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John received his PhD in chemistry in the research group of Nobel Laureate Donald Cram in 1987 and his MBA from the Anderson School of Management at UCLA in 2009. His research career spans 16 years performing drug discovery research in metabolic diseases, cancer, HIV infection, antibacterials,... More
  • Challenges and Questions for Vivus at the July 15 FDA Advisory Committee Meeting 4 comments
    Jun 28, 2010 4:56 PM | about stocks: VVUS, OREX, ARNA

    Vivus’ developmental anti-obesity drug Qnexa will be reviewed by the FDA Endocrinology and Metabolic Drugs Advisory Committee panel on July 15.  The outcome of this meeting will be a major inflection point for Vivus, and possibly for its potential competitors, Orexigen and Arena, as well. 

    Qnexa clearly is the most efficacious of the three anti-obesity drugs (Qnexa, Contrave, and lorcaserin) awaiting FDA approval.  In the CONQUER and EQUIP trials, patients treated with the highest dose of Qnexa exhibited average weight losses of 10.4% and 11.0% (intent-to-treat basis) over 12 months.  At this dose, 67% to 70% of Qnexa treated subjects lost at least 5% of their body weight, compared with 17% to 21% of placebo-treated patients.

    As Qnexa’s efficacy clearly exceeds the standards set in the FDA’s draft guidance for the development of obesity drugs[1], speculation around its potential for approval revolves around its safety profile.  Because obesity is not an immediately life-threatening state, and because obesity drugs are likely to be used chronically, the safety requirements for an obesity drug are extraordinarily high.  Indeed, a recent meta analysis suggests that for an average patient with a body mass index of 35, a 10% weight loss reduces the risk of death by only 0.3% per year[2].  Thus adverse events (AEs) too rare to be detected in clinical development could cancel out or exceed the therapeutic benefits of weight loss drugs.  For these reasons, both the FDA and potential corporate partners are likely to closely examine even weak signals of potential safety problems.  Furthermore, since Qnexa is a combination pill containing two drugs with lengthy clinical histories, clinical experience with the individual component drugs will also play a significant role in the FDA’s assessment of Qnexa.

    Qnexa is an oral, once a day, controlled release formulation of the generic drugs phentermine and topiramate.  It’s mechanism of action includes reducing appetite and increasing satiety.  The “Full Dose” formulation contains 15 of phentermine and 92 mg of topiramate, while the “Mid Dose” formulation contains 7.5 mg of phentermine and 46 mg of topiramate.  A “Low Dose” formulation was also examined in clinical trials, but appears less likely to be commercially developed. 

    Phentermine is a widely used anti-obesity drug of the amphetamine class.  The FDA approved it in 1959, thus its safety and efficacy as a single agent has not been studied in clinical trials at the level of detail expected for new drugs today.  Approximately 2 million prescriptions per year are written for phentermine in the US, where it is available as a time release formulation of 15 or 30 mg and as an immediate release formulation of 15, 30, or 37.5 mg.  Phentermine is the “Phen” component of the 1990’s infamous Fen-Phen weight loss combination, but the other component, fenfluramine, is generally regarded as responsible for the cardiac valve damage associated with this drug combination.  Phentermine’s side effects include agitation and insomnia, and it has been linked to rare cases of pulmonary hypertension.  The EMEA withdrew marketing authorization for phentermine in the EU in 1999, citing an “unfavorable risk / benefit balance”.

    Topiramate was originally developed as an anticonvulsant, typically used at doses of 200 to 400 mg per day.  More recently, its label was expanded to include prophylaxis of migraine headache at doses similar to those found in Qnexa, 50 to 100 mg per day.  It was also examined in clinical trials as a single agent for use in the treatment of obesity.  Topiramate and other anticonvulsant drugs have been associated with psychiatric side effects including depression, suicidal ideation, and anxiety.  Other side effects include somnolence and cognitive problems such as concentration deficits, memory problems, and intellectual slowing.  Several of these reports come from clinical trials that were performed using doses as low as 50 to 100 mg per day[3],[4],[5].  Topiramate causes birth defects in multiple animal species at clinically relevant doses, and pregnancy registry data suggests an association between the use of topiramate in pregnancy and certain congenital malformations.

    The phase 3 development program of Qnexa included one 6-month trial (EQUATE) and two 12‑month trials (EQUIP and CONQUER).  The 12-month trials included approximately 870 patients who completed at least 12 months of treatment at the highest dose.  Highlights of Qnexa’s disclosures regarding the safety findings in the EQUIP and CONQUER trials include the following:

    • The overall serious adverse event incidence was the same (3.3%) for the treatment and placebo groups.
    • Common side effects were those expected from the known safety profiles of single‑agent phentermine and topiramate, including dry mouth, constipation, tingling sensations, and insomnia.
    • The rate of discontinuation due to any cause was lower for all treated groups (31% to 43%) than the placebo group (47%), suggesting that subjects considered the drug’s side effects to be an acceptable trade-off for its weight-loss inducing properties.
    • Discontinuation due to AEs was 9% in the placebo group, 12% in the Mid Dose group, and 18% in the Full Dose group.  Discontinuation-associated AEs for which a dose‑response relationship was apparent are summarized in Table 1.

    Table 1.   Incidence of discontinuations due to selected adverse events

    Adverse Event

    Placebo

    Mid Dose

    Full Dose

    Insomnia

    0.4%

    0.4%

    1.7%

    Depression

    0.2%

    0.8%

    1.4%

    Tingling Sensations

    0.0%

    1.0%

    1.2%

    Irritability

    0.1%

    0.8%

    1.2%

    Anxiety

    0.3%

    0.2%

    1.1%

    • Patients were monitored for depressive symptoms using the Patient Health Questionnaire‑9 (PHQ-9), a validated instrument for depression screening, and the Columbia Suicide Severity Scale (C-SSR), a validated instrument for the detection and assessment of suicidal ideation.  No signal for an increased incidence of depression or suicidal ideation was observed.  Moderate-to-severe depression was observed in 1.7% of subjects in the placebo groups, 1.2% in the Mid-Dose groups, and 1.9% in the Full Dose groups.
    • Patients were monitored for cognitive dysfunction and psychomotor deficits using undisclosed methodologies, with no signal seen for any drug-induced effect.

    Overall, the picture presented by Management is a very attractive one, suggesting a product candidate that is well-characterized, highly efficacious, and completely lacking in detectable safety signals.  Nonetheless, the Qnexa clinical trial data and historical experience with its component drugs suggest several potential safety issues.  In the context of the very high standards of safety expected for an anti-obesity drug, these issues have significant potential to lead to a negative advisory committee decision and rejection of the Qnexa NDA.

    Enhanced rates of suicidal ideation formed the basis of the FDA’s 2007 rejection of the Acomplia NDA, and of Acomplia’s eventual withdrawal from the European market.  Given the well-established association of topiramate and other anticonvulsant drugs with mood disorders and suicidal ideation, the advisory committee is likely to examine this issue very closely.  In spite of Management’s characterization of Qnexa as showing “no signal” for depression and enhanced suicidal ideation, several troubling signals are apparent in clinical trial data.  As shown in Table 1, subjects at the highest dose discontinued due to depression at a rate of 1.4%, a seven‑fold increase relative to placebo.  Discontinuation due to irritability and anxiety were also increased relative to placebo, such that the overall rate of discontinuation due to topiramate-associated mood AEs was 3.7% in the Full Dose group and 0.6% in the placebo group.

    The dichotomy between these discontinuation data and the clean product profile observed in the PHQ-9 and C-SSR screening process raises questions about the adequacy of the latter for detecting suicidal ideation and mood-related AEs.  The FDA Department of Psychiatric Drugs has questioned the validity of such tools for the detection of enhanced rates of suicidal ideation in the clinical trial setting.  Boehringer-Ingelheim included a similar screening tool in its development program for its hypoactive sexual desire disorder drug flibanserin.  In spite of the absence of any signal for suicidal ideation in this screen, the Department recommended a black box warning for suicidal ideation in the event of approval, based on the hypothesis of drug class effect[6].  Given this precedent, the known effects of topiramate on mood, and the increased rate of discontinuation due to mood AEs in the active treatment groups, the issue of suicidal ideation represents a significant risk to a positive advisory committee decision on Qnexa.

    Similarly, Vivus’ reported finding of no cognitive AEs in Qnexa-treated subjects begs the question of whether their screening tools were adequate.  Little has been disclosed about the nature of the screening tools used to assess topiramate-associated cognitive problems such as deficits, memory problems, and intellectual slowing.  In previous double-blinded clinical trials examining the use of low dose topiramate for epilepsy, obesity, and migraine prophylaxis, the combined incidence of these side effects totaled 20% to 44%.

    A final troubling aspect of the application of topiramate for the treatment of obesity is its potential to cause birth defects.  Topiramate is a Pregnancy Class C compound, described in the package insert as causing birth defects in multiple animal species at doses that comparable to or less than those used therapeutically.  Data from pregnancy registries suggest an association of topiramate with “craniofacial defects, such as cleft lip/palate, hypospadias, and anomalies involving various body systems”.  The advisory committee may be expected to raise questions about the public health tradeoffs involved in approving a topiramate-containing product that will largely be targeted to healthy women of childbearing age.

    Phentermine is known to raise blood pressure, Although Vivus has released data showing significant decreases in blood pressure after several months of therapy (and concomitant weight loss), publicly disclosed data do not reveal whether there is an initial increase in blood pressure that might create a window of cardiac risk in highly obese patients.  The association of phentermine with rare cases of pulmonary hypertension presents an additional risk factor, and this issue alone may prevent approval of Qnexa in the EU, where phentermine has been banned.

    Ultimately the strong data accumulating on Qnexa in diabetes and sleep apnea suggest that this drug will be approved in some indications, but the broadest and most profitable indication of obesity is a tough sell.  Given the nearly $800M market capitalization of Vivus, it appears that much of the upside and little of the potential downside is already baked into the price of the stock, and that the risk of owning shares outweighs the likely benefit.



    [1] Guidance for Industry: Developing Products for Weight Management: Draft Guidance, revision 1, February 2007.  United States Food and Drug Administration, Center for Drug Evaluation and Research.  Accessed on the Web at http://www.fda.gov/downloads/Drugs/GuidanceComplianceRegulatoryInformation/Guidances/ucm071612.pdf.

    [2] Prospective Studies Collaboration. Body-mass index and cause-specific mortality in 900 000 adults: collaborative analyses of 57 prospective studies.  Lancet 2009; 373: 1083-1096.

    [3]   Wilding J, Van Gaal L, Rissanen A, Vercruysse F, Fitchet M and the Obesity Study Group. A randomized double-blind placebo-controlled study of the long term efficacy and safety of topiramate in the treatment of obese subjects.  Internat. J. Obesity 2004; 28: 1399-1410.

    [4] Bussone G, Diener H-C, Pfeil J, Schwalen S. Topiramate 100 mg/day in migraine prevention: A pooled analysis of double-blind, randomized controlled trials. Internat. J. Clin. Pract. 2005; 59: 961-968.

    [5] Lee H-W, Jung D-K, Suh C-K, Kwan S-H, Park S-P. Cognitive effects of low dose topiramate in epilepsy patients: A one year follow-up. Epilepsy Behav. 2006; 8: 736-741.

    [6] United States Food and Drug Administration. Background Document for Meeting of Advisory Committee for Reproductive Health Drugs (June 18, 2010). NDA 22-526, Flibanserin, page 48.


    Disclosure: Long OREX
    Stocks: VVUS, OREX, ARNA
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Comments (4)
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  • KWatanabe
    , contributor
    Comments (8) | Send Message
     
    Dr. Tucker,

     

    Thank you for this timely piece on Qnexa. I think your point of if the PHQ-9 adequately captures the higher risk in psychological SEs is a fair one. I was wondering if you could shed some light for a few questions:

     

    1) Has the increased rate in dropouts for selected SEs been statistically verified (statistically significance)?

     

    2) Some believe the higher risk of dropouts should be evaluated in the context of absolute % in dropouts. Is there any guidance/communication from the FDA regarding this?

     

    3) If PHQ-9 is not an adequate tool for detecting suicidal ideation and other mood-related SEs, what is? Also given that the studies were done under a SPA, would the FDA penalize the company despite the questions about its validity?

     

    4) Some bears believe a CV outcome study will be need given the large obese population and the potential for long-term use since Phentermine is a known sympathomimetic. Despite the sufficiency of data before approval, the drug has been approved since 1959 (long period of data collection) and the FDA decided to keep the drug in the marketplace even after the fen-phen ordeal. Do you think the FDA will require a CV outcome study?

     

    Thanks you,

     

    KW
    12 Jul 2010, 02:55 PM Reply Like
  • John Tucker
    , contributor
    Comments (390) | Send Message
     
    Author’s reply » KW, these are excellent questions, which is another way to say that I don't have great answers for most of them.

     

    The statistics here go a little over my head, but I found a statistics website that suggested a chi square test would be the most appropriate one, and using the site's calculator on the difference in discontinuation due to depression gave me a value of p<0.0005.

     

    I think the absolute dropout rate and the relative rate are both important, the relative rate to show a statistical difference between treated and placebo and the absolute rate to show clinical significance. Whether 1.4% dropout due to depression is clinically significant I don't know. I'm actually a lot more concerned about toprimiate's known mood altering properties than I am with the 1.4% dropout rate due to depression that was seen in the trial. In my mind the 1.4% dropout rate really just suggests that their screen for depression may be inadequate, as they claim to have seen no signal. I wonder if depression issue will kick in more when people are taking the drug chronically but their weight has plateaued and they are no longer enjoying the benefit of watching the pounds melt away.

     

    I've heard stories of the FDA giving advice in the past and not feeling bound to it come approval time, but I don't know about SPAs in particular.

     

    Based on the example of phentermine, I think the FDA (but not the EMEA) considers the rare cases of pulmonary hypertension acceptable. I think for Qnexa I'd mainly be interested in whether there were significant short term blood pressure increases before the weight loss kicked in.

     

    I'm not completely confident that the FDA is going to kick this thing. The purpose of the article was just to point out a few risks that I felt people were overlooking. For example, if Qnexa is approved I think we are going to see 1000 babies a year with 1st trimester exposure to topiramate. Wikipedia has a picture of a hypospadia that has somehow avoided being censored. Not the worst possible thing in the world, but not something I would want for my kids.
    12 Jul 2010, 07:36 PM Reply Like
  • JPG101
    , contributor
    Comments (169) | Send Message
     
    Excellent article.

     

    Thanks,

     

    JPG101
    27 Jul 2010, 09:54 PM Reply Like
  • Chimera Research Group
    , contributor
    Comments (388) | Send Message
     
    Hit the nail on the head with this one
    29 Jul 2010, 02:36 PM Reply Like
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