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This series investigates how the BiovaxID lymphoma vaccine may win FDA approval to make Biovest (OTC:BVTI) “the next Dendreon,” according to criteria elaborated in David Miller’s Minyanville article of the same name. Dendreon (NASDAQ:DNDN), you will recall, is the first company ever to achieve FDA approval of a cancer vaccine, with it flagship product, Provenge (sipuleucel-T).

Part 1 of this article dealt with vaccine manufacturing issues, Part 2 with multi-antigen targeting by cancer vaccines.

Let’s dig into more of Miller’s considerations for active immunotherapy companies.

Technology (continued from part 2)

3. SPA treatment

Miller opines:

So the question here is, “Does your treatment focus on just one antigen at a time or multiple antigens simultaneously?” If the answer is multiple antigens simultaneously, don’t invest until they’ve proven in a prospectively designed, FDA Special Protocol Assessment-governed, randomized, and pivotal Phase III trial... or even wait until after they are FDA approved.

Miller’s advice is good for companies with clinical trials started in 2002 or later, not for Biovest. That’s because Special Protocol Assessments (SPAs), which are declarations from the FDA that a planned phase 3 trial's design, clinical endpoints, and statistical analyses are acceptable for FDA approval, first became available with guidance from the FDA in 2002. Focusing on patients’ lymphoma idiotype, BiovaxID has shown statistically significant results in its prospectively designed, randomized, pivotal phase 3 trial. The trial was conducted without an SPA because it began in 2000, two years before the FDA made SPAs available.

Biovest and its parent company, Accentia Biopharmaceuticals (OTC:ABPIQ), say they plan to work carefully with the FDA later in 2010 to prepare a biologic license application (BLA) for BiovaxID. First, both Accentia and Biovest are expected to emerge from Chapter 11 bankruptcy this summer with their common shares preserved.

4. Cancer antigens: enemies in hiding

Miller notes an important problem with active cancer vaccines:

Cancer is tricky. It uses your own cells against you. It's not a foreign invader like a virus or bacteria, so your immune system doesn't recognize it until too late -- if at all. Worse, cancer has developed the ability to hide from the immune system. If the immune system gets close to catching on that something is very wrong, cancer sacrifices bits of itself to the immune system. When that doesn’t work, cancer releases cytokines to “drug” the immune system. This collectively is called “immune tolerance.”

Breaking immune tolerance is the goal of any active immunotherapy. Doing it is a big deal, which is why science geeks are so excited about Provenge. In 100 years of trying, Provenge is the first drug to do it.

Miller is correct that tumor antigens usually fail to elicit an immune response.

To solve this problem of stealth targets, Biovest chemically assists the idiotype in BiovaxID to urge a patient’s immune system to attack her lymphoma cells, which all bear the idiotype. The company accomplishes this in two ways:

First, it binds each copy of the idiotype in the vaccine to a carrier protein, keyhole limpet hemocyanin (KLH). Although the idiotype is a weak antigen by itself, KLH is strongly immunogenic, causing one’s B-cells and T-cells to become primed for attack.[1],[2]

Second, the vaccine contains granulocyte-macrophage colony-stimulating factor (GM-CSF) to stimulate an immune response. When added to the KLH-containing vaccine, T-cell immunity is significantly enhanced.[3]

Both these immune stimulants, KLH and GM-CSF, were used in the control arm of BiovaxID’s phase 3 study. The significant improvement in disease-free survival in the treatment arm is therefore attributable to the idiotype/immunoglobulin component of the vaccine, or to the combination of this component and the immune stimulants.

5. Out of body experience

Miller cites another preference:

Because cancer is so crafty, I'm heavily biased toward approaches that train the immune system outside the body. . . .

[F]or now my investing sights will be biased toward companies that duplicate Dendreon’s approach. Get the immune system cells outside the body, train them there, and then give them back to the patient. . . .

Dendreon’s approach trains the APCs [antigen presenting cells] -- those cells that, in turn, train T-cells. This appears to be the right approach. Recent advancements in T-cell technology and understanding may break the 1990s curse on that technology, but I’d be darn careful and invest very small in any of these technologies until they prove they’ve fixed their problems.

The next question then is, “Do you train immune cells inside or outside the body, and which immune cells are you focusing on?” The right answer is “outside” and “antigen presenting cells” (or dendritic cells).

Dendreon’s approach – training APCs outside the body to transform T-cells inside the body into little "killers" – has indeed proven effective. But it’s not the only way to overcome immune tolerance. This paper by Kwak and colleagues shows that idiotype vaccines like BiovaxID indeed train APCs (antigen presenting cells), which then activate T-cells to recognize lymphoma antigens for attack. Thus, BiovaxID uses Miller’s choice of immune cell target, as well as other targets such as B-cells.

BiovaxID doesn’t train APCs outside the body, however. It doesn’t need to do so to be effective. Instead, the vaccine breaks immune tolerance of lymphoma antigens by training APCs, and by stimulating other parts of the immune system, inside the body. The efficacy of this approach is demonstrated by BiovaxID’s ability, as shown in its phase 3 trial, to prolong disease-free survival in non-Hodgkin’s lymphoma from 30.6 months for control subjects to 44.2 months for BiovaxID-treated subjects (p = 0.047).

In Part 4, we’ll discuss, inter alia, the patients studied in developing cancer vaccines.

[1] Kaminski, M. S., Kitamura, K., Maloney, D. G. & Levy, R. Idiotype vaccination against murine B cell lymphoma. Inhibition of tumor immunity by free idiotype protein. J. Immunol. 138, 1289–1296 (1987).

[2] Harris, J. R. & Markl, J. Keyhole limpet hemocyanin: molecular structure of a potent marine immunoactivator. A review. Eur. Urol. 37 (Suppl. 3), 24–33 (2000).

[3] Kwak, L. W., Young, H. A., Pennington, R. W. & Weeks, S. D. Vaccination with syngeneic, lymphoma-derived immunoglobulin idiotype combined with granulocyte/macrophage colony-stimulating factor primes mice for a protective T cell response. Proc. Natl Acad. Sci. USA 93, 10972–10977 (1996).

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

Source: Biovest Meets Skeptic's Requirements for 'The Next Dendreon' - Part 3