Human Immunodeficiency Virus (HIV-1)

HIV-1 is a human pathogenic virus.  After infection, it runs a slow course in which certain of the cells in the immune system (CD4+ cells) are progressively destroyed.   This results in a state in which the infected person can no longer mount an immune response.   This loss of immune responsiveness is the cause of the complex of diseases known as AIDS and ultimately of death.

According to estimates by the Joint United Nations Programme on HIV/AIDS , over 40 million people are infected with the human immunodeficiency virus worldwide.   At present, two classes of products have received FDA marketing approval for HIV-1 infection: reverse transcriptase inhibitors and protease inhibitors.   These drugs are typically used in combination and require more than a dozen tablets to be taken at specific times each day.   The cost for treatment of HIV infected individuals, once the disease has progressed to AIDS, is estimated to exceed $38,000 per person annually.

While combination therapy slows the progression of disease, it is not a cure.   HIV's rapid rate of mutation results in the development of viral strains that no longer respond to these medications.   This problem is often exacerbated by interruptions in dosing as non-compliance is common in patients on combination therapies.   Moreover, currently approved drugs produce toxic side-effects in many subjects , affecting a variety of organs and tissues, including the peripheral nervous system and gastrointestinal tract, which side-effects also often result in subjects interrupting or discontinuing therapy.

Enzo’s HGTV43 gene medicine. HGTV43, Enzo’s proprietary Stealth Vector™ carrying anti-HIV-1 antisense RNA genes directed against the genes responsible for viral replication.   HGTV43 is designed to deliver the antisense genes to targeted blood cells of patients infected with HIV-1.   These genes are incorporated into the DNA of the subjects’ blood stem cells and subsequent production of the anti-HIV-1 antisense RNA is designed to prevent replication of the virus, providing resistance to the virus.

Preclinical in vitro studies, performed in conjunction with our academic collaborators demonstrated resistance to HIV-1 in human immune cells into which the antisense genes had been inserted.   Our Phase 1 clinical trial of the HIV-1 product is in the followup phase.   In this study, white blood cell precursors, known as stem cells, were collected from the subject.   These stem cells were then treated with HGTV43 ex vivo and infused into the subject.   Results of the trial have shown that all subjects tolerated the procedure, that the engineered cells engrafted into the bone marrow, and that anti-HIV-1 antisense RNA continued to be expressed in the patient’s circulating CD4+ immune cells for as long as 24 months to date.

Based on these Phase 1 trial results demonstrating long-term survival and functioning of anti-HIV-1 antisense RNA in white blood cells and in CD4+ cells we are preparing for the next phase of the study in which we will test strategies to increase the percentage of CD4+ cells that contain the anti-HIV-1 antisense genes.

One arm of the next phase of clinical trials is expected to be conducted at New York Presbyterian Hospital-Cornell Medical Center.  Enzo’s protocol for this phase of the study was successfully presented to and approved by the National Institutes of Health Recombinant DNA Advisory Committee (RAC).  The Cornell site will focus on a strategy to increase the percentage of engineered CD4+ cells by using a combination of radiation and immune conditioning.  We anticipate beginning expanded studies of the trial at additional sites.

Hepatitis B (HBV) EHT899

Enzo is developing HBV therapeutics utilizing our immune regulation technology.

HBV is a viral pathogen that can lead to a condition in which the body destroys its own liver cells through an immune response.  This condition is commonly referred to as chronic active hepatitis.  According to the latest figures published by the World Health Organization, approximately 2 billion people are infected by HBV, in whom an estimated 350 million are chronically infected and therefore at risk of death from liver disease.

Chronic active hepatitis is generally treated with interferon or lamivudine.  Both of these drugs, however, are toxic, and many patients cannot tolerate their side effects.   These treatments have a limited success rate (5-15%).

Enzo’s EHT899 immune regulation product. EHT899 is a proprietary formulation of an HBV viral protein designed to eliminate the undesirable immune response elicited by the HBV infection.  It also apparently enhances a secondary immune response to clear the viral infection, resulting in reduction in liver damage and decrease in viral load.

In a clinical trial, conducted at the Liver Unit of Hadassah-Hebrew University Medical Center, in Jerusalem, Israel, a formulation of EHT899 was administered orally to a total of 42 patients with chronic active hepatitis.   Patients received the medication three times a week for 20 – 30 weeks and were followed for an additional 20 weeks.  Results of the trial have shown that the drug was well tolerated in all subjects; 46% of subjects showed a decrease in HBV viral load and improvement in liver function tests; and 33% of subjects showed a decrease in inflammation seen on liver biopsy.

Based on these results, Enzo is preparing to begin a multi-center Phase II random-label double blind clinical study.

Preclinical animal studies with EHT899 showed that this medication was able to achieve complete suppression of HBV-associated human liver cancer and significantly reduced mortality in laboratory mice.  These studies may have significant potential application for treatment of liver and other cancers in humans.

Hepatitis C (HCV) EHC18

Enzo is using its proprietary immune regulation platform to develop a therapy for treating HCV.  This disease affects approximately 170 million people worldwide, including 3.9 million in the U.S., of which approximately 69%, or 2.7 million, are chronically infected, according to the National Center for Infectious Diseases.   Approximately 30,000 new infections are recorded each year in the U.S.  About 85% of people infected with HCV are reported to develop chronic hepatitis, and about 20% develop cirrhosis, an incurable disease, with approximately half of these cases progressing to end-stage liver disease, including liver cancer.  It has been predicted that HCV-related deaths in the U.S. may soon overtake the number of AIDS-related deaths in the U.S.

The Phase I clinical trial conducted by physicians at the Liver Unit of Hadassah University Medical Center in Jerusalem, Israel has met its safety endpoints. Enzo is currently looking to the next level of study.

Crohn's Disease

Inflammatory bowel diseases.   We are applying our immune regulation technology to treat inflammatory bowel disease (IBD), including Ulcerative Colitis and Crohn’s Disease.   According to the Inflammatory Bowel Disease Foundation, approximately one million persons in the United States suffer from IBD.   Although the cause of these disorders remains unknown, various features suggest immune system involvement in their pathogenesis.

There is currently no effective treatment for these diseases.   Subjects are managed during short-term episodes through the use of anti-inflammatory medications, or immunosuppressants, that provide symptomatic relief over short periods of time but do nor provide a cure. These drugs are all based on a generalized suppression of the immune response and are non-specific.   As such, they have considerable side effects and cannot be used for long periods of time because of their inherent toxicity.

Preclinical studies were carried out in an animal model system. The results of these studies showed that when laboratory animals with experimentally induced colitis were given specific proteins by oral administration, a remission of the condition was seen. The experimental animals exhibited a marked amelioration of the symptoms, including significant reduction in tissue inflammation, as well as a decrease in the levels of gamma interferon in the serum, both indicative of remission.

Based on these preclinical results, Enzo began human clinical studies to test an innovative immune regulation medicine for treating Crohn’s Disease and recently completed a Phase 1 clinical trial. Ten subjects with mild to moderate Crohn’s disease were admitted to the trial and were treated with the study drug. The drug was administered orally three times a week for 16 weeks. During the course of the treatment period, all 10 subjects had a clinical response to the treatment and seven achieved clinical remission. Response was measured by a significant decrease in CDAI (Crohn’s Disease Activity Index), a standard measure of the severity of the disease. The Phase I study was an open label trial of six male and four female subjects, ages 19 to 58 who have suffered from Crohn’s Disease for an average of 11 years. The median time of response to the treatment was five weeks. No treatment related adverse events were noted in any of the subjects.

We are currently conducting a Phase II randomized double-blind clinical trial of our immune regulation medicine for Crohn’s Disease. Approximately 30 individuals will ultimately be enrolled. Each subject will be treated for 15 weeks and followed for an additional 12 weeks after treatment is completed.

Graft versus Host Disease  

We are applying our immune regulation technology to treat graft versus host disease.   Graft versus Host Disease (GvHD) is a major complication of bone marrow and stem cell transplantation accounting for many of the failures of these transplant procedures.   GvHD is characterized by an immune response mounted by the immune cells within the engrafted tissue against the recipient that leads to a wasting syndrome and occasionally death.   It is estimated that there are only 15,000 bone marrow transplants performed annually worldwide due, in part, to GvHD.   It is assumed that the elimination of GvHD would lead to a dramatic rise in the number of these procedures.   GvHD is currently treated by immunosuppressant drugs, which are toxic and only reduce the extent of the wasting reaction.

We are conducting pre-clinical and animal studies on this therapeutic strategy.   The results of these studies show that our immune regulation technology could be effective in treating GvHD.