What’s Next in Obesity Treatment?


What’s Next in Obesity Treatment?

QNEXA® (Vivus, Inc.) looks promising. QNEXA is a once-daily weight loss therapy that contains a combination of immediate-release phentermine hydrochloride (PHEN) and extended-release topiramate (TPM). These two agents suppress appetite through complementary mechanisms (decreased hunger and increased satiety), leading to greater weight loss than with either agent alone. Both PHEN and TPM are FDA approved at higher doses than those contained in QNEXA. The Endocrinologic and Metabolic Drugs Advisory Committee voted 20 to 2 to recommend FDA approval on 2/22/12 and the FDA is expected to release a decision in April. The FDA is waiting for Vivus, Inc. to provide assessment of topiramate’s and phentermine/topiramate’s teratogenic potential and a detailed plan and strategy to evaluate and mitigate any potential teratogenic risks in women of childbearing potential (WOCBP) and evidence that QNEXA-associated elevations in heart rate (mean increase of 1.6 bpm on the highest dose) do not increase the risk for major adverse cardiovascular events.

Currently phentermine is restricted to short-term management of obesity. Topiramate is approved for treatment of seizure disorders. The prescription use of these drugs spans more than 52 years for phentermine and more than 15 years for topiramate.

At present, approved pharmacotherapies for obesity are generally associated with <5% weight loss and are often poorly tolerated. The only treatment demonstrated to reliably produce more than 10% sustained weight loss for obesity is bariatric surgery, but is associated with surgical risks, nutritional deficiencies and infections.

From the FDA Advisory Committee briefing document below: The study population evaluated in the QNEXA pivotal clinical development program included a range of adult subjects, from overweight (BMI >27 kg/m2) to severely obese (BMI >60 kg/m2), with a range of obesity-related comorbidities, including type 2 diabetes, hypertension, and hypertriglyceridemia. Within a total of 3807 patients in the one-year cohort, 752 subjects (19.8%) fell into the “low” cardiovascular risk category , 2498 (65.6%) into “moderate” risk, and 557 (14.6%) into the “high” risk group. Thus, the QNEXA clinical sample of patients represents a broad spectrum of cardiovascular risk, and one that represents the range of patients likely to use QNEXA, if approved.

Two trials and an extension of the second trial [1,2,3] and other data [see link at bottom] comprise evidence provided to the FDA by Vivus. [We have not performed any critical appraisals, FYI.]  The two trials reported that a phentermine/topiramate 15 mg/92 mg combination produced a magnitude of weight loss (~10%) that exceeded levels associated with current pharmacotherapies which produce <5% weight loss. Adverse events on the highest dose include paresethesias ~20%, dry mouth ~17%, constipation ~14%, dizziness ~6% to 10%, dysgeusia ~10%, depression ~5% to 8% and irritability ~3% to 5%. Only 1% to 2% discontinued treatment due to adverse events. It appears likely that many will conclude that benefits outweigh harms.

For more information and details of the Phase 3 studies presented to the FDA, go to http://www.fda.gov/downloads/AdvisoryCommittees/CommitteesMeetingMaterials

1: Allison DB, Gadde KM, Garvey WT, Peterson CA, Schwiers ML, Najarian T, Tam PY,  Troupin B, Day WW. Controlled-Release Phentermine/Topiramate in Severely Obese  Adults: A Randomized Controlled Trial (EQUIP). Obesity (Silver Spring). 2012  Feb;20(2):330-42. doi: 10.1038/oby.2011.330. Epub 2011 Nov 3. PubMed PMID:  22051941.

2. Gadde KM, Allison DB, Ryan DH, Peterson CA, Troupin B, Schwiers ML, Day WW.  Effects of low-dose, controlled-release, phentermine plus topiramate combination   on weight and associated comorbidities in overweight and obese adults (CONQUER):   a randomised, placebo-controlled, phase 3 trial. Lancet. 2011 Apr  16;377(9774):1341-52. Epub 2011 Apr 8. Erratum in: Lancet. 2011 Apr  30;377(9776):1494. PubMed PMID: 21481449.

3. Garvey WT, Ryan DH, Look M, Gadde KM, Allison DB, Peterson CA, Schwiers M, Day  WW, Bowden CH. Two-year sustained weight loss and metabolic benefits with  controlled-release phentermine/topiramate in obese and overweight adults  (SEQUEL): a randomized, placebo-controlled, phase 3 extension study. Am J Clin  Nutr. 2012 Feb;95(2):297-308. Epub 2011 Dec 7. PubMed PMID: 22158731.


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Controlling Hypertension and Hypotension Immediately Post Stroke Study (CHHIPS Study): Evidence-based Student Review


Controlling Hypertension and Hypotension Immediately Post Stroke Study (CHHIPS Study): Evidence-based Student Review

New publication of an evidence-based student review at our California Pharmacist page: Controlling Hypertension and Hypotension Immediately Post Stroke Study (CHHIPS Study).

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Is “Biologics Versus Biosimilars” A Different Story Than Brand Names Versus Generics?


Is “Biologics Versus Biosimilars” A Different Story Than Brand Names Versus Generics?

In 1984, the Drug Price Competition and Patent Term Restoration Act (Hatch-Waxman Act) created a shortened new drug application pathway for generics by eliminating the need for preclinical and clinical studies if bioequivalence—i.e., the rate and extent of absorption—could be demonstrated. The FDA defines a generic drug as follows: “A generic drug is identical–or bioequivalent—to a brand name drug in dosage form, safety, strength, route of administration, quality, performance characteristics and intended use.”[1] For many drugs, the process was straightforward and payers hoped to reduce expense by purchasing generics.

Although the FDA frequently uses the term “biologic drug,” we have been unable to find an official FDA definition for “biologic drug.” The FDA instead separately defines “biological product” and “therapeutic biological product.” These are the current FDA definitions—Biological Product: “Biological products include a wide range of products such as vaccines, blood and blood components, allergenics, somatic cells, gene therapy, tissues, and recombinant therapeutic proteins. Biologics can be composed of sugars, proteins, or nucleic acids or complex combinations of these substances, or may be living entities such as cells and tissues. Biologics are isolated from a variety of natural sources—human, animal, or microorganism—and may be produced by biotechnology methods and other cutting-edge technologies. Gene-based and cellular biologics, for example, often are at the forefront of biomedical research, and may be used to treat a variety of medical conditions for which no other treatments are available.” The FDA then defines a therapeutic biological product as follows: “A therapeutic biological product is a protein derived from living material (such as cells or tissues) used to treat or cure disease.”[2] Thus, biologics are large-molecule medications produced by living cells. They are produced by using recombinant DNA technology to direct protein synthesis within cells which can then be used to produce medications.

The Patient Protection and Affordable Care Act (Affordable Care Act), signed into law by President Obama on March 23, 2010, amends the Public Health Service Act (PHS Act) to create an abbreviated licensure pathway for biological products that are demonstrated to be “biosimilar” to or “interchangeable” with an FDA-licensed biological product. This pathway is provided in the part of the law known as the Biologics Price Competition and Innovation Act (BPCI Act). Under the BPCI Act, a biological product may be demonstrated to be “biosimilar” if data show that, among other things, the product is “highly similar” to an already-approved biological product. [3] Biosimilars, also called “follow-on biologics,” are in many ways analogous to generics, but are not generic drugs. In Canada they are aptly labeled “subsequent entry biologics (SEBs).” [4] We like the clarity of the Canadian term, but Americans will hear the terms “biologics” and “biosimilars.”

Biologics and biosimilars are large protein molecules. Manufacturing a biosimilar drug poses numerous complexities not seen in the manufacturing of “small molecules” created as generic drugs. A company wishing to manufacture a biosimilar does have access to the commercial biologic product, but does not have access to the biologic cell line used by manufacturerof the reference biologic or details of the manufacturing process such as how fermentation and purification were carried out. This lack of information (and therefore the lack of identical manufactured cellular material), together with the molecular and structural complexity of large biologic proteins makes for immense complexity for the companies who will be creating biosimilars. The bottom line is that even though a biosimilar has the same recombinant DNA sequencing, small differences in structure or chemistry due to the processes and chemicals used in the culture, purification, storage, etc. may result in differences in efficacy, safety and immunological outcomes.

The Health Care Reform Act has outlined a process for abbreviated approval for biosimilars. The FDA has conducted public meetings and published requirements for a drug to be considered biosimilar, emphasizing clinical studies demonstrating that the product is “highly similar” to the reference product, although minor differences are allowed if the differences do not result in clinically meaningful safety, purity and potency differences. In addition, interchangeable biological products may be substituted at the pharmacy level without the intervention of a healthcare provider. [3]

The strength of evidence necessary to result in a decision of biosimilarity and interchangeability remains unclear. It is also currently unclear if separate evidence for each indication will be required. Currently The European Medicines Agency (EMA) has outlined important elements and considerations required to support the designation of biosimilarity in comparison with existing biologics along with fairly detailed scientific guidance documents on biosimilar medicines.[5] Key requirements include similar pharmacokinetics and pharmacodynamics in humans and the demonstration of similar clinical efficacy and safety of the biosimilar compared to that of the reference biologic. Several biosimilar agents have already been licensed in Europe. The American College of Rheumatology has developed a concise position paper which takes a patient-centered approach to biosimilars. The paper is available online. [6] Key points are—

  • Biologics are proteins produced by living cells, including monoclonal antibodies, soluble receptors, receptor antagonists, novel molecules derived by genetic engineering and other types of proteins that can be used to treat human diseases.
  • Biosimilars may represent a cost-saving alternative to reference biologics.
  • Currently the FDA has not provided details of the kind of testing required to demonstrate sufficient similarity in efficacy and safety for approval.
  • A similar production process does not ensure that the biosimilar is functionally equivalent to a reference biologic. Extensive human testing will be required.
  • Even though the FDA has been establishing standards for licensure to ensure the safety and effectiveness of biosimilars and issued a guidance in February 2012 [7], the FDA has not approved a biological product as biosimilar or interchangeable.
  • Several companies are developing biosimilar products and will almost certainly submit applications for licensure under the new law. It is not yet known when the first biosimilar will be on the U.S. market.
For more evidence-based clinical quality improvement help, visit our website at www.delfini.org.  For more commentaries, visit our DelfiniClick™.



Accessed 2/1/12.

2. FDA definitions.

3.BPCI Act.

Accessed 2/1/12.

4. Subsequent Entry Biologics (SEBs).
Accessed 2/1/12

5.Biosimilars EMA.

Accessed 2/1/12.

6. American College of Rheumatology. http://www.rheumatology.org/practice/clinical/position/biosimilars.pdf
Accessed 2/1/12.

7. Biosimilars FDA Guidance. http://www.fda.gov/Drugs/GuidanceComplianceRegulatoryInformation/Guidances/ucm259797.htm
Accessed 2/13/12.

Other Sources

8. Colbert RA, Cronstein BN. Biosimilars: the debate continues. Arthritis Rheum. 2011 Oct;63(10):2848-50. doi: 10.1002/art.30505. PubMed PMID: 21702015.

9. Reichert JM, Beck A, Iyer H. European Medicines Agency workshop on biosimilar monoclonal antibodies: July 2, 2009, London, UK. MAbs. 2009 Sep-Oct;1(5):394-416. Epub 2009 Sep 25. PubMed PMID: 20065643.

10. Kozlowski S, Woodcock J, Midthun K, Sherman RB. Developing the nation’s biosimilars program. N Engl J Med. 2011 Aug 4;365(5):385-8. PubMed PMID: 21812668.


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Happy Valentine’s! A New Delfini Day Dawns & A Treat For You!


Our Blog
This is the official announcement of our blog!  We are in the midst of moving to a social media-mode.  Go to our website to get just-in-time updates to our blog and website as we dip our toes in these waters that are new for us…on a trial basis, FYI…we need to hear that you are using this information and sharing it to warrant our efforts. It’s a lotta work for us to keep all of this up!  Follow us on Twitter (easy instructions at our website to get just-in-time updates…next entry will be next Thursday, 2/16/2012).

Our Website
And we are retooling our website.  We are in the midst of this gargantuan effort.  (We have a very big site!  Whew!)  But we hope access will be even easier because of our changes.  Key pages have been converted, but many have not yet been, so page-to-page will look a little chaotic and not function the same until we are done: www.delfini.org.

Your Treat
And now, for a fantastic treat!  The generous, creative and brilliant Paul Vallett, PhC, had a frustrating day one day in his lab, and while we would never wish him that, we are grateful for his transmogrifying that evil event into something brilliant and wonderful that sooooo exquisitely captures what life often looks like on the outside, but what insiders actually experience and know.  We’ve all been here, right!!?!?? (Oh, yeah, like my web site redesign! It’s no cut-and-paste job.  I am now as bald as Mike!)  Paul’s is about one of our most beloved topics, “Doing Science,” but it can stand in as metaphor to so much more…to.so.much.more…  And it is hilarious!!!  The URL title gives you a hint.  Thank you, Paul!  Happy Day all, Sheri


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