Autologous Vaccine
for Non–Hodgkin's Lymphoma

BiovaxID is being developed by Biovest International, Inc., Accentia's publicly–held, majority–owned subsidiary. While Accentia and Biovest have great expectations for BiovaxID based on highly encouraging clinical trial results, this product has not yet been approved by the U.S. FDA or any international regulatory agency.

About BiovaxID®

BiovaxID is a personalized, patient–specific therapeutic vaccine designed to stimulate the patient's own immune system to recognize and destroy cancerous B–cells (a specific type of white blood cell or lymphocyte) that may remain in the body or may arise after the patient has been treated with chemotherapy. Unlike many other approaches to treating non–Hodgkin's lymphoma, BiovaxID is designed to kill only cancerous B–cells, with the initial indication of indolent follicular non–Hodgkin's lymphoma. Additionally, it is anticipated that BiovaxID could potentially be used to treat other types of blood cancers, such as Mantle Cell Lymphoma, Chronic Lymphocytic Leukemia and Multiple Myeloma.

Originally developed by researchers at the National Cancer Institute and Stanford University, BiovaxID holds the potential to be the very first anti–cancer vaccine to achieve U.S. and/or broad global approvals. Of the 130,000 new cases of non–Hodgkin's lymphoma (NHL) diagnosed every year in the U.S. and Europe, approximately 30% fall into the category of indolent, follicular B–cell NHL, which is the segment that BiovaxID is initially targeting. Although chemotherapy, radiation and certain immunotherapies are routinely used to treat indolent, follicular B–cell NHL, such treatments are by no means considered a cure, are often very difficult to tolerate, with relapse likely if not inevitable. There is an urgent need to improve existing regimens in order to indefinitely sustain remission rates, thus representing an enormous opportunity for BiovaxID.

What is a Cancer Vaccine?

Unlike a preventative vaccine, such as for measles or mumps, BiovaxID, is administered as a cancer treatment, designed to stimulate and "train" the patient's immune system to respond and attack cancerous cells, even long after therapy has been stopped — each vaccine being unique to that particular patient.

How is BiovaxID Unique from other Failed Cancer Vaccines?

Biovest harnesses each patient's own cancer cells to produce extremely high-fidelity BiovaxID vaccines. Using AutovaxID instruments, Biovest's production process creates vaccines which maximize the likelihood of establishing strong anti-tumor responses in vaccinated patients. By comparison, previous vaccine efforts relied on only gene fragments from isolated cancer cells which led to substantially reduced efficacy and immune responses following vaccination.

Mechanism of Action:

BiovaxID capitalizes on key features of B-cell and T-cell biology. Normally, B-cells produce antibodies. Each B-cell exhibits a unique protein on its surface (known as an idiotype) that is expressed when exposed to a foreign protein or substance. Because NHL arises from a single cancerous B-cell, every lymphoma cell in a patient's body will express the same idiotype. Each NHL patient will have a unique idiotype on his or her malignant B-cells. BiovaxID uses this idiotype to create a patient-specific vaccine that stimulates the patient's T-cells (immune cells that kill cancerous or virally infected cells) to seek out and destroy the cancerous B-cells, in addition to a B-cell immune response (humoral).

Significantly, a subset of T-cells activated by the vaccine appears to give rise to "memory" T-cells that enable the immune system to respond to the presence of remaining lymphoma cells long after therapy has been stopped. The effect may even be enhanced by maintaining a periodic BiovaxID booster-shot regimen. This is expected to be important in maintaining remissions for long periods of time.

To make BiovaxID, a sample of the patient's tumor is obtained during a biopsy. The cancerous B-cells are extracted from the sample and fused to cells that grow very well in culture, creating a custom-made cell line that produces large quantities of the unique idiotype protein. The idiotype is then purified. In order to induce a robust immune response (both B-cell and T-cell), the purified idiotype is linked to a molecule called KLH, an immune stimulant used in many approved vaccines.

BiovaxID consists of the cancer-specific idiotype antibody linked to KLH (also known as idiotype-KLH conjugate) injected under the skin with a protein known as GM-CSF. This protein is a potent stimulator of granulocytes and macrophages, cells of the immune system that play a key role in T-cell activation. These cells ingest the idiotype-KLH conjugate, process it into small fragments and display these fragments on the cell surface. The fragments are then "presented" to T-cells. Binding of the fragments to appropriate T-cell receptors activates these T-cells to proliferate and to destroy only those cells expressing the idiotype on their surface - the targeted lymphoma cells. As such, BiovaxID is expected to demonstrate an efficacious approach for the treatment of many B-cell blood cancers.

Clinical Trial Results

Completed Phase II Study: After completing the vaccination protocol (n=20), with a median 9-year following complete response to chemotherapy (PACE):

• 45% of patients remained tumor-free (continuous complete remission) after a median of 8-years.
• 95% of patients were still alive after 9-years.
• 95% had significant T-cell activity and/or 75% B-cell activity against their lymphoma cells

Completed Phase III Study: Enrollment was for newly diagnosed patients with follicular non-Hodgkin’s lymphoma. Randomization required that patients achieve a complete clinical remission (CR or CRu) following chemotherapy. Both arms of the clinical trial were well-balanced in terms of stage and degree of malignancy and in terms of patient characteristics at enrollment and randomization. The modified intent-to-treat (ITT) analysis from the point of randomization for all patients in the trial who received at least one dose of BiovaxID or control vaccination (n=117; 2:1 ratio of BiovaxID versus control) showed that the median duration of complete remission in the BiovaxID arm of the study was 44.2 months which is clinically and statistically significant compared to the control arm, median duration of cancer-free survival of 30.6 months. BiovaxID prolonged the cancer-free survival by 13.6 months or 44% (p-value = 0.045; HR = 1.6) with a median follow up of 56.6 months (range 12.6 to 89.3 months). (Publication Pending)

The Role of AutovaxID™ in the Production of BiovaxID

AutovaxID instruments form the core of the rapid, automated production process for BiovaxID. This system by design generates *full copies* of the immunoglobulin proteins which in turn efficiently "teach" the patient's immune system to establish a potent anti-cancer immune response. Moreover, competing vaccines are formulated using non-human mammal or insect-based production processes. While these systems seem initially simpler than Biovest's mouse/human heterohybridoma system, they may not also not fully duplicate the high-fidelity proteins produced within AutovaxID. Biovest believes this allows BiovaxID to induce in patients a characteritically durable, potent immune response to cancer.

Named-Patient (Compassionate-Use) Program:

IDIS Limited, a leading UK-based drug distributer, has agreed to exclusively supply BiovaxID under a Named-Patient (Compassionate-Use) Program in France, Germany, Italy, Greece, Spain and the United Kingdom. The product will be made available upon specific request by physicians and patients, provided the appropriate protocols are followed.

A Named-Patient Program is a compassionate-use drug access program under which physicians can legally prescribe investigational drugs to qualifying patients. Under this program, investigational drugs are administered to patients who are suffering from serious illnesses until the drug is approved by the European Medicines Agency (EMEA). The Named-Patient Program will make BiovaxID available to patients with various B-cell related blood cancers including: chronic lymphocytic leukemia; mantle cell lymphoma; multiple myeloma; and non-Hodgkin’s lymphoma.

Interested physicians/patients should contact Accentia/Biovest by calling Douglas Calder at 813-864-2558 or emailing him at dwcalder@accentia.net. Physicians/patients may also contact IDIS Pharma, Inc.for more information.