Functional HIV cure
Bionor’s strategy is to advance its proprietary therapeutic vaccine Vacc-4x in combination with other medicines toward major value inflection points in order to significantly contribute to a functional cure for HIV.
There are 2 broadly defined cure categories for HIV infection: “functional” and “sterilizing.” “Sterilizing cure” is defined as complete eradication of HIV and is currently not considered a realistic possibility for years to come. “Functional cure” is defined as the “host-mediated control of HIV replication, in the absence of cART.” In the course of a functional cure, the virus in the blood is controlled at a level low enough to prevent disease progression and transmission.
The International AIDS Society considers cure research as a worthwhile approach stating: “A safe, affordable and scalable cure will improve the health and quality of life for those with established infection, reduce the risk of viral transmission to those not infected and ultimately allow resources to be shifted to other needs. A cure will thus achieve what preventive and therapeutic approaches aim to do, which is to essentially stop transmission of HIV to those who are uninfected and restore immunological function and normal health to those who are infected.”
Functional cure is a relatively new approach and there are currently no common recommendations with regard to regulatory requirements for clinical studies or marketing authorizations in this area.
Central to the clinical studies concerning functional cure are therapies targeting the latent HIV reservoir in resting memory CD4+ T cells at various anatomical sites. Resistance of the latent reservoir to cART or other treatment methods is the main barrier to HIV eradication. HIV latency is maintained by several mechanisms that make infected cells “invisible” to the immune cells that would otherwise target and kill them. Functional cure strategies include pharmacological reactivation of the latent reservoir to make infected cells “visible” to the body’s immune system.
The feasibility of an HIV functional cure strategy is supported by clinical evidence that some HIV infected individuals are able to achieve natural and persistent control of viral replication (i.e., HIV RNA <50 copies/milliliter) in the absence of cART. These “elite controllers” show low concentration of HIV DNA in different subsets of circulating CD4+ T cells in blood as well as in rectal tissue, both indicating that these patients have lower HIV viral reservoir.
A proposed strategy for a functional cure under the name “Shock and Kill” was presented by Dr. Steven Deeks from UCLA in 2012. Bionor has adopted this strategy employing Vacc-4x as a backbone treatment in combination with a latency reversing agent and likely also an immune regulating agent.
The Shock & Kill functional cure strategy as applied by Bionor in the successfully completed REDUC trial
As a step in pursuing this strategy, Bionor completed the REDUC clinical trial in December 2015 evaluating whether priming the immune system with Vacc-4x to attack HIV infected CD4+ T cells upon activation of the latent reservoir can improve viral control after administration of the latency reversing agent, romidepsin. REDUC with Vacc-4x and romidepsin successfully met its primary endpoint by significantly reducing latent HIV reservoir and demonstrated control of viral load.
The headline results in REDUC were:
- The latent HIV reservoir was significantly reduced by 40% (Total HIV DNA and qVOA)
- Viral load remained below the level of detection in 11 out of 17 patients on combination antiretroviral therapy (cART) despite reservoir reactivation. Four patients had measureable but low viral load and only at one of the three romidepsin infusions
- The pharmacodynamic effect of romidepsin, i.e., reactivation of the latent HIV reservoir, was confirmed by increases in histone acetylation levels and viral expression
- The combination of Vacc-4x and romidepsin was safe and well tolerated.
The results create a strong foundation for further advancement of Vacc-4x as a core component in a functional cure for HIV. Bionor expects to initiate the BIOSKILL clinical trial to confirm “Shock and Kill” in a randomized, placebo controlled and double blind design when funding has been secured to execute and complete the full scope of the trial. To date, Bionor has filed clinical trial applications for BIOSKILL in the United Kingdom, Germany, and Denmark.
Read more about Bionor's strategy here