Approval Probability
TA Base Rate
Adjusted LOA
ML Risk
Also known as KAF, Ganaplacide
KAF156 · 7 trials · 3 indications
PCR-corrected ACPR, defined as the absence of parasitemia(PS), was evaluated on Day29. Microscopic species identification was confirmed and determined by PCR genotyping methods to establish malaria recrudescence/reinfection.A participant was considered as PCR corrected ACPR at Day29 if the participant did not meet any of the criteria of early treatment failure (up to Day4), late clinical failure(Day5 to Day29) or late parasitological failure(Day8 to Day29), and had absence of PS on Day29 irrespective of axillary temperature unless the presence of PS after 7days(Day8 or later) was due to reinfection based on PCR genotyping.A presence of PS after 7days of treatment initiation was considered as a reinfection only if the PS was clear before Day8 and none of the parasite strain(s) detected on Day8 or later match with the parasite strain at baseline based on PCR genotyping.Given the age-independent symptoms of acute malaria, and to increase statistical power,the cohorts 1 and 2 were pooled.
PCR-corrected ACPR defined as the absence of parasitaemia was evaluated at Day 29 (i.e., 28 days post first dose) based on the short half-life of the study drugs. Microscopic species identification was confirmed and determined by PCR genotyping methods to establish malaria recrudescence/reinfection. A participant was considered as PCR-corrected ACPR at Day 29 if the participant did not meet any of the criteria of early treatment failure, late clinical failure or late parasitological failure and was absence of parasitaemia on Day 29 irrespective of axillary temperature unless the presence of parasitaemia after 7 days was due to reinfection based on PCR. A presence of parasitaemia after 7 days of treatment initiation was considered as a reinfection only if the parasitaemia was clear before Day 8 and none of the parasite strain(s) detected on Day 8 or later matched with the parasite strain at baseline based on PCR.
Pharmacokinetic (PK) parameters were calculated based on KAF156 blood concentrations determined by a validated liquid chromatography and tandem mass spectrometry (LC-MS/MS) method. AUC0-24h was determined using non-compartmental methods.
Parasite clearance was determined by assessing the parasite count in blood, using thin film, thick film and blood density assessments.
28-day cure rate was defined as the percentage of participants with blood parasite count of zero after 28 days of treatment.
Venous whole blood samples will be collected for activity-based pharmacokinetics characterization. Cmax will be listed and summarized using descriptive statistics.
Venous whole blood samples will be collected for activity-based pharmacokinetics characterization. AUClast will be listed and summarized using descriptive statistics.
Venous whole blood samples will be collected for activity-based pharmacokinetics characterization. AUCinf will be listed and summarized using descriptive statistics.
Venous whole blood samples will be collected for activity-based pharmacokinetics characterization. AUC\^0-24 will be listed and summarized using descriptive statistics.
Venous whole blood samples will be collected for activity-based pharmacokinetics characterization. Tmax will be listed and summarized using descriptive statistics.
Venous whole blood samples will be collected for activity-based pharmacokinetics characterization. CL/F will be listed and summarized using descriptive statistics
Venous whole blood samples will be collected for activity-based pharmacokinetics characterization. Vz/F will be listed and summarized using descriptive statistics.
Venous whole blood samples will be collected for activity-based pharmacokinetics characterization. T\^1/2 will be listed and summarized using descriptive statistics.
Venous whole blood samples will be collected for activity-based pharmacokinetics characterization. Cmax will be listed and summarized using descriptive statistics.
Venous whole blood samples will be collected for activity-based pharmacokinetics characterization. AUClast will be listed and summarized using descriptive statistics.
Venous whole blood samples will be collected for activity-based pharmacokinetics characterization. AUCinf will be listed and summarized using descriptive statistics.
Venous whole blood samples will be collected for activity-based pharmacokinetics characterization. Tmax will be listed and summarized using descriptive statistics.
Venous whole blood samples will be collected for activity-based pharmacokinetics characterization. CL/F will be listed and summarized using descriptive statistics.
Venous whole blood samples will be collected for activity-based pharmacokinetics characterization. Vz/F will be listed and summarized using descriptive statistics.
Venous whole blood samples will be collected for activity-based pharmacokinetics characterization. T\^1/2 will be listed and summarized using descriptive statistics.
Venous whole blood samples will be collected for activity-based pharmacokinetics characterization. Cmax will be listed and summarized using descriptive statistics.
Venous whole blood samples will be collected for activity-based pharmacokinetics characterization. AUClast will be listed and summarized using descriptive statistics.
Venous whole blood samples will be collected for activity-based pharmacokinetics characterization. AUCinf will be listed and summarized using descriptive statistics.
Venous whole blood samples will be collected for activity-based pharmacokinetics characterization. Tmax will be listed and summarized using descriptive statistics.
Venous whole blood samples will be collected for activity-based pharmacokinetics characterization. CL/F will be listed and summarized using descriptive statistics.
Venous whole blood samples will be collected for activity-based pharmacokinetics characterization. Vz/F will be listed and summarized using descriptive statistics.
Venous whole blood samples will be collected for activity-based pharmacokinetics characterization. T\^1/2 will be listed and summarized using descriptive statistics.
The number of subjects that became infected with malaria at each dose
The exposure-response relationship of KAF156 was explored in a PK/PD model to relate drug exposure to prophylactic efficacy using standard statistical methods such as CART or non-linear regression. Summary statistics were also provided for the malaria incidence rate by cohort and treatment arm
| Arm | Type | Description |
|---|---|---|
| Run-in - KAF156 and LUM-SDF QD for 2 days in fasted condition | EXPERIMENTAL | KAF156 and LUM-SDF QD (once daily) for 2 days in fasted condition |
| Run-in - KAF156 and LUM-SDF QD for 2 days in fed condition | EXPERIMENTAL | KAF156 and LUM-SDF QD (once daily) for 2 days in fed condition |
| Cohort 1/2 - KAF156 and LUM-SDF QD (once daily) in 3-day dose regimen | EXPERIMENTAL | KAF156 and LUM-SDF QD (once daily) in 3-day dose regimen. It was administered with a light meal and the full dose was adjusted based on patient´s body weight. |
| Cohort 1/2 - Coartem® BID (twice a day) for 3 days | ACTIVE_COMPARATOR | Coartem® BID twice a day for 3 days (It was administered with a light meal and doses were based on patient's body weight as per product label). |
| Part A - Cohort 1: KAF 400 mg and LUM 960 mg QD for 1 day | EXPERIMENTAL | Participants received a single oral dose of KAF156 400 mg and LUM-SDF 960 mg |
| Part A - Cohort 2: KAF 800 mg and LUM 960 mg QD for 1 day | EXPERIMENTAL | Participants received a single oral dose of KAF156 800 mg and LUM-SDF 960 mg |
| Part A - Cohort 3: KAF 400 mg and LUM 960 mg QD for 2 days | EXPERIMENTAL | Participants received KAF156 400 mg and LUM-SDF 960 mg once daily via oral administration for 2 days |
| Part A - Cohort 4: KAF 200 mg and LUM 480 mg QD for 3 days | EXPERIMENTAL | Participants received KAF156 200 mg and LUM-SDF 480 mg once daily via oral administration for 3 days |
| Part A - Cohort 5: KAF 400 mg and LUM 480 mg QD for 3 days | EXPERIMENTAL | Participants received KAF156 400 mg and LUM-SDF 480 mg once daily via oral administration for 3 days |
| Part A - Cohort 6: KAF 400 mg and LUM 960 mg QD for 3 days | EXPERIMENTAL | Participants received KAF156 400 mg and LUM-SDF 960 mg once daily via oral administration for 3 days |
| Part A - Cohort 7: Coartem | ACTIVE_COMPARATOR | Participants received Coartem twice daily via oral administration for 3 days |
| PK Run-in Cohort: KAF 200 mg and LUM 960 mg QD for 1 day | EXPERIMENTAL | Participants received a single oral dose of KAF156 200 mg and LUM-SDF 960 mg |
| Part B - Cohort 1: KAF 400 mg and LUM 960 mg QD for 1 day | EXPERIMENTAL | Participants received a single oral dose of KAF156 400 mg and LUM-SDF 960 mg |
| Part B - Cohort 2: KAF 400 mg and LUM 960 mg QD for 2 days | EXPERIMENTAL | Participants received KAF156 400 mg and LUM-SDF 960 mg once daily via oral administration for 2 days |
| Part B - Cohort 3: KAF 400 mg and LUM 960 mg QD for 3 days | EXPERIMENTAL | Participants received KAF156 400 mg and LUM-SDF 960 mg once daily via oral administration for 3 days |
| Part B - Cohort 4: Coartem | ACTIVE_COMPARATOR | Participants received Coartem twice daily via oral administration for 3 days |
| Part 1 - Cohort 1: P. vivax: KAF156 400mg QD | EXPERIMENTAL | Participants with Plasmodium vivax malaria received KAF156 400 mg once a day for three days. |
| Part 1 - Cohort 2: P. falciparum: KAF156 400mg QD | EXPERIMENTAL | Participants with Plasmodium falciparum malaria received KAF156 400mg once a day for three days. |
| Part 2 - Cohort 3: P. falciparum: KAF156 800mg single dose | EXPERIMENTAL | Participants with Plasmodium falciparum malaria received a single dose of KAF156 800mg. |
| Period 1: KAF156 + LUM566 / Period 2: KAF156 + LUM566 + Efavirenz | EXPERIMENTAL | Participants enrolled will receive a single oral dose of ganaplacide and lumefantrine combination on Day 1 of Period 1. In Period 2, participants will receive an oral dose of efavirenz q.d. in the evening on Days 1 through 24 and a single dose of ganaplacide and lumefantrine combination on the morning of Day 11. |
| Cohort 1 | EXPERIMENTAL | Each participant will receive a single oral dose of the 4-probe substrate cocktail consisting of midazolam, repaglinide, dextromethorphan and metformin in the morning of Day 1 of Period 1. In Period 2, participants will receive ganaplacide and lumefantrine combination orally once daily (q.d.) in the morning on Days 1 through 3, with a single oral dose of the 4-probe substrate cocktail co-administered on Day 3. |
| Cohort 2 | EXPERIMENTAL | Each participant will receive a single oral dose of the 2 probe substrate cocktail consisting of rosuvastatin and dolutegravir in the morning on Day 1 of Period 1. In Period 2, participants will receive ganaplacide and lumefantrine combination orally q.d. in the morning on Days 1 through 3, with a single oral dose of the 2 probe substrate cocktail co-administered on Day 3. |
| Group 1 | EXPERIMENTAL | Each participant will receive a single oral dose of ganaplacide and lumefantrine combination on Day 1 of Period 1. In Period 2, participants will receive itraconazole q.d. on Days 1 to 18 and a single dose of ganaplacide and lumefantrine combination on Day 5, approximately 2 hours after the itraconazole dose |
| KAF156 800 mg pre-challenge | EXPERIMENTAL | Single dose 800 mg KAF156 oral administration in healthy subjects, prior to exposure to P. falciparum sporozoite-infected mosquitos |
| Placebo 800 mg pre-challenge | PLACEBO_COMPARATOR | Single dose 800 mg placebo oral administration in healthy subjects, prior to exposure to P. falciiparum sporozoite-infected mosquitos |
| KAF156 800 mg post-challenge | EXPERIMENTAL | Single dose 800 mg KAF156 oral administration in heatlhy subjects, after exposure to P. falciparum sporozoite-infected mosquitos |
| Placebo 800 mg post-challenge | PLACEBO_COMPARATOR | Single dose 800 mg placebo oral administration in heatlhy subjects, after exposure to P. falciparum sporozoite-infected mosquitos |
| KAF156 300 mg post-challenge | EXPERIMENTAL | Single dose 300 mg KAF156 oral administration in heatlhy subjects, after exposure to P. falciparum sporozoite-infected mosquitos |
| Placebo 300 mg post-challenge | PLACEBO_COMPARATOR | Single dose 300 mg placebo oral administration in heatlhy subjects, after exposure to P. falciparum sporozoite-infected mosquitos |
| KAF156 100 mg post-challenge | EXPERIMENTAL | Single dose 100 mg KAF156 oral administration in heatlhy subjects, after exposure to P. falciparum sporozoite-infected mosquitos |
| Placebo 100 mg post-challenge | PLACEBO_COMPARATOR | Single dose 100 mg placebo oral administration in heatlhy subjects, after exposure to P. falciparum sporozoite-infected mosquitos |
| KAF156 20 mg post-challenge | EXPERIMENTAL | Single dose 20 mg KAF156 oral administration in heatlhy subjects, after exposure to P. falciparum sporozoite-infected mosquitos |
| Placebo 20 mg post-challenge | PLACEBO_COMPARATOR | Single dose 20 mg Placebo oral administration in heatlhy subjects, after exposure to P. falciparum sporozoite-infected mosquitos |
| KAF156 50 mg post-challenge | EXPERIMENTAL | Single dose 50 mg KAF156 oral administration in heatlhy subjects, after exposure to P. falciparum sporozoite-infected mosquitos |
| Placebo 50 mg post-challenge | PLACEBO_COMPARATOR | Single dose 50 mg Placebo oral administration in heatlhy subjects, after exposure to P. falciparum sporozoite-infected mosquitos |
| Name | Type | Description |
|---|---|---|
| KAF156 | DRUG | Provided as 100 mg tablets, to be taken QD 2 or 3 Days in combination with LUM-SDF, dose is based on body weight |
| LUM-SDF | DRUG | Provided as 120 mg or 240 mg powder in sachet, to be taken QD 2 or 3 Days in combination with KAF156, dose is based on body weight |
| Coartem | DRUG | Coartem® (Artemether/Lumefantrine dispersible tablets 20/120mg in blister pack) (for Cohorts 1 and 2), dose is based on body weight |
| Lumefantrine Solid Dispersion Formulation | DRUG | LUM-SDF comes in 240 mg or 480 mg sachets for oral administration. LUM-SDF was administered in combination with KAF156 once daily (QD) for 1, 2 or 3 days at 480 mg or 960 mg doses. |
| Ganaplacide | DRUG | Period 1: 400 mg (4 x 100 mg tablets) for oral administration Period 2: 400 mg (4 x 100 mg tablets) for oral administration |
| Lumefantrine | COMBINATION_PRODUCT | Period 1: 480 mg (2 x 240 mg sachets) for oral administration Period 2: 480 mg (2 x 240 mg sachets) for oral administration |
| Efavirenz | DRUG | Period 2: 600 mg (1 x 600 mg tablet) for oral administration once daily (q.d.) |
| Midazolam | DRUG | Midazolam 2 mg (1 mL of 2 mg/mL oral solution) administered as a single dose in a 4-probe cocktail in the morning in Period 1 on Day 1 and in Period 2 on Day 3. |
| Repaglinide | DRUG | Repaglinide 0.5 mg (1 x 0.5 mg tablet) administered as a single dose in a 4-probe cocktail in the morning in Period 1 on Day 1 and in Period 2 on Day 3. |
| Dextromethorphan | DRUG | Dextromethorphan 15 mg (10 mL of 7.5 mg/5 mL syrup) administered as a single dose in a 4-probe cocktail in the morning in Period 1 on Day 1 and in Period 2 on Day 3. |
| Metformin | DRUG | Metformin 500 mg (1 x 500 mg tablet) administered as a single dose in a 4-probe cocktail in the morning in Period 1 on Day 1 and in Period 2 on Day 3. |
| Rosuvastatin | DRUG | Rosuvastatin 5 mg (1 x 5 mg tablet) administered as a single dose in a 2-probe cocktail in the morning in Period 1 on Day 1 and in Period 2 on Day 3. |
| Dolutegravir | DRUG | Dolutegravir 50 mg (1 x 50 mg tablet) administered as a single dose in a 2-probe cocktail in the morning in Period 1 on Day 1 and in Period 2 on Day 3. |
| Itraconazole | DRUG | 200 mg (20 mL of 10 mg/mL oral solution) q.d. on Days 1 to 18 |
| Placebo | DRUG | 100 mg tablet, 20 mg tablet, 50 mg tablet |
Inclusion Criteria: 1. In run-in cohort: Male and female patients 12 to \< 18 years of age, with a body weight * 35.0 kg In Cohort 1: Male and female patients 2 to \< 12 years of age, with a body weight ≥ 10.0 kg In Cohort 2: Male and female patients 6 months to \< 2 years of age, with a body w...
KAF156 is an investigational small molecule being developed for the treatment of acute uncomplicated Plasmodium falciparum malaria and uncomplicated Plasmodium falciparum malaria. It is also being studied for malaria caused by Plasmodium vivax. KAF156 is in Phase 2 clinical development and is not yet approved by regulatory authorities.
KAF156 is being developed by Novartis AG, a multinational pharmaceutical company traded on the New York Stock Exchange under the ticker symbol NVS. Novartis is conducting clinical trials to evaluate the safety and efficacy of KAF156 in adult and pediatric patients with uncomplicated malaria.
KAF156 is in Phase 2 clinical development. Multiple Phase 2 trials have been completed, including studies in adults and children with uncomplicated Plasmodium falciparum malaria. KAF156 is an investigational drug and has not received FDA approval for any indication.
KAF156 has been studied in several completed clinical trials. NCT01753323 evaluated KAF156 in adults with acute uncomplicated malaria in Thailand and Vietnam. NCT03167242 and NCT04546633 tested KAF156 in combination with lumefantrine solid dispersion formulation in adults and children across multiple countries in Africa and Asia.
KAF156 is a distinct investigational compound developed by Novartis. It is being studied alone and in combination with lumefantrine solid dispersion formulation (LUM-SDF) for the treatment of uncomplicated Plasmodium falciparum malaria. No alternative names for KAF156 have been reported in clinical trial records.
KAF156 is a small molecule antimalarial drug. Its specific molecular target has not been disclosed in the available clinical trial information. The drug is being evaluated for its efficacy in clearing Plasmodium falciparum and Plasmodium vivax infections in patients with acute uncomplicated malaria.