Ivermectin Mass Drug Administration for Malaria Elimination in the Greater Mekong Subregion

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ARMED FORCES RESEARCH INSTITUTE OF MEDICAL SCIENCES ( AFRIMS) Ivermectin Mass Drug Administration for Malaria Elimination in the Greater Mekong

Podjanee Jittamala, Sasithon Pukrittayakamee, Borimas Hanboonkunupakarn, Rob van der Pluijm, Mavuto Mukaka, Thanaporn Wattanakul, Richard Hoglund,

org Principal Investigator, The Geneva Foundation (6 December 2017) JITMM The views expressed in this presentation are those of the authors and do

1 ARMED FORCES RESEARCH INSTITUTE OF MEDICAL SCIENCES ( AFRIMS) Ivermectin Mass Drug Administration for Malaria Elimination in the Greater Mekong Subregion Kevin Kobylinski*, Silas Davidson, Jason Richardson, Wes McCardle, Alongkot Ponlawat, Ratawan Ubalee, Siriporn Phasomkusolsil, Brian Foy, Podjanee Jittamala, Sasithon Pukrittayakamee, Borimas Hanboonkunupakarn, Rob van der Pluijm, Mavuto Mukaka, Thanaporn Wattanakul, Richard Hoglund, Joel Tarning, Arjen Dondorp, Nick Day, Nick White * Kevin.kobylinski.gst@afrims.org Principal Investigator, The Geneva Foundation (6 December 2017) JITMM The views expressed in this presentation are those of the authors and do not reflect the official policy of the Department of Army, Department of Defense, nor the U.S. Government. Trade names are used for identification purposes only and do not imply endorsement. UNCLASSIFIED 1

Ivermectin - background Endectocide activity against internal and external parasites Macrocyclic lactone isolated from the bacteria Streptomyces

to open, hyperpolarizing the cell (Hibbs and Gouaux 2011) which leads to the paralysis of the nematode or ectoparasite musculature (Cully et al.

2 Ivermectin - background Endectocide activity against internal and external parasites Macrocyclic lactone isolated from the bacteria Streptomyces avermitilis Mode of action binds at subunit interfaces next to the glutamategated chloride (GluCl) ion channels, which distorts the channel from closed to open, hyperpolarizing the cell (Hibbs and Gouaux 2011) which leads to the paralysis of the nematode or ectoparasite musculature (Cully et al. 1994, 1996, Cane et al. 2000) Lethal against Anopheles mosquitoes! Different class of insecticides than those used for ITNs or IRS (Omura and Crump 2004) UNCLASSIFIED 2

3 Ivermectin - Neglected Tropical Diseases Onchocerciasis Onchocerca volvulus Lymphatic filariasis Wuchereria bancrofti, Brugia malayi, and Brugia timori ->300 million people given ivermectin mass drug administration (MDA) annually - 11/13 onchocerciasis foci in Latin America eliminated (x1-4 MDAs/year) Ascariasis Ascaris lumbricoides Trichuriasis Trichuris trichiura Strongyloidiasis Strongyloides stercoralis - Currently approved treatment in Thailand (oral 200 μg/kg) Pediculosis Pediculus humanus humanus and P. h. capitus Scabies Sarcoptes scabei - One person treated 150 times in 13 years, 12 times in 1 month (Mounsey et al. 2008) - Safe in healthy volunteers up to 2000 μg/kg (Guzzo et al. 2002) UNCLASSIFIED 3

4 MDA by Community Directed Treatment with Ivermectin (CDTI) UNCLASSIFIED 4

AFRICA An. gambiae s.s. (Fritz et al. 2009, Sylla et al. 2010, Chaccour et al. 2010, Kobylinski et al. 2010, 2012, 2014, Butters et al. 2012, Ouédraogo et al. 2015, Alout et al. 2014, Derua et al.

farauti (Foley et al. 2000, Kositz et al. 2017) An. punctulatus (Bockarie et al. 1999) ASIA An. stephensi (Pampiglione et al. 1985, Iakubovich et al. 1989, Naz et al. 2013, Bastiens et al. 2012) An.

5 AFRICA An. gambiae s.s. (Fritz et al. 2009, Sylla et al. 2010, Chaccour et al. 2010, Kobylinski et al. 2010, 2012, 2014, Butters et al. 2012, Ouédraogo et al. 2015, Alout et al. 2014, Derua et al. 2015, 2016, Seaman et al. 2015) An. arabiensis (Fritz et al. 2009, 2012, Yamada et al. 2013) An. coluzzi (Poché et al. 2015) An. funestus (Ouédraogo et al. 2015) SOUTH PACIFIC An. farauti (Foley et al. 2000, Kositz et al. 2017) An. punctulatus (Bockarie et al. 1999) ASIA An. stephensi (Pampiglione et al. 1985, Iakubovich et al. 1989, Naz et al. 2013, Bastiens et al. 2012) An. culicifacies (Naz et al. 2013) An. sacharovi (Iakubovich et al. 1989) GREATER MEKONG SUBREGION An. dirus (Kobylinski et al. 2017a) An. minimus (Kobylinski et al. 2017a) An. sawadwongporni (Kobylinski et al. 2017a) An. campestris (Kobylinski et al. 2017a) AMERICAS An. quadrimaculatus (Jones et al. 1992, Gardner et al. 1993) An. aquasalis (Sampaio et al. 2016, 2017) An. darlingi (Kobylinski et al. 2017b) UNCLASSIFIED 5

2017b) dirus sawadwongporni campestris minimus gambiae darlingi aquasalis n=5029, r=6 n=1431,

6 In vitro estimated ivermectin lethal concentrations in Anopheles = LC 50 = LC 25 = LC 5 (Kobylinski et al. 2017a) (Kobylinski et al. 2010) (Kobylinski et al. 2017b) dirus sawadwongporni campestris minimus gambiae darlingi aquasalis n=5029, r=6 n=1431, r=4 n=2786, r=4 n=2376, r=6 n=2013, r=8 n=6061, r=13 n=1415, r=5 (5-day LC 50 ) (5-day LC 50 ) UNCLASSIFIED (Sampaio et al. 2016) 6

7 Population age structure shift numbers numbers of of females females = 0.7 P = 0.85 x 0.2 x = 0.2 all females all females infective females infective females V = 0 0 ma 2 p n b -lnp days days p daily probability of adult mosquito survivorship Vectorial Capacity Equation (Garrett-Jones 1964, Black and Moore 2005) UNCLASSIFIED 7

9 Entomology Field Results Senegal 2008 Aug Senegal 2009 Aug. Senegal 2009 Oct. Liberia 2013 Jun. Burkina Faso 2013 Aug. - -MDA coverage 76-84% - ITN coverage 38-82% Senegal 2012 Aug. Burkina Faso 2013 Aug. V = ma 2 p n b -lnp Senegal 2012 Aug. Liberia 2013 Jun. Burkina Faso 2013 Aug. Sporozoite rate Time relative to MDA (days) V average number of potentially infective bites that will be delivered by all vectors feeding on a single host in one day (Alout et al. 2014, Sylla et al. 2010, Kobylinski et al. 2011)

10 Anopheles LC 50 ( ) and LC 25 ( ) values plotted on PK model estimates Ivermectin concentration (ng/ml) (Alout et al. 2014) Time (hours) (Kobylinski et al. 2017a) 200 μg/kg 400 μg/kg 800 μg/kg dirus sawadwongporni campestris minimus gambiae darlingi aquasalis

Targeted Malaria Elimination - MDAs with dihydroartemisinin-piperaquine and primaquine reduce infectious human reservoir and prevent onwards transmission from treated individuals - However,

11 Targeted Malaria Elimination - MDAs with dihydroartemisinin-piperaquine and primaquine reduce infectious human reservoir and prevent onwards transmission from treated individuals - However, primaquine has no effect on oocysts or sporozoites in already infected mosquitoes (Coleman et al. 1994), so there will be NO IMMEDIATE effect on mosquito-to-human transmission - Ivermectin MDA targets the vector with mosquito-lethal endectocides which IMMEDIATELY suppresses mosquito-to-human transmission (Sylla et al. 2010, Kobylinski et al. 2011, Alout et al. 2014) - Ivermectin MDA would reduce number of new infections in treated and UNTREATED persons - Disparate modes of action on transmission make ivermectin plus primaquine MDA ideal - Direct personal benefits are observed during ivermectin MDAs (Okeibunor et al. 2011), therefore, combining ivermectin with antimalarial MDAs may enhance compliance

Ivermectin & Eurartesim Clinical Trial Open-Label Study to Evaluate Safety, Tolerability, Potential Pharmacokinetic Interaction and Mosquito-Lethal Effects of Orally Administered Ivermectin,

Podjanee Jittamala (Principal Investigator) Sequential trial in healthy Thai adults (x16 7M:9F) Determine safety, tolerability, pharmacokinetic interaction, and mosquito-lethal efficacy of single

12 Ivermectin & Eurartesim Clinical Trial Open-Label Study to Evaluate Safety, Tolerability, Potential Pharmacokinetic Interaction and Mosquito-Lethal Effects of Orally Administered Ivermectin, Primaquine, Dihydroartemisinin-Piperaquine, and Albendazole in Healthy Adult Subjects NCT [TMEC , OxTREC 4-15, WRAIR#2228] Collaboration between Mahidol University, MORU, and AFRIMS Dr. Podjanee Jittamala (Principal Investigator) Sequential trial in healthy Thai adults (x16 7M:9F) Determine safety, tolerability, pharmacokinetic interaction, and mosquito-lethal efficacy of single doses: 1) Ivermectin (Vermectin, Atlantic Laboratories (400 µg/kg)) 2) Ivermectin + Primaquine (Primaquine Phosphate, Thai GPO (30 mg)) 3) Ivermectin + Dihydroartemisinin-Piperaquine (Eurartesim, Sigma-Tau (120/960 mg)) 4) Ivermectin + Dihydroartemisinin-Piperaquine + Primaquine 5) Primaquine 6) Dihydroartemisinin-Piperaquine 7) Dihydroartemisinin-Piperaquine + Primaquine UNCLASSIFIED 12

13 Non-compartmental pharmacokinetic interactions of ivermectin The exposure (AUC 0-T and C max ) of ivermectin is slightly increased when co-administrated with primaquine (PQ) A significant increase in ivermectin exposure observed when co-administrated with dihydroartemisinin-piperaquine (DHA-PQP) A significant additive increase in exposure observed when co-administrated with DHA-PQP and PQ IVM + PQ IVM + DHA-PQP IVM + DHA-PQP + PQ UNCLASSIFIED (Tarning, unpublished data) 13

Mosquito Survival Studies 1) Venous whole blood

volunteers in sodium heparin tubes 2) Collected

and 2, 3, 6, 10 days post dose 3) Blood (600µl)

minimus (x100 each) 4) x40 blood-fed of each

14 Mosquito Survival Studies 1) Venous whole blood collected at Mahidol Healthy Volunteer Ward from volunteers in sodium heparin tubes 2) Collected before and post drug ingestion at 0, 4, 24 hours, and 2, 3, 6, 10 days post dose 3) Blood (600µl) membrane fed at 37ºC to An. dirus and An. minimus (x100 each) 4) x40 blood-fed of each species saved for survival monitoring at 25ºC, 80% r.h. 5) Daily mosquito survival monitoring for ten days post blood meal Volunteer sample collection timeline (days)

15 Ivermectin (400 μg/kg) mosquito survivorship results Anopheles dirus Anopheles minimus Hours (days) of blood collection Volunteer sample collection timeline (days) (Kobylinski, unpublished data)

16 Mean mortality (95% CI) of An. dirus after volunteer blood ingestion by regimen 100 Mosquito mortality (%) Combination with DHA-PQP enhances mosquito-lethal efficacy (1) 48(2) 72(3) 144(6) 240(10) Hours (days) since drug ingestion by volunteer - SMFAs with An. dirus and piperaquine compound showed no mortality effect (1-100,000 ng/ml) (Kobylinski, unpublished data)

An. dirus mortality following ingestion of ivermectin spiked blood or ivermectin-administered volunteer blood (7 days) Ivermectin-spiked blood Volunteer blood LC 50 = 56.9 [53.69-60.

17 An. dirus mortality following ingestion of ivermectin spiked blood or ivermectin-administered volunteer blood (7 days) Ivermectin-spiked blood Volunteer blood LC 50 = 56.9 [ ] (ng/ml) Reps = 6, mosq = 5,029 LC 50 : all regs = [ ] (ng/ml) IVM only = [ ] (ng/ml) Vols = 16 mosq = 17,946 mosq = 4,477 (Kobylinski et al. 2017) LC 50 s estimated using a normalized concentration-response analysis (IC 50, Hill) LC 50 with volunteer blood is x20 fold lower than ivermectin-spiked blood, possibly due to metabolites with mosquito-lethal activity Recent award from the Bill & Melinda Gates Foundation to characterize ivermectin metabolites and their impact on mosquito survival (Kobylinski, unpublished data)

5-10 ULN) and ALT (x5 ULN) when Ivermectin and DHA-PQP co-administered Combinations well tolerated dqtcfridericia (ms) -20-10 0 10 20 30 40 50 60

18 Clinical Results Change QTcF-values between H0 and H4 No QTc-interval >500 ms, and change from baseline >60 ms (FDA limit) 1/16 volunteers had transient elevations of AST (x ULN) and ALT (x5 ULN) when Ivermectin and DHA-PQP co-administered Combinations well tolerated dqtcfridericia (ms) FDA treshold No safety concerns with ivermectin and primaquine (30mg) Ongoing trial in Kenya will investigate combination of ivermectin and DHA-PQP in 141 falciparum patients DHA-PQP PQ IVM IVM+PQ DHA-PQP+PQ DHA-PQP+IVM DHA-PQP+IVM+PQ (Jittamala, unpublished data)

Sporozoite 14 Sporozoite χ 2 = 15.48, P = 0.0002 χ 2 = 13.47, P = 0.0003 χ 2 = 19.96, P < 0.

19 Ivermectin (LC 25 ) sporontocidal to P. falciparum NF54 in An. gambiae * * LC 25 = 10.7 ng/ml * V = ma 2 p n b -lnp b vector competence n extrinsic incubation period DDPI Stage 7 Oocyst 12 Sporozoite 14 Sporozoite χ 2 = 15.48, P = χ 2 = 13.47, P = χ 2 = 19.96, P < (F-value = 0.01, P = , n = 233) Plasmodium blood feed Ivermectin blood feed dissection time point (Kobylinski et al. 2012)

Ivermectin (LC 25 and LC 5 ) sporontocidal to P. vivax in An. dirus and An. minimus An.

dirus χ 2 = 29.52, P < 0.0001 reps = 6, n = 285 χ 2 = 17.9, P < 0.

3 ng/ml LC 5 = 6.7 ng/ml Oocyst prevalence in An. minimus An. minimus oocyst prevalence χ2 = 21.72, P < 0.

20 Ivermectin (LC 25 and LC 5 ) sporontocidal to P. vivax in An. dirus and An. minimus An. dirus oocyst prevalence An. dirus oocyst intensity LC 25 = 38.1 ng/ml LC 5 = 22.1 ng/ml Oocyst prevalence in An. dirus χ 2 = 29.52, P < reps = 6, n = 285 χ 2 = 17.9, P < reps = 6, n = 300 Oocyst intensity per An. dirus P = , n = 156 P = , n = 178 LC 25 = 11.3 ng/ml LC 5 = 6.7 ng/ml Oocyst prevalence in An. minimus An. minimus oocyst prevalence χ2 = 21.72, P < reps = 5, n = 172 χ2 = 12.93, P = reps = 5, n = 235 Oocyst intensity per An. minimus An. minimus oocyst intensity P = , n = 60 P < , n = 139 (Kobylinski et al. 2017a)

Repeat ivermectin MDA trial (RIMDAMAL) - Burkina Faso -

18 weeks - 1-5 yo monitored for clinical malaria (Mendes et

no P. falciparum infection - Delay to first P.

21 Ivermectin inhibits P. berghei liver stage development in mice 10 mg/kg 10 mg/kg Repeat ivermectin MDA trial (RIMDAMAL) - Burkina Faso - Ivermectin (150 µg/kg) given to >90 cm (>15kg) x6 MDAs in 18 weeks yo monitored for clinical malaria (Mendes et al. 2017) Significant Findings: - Increase in children with no P. falciparum infection - Delay to first P. falciparum infection - Ivermectin treated children were less likely to develop P. falciparum clinical malaria!!!

Ivermectin MDA Field Study in Thailand Collaboration between Mahidol University and AFRIMS -

in southern Thailand Assess parameters of malaria transmission: Entomological (population

prevalence 1 and incidence, drug-resistant parasite ratio, and anemia) Funded by

22 Ivermectin MDA Field Study in Thailand Collaboration between Mahidol University and AFRIMS - Dr. Jetsumon Sattabongkot Prachumsri (Principal Investigator) Field site Rubber plantations in southern Thailand Assess parameters of malaria transmission: Entomological (population age structure 1, vector composition and density, sporozoite rate) Epidemiological (malaria prevalence 1 and incidence, drug-resistant parasite ratio, and anemia) Funded by Congressionally Directed Medical Research Program Peer Reviewed Medical Research Program (W81XWH )

23 Acknowledgements Ivermectin LC 50 and P. vivax Sporogony Assays: Malaria patients for donating P. vivax samples Thailand Malaria clinic staff in Tak Province for their support obtaining P. vivax samples AFRIMS Department of Entomology Malariology, Insectary, and Vector Biology & Control sections for field and laboratory support Ivermectin & Eurartesim Study: Volunteers for their participation Mahidol University Healthy Volunteer Ward staff for clinical trial support AFRIMS Department of Entomology Insectary, Malariology, and Vector Biology & Control sections and Joi Larson for laboratory support Funding Disclaimer Material has been reviewed by the Walter Reed Army Institute of Research. There is no objection to its presentation and/or publication. The opinions or assertions contained herein are the private views of the author, and are not to be construed as official, or as reflecting true views of the Department of the Army or the Department of Defense. The investigators have adhered to the policies for protection of human subjects as prescribed in AR UNCLASSIFIED 23

Ivermectin susceptibility and sporontocidal effect in Greater Mekong Subregion Anopheles

DOI 1.1186/s12936-17-1923-8 Malaria Journal RESEARCH Open Access Ivermectin susceptibility and sporontocidal effect in Greater Mekong Subregion Anopheles Kevin C. Kobylinski 1,2*, Ratawan Ubalee 1, Alongkot