Change in composite symptom scores Proportion of afebrile subjects Change in influenza titer from baseline Time to resume usual activity Incidence of influenza related illness Kohno S et al. AAC. 2010 Nov, 54(11): 4568-4574

Rapivab™ - peramivir injection Literature Review Statistical Analysis: Intention to Treat 67 subjects needed per group to have 80% power Treatment Arms: 300 mg peramivir (n=99) 600 mg peramivir (n=97) Placebo (n=100) Kohno S et al. AAC. 2010 Nov, 54(11): 4568-4574

Rapivab™ - peramivir injection Literature Review Primary Endpoint: Rapivab significantly reduced the time to alleviation of influenza symptoms compared to the placebo. HR: 0.681 (adjusted P value, 0.0092) in the 300 mg group HR: 0.666 (adjusted P value, 0.0092) in the 600 mg group Patients reported shorter time in resumption of there usual activities Kohno S et al. AAC. 2010 Nov, 54(11): 4568-4574

Rapivab™ - peramivir injection Literature Review Effect of Rapivab on viral shedding: At baseline viral titers similar in all groups At 3 days: virus positive patients were lower in the treatment arms 300 mg P: 0.0485, 600 mg P: 0.0003 At 9 days: virus was not detected in most patients Kohno S et al. AAC. 2010 Nov, 54(11): 4568-4574

Rapivab™ - peramivir injection Literature Review - Results Population Parameter Peramivir 300 mg Peramivir 600 mg Placebo Overall N Median (hr) HR Adjusted P 99 59.1 0.681 0.0092 97 59.9 0.666 100 81.8 Influenza A/H1 74 52.5 0.779 0.145 69 62.6 0.899 0.5384 72 81.4 A/H3 21 76.1 0.542 0.0556 25 50.5 0.326 0.0008 24 81.0 Symptom duration 0 – 24 hr 59 57.2 0.653 0.0516 51 56.1 0.663 48 86.7 24-48 hr 40 69.1 0.708 0.1118 46 64.7 0.694 52 70.8 Kohno S et al. AAC. 2010 Nov, 54(11): 4568-4574

Rapivab™ - peramivir injection Literature Review – Adverse Events Parameter Rapivab 300 mg Rapivab 600 mg Placebo Number of Events 252 257 Increased Glucose 18 (18.25) 17 (17.2%) 18 (18%) Decreased WBC 9 (9.1%) 7 (7.1%) 4 (4%) Diarrhea 14 (14.1%) 15 (15.2%) 17 (17%) Nausea 3 (3%) 6 (6.1%) 1 (1%) Increase ALT 8 (8%) Increase AST 6 (6%) Prolonged QT Interval 2 (2%) Kohno S et al. AAC. 2010 Nov, 54(11): 4568-4574

Rapivab™ - peramivir injection Literature Review Discussion: Rapivab was well tolerated by most patients Patients saw improvement in influenza symptoms within 24 hours of administration Rapivab showed high activity against neuraminidase with a slow off rate Plasma concentrations of Rapivab were higher than those from standard dose of Tamiflu Kohno S et al. AAC. 2010 Nov, 54(11): 4568-4574

Rapivab™ - peramivir injection Summary Rapivab, peramivir, is a 600 mg, one time 15 minute IV infusion for patients who have uncomplicated influenza symptoms for less than 2 days Not significantly metabolized, is renally cleared and should be administered at lower doses with impaired renal function May decrease the efficacy of the influenza vaccine, and should not be used 48 hours prior to 2 weeks after vaccine administration Can cause diarrhea, hyperglycemia or neutropenia. Rarely causes serious skin reactions or neurologic complications

Rapivab™ - peramivir injection References http://www.rapivab.com Rapivab package insert. BioCryst Pharmaceuticals. December 2014. Peramivir: Drug information. Lexicomp Drug Information. Accessed through UpToDate. Accessed on January 10, 2015. Kohno S et al. AAC. 2010 Nov, 54(11): 4568-4574