Biotron Ltd.'s Vpu Inhibitor, BIT225 Biotron Ltd. is yet another...

Biotron Ltd.'s Vpu Inhibitor, BIT225
Biotron Ltd. is yet another important yet relatively unknown player in HIV research. With a focus on combating latent HIV reservoirs, the company believes that its first-in-class vpu inhibitor BIT225 can sound death knell to the incurable disease.
The vpu is an accessory HIV-1 regulatory protein which has been found to degrade an infected immune cell's CD4 receptors (an important biomarker for disease progression and extent as well as the site of viral entry), enhance virion release by downregulating tetherin/BST-2 and opening ion channels in cell membranes, and inhibiting natural killer (NK) and natural killer T-cell (NKT) mediated killing by trapping NTB-A and CD1d glycoprotein receptors, respectively, in intracellular compartments and away from the cellular surface. Although vpu plays many roles in the life cycle of HIV, it has been found that Biotron's BIT225 serves as a specific inhibitor of vpu's viroporin mechanism. A recent study by Kuhl et al. has found that BIT225 works by targeting vpu's ability to form permeable hydrophilic pores in cellular membranes and thus enhancing the release of viral particles from the infected cell. The study also found that the BIT225's antiviral activities were more pronounced in myeloid-lineage cells than CD4+ lymphocytes and prevented viral transfer from myeloid-derived dendritic cells (MDDC) to CD4+ T-Cells. Another study by Khoury et al. found that BIT225 also inhibit virion release from HIV-infected macrophages.

While current antiretroviral therapy works efficiency against disease progression in CD4+ lymphocytes, they have been unable to successfully target latent viral reservoirs located in myeloid-lineage cells (monocytes, macrophages, and dendritic cells). With the ability to cross the blood-brain barrier and spread the disease to the central nervous system, myeloid-lineage cells have been able to conceal themselves from traditional medicines and represent the last major battleground in the fight against HIV.

Figure 7: Viroporin Mechanism of Action in Cells. Source: Nature Reviews Microbiology
Biotron's BIT225 may serve as the key in the fight against inaccessible pockets of HIV. Biotron's phase 1b/2a clinical trials results indicated that in combination with cART, BIT225 successfully reduced HIV RNA, inhibited replication in myeloid -lineage cells, and crossed the blood-brain barrier to reach latent viral reservoirs. With the promise of reaching previously untouched sites of disease, BIT225 may work in combination with today's approved cART medicines to collectively annihilate HIV once and for all. With preparations being made for a phase 2b study, it has yet to be seen just how safe and effective it will be in treating large cohorts of HIV-positive patients.

Figure 8: Summary of the Effects of a Single Dose of BIT225. Source: Biotron, Ltd.​

Risks, Rewards, and Portfolio Allocation​

Gilead Sciences' GS-CA1, ViiV Healthcare's GSK3640254, Abivax's ABX464, and Biotron's BIT225 are novel small-molecule which are designed to target viral proteins that have eluded today's complex cART medicines. Each of the four companies mentioned here hopes that by successfully inhibiting the workings of their respective targeted viral proteins, they would be able to offer patients a safer, more convenient, and more effective treatment than ever before. As none of these agents have been tested in late-stage clinical trials, it is too early to predict whether any of these agents hold any real therapeutic promise. However, for any investor who is interested in the promise of better HIV drugs and a $27 billion-a-year market, it would be prudent to diversify their portfolio by allocating funds to all four individual companies. However, deciding how to diversify one's HIV therapeutics portfolio depends largely upon an individual risk tolerance assessment.​