Biovest Issues Post-ASH Update for BiovaxID® Personalized Cancer Vaccine including Significance of Isotype Phase III Data

Files Annual Report and Reports Antibody Manufacturing Contract

TAMPA, Fla. & MINNEAPOLIS--(BUSINESS WIRE)-- Biovest International, Inc. (OTCQB: “BVTI”) today issued the following update in the form of a “Frequently Asked Questions” report in response to the high volume of inquiries received following the Company’s recent presentation at the 2010 American Society of Hematology Annual Meeting (ASH 2010) in Orlando, Florida.

BiovaxID Phase III Overview

In the BiovaxID Phase III clinical trial, patients with follicular lymphoma in first remission were treated with BiovaxID®, a personalized cancer vaccine originally developed at the National Cancer Institute, or a control vaccine. In the study, patients who received BiovaxID demonstrated an average of 13.6 months of additional disease-free survival (duration of remission) compared to patients who received a non-specific control vaccine. BiovaxID represents the only lymphoma vaccine, and the second cancer vaccine overall, to demonstrate positive clinical benefit in a completed, randomized Phase III clinical trial.

Because of the significance of these findings, the results of the BiovaxID Phase III clinical trial were selected for presentation on May 31, 2009 at a Plenary Session of the American Society of Clinical Oncology (ASCO) Annual Meeting.

ASH 2010 Summary

In December 2010, Biovest was selected to present additional data from its Phase III clinical trial at ASH 2010. These data expand and refine the Phase III study findings previously reported at ASCO and further establish BiovaxID’s clinical benefit in the treatment of lymphoma. The data arise from a detailed analysis of Biovest’s manufacturing process in conjunction with the clinical outcomes observed in the Phase III clinical trial. The findings demonstrate that a fundamental protein characteristic of BiovaxID profoundly impacts clinical benefit following vaccination in follicular lymphoma.

In summary, the data reported at ASH 2010 demonstrate that the improved disease-free survival observed in BiovaxID-treated patients depends upon a specific variant of the tumor-derived protein fragment present on each patient’s BiovaxID vaccine. In lymphoma, this protein variant (or isotype) can be determined at time of initial tumor biopsy to be of either “IgM” or “IgG” type. Due to the unique nature of BiovaxID’s manufacturing process, Biovest reproduces each patient’s specific tumor isotype in the manufacture of BiovaxID, and therefore, every patient ultimately receives a vaccine which matches their specific tumor isotype (“IgM” or “IgG”). (See Figure 1)

Approximately half of the patients (46%) in the Phase III clinical trial had tumor cells bearing the IgM isotype protein (and therefore were provided with BiovaxID manufactured with IgM isotype), and the remainder had tumor cells bearing IgG isotype protein (and therefore were treated with BiovaxID manufactured with IgG isotype). The tumor isotype of the vaccine was previously believed to be unimportant to clinical benefit.

The new analysis revealed that patients receiving BiovaxID manufactured with an IgM isotype experienced a dramatic disease-free survival benefit, while patients receiving BiovaxID manufactured with the IgG isotype did not experience a clinical benefit from vaccination.

Frequently Asked Questions:

Q: What was reported at ASH 2010?

A: At ASH 2010, Biovest scientists and collaborators reported that the isotype used in the manufacture of BiovaxID profoundly impacts the duration of remission (disease-free survival). Patients vaccinated with the IgM version of BiovaxID experienced a highly statistically significant increase in disease-free survival (duration of remission) of over two years compared to control-treated patients. These data reported at ASH 2010 clearly and unambiguously demonstrate that BiovaxID provides a substantial benefit to patients diagnosed with follicular lymphoma.

The findings presented at ASH 2010 are highly statistically significant and clarify the outcomes presented for the Phase III clinical trial.

Q: Do the ASH 2010 findings represent a new scientific discovery?

A: Yes; prior to the data presented by Biovest at ASH 2010, scientists did not recognize the crucial impact that vaccine isotype has on extension of remission following idiotype vaccination. As an example, in two previous Phase III clinical trials of idiotype vaccines to treat follicular lymphoma, manufacturers universally produced vaccine exclusively with IgG isotype. Both of these studies, by Genitope Corporation and Favrille, Inc., failed to demonstrate a statistically improvement in disease-free survival. As reported at ASH 2010, the outcomes of the Genitope and Favrille trials resemble the outcomes reported for BiovaxID when it is manufactured with IgG isotype, but they contrast significantly with the robust clinical benefit reported for patients treated with BiovaxID when it is manufactured with IgM isotype. In the Phase III clinical trial, patients receiving IgM BiovaxID experienced a median of over two years of disease-free survival compared to IgM-control patients (p=0.001).

Q: How did the IgM-version of BiovaxID perform when compared to the IgG-version of BiovaxID?

A: As reported at ASH 2010, patients treated with IgM-isotype BiovaxID experienced a median disease-free survival of over two years compared to IgM tumor isotype control-treated patients (p=0.001). Patients vaccinated with IgG-isotype BiovaxID did not experience a significant improvement in disease-free survival compared to patients in the control vaccine arm. Furthermore, patients treated with BiovaxID manufactured with IgM isotype experienced a median disease-free survival of 52.9 months compared to 30.6 months for all control vaccinated patients (including both IgG and IgM control patients). These results were also statistically significant (p=0.01).

Q: Do the ASH 2010 data impact Biovest’s regulatory strategy to seek marketing approval for BiovaxID?

A: Yes; we expect the ASH data will bolster the efficacy determination for BiovaxID and support our regulatory strategy.

We are preparing for discussions with the regulatory agencies to clarify the next steps required by the regulatory agencies in order for Biovest to seek marketing approval for BiovaxID. While we consider our planned discussions with regulatory agencies to be confidential, we can broadly outline our regulatory strategy.

Our regulatory strategy is based on our Phase III clinical trial, which we believe clearly and unambiguously demonstrates that BiovaxID is both highly safe and efficacious. The BiovaxID Phase III clinical trial, which was designed by the National Cancer Institute (NCI), confirms the results of our Phase II clinical trial which was also designed by the NCI. Accordingly, under our regulatory strategy, we plan to pursue marketing approval for BiovaxID based on the cumulative clinical trials completed to date and without conducting additional lengthy pre-approval clinical trials. Our strategy is based on the entire body of evidence from BiovaxID’s clinical trials which we believe were conducted in an adequate and well-controlled clinical setting. Further, we believe that the data reported at ASH 2010 supports and clarifies the efficacy of BiovaxID and clearly demonstrates that BiovaxID provides a robust clinical benefit to vaccinated patients.

As a patient-specific cancer vaccine, BiovaxID represents a new class of drugs designed to elicit the immune system’s natural disease fighting mechanism in a highly personalized and targeted manner. The mode of action and target of BiovaxID is entirely different from any other drug that is approved to treat follicular lymphoma, which remains uncured and frequently fatal notwithstanding current treatment regimens. Our regulatory strategy recognizes that accelerated/conditional approval may be an appropriate regulatory pathway, in part because BiovaxID has received orphan designation in both the U.S. and the EU for the treatment of follicular lymphoma; the use of BiovaxID is supported by a body of evidence from three separate clinical trials; follicular lymphoma is an uncured, fatal disease and BiovaxID represents a new mode of action with robust clinical benefit. Under our conditional approval strategy, we would anticipate that additional studies would be required and accordingly, our regulatory strategy includes Phase IV, post-approval trials to be designed with input from the regulatory agencies.

While we believe that our regulatory strategies are sound, ultimately we are subject to decisions as rendered by regulators.

Q: How do the isotype findings presented at ASH 2010 impact the Phase III clinical trial outcomes presented at ASCO 2009?

A: The data presented at ASH are highly supportive of the Phase III clinical trial outcomes reported at ASCO 2009. In our Phase III trial, patients with follicular lymphoma in first remission were treated with BiovaxID and compared to patients vaccinated with a control treatment. As reported at ASCO, patients receiving BiovaxID demonstrated an average of 13.6 months of additional disease-free survival compared to patients who received a non-specific control vaccine. This outcome was statistically significant (p=0.045), and these results, as a whole, form the basis for our regulatory strategy. The ASH data place these Phase III results in context by clarifying that the cohort of patients in the Phase III trial that received BiovaxID manufactured with IgM isotype more than doubled the months of disease-free survival (24-months) when compared to IgM-control patients (log-rank p=0.001). In stark contrast, BiovaxID manufactured with IgG isotype showed no statistically significant treatment benefit when compared to IgG-control.

Accordingly, the overall Phase III outcomes for all vaccinated patients are even more impactful now that it is clear that of the patients treated with BiovaxID, only those treated with the vaccine manufactured with IgM isotype, representing approximately one half of all patients treated, received benefit.

Q: Are the BiovaxID efficacy results reported at ASH 2010 retrospective or prospective in nature?

A: The ASH 2010 isotype outcomes, although not originally planned in the study protocol, analyzed data that were collected prospectively as part of the study. The study protocol prospectively established enrollment criteria that only patients with IgM or IgG-positive tumors could enroll in the study. Furthermore, the individualized nature of BiovaxID required prospective determination of each vaccine’s isotype prior to vaccine manufacture. The ASH 2010 findings, although discovered after the study concluded, were not arrived at as a result of statistical “data mining” techniques, nor are the findings biased in nature; detailed statistical analyses conducted following the discovery furthermore suggest that no other factors (e.g. prior cycles of chemotherapy received, IPI status at enrollment, etc.) were responsible for the observed differences in outcomes. Ultimately, however, these data are not being offered as a subset analysis intended to replace the overall positive outcomes for vaccinated patients in Phase III clinical trial; rather, these data strongly support the determination of vaccine efficacy.

Q: In follicular lymphoma, do IgG and IgM-positive patients differ substantially in terms of prognosis?

A: Previous studies do not seem to suggest a strong or significant difference in prognosis between IgM and IgG-positive patients. In our Phase III clinical trial, IgM-positive control patients experienced shorter median duration of remission than IgG-positive patients (28.7 months versus 32.4 months; log-rank p=0.32), but these results were not statistically-significant.

In our Phase III trial, BiovaxID IgM-vaccine treated patients demonstrated a highly statistically significant improvement in disease-free survival (52.9 months versus 30.6 months; log-rank p=0.01) when evaluated against all control patients (regardless of their isotype status). Furthermore, we have conducted extensive statistical analysis of all covariates (including disease status, number of chemotherapy cycles prior to vaccination, age, sex, etc.) obtained in the trial between IgG and IgM active and control cohorts, and there does not appear to be a significant imbalance between these factors in each cohort. The study overall was well-balanced between arms (data presented at ASCO 2009 and ASH 2010 provide these results in detail).

Accordingly, we believe there are no significant factors in the clinical trial that would explain the difference in the clinical benefit between the IgM and the IgG cohort except the impact of BiovaxID manufactured with IgM isotype compared to BiovaxID manufactured with IgG isotype.

Q: How do prior Phase III clinical trial outcomes reported by Genitope and Favrille in follicular lymphoma impact the Biovest Phase III clinical trial?

A: The Phase III clinical trials conducted by Genitope and Favrille each evaluated idiotype vaccines manufactured only with IgG isotype (regardless of tumor isotype). These studies unfortunately failed to show statistically significant clinical benefit. From the outset, Biovest has publicly asserted that high-fidelity reproduction of lymphoma idiotype protein could be fundamental to the efficacy of cancer vaccines in follicular lymphoma. Biovest’s hybridoma manufacturing system produces vaccines fundamentally distinct from the recombinant methods employed in Genitope and Favrille’s vaccines which used a universal IgG isotype.

The BiovaxID clinical trials studied vaccines manufactured with IgM isotype vaccine if the patient’s cancer cells were classified as IgM and manufactured vaccines with IgG isotypes if the patient’s cancer cells were classified as IgG. The Genitope and Favrille trials each failed to report clinical benefit while the BiovaxID trial reported statistically significant clinical benefit both for all vaccinated patients and in particular for the IgM vaccinated patient population. Interestingly, the results for Genitope and Favrille’s IgG-isotype vaccines generally correspond with the results observed for the IgG-isotype vaccines studied in the BiovaxID clinical trial (in which IgG-vaccinated patients did not receive benefit from vaccination). These results dramatically differ from results seen with the patients treated with BiovaxID manufactured with IgM-isotype who experienced a highly statistically significant improvement in disease-free survival.

Accordingly, the data reported at ASH 2010 support BiovaxID as the only cancer vaccine to provide robust clinical benefit in follicular lymphoma. The ASH 2010 data clearly distinguish the BiovaxID clinical trial from prior studies by Favrille and Genitope, thus definitively eliminating any suggestion that the studies by Genitope and Favrille in any way impact the reliability of the BiovaxID clinical trial outcomes. (See Figure 2)

Q: How do the ASH 2010 data affect the potential market opportunity for BiovaxID?

A: Compelling clinical data only enhances the likelihood of physician/patient adoption which may increase market penetration following approval. Additionally, the ASH 2010 data refine our understanding of patient benefit gained from vaccination which will impact our cost/benefit analysis and potentially the reimbursement matrix for BiovaxID if approved.

Q: What percentage of patients with follicular lymphoma are IgM-positive?

A: It is believed that at least 50% of follicular lymphoma patients are IgM-positive, although some key opinion leaders believe the percentage could be closer to 70% being IgM-positive. For mantle cell lymphoma and certain other types of lymphoma, including aggressive diseases for which there are no standard of care, virtually all patients are IgM-positive.

Q: How long does it take to manufacture BiovaxID?

A: We estimate that an average of 3-months is required to manufacture the vaccine for each patient. While the manufacturing process for the BiovaxID vaccine is highly personalized to each patient, we consider it to be highly controlled and predictable. During the Phase III clinical trial we experienced approximately 95% success rate in manufacturing vaccines. The most common reason for a failure to successfully produce a patient’s vaccine was the presence of rare idiotype variants as opposed to the failure of a step in the manufacturing process.

Q: Is the clinical benefit reported at ASCO 2009 measured from randomization?

A: Yes; the data reported at ASCO was measured from time of randomization. For clarification there was not a 6-month delay in such measurement as some internet reports have recently suggested. The BiovaxID data reported at the 2009 ASCO Plenary Session measured disease-free survival for two prospectively-defined populations from randomization: all randomized patients, and; all randomized patients that were vaccinated with either BiovaxID or the control vaccine. The statistically significant results (p=0.045) achieved by comparing patients treated with BiovaxID versus patients treated with control showed that patients who received BiovaxID experienced a median disease-free survival of 44.2 months compared to 30.6 months for those who received a control vaccine – an increase of over a year on average. In the study, with a median follow-up of 4.7 years, patients receiving BiovaxID experienced a 38% lower risk of disease recurrence compared to patients receiving the control vaccine.

Q: Is BiovaxID important since rituximab-containing chemotherapy is the current standard of care?

A: Yes; BiovaxID represents a potentially very important therapeutic option. Follicular lymphoma remains almost universally incurable and frequently fatal notwithstanding currently approved therapies, including rituximab. While it seems clear that rituximab extends survival by delaying time to relapse, many patients do not respond to or are contraindicated for rituximab, and most patients will eventually become resistant to rituximab. Thus, additional therapies are urgently needed notwithstanding the current standard of care.

BiovaxID represents an entirely new class of therapy for follicular lymphoma. BiovaxID relies on an entirely new mode of action which targets the idiotype protein expressed on the surface of cancerous B-cells, but not expressed on healthy B-cells. Thus, BiovaxID seeks to elicit the immune system to identify cancerous B-cells as foreign in order to employ the immune system’s natural disease fighting mechanism. In contrast, rituximab targets the “CD20” receptor which is on the surface of almost all B-cells including healthy B-cells. Thus, rituximab’s mode of action seeks to destroy B-cells indiscriminately in the body as a way to control cancer progression. Because follicular lymphoma relapse remains extremely common and eventually affects nearly all patients even with current therapies, new therapeutic options with different modes of action are highly important.

Q: Are the results of the Phase III clinical trial reliable because the study accrued fewer patients than originally intended?

A: Yes; we believe that the results are highly reliable despite the fact that enrollment concluded before accruing as many patients as originally anticipated. At ASCO 2009, we reported that despite this reduced sample size, our clinical trial showed a statistically significant improvement (p=0.045) in disease-free survival for patients treated with BiovaxID as compared to control. It is important to consider that a decrease in sample size (also referred to as a decrease in power) increases the risk of not detecting a true clinical benefit when one actually exists. Small sample sizes effectively increase the risk for sponsors that planned studies will not reliably detect a significant clinical benefit where such benefits truly exist. The size or power of a clinical trial is in many ways a function of the sponsor creating a reasonable likelihood of demonstrating statistical benefit. These considerations are frequently evident in the general design and conduct of clinical trials, and include examples where sponsors anticipate that extremely large sample sizes are required to reliably demonstrate differences in drugs with relatively weak or difficult to measure effects. Therefore, we believe that the statistically significant results reported for the BiovaxID Phase III trial may be even more compelling given the increased risk of study failure from the reduced sample size.

The reduced sample size may, however, raise certain considerations which as a whole may be overcome if the final study baseline characteristics are well balanced, allocation is concealed, and the study is double-blinded. At ASCO 2009, we reported the results of 117 treated patients in a randomized, double-blinded Phase III clinical trial in which both study arms were extremely well-balanced in all relevant criteria.

Q: Is BiovaxID safe?

A: Yes; the Phase III clinical trial demonstrated that BiovaxID is highly safe. In our clinical trial, both idiotype-vaccine and control were safe and well tolerated. There were no statistically significant differences in frequency or types of adverse events observed between groups. As reported at ASCO 2009, mild (grade 1-2) adverse events were common in both BiovaxID and control groups, and the most common adverse events were mild injection site reactions (>80% of patients on each arm). In our study, grade 3-4 adverse events were extremely rare. There were no vaccine-attributable severe adverse events. These results correspond to results observed in all clinical trials of idiotype vaccination to date and correspond to the highly selective and targeted nature of immunization.

Biovest Reports New Manufacturing Contract

In other news, Biovest reported that a leading global medical technology company has contracted Biovest to produce a monoclonal antibody diagnostic product to be manufactured at the Biovest cell culture center in Minneapolis, Minnesota. The contract is valued at approximately $350,000.

Biovest’s Chief Scientific Officer, Mark Hirshel, Ph.D., stated, “We’re pleased to have been selected as the Contract Manufacturer for this new client, a wholly-owned subsidiary of an $18 billion dollar global organization. Their product, which is an approved monoclonal antibody intended for diagnostic application, will be produced using our Acusyst Hollow Fiber Bioreactor instrumentation, and it’s gratifying when customers recognize the many key advantages offered by this technology. Further, other new clients have expressed strong interest in our services, and we expect to report additional contracts early next year.”

Biovest also announced that it filed its Annual Report on Form 10-K with the Securities and Exchange Commission (SEC) for the fiscal year ended September 30, 2010, with the report containing a going concern qualification from its independent registered accounting firm, Cherry Bekaert & Holland LLP.

Biovest’s President, Mr. Samuel S. Duffey, stated, "We highly encourage our stockholders to review our Annual Report, as it also includes a detailed review of the updated Phase III results for BiovaxID presented at the ASH Conference. In our view, this striking discovery showing that the isotype plays a defining role in determining clinical benefit for idiotype-based lymphoma vaccination further improves the value proposition for BiovaxID."

About Biovest International, Inc.

Biovest International, Inc. is an emerging leader in the field of active personalized immunotherapies. In collaboration with the National Cancer Institute, Biovest has developed a patient-specific, cancer vaccine, BiovaxID®, with three clinical trials completed, including a Phase III study, demonstrating evidence of safety and efficacy for the treatment of indolent follicular non-Hodgkin’s lymphoma.

Headquartered in Tampa, Florida with its bio-manufacturing facility based in Minneapolis, Minnesota, Biovest is publicly-traded on the OTCQB™ Market with the stock-ticker symbol “BVTI”, and is a majority-owned subsidiary of Accentia Biopharmaceuticals, Inc. (OTCQB: “ABPI”).

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Statements in this release that are not strictly historical in nature constitute "forward-looking statements." Such statements include, but are not limited to statements about BiovaxID®, AutovaxID™, events occurring after dates hereof, and any other statements relating to products, product candidates, product development programs, the FDA or clinical study process including the commencement, process, or completion of clinical trials or the regulatory process. Such statements may include, without limitation, statements with respect to the Company's plans, objectives, expectations and intentions, and other statements identified by words such as "may," "could," "would," "should," "believes," "expects," "anticipates," "estimates," "intends," "plans," or similar expressions. Such forward-looking statements involve known and unknown risks, uncertainties, and other factors that may cause the actual results of Biovest to be materially different from historical results or from any results expressed or implied by such forward-looking statements. These factors include, but are not limited to, risks and uncertainties related to the progress, timing, cost, and results of clinical trials and product development programs; difficulties or delays in obtaining regulatory approval for product candidates; competition from other pharmaceutical or biotechnology companies; and the additional risks discussed in filings with the Securities and Exchange Commission. All forward-looking statements are qualified in their entirety by this cautionary statement, and Biovest undertakes no obligation to revise or update this news release to reflect events or circumstances after the date hereof. The product names used in this statement are for identification purposes only. All trademarks and registered trademarks are the property of their respective owners.

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Biovest International, Inc.
Douglas Calder, 813-864-2558
Director of Investor Relations & Public Relations
Email: [email protected]

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