DRUG DISCOVERY RATIONALE
The collective global burden of tuberculosis, malaria and schistosomiasis accounts for approximately 460 million infections and nearly two million deaths on an annual basis. However, the impact of these neglected tropical disease (NTDs), and others, cannot be simply measured with these metrics. Importantly, NTDs disproportionately affect low-resource countries and can inflict socioeconomic inequalities within endemic regions. Interventions, ranging from public health education, vector control strategies (when applicable), therapeutics and vaccines, are all critical to the control, elimination and eventual eradication of NTDs. Therapeutics tend to favor small molecules because they can be administered orally, stably stored at ambient conditions for years, and have a relatively low cost of goods. These criteria are essential for the successful development, deployment, and sustained use within endemic regions. Of course, the continual emergence of drug-resistant pathogens underscores the importance of maintaining a robust pipeline of new medicines. Our team is focused on the identification and preclinical development of novel, small-molecule interventions that can contribute to the global drug discovery pipeline to combat the ramifications of endemic NTDs.
MALARIA
Despite excellent efforts from the Medicines for Malaria Venture (MMV) and the malaria drug discovery community, additional strategies and medicines are still needed to further reduce the malaria prevalence throughout Africa, Southeast Asia and South America. The Calibr team is taking multiple approaches to contribute to the needed armamentarium of interventions:
Inhibitors of novel Plasmodium drug targets. In collaboration with the Malaria Drug Accelerator (MalDA), a Gates Foundation-funded consortium of malaria researchers, Calibr is a contributing consortium member committed to translating validated drug targets into early drug discovery.
Long-acting injectables, a new strategy for malaria prevention in low-endemic regions with seasonal transmission. Prodrug or salts of approved antimalarials are formulated for parenteral administration to overcome the limitations of repeated oral administration and to extend efficacious exposure from a single injection for >1 month (and ideally 3 months). A prodrug of atovaquone, which was developed by the Calibr malaria team is now in a Phase 1 study sponsored by MMV.
Liver-stage inhibitors for malaria prevention. Development of small-molecule inhibitors to eliminate parasite development within the liver before progression into the symptomatic blood stages.
Endectosides, a transmission-blocking strategy. Targeting the development of oral, systemic mosquitocidal compounds that will subsequently kill mosquitoes after a blood meal to help reduce vector-to-human transmission.
Inhibitors of novel Plasmodium drug targets. In collaboration with the Malaria Drug Accelerator (MalDA), a Gates Foundation-funded consortium of malaria researchers, Calibr is a contributing consortium member committed to translating validated drug targets into early drug discovery.
Long-acting injectables, a new strategy for malaria prevention in low-endemic regions with seasonal transmission. Prodrug or salts of approved antimalarials are formulated for parenteral administration to overcome the limitations of repeated oral administration and to extend efficacious exposure from a single injection for >1 month (and ideally 3 months). A prodrug of atovaquone, which was developed by the Calibr malaria team is now in a Phase 1 study sponsored by MMV.
Liver-stage inhibitors for malaria prevention. Development of small-molecule inhibitors to eliminate parasite development within the liver before progression into the symptomatic blood stages.
Endectosides, a transmission-blocking strategy. Targeting the development of oral, systemic mosquitocidal compounds that will subsequently kill mosquitoes after a blood meal to help reduce vector-to-human transmission.
TUBERCULOSIS
Much like the malaria drug discovery program, Calibr participates in the Tuberculosis Drug Accelerator (TBDA), which is also supported by the Gates Foundation. The primary goal of the TBDA is to support development of new frontline drugs that will decrease treatment to three months or less. This expansive consortium involves numerous key academic and pharma partners to drive drug development against high-value drug targets. In collaboration with many TBDA partners, Calibr is taking the following strategies to develop novel treatments:
Innovative chemistry. Scripps Research is renowned for its world-class chemistry, which creates a unique opportunity for the Calibr infectious disease team to apply these approaches to drug develop for differentiated medicines with the potential to have superior attributes compared to traditional medicinal chemistry.
Targeting cholesterol catabolism. In addition, the Calibr TB team, in collaboration with Gates MRI, has developed a promising clinical candidate (TBD11) with the potential to sterilize infected mice when administered in combination with bedaquiline, pretomanid and linezolid, a recently approved combination therapy.
Innovative chemistry. Scripps Research is renowned for its world-class chemistry, which creates a unique opportunity for the Calibr infectious disease team to apply these approaches to drug develop for differentiated medicines with the potential to have superior attributes compared to traditional medicinal chemistry.
Targeting cholesterol catabolism. In addition, the Calibr TB team, in collaboration with Gates MRI, has developed a promising clinical candidate (TBD11) with the potential to sterilize infected mice when administered in combination with bedaquiline, pretomanid and linezolid, a recently approved combination therapy.
SCHISTOSOMIASIS
Under previous funding from the Wellcome Trust, we formed an integrated set of key academic partners with diverse expertise in Schistosome biology to complement Calibr's drug discovery acumen.
ReFRAME library. In collaboration with Prof. Conor Caffrey (UC, San Diego), the ReFRAME library was screened against adult S. mansoni to identify drug repurposing opportunities and to build a collection of elegant chemical tools to investigate the biology of the Schistosomes. We have identified multiple series that demonstrate some level of in vivo efficacy in a mouse infection model and have generated promising starting points for optimization by medicinal chemistry.
ReFRAME library. In collaboration with Prof. Conor Caffrey (UC, San Diego), the ReFRAME library was screened against adult S. mansoni to identify drug repurposing opportunities and to build a collection of elegant chemical tools to investigate the biology of the Schistosomes. We have identified multiple series that demonstrate some level of in vivo efficacy in a mouse infection model and have generated promising starting points for optimization by medicinal chemistry.
Additional drug discovery programs
Our funding from the Gates Foundation supports a significant investment against a diverse set of important pathogens. Malina Bakowski, who helps to co-lead the infectious disease portfolio, helps to manage three primary projects:
AMR is a newer initiative and one that we have a great passion. There is an urgent need for new drugs to combat the drug-resistant strains that compromise frontline drugs. Malina will focus on Klebsiella pneumoniae, a gram-negative bacterium, and to a lesser extent, Acinetobacter baumannii and E. coli.
- Influenza (Team leader: Malina Bakowski)
- Poliovirus (Team leader: Malina Bakowski)
- Antimicrobial Resistance (AMR) (Team leader: Malina Bakowski)
AMR is a newer initiative and one that we have a great passion. There is an urgent need for new drugs to combat the drug-resistant strains that compromise frontline drugs. Malina will focus on Klebsiella pneumoniae, a gram-negative bacterium, and to a lesser extent, Acinetobacter baumannii and E. coli.