Science

Adamis Pharmaceuticals TeloB-VAX vaccine is composed of the patients’ own circulating B lymphocytes harboring a unique patented engineered plasmid DNA. The transfection procedure is “spontaneous”, requiring no facilitating molecules or devices. After 60 minutes of incubation with the plasmid, the cells can be re-infused back into the patient. In studies conducted to date, TeloB-VAX cancer vaccine induces a potent cellular immune response against the first truly common cancer antigen, the telomerase reverse transcriptase (TERT).

Telomerase is an enzyme that adds DNA sequence repeats (e.g., "TTAGGG") to the 3' end of DNA strands in the telomere regions of chromosomes at every cell division. Telomerase confers the immortality trait that converts normal cells into cancer cells and prevents the erosion of telomeres and end-to-end chromosomal fusion. As such, telomerase is over-expressed in the vast majority of differentiated cancer cell types. Importantly, telomerase is also necessary for self-renewal of cancer stem cells and cancer cell progenitors. Based on the foregoing, TERT is an antigen expressed in both differentiated and progenitor cancer cells making vaccination against TERT a potentially effective measure to induce an immune response against cancer cells at both stages of differentiation.

In a Phase 1 study completed at the University of California, San Diego, in castrate resistant prostate cancer (CRPC) patients, this vaccine was safe, non-toxic and immunogenic. A single immunization using transgenic lymphocytes induced a specific CD8 T cell response against a dominant TERT peptide. Two injections of TeloB-VAX, spaced one month apart, was shown to increase the response against TERT. More important, the T cells induced post vaccination were shown to specifically kill prostate cancer cells.

Currently Adamis is planning a Phase 2 study in CRPC patients. The study will be conducted at UCSD and at the University of Wisconsin Carbone Cancer Center.

If successfully developed, Adamis believes the technology offers certain significant advantages over the existing FDA approved vaccine, Provenge. Some of the advantages include: 1) prolonged antigen presentation by B cells (5 days) as compared to the short presentation time by dendritic cells (12 hours), 2) a unique patented technology using a universal cancer antigen (marker) that is increased to approximately 85% of all tumors, 3) induces an immune response after a single injection, 4) no need for complicated culture procedures, 5) much fewer steps, and 6) lower cost.

If future clinical trials are successful, TeloB-VAX may very well be called a “universal cancer vaccine” that could induce immunity against multiple cancer types as well as targeting the specific cancer stem cell.

APC-100 is an orally administered compound that inhibits growth of cultured androgen-independent and dependent human prostate cancer cells, and has been shown to be an oxidative stress modulator drug that markedly reduces reactive oxygen species (ROS) in prostate cancer cells. In addition, APC-100 binds to the androgen receptor and acts as an androgen antagonist. Therefore, APC-100 exhibits a dual mechanism of action as both an inhibitor of the androgen signaling pathways as well as an anti-inflammatory oxidative stress modulator. In the TRAMP model of mouse prostate cancer, APC-100 is far superior to the marketed standard of care (90% efficacy vs. 55% efficacy). In mice, APC-100 increases time to tumor progression and increases survival. It has also been shown to decrease PSA production. An IND has been submitted to the FDA for Phase 1 studies in CRPC patients.

1. In 2006, received a $4.5 million NCI Rapid Award as a first-in-class therapeutic oral drug for Castrate-Sensitive and Castrate-Resistant Prostate Cancer. The total funding received was approximately $8 million.
2. Binds Androgen Receptor (AR) and is a potent anti-androgenic, anti-inflammatory and signal transduction inhibitor
3. No effect on Androgen Receptor protein expression
4. Increases Time to Tumor Progression (TTP) & increases Survival
5. Tests in the TRAMP model of mouse prostate cancer show that APC-100 is far superior to the marketed standard of care (90% efficacy vs. 55% efficacy)
6. Decreases Prostate Specific Antigen (PSA) production
7. Versatile, safe and stable
8. Bio-available: oral or injectable or implantable
9. Low toxicity, no pro-Estrogenic feminizing side-effects
10. High stability of stored API lots (active ingredients)
11. Recurrent PCa (prostate cancer) patients more likely to be scripted, reimbursed, remain on non-toxic, orally available potent APC-100 therapeutic drug
12. Broad world-wide IP including Japan: issued, pending & in progress
13. U.S. IND was submitted in Feb. 2011

In pre-clinical studies, APC-200 has demonstrated the ability to inhibit reactive oxygen species (ROS) formation specifically in prostate cancer cells and thereby blocks inflammation and androgen induced oxidative stress. Whereas acute inflammation is important for host defense, chronic inflammation contributes to tumor growth, progression to castrate resistant tumors and metastatic progression. In animal studies conducted to date, APC-200 was not only an excellent inhibitor of chronic inflammation, but also significantly delayed prostate cancer progression and increased survival in animal disease models. APC-200 is being developed as an orally administered drug and is in late-stage preclinical development.

1. In 2007, received $5 million NCI Rapid Award as a first-in-class therapeutic oral drug for Castrate-Sensitive and Castrate-Resistant Prostate Cancer. Total funding has been approximately $7 million with $1.5 million still remaining to complete the IND data
2. Irreversible inhibitor of the acetylpolyamine oxidase enzyme & effectively blocks inflammation and androgen induced oxidative stress; polyamine oxidation is a major path for ROS production in prostate and inhibition successfully delays PCa progression and increases survival
3. Significantly delays PCa progression & death in TRAMP mice (prostate cancer model) with spontaneous prostate cancer
4. Could be a good candidate for patients for whom Androgen Deprivation Therapy may not be approved or appropriate
5. Versatile, safe and stable
6. Bio-available: oral or injectable or implantable
7. Low toxicity, no pro-Estrogenic feminizing side-effects
8. High stability of stored API (active ingredients)
9. IND-enabling data is over 90% complete; will be completed by mid 2011
10. Straight-forward &cost-effective API manufacturing & formulation; manufacturing has begun
11. Broad world-wide IP including Japan: pending & in progress
12. U.S. IND to be submitted 4Q 2011- 1Q 2012

APC-300 is a natural compound that, in pre-clinical studies, has been shown to not only inhibit the growth, but also stimulates the death of human prostate cancer cells. APC-300 is a small molecule signal transduction inhibitor that acts as an anti-inflammatory agent and blocks prostate cancer progression in in vivo models of the disease. In addition to prostate cancer, APC-300 has also demonstrated efficacy in disease models of human melanoma and pancreatic cancer. Adamis believes that APC-300 may have potential applications in the treatment of several tumor types. APC-300 is currently in preclinical development.

1. Received $6.4 million in grant awards as a therapeutic oral drug for Castrate-Sensitive and Castrate-Resistant Prostate Cancer.
2. Inhibits growth & kills both Castrate Sensitive- and Castrate Resistant –PCa
3. Reduces prostate specific antigen (PSA) levels
4. Decreases protein expression of Androgen Receptor
5. Kills human PCa cells in vitro & in vivo
6. Kills human prostate &other solid cancer cells, while sparing normal cells
7. Induces Fas Receptor mediated-apoptotic signaling
8. Is pro-apoptotic, inhibits multiple signaling targets and disrupts microtubule assembly
9. In vitro significantly increased apoptotic death
10. Versatile, safe and stable
11. Bio-available: oral or injectable or implantable
12. Low toxicity, no pro-Estrogenic feminizing side-effects
13. High stability of stored API lots (active ingredients)
14. Effective API manufacturing & formulation
15. U.S. claims in prosecution (and relevent analogs) for broad world-wide IP (intellectual property) including Japan: in progress
16. IND enabling tox data package needs to be collected

Adamis’ contraceptive gel product named Savvy® (C31G) recently completed a positive Phase 3 study. The study was conducted by the Eunice Kennedy Shriver National Institute of Child Health and Human Development, National Institute of Health, in the Contraceptive Clinical Trials Network at 14 sites in the U.S. The study met its primary and secondary endpoints. The study was a multi-center, randomized, double-masked, controlled trial to assess whether a gel containing the spermicide C31G was non-inferior to Conceptrol®, a commercially available product containing nonoxyno1-9 (N-9). The study results were recently published (Dec, 2010) in Obstetrics and Gynecology, v. 116 pp. 1265-1273. Earlier studies of C31G assessed safety, acceptability and tolerability, as well as effect on vaginal microflora and irritation on the genitalia. Results from these studies showed C31G to have an excellent safety profile. Additionally, post-coital studies showed that C31G is effective in preventing sperm from penetrating mid-cycle mucus and male tolerance studies showed that male partners of women using C31G did not suffer penile irritation from the product. Taken together, the human studies showed C31G to be well tolerated, safe and effective, with less cervicovaginal toxicity than the commercially available N-9. No drug related serious adverse events were observed with C31G. Drug-related side effects were generally mild and did not lead to discontinuance.

Certain recent clinical trial results reported that N-9 can cause genital irritation and use was associated with an increased likelihood of HIV infection transmission in frequent users. These findings led to labeling changes, which limited recommendations for use. Therefore, the development of alternative spermicides, especially ones that offer dual protection with enhanced spermicidal and antimicrobial effects has emerged as a priority.

C31G has the potential to be a product with many positive attributes. It is a broad-spectrum antibacterial agent as well as a spermicide. In addition to its activity against both gram positive and gram negative organisms, in preclinical studies, it was also active against Chlamydia and Herpes virus. The commercial availability of products containing C31G would provide more options to women who seek a coitally-dependant, nonhormonal, method of contraception.

Additionally, because of its broad spectrum activity against important bacteria and viruses, C31G could prove to have multiple applications, including in the area of Herpes eye infections. In a pre-clinical Herpes eye model study, C31G showed excellent activity. In vitro studies also showed that C31G kills methicillin resistant Staphylococus aureus and organisms involved in periodontal disease. Therefore, other potential uses could include hand washes, body washes and mouth washes.

Since C31G does not fit into the core business of Adamis, the company is currently evaluating various out-licensing opportunities.