Red Vascular Branch Endograft System: Aortic Aneurysm


The Red Vascular Branch Endograft System allows percutaneous stent grafting of aortic aneurysms with branch artery involvement.

Both the aorta and its branches can be grafted, and both endograft sheaths withdrawn, from a single access site like the femoral artery.

Suitable aortic branches for endograft placement include the iliac, brachiocephalic, carotid, subclavian, renal, hepatic, and superior mesenteric arteries.

The system is nonmodular, meaning the main aortic graft and branch graft are delivered as a single unit and are covered by the same continuous fabric. This eliminates risk of endoleak (blood leakage into the aneurysm) caused by junctional separation of the aortic and branch grafts.

By contrast, modular systems like Endologix’s Ventana require that separate branch grafts be placed through openings (fenestrations) in the aortic graft. These systems can encounter problems, such as endoleak or branch graft migration, that compromise blood flow to organs (e.g., the kidneys) perfused by the branch arteries. Patients then require repeat procedures to fix these problems.

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AtheroNova’s Allowed Patent Claims to Bile Acid Treatment of Atherosclerosis

The U.S. Patent Office allowed AtheroNova’s patent application directed to treating atherosclerotic plaque using a bile acid that’s present in all of us, hyodeoxycholic acid (HDCA).  The press release is here.

The patent soon to issue from this application, which I prosecuted before the Patent Office, is apparently the first to claim using an unmodified, naturally occurring bile acid to treat vascular disease.

Another bile acid, ursodeoxycholic acid (UDCA), marketed as Actigall, dissolves gallstones.

AtheroNova conducted studies at the University of California, Los Angeles, to determine whether HDCA reduces plaque development in LDL receptor-knockout (LDLRKO) mice in a manner reflecting an ability to produce plaque regression in humans.  UCLA study investigator Diana Shih, PhD, concluded that it does.

Disclosure: I have no equity position in AtheroNova.

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Part 4: Biovest Meets Skeptic’s Requirements for “The Next Dendreon”

We’re looking at why Biovest (BVTI.PK) 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 arrest — much less 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 (ABPIQ.PK), 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: RHHBY.PK), 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).

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Part 3: Biovest Meets Skeptic’s Requirements for ‘The Next Dendreon’

This series investigates how the BiovaxID lymphoma vaccine may win FDA approval to make Biovest (BVTI.PK) “the next Dendreon,” according to criteria elaborated in David Miller’s Minyanville article of the same name. Dendreon (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 (ABPIQ.PK), 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.

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Part 2: Biovest Meets Skeptic’s Requirements for “The Next Dendreon”

Part 1 of this series examined the emphasis Minyanville’s David Miller rightly places on manufacturing in determining whether a company can become a cancer vaccine success, like Dendreon (DNDN) has with the FDA’s recent approval of Provenge (sipuleucel-T).

Besides Dendreon and Biovest (BVTI.PK), other companies are developing active immunotherapies for cancer. Celldex (CLDX) is working on a brain cancer vaccine. So is ImmunoCellular Therapeutics (IMUC.OB). Same for Antigenics’ (AGEN) Oncophage, for recurrent high-grade glioma. GlaxoSmithKline (GSK) is conducting the largest ever phase 3 clinical trial for lung cancer with its MAGE-A3 treatment.

With partner Merck KGaA [German: MRK], Oncothyreon (ONTY) is studying its cancer vaccine Stimuvax in two phase 3 trials for lung cancer and a phase 3 trial for breast cancer. Merck Serono halted the trials on March 23, 2010, for a single case of encephalitis (brain inflammation) in a patient receiving intensive cyclophosphamide – which itself could explain the encephalitis – in a separate multiple myeloma trial. The FDA also placed a clinical hold on the vaccine. That the Stimuvax trials have not resumed in two months now begs clinical explanation.

Let’s return to evaluating Biovest’s BiovaxID vaccine in light of David Miller’s other success considerations.

Technology

1. BiovaxID background

Understanding how the BiovaxID vaccine works depends on knowing some terms and relationships:

B-cells, or B-lymphocytes, are white blood cells that make antibodies.

Antibodies bind to antigens, which are usually proteins that are abnormal or foreign to the body, such as are found in some bacteria and viruses.

Immunoglobulins are antibodies. They either circulate freely or, when bound to the surface of B-cells, act as B-cell receptors.

The region of a B-cell receptor (or antibody) that binds an antigen is the idiotype, or antigen binding site.


The region of the antigen to which the B-cell receptor (or antibody) binds is the epitope, or antigenic determinant.

Every cell in a patient’s B-cell cancer, such as a lymphoma, is genetically identical (monoclonal) and carries an identical B-cell receptor, whose unique idiotype is expressed only on those cancer cells. This idiotype does not exist on normal cells.

Although an idiotype normally binds to an antigen, BiovaxID uses the unique idiotype of a patient’s lymphoma cells as an antigen itself, to trigger the patient’s immune system (especially T-cells) to attack the lymphoma.

BiovaxID is produced by focusing principally on one protein target: the idiotype.

To make BiovaxID, Biovest fuses a patient’s B-cells, obtained by lymph node biopsy, to hybrid cells licensed from Stanford. The fused cells grow millions of whole copies of the patient-specific B-cell receptor, the immunoglobulin containing the patient’s idiotype.

2. One or more targets

Miller finds many companies’ approach of targeting multiple cancer antigens simultaneously to be problematic because not enough molecular effort is spent targeting any one.

He states:

Companies will sell you hard that the polyantigen approach is the right one. They’ll tell you about antigen evasion and a bunch of other stuff all scientifically 100% accurate. The problem is we don’t know how to break immune tolerance to more than one antigen at a time. The scope of all clinical trials in [Dendreon’s] Provenge tells us that. We have to train in excess of 500,000,000 antigen presenting cells (APCs) for each antigen to break immune tolerance. . . .

I believe we will someday overcome this issue and be able to construct a technology capable of simultaneous antigen training. I don’t believe we’ll see it this decade.

Indeed, breaking immune tolerance to cancer antigens has been challenging. But if a therapeutic agent could sufficiently overcome immune tolerance to one cancer antigen, as Provenge does, there would be nothing inherently self-defeating if the agent also targeted additional antigens from the same cancer.

Miller is aware oncologists and immunologists disagree with his opinion. “Nothing is more controversial than my view that active immunotherapies focusing on more than one antigen target at the same time will fail,” he concedes.

He’s right: his view is controversial, perhaps partly because it forecloses possibilities without the existence of a sufficient condition for doing so. It’s like the emergency room doctor who says, “If we try fixing your both your leg fracture and your scalp laceration, we’ll surely fail. So we’ll just treat one of them.” Why not aim for both if you can?

The same is true for active immunotherapies. Even if prior attempts by others have failed, there’s no good reason a vaccine can’t work in provoking an immune attack against more than one cancer antigen. In fact, BiovaxID does just that.

Black swans, those events that seem extremely unlikely but in fact are not, exist in the eye of the observer. As author Nassim Nicholas Taleb puts it, “For the turkey, Thanksgiving is a black swan, but not for the butcher.”[1] David Miller’s apparent black swan, an effective multi-target cancer vaccine, may have been less of a surprise to the National Cancer Institute’s Sivasubramanian Baskar, who observed a T-cell response to multiple epitopes in patients whose lymphomas were kept in remission by BiovaxID.

Nevertheless, by being built around just one antigen set, the idiotype, BiovaxID should satisfy Miller’s preference for mono-targeting.

But unlike the recombinant vaccines made by Genitope and Favrille that failed phase 3 trials, BiovaxID employs not just the idiotype, but whole copies of the tumor’s unique B-cell receptor, the antibody containing the idiotype.

Injected into a lymphoma patient as the BiovaxID vaccine, the millions of copies of the B-cell receptor train a patient’s immune system to attack a range of antigens, not just one, on the lymphoma. These antigens include parts of the idiotype protein sequence, and some may overlap with other portions of the B-cell receptor. A multiple-antigen targeting effect has been demonstrated clinically, in BiovaxID’s phase 2 study, as a polyclonal T-cell response to the vaccine. This response makes for a robust therapy that appears to resist antigenic “escape” from the vaccine by the tumor. NCI lead investigator Dr. Larry Kwak discusses this issue at 3:45 and 24:45 of this ASCO presentation video, and in this paper (pdf file).

In Part 3, we’ll examine other vaccine technology hurdles companies must overcome in fighting cancer.


[1] Nassim Nicholas Taleb interview, Bloomberg TV, May 13, 2010, at http://www.youtube.com/watch?v=OVxcDgfTzuk (2:45).

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

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Biovest meets skeptic’s requirements for “The Next Dendreon” (Part 1)

Minyanville’s biotech analyst David Miller may not recognize it, but Biovest International (BVTI.PK) appears to meet his qualifications for the next big success story in cancer vaccines.

Following the FDA’s April 2010 landmark approval of Dendreon’s (DNDN) Provenge as the first active vaccine for cancer, enthusiasm runs high for other immunotherapy companies to find similar success.  But Miller appropriately urges caution.

In his May 12 article Finding the Next Dendreon, Miller employs his considerable industry experience to elucidate factors one should consider before investing in any cancer vaccine company.

By Miller’s criteria, Biovest, Accentia Biopharmaceuticals’ (ABPIQ.PK) majority-owned subsidiary, has what it takes to become “the next Dendreon” by gaining conditional FDA approval for its lymphoma vaccine, BiovaxID.

Let’s examine Biovest under Miller’s standard for achieving success as a cancer vaccine company.

Manufacturing

Miller notes that vaccine production failures are important:

The manufacturing success rate for Provenge is above 95%. If there is a manufacturing failure, it takes a few days to fix. This is one of two key advantages of Provenge compared to other active immunotherapies, and one almost nobody talks about. . . .

So, the first question you ask of your prospective next Dendreon is, “What’s your manufacturing success rate and is there any peer-reviewed literature documenting it?” Anything under 90% should cause you to move to the next company.

BiovaxID handily meets this requirement, with a manufacturing success rate of 95% to 98%.

The National Cancer Institute’s Larry Kwak, MD, PhD, lead investigator in BiovaxID’s phase 3 clinical trial, discussed this issue in his plenary presentation at the 2009 American Society of Clinical Oncology.  Dr. Kwak and his colleagues revealed in their ASCO abstract that only four manufacturing failures occurred.

Out of the 177 patients randomized in the trial, that’s a failure rate of 2.3%.  Or, out of the 117 patients who actually received either vaccine or control, it’s a failure rate of 3.4%.  And even if you count only the 76 patients who received the vaccine, it’s a failure rate of 5.3%. No matter how the peer reviewer will slice it in Dr. Kwak’s forthcoming academic article on the trial, that’s an admirably low rate.

Angelos Stergiou, MD, Biovest’s vice president of product development, stated after Dr. Kwak’s ASCO presentation that the BiovaxID manufacturing failure rate was only 2%: “The success rate in the BV301 study was actually 98 percent,” he said.  “[That was the rate at which] we were able to successfully manufacture the vaccine.”  His comment is at 32:50 in Dr. Kwak’s ASCO presentation video here:


Miller continues
:

Question number two is, “How fast can you manufacture the drug?” If the answer is longer than 14 days, look elsewhere.

This is true for Provenge and other treatments administered independently of chemotherapy, when time can be of the essence to arrest a cancer’s spread.

It’s not true for the BiovaxID vaccine, which is administered after immunosuppressive chemotherapy has induced remission of a patient’s lymphoma, and after the physician has waited at least another six months for the patient’s immune system to recover.  In this setting, the vaccine need only take less time to manufacture than the waiting period for immune reconstitution.  Currently, BiovaxID takes three months to manufacture, according to Dr. Stergiou (at 33:15 in the video above), well under the time it takes for a patient’s T-cell counts to recover enough to receive the vaccine.

In Part 2, we’ll look at cancer vaccine technology and more.

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Dr. Kwak’s 2009 ASCO presentation on BiovaxID lymphoma vaccine trial

2009 American Society of Clinical Oncology (ASCO) presentation Larry Kwak, MD, PhD, on the successful BiovaxID vaccine phase 3 trial for follicular non-Hodgkin’s lymphoma, sponsored by the National Cancer Institute.  The vaccine is made by Biovest International, a subsidiary of Accentia Biopharmaceuticals.

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Biovest clarifies post-bankruptcy royalties

Doug Calder, of Accentia and Biovest Investor Relations, told me today that after bankruptcy, Biovest will owe a perpetual royalty of 6.25% to Laurus, and 0.05% to Stanford for use of a cell line, for a total of 6.30%.

Ambiguously phrased and discussed in my 5/14 post, the reorganization plan’s drop in royalty to zero must therefore refer to the royalty existing prior to bankruptcy closing.

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Blog posts on Seeking Alpha

I have a couple of posts at Seeking Alpha.

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Who Has the Next Approvable Cancer Vaccine?

[Updated 5/19/10 in brackets below]

Biovest International
(BVTI.PK) appears to have the next potentially marketable cancer immunotherapy in its lymphoma treatment vaccine, BiovaxID.

Doctors and scientists have tried for half a century to develop a vaccine that harnesses a patient’s own immune system to fight cancer, but until this year, no one has produced such a vaccine that could be approved by the U.S. Food and Drug Administration (FDA).

With the FDA’s April 2010 approval of Dendreon’s (DNDN) prostate cancer vaccine Provenge, however, a new era in medicine has begun.  Biotech investors are now looking for the next approvable immune treatment for cancer.

Biovest is the only other company ever to have positive phase 3 clinical trial data for a therapeutic cancer vaccine.

In the plenary session of the 2009 American Society of Clinical Oncology (ASCO) meeting, Biovest presented results of its eight year pivotal, randomized, multi-center, double-blind, controlled phase 3 study.  In the trial, BiovaxID significantly prolonged disease-free survival in follicular non-Hodgkin’s lymphoma.

http://www.accentia.net/media/pr/biovestpr053109.html

Few investors are paying attention to vaccine maker Biovest or its majority owner, Accentia Biopharmaceuticals (ABPIQ.PK), because both companies are in Chapter 11 bankruptcy and are on the pink sheets.  Institutional investors currently show no interest, as they are generally required to avoid bankrupt stocks.  This poses an opportunity for retail investors.

Both Biovest and Accentia are close to emerging from bankruptcy with their common stock preserved.  Biovest filed its reorganization plan with the bankruptcy court on May 14 to that effect, and Accentia is expected to follow suit by June 4, 2010.

Biovest’s reorganization plan includes removing [reducing to 6.3%] the [35%] royalty it would otherwise owe others on future vaccine sales.  Interest and principal on its renegotiated debt are not due until maturity dates ranging from 24-40 months from the close of bankruptcy.  A 9.99% interest in Biovest is to be given to its largest secured creditor, Laurus Master Fund, in exchange for canceling all warrants.  And 17.6 million shares of Biovest will be given, in a swap for debt, to its parent, Accentia, which already owns about 76% of Biovest.  Further conversion of debt to equity is available to certain other creditors if they opt in by a voting deadline soon to be fixed.

Biovest’s current market cap is $154M, low relative to the company’s apparent potential, with 96M shares outstanding.

The next step is for creditors to accept the reorganization plans, followed by the court’s approval of the plans.  These events should happen within the next 1-3 months.

Disclosure: Long Accentia and Biovest; no company affiliation.

Beyond Provenge, investors are becoming excited by a resurgence of enticing progress utilizing cancer immunotherapies: Cel-Sci (CVM) is gearing up to manufacture sufficient Multikine to run its pivotal phase III trial in head and neck cancer. Bristol-Myers Squibb Company (BMY) announced that it will present the data from its phase III trial at the American Society for Clinical Oncology (ASCO) in June. In addition, GlaxoSmithKline (GSK) may present mid term data on its immunotherapy phase III clinical trial in lung cancer at ASCO. In addition to these much anticipated results, there are nearly a dozen other companies who are running phase III trials utilizing active immunotherapy, and the “fever” (no pun intended) is starting to spread.

One currently overlooked company which is in fact much farther along than all the above mentioned companies is Antigenics (AGEN). Since its inception in March 1994, Antigenics has been developing Oncophage (vitespen). Oncophage is a therapeutic cancer vaccine that is patient-specific, meaning it is derived from the patient’s own tumor. In contrast, Provenge is a vaccine derived from an external immunogen specific to prostate cancer.

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