LHF535 is a first-in-class antiviral in development for Lassa fever and other arenaviruses. LHF535 is a once daily oral therapeutic. Kineta completed a Phase 1 single ascending dose (SAD) and multiple ascending dose (MAD) study in healthy volunteers establishing the safety, tolerability and pharmacokinetics profile of LHF535. In preclinical models, complete survival has been demonstrated in Lassa infection. Kineta is currently planning the Phase 2/3 clinical study in Lassa infected patients in Africa in collaboration with the Wellcome Trust and International Severe Acute Respiratory and Emerging Infection Consortium (ISARIC).
LHF-535 is a potent small molecule inhibitor of Lassa and other arenavirus entry that targets virally-encoded envelope glycoprotein (GP) and blocks GP-mediated fusion. Sensitivity maps to a conserved region in and around the predicted transmembrane domain of the GP2 subunit. The viral entry step is an attractive target for the development of antivirals because it is an essential component of the viral life cycle.
The recent COVID pandemic is a perilous example of the potential for emerging viral outbreaks. Arenaviruses including Lassa fever and other arenaviruses like Junin and Machupo pose a global health threat in developing countries in Africa and South America where the infections are endemic. Additionally, there is growing concern that viruses such as Lassa fever can be a biodefense threat to developed countries.
Africa: Lassa hemorrhagic fever is an acute viral illness that is endemic in West Africa. Lassa fever causes 100,000-300,000 infections annually although one estimate of the true incidence in just Guinea, Sierra Leone, and Nigeria is closer to 3,000,000.1,2 Lassa fever is responsible for ~5000 deaths annually in West Africa with death rates particularly high for women in the third trimester of pregnancy.1 Fetal loss occurs in nearly all infected pregnant women.3 There are currently no therapeutics or vaccines that are indicated to treat Lassa fever.
Biodefense: Lassa fever is listed as a Priority A pathogen by the CDC and NIAID. Consequently, government agencies like BARDA, DTRA are focused on funding development of medical countermeasures for Lassa fever. Additionally, there is a potential commercial opportunity for stockpile purchasing from the federal government through these agencies.
Priority Review Voucher (PRV): Lassa fever was added to the FDA Priority Review Voucher program in August 2018. This transferrable voucher can be used to reduce FDA review time of another drug from ten months to six months to accelerate regulatory approval and market launch. Recent sales of PRV’s have ranged from $100-$120M over the past two years.4
Sean Amberg, PhD, Director Biodefense Initiatives at Kineta; International Conference on Antiviral Research (ICAR) Virtual Conference 2021; Clinical Evaluation of Lassa Fever Antiviral LHF-535 in a 14-day Repeat Dose Study in Healthy Volunteers; March 24, 2021
Discovery and optimization of potent broad-spectrum arenavirus inhibitors derived from benzimidazole and related heterocycles. Bioorg Med Chem Lett. 2013 Feb 1;23(3):750-6. PMID: 23265900.
Discovery and optimization of potent broad-spectrum arenavirus inhibitors derived from benzimidazole. Bioorg Med Chem Lett. 2013 Feb 1;23(3):744-9. PMID:23265895.
1. McCormick JB. 1987. Epidemiology and control of Lassa fever. Curr. Top. Microbiol. Immunol. 134:69-78
2. Richmond JK, Baglole DJ. 2003. Lassa fever: epidemiology, clinical features, and social consequences. BMJ (Clinical research ed.) 327:1271-1275
3. Price ME, Fisher-Hoch SP, Craven RB, McCormick JB. 1988. A prospective study of maternal and fetal outcome in acute Lassa fever infection during pregnancy. BMJ (Clinical research ed.) 297:584-587.