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James Hill, MD
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James Hill is a clinical assistant professor of radiology at the University of Southern California Medical School, and a patent lawyer and partner at McDermott Will & Emery. Although he relies on publicly available information and makes reasonable efforts to confirm its accuracy, all... More
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  • FDA Panel Flubbed in Arena’s Lorcaserin Disapproval

    Last week’s FDA panel that voted 9-to-5 against approving Arena Pharmaceuticals’ (NASDAQ:ARNA) obesity drug Lorqess (lorcaserin) apparently blundered in its assessment that the company’s rat breast tumor findings merit concern, according to the FDA’s own published standards.

    Bloomberg reported that "a panel of outside advisers to the FDA voted against recommending the drug for approval, citing concerns about tumors seen in rats in early-stage testing of the drug. … Of particular concern was the increase of mammary tumors in rats treated with lorcaserin, the committee said."


    But here’s how the FDA panel was earlier briefed:

    Lorcaserin was investigated in a standard battery of genotoxicity, reproductive toxicity, general toxicity, and carcinogenicity studies. Lorcaserin showed no reproductive toxicity or genotoxicity. General toxicity studies were conducted in mice, rats, and monkeys at doses that produced very high exposure multiples relative to the human maximum recommended dose (NASDAQ:MRD). In repeated dose Good Laboratory Practice (NYSE:GLP) toxicity studies, lorcaserin was generally well tolerated at doses below the maximum tolerated dose (NYSE:MTD) in all three species and there appeared to be no adverse findings of direct relevance to humans at therapeutic doses [emphasis added].

    Two-year carcinogenicity studies were conducted in mice and rats. There was no evidence of carcinogenicity in mice. In rats, and almost exclusively male rats, tumors were found in multiple organs primarily at the highest dose, which provided an exposure that was 56-fold greater than human and was clearly above the MTD [emphasis added].


    So lorcaserin was found not to be genotoxic, meaning it does not harm a cell’s genetic material, especially DNA.  Rather, lorcaserin’s mechanism for promoting breast tumors at only high, toxic doses may be hormonal, in a way that apparently does not exist in humans.  According to the FDA brief, “The mammary tumors are attributable to increased prolactin, a mechanism peculiar to the rat.”   


    Prolactin is the pituitary hormone that causes milk production in the breast.  Although a role for prolactin in the promotion of breast cancer has been proposed, recent research indicates that prolactin protects against aggressive human breast cancer, at least by blocking an oncogene called BCL6.

    Besides, lorcaserin does not raise prolactin levels in humans.


    The FDA brief:

    [T]he relevance of these tumors to humans is questionable because: 1) lorcaserin is not genotoxic; 2) substantial margins and/or rodent specific mechanisms were identified for each of the tumors; 3) the tumors were found primarily in one gender of one species at a toxic dose; and 4) no preneoplastic or neoplastic lesions were found in any other toxicity studies in the rat, mouse or monkey.


    Rat tumors, benign and malignant

    Male rats had a significant benign breast tumor (fibroadenoma) incidence only if they received 56 times the lorcaserin exposure humans would get at the proven-effective dose of 20 mg per day.

    Male rats had no significant increase in breast cancer (adenocarcinoma) at any dose of lorcaserin.

    control rats, who received no lorcaserin, showed high rates of spontaneous benign and malignant breast tumors at baseline. Forty-three percent of female rats that never touched lorcaserin developed cancer!  That's just how these animals' bodies operate.

    Female rats developed significantly more benign
    breast tumors (fibroadenomas) at all doses of lorcaserin, but this has no known implication for human cancers.

    Female rats showed a significant increase in
    breast cancer (adenocarcinoma) only if they received 84 times the lorcaserin exposure humans would get at the standard dose of 20 mg per day.

    Excerpts of the FDA briefing tables:

    Male Rats

    Mammary Gland Neoplasms in Male Rats and
    Lorcaserin Exposure Margins Above Human Exposure

    Dose (mg/kg)





    Lorcaserin margin over human





    Number of male rats










    Benign fibroadenoma*





     * Trend is significant (p = 0.0001). Significantly different from control at 100 mg/kg (p = 0.002).



    Female Rats 

    Mammary Gland Neoplasms in Female Rats and
    Lorcaserin Exposure Margins Above Human Exposure

    Dose (mg/kg)





    Lorcaserin margin over human





    Number of female rats






    28 (43%)

    34 (52%)

    35 (54%)

    60* (80%)

    Benign fibroadenomaa

    20 (31%)

    47* (72%)

    54* (83%)

    45* (60%)


    a Trend is significant (p < 0.0001).

    * Significantly different from control (p < 0.0001)


    Should the FDA worry if megadoses of lorcaserin cause tumors in rats?

    Is a significant increase in female rat breast cancer, seen at no less than 84 times the human exposure level of lorcaserin, even a problem for humans?

    Not according to the FDA’s prior reviews of scientific studies and its published guidance to drugmakers. 

    The FDA’s September 2008 Guidance for Industry: S1C(R2) Dose Selection for Carcinogenicity Studies says:

    It has been agreed that if a drug is only positive [for a cancer association] in rodents at doses above those producing a 25-­fold exposure over exposure in humans, such a finding would not be considered likely to reflect a relevant risk to humans.

    found a significant benign tumor rate in male rats exposed to no less than 56-fold amounts of lorcaserin compared to what humans would receive, and a significantly increased cancer rate in female rats exposed to no less than 84-fold amounts.  These dosages are well above the FDA threshold of "25-­fold exposure over exposure in humans."  Therefore, "such a finding would not be considered likely to reflect a relevant risk to humans," according to the FDA’s prior, considered scientific findings and advice to pharmaceutical manufacturers.

    No wonder Arena CEO Jack Lief said in a conference call with analysts last Friday that it was a “shame” there were no experts in carcinogenesis or toxicology on the panel.

    "My view is they were having difficulty understanding the presentation," he said.


    How well did FDA no-vote panelists grasp Arena's rat tumor findings?


    BioWorld’s Donna Young reported:

    [FDA panelist] Edward Gregg, chief of epidemiology and statistics in the Centers for Disease Control and Prevention's Division of Diabetes Translation, said he was "spooked" by the rat study tumor results.

    Many on the panel of metabolic and endocrinology experts, however, acknowledged that their particular expertise was not in cancer, and therefore, had difficulty interpreting the rat study results. ...

    Given the potential for lorcaserin to be used by hundreds of thousands of women once it enters the U.S. market, "there is just too much uncertainty" without more studies to answer the tumor question, said [FDA] panelist Jacqueline Gardner, a professor of pharmacy at the University of Washington.


    What is the uncertainty to which pharmacist Gardner refers?  Could it be based on some panelists’ difficulty in interpreting Arena’s data, or in determining its applicability to humans in accordance with cancer biology principles? 

    Panelist Michael Proschan, a mathematical statistician at the National Institute of Allergy and Infectious Diseases, seemed honest about his perception of the rat tumor data. "I feel totally lost," he said. "I have no idea how to translate from animals to people."

    Lorcaserin may play an important role not just in weight loss, but also in treating complications of obesity.  According to the FDA brief, “Lorcaserin 10 mg BID caused significant improvements in blood pressure, lipid profiles, and insulin resistance in parallel with weight loss.”

    In a July 2010 New England Journal of Medicine editorial, obesity expert Arne Astrup, MD, wrote, “The justification for using lorcaserin to manage obesity is not greater efficacy than currently available drugs [orlistat (Xenical by Roche (OTCQX:RHHBY) and Alli by GlaxoSmithKline (NYSE:GSK)), and sibutramine (Meridia by Abbott Laboratories (NYSE:ABT))], but rather an apparently much better safety and adverse-event profile and very clear-cut beneficial effects on risk factors for type 2 diabetes and cardiovascular disease.”

    The FDA owes the public a commitment to competent scientific evaluation in its drug-approval decisions.  It should act consistently with its prior scientific findings and industry guidance, promptly overrule the lorcaserin panel's mistaken vote, and set the record straight on lorcaserin’s cancer safety findings.




    Disclosure: Long ARNA
    Sep 21 3:26 AM | Link | 58 Comments
  • Who has the next approvable cancer vaccine?

    [Updated 5/19/10 in brackets below]

    Biovest International (OTC:BVTI) 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 (NASDAQ: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 (OTC: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.

    Few investors are paying attention to vaccine maker Biovest or its majority owner, Accentia Biopharmaceuticals (OTC:ABPIQ), 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 BVTI.PK, ABPIQ.PK at time of writing. No company affiliation.
    May 16 4:11 PM | Link | 8 Comments
  • Biovest files bankruptcy reorganization plan that preserves shares

    [Updated 5/19/10 in brackets below]

    Lymphoma vaccine maker Biovest International (OTC:BVTI) is getting close to resolving its Chapter 11 bankruptcy.

    Biovest’s bankruptcy plan, filed in federal court May 14 in Tampa, keeps all Biovest common stock intact.  That’s right: unlike as in nearly all corporate bankruptcies, shares will not be canceled.

    Here is the plan:

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

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

    Biovest’s parent, Accentia Biopharmaceuticals (OTC:ABPIQ), which owns at least 76% of Biovest stock and is also in bankruptcy, asked for an extension to June 4, 2010, to file its own reorganization plan with the court.  Accentia told the judge it intends to file the plan next week, i.e., by May 21.

    Accentia has indicated in public statements that it, too, intends to preserve shareholder value in reorganization, just as Biovest’s plan has done today.

    Notably, Biovest’s press release says that the royalty it must pay to its largest secured creditor, Laurus Master Fund, falls from 35% to 6.30% in the reorganization.

    But the press release fails to mention an important event: the plan actually says the royalty will fall first to 6.25%, then to zero upon closing the settlement between Biovest and Laurus (plan sec., pp. 39-40).

    [Update: Accentia's investor relations spokesman Doug Calder confirmed on 5/19/10 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, the reorganization plan's drop in royalty to zero must therefore refer to the royalty existing prior to bankruptcy closing.]

    That settlement was approved May 14 by the court, although the closing will happen when (a) the court gives a final order confirming Accentia’s and Biovest’s reorganization plans, and (b) both companies get current with their SEC filings.   These events are on track to happen fairly soon.

    A zero [6.30%] royalty to be paid by Biovest on future vaccine sales (after FDA approval) means the company has now better positioned itself for a partnership or buyout.

    This news is important because Biovest is only the second company in history to run a successful phase 3 human trial for a cancer vaccine.  The first was Dendreon (NASDAQ:DNDN), whose Provenge vaccine for prostate cancer was recently approved by the FDA.

    The Biovest phase 3 trial, conducted with the National Cancer Institute, showed that the vaccine (BiovaxID) significantly (p < 0.05) prolongs disease-free survival of patients with follicular non-Hodgkin’s lymphoma who are in chemotherapy-induced remission for 6-12 months when they receive the vaccine.


    Disclosure: Long ABPI and BVTI at time of writing; no company affiliation
    May 16 1:57 AM | Link | 1 Comment
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