LHF535

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).

Target

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.

Market

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.Fetal loss occurs in nearly all infected pregnant women. 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

Partnerships

Kineta is receiving funding from the Wellcome Trust and the National Institutes of Health to advance the clinical development of LHF-535 in patients with Lassa fever and to evaluate its activity against other arenaviruses.

Publications

Kineta LHF-535 Poster Presentation at ICAR Virtual Conference 2021

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

Burgeson JR, Gharaibeh DN, Moore AL, Larson RA, Amberg SM, Bolken TC, Hruby DE, Dai D. Lead optimization of an acylhydrazone scaffold possessing antiviral activity against Lassa virus. Bioorg Med Chem Lett. 2013 Nov 1;23(21):5840-3. PMID: 24064500PMCID: PMC3836667.

Burgeson JR, Moore AL, Gharaibeh DN, Larson RA, Cerruti NR, Amberg SM, Hruby DE, Dai D. 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.

Dai D, Burgeson JR, Gharaibeh DN, Moore AL, Larson RA, Cerruti NR, Amberg SM, Bolken TC, Hruby DE. 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.

Cashman KA, Smith MA, Twenhafel NA, Larson RA, Jones KF, Allen RD 3rd, Dai D, Chinsangaram J, Bolken TC, Hruby DE, Amberg SM, Hensley LE, Guttieri MC. Evaluation of Lassa antiviral compound ST-193 in a guinea pig model. Antiviral Res. 2011 Apr;90(1):70-9. PMID: 21371508PMCID: PMC3319460.

Thomas CJ, Casquilho-Gray HE, York J, DeCamp DL, Dai D, Petrilli EB, Boger DL, Slayden RA, Amberg SM, Sprang SR, Nunberg JH. A specific interaction of small molecule entry inhibitors with the envelope glycoprotein complex of the Junín hemorrhagic fever arenavirus. J Biol Chem. 2011 Feb 25;286(8):6192-200. PMID: 21159779PMCID: PMC3057843.

York J, Dai D, Amberg SM, Nunberg JH. pH-induced activation of arenavirus membrane fusion is antagonized by small-molecule inhibitors. J Virol. 2008 Nov;82(21):10932-9. PMID: 18768973PMCID: PMC2573205.

Larson RA, Dai D, Hosack VT, Tan Y, Bolken TC, Hruby DE, Amberg SM. Identification of a broad-spectrum arenavirus entry inhibitor. J Virol. 2008 Nov;82(21):10768-75. PMID: 18715909PMCID: PMC2573164.

References:
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.
4. www.priorityreviewvoucher.org