Nonincretin Drugs in Later-Stage Development

Obesity continues to be a growing health concern. The number of adults classified by the Centers for Disease Control and Prevention (CDC) as being overweight or obese, with a body mass index (BMI) of 25 kg/m2 or higher, is almost 155 million; those considered obese (BMI ≥30.0 kg/m2) number 79 million. If left unchecked, obesity-related healthcare costs could top $950 billion by 2030.¹ Based on the number of people affected and the associated cost, stakeholders are taking steps to reduce this burden. However, challenges remain (see Highlight Box).

Until 2012, the US Food and Drug Administration (FDA) had not approved a drug to treat obesity since orlistat won approval 13 years ago.² Safety concerns had limited the number of drugs available to treat obesity, and safety continues to remain a concern. Lorcaserin, marketed as Belviq by Arena Pharmaceuticals, and phentermine/topiramate extended release, marketed as Qsymia by Vivus Inc, were both approved in 2012 to treat obesity alongside a reduced-calorie diet and exercise.

Both drugs have FDA-approved labeling stating the drugs should be discontinued if 5% weight loss is not achieved after 12 weeks of therapy.^3,4 The nonincretin medications that are currently in phase III development have mechanisms of action similar to antiobesity drugs that are currently available. Only 1 drug in phase II development has a mechanism of action that does not involve the central nervous system (CNS).

Drugs in Phase III Development

Bupropion/naltrexone. Currently, the only nonincretin product in phase III development in the United States is a combination of bupropion and naltrexone being developed by Orexigen. If approved, it will be marketed as Contrave. Both components of this centrally acting agent affect the pro-opiomelanocortin (POMC) neurons (Figure). So far, this agent has had a bumpy road to approval.

The FDA initially rejected Orexigen’s new drug application (NDA) in January 2011, indicating a concern about the product’s cardiovascular safety. The pivotal study cited in the initial filing was a phase III trial of 1496 patients who were enrolled for 56 weeks of treatment with bupropion/naltrexone or placebo. Fifty-four percent of patients in each treatment arm completed the study. Weight loss was significantly greater at 28 weeks in the bupropion/naltrexone group compared with the placebo group, and the same result was seen at 56 weeks (6.5% vs 1.9%, P <.001; 6.4% vs 1.2%, P <.001; respectively).⁵ More patients dropped out of the study due to adverse events in the treatment group than in the placebo group (241 vs 68 patients). Nausea, headache, and constipation were the most frequently reported adverse events. Serious adverse events were reported in 2.1% of the treatment group and 1.4% in the placebo group. A myocardial infarction was reported by a patient in the treatment group with active coronary artery disease, and 1 patient in the treatment group who did not have a history of seizures suffered one during the study.⁵

In its complete response letter, the FDA mandated in 2011 that Orexigen conduct a randomized, double-blind, placebo-controlled trial to demonstrate that the risk of major adverse cardiovascular events in overweight and obese subjects does not adversely affect the drug’s benefit risk profile.⁶ To address these concerns, the Light Study was designed and approved by the FDA.

The study began in June 2012 and is expected to be completed in the second quarter of 2017. The FDA proposed that findings from the interim analysis report compiled by the Light Study’s independent data monitoring committee be the basis for the NDA resubmission filing. The primary outcome measure of the Light Study is the length of time to the first confirmed occurrence of a major cardiovascular event in a 4-year period.⁷ The secondary outcomes measures are also related to safety issues. On November 25, 2013, Orexigen announced that the interim results of the Light Study had been successful, and on December 11, 2013, it resubmitted its NDA filing with approval aimed for June 2014.⁸

In February 2013, Orexigen initiated another study, the Ignite Study, to assess the percent change in body weight during a 26-week time period. The secondary outcomes measures include both efficacy and safety measures.⁹ The company anticipates that the study will be completed in December 2014.

Cetilistat. A lipase inhibitor dubbed cetilistat, to be marketed as Cametor by Takeda, is in phase III trials in Japan. A 12-week study compared cetilistat with orlistat, both given 3 times daily, demonstrated similar weight reduction results compared with a placebo. With cetilistat treatment, weight reduction was 3.85 kg (P = .01) in those receiving an 80-mg dose and 4.32 kg (P = .0002 in the placebo comparison) in those receiving a 120-mg dose. The weight reduction was 3.78 kg (P = .008) in the 120-mg orlistat group. There were fewer discontinuations in the cetilistat group than in the orlistat group; the discontinuations due to adverse events in the cetilistat were similar to those patients receiving placebo.¹⁰ Norgine, a European company, is developing the product for approval by regulatory agencies outside of Japan and is currently seeking partnerships for such programs.¹¹

Drugs in Phase II Development

Beloranib. A drug with a new mechanism of action for treating obesity is beloranib. The drug is a methionine aminopeptidase 2 (MetAP2) inhibitor that targets imbalances in fat metabolism that are present in patients with obesity.¹² Specifically, it reduces the production of new fatty acid molecules by the liver and also helps to convert stored fats into useful energy. Results announced by Zafgen Inc on November 15, 2013, showed significant weight loss and improvements in cardiometabolic risk markers in 147 obese patients over a 12-week period. Study participants taking 0.6 mg, 1.2 mg, or 2.4 mg of the drug lost, on average, 5.5 kg, 6.9 kg, and 10.9 kg, respectively, compared with 0.4 kg for those on a placebo. No serious adverse events deemed related to the drug were reported.¹³

Bupropion SR/Zonisamide SR. Both components of a new combination drug that will be marketed as Empatic (bupropion SR 360 mg/zonisamide SR 360 mg) affect the CNS. It has shown favorable weight-loss effects. Bupropion increases dopamine levels, while zonisamide increases dopamine and serotonin neurotransmission.¹² After 24 weeks of treatment, patients in the treatment group had a mean weight loss of 7.5% vs 1.4% in the placebo group (no P value given). The combination drug was also compared with its components. Greater mean weight loss was seen with the combination drug (7.5% for combination, 2.3% for bupropion, and 5.3% for zonisamide; P <.001). The most commonly reported adverse events were headache, insomnia, and nausea as would be expected with drugs affecting the CNS.¹⁴

RM-493. A melanocortin-4 receptor (MC4R) agonist, RM-493 modulates leptin-receptor signaling, resulting in decreased appetite; it has also been implicated as a common genetic variant in obesity is in early phase II trials.^15,16 Results for weight loss in humans have been mixed.^17,18 Adverse events observed have included nausea, diarrhea, and loose stools, and skin rash, but it was considered well tolerated overall.¹⁹ Potential unwanted adverse effects may be increased blood pressure and heart rate as well as penile erection, as MC4 agonists stimulate the sympathetic nervous system.^15,16

Tesofensine. Tesofensine inhibits dopamine, norepinephrine, and serotonin uptake. Initial development of the drug was for Parkinson disease and Alzheimer disease; however, researchers discovered weight loss was associated with its use without changing blood pressure.²⁰ In a trial of 203 patients, participantswere assigned to either restrict their diets or take tesofensine in doses of 0.25 mg, 0.5 mg, or 1 mg for 24 weeks. Those in the diet-restricted group lost 2% of their body weight, whereas those in the tesofensine groups lost a mean of 4.5%, 9.2%, and 10.6%, respectively, more body weight greater than did the control group (all P = .0001). Significant increases in diastolic or systolic blood pressure were not observed in the 0.25-mg and 0.5-mg groups, but an increased heart rate (7.4 beats/min) was seen in the 0.5-mg group (P = .0001). The most frequently observed adverse events were dry mouth, nausea, constipation, diarrhea, and insomnia.²¹

On the Horizon

There are only a few nonincretin drugs in the pipeline for the treatment of obesity. This is disappointing because of the enormous health and financial consequences of obesity. However, it appears that there is beginning to be a convergence of thinking about the importance of addressing obesity in the United States. The government and the AMA appear ready to accept the challenge of reducing obesity. As demand for drugs increases, pharmaceutical and biotechnology companies will undoubtedly respond with new therapeutic entities to treat overweight and obese patients.

It will be up to patients, employers, insurers, and health plans as to whether we proceed on a course to address the challenge.

HIGHLGHT BOX. Stakeholder Activity on Obesity Coverage

Federal Government. The federal Health Care and Education Reconciliation Act of 2010 included provisions relative to the treatment and insurance coverage of conditions related to obesity.

All Medicaid and Medicare beneficiaries as well as those patients with private insurance will be eligible to receive preventative services for obesity as recommended by the US Preventive Services Task Force (USPSTF). Private insurers will be required to pay medical claims for preexisting conditions identified as obesity or an obesity-caused comorbid condition.²² In June 2012, the USPSTF, an independent panel of experts, recommended that doctors screen all patients for obesity. They also recommended that clinicians should refer patients with BMI ≥ 30 kg/m² to an intensive, multicomponent behavioral intervention program. However, the USPSTF did not identify programs that meet the criteria for an intensive, multicomponent behavioral intervention that helps patients lose weight.²³

To date, Medicare part D does not cover obesity drugs. Under Medicaid, only 10 states provided coverage of obesity drugs for adults as found by a survey in 2008.²⁴ Due to this legislation and recommendations of the USPSTF, the US Secretary of Health and Human Services (HHS) may develop rules and regulations to address or expand coverage of services related to the treatment of obesity.

States. Most state insurance laws do not include language about the coverage of obesity treatments. A survey of state insurance laws in 2008 found that relative to obesity, 6 states required or explicitly allowed coverage of certain obesity treatments in their group markets. For individual markets, only 5 states had language about coverage in the policies.²⁴ Obesity treatments included bariatric surgery and drugs. A retrospective study conducted by the Veterans Affairs medical centers could further deemphasize coverage for bariatric surgery. The analyses of 850 veterans (mean age 49.5 years) showed that after a mean follow-up of 6.7 years, bariatric surgery did not reduce mortality compared with usual care.²⁵

Professional Societies. In June 2013, the American Medical Association (AMA) recognized obesity as a disease. This policy acknowledges that obesity is a complex issue that requires a range of medical interventions to advance obesity treatments and prevention.²⁶ To date, the American Heart Association and American Diabetes Association have not updated their guidelines on obesity to include drugs for the treatment of obesity.

Employers. Although employers are aware of the financial impact of obesity, they generally consider obesity as a lifestyle choice rather than a disease. Some offer onsite weight-control programs or health coaches, and some have modified cafeteria menus. Health risk assessments and financial incentives associated with healthcare premiums are also strategies being utilized to “encourage” employees to adhere to a healthy weight-friendly lifestyle.²⁷

Health Plans and PBMs. As noted, government agencies (Centers for Medicare & Medicaid Services for Medicare Part D and Medicaid in most states) do not broadly provide drug coverage for obesity drugs. The stance of managed care organizations (MCOs) is similar. A survey conducted in early 2013 found that nearly half of surveyed MCOs and medical directors do not cover drugs for obesity.²⁸ Reasons for not covering these drugs include: safety, long-term efficacy, no improvement in cardiovascular outcomes, and the perception that these are “lifestyle”

drugs that are used for cosmetic reasons.^27-29 Express Scripts, one of the largest pharmacy benefit management companies, added phentermine/topiramate extended release (Qsymia) to its national formulary in 2012 with availability only through its mail order service.³⁰ Of course, employers and health plans will be the determining factor as to whether they offer the drug to their patients. Also in 2012, Aetna added locaserin and phentermine/topiramate in a clinical policy bulletin describing the insurer’s approach to weight reduction.³¹ This weight reduction policy bulletin included all drugs approved by the FDA for obesity.

References

1. Statistical Fact Sheet 2013 Update: Overweight & Obesity. American Heart Association website. http://www.heart.org/idc/groups/heart-public/@wcm/@sop/@smd/documents/downloadable/ucm_319588.pdf. Accessed October 1, 2013.

2. Orlistat (marketed as Alli and Xenical) information. US Food and Drug Administration website.http://www.fda.gov/Drugs/DrugSafety/PostmarketDrugSafetyInformationforPatientsandProviders/ucm180076.htm. Updated June 17, 2013. Accessed October 1, 2013.

3. FDA approves Belviq to treat some overweight or obese adults [press release]. Silver Spring, MD: US Food and Drug Administration; June 27, 2012. http://www.fda.gov/NewsEvents/Newsroom/PressAnnouncements/ucm309993.htm. Accessed September 30, 2013.

4. FDA approves weight-management drug Qsymia [press release]. Silver Spring, MD: US Food and Drug Adminstration; July 17, 2012. http://www.fda.gov/NewsEvents/Newsroom/PressAnnouncements/ucm312468.htm. Accessed September 30, 2013.

5. Apovian CM, Aronne L, Rubin D. et al. A randomized, phase 3 trial of naltrexone SR/bupropion SR on weight and obesity-related risk factors (COR-II). Obesity. 2013;21:935-943.

6. FDA issues complete response to new drug application for Contrave for the management of obesity [press release]. San Diego, CA: Orexigen website; February 1, 2011. http://ir.orexigen.com/phoenix.zhtml?c=207034&p=irol-news Article&id=1522207. Accessed September 29, 2013.

7. Cardiovascular outcomes study of naltrexone SR/bupropion SR in overweight and obese subjects with cardiovascular risk factors (The Light Study). US National Institutes of Health. http://clinicaltrials.gov/ct2/show/NCT01601704?term=Light+study&rank=2. Published May 6, 2013. Accessed September 29, 2013.

8. Orexigen resubmits Contrave new drug application [press release]. San Diego, CA: Orexigen website; December 11, 2013. http://ir.orexigen .com/phoenix.zhtml?c=207034&p=irol-newsArticle_print&ID=1883850&highlight=. Accessed December 31, 2013.

9. Method-of-use study assessing the effect of naltrexone sustained release (SR)/bupropion SR on body weight and cardiovascular risk factors in overweight and obese subjects. US National Institutes of Health. http://clinicaltrials.gov/ct2/show/NCT01764386?term=Ignite+study&rank=1. Published February 8, 2013. Accessed September 29, 2013.

10. Kopelman P, Groot GH, Rissanen A, et al. Weight loss, HbA1c reduction, and tolerability of cetilistat in a randomized, placebo-controlled phase 2 trial in obese diabetics; comparison with orlistat (Xenical). Obesity. 2010;18:108-115.

11. Partnering opportunities. Norgine website. www.norgine.com/pages/partnering/opportunities.html. Accessed September 30, 2013.

12. Chugh PK, Sharma S. Recent advances in the pathophysiology and pharmacological treatment of obesity. J Clin Pharm Ther. 2012;37:525-535. 13. Zafgen announces new weight loss and safety data from phase 2 study of beloranib in obesity at Obesity Week 2013 [press release]. Atlanta, GA: November 15, 2013. http://www.zafgen.com/zafgen/newsroom/news-details?ID=d0dbc3b2-5885-6f14-8089-ff0000fc4595 Accessed December 31, 2013.

14. Orexigen therapeutics phase 2b trial for Empatic meets primary efficacy endpoint demonstrating significantly greater weight loss versus comarators in obese patients [press release]. San Diego, CA:Orexigen website; September 30, 2009. http://ir.orexigen.com/phoenix.zhtml?c=207034&p=irolnewsArticle&ID=1336796&highlight=. Accessed September 30, 2013.

15. Adan RAH. Mechanisms underlying current and future antiobesity drugs. Trends Neurosci. 2013;36:133-140.

16. Misra M. Obesity pharmacotherapy: current perspectives and future directions. Current Cardiology Reviews. 2013;9:33-54.

17. Krishna R, Bumbiner B, Stevens C, et al. Potent and selective agonism of the malanocortin receptor 4 with MK-0493 does not induce weight loss in obese human subjects—energy intake predicts lack of weight loss efficacy. Clin Pharmacol Ther. 2009;86:659-666.

18. Schakenbach J. BioFlash Newsletter. http://www.bizjournals.com/boston/blog/bioflash/2013/01/rhythm-begins-phase-2-trials-for.html?page=all. Published January 4, 2013. Accessed October 3, 2013.

19. Khan A, Raza S, Khan Y, et al. Current updates in the medical management of obesity. Recent Pat Endocr Metab Immune Drug Discov.2012;6:1-12.

20. Astrup A, Meier DH, Mikkelsen BO, et al. Weight loss produced by tesofensine in patients with Parkinson’s or Alzheimer’s disease. Obesity. 2008;16:1363-1369.

21. Astrup A, Madsbbad S, Breum L, et al. Effect of tesofensine on bodyweight loss, body composition, and quality of life in obese patients:a randomized, double-blind, placebo-controlled trial. Lancet. 2008;372:1906-1913.

22. Downey M. What does health care reform mean for obesity? the Downey Obesity Report. http://www.downeyobesityreport.com/2010/03/what-does-health-care-reform-mean-forobesity/. Published March 23, 2010. Accessed October 3, 2013.

23. US Preventive Services Task Force Recommendation. Statement Screening for and Management of Obesity in Adults. http://www.uspreventiveservicestaskforce.org/uspstf11/obeseadult/obesers.htm. Published June 2012. Accessed October 3, 2013.

24. Lee JS, Sheer JLO, Lopez N, et al. Coverage of obesity treatment: a state-by-state analysis of Medicaid and state insurance laws. Public Health Reports. 2010;125:596-604.

25. Maciejewski ML, Livingston ED, Smith VA, et al. Survival among high-risk patients after bariatric surgery. JAMA. 2011;305:2419-2426.

26. AMA adopts new policies on second day ofvoting at annual meeting [press release]. American Medical Association website. Chicago, IL: June 18, 2013. http://www.ama-assn.org/ama/pub/news/news/2013/2013-06-18-new-ama-policiesannual-meeting.page. Accessed October 4, 2013.

27. Reinke T. Employers, others not sold on new anti-obesity drugs. Managed Care. http://www.managedcaremag.com/archives/1209/1209.obesity.html. Published September 2012. Accessed October 4, 2013.

28. Report: Uptake of obesity drugs will be hampered by managed care formulary exclusion. P&T Community. http://www.ptcommunity.com/news/DailyDetail.cfm?chosen=67296. Published April 16, 2013. Accessed October 4, 2013.

29. Shek A, Derbyshire MB, Szkotak J. Review of the pharmacologic arsenal for the war on obesity. Formulary. April 1, 2013. http://formularyjournal.modernmedicine.com/formulary-journal/RC/diabetes/review-pharmacologic-arsenal-warobesity. Accessed October 4, 2013.

30. Vivus’s obesity pill to be covered by Express Scripts. Reuters. December 20, 2012. http://www.reuters.com/article/2012/12/20/us-vivus-obesitydrug-coverage-idUSBRE8BJ0KW20121220.

Accessed October 4, 2013.

31. Clinical policy bulletin: weight reduction medications and programs. Aetna website.http://www.aetna.com/cpb/medical/data/1_99/0039.html. Published November 20, 2012. Accessed October 4, 2013