Table 3.
Clinical prioritisation of therapeutic candidates against NiV and HeV diseases
| Efficacy | Safety | Feasibility | Clinical prioritisation and proposed further evaluation | |
|---|---|---|---|---|
| Monoclonal antibodies (see also table 1) | ||||
| m102.4 (anti-HeV-G) | Protected monkeys from death and pathology when administered as two doses 48 h apart, starting on day 1 or 3 after NiV-B27 (n=6) challenge or on day 1, 3, or 5 after NiV-M28 (n=12) and HeV29 (n=12) challenge. Also protected ferrets from death when administered 10 h after NiV-M30 (n=3) challenge |
No serious adverse events, similar rate of mild treatment emergent adverse events between treatment and placebo groups, and no anti-m102.4 antibodies in phase 1 RCT in healthy adults (n=30 treated)26 | High cost of goods,20 low drug supply, parenteral route only | High priority. Phase 2a postexposure prophylaxis or early treatment RCT, or both, during NiV or HeV disease outbreak. Shorter treatment window for NiV-B than for NiV-M. Dose optimisation for cost recommended. |
| 1F5 (anti-NiV-F) | Protected monkeys from death and alleviated symptoms and viraemia when administered at doses of 25 mg/kg (n=6) and 10 mg/kg (n=3) on day 5 after NiV-B challenge, as compared with m102.4, which provided only partial protection at a dose of 25 mg/kg (1 of 6)32 | No human studies to date. No safety data reported in animal studies |
High cost of goods,20 low drug supply, parenteral route only | High priority. Phase 1 first-in-human RCT for safety and pharmacokinetics. Longer treatment window than that for m102.4 in animals with NiV-B. Dose optimisation for cost recommended. |
| h5B.3 (anti-NiV-F) | Protected ferrets from death but not minor clinical signs when administered at a dose of 20 mg/kg in two doses 48 h apart, starting on day 1 or 3 after NiV-M (n=6) or HeV (n=3) challenge33 | No human studies to date. No safety data reported in animal studies. | High cost of goods,20 low drug supply, parenteral route only | Intermediate priority. Monkey studies with NiV-B challenge. Dose optimisation for cost necessary |
| NiV41-6 (anti-NiV-RBP) | Protected hamsters from death when administered at a dose of 10 mg/kg (n=6) 24 h before NiV-M challenge34 | |||
| HENV-26 (anti-HeV RBP) | Protected ferrets (n=5) from death, symptoms, and viraemia when administered at a dose of 15 mg/kg on days 3 and 5 after NiV-B challenge36 | |||
| HENV-103 plus HENV-117 (anti-HeV RBP) | HENV-103 plus HENV-117 cocktail (5 mg/kg each) protected hamsters (n=5) from death when administered a day after NiV-B challenge35 | |||
| Small molecules (see also table 2) | ||||
| Remdesivir (nucleoside analogue) | Protected monkeys (n=4) from death at a dose of 10 mg/kg when administered from day 1 after NiV-B challenge for 12 days,50 but provided only partial protection when administered from day 3 after challenge, with fewer monkeys protected at a dose of 3 mg/kg (2 of 6) than that of 10 mg/kg (4 of 6);49 in-vitro EC50 values=0·029–0·066 μM61 | Sinus bradycardia and hepatotoxicity observed in humans65 | Approved globally for COVID-19 Less affordable,20 parenteral route with oral formulation in development62 |
High priority. Phase 2a postexposure prophylaxis or early treatment RCT, or both, during NiV or HeV outbreak. Short treatment window for NiV-B. Dose optimisation for efficacy recommended. |
| Favipiravir (nucleoside analogue) | Fully protected hamsters (n=10) from death and alleviated symptoms and pathology when administered daily from time of NiV-M challenge; in-vitro EC50 values=11–44 μM52 | Lethal toxicity in dogs and monkeys (>1 g/kg),66 teratogenicity across four animal species,66 transient hyperuricaemia in humans66,67 | Approved in Japan for novel influenza.66 Affordable,20 oral route, but non-linear pharmacokinetics complicates dosing.68 |
Intermediate priority. Monkey study with NiV-B challenge. Dose optimisation for efficacy necessary. |
| Ribavirin (nucleoside analogue) | Delayed but did not prevent death when administered before or within 12 h to monkeys (n=6) after HeV45 challenge and to hamsters (n=17) after NiV-M46,47 challenge; in-vitro IC50 values=4·2–5·0 μM47 | Dose-dependent toxicity in hamsters (>100 mg/kg)47 and humans41 restricts safety and tolerability | Approved globally for chronic hepatitis C. Affordable20 but equivocal risk-to-benefit ratio. |
Intermediate priority. Monkey study with NiV-B challenge. Dose optimisation for safety and efficacy crucial. Time-to-event outcome measure when in phase 2a RCT. |
| Chloroquine (4-amino-quinoline) | Did not protect ferrets48 (n=6) and hamsters47 (n=19) from death when administered as monotherapy before or within 12 h after NiV-M or HeV challenge | Dose-dependent lethal toxicity in hamsters (>100 mg/kg)47 and humans (>3 μM plasma)69 | Approved globally for malaria. Affordable20 but unfavourable risk-to-benefit ratio. |
Low priority. Should not be used for the prophylaxis or treatment of NiV or HeV infection. |
EC50=50% maximal effective concentration. HeV=Hendra virus. IC50=50% maximal inhibitory concentration. NiV-B=Nipah virus Bangladesh. NiV-M=Nipah virus Malaysia. RBP=receptor binding protein. RCT=randomised controlled trial.
High priority indicates that ample evidence exists for efficacy and safety for phase 2a trials. Intermediate priority indicates that further evidence is required for efficacy or potential major limitations in safety or feasibility, or both. Low priority indicates that no evidence exists for efficacy and major limitations in safety or feasibility, or both.