A recent article on Seeking Alpha compared the efficacy of two newly approved obesity medications, Vivus Pharmaceuticals' (VVUS) drug Qsymia Vs. Arena Pharmaceuticals' (ARNA) drug Belviq. This article focuses on the other side of the approved drug equation - safety.
Before approval, FDA performs a risk/benefit analysis looking at the safety and efficacy of any potential new drug and doctors perform a similar analysis when choosing which medicine to prescribe to a patient. Note the order of those two words, safety and efficacy. For diseases that are not immediately life threatening safety is always the first priority: "first do no harm".
All new drugs may carry unknown or rare event risks that only turn up in clinical use, but looking at the approved drug labels and full prescribing information for Qsymia and Belviq will let us compare safety issues known at this time.
Let's start with reasons why a doctor should NOT prescribe a certain medication. This information is found in the contraindications section the drug label.Contraindications for Belviq and Qsymia
|While taking or within 14 days of taking MAOIs|
|Known hypersensitivity or idiosyncrasy to sympathomimetic amines|
The pregnancy contraindication is standard for all weight loss medications because losing weight offers no clinical benefit while you are pregnant. The remaining contraindications for Qsymia relate to potentially serious and well-known safety risks in patients with the stated conditions. For example, according to the Mayo Clinic:
Hyperthyroidism (overactive thyroid) is a condition in which your thyroid gland produces too much of the hormone thyroxine. Hyperthyroidism can significantly accelerate your body's metabolism, causing sudden weight loss, a rapid or irregular heartbeat, sweating, and nervousness or irritability.
The phentermine in Qsymia speeds up your metabolism so taking it when you have hyperthyroidism can be dangerous.
Regarding glaucoma, the FDA approved label states:
A syndrome consisting of acute myopia associated with secondary angle closure glaucoma has been reported in patients treated with topiramate, a component of Qsymia. Symptoms include acute onset of decreased visual acuity and/or ocular pain.
In other words, eye pain and eventually blindness can potentially be precipitated by the topiramate in Qsymia. Luckily this risk goes away simply by stopping the medication.
Warnings and Precautions
Both drugs have a long list of warnings and precautions. Doctors look to this section of the label after the contraindications section to make sure their patients will not be put in harm's way by taking the medicine in question. Below we look at a side-by-side comparison of the Warnings and Precautions sections from the labels of the two drugs. We have preserved the wording of the FDA label but rearranged the order of the bullets so that the warnings that both drugs have in common can be seen together.Warnings and Precautions for Belviq and Qsymia
|Serotonin Syndrome or Neuroleptic Malignant Syndrome (NMS)-like Reactions: The safety of co-administration of BELVIQ with serotogenic or antidopaminergic agents has not been established. manage with discontinuation of BELVIQ and provide supportive treatment||Fetal Toxicity: Females of reproductive potential - obtain negative pregnancy test before treatment and monthly thereafter; use effective contraception. Qsymia is available through a limited program under a Risk Evaluation and Mitigation Strategy (REMS).|
|Valvular Heart Disease: If signs or symptoms develop, consider BELVIQ discontinuation and evaluate the patient for possible valvulopathy.||Increase in Heart Rate: Monitor heart rate in all patients, especially those with cardiac or cerebrovascular disease.|
|Cognitive Impairment: May cause disturbances in attention or memory. Caution with use of hazardous machinery when starting BELVIQ treatment.||Cognitive Impairment: May cause disturbances in attention or memory. Caution patients about operating automobiles or hazardous machinery when starting treatment.|
|Monitor for Depression or suicidal thoughts: Discontinue if symptoms develop.||Suicidal Behavior and Ideation: Monitor for depression or suicidal thoughts. Discontinue Qsymia if symptoms develop.|
|Psychiatric Disorders, including euphoria and dissociation: Do not exceed the recommended dose of 10mg twice daily.||Mood and Sleep Disorders: Consider dose reduction or withdrawal for clinically significant or persistent symptoms.|
|Use of Antidiabetic Medications:weight loss may cause hypoglycemia. Monitor blood glucose. BELVIQ has not been studied in patients taking insulin.||Use of Antidiabetic Medications:weight loss may cause hypoglycemia. Measure serum glucose before/during treatment.|
|Priapism: Patients should seek emergency treatment if an erection lasts >4 hours. Use BELVIQ with caution in patients predisposed to priapism.||Acute Myopia and Secondary Angle closure Glaucoma: Discontinue Qsymia.|
|Metabloic Acidosis: Measure electrolytes before/during treatment|
|Elevated Creatinine: Measure creatinine before/during treatment.|
Clearly, both drugs can have potentially serious complications for certain patients.
Topiramate is known to cause birth defects such as cleft-lip and cleft-palate at the higher doses used for treatment of epilepsy and migraines.
Belviq carries a potential risk for valvulopathy. The full prescribing information in the label says:
At therapeutic concentrations, BELVIQ is selective [ed. emphasis added] for 5-HT2C receptors as compared to 5-HT2B receptors. In clinical trials of 1-year duration, 2.4% of patients receiving BELVIQ and 2.0% of patients receiving placebo developed echocardiographic criteria for valvular regurgitation at one year (mild or greater aortic regurgitation and/or moderate or greater mitral regurgitation): none of these patients was symptomatic.
Note that FDA believes that Belviq is selective for the receptors that affect appetite (5-HT2C) compared to those that affect heart valves (5-HT2B).
Qsymia increases heart rate (again from the label):
Qsymia can cause an increase in resting heart rate. A higher percentage of Qsymia-treated overweight and obese adults experienced heart rate increases from baseline of more than 5, 10, 15, and 20 beats per minute (bpm) compared to placebo-treated overweight and obese adults. ...
the label goes on to say:
... The clinical significance of a heart rate elevation with Qsymia treatment is unclear, especially for patients with cardiac and cerebrovascular disease (such as patients with a history of myocardial infarction or stroke in the previous 6 months, life-threatening arrhythmias, or congestive heart failure).
A Table in the Qsymia label indicates that 74.7% of patients treated with the recommended dose of Qsymia had a resting heart rate increase of at least 5 beats per minute. At the highest dose which gives the best weight loss, almost 20% of patients had a heart rate increase of 20 beats per minute or more.
Belviq actually lowers heart rate and contains a cautionary note about prescribing it for patients with slow heartbeat:
In clinical trials of at least 1-year in duration, the mean change in heart rate (HR) was -1.2 beats per minute (bpm) in BELVIQ and -0.4 bpm in placebo-treated patients without diabetes and -2.0 beats per minute (bpm) in BELVIQ- and -0.4 bpm in placebo-treated patients with type 2 diabetes. The incidence of HR less than 50 bpm was 5.3% in BELVIQ and 3.2% in placebo-treated patients without diabetes and 3.6% in BELVIQ and 2.0% in
placebo-treated patients with type 2 diabetes. In the combined population, adverse reactions of bradycardia occurred in 0.3% of BELVIQ and 0.1% of placebo-treated patients. Use with caution in patients with bradycardia or a history of heart block greater than first degree.
Neither drug has been tested on diabetics who use insulin. The summary information for Qsymia does not state this fact but it is listed in the full prescribing information.
On the surface, the cognitive impairments language appears very similar. The full prescribing information reveals that 1.9% of Belviq patients experienced these type of events. For Qsymia 5.0% and 7.6% of trial participants experienced such events on the recommended and top dose respectively. Two to three times as many patients taking Qsymia experienced cognitive side effects compared to those taking Belviq.
According to the FDA advisory committee briefing document (pdf) for Qsymia, 30% of the high dose Qsymia patients experienced metabolic acidosis. When untreated this condition can lead to kidney stones, osteoporosis and increased risk of fractures.
For the elevated creatinine, the Qsymia label says:
Elevations in serum creatinine often signify a decrease in renal function, but the cause for Qsymia-associated changes in serum creatinine has not been definitively established.
The adverse reactions section of a drug's label outlines common reactions seen during the clinical trials. Belviq's label reads:
Most common adverse reactions (greater than 5%) in non-diabetic patients are headache, dizziness, fatigue, nausea, dry mouth, and constipation, and in diabetic patients are hypoglycemia, headache, back pain, cough, and fatigue.
Qsymia's label reads:
Most common adverse reactions (incidence greater than or equal to 5%) are: paraesthesia [ed. tingling in extremities], dizziness, dysgeusia [ed. metallic taste in mouth], insomnia, constipation, and dry mouth.
More telling perhaps is the information in the full prescribing information section wherein we find for Belviq:
In clinical trials of at least one year in duration, 8.6% of patients treated with BELVIQ prematurely discontinued treatment due to adverse reactions, compared with 6.7% of placebo-treated patients.
For Qsymia we have:
In the 1-year placebo-controlled clinical studies, 11.6% of Qsymia 3.75 mg/23 mg, 11.6% of Qsymia 7.5 mg/46 mg, 17.4% of Qsymia 15 mg/92 mg, and 8.4% of placebo-treated patients discontinued treatment due to reported adverse reactions.
For 1 in 6 patients, the side effects of high dose Qsymia led them to stop using the drug. This is a potential problem for top dose Qsymia sales if doctors follow the recommended prescribing guidelines. The Qsymia prescribing information suggests that only those who do not respond to the recommended dose by losing at least 3% of their body weight within 12 weeks should switch over to the top dose. Whether patients will put up with the higher side effects of the top dose despite being marginal responders in the first place remains to be seen. Tolerability of a drug is a genuine concern. Patients in a clinical trial are more likely to put up with side effects than the public at large because they are getting free treatment.
Next let's look at potential drug interactions. Doctors have to be aware of how adding either Belviq or Qsymia to their patients' other medications might cause a safety problem.
Belviq has concerns around interactions with:
Serotonergic drugs (selective serotonin reuptake inhibitors (SSRIs), serotonin-norepinephrine reuptake inhibitors (SNRIs), monoamine oxidase inhibitors (MAOIs), triptans, bupropion, dextromethorphan, St. John's Wort): use with extreme caution due to the risk of serotonin syndrome.
There are quite a few people taking some form of anti-depressant (SSRI, SNRI or MAOI). It remains to be seen whether or not doctors would feel comfortable co-administering Belviq for such a patient.
Drug interactions for Qsymia include:
- Oral contraceptives: Altered exposure may cause irregular
bleeding but not increased risk of pregnancy. Advise patients not to discontinue oral contraceptives if spotting occurs.
- CNS depressants including alcohol: Potentiate CNS depressant effects. Avoid concomitant use of alcohol.
- Non-potassium sparing diuretics: May potentiate hypokalemia. Measure potassium before/during treatment.
Topiramate interferes with hormonal birth control by decreasing exposure to some hormones and increasing exposure to others. All women taking Qsymia and using oral contraceptives are instructed to also use a barrier method of birth control to avoid the risk of birth defects.
The use of alcohol with Qsymia is not recommended and this is possibly a deal-breaker for some patients. We note that obese patients needing Qsymia or Belviq probably should not be drinking alcohol in the first place due to the empty calories.
Post Approval Studies
Now that we have a good understanding of the approved labels for both drugs, let's take a look at the possible safety implications related to the post-marketing commitments required of each company by the FDA.
Both Vivus and Arena will be conducting 5 post-marketing studies to assess safety and efficacy of their products in children. This is standard procedure for all new drugs and is mandated by the Pediatric Research Equity Act (PERA).
Arena is required to conduct one additional safety study for Belviq according the their FDA approval letter. In contrast Qsymia's approval letter states that 5 additional safety studies are required. Both companies will be conducting a cardiovascular outcomes trial (CVOT). Vivus will also be conducting studies (in-vitro) related to human organic cation and anion transporters and multi-drug and toxin extrusion proteins, studies of potential adverse effects on bone health, a clinical trial regarding Qsymia's effect on kidney function, a study on rates of pregnancy amongst females using Qsymia, and a study and monitoring of rates of birth defects amongst actual Qsymia users.
Qsymia has a Risk Evaluation and Mitigation Strategy (REMS) aimed at preventing birth defects. Details can be found at qsymiarems.com. The REMS program consists of prescriber education, a patient medication guide, and a patient brochure entitled "Risk of Birth Defects with Qsymia". Additionally, the REMS program initially calls for Qsymia to be distributed only through specially certified mail-order pharmacies.
One of the conditions for pharmacies that distribute Qsymia is that they have to send both the medication guide and the patient brochure with each prescription. This means that every time a patient refills a prescription they get a reminder in the mail about the birth defect risk - we see this as a positive for risk mitigation but potentially a negative for drug marketing.
A patient taking Qsymia will read in the medication guide that they should "stop taking Qsymia immediately" if they find out that they are pregnant. Elsewhere in the medication guide they are instructed:
Stopping Qsymia suddenly can cause serious problems, such as seizures. Your healthcare provider will tell you how to stop taking Qsymia slowly.
The risk of precipitating a seizure when suddenly stopping Qsymia stems from topiramate and it is a very real risk even for patients without seizure disorder. Since almost 20% of top dose Qsymia patients dropped out of the clinical trials due to side effects, doctors will be having the "how to safely stop taking Qsymia" conversation with a lot of patients.
Belviq has no REMS program because the identified serious risks did not rise to the level of requiring REMS.
What is clear from this side-by-side comparison is that both Belviq and Qsymia carry risks for certain patients. Qsymia carries several more a-priori known risks than Belviq; but, keep in mind that additional risks can always emerge later for either drug once they go in to broader use.
Any discussion of how the medicines will compete in the marketplace that simply looks at placebo-subtracted average weight loss while ignoring completer and responder statistics and in the absence of an analysis of safety information is a cursory comparison at best. Unfortunately delving deep into these issues is often skipped by many reporters and investors.
If you believe that efficacy will trump safety in most patients' and doctors' choice of anti-obesity medication, then you may give a larger market share to Qsymia. On the other hand, if you feel that a safer drug with moderate efficacy is likely to win out, then your investment thesis will favor Belviq.
One point that all of this analysis misses is that Belviq has conducted a clinical trial specifically in diabetics whereas Qsymia has not. In the diabetic population, not only did Belviq provide weight loss, but the drug reduced glycated hemoglobin (Hba1c) by 0.9%. Since this happened at both the approved dose of 10mg twice daily, and at the lower dose of 10 mg once per day, it is quite likely that the anti-hyperglycemic properties of Belviq are due to a mechanism other than merely the lost weight. Qsymia resulted in an Hba1c reduction of 0.4% from baseline in the 388 diabetics in their clinical trial. The FDA approved label for Belviq calls out issues specific to diabetics and the full prescribing information includes the BLOOM-DM clinical trial data to make it easier for doctors to understand Belviq's benefits for their diabetic patients. In our opinion, Belviq is a clear winner in the obese and overweight diabetic population because the Hba1c reductions are on-par with oral and injected diabetes medications. As we have indicated in previous articles, we expect Arena and Eisai to eventually pursue a label expansion for a diabetes indication.
Investors should formulate an investment thesis based on both the safety and efficacy of the new medications as well as taking in to account other operational risk factors such as the track record of each company in marketing their medicines. We see ARNA as having an advantage here because their partner, Eisai, has more experience than VVUS in marketing new medicines. Other risks such as VVUS' IP position have also been recently raised and should be analyzed as part of the investment decision. Vivus has more cash and less debt than Arena, but they will be spending a large portion of their cash on sales and marketing and on the required clinical trials. Arena will be receiving milestone payments from Eisai, share none of the sales and marketing expenses, and will pay for 50% and 10% of the cost of pediatric and cardiovascular outcomes trials respectively. They receive 31.5% to 36.5% of Belviq's net sales along with one-time purchase price adjustments of up to $1.2 Billion that can be earned over the patented life of the drug. This seems like a fair trade off for the burden Eisai will shoulder.
Potential future catalysts can also make up part of the investment equation. Both ARNA and VVUS have European approval decisions coming up within the next 6 months as well as announcement of pricing, coverage by insurers, and first sales numbers. We do not recommend placing much emphasis on buyout speculation for either company at this time since likely suitors will probably wait until sales numbers come in before making offers - if they do at all.
Additional disclosure: Author was long VVUS through the Qsymia approval date.