There are more than 30 antiretroviral (ART) drugs available in the market; yet the disease is far from being cured. ART alone cannot eradicate HIV due to the persistence of viral reservoirs and the disease can rebound following discontinuation of ART. Currently, patients infected with HIV need to take a combination of ART daily to keep the virus suppressed. The burden for patients of taking pills every day for life time and the unappreciated long-term toxicity and stigma are the unmet needs. In addition, patient’s low compliance in such a daily regimen could induce viral mutation and become resistant to the treatment and as such, there is a trend to move into less frequently administered injectable HIV drugs. New treatment options with novel mechanisms of action should be explored in order to achieve ART-free virologic remission, i.e., a functional cure.

UB-421 is an Fc-aglycosylated, non-T cell depleting and CD4-specific humanized IgG1 antibody derived from the parent murine antibody B4, which binds to discontinuous, conformational epitopes on the HIV-receptor complex, including CD4 (domain 1). Basically, UB-421 is an antibody that binds with competition edge to the site where all HIV variants attach, blocking their entry into the host cell and preventing the virus’ activity. By doing so, essentially all HIV variants including resistant viral mutants are highly sensitive to inhibition by UB-421.

In clinical trials, repeat-dose UB-421 exhibited remarkable high viral suppressing activities that are unprecedented.

UB-421 has additional immunomodulatory activity bolstering the immune system which has implications in HIV and cancer treatments.

The only treatment currently available for patients with HIV is virus-targeting antiretroviral therapy (ART). While ART can minimize the viruses spread, it is not a cure. It also requires a cocktail of up to 6 different classes of drugs that must be taken daily for the rest of a patient’s lifetime. If a patient misses dosing or doesn’t take all the prescribed drugs for a period of time, their HIV can rebound and may mutate and become resistant to treatment.

UBP is developing a novel antibody in the treatment of HIV that inhibits the entry of the virus into T cells, preventing the virus’ replication. What makes our antibody unique is that it competes with HIV to bind to the same site on T cells, blocking their entry into the cell and preventing the virus’ activity without generating resistant strains. Therefore, even drug-resistant HIV strains could be treated with this host-targeting antibody.

After pre-clinical studies showing that our antibody arrested the viral spread of HIV, we continued with studies in human subjects in Phase 1, 2a and Phase 2 clinical trials with our antibody, UB-421. In our Phase 2 study, over 2-4 months, we saw that UB-421 as a single agent was highly effective at suppressing HIV levels and maintaining viral control in patients. We also saw indicators that UB-421 could reduce HIV proviral DNA as well as bolster the patient’s own immune system. This property suggests that UB-421 could also be a good candidate in developing a functional cure for HIV, a state of sustained ART-free HIV remission.

The clinical results from our Phase 2 trial, which are presented in an article published in the April 18, 2019 issue of the New England Journal of Medicine, demonstrated UB-421 was a potent entry inhibitor. Using UB-421 as a single agent for the treatment of HIV-1 infected persons exhibited remarkably high viral suppression activity in all study participants that is unprecedented as compared to other ART by reducing the viral load and sustaining viral remission for at least 16 weeks.

Currently, the completed clinical trials with UB-421 as a single agent are only up to 16 weeks of treatment. Yet, our preliminary data suggested a reduction of HIV proviral DNA, a marker for measuring the size of latently infected HIV reservoirs. Although this needs to be confirmed in a larger trial, we believe this is an encouraging outcome that could potentially facilitate clearance of HIV reservoirs.

Current ART acts only on the life cycle of viruses and is non-curative due to the lifelong persistence of latent viral reservoirs which remain invisible to the immune system. We have seen signs that UB-421 as a single agent can reduce the latent reservoirs of HIV infected T cells while preventing further viral transmission to uninfected cells. Taken together with other HIV studies, our results indicate that UB-421, when used in proper combination with ART, could lead to a “functional cure” in treated patients, who would have viral remission without a need of medication for a certain long period of time.

Stem cell transplant is a medical procedure for seriously ill cancer patients, not for general HIV infected populations and it comes with a high probability of complications and risks. In addition, not all HIV patients who underwent stem cell transplants were cured; the outcome is highly variable and unpredictable. To date, there are only a few cases in the world that show the success of achieving HIV remission by stem cell transplant. Compared to a stem cell transplant procedure, our UB-421 antibody treatment is more suitable for patient populations and the risks may be significantly lower.

UB-421’s unique properties mean that it is applicable for almost all HIV patient populations. UB-421’s binding affinity to its target site has been shown to be the same in four studied ethnic populations. We are planning additional trials on UB-421 for a variety of patient populations including those with stably suppressed HIV and patients who are no longer responding to ART.

Unlike organic small molecule drugs, antibody therapies contain large immunoglobulin proteins that have to be administered by injection, either via infusion, intramuscular or subcutaneous injections. For infusion or intramuscular injection the procedure requires medical personnel at a clinic or hospital setting; while the subcutaneous injection procedure can be performed by patients at home. There are common adverse effects associated with infusion or injection, such as infusion reactions and injection site reactions.

Nevertheless, there are significant benefits with antibody drugs: 1) antibodies have long half-lives and can be administered with less frequent dosing schedule (such as administering weekly, semi-monthly or even monthly), 2) biological protein drugs have lower toxicities to liver, kidneys, etc., and 3) certain antibody drugs, such as UB-421, can exhibit beneficial immunomodulatory effects that cannot be achieved by small molecule drugs.

The completed Phase 1, 2a and 2 trials were conducted in Taiwan. UBP is expanding the trials with UB-421 to other countries. The phase 3 multi-regional multi-center trial with UB-421 monotherapy as substitution for ART will be conducted in Taiwan, China and Thailand. The trial for multi-drug resistance population will be conducted in the US and China. The Phase 2 functional cure trial in collaboration with NIH/NIAID is to be conducted in Taiwan but will be expanded to China and potentially in the US.

There are a number of clinical trials being planned globally in various stages. Those with regulatory approvals will be initiated in the coming months.

In addition, UBP is establishing liaison offices in Long island, NY, and subsidiary companies in China, including a clinical and regulatory development center in Shanghai, and a GMP manufacturing plant in Yangzhou. These are in preparation for the launch of several clinical trials in the US and China.

Near term, we are planning:

a) A Phase 3 trial for UB-421 as a substitution for ART in the treatment of experienced aviremic (viral load undetectable) patients. The trial will enroll 520 patients and be conducted in Taiwan, Thailand and China.

b) A Phase 2 open label, multi-center, trial for functional cure indication. It will be conducted in Taiwan and China to study the effectiveness of UB-421 in the reduction of HIV proviral DNA, a marker for measuring the size of latently infected HIV reservoirs. Our longtime collaborator at NIH/NIAID will participate in this study, applying their highly sensitive PCR assays in determining the reduction of HIV reservoirs during UB-421 treatment.

c) A Phase 2 open label, multi-center, trial for the treatment of multi-drug resistance with UB-421 as an add-on agent to the optimal background therapy. The trial will be conducted in the U.S. as well as in Asian countries.

a) United Biopharma has been collaborating with Dr. Tae-Wook Chun, Chief of Immunovirology Unit and his lab at NIAID since 2015. Dr. Chun and his associates are the co-authors of the UBP’s article in the April 18 issue of NEJM.

b) Dr. Chun and his staffs performed a number of important experiments to prove UB-421’s effectiveness, such as:

1) UB-421 binds to CD4 receptors on immune T cells, the first step of blocking HIV entry, with same effectiveness in four major ethnic populations in the United States, including Caucasian, African American, Hispanic and Asian. This data is included in the April 18 issue of NEJM.

2) A single injection of UB-421 can suppress HIV growth up to 49 days in humanized mouse model.

3) UB-421 is effective in neutralizing the HIV viruses resistant to at least 4 different kinds of anti-HIV antibodies, the so called “broadly neutralizing antibodies”, currently being studied in clinical trials. One of them is VRC01, being developed by NIAID itself. This data was published in Dr. Chun’s article in the November 9, 2016 issue of NEJM.

4) UB-421 is able to reactivate latently infected HIV virus from immune T cells of HIV patients. This is the critical first step to eradicate the latent HIV reservoirs.

c) United Biopharma has signed agreement with NIAID for Dr. Chun to participate in our upcoming clinical trials for functional cure indication. He and his staffs will use the most sensitive PCR assays to measure the reduction of HIV proviral DNA in patients during the treatment with UB-421.

UB-421 is developed for treatment of HIV infection potentially in four different indications:
a) Substitution – UB-421 monotherapy (single agent treatment) for substitution of ART in ART experienced patients whose viral load is stably suppressed.

b) Multi-drug resistance - combination therapy with UB-421 together with optimal background regimen of ART drugs for patients who fail treatment and show resistance to multiple classes of ART drugs.

c) First line failure – combination therapy of UB-421 and ART for patients who fail treatment from taking the first line ART.

d) Functional cure – combination therapy with UB-421 together with ART for all patients infected with HIV and have a significant size of latent HIV reservoirs.

The pipeline of United Biopharma consists of therapeutic antibody drugs in three major disease areas, infectious disease, immune disorder and oncology. In addition to UB-421, there are 5 products in various stages of development.

The virus-directing broadly neutralizing antibodies (bNAbs) target HIV-gp120 where resistance mutation can easily develop, while the host-directing UB-421 is capable of complete inhibition of infection by all variants of HIV.

No viral rebound occurred with UB-421 monotherapy, while viral resistance rapidly developed to bNAbs as a single agent. Moreover, participants enrolled to the bNAb’s trial need to be pre-screened to exclude those already showing resistance to the study drugs. HIV mutants resistant to bNAbs (e.g., VRC01, 3BNC117, 10-1074, and PGT121) are highly sensitive to the inhibition by UB-421. This data was published in the November 9, 2016 issue of NEJM.

We manufacture UB-421 at United Biopharma’s GMP facilities in Taiwan, and the production capacity will soon be expanded to UBP Greater China’s facility in Yangzhou, China. The manufacturing process has been upgraded to commercial scale, employing 2000L single-use bioreactor and state-of-the-art downstream chromatography system.

We are developing a proprietary cell line and cell culturing which can produce UB-421 at 8 to 10 grams per liter., again a record of high yield from production level aspect.