What is Multikine®

Multikine, CEL-SCI's lead investigational immunotherapy, is an immunotherapeutic agent that is being developed as a potential first-line neoadjuvant therapy in patients with advanced primary squamous cell carcinoma of the head and neck. If it were to be approved for use following completion of CEL-SCI's clinical development program, Multikine would be a different kind of therapy in the fight against cancer; one that appears to have the potential to work with the body's natural immune system in the fight against tumors. Multikine may also have the potential to be a first in a new class of cancer immunotherapy drugs. It is the first investigational combination immunotherapy thought to have both passive and active immune properties and has displayed the following characteristics in studies to date:

• Potential first-line treatment: Multikine is administered prior to any other therapy because CEL-SCI believes that this is the period when there is a greater potential likelihood of activating an anti-tumor immune response. Once the patient has had surgery or has received radiation and/or chemotherapy, the immune system may become weakened and may be less able to mount an anti-tumor immune response.
• Potential to work with the body: Multikine investigational immunotherapy is directed at activating and boosting the body's own anti-tumor immune response to potentially help the body in addressing the tumor.
• A mixture of different immune molecules, potentially simulating the natural immune system: Multikine is composed of a defined mixture of naturally occurring molecules which in early-phase studies have been reported to be biologically/immunologically active.

Clinical Trial Status

The first indication we are pursuing for our Multikine investigational immunotherapy product candidate is for the use as a neoadjuvant therapy in patients having advanced primary (not yet treated) squamous cell carcinoma of the head and neck, SCCHN. SCCHN represents about 90% of head and neck cancer, and CEL-SCI believes that there is a large, unmet medical need among head and neck cancer patients. To the best of our knowledge, the last FDA approval of a therapy indicated for the treatment of advanced primary head and neck cancer was decades ago. Head and neck cancer represents approximately 890,000 patients diagnosed worldwide each year, and nearly 60,000 patients diagnosed annually in the United States. Multikine investigational immunotherapy was granted Orphan Drug designation for neoadjuvant therapy in patients with SCCHN by the FDA in the United States.

Mechanism of Action

Clinical and pathology data from Phase I and Phase II clinical trials with Multikine investigational immunotherapy published in peer reviewed scientific journals (Feinmesser et al Arch Otolaryngol. Surg. 2003; Timar et al 2003 and 2005) suggest that Multikine has the potential to produce an anti-tumor response, as the reported data from these early-stage studies suggests:

• Multikine potentially may recognize and/or bind to multiple (different) antigens (or receptors) on the cancer cells.
• Multikine potentially may directly affect/kill cancer cells: The various cytokines present in the Multikine investigational therapy, such as TNF, IL-2, IFN, along with other cytokines, could be responsible for this potential activity.
• Multikine may signal the immune system to produce an anti-tumor immune response: Clinical data (reported from Phase II studies) also suggest that Multikine could augment the type of cells that infiltrate and attack the tumor changing the tumor microenvironment ratio of CD4/DC8 cells from CD-8 cells to predominantly CD-4 cells. These CD-4 cells have the potential to bring about an anti-tumor immune response (Timar et al 2005).

Multikine may have the potential to render the remaining cancer cells susceptible to radiation treatment (Timar et al 2003).

Potential indications/
relevance to the medical community

The first indication we are pursuing for our Multikine product candidate is for the use as first-line neoadjuvant treatment in newly diagnosed patients with advanced primary squamous cell carcinoma of the head and neck, SCCHN. SCCHN is a type of head and neck cancer. In Phase I and Phase II clinical trials and in the recently completed Phase III clinical trial, Multikine was administered right after diagnosis and prior to any other cancer therapy because CEL-SCI believes that this is the period when there is a greater likelihood of activating an anti-tumor immune response. The Phase III study in newly diagnosed advanced primary head and neck cancer with our Multikine immunotherapy produced a statistically significant 5-year survival benefit in patients receiving surgery plus radiotherapy, representing approximately 40% of the study population and it is estimated that globally about 210,000 patients annually could potentially benefit from it should it be approved. The 5-year overall survival (OS) benefit in this study treatment arm was robust and durable, with no safety issues, something not commonly seen with cancer drugs. In fact, the survival benefit increased over time and at 5-years the overall survival benefit reached an absolute 14.1% advantage for the Multikine treated arm over control (n=380, total study patients treated with surgery plus radiation), Multikine arm 62.7% and control arm 48.6%, survival.