Excision BioTherapeutics has raised money to move what it sees as a cure for HIV into the clinic. Stemcentrx backer Artis Ventures led the $10 million seed round to equip Excision to start human testing of its CRISPR-enabled attack on latent HIV virus.
Philadelphia-based Excision is built on research conducted at Temple University’s Lewis Katz School of Medicine. The work led to a paper published last year, in which Excision co-founder Kamel Khalili, Ph.D., and his partners administered a multiplex of guide RNAs (gRNAs) and Staphylococcus aureus Cas9 to HIV-infected mice. The team designed the treatment to remove a large, essential DNA fragment from HIV.
Results from the study furthered Excision’s belief its candidate can wipe out HIV provirus from all tissues in the body without causing genotoxic effects and off-target editing.
That belief prompted the founding of Excision in 2015. Having generated animal data to back up the belief, Excision has high hopes for the approach.
“We're in this to cure patients of HIV,” Excision CEO Thomas Malcolm, Ph.D., said.
Excision sees an HIV CRISPR Cas9/gRNA multiplex biologic based on Khalili’s work—EBT101—as its best shot of meeting this lofty goal. The plan is to wrap up IND-enabling studies of the candidate in the months to come and get it into the clinic around the end of next year. That small trial will act as an early test of the safety and, to a lesser extent, the efficacy of EBT101 and its delivery system.
Some of Khalili’s projects used adeno-associated virus (AAV) vectors to deliver sgRNAs and Cas9. But Excision is now looking at a lentiviral approach.
“It's really more specific for the types of cells that have that latent virus. HIV itself is a lentivirus so it makes sense to use a lentiviral shell to deliver the therapeutic,” Malcolm said. “We’re showing we can easily access all of these reservoirs with this approach.”
The plan for later trials is to use EBT101 to target these reservoirs in patients taking cocktails of HIV inhibitors to control the virus. These cocktails, such as Gilead’s Genvoya, lower HIV viral loads to undetectable levels in most patients. But, while that has improved outcomes significantly, Excision is confident a product that eradicates the virus would still find a market.
This confidence is based on what Malcolm calls the “baggage” that comes with cocktails. That term covers the risk of noncompliance to the daily treatment regimen and the comorbidities common in people who live with HIV, although there is evidence suggesting treatment with modern antiretroviral therapy cuts the risk of these complications.
The other shortcoming, which is linked to the risk of noncompliance, stems from the potential for HIV to develop resistance to drugs. That is happening today. A CDC study found 16% of patients diagnosed with HIV in 10 metropolitan areas from 2007 to 2010 carried antiretroviral-resistant virus. A WHO study found more than 10% of patients starting treatment in six of 11 surveyed countries in Africa, Asia and Latin America had a resistant strain.
Malcolm sees this causing big problems down the line.
“It's a ticking time bomb,” he said. “It's just a matter of time before you're going to get another patient zero who is going to be completely unsusceptible to these inhibitor cocktails and we're going to be right back to where we were in the '80s.”
Excision plans to head off that scenario by developing EBT101. In parallel, the biotech is working on a clutch of earlier-stage programs, two of which it will move into animal studies using the seed money. Success in those studies would tee Excision up to move candidates against JC virus—the cause of progressive multifocal leukoencephalopathy—and herpes simplex virus into the clinic in the next couple of years.