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We’re looking at why Biovest (OTC:BVTI) may qualify as “the next Dendreon” under standards biotech analyst David Miller describes in his May 12 Minyanville article. Dendreon’s (DNDN) prostate cancer vaccine, Provenge (sipuleucel-T), received FDA approval in April 2010, creating a paradigm shift in cancer treatment.

In this series, Part 1 discussed vaccine manufacturing; Part 2 and Part 3, cancer vaccine technology.

Now for Miller’s other points on active immunotherapies.

Patients

Miller states:

I believe prostate cancer is the only place where an active immunotherapy is likely to be effective in later stages of the disease when used as a monotherapy. Prostate cancer is unique in its slow growth, though it can get out of hand quickly once metastatic and causing symptoms.

True, prostate cancer is generally slow growing, but it’s not unique in that respect. The cancer targeted by BiovaxID, follicular non-Hodgkin’s lymphoma, is also slow growing, as are many other cancers, such as in the ovary, colon, kidney, cervix, stomach, and bile ducts.

Miller:

Everyone believes the place to use active immunotherapies is in the earliest-stage patients [a company] can afford [to spend the time and money it takes to perform the clinical trials needed to demonstrate efficacy]. . . .

Earlier-stage patients live a long time. That means it takes a long time to get results from a clinical trial in earlier-staged patients. Long time equals more money.

Miller is right. Animal studies suggest immunotherapies tend to work better in earlier stages of cancer, and an active vaccine that works in an early human cancer stage could fail in a later one. There is a tension, then, between wanting to test a vaccine in patients with early disease, and not being able to afford to wait 15-50 years to determine whether the vaccine prolongs those patients’ survival.

Despite having late-stage cancer patients as subjects, both Dendreon’s and Biovest’s phase 3 trials took a long time to complete. Dendreon’s phase 3 (IMPACT) trial ran six years (2003-2009), and Biovest’s phase 3 ran eight years (2000-2008). If the companies had tested their vaccines in earlier stages of the cancers they treated, the time and cost involved could well have been prohibitive.

Miller’s further suggestion:

The next question is, “What stage patients are you targeting?” If the answer is “late stage,” then you should consider looking elsewhere as the data in late-stage patients for active immunotherapies aren't promising (outside prostate cancer).

That is ordinarily true. It’s tough to show good vaccine results in patients with advanced cancers, as there is often insufficient time, despite a primed immune system’s best efforts, to reverse the organ-destroying ravages of billions of cancer cells that have escaped years of the body’s attempted inhibition.

Fortunately, though, both Dendreon and Biovest have done it. In their pivotal phase 3 trials, each company studied patients with late-stage disease. Dendreon tested, and the FDA approved, Provenge use in asymptomatic or minimally symptomatic metastatic, castrate-resistant (hormone-refractory) prostate cancer. Biovest tested its BiovaxID vaccine in patients with stage III, IV and bulky stage II follicular non-Hodgkin’s lymphoma.

Both companies achieved statistically significant, positive results. Provenge extended median survival in prostate cancer patients by 4.1 months compared to controls (25.8 months versus 21.7 months). And BiovaxID prolonged median disease-free survival in follicular lymphoma patients, who were in at least six months of chemotherapy-induced remission, by 13.6 months compared to controls (44.2 months versus 30.6 months) (p = 0.045; HR = 0.62).

Furthermore, for BiovaxID, the difference in disease-free survival between patient groups who received either BiovaxID or a control vaccination was greatest around 36 months after randomization, when 61% of BiovaxID patients and 37% of control patients were free of disease. In other words, BiovaxID patients were 65% more likely to be cancer-free than were control patients (p = 0.023; HR = 1.9).

Biovest and its majority owner, Accentia Biopharmaceuticals (OTC:ABPIQ), say they plan to ask the FDA for Accelerated Approval when they file their biologic license application (BLA) for BiovaxID later this year. Accelerated Approval would allow Biovest to sell the vaccine in the U.S. while it runs a confirmatory (phase 4) trial further to prove the vaccine’s effectiveness.

A confirmatory trial may be needed because the treatment of non-Hodgkin’s lymphoma changed after the BiovaxID phase 3 trial began in 2000: Rituxan (rituximab), made by Genentech, a wholly owned member of the Roche Group (SIX: RO, ROG; OTCQX: OTCQX:RHHBY), and Biogen Idec (BIIB), became part of the standard of care for treating follicular lymphoma. Any confirmatory trial for BiovaxID, therefore, will likely involve use of Rituxan.

BiovaxID has shown it can sustain a patient’s second complete remission, induced with chemotherapy alone and followed by the vaccination, for longer than the duration of the same patient’s first complete remission obtained through chemotherapy plus Rituxan.[1] Because of this, and because of its excellent safety profile, it’s possible BiovaxID could complement or even compete with Rituxan as a therapy for maintaining remission in lymphoma patients.

Such a confirmatory trial could (1) measure disease-free survival in a larger group of patients than did Biovest’s completed phase 3 trial; (2) compare the effect of BiovaxID versus Rituxan on disease-free survival following chemotherapy-induced remission; (3) compare the effect of BiovaxID versus control vaccination on disease-free survival following remission induced by both chemotherapy and Rituxan; (4) administer BiovaxID not just to patients in complete remission, but also to those with stable disease, in partial remission, or both; (5) administer BiovaxID to patients sooner than six months after remission is induced; or (6) utilize some combination of these or other designs.

Target

Miller comments:

Targeted therapies are only as good as their target. Herceptin is a multi-billion dollar drug because they chose a great target and they screen all their patients for it. . . . Targeted therapies are the future of cancer therapy, especially when companies limit their patient enrollment to patients who have the target.

There are a series of questions here:

1. Is your target overexpressed or is it uniquely expressed on cancer cells?

Answer: BiovaxID’s target, the idiotype, is uniquely expressed, not just overexpressed, on patients' lymphoma cells.

2. Is your target present on normal tissue?

For BiovaxID, the answer is no. The idiotype target is present only on patients’ cancer cells, not their normal cells. Moreover, the idiotype appears essential for the cancer cells’ survival, making it nearly an ideal cancer antigen for targeting.

3. What percentage of patients express your target and do you screen for the target in your clinical trials?

One hundred percent of follicular lymphoma patients express a unique idiotype antigen set, BiovaxID’s target, on their B-cells. And yes, Biovest screens for the target, in the sense that it isolates, and makes many copies of, the idiotype in making each patient’s vaccine. This idiotype varies among lymphoma patients, making it a patient-specific antigen, not a universal tumor antigen. As a result, BiovaxID is personalized, made to target the patient’s unique idiotype protein sequence present on the B-cell receptors, or antibodies, bearing the idiotype.

Notably, BiovaxID is more targeted, more tailored to attack cancer cells and to avoid normal cells, than Dendreon’s Provenge is. Provenge trains a person’s T-cells to attack cancer cells that express an enzyme called prostatic acid phosphatase [PAP]. Not all prostate cancer cells produce PAP (about 95% do), and some normal cells do, including some nerve cells.

Based on Miller’s targeting preferences, BiovaxID is an unqualified winner.

Of Managers and Money

Miller’s final requirements for a cancer vaccine company:

The questions above will get you 70% of the way there for finding the next Dendreon. Truthfully, every company I've looked at in the past has flunked -- but if you find one that answers the questions correctly please let me know. I’d love to find another company that can get one of these wonderful products across the finish line for cancer patients.

The other 30% is, of course, the tangibles and intangibles that make any publicly traded company successful. Good IR, smart management, experienced clinical teams, and cash, cash, cash.

Miller’s points are well taken. In the case of Biovest and Accentia, both have good investor relations [IR], smart management, and an experienced clinical team. BiovaxID’s clinical trials were designed and run by the National Cancer Institute and led by Larry Kwak, MD, PhD, professor and chairman of the Department of Lymphoma / Myeloma, Division of Cancer Medicine, at the University of Texas M.D. Anderson Cancer Center, where he is also the Justin Distinguished Endowed Chair in Leukemia Research.

The biggest challenge Biovest and Accentia currently face is, in Miller’s words, “cash, cash, cash.” They each incurred substantial debt over the years running their clinical trials, leading both companies to declare bankruptcy in November 2008.

Like the phoenix rising from the ashes, however, Biovest filed its Chapter 11 reorganization plan with the bankruptcy court in Tampa on May 14, and Accentia filed its plan on May 28. Both companies’ plans involve converting a portion of the debt they owe creditors to equity (entailing some dilution for Biovest), delaying repayment of their remaining debt for at least two years, and preserving stockholders’ common shares. Investor relations says the plans should soon be approved by the judge.

For those who enjoy reading court filings, here are the bankruptcy plans (pdf files):

Biovest reorg plan 5-14-10 (1 of 2)

Biovest reorg plan 5-14-10 (2 of 2)

Accentia reorg plan 5-28-10

Both companies are now poised for a Biovest partnership or buyout, or for raising more cash in the capital markets. This will allow them, over the next 4-12 months, to file their BLA, update their SEC filings, and return from the pink sheets to the NASDAQ. As these events occur, one can expect to see institutional buying begin, pushing Accentia’s and Biovest’s share prices higher.

Conclusion

Investors looking to invest in companies developing active immunotherapies would do well to heed David Miller’s advice. Appearing to meet and, in some ways, exceed his criteria for success, Biovest is on track to become the next Dendreon.


[1] Bendandi, M: Idiotype vaccines for lymphoma: proof-of-principles and clinical trial failures. Nature Reviews Cancer 9, 675-681 (September 2009).



Disclosure: Long BVTI.PK, ABPIQ.PK, and DNDN. No company affiliation.

Source: Biovest Meets Skeptic's Requirements for 'The Next Dendreon' - Part 4