Agenus (AGEN) has outperformed. Of course some profit-taking was expected, but the firm has definitely done a good job rebuilding a new pipeline backed by updated information and more mature understanding of the immune system and the requirements for a successful immunotherapy. Investors might have been missing the transformation but when they got the chance to look deeper into the firm’s programs, they liked what they saw. AGEN’s  price has more than doubled since January 2012 on large trading volume, insinuating that the rally is for real and that investors are expecting good news to finally emerge from the firm’s labs and finances in the same time. A relevant comforting symptom is that Agenus’ partnership with GlaxoSmithKline (GSK) has proven solid like a rock, which might have helped convince the skeptics that Agenus’ QS-21 Stimulon is genuine adjuvant essential for to the efficacy of vaccines both preventive and therapeutic.

Agenus’ vaccines cover oncology and infectious diseases. The firm has advanced multiple product candidates through the clinic. It has been able to define the most suitable patient populations that would benefit from each of its various vaccines. Being around, struggling for years to get around the many factors that contributed to delaying its programs, the firm has learned a lot from its own setbacks, from the evolution in information about the immune system ways of fighting various diseases or foreign infective organisms. At the time when analysts believed the firm is going nowhere with its therapeutic vaccines, which led to the selloff of AGEN, Agenus was taking advantage of the breakthrough knowledge and of the experience it gained to improve on its existing programs and build new state-of-the-art promising new ones. 

As AGEN’s recent rally took place, we began to hear speculation about GlaxoSmithKline (GSK) acquiring Agenus and that GSK is just waiting for the results of the ongoing trials before determining the small firm’s full fair value. We also heard opinions suggesting that GSK might prefer to acquire Agenus’ QS-21 Stimulon only, which it has incorporated in its preventive and therapeutic vaccines. This second speculation does not seem relevant. Agenus would not give away its unique adjuvant, which is an effective component of most of its own proprietary vaccines.   Indeed, QS-21 Stimulon has become an essential component of 15 investigational preventive and therapeutic vaccine formulations, four of them have reached Phase 3 clinical trials. These are: RTS,S for malaria, MAGE-A3 for non-small cell lung cancer, MAGE-A3 for melanoma herpes Zoster shingles for Alzheimer’s disease.

More important than gossip about takeover is the mere current scientific and potential promising reality of Agenus vaccines in clinical trials. Positive results from the trials have begun to capture investors’ attention. It is difficult for one to overlook the data from Phase 2 trial of Prophage Series vaccine, G-200 for recurrent glioma. Results presented at the 2011 American Society of Clinical Oncology (ASCO) Annual Meeting showed that 93% of the patients were alive at 26 weeks after surgery with a median overall survival of 11 months (47.6 weeks). Measures of immune response post-vaccination with Prophage Series G-200 demonstrated a significant localized tumor-specific CD8+ T cell response as well as innate immune responses, recognized by the significant increase in circulating natural killer (NK) cells. Overall survival results from this trial supported advancement of Prophage Series G-200 into a randomized study using a combination regimen.

A Phase 2 trial testing Prophage Series vaccine G-100 in patients with newly diagnosed glioma is actively enrolling with approximately 24 patients treated. In this trial, G-100 is used on top of the standard of care, which includes Temodar (temozolomide) and radiation. It is believed that the efficacy of G-100 could potentially be enhanced through this combination regimen. 

The Prophage Series vaccines are tested in more than 850 patients in multiple cancers in more than 15 Phase trials. Included are the R-Series for renal cell carcinoma (RCC), the M-Series for melanoma, G-Series for glioma, and NP-Series for pediatric neurological tumors. Data from multiple studies revealed that the Prophage Series vaccines are well tolerated with a very low toxicity profile. These vaccines elicit tumor-specific T cell responses and innate immune response irrespective of tumor type. The efficacy of these vaccines appears most significant in patients with early-stage disease/low tumor burden.   

Oncologists’, patients’, and investors’ eye are also focused on Agenus’ HerpV immunotherapy - a polyvalent off-the-shelf therapeutic heat shock protein-based vaccine for genital herpes. This vaccine consists of recombinant human heat shock protein-70 complexed with multiple distinct antigens from the HSV-2 proteome. The broad spectrum herpes antigens allows for more accurate immune targeting and surveillance, hence reducing the likelihood of immune escape. The diversity of antigens is said to provide protection for a wider patient population.

HerpV has completed Phase 1 randomized, blinded study for safety and immunogenicity, with particular focus on the cellular immune response. Results from a study published in vaccine demonstrate that HerpV + QS21, boosted two immune system cells, CD4+ in 7/7 subjects (100%) and CD8+ in 6/8 subjects (75%). HerpV is the first polyvalent herpes vaccine candidate that elicits both CD4 and CD8 cellular immunity in human subjects.

The rationale behind developing a herpes vaccine that is focused on T cell generation is that CD8+ and CD4+ T cells localize to herpes skin lesions in humans and persist for many weeks after lesion healing; also, persistence of HSV-specific CD8+ T cells in neurons is associated with maintenance of viral latency. Further, it has been observed that robust CD4+ and CD8+ T cell activity against HSV-2 antigens can be detected in individuals who have clearly been exposed to HSV-2, yet remain HSV-2 seronegative and asymptomatic.

Licensees: GlaxoSmithKline, Janssen Alzheimer Immunotherapy (a wholly owned subsidiary of Johnson & Johnson) and Integrated Biotherapeutics are all QS-21 Stimulon^® users.  Agenus has granted NewVac LLC (a subsidiary of ChemRar High Tech Center in Russia) an exclusive license to manufacture, market and sell Oncophage as well as pursue a development program of Oncophage in combination with NewVac’s co-adjuvant technology in the Russian Federation and CIS countries.

Conclusion: Agenus is going forward with its proprietary vaccines. It is waiting for the final results coming from GSK vaccines, expecting successful outcome and approvals of these vaccines. Recent results from the malaria vaccine are promising, which confirms the promises of Agenus Q-21 Stimulon as indispensable adjuvant for vaccines. The near approval of the products developed by the licensees have elevated investors’ trust in the firm and will soon bring a steady revenues to the development-stage firm. We believe that HerpV vaccine for genital herpes has a great chance of success. Its approval would change the outcome of this genital infection forever and with it the firm’s status.

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