Posts tagged ‘diet drugs’

QNEXA Advisory Committee 2012

On Wed, Feb 22, 2012, the Metabolic and Endocrine Advisory Committee will meet once again to discuss the Vivus QNEXA NDA for the treatment of obesity. This Advisory Committee met in July of 2010 to discuss this same NDA.  Several members of the earlier Advisory Committee are returning either as full AdComm members or as temporary members.

The 2010 AdComm voted 6 to 10 against recommending approval for QNEXA.  The reasons given were primarily safety concerns in the areas of neurological/cognitive, cardiovascular, metabolic acidosis and teratogenicity and the need for studies in a broader population of patients.  The sponsor has responded to the concerns raised and has included a 1 year extension of one of the pivotal Phase 3 studies which measured both efficacy and attempted to address the safety concerns.

 Efficacy

This is another example of a company doing more and proving less.  The one year extension study was flawed.  The FDA stated that the selection process for patients entering the study was biased and the results should be considered “observational”.  None the less, the observation made is that there is no benefit from continuing patients beyond one year on QNEXA because even on the highest dose, patients start to regain the weight they lost in the first year.

Safety

NOTE: At 2010 AdComm, the Committee consistently noted that for each of the concerns they had, the risk in a broader population was unknown.  The new 2 year data do not represent a broader population but rather a subjective selection of patients from the 1 year study, the results of which the FDA calls “observational”.  I think “observational” means “we’re sorry you took the time to assemble these data because we had to take the time to “look” at it”.

Metabolic acidosis.  2 year safety cohort showed same reduction in serum bicarbonate.

Cardiovascular risk.  The FDA concluded that while the results were “directionally favorable”, its unknown what would happen in a high risk population or during chronic use.  Sounds like a limited indication, if approved at all, and more work to be done.  But what kind of work?  We won’t know and the sponsor won’t know until after the March AdComm which will be addressing the specific issue.

Suicidal/cognitive effects. 2 year extension did not report any additional concerns about suicidal tendency.  Probably didn’t answer original questions either.  The incidence of cognitive related adverse events was the same in the 2 year study as reported in the 1 year study.

Teratogenic effects.  There is no doubt, the topiramate component of QNEXA is a teratogen.  The sponsor agreed and amended the application to provide for a warning against use by women of child bearing potential.  The FDA responded with the rejection of their proposed labeling.  Why?  Probably several reasons.  One of which is if they excluded women of child bearing potential, the pivotal trials would be invalid as the majority of patients in the studies were women.

I’m surprised that the bulk of the questions from the FDA focus on the teratogenic effect.  I’m surprised that the Risk Management review says that this is a concern for the patients taking topiramate for epilepsy.  What is the problem people?  Go back to FDA 101 – its all about benefit risk.  Topiramate for epilepsy has one benefit risk while topiramate for obesity has another benefit risk.  As a fraction, the former is 10/5 while the latter is 1/5.   But that’s a problem for the FDA to work out for approval.

For the Advisory Committee, lets summarize, comparing what we knew after 2010 and what we know now:

-efficacy – no improvement in weight loss in second year, in fact, weight gain.

-metabolic acidosis – no new data, its still an unknown in broader population

-suicidal/cognitive – no new data, its still an unknown in broader population

-cardiovascular – no new data, its still an unknown in high risk patients and broader population

-teratogen – no new data and company acknowledges teratogenicity.  Risk management program currently seems less stringent than controls the sponsor used in controlled clinical trials and they couldn’t make that work.

I doubt the Advisory Committee will be as generous with the “yes” votes as they were in 2010.

Diet Drugs in 2012

We’ve had several questions from readers asking if our opinion on the diet drugs that failed in 2011 has changed. Specifically, will Qnexa (or by extrapolation) or any of the other diet drugs have an easier go of it the next time around, ie, is the Cupcake Commentary still valid?

We’re going to take a slightly different approach with this posting and give our readers an insight into one of the changes we are thinking about for 2012 and beyond. We’re going to provide a more detailed commentary in this, the first response to our new feature, the Readers Forum.

Let’s start with the basic criteria for approval from the FDA Guidance on Diet Drugs. The draft guidelines from 2007 state that to prove efficacy, a diet drug must have two adequate and well controlled studies that demonstrate:

After 1 year treatment either:

  • There is a difference of 5% or greater between placebo and active drug OR
  • Greater than 35% of patients treated with drug have a difference of greater than 5% from baseline and twice the difference from placebo.

In earlier postings, we pointed out that the 5% difference is a very modest decrease in weight for a year and is comparable to having one less cupcake a week for a year for a 200 pound person. (200 lbs x 5% = 10 pounds; 10 lbs/52 weeks = 0.192 pounds per week, or about 3 oz, the size of a typical cupcake).

Let’s look at the data that were reported in the Briefing Documents prepared by the sponsors and the FDA for the Advisory Committee meetings that were held to discuss the diet drugs submitted for approval.

DrugEfficacySafety
LorqesFailed 5%- Tumorogenicity
QnexaPassed 5%
- Depression
- Memory Loss
- Metabolic Acidosis
- Increased HR
- Potential teratogen
- Lack of CV Date
ContraveFailed 5%
Passed 35%
- Increased SBP, DBP and HR
- MACE Inadequate
- Psychiatric AE

Let’s look at the alternatives to diet drugs. On one side are the diets and exercise that offer limited benefit and little risk. From purely anecdotal reports, if would appear that the General Motors Diet is the most successful. Many have not heard of this diet because nobody can make any money writing about it. It is the diet that has been used by the General Motors health professionals for years and is freely available on the Internet. Success is often reported as 5% weight loss in a week and safety is not an issue. Attendant with the success is often a change in eating habits.

On the other side of the diet drugs is gastric bypass surgery and its alternative, the stomach band. Success is reported as high as 30% weight loss in a year, a normalization of the diabetic state and a change in eating habits. Safety concerns include those associated with surgery and potential long term metabolic changes. It should be noted that this extreme surgical intervention is limited to those identified as obese and there is significant pre-screening qualification before the surgery and extensive monitoring afterward.

So, as a generality, diets can be said to be the least effective (as measured by sustained weight loss) for the majority of people but the safest, while gastric bypass surgery is currently the most effect but carries the most danger. Diet drugs tend to be between these two extremes, marginally more effective than diet alone but significant potential for more adverse effects.

Of course, the patient populations of these three treatments tend to be different. Diet and exercise is a treatment available to anyone, diet drugs for patients who need a bit more than the diet and exercise and bypass surgery generally reserved for those described as obese.

The FDA and its Advisors must determine if the diet drugs are safe and effective for the intended population, that is, those who fail diet and exercise alone but not so obese that they require bypass surgery.

Is there a regulatory precedent for this kind of treatment and this kind of population? I say yes. Recall the acne treatment isotretinoin or ACCUTANE as it was first marketed. Acne is a disease that can be treated with non-prescription drugs in the mildest condition, prescription drugs for those who don’t respond to the non-prescription drugs and for the most severe forms of acne, treatment with ACCUTANE is effective. Also like the use of diet drugs, acne treatment has a certain cosmetic component to it. By that I mean while there are certainly positive health components to treating both obesity and acne, treatment of both also usually results in a more attractive individual.

The ACCUTANE approval was held up because, like some of the diet drugs, it produced birth defects. The conventional wisdom whispered but never overtly expressed at the time was that this was a time bomb waiting to explode. One potential patient group was women of child bearing potential and clearing up acne had the potential to make their child bearing potential greater. Very restrictive labeling was proposed and rejected. The approval of ACCUTANE was delayed while this aspect of benefit risk was debated. When it was approved, and to this day, it carries a severe restriction requiring that women of child bearing potential have 2 negative pregnancy tests and be using 2 methods of birth control before it can be prescribed to them.

There is no reason to believe that the FDA has reduced its standards for drugs that have a potential for birth defects, especially if the drug has the potential for wide spread use in women of child bearing potential. Like ACCCUTANE, diet drugs have the potential to to make the child bearing potential of women of child bearing potential more potential.

Vivus has resubmitted its NDA for QNEXA with requested additional cardiovascular safety data to address issues that arose during the previous NDA review. These data will be reviewed at an upcoming Advisory Committee in February when the committee will have the opportunity to see the FDAs view of these limited data. It is likely the FDA will also ask the committee to comment on QNEXA use in women of child bearing potential, perhaps the reason the FDA has not insisted on included this population as a contraindication. Or perhaps they just feel it doesn’t make any difference because the drug still doesn’t have a benefit risk ratio that justifies approval.

NEXT TIME: Is it time for the FDA to revise the Guidance document for drugs used to treat obesity?