New approvals and pipeline drugs for malaria

1. RECENT
ADVANCES IN
MALARIA
Shreya Gupta
PG 1st year resident
Department of Pharmacology

2. CONTENTS
• Introduction
• Global disease burden
• Indian scenario
• Pathophysiology
• Diagnosis
• Current treatment
• Need for new drugs
• Recent advances
• Conclusion

3. INTRODUCTION
• Derived from the Italian word ‘Mal’ aria or ‘bad air’.
• Malaria is caused by protozoan Plasmodium and transmitted by the bite of
infected female Anopheles mosquito.
• Between 2000 and 2015, 17 countries eliminated malaria including the
United States, Canada, Europe, and Russia, however, its prevalence rose in
many parts of the tropics.
• Kyrgyzstan and Sri Lanka were certified by WHO as malaria free in 2016.
• Species of Plasmodium: P. falciparum
P. vivax
P. ovale
P. malariae
P. knowlesi- the ‘monkey parasite’ in South East Asia
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5708604/

4. GLOBAL MALARIA BURDEN
According to the latest World Malaria Report, released in November
2017:
• There were 216 million cases of malaria in 2016, up from 211
million cases in 2015.
• Estimated number of malaria deaths stood at 445 000 in 2016, a
similar number to the previous year (446 000).
• Incidence rate of malaria is estimated to have decreased by 18%
globally, from 76 to 63 cases per 1000 population at risk, between
2010 and 2016.
Source:http://www.who.int/en/news-room/fact-sheets/detail/malaria (Accessed on:
30/7/2018)

5. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5708604/

6. EPIDEMIOLOGICAL PROFILE – INDIA 2016 2016 %
High transmission (>1 case per 1000 population) 160,500,000 12
Low transmission (0-1 case per 1000 population) 1,080,000,000 81
Malaria free(0 case) 83,500,000 7
Total 1,328,000,000
PARASITES AND VECTORS
PLASMODIUM species: P. falciparum (66%), P. vivax (34%)
Major ANOPHELES species: An.culifaciens, An.fluviatilis, An.stephensi, An.minimus,
An.diris, An.annularis
Reported confirmed cases :1.3 million (0.94-1.83 million)
Reported deaths :23,990 (1600-46500)
6% of total malaria cases worldwide; 51% of global P. vivax cases.
6% of total malaria deaths worldwide.
Source : http://www.who.int/malaria/publications/country-profiles/profile_ind_en.pdf
(accessed on 30/7/2018)

7. https://www.thelancet.com/cms/attachment/2112997221/2084195928/gr1.jpg

9. Classical malarial paroxysm: Chills, rigors, fever, followed by sweating.
1. Cold stage: (15-60 minutes) cold and shivering.
2. Hot stage: (2-6 hours) with fever from 39-41.5°C a/w flushed, dry
skin,headache, nausea, and vomiting.
3. Sweating phase: (2-4 hours) fever drops rapidly & patient sweats profusely
P. malariae -72 hours cycle,
Fever occurs every fourth day
with two days of afebrile
interval and is called Quartan
malaria.
P. vivax and P. ovale with 48 hours
cycles have the paroxysms every
third day, termed as Tertian
malaria.
P. knowlesi, with a 24 hour
cycle, manifests with fever
every day Quotidian malaria
Mixed infections of P. malariae with
the other parasites can result
in Double Quartan fever, with
paroxysms for 2 consecutive days
followed by one day of remission.

10. SEVERE/COMPLICATED MALARIA
P.falciparum infection + 1/more:
• Hyperparasitemia
• Hyperpyrexia
• Fluid, electrolyte imbalance
• Acidosis
• Hypoglycaemia
• Cardiovascular collapse
• Jaundice
• Severe anaemia
• Spontaneous bleeding
• ARDS
• Pulmonary oedema
• Black water fever
• Renal failure
• Cerebral malaria
Source: Essentials of Medical Pharmacology by KD Tripathi 8th edition

11. 4-Amino
quinolones
Chloroquine
Amodiaquine
Piperaquine
Quinoline
methanol
Mefloquine
Cinchona
alkaloid
Quinine
Quinidine
Biguanide
Proguanil
Diamino
pyrimidine
Pyrimethamine
8-aminoquinolines
Primaquine
Tafenoqine
Sulphonamide
Sulphadoxine
Sulphamethopyrazine
Dapsone
Antibiotics
Doxycycline
Clindamycin
Amino alcohols
Halofantrine
Lumefantrine
Sesquiterpene
lactones
Artesunate
Artemether
Arterolane
Dihydro
artemisinin
Naphthoquinone
Atovaquone
Naphthpyridine
Pyronaridine
ANTIMALARIAL DRUGS

12. ANTIMALARIALS
DRUG MECHANISM ADVERSE EFFECTS CLINICAL USES
Quinine
Quinidine
Blood schizonticidal
& gametocidal (except
P.falciparum)
 Cinchonism (nausea,
headache, tinnitus,
dizziness, visual problems)
 Haemolysis(G6PD
deficiency.)
 QTc prolongation
 Black water fever(rare)
Oral & IV treatment of
P.falciparum.
IV preparations used rarely
in US.
Quinine resistance seen
common in Southeast Asia
(Thailand)
Chloroquine
Blood schizonticidal
& gametocidal
Prevents bio
cystallization of
heme to haemozoin,
causing parasite
toxicity.
Pruritis, Rare:
haemolysis(G6PD def.),
confusion, psychosis, seizures,
dermatitis, alopecia, bleaching
of hair, ECG changes
DOC for treatment &
chemo prophylaxis of
sensitive parasites.
C/I in Psoriasis and
Porphyria
Mefloquine Blood schizonticidal
N/V, dizziness, sleep &
behavioural disturbance, rash.
BLACK BOX WARNING
potential neurological &
psychiatric toxicities (CDC
2013)
Prophylaxis & treatment
of P.falciparum, including
CQ- resistant strains
C/I epilepsy, psychiartric
pts., Cardiac conduction
defects

13. DRUG MECHANISM ADVERSE EFFECTS CLINICAL USE
Primaquine
Tissue-stage
schizonticidal &
gametocidal
Well tolerated.
Rare- nausea, abdominal
pain cramps,leukopenia,
agranulocytosis,
leukocytosis, arrythmia.
Avoided in G6PD patients.
 DOC for eradication of
dormant liver forms of
P.vivax, P. ovale
 Prophylaxis against all
species.
Halofantrine
Lumefantrine
Pyronaridine
Erythrocytic
schizonticidal
H: alters cardiac
conduction, QT & PR
prolongation
C/I in pregnancy
Against P.falciparum
Atovaquone Tissue and blood
schizonticidal.
Disrupt electron
transport chain
GI effects, headache
C/I in renal impairment
• CQ resistant P.
falciparum
• P.vivax
Doxycycline Blood
schizonticidal
GI effects, dizziness,
photophobia, headache,
esophagitis
P.falciparum & P.vivax in
CQ resistant areas.
C/I in children<8 years,
pregnancy, known
hypersenstivity to TC

14. DRUG MECHANISM ADVERSE
EFFECTS
CLINICAL USE
Artimisinin
derivatives
Erythrocytic
schizonticidal and
gametocytocidal
Headache, arthralgia,
dizziness, myalgia
P.falciparum from
CQ resistant &
unknown areas
C/I in pregnancy
Pyrimethamne/
Sulfadoxine
Blood schizonticidal
Inhibit DHFR and
Dihydropteroate
synthase
Headache, SJS, rash CQ resistant
P.falciparum
Proguanil Erythrocytic
schizonticidal.
Inhibit DHFR and stops
pyrimidine biosynthesis
GI upset, nausea,
vomiting
Chemoprophylaxis
(with CQ)
Source: Basic & Clinical Pharmacology, Katzung, 14th edition

15. TREATMENT OBJECTIVES
CAUSAL PROPHYLAXIS: Targets the pre-erythrocytic phase which causes
the clinical attacks.
1. Primaquine 2. Proguanil
SUPPRESIVE PROPHYLAXIS: Before travelling to an endemic area
1. Chloroquine (CQ resistance widespread in India , no longer used as
prophylactic)
2. Mefloquine 250mg 1-2 weeks before travel till 4 weeks post return
3. Doxycycline 100mg daily from day before travel to 4 weeks post return
4. Proguanil (ineffective in India , not used)
CLINICAL CURATIVE
RADICAL CURATIVE- Targets the hypnozoits (exoerythrocytic stage)
1. Primaquine 15mg OD x 14 days
GAMETOCIDAL- Kill male and female gametes in patient’s blood
1. Primaquine single dose 45mg (NVBDCP)/ 15mg (WHO)

16. Clinical suspicion of malaria/history of travel to endemic area
Perform thick and thin blood smears
Blood film
positive?
NO YES
Repeat blood films every 12-24
hrs for a total of 3 sets
Calculate parasitemiaBlood film positive
YESNO
Consider alternate
diagnosis Evaluate clinical severity & disease activity
Uncomplicated malaria Severe malaria/ Pt.unable to take oral medication
IV Quinidine / Artesunate + TC/Doxy/clindamycin
Admit to ICU for cardiac monitoring. Switch to oral therapy after stabilization
DECISION ALGORITHM FOR TREATMENT OF MALARIA

17. Non falciparum P.falciparum/unknown species
P. Ovale/
P. vivax
P.malariae In chloroquine
sensitive area
Chloroquine x
3 days
+ Primaquine
30mg x 14
days
Chloroquine/
hydroxychloroquine
P. knowlesi
Chloroquine/hydroxy-
chloroquine
Chloroquine
resistant area
Mefloquine
resistant
area
Atovaquone-proguanil/
Artemether-lumefantrine/
Quinine+Doxy/clindamycin/
Mefloquine
Atovaquone-
proguanil/
Artemether-
lumefantrine/
Quinine+Doxy/
clindamycin
Admit to hospital to monitor progress of disease activity
Determine species
Source: Goodman&Gillman, Pharmacologcal basis of therapeutics, 13th ed, page no. 982

18. ACT regimens for uncomplicated falciparum malaria
1. Artemether+lumefantrine (1:6)
Artemether 80mg BD+lumefantrine 480mg BD x 3 days (dose reduce in
children)
2. Artesunate+mefloquine
AS 100mg BD x 3 days + MQ 750mg on day 2, 500 mg on day 3
3. Artesunate+amodiaquine
AS 200mg + AQ 600mg x 3 days
FDC also available
4. Artesunate+sulphadoxine-pyrimethamine(AS+S/P)
AS 100mg BD x 3 days + S 1500mg single dose + P 75mg single dose
5. Dihydroartemisinin-piperaquine
DHA 120mg + PPQ 960 mg x 3 days (dose reduce in children)
6. Arterolane-piperaquine
Arterolane 150 mg + PPQ 750 mg x 3 days (approved only for adults)
Source: Essentials of Medical Pharmacology by KD Tripathi 8th edition; page no. 890

19. MALARIA IN PREGNANCY
Malaria during pregnancy increases the risk for adverse
pregnancy outcomes, including maternal anemia, prematurity,
spontaneous abortion and stillbirth.
Falciparum malaria:
1. Quinine 600mg TDS x 7days + clindamycin 300mg
TDS/QID x 7days; for all trimesters
2. Artemisinin based combination therapy in 2nd and 3rd
trimester (preferred over Q+CL)
Vivax malaria:
1. Chloroquine
2. Primaquine postponed till delivery
Source: Essentials of Medical Pharmacology by KD Tripathi 8th edition

20. VECTOR CONTROL (NVBDCP)
• Malathione
• Cyphenothrin
OUTDOOR
FOGGING
• Malathione
• Deltamethrin
• Cyfluthrin
• Lambdacyhalothrin
• Alphacypermethrin
INDOOR
RESIDUAL
SPRAY
• Gambusia affinis
• Poecilia
reticulata(GUPPY)
• Bacillus
thuringenesis
LARVICIDALS
LONG LASTING INSECTICIDE NETS:
Deltamethrin, Cyfluthrin
http://nvbdcp.gov.in/index1.php?lang=1&level=1&sublinkid=5788&lid=3686

21. NEED FOR NEW DRUGS
• Emerging resistance to conventional drugs.
• Intolerable side effects eg. neuropsychiatric side effects at
prophylactic doses of mefloquine.
• Need for effective drug with a potential for improved compliance
and safety profile.
• Post-exposure prophylaxis is complex and cumbersome so there
is an additional unmet need for a simple effective post-exposure
drug regimen.
Source:https://www.fda.gov/downloads/advisorycommittees/committeesmeetingmaterials/drugs/a
nti-infectivedrugsadvisorycommittee/ucm614202.pdf Accessed on: 31/7/2018

22. NATIONAL FRAMEWORK FOR MALARIA
ELIMINATION IN INDIA (2016–2030)
GOALS:
• Eliminate malaria throughout the entire country by 2030
• Maintain malaria–free status in areas where transmission has been interrupted.
CATEGORY DEFINITION
Category 0 Prevention of re-
establishment
phase
Zero indigenous cases of malaria.
Category 1 Elimination
phase
Entire state/ UT API < 1/1000 population at risk
(15)
Category 2 Pre-elimination
phase
API <1/1000 population at risk, but some
districts are reporting an API of 1 case per 1000
population at risk or above (11)
Category 3 Intensified
control phase
API of 1 /1000 population at risk or above.(10)

23. OBJECTIVES:
• Eliminate malaria from 26 low (Category 1) and moderate
(Category 2) transmission states/UTs by 2022
• Reduce the incidence of malaria <1/1000 population per year
in all states and UTs and their districts by 2024
• Interrupt indigenous transmission of malaria, Category 3 areas
by 2027
• Prevent the re-establishment of local transmission of malaria
in areas where it has been eliminated and maintain national
malaria-free status by 2030 and beyond
http://nvbdcp.gov.in/WriteReadData/l892s/National-framework-for-malaria-elimination-in-India-
2016%E2%80%932030.pdf

24. INSIGHTS INTO NEW MEDICINES
https://malariajournal.biomedcentral.com/articles/10.1186/s12936-016-1675-x
Malaria Journal201716:151 Accessed on 1/8/2018

25. Tafenoquine
• US FDAApproval: July 20th 2018
• Group : 8-aminoquinoline
• Active ingredient: Tafenoquine
succinate
• Synthetic analogue of primaquine
with improved pharmacodynamic,
toxicological, and safety profiles.
• Indication : Prophylaxis of malaria
in adults for up to 6 months of
continuous dosing.
Source:https://www.fda.gov/downloads/advisorycommittees/committeesmeetingmaterials/drugs/anti-
infectivedrugsadvisorycommittee/ucm614202.pdf. Accessed on 1/08/2018

26. • Indication: All species of Plasmodia
prophylaxis both in the endemic
region (“in-country prophylaxis”)
and post-exposure (“post-exposure
prophylaxis”).
• Exact Mechanism: Unknown
In vitro : Effective against multiple Pf
clones in isolates from Africa, Honduras
and Indochina including highly drug-
resistant forms of Pf (i.e. chloroquine
and antifolates & reduced sensitivity to
mefloquine and quinine).
In vivo : 1. Clears liver stage infection
(causal prophylactic action)
2. Blood stage infections (schizonticidal
or suppressive action) in mice (P. berghei,
P. yoelli) and monkeys (P. cynomolgi, Pv
and Pf strains).
Loading dose: 2x100mg tab. Once
daily for 3 days before travel
Maintenance dose: Weekly 2x100mg
while in malaria area
1 dose of 2x100mg in the week after
exit from the area
DOSING SCHEDULE
https://www.fda.gov/downloads/advisorycommittees/committeesmeetingmaterials/drugs/antiinfectivedru
gsadvisorycommittee/ucm614202.pdf. Accessed on 1/08/2018
After 7 days

27. CONTRAINDICATIONS
• G6PD deficiency- risk of
hemolytic anemia
• Lactating women when the
infant is G6PD deficient or if the
G6PD status of the infant is
unknown
• History of psychotic disorders
• Known hypersensitivity
reactions to 8-aminoquinolines
• Not recommended during
pregnancy: May cause
hemolytic anemia in a G6PD-
deficient fetus.
• Avoid pregnancy during
treatment and for 3 months after
the last dose
• If a pregnancy is detected during
its use, discontinue as soon as
possible and switch to an
alternative prophylactic drug.
DRUG INTERACTIONS
• Organic Cation Transporter-2
(OCT2) and Multidrug and
Toxin Extrusion (MATE)
Substrates
• The effect of humans is unknown.
In vitro: Potential for increased
the risk of toxicity of these drugs.
• Avoid coadministration with
OCT2 and MATE substrates (e.g.,
dofetilide, metformin).
• If coadministration cannot be
avoided, monitor for drug-related
toxicities and consider dosage
reduction if needed
https://www.fda.gov/downloads/advisorycommittees/committeesmeetingmaterials/drugs/antiinfec
tivedrugsadvisorycommittee/ucm614202.pdf. Accessed on 1/08/2018

28. SIDE EFFECTS
1. Allergic reactions immediate/delayed:
• swelling of the face, lips, tongue or throat
• Itching
• troubled breathing
• wheezing
• Rash
2. Blood: Hemolytic anemia in G6PD deficiency, Methemoglobinemia
3. GI effects: Diarrhea, nausea, vomiting
4. CNS effects: headache, dizziness, motion sickness, insomnia, depression,
abnormal dreams and anxiety.
5. Vortex keratopathy: reversible
https://www.fda.gov/downloads/advisorycommittees/committeesmeetingmaterials/drugs/antiinfective
drugsadvisorycommittee/ucm614202.pdf

29. NEW DRUG TARGETS
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6013505/

31. P218
• Current status: Completed PHASE 1: Phase I Study to
Investigate the Safety, Tolerability and Pharmacokinetic
Profile and Food Effect of P218 in Healthy Adult Volunteer
• Mechanism: P. falciparum dihydrofolate reductase (DHFR)
inhibitor
• Potential for chemoprotection
• Results not yet published.
https://clinicaltrials.gov/ct2/show/NCT02885506

32. FERROQUINE
• GROUP: 4 aminoquinoline
• Active in vitro against chloroquine (CQ)-sensitive and
CQ-resistant Plasmodium falciparum and Plasmodium
vivax isolate.
• MECHANISM: Haemozoin metabolism inhibitor
• Half-life of 16 days.
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6013505/

33. Evaluated for combination with Artesunate and Artefenomel:
1. AS-FQ COMBINATION
Completed PHASE 2A: Open-Label, 4-Escalating-Dose, Randomized
Multicenter Study Evaluating the Safety and Activity of Ferroquine Plus
Artesunate, versus Amodiaquine Plus Artesunate, in African Adult Men
with Uncomplicated Plasmodium falciparum Malaria.
Result: PCR-corrected efficacy at 28 days for the treatment of
uncomplicated falciparum malaria was 99%.
2. Artefenomel-FQ COMBINATION
Currently in PHASE 2B: To Evaluate the Efficacy of a Single Dose
Regimen of Ferroquine and Artefenomel in Adults and Children With
Uncomplicated Plasmodium Falciparum Malaria (FALCI)
https://clinicaltrials.gov/ct2/show/NCT02497612
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6013505/

34. DSM265
• Novel antimalarial compound
• Against uncomplicated Plasmodium falciparum and Plasmodium
vivax malaria.
• Mechanism: Inhibit the plasmodium Dihydroorotate Dehydro-genase
enzyme(DHOD) required for pyrimidine biosynthesis.
• Current status: Completed PHASE 2A study analysing different doses
of DSM265 against uncomplicated P. falciparum and P. vivax malaria
in Iquitos, Peru.
• Primary endpoints: Proportion of patients achieving PCR-adjusted
adequate clinical and parasitological response (ACPR) by day 14 for
patients infected with P falciparum and the proportion of patients
achieving a clincal cure by day 14 for those infected with P vivax.
HTTPS://WWW.MMV.ORG/NEWSROOM/INTERVIEWS/DSM265-1
HTTPS://WWW.THELANCET.COM/JOURNALS/LANINF/ARTICLE/PIIS1473-3099(18)30309-8/FULLTEXT VOLUME 18, ISSUE 8, P874-883, AUGUST
01, 2018

35. RESULTS
 After a single dose of DSM265, P falciparum parasitaemia was
rapidly cleared within 48hrs,
 Whereas less effective clearance kinetics against P vivax
 DSM265 was well tolerated.
 No treatment-related serious adverse events or adverse events
leading to study discontinuation.
 Long duration of action provides the potential to prevent recurrence
of P falciparum after treatment with a single dose,
https://www.thelancet.com/journals/laninf/article/PIIS1473-3099(18)30309-8/fulltext
VOLUME 18, ISSUE 8, P874-883, AUGUST 01, 2018

36. FOSMIDOMYCIN
• Inhibitor of 1 deoxy 5 phosphate reducto-isomerase required for
isoprenoid synthesis in Plasmodium
• Active against uncomplicated PF, Blood schizonticidal
• Completed PHASE 2A study in 2017: Phase 2A Study to Explore the
Efficacy, Tolerability and Safety of Fosmidomycin Sodium When
Administered With Piperaquine Tetraphosphate to Adults and Older
Children With Acute Uncomplicated Plasmodium Falciparum Malaria.
• Primary endpoint : PCR-corrected cure rate on Day 28.
RESULTS
 In combination with piperaquine, highly efficacious for the treatment of
acute uncomplicated falciparum malaria in an area of intense malaria
transmission.
 Well tolerated, even in children.
https://gh.bmj.com/content/2/Suppl_2/A22.3

37. METHYLENE BLUE
• Group: Phenothiazine derivative
• Mechanism: Prevents haem polymerization by inhibiting P.falciparum
glutathione reductase.
• PF schizonticidal and gametocidal
• First described for use in malaria in 1891.
• Completed PHASE 2 study in Feb 2018: Efficacy and safety of
primaquine and methylene blue for prevention of Plasmodium
falciparum transmission in Mali: a phase 2, single-blind, randomised
controlled trial
https://www.thelancet.com/journals/laninf/article/PIIS1473-3099(18)30044-
6/fulltext#seccestitle150

38. RESULTS
 Both groups were highly efficacious for preventing P
falciparum transmission.
 Both primaquine and methylene blue were well tolerated.
 Vomiting has been associated with methylene blue
 Development of blue urine could affect compliance
https://www.thelancet.com/journals/laninf/article/PIIS1473-3099(18)30044-
6/fulltext#seccestitle150

39. AQ13
• GROUP: 4- Aminoquinolones
• Active against uncomplicated P falciparum malaria
• Recently completed PHASE 2 trial.: Investigational antimalarial, vs
artemether plus lumefantrine for the treatment of uncomplicated Plasmodium
falciparum malaria: a randomised, phase 2, non-inferiority clinical trial.
Primary endpoint was clinical cure-
1. Clearance of parasites from the blood and fever by day 7
2. Absence of recrudescent infection between the time of initial parasite
clearance and the final outpatient visit on day 42.
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5700806/

40. Secondary endpoint included adverse events seen within 28 days of
treatment:
1. Decrease in the hemoglobin concentration from days 1 to 4
2. New atrial or ventricular arrhythmias/ New 1st , 2nd or 3rd degree heart block
3. Prolongation of the QT interval
4. Decreases in visual acuity.
RESULTS
 No serious adverse events
 Asexual parasites were cleared by day 7 in both groups.
 Both groups had similar proportions cured
 AQ-13 was not inferior to artemether plus lumefantrine
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5700806/

41. MMV 390048
• Group: Aminopyridine
• Currently in PHASE 2A
• Multistage antimalarial
• Blood schizonticidal, inhibits gametogenesis and oocyte
formation
• Potential for single dose treatment and chemoprevention.
Drugs (2018) 78:861-879
https://doi.org/10.1007/s40265-018-0911-9

42. KAF156
• Group : Imidazolopiperazines
• Currently in PHASE 2B: Open-label, two-part study at five
centers in Thailand and Vietnam to assess the antimalarial
efficacy, safety, and pharmacokinetic profile of KAF156 in
adults with acute Plasmodium vivax or P. falciparum malaria
• Mechanism of action: Targets asexual and sexual blood stages
and the pre erythrocytic liver stages of malarial parasites
https://www.nejm.org/doi/full/10.1056/NEJMoa1602250

43. RESULTS
• Median parasite clearance time:
 45 hours in 10 patients with falciparum malaria
 24 hours in 10 patients with vivax malaria
 49 hours in 21 patients with falciparum malaria after treatment with the single
dose.
• Cure rate = 67%.
• Half-life was 44.1±8.9 hours.
• After treatment with KAF156:
MULTIPLE DOSING
Rate of parasite clearance
slightly slower than those
associated with
artemisinin treatment
Substantially lower than
KAE609 (fastest parasite
clearance)
More rapid than
sulfadoxine–
pyrimethamine,
atovaquone–proguanil,
quinine, or mefloquine
https://www.nejm.org/doi/full/10.1056/NEJMoa1602250

44. LUMEFANTRINE-KAF156
• Being evaluated, currently in PHASE 2B TRIAL :
Efficacy and Safety of KAF156 in Combination With
LUM-SDF in Adults and Children With
Uncomplicated Plasmodium Falciparum Malaria
• LUM-SDF (Lumefantrine Solid Dispersion
Formulation) : New formulation of lumefantrine,
that can be given once daily is being studied in this
trial .
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6013505/
https://clinicaltrials.gov/ct2/show/NCT03167242

45. SEVUPARIN
• Group: Anti adhesive polysaccharide derived from Heparin with eliminated anti
thrombin binding site.
• Mechanism : inhibits rosette formation and cyto-adherence of RBCs
• Completed PHASE 1 study last year: Inhibition of merozoite invasion and
transient de-sequestration by sevuparin in humans with P. falciparum malaria
Results
 safe and well tolerated.
 No bleeding adverse events
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5731734/
Published online 2017 Dec 15. doi:10.1371/journal.pone.0188754

46. KAE609(Cipargamin)
• Group: Spiroindolones
• Mechanism: PfATP4 Na-H pump inhibitor
• Active against Uncomplicated Plasmodium Falciparum Malaria.
• Current status: Undergoing PHASE 2, Multi-center, Randomized,
Open-label, Dose-escalation study to Determine Safety of Single
(QD) and Multiple (3 QD) Doses of KAE609, Given to Adults With
Uncomplicated Plasmodium Falciparum Malaria.
• Key features: First new class of antimalarial in 20 years; very
rapid killing of parasites
https://www.mmv.org/node/11219/overlay
https://clinicaltrials.gov/ct2/show/NCT03334747

47. SUMMARY OF UPCOMING DRUGS
DRUG/MOLECULE MECHANISM/GROUP STATUS
KAE609 PfATP4 inhibitor In PHASE 2
SEVUPARIN Heparin derivative Completed PHASE 1
-KAF156 Imidazolopiperazines In PHASE 2B
MMV 390048 Aminopyridine In PHASE 2A
AQ13 4- Aminoquinolones Completed PHASE 2
METHYLENE BLUE Phenothiazine derivative Completed PHASE 2B
FOSMIDOMYCIN Inhibit isoprenoid
synthesis
Completed PHASE 2A
DSM265 Inhibit DHOD Completed PHASE 2A
FERROQUINE DHFR inhibitor Completed PHASE 1

48. VACCINES IN MALARIA
RTS,S/AS01(Mosquirix™) Vaccine : PHASE IV
• Subunit malaria vaccine against P.falciparum.
• Completed phase III trials in 2015.
• In the phase III multicenter efficacy trial that enrolled 15,459 children in 11
centers across seven African countries, vaccine is estimated to have prevented
829 clinical malaria episodes per 1000 children over 18 months of study
follow-up.
• RTS,S is designed to prevent the malaria parasite from infecting, maturing,
and multiplying in the liver: PRE ERYTHROCYTIC VACCINE
• Recommended for use in young children living in malaria-endemic regions
of Sub Saharan Africa.
https://www.nature.com/articles/s41541-017-0035-3
https://www.malariavaccine.org/sites/www.malariavaccine.org/files/content/page/files/RTSS%20FAQs_F
INAL.pdf

49. • WHO recommends pilot implementation use of 4-dose schedule, covering
moderate-to-high transmission settings.
• 3 doses administered to children (between 5 and 9 months of age)
1 month apart, followed by a fourth dose 15–18 months later.
• Administered 0.25 ml IM anterolateral aspect of thigh/ deltoid.
• Safety profile of this vaccine is acceptable, apart from a higher risk for
febrile convulsions in the older age group within 7 days after a dose
(mostly the third dose).
• Future studies will evaluate RTS,S integration into the EPI (expanded
program of immunization) schedule.
https://www.malariavaccine.org/sites/www.malariavaccine.org/files/content/page/files/RTSS%
20FAQs_FINAL.pdf

50. Parasite stage Vaccine classification Current status
PRE-ERYTHROCYTIC STAGE
PfSPZ vaccine Whole organism Phase II
GAP vaccines Whole organism Phase I
RTS,S Subunit Phase IV
CVac Whole organism Phase I
BLOOD STAGE
Chemically attenuated parasites Whole organism Preclinical
AMA1-RON2 Subunit Preclinical
PfRH5 Subunit Phase I
MOSQUITO STAGE
Pfs25 Subunit Phase I
Pfs230 Subunit Phase 1
Pfs47 Subunit Preclinical
https://www.nature.com/articles/s41541-017-0035-3/tables/1

51. DRUGS IN PRE CLINICAL PHASE
NAME TYPE/TARGET ACTIVITY
SPECTRUM
MMV 253 ATPase inhibitor Blood schizonticide
AN 13762 Benzoxaborole Blood schizonticide
JPC 3210 Aminomethylphenol Blood schizonticide
UCT 943 PfPIK inhibitor Multi stage, falciparum
and vivax
NPC 1161B 8- aminoquinoline Multi stage
SC83288 Amicarbalide derivative Blood schizonticide
Drugs (2018) 78:861-879
https://doi.org/10.1007/s40265-018-0911-9

52. CHALLENGES TO ELIMINATION
http://apps.who.int/iris/bitstream/handle/10665/272724/WHO-CDS-GMP-2018.10-eng.pdf?ua=1

53. http://apps.who.int/iris/bitstream/handle/10665/272724/WHO-CDS-GMP-2018.10-eng.pdf?ua=1

54. CONCLUSION

55. Thank You!