CO-1
Single-Dose Tafenoquine 300 mg for Radical Cure of Plasmodium vivax Malaria
July 12, 2018 GlaxoSmithKline Antimicrobial Drugs Advisory Committee Meeting CO-2
Introduction
Jörg-Peter Kleim Medicine Development Leader, Tafenoquine GlaxoSmithKline CO-3
Plasmodium vivax Malaria: Global Health Problem
Global effort to eradicate malaria around world GSK and Medicines for Malaria Venture (MMV) developed Tafenoquine (TQ) as part of Global Health program Needed for orphan indication in US Tafenoquine would also assist global malaria eradication efforts . Aligns with US initiatives and global treatment efforts CO-4
Tafenoquine 300 mg
Single-dose tafenoquine (TQ) 300 mg in combination with standard chloroquine (CQ) . Efficacious treatment for relapse prevention of P. vivax malaria . Similar safety profile to currently-approved primaquine (PQ) + CQ . High treatment compliance First new treatment for prevention of relapse in > 60 years CO-5
Tafenoquine Inactivates Dormant Liver Stage
Molecular mechanism of action of tafenoquine is unknown P. vivax can hide in patient’s liver for weeks or months Dormant liver stage causes malaria relapses, without need for another infected mosquito bite Primaquine only current medicine to inactivate dormant liver stage and prevent relapse . 14-day treatment and compliance can be difficult Tafenoquine offers novel, single-dose treatment for relapse prevention CO-6 Tafenoquine: 8-Aminoquinoline Analogue of Primaquine
Primaquine Tafenoquine Half-life: 6 hours Half-life: 15 days CO-7
Tafenoquine Regulatory History
Originally discovered by Walter Reed Army Institute of Research 13 studies support radical cure indication . 3 randomized, double-blind studies conducted outside US . Pivotal study: Study 582 Part 2 . Supportive studies: Study 582 Part 1 and Study 564 20 additional studies analyzed for safety Orphan Drug status (Jan 2013) Breakthrough Therapy designation (Dec 2013) CO-8
Proposed Indication and Dosing
Indicated for radical cure (prevention of relapse) of Plasmodium vivax malaria in patients aged 16 years and older Recommended dosing and administration . Single 300 mg dose co-administered with chloroquine CO-9
Clinical Overview
Single-dose TQ 300 mg with standard doses of CQ . 70% reduction in risk of recurrence of P. vivax malaria at 6 months compared with chloroquine alone (p < 0.001) Consistent efficacy across supportive studies Acceptable safety profile and similar to 14-day PQ regimen Primary risk: hemolysis in patients with G6PD deficiency . Appropriately managed with labeling and G6PD testing . No cases of clinical hemolysis in studies No increased risk of clinically relevant hemoglobin decline, ophthalmic, CNS, hepatic, or QT prolongation events CO-10
Agenda
J. Kevin Baird, PhD Unmet Need Eijkman Oxford Clinical Research Unit University of Oxford
Study Design and Justin A. Green, MD, PhD Efficacy Results GlaxoSmithKline
Safety Results Alison Webster, MD GlaxoSmithKline
Clinical Perspective Ric Price, MD Menzies School of Health Research CO-11
Additional Responders
University of Rochester Departments of Neurology and Gretchen Birbeck, MD, MPH Medical Center Public Health Christian Baumann, PhD GSK Sr. Director, Global Regulatory Affairs
Navin Goyal, PhD GSK Director, Clinical Pharmacology Medical Director, Global Clinical Safety Liz Hardaker, MD GSK and Pharmacovigilance Jim Harvey, PhD GSK Director, Non-clinical Toxicology
Katie Rolfe GSK Director, Statistics and Programming Investigator, Drug Metabolism and Maxine Taylor GSK Pharmacokinetics CO-12
Unmet Need
J. Kevin Baird, PhD Professor of Malariology Eijkman Oxford Clinical Research Unit (Jakarta, Indonesia) University of Oxford CO-13
P. vivax is Most Widespread Human Malaria
~200 cases imported to US by travelers in 20153
64% of malaria cases in 2.5 billion living at Americas due risk of infection1 to P. vivax2
1. Price, 2007; Hwang, 2014; 2. World Health Organization, 2017; 3. Center for Disease Control, 2018; 4. Howes, 2016 CO-14
While Rare, Small Local Outbreaks Reported in US
Caused by local transmission by American anopheles mosquitoes 63 outbreaks of malaria in US from 1957–20061 . Annual range 1–32 subjects Outbreak reported in Houston in 2017 Frequently raise concerns and require public health resources
1. Filler, CDC, 2006. [includes all malarias] CO-15 P. vivax Malaria: Parasitic Disease That Can Relapse from Liver Stage
Skin
Dormant Infected Gametocytes hypnozoite hepatocyte
LIVER Symptoms of acute STAGE malaria attack BLOOD STAGE Develops without symptoms Infected red blood cells
Image adapted from Lima, 2016 CO-16 Symptoms Include Fever, Chills, Vomiting, Malaise, Headache, and Myalgia
Increasing evidence that burden, economic impact and severity of disease from P. vivax have been underestimated1 Even with access to antimalarials, severe and fatal infections occur1 . Splenic rupture, severe anemia, respiratory distress, and possibly coma Review of > 12,000 P. vivax cases in travelers returning to US2 . 0.1% resulted in death . 1.3% severe cases: acute respiratory distress syndrome, cerebral malaria, renal or hepatic dysfunction, severe anemia or thrombocytopenia and shock
1. Price, 2007; 2. Hwang, 2014 CO-17 Risk of Relapse is a Serious Clinical Threat Without Treatment of Liver Stage
2,495 US soldiers repatriated from Asia Pacific 1943-1945
1000 Episodes Incidence 1 to 3 9% 4 to 6 13% 800 7 to 9 20% 10 to 14 35% 15 to 19 14% 600 20 to 24 6% Number of 25 to 34 3% Patients ≥ 35 1% 400
200
0 1 to 3 4 to 6 7 to 9 10 to 14 15 to 19 20 to 24 25 to 34 35+
Kitchen, in Boyd M, 1949. Number of Relapses CO-18 Serious Public Health Threat: > 80% of Clinical Attacks Caused by Relapse
Clinical attacks of P. vivax derived from hypnozoites 1 . 98% near Thai-Myanmar PQ 0.75 border1 . 0.5 82% in Papua New Placebo (PL) Guinea2 0.25 Proportion uninfected by PCR 0
1. Adekunle, 2015; 2. Robinson, 2015 CO-19
Goal of P. vivax Malaria Treatment is Radical Cure
P. vivax can be refractory to current elimination efforts . Persistence of mosquito vectors . Relapse from dormant liver stage . Can lead to outbreaks where malaria previously eliminated Suppressive chemoprophylaxis (prevention) widely available in US Treatment required to prevent local transmission and relapse CO-20
Selection of Current US CDC Treatment Options
Option Blood Stage Treatment Liver Stage Treatment
1st Chloroquine (x 3 days)
Atovaquone-proguanil or 2nd artemether-lumefantrine Primaquine phosphate (x 14 days) Quinine sulfate combinations 3rd (+ doxycycline, tetracycline, or clindamycin)
4th Mefloquine
Center for Disease Control, 2018 CO-21 Primaquine Effectiveness Dependent on Treatment Adherence
0.15 Self-administered therapy
0.10 Log rank test p = 0.021 Nelson-Alden Cumulative Hazard 0.05 Directly-observed therapy
0.00 0 20 40 60 80 100 Time (days) Primaquine treatment compliance as low as 30%1,4 Primaquine efficacy reduced 3- to 4-fold when ≥ 3 of 14 doses missed1,2,3,4
1. Abreha, 2017; 2. Takeuchi, 2010; 3. Douglas, 2017; 4. Khantikul, 2009 CO-22 G6PD Testing Can Protect Patients from 8-Aminoquinoline-Induced Hemolysis
8-aminoquinolines cause hemolysis in G6PD deficiency Identified risk can be mitigated with G6PD testing G6PD deficiency high in many malaria endemic areas . Co-incidence with malaria common Sex-linked condition . Exclude patients from treatment Diagnostic tests for G6PD deficiency readily available in US CO-23
Summary
Untreated liver stage of P. vivax infection causes malaria relapse P. vivax is widespread globally . Cases reported in both endemic areas and countries that have previously eliminated malaria Primaquine is only treatment option to prevent relapse . Poor adherence limits effectiveness Need for simple, single-dose regimen for radical cure of P. vivax malaria Successful attack on hypnozoite reservoir of P. vivax likely to result in collapse of transmission cycle CO-24
Efficacy
Justin A. Green, MD, PhD Project Physician, Tafenoquine Clinical Development GlaxoSmithKline CO-25
Key Tafenoquine Efficacy Studies
Study Phase Treatment Groups N Role CQ 54 TQ 50 mg + CQ 55 TQ 100 mg + CQ 57 Study 582 Part 1 Phase 2b Dose finding TQ 300 mg + CQ 57 TQ 600 mg + CQ 56 PQ 15 mg + CQ 50 CQ 133 Study 582 Part 2 Phase 3 TQ 300 mg + CQ 260 Pivotal PQ 15 mg + CQ 129 TQ 300 mg + CQ 166 Study 564 Phase 3 Supportive PQ 15 mg + CQ 85 . CQ = chloroquine x 3 days . TQ = tafenoquine single dose . PQ = primaquine x 14 days CO-26
Clinical Pharmacology of Tafenoquine 300 mg
300 Administer with food . Increased absorption . 100 Improved GI tolerability Linear PK up to 1200 mg TQ 50 Conc. t1/2 ~15 days (ng/mL) 20 No impact of age, race, weight, gender, or G6PD deficiency on PK
5 Slow metabolism . No major circulating 0 1 2 3 4 5 6 7 8 9 10 metabolites Time (weeks) CO-27 Study 582 (Part 1): Rationale for 300 mg Single Dose TQ Treatment
100% TQ 600 mg + CQ TQ 300 mg + CQ 80% PQ + CQ
Recurrence- 60% TQ 50 mg + CQ free TQ 100 mg + CQ (%) 40% CQ
20%
0% 0 30 60 90 120 150 180 210 Time (days) N at risk PQ + CQ 50 49 44 37 37 37 11 0 CQ 54 52 39 31 26 24 11 0 TQ 50 mg + CQ 55 54 46 43 34 32 8 0 TQ 100 mg + CQ 57 55 46 38 33 30 7 0 TQ 300 mg + CQ 57 56 56 53 50 50 18 0 TQ 600 mg + CQ 56 55 53 50 49 46 11 0 CO-28
Study 582 (Part 2): Statistical Analysis Plan
90% recurrence-free efficacy in TQ arm with 30% treatment difference to CQ Study overpowered for efficacy comparisons . Original sample size: N=600 Slow recruitment and global shortage of study chloroquine . Smaller sample size negotiated . Still powered for significance CO-29 Study 582 (Part 2) Design: Multi-Center, Double- Blind, Placebo-Controlled Study
Placebo CQ N=133 CQ: Days 1 to 3 Followed for 6 months
TQ: Day 1 or 2 Randomized TQ 300 mg + CQ N=522 N=260 CQ: Days 1 to 3 Followed for 6 months
PQ: Days 1–14 PQ + CQ N=129 CQ: Days 1 to 3 Followed for 6 months CO-30 Study 582 (Part 2): Key Inclusion / Exclusion Criteria
Microscopically diagnosed P. vivax malaria at screening No mixed malaria infections ≥ 16 years old No severe P. vivax malaria (WHO criteria) Corrected QT interval (QTcF) < 450 msec at screening Screening hemoglobin (Hb) concentration ≥ 70 g/L No G6PD enzyme level < 70% CO-31
Study 582 (Part 2): Primary Efficacy Endpoint
Recurrence-free efficacy at 6M: CQ vs TQ 300 mg + CQ (mITT*) . Recurrence includes relapse and reinfection Analyzed using 2 methodologies 1. Survival analysis (WHO1) . Time to first recurrence . Kaplan-Meier and Cox proportional hazards 2. Categorical analysis (FDA) . Logistic regression . Missing = failure
*mITT: microbiological intent-to-treat 1. World Health Organization, 2003 CO-32
Study 582 (Part 2): Disposition
CQ TQ 300 mg + CQ PQ + CQ mITT Population N=133 N=260 N=129 Completed 97% 96% 95% Reason for study withdrawal Lost to follow-up 2% 2% 2% Physician decision < 1% < 1% 0 Withdrawal by patient < 1% 2% 3% CO-33 Study 582 (Part 2): Demographics Balanced Across Treatment Groups
CQ TQ 300 mg + CQ PQ + CQ mITT Population N=133 N=260 N=129 Age, mean 35 years 35 years 35 years Male 73% 75% 77% Background [Region] Multiple [Brazil] 35% 37% 36% Native American [Peru] 32% 31% 32% Asian [SE Asia] 20% 19% 20% Black [Ethiopia] 11% 11% 10% White [Brazil] 2% 2% 2% Min. G6PD enzyme activity 72.6% 70.2% 70.4% CO-34 Study 582 (Part 2): Baseline Disease Characteristics
CQ TQ 300 mg + CQ PQ + CQ mITT Population N=133 N=260 N=129 Previous malarial episode 80% 84% 84% Asexual parasite count* 5,615 x 106/L 5,314 x 106/L 4,380 x 106/L Gametocyte parasite count* 55 x 106/L 54 x 106/L 31 x 106/L
*Median counts. Day 1 Assessment 1 value used as Baseline CO-35
Study 582 (Part 2): High Compliance
Tafenoquine = 100% compliance (n/N = 260/260) Primaquine = 96% compliance (n/N = 124/129) . Assessed by pill counts (≥ 12 pills taken) CO-36 Study 582 (Part 2): Primary Endpoint Met (Survival Analysis), Recurrence-Free Efficacy Over 6 Months
mITT TQ 300 mg + CQ vs CQ PQ + CQ vs CQ HR (95% CI) 0.299 (0.222, 0.404) 0.262 (0.178, 0.387) < 0.001 100% p-value < 0.001
80% 69.6% PQ + CQ Recurrence- 60% 62.4% TQ 300 mg + CQ free (%) 40% 27.7% CQ 20%
0% 0 30 60 90 120 150 180 210 Time (days) N at risk CQ 133 125 77 61 48 41 7 0 TQ 300 mg + CQ 260 251 244 217 183 163 27 0 PQ + CQ 129 124 112 101 91 87 10 0 Recurrence = reinfection or relapse CO-37 Study 582 (Part 2): Primary Endpoint Met (Categorical Analysis), Significant Reduction in Odds of Recurrence mITT Population CQ TQ 300 mg + CQ PQ + CQ Categorical (missing = failure) N=133 N=260 N=129 Recurrence-free at 6 months 26% 60% 64% Odds ratio vs CQ alone 0.241 0.198 - (95% CI) (0.152, 0.382) (0.117, 0.335) p-value - < 0.001 < 0.001 CO-38
Analysis of Apparent Treatment Failures
Factors analyzed include . Gender, age, BMI, region, parasite genotype, exposure Conclusions . PK/PD analyses demonstrated AUC > 56 μg*hr/mL greatest predictor of positive treatment outcome . > 95% of patients in Phase 3 achieved this exposure . Reinfection more likely to explain recurrences than relapse CO-39
Efficacy Results in Other Key Studies CO-40
Study 582 (Part 1): Efficacy at 6 Months
100% 89.2% TQ 300 mg + CQ 80% 77.3% PQ + CQ
Recurrence- 60% free (%) 40% 37.5% CQ
20%
0% 0 30 60 90 120 150 180 210 Time (days) N at risk CQ 54 52 39 31 26 24 11 0 TQ 300 mg + CQ 57 56 56 53 50 50 18 0 PQ + CQ 50 49 44 37 37 37 11 0 CO-41
Study 564: Comparable Efficacy to Primaquine
100%
80% 75.1% PQ + CQ 72.7% TQ 300 mg + CQ Recurrence- 60% free (%) 40%
20%
0% 0 30 60 90 120 150 180 210 Time (days) N at risk TQ 300 mg + CQ 166 161 156 143 131 115 19 0 PQ + CQ 85 83 74 69 64 60 9 0 CO-42 Efficacy Summary: Tafenoquine an Effective Treatment for Radical Cure of P. vivax Malaria
TQ 300 mg single-dose co-administered with CQ significantly reduced risk of P. vivax recurrence compared to CQ alone . Consistent efficacy across studies Reduction in recurrence numerically comparable with PQ CO-43
Safety
Alison Webster, MD Head of Clinical, Global Health GlaxoSmithKline CO-44
Tafenoquine Safety Agenda
Well-characterized and similar to already approved primaquine Safety data from placebo-controlled studies Adverse events of special interest across development Proposed post-approval plans CO-45
Safety Exposures
Dataset / Subjects Total Tafenoquine Dose N Any 4,129 < 300 mg 392 All studies / All treated = 300 mg 810 > 300 mg 2,927 All primary studies / P. vivax infected = 300 mg 483 Placebo-controlled studies / P. vivax infected = 300 mg 317 CO-46
Safety Overview
CQ TQ 300 mg + CQ PQ + CQ Placebo-controlled Studies N=187 N=317 N=179
Any AE 68% 64% 60%
Any SAE 5% 7% 6%
Any fatal SAE 0 0 0
Any AE leading to study 0 0 0 withdrawal Any AE leading to study drug 3% 4% < 1% discontinuation CO-47 Overall AEs Across 6 Months of Follow-Up in ≥ 6% of Patients in Any Arm
CQ TQ 300 mg + CQ PQ + CQ Placebo-controlled Studies N=187 N=317 N=179 Any AE 68% 64% 60% Pruritus 14% 13% 9% Headache 21% 12% 13% Dizziness 9% 9% 8% Nausea 8% 8% 7% Vomiting 5% 8% 9% Diarrhea 5% 6% 5% Viral upper respiratory tract infection 5% 6% 7% Myalgia 12% 5% 7% Abdominal pain upper 10% 5% 8% Pharyngitis 4% 5% 6% Pyrexia 12% 4% 9% Chills 11% 2% 7% CO-48
Overall AEs ≥ 5% Reported During First 29 Days
CQ TQ 300 mg + CQ PQ + CQ Placebo-controlled Studies N=187 N=317 N=179 Any AE 48% 50% 49% Pruritus 13% 12% 9% Dizziness 3% 8% 6% Nausea 6% 6% 4% Hemoglobin decreased 2% 5% 2% Headache 6% 5% 5% Vomiting 4% 5% 6% Abdominal pain upper 7% 4% 7% CO-49 AEs Leading to Discontinuation of Study Drug Across 6 Months
CQ TQ 300 mg + CQ PQ + CQ Placebo-controlled Studies N=187 N=317 N=179 Any AE leading to study drug 3% 4% < 1% discontinuation Hemoglobin decreased 1% 3% 0 ECG QT prolonged 2% 0 < 1% P. falciparum infection 0 < 1% 0 CO-50
Protocol-Defined SAEs of Hemoglobin Decline
Hemoglobin decrease definition in Phase 3 . ≥ 30% or > 30 g/L from baseline or decrease in absolute hemoglobin < 60 g/L in first 15 days Otherwise did not meet standard SAE criteria . None life-threatening or required hospitalization Resolved without intervention None classified as severe hemoglobin AEs CO-51
SAEs in ≥ 2 Patients Across 6 Months
CQ TQ 300 mg + CQ PQ + CQ Placebo-controlled Studies N=187 N=317 N=179 Any SAE 5% 7% 6% Hemoglobin decreased* 2% 5% 2% QT prolongation 3% < 1% 2% Any SAEs 4% 3% 4% (excluding hemoglobin decreased)
*Hemoglobin decreased protocol-defined SAE: ≥ 30% or > 30 g/L from baseline or decrease in absolute hemoglobin < 60 g/L in first 15 days CO-52
Adverse Events of Special Interest
Hematologic events Ophthalmic events CNS events Hepatic events Other events (QT and hypersensitivity) CO-53 Placebo-Controlled Studies: AESIs Comparison at 6 Months TQ + CQ vs CQ
AESI Incidence Relative Risk
Hematological events
Ophthalmic events
Psychiatric disorders
Nervous system disorders
Hepatobiliary disorders
Renal and urinary disorders
CQ (N=187) 0 10 20 30 0.01 0.1 1 10 100 TQ + CQ (N=317) Percent Risk Ratio (95% CI) CO-54 Placebo-Controlled Studies: No Clinically Relevant Effect on Hemoglobin
CQ TQ 300 mg + CQ PQ + CQ 200
180
160
140 Hemoglobin (g/L) 120
100
80
60 Day 1 Day 3 Day 5 Day 8 Day 11 Day 15 Day 22 Day 29 Day 60 Day 90 Day 120
CQ 187 187 186 185 184 186 184 183 181 181 132 TQ 300 mg + CQ 317 315 313 312 310 310 308 309 309 308 251 PQ + CQ 179 179 177 175 173 173 173 172 173 168 123 CO-55 Placebo-Controlled Studies: Hemoglobin Declines Do Not Fall to Levels of Clinical Concern
Hemoglobin declines in G6PD-normal patients not drug- induced hemolytic events . No evidence from any laboratory markers Data suggest underlying infection and subsequent rehydration could be contributing factors All declines resolved without intervention Hemoglobin nadir in same range in patients with / without SAE CO-56
Study 564: Focusing on Hematologic Safety
Study 564 design . TQ 300 mg + CQ vs PQ + CQ Primary endpoint . Decrease in hemoglobin of ≥ 30% or > 30 g/L from baseline, or absolute level < 60 g/L CO-57 Study 564: No Clinically Relevant Hemoglobin Decline
TQ 300 mg + CQ PQ + CQ N=166 N=85 Hemoglobin decline 4 (2.4%) 1 (1.2%) 95% CI 0.94, 6.03 0.21, 6.37 Difference in proportion 1.23% 95% CI -4.16, 4.98
No evidence of hemolysis from laboratory markers No patients required blood transfusion Majority of hemoglobin drops in both treatment groups small (< 20 g/L) and with no clinical sequelae CO-58 All Primary Studies: No Ophthalmic SAEs for Tafenoquine 300 mg Single Dose
Across primary studies no evidence of retinal toxicity or corneal changes associated with vision changes Adverse events associated with ocular changes . Infrequent and similar across treatment groups All events mild or moderate in severity All resolved No ophthalmic SAEs Onset within first 29 days CO-59 Study 807: Ophthalmic Events with Tafenoquine 300 mg Single Dose Compared with Placebo
N=330 TQ, N=168 placebo No changes to ophthalmic safety parameters using highly sensitive techniques Eye disorder AEs observed in lower proportion of patients on tafenoquine vs placebo CO-60
CNS Safety for Tafenoquine 300 mg Single Dose
No serious CNS AEs reported in > 800 individuals at proposed treatment dose Observed effects mild to moderate and resolved No subjects withdrew from studies or discontinued treatment due to CNS AEs CO-61 Placebo-Controlled Studies: CNS AEs Over 6 Months
CQ TQ 300 mg + CQ PQ + CQ Placebo-controlled Studies N=187 N=317 N=179 Any nervous system AE 27% 18% 20% Headache 21% 12% 13% Dizziness 9% 9% 8% Migraine < 1% < 1% 0 Syncope 0 < 1% < 1% Tremor 0 < 1% < 1% Burning sensation 0 0 < 1% Dysesthesia 0 0 < 1% Somnolence 0 < 1% 0 Any psychiatric AE 3% 4% 4% Insomnia 3% 4% 4% Anxiety 0 < 1% 0 CO-62 Placebo-Controlled Studies: CNS AEs in First 29 Days
CQ TQ 300 mg + CQ PQ + CQ Placebo-controlled Studies N=187 N=317 N=179 Any nervous system AE 10% 11% 10% Dizziness 3% 8% 6% Headache 6% 5% 5% Syncope 0 < 1% 0 Tremor 0 < 1% < 1% Dysesthesia 0 0 < 1% Migraine < 1% 0 0 Somnolence 0 < 1% 0 Any psychiatric AE 3% 4% 4% Insomnia 3% 4% 4% Anxiety 0 < 1% 0 CO-63 Single-Dose Tafenoquine: Psychiatric Disorders Across Program
All received dose of TQ > 300 mg All recovered 3 of 4 had history of pre-existing psychiatric disorder . HV - 350 mg: acute psychotic episode (severe)* . HV - 500 mg: psychotic episode (severe)* . HV - 600 mg: depressed mood (mild) . P. vivax patient - TQ 600 mg + CQ: depressed mood (mild)*
*History of pre-existing psychiatric disorder HV = healthy volunteer CO-64 No Signal of Liver Toxicity With Tafenoquine (Placebo-Controlled, from Day 3)
CQ TQ 300 mg + CQ PQ + CQ N=187 N=317 N=179 ALT ≥ 3x ULN 14 (7%) 15 (5%) 7 (4%) ALT ≥ 5x ULN 4 (2%) 6 (2%) 3 (2%) Bilirubin ≥ 2x ULN 10 (5%) 10 (3%) 4 (2%) ALT ≥ 3x and bilirubin ≥ 2x ULN 0 2 (< 1%) 0
Across development program Transient, sporadic, reversible increases in liver transaminases No Hy’s Law cases . 2 patients fulfilled lab criteria of ALT ≥ 3x and bilirubin ≥ 2x ULN with alternative causes . 27 year-old female on day 89 diagnosed with hepatitis E . 29 year-old male on day 22 with concomitant herbal medicine use CO-65 Multiple Studies Demonstrate No QT Prolongation for Tafenoquine 300 mg
TQT Study . Maximum effect on QTcF < 10 msec at supratherapeutic dose of 1200 mg compared to placebo Study 491 . Co-administration of tafenoquine with chloroquine . No additional effect on QTcF observed Placebo-controlled studies . No differences observed CO-66
Two Subjects with Delayed Hypersensitivity
Both had urticaria / angioedema Healthy volunteers in same study Delay of onset and duration not consistent with anaphylaxis Both subjects recovered Treated with antihistamines and steroids No alternative explanation identified TQ proposed label to include precaution for hypersensitivity CO-67 Proposed Post-Approval Activities to Include Active Enhanced Pharmacovigilance
Enhanced pharmacovigilance in US . Post-marketing requirement . Active follow-up of US patients in collaboration with CDC Observational studies of real-world TQ use in endemic countries WHO, MHRA*, Bill and Melinda Gates Foundation . Smart Safety Surveillance
*UK Medicines and Healthcare Products Regulatory Agency CO-68 Safety Summary of Tafenoquine 300 mg Single Dose
Safety profile well-characterized and similar to primaquine No evidence that TQ exacerbated effects of CQ Known risk of hemolysis in G6PD-deficient patients managed . G6PD testing proposed in label No clinical hemolytic events in G6PD-normal patients Observed hemoglobin declines, not clinically meaningful No evidence of retinal toxicity CNS AEs mild to moderate and resolved . Label to include precaution for patients with history of serious psychiatric disorders CO-69
Tafenoquine: Pivotal Advance in Malaria Therapeutics
Ric Price, MD Professor of Global Health Senior Principal Research Fellow Menzies School of Health Research CO-70 Predominant Morbidity and Mortality of P. vivax Related to its Propensity to Recur
Risk and frequency of relapse varies with Incidence of Malaria origin of infection1 (per patient-year)
Relapses can occur every 21 to 42 days P. falciparum Mix 1.6 P. vivax Other Each episode associated with further 1.4 1.2 2 hemolysis and cumulative risk of anemia 1.0 0.8 Morbidity and mortality likely function of 0.6 incidence density3 0.4 0.2 Clinical trials focus on incidence risk of 0.0 Survived Dead infection
1. White, Malaria Journal 2011; 2. Douglas et al PLoS Med 2013; 3. Patriani Under Review 2018 CO-71
Primaquine Radical Cure
1963 55 years later
No optimal dosing regimen
Clinicians reluctant to prescribe PQ
Patients don’t take complete course
“Group recommends that intensive research be carried out with a view to developing an anti-relapse drug free from side effects and radically curative at a single dose or at most after a three day treatment” CO-72 Clinical Trial: Patients Don’t Complete 14-Day Regimen for Acute Febrile Illness
Primaquine efficacy related to total mg/kg dose ingested
1.00 Complete Course * 92.0%
0.75 Incomplete Course 73.7% Efficacy Unsupervised Course 63.2%
0.50
0.25 0 50 100 150 200
* > 10/14 doses taken Duration of Follow-up (days) Abreha et al Plos Med 2017 CO-73 Study 582 (Part 2): Tafenoquine Efficacy is Similar to 14-Day Course of Primaquine
1.0
Actual efficacy of PQ expected to be 0.8 lower due to PQ + CQ reduced adherence 0.6 TQ 300 mg + CQ Recurrence-free Probability 0.4
CQ 0.2
0.0 0 30 60 90 120 150 180 210 Time (days) CO-74 Reality: Patients Don’t Complete Unsupervised 14-Day Regimen for Acute Febrile Illness
Papua, Indonesia1 Pharmacy Records 2004-2013: 46,221 Patients treated with 14 days unsupervised primaquine
0.4 No PQ High Dose 0.3 Low Dose Risk of P. vivax 0.2 Recurrence 0.1 Overall Effectiveness: 10.0% [95%CI 0.05-0.14]* 0.0 0 3 6 9 12 Months of Follow-up *after controlling for age, gender, ethnicity 1. Douglas et al PLoS Med 2017 CO-75 Safety Well-Characterized and Identified Risks Manageable
Primaquine exposure in > 36 million individuals1,2 . 219 SAEs - mostly severe hemolysis1 (none in G6PD normal individuals) Population SAEs Risk 16 severe hemolysis MDA 15–30 mg daily 9 million 2 methemoglobinemia 1.8 per million 1 severe urticaria 24 severe hemolysis Patients 15–30 mg daily 1 neuropsychiatric3
14 deaths: 12 hemolysis, 1 hepatic necrosis, 1 unknown . Risk = 1 in 621,428
1. WHO Safety of 8 aminoquinolines 2014; 2 Ashley MalJ 2014; 3 Schlossberg Annals Int Med 1980 CO-76 Risk of Early Hemolysis Outweighed by Fewer Episodes of Recurrent Parasitemia
Hemoglobin (g/dL) Pooled Individual Data Analysis1 Hemolysis is attributable to 29 clinical trials with 3421 patients 14.0 both parasitemia and treatment 13.5
Radical cure prevents early 13.0 recurrence, providing faster hematological recovery 12.5
12.0 Primaquine No primaquine 11.5 0 7 14 21 28 35 42
Time (days) 1. Commons et al Submitted CO-77
Conclusions
Radical cure essential for control and elimination of P. vivax
Radical cure has potential to reduce direct and indirect morbidity and mortality
AEs of PQ and TQ well-identified and manageable
Primaquine radical cure is a broken strategy
Single-dose radical cure with tafenoquine represents pivotal advance in malarial therapeutics CO-78
Single-Dose Tafenoquine 300 mg for Radical Cure of Plasmodium vivax Malaria
July 12, 2018 GlaxoSmithKline Antimicrobial Drugs Advisory Committee Meeting CO-79
Backup Slides Shown CO-80 CO-81 CO-82