The Obesity Crisis: Well Known Culprits—Few Focus Extensive R&D Investments, Except Danish Biopharmaceutical Company

Oct 15, 2018 | Blog, Obesity

A Global Crisis With USA at The Epicenter
Obesity represents a growing crisis worldwide.  According to the World Health Organization:

  • Worldwide obesity has nearly tripled since 1975
  • By 2016, nearly 1.9 billion adults (18 and older) were overweight. Of these 650 million were obese
  • Most of the world’s population lives in countries where obesity kills more than people than being underweight
  • 41 million children under the age of 5 were overweight or obese in 2016
  • Over 340 million children and adolescents aged 5-19 were overweight or obese in 2016
  • Obesity is preventable

The United States marks the epicenter of this crisis.  According to State of Obesity, obesity represents a major driver of preventable chronic diseases in the United States.  Obesity healthcare system economic impacts range from $147 billion to almost $210 billion annually.  Obesity is associated with job absenteeism with $4.3 billion impact annually (Robert Wood Johnson Foundation).

Although only 5 percent of the global population, 13 percent of the world’s obese reside in America.  An estimated 160 million Americans are overweight or obese.  Approximately 67 percent of American men and 60 percent of American women could be categorized as overweight or obese.  Compounding the crisis, nearly 30 percent of boys and girls under 20 are either overweight or obese, up from 19 percent in 1980.  This is a frightening growth rate given the comorbidity health consequences. 

In the United States, according to a Robert Wood Johnson Foundation study, 20 percent of obesity accounts for 20 percent of the annual direct healthcare costs as well as the Journal of Health Economics study here.  In the latest Robert Wood Johnson Foundation 2017 study, it reports that obesity represents a national security crisis, in that 70 percent of today’s American youth are not fit to serve in the military due to obesity, being overweight and other factors.  Obesity also represents a community health and social determinant of health/health equity crisis. 

Although obesity may be initiated via lifestyle behavioral and socioeconomic factor forces, it ultimately represents a rapidly growing, raging chronic disease that impacts just about every bodily system and results in dangerous comorbidities including hypertension, diabetes, cardiovascular disease, osteoarthritis, infertility, depression and cancer.  Consequently, such comorbidities translates to growing health care costs.

Coverage Not Consistent

In the United States, managed care often doesn’t cover obesity treatment directly, but rather, its consequent comorbidities.  Managed HealthCare Executive, Taraneh Soleymani, MD FTOS, assistant professor, department of nutrition services, University of Alabama, recently noted that “across the United States, many healthcare systems do not cover these treatment options or there is inconsistent coverage of them leaving the beneficiary to gain more weight and acquire obesity related comorbidities.” 

As payers ultimately come around to direct coverage, the results are mixed, as is summarized by NCBI NIH’s article titled “the Challenge of Treating Obesity and Overweight: Proceedings of a Workshop.” 

It can be summarized as the following:

  • 70 percent of employers believe wellness programs provide value to employees, and only 17 percent of people with obesity believe their employers’ wellness programs are effective for them (Parry)
  • Employers’ realization of true economic loss will require understanding of absenteeism and lost productivity (Parry)
  • Convenient, credible and evidenced-based interventions can make a difference (Williams)
  • State Medicaid agencies vary widely in how they cover and report on obesity prevention and treatment services (Stockmann)
  • Introduction of obesity services coverage doesn’t automatically lead to utilization of such services or imply a particular quality of care (Stockmann)

Current Treatments

Current obesity treatments include the following: 1) modification (e.g. diet, activity, behavioral change) 2) medications and 3) bariatric surgery.  According to a recent Managed Healthcare Executive article common medication include genetic phentermine and bupropion.  Additionally, Vivus Inc. offers phentermine-topiramate (Qsymia) and Novo Nordisk markets liraglutide (Saxenda).  Orlistat is marketed as Alli over the counter in the United States and United Kingdom and Xenical by Roche elsewhere worldwide.  It promotes weight loss by slowing down the digestion and absorption of food fat.

As reported in Managed Healthcare Executive, current medications are not offering material improvements to long-term positive outcomes.  As reported in the referenced article, Craig Mattson, RPh, senior director of formulary development at Prime Therapeutics noted, “many weight loss medications lack proven long-term clinical outcomes and return on investment and most commercially insured employers exclude coverage for weight loss medications.” 

Most Prominent Drug Treatments

According to a recent Harvard publication, obesity itself is a primary risk factor—not just its standard comorbidity risks such as cardiovascular disease.  Harvard acknowledges that the “quest has been elusive” to cure obesity via obesity drugs.  It reports that FDA medications approved since 2012 may represent some advancement.  We include a table with the obesity drugs below.  It should be noted that they include considerable safety concerns despite ultimate approvals:

 

Medication/Sponsor Approval History (some comments originate from Wikipedia)
Qsymia (phentermine & topiramate)/

Vivus Inc.

In December 2009 VIVUS, Inc. submitted a new drug application (NDA) to the FDA and on March 1, 2010, VIVUS, Inc. announced that the FDA accepted the NDA for review.

In October 2010, the FDA announced its decision to not approve phentermine/topiramate ER in its current form and issued a Complete Response Letter (CRL) to VIVUS due to lack of long-term data and concerns about side effects, including elevated heart rate, major adverse cardiovascular events, and birth defects.

The FDA expressed concerns about the potential for phentermine/topiramate ER to cause birth defects and requested that Vivus assess the feasibility of analyzing existing healthcare databases to determine the historical incidence of oral cleft in offspring of women treated with topiramate for migraine prophylaxis (100 mg).

In October 2011, VIVUS resubmitted the NDA to the FDA with responses to the issues addressed in the CRL. The FDA accepted the NDA in November 2011.

On September 18, 2012, Qsymia became available on the US market.

Belviq (lorcaserin)/

Arena Pharmaceuticals

On December 22, 2009, a New Drug Application (NDA) was submitted to the Food and Drug Administration (FDA) in the United States.  On September 16, 2010, an FDA advisory panel voted to recommend against approval of the drug, based on concerns over both safety and efficacy.  In October 2010, the FDA stated that it could not approve the application for lorcaserin in its present form.

Lorcaserin had a Prescription Drug User Fee Act (PDUFA) date of October 22, 2010. On September 16,  2010, a federal advisory committee voted against recommending approval for lorcaserin.  In their 9-5 vote, the committee raised concerns about the safety of the drug, particularly the findings of tumors in rats.  On October 23, 2010, the FDA decided not to approve the drug based on the available data. This was not only because cancer promoting properties could not be ruled out, but also because the weight loss efficacy was considered “marginal.”

After additional studies were completed and additional information submitted to the FDA, an advisory panel was convened on May 10, 2012. The advisory panel voted 19-4-1 to recommend lorcaserin to the FDA. The FDA stated that the weight loss data passed FDA standards for efficacy and that the drug did not have cancer risks based on clarifications in the data. The FDA panelist recommended that post marketing studies regarding potential heart valve issues be completed.  The FDA has not stated one way or the other whether they believe this is necessary at this time although no related safety markers have been indicated during clinical studies. On June 27, 2012, the FDA officially approved lorcaserin for use in the treatment of obesity for some adults.

On May 10, 2012, after a new round of studies submitted by Arena, an FDA panel voted to recommend lorcaserin with certain restrictions and patient monitoring.  The restrictions include patients with a BMI of over 30, or with a BMI over 27 and a comorbidity such as high blood pressure or type 2 diabetes. On June 27, 2012, the FDA officially approved lorcaserin for use in the treatment of obesity for adults with a BMI equal to or greater than 30 or adults with a BMI of 27 or greater who “have at least one weight-related health condition, such as high blood pressure, type 2 diabetes, or high cholesterol

Contrave (naltrexone and bupriopion)/

Orexigen Inc

Orexigen submitted a New Drug Application (NDA) for this drug combination to the FDA on March 31, 2010.  Having paid a fee under the Prescription Drug User Fee Act, Orexigen was given a deadline for the FDA to approve or reject the drug of January 31, 2011. On December 7, 2010, an FDA Advisory Committee voted 13-7 for the approval of Contrave and voted 11-8 for the conduct of a post-marketing cardiovascular outcomes study.  Subsequently, on February 2, 2011, the FDA rejected the drug and it was decided that an extremely large-scale study of the long-term cardiovascular effects of Contrave would be needed, before approval could be considered. It was ultimately approved in the United States in the fall of 2014.

In December 2014, the EU’s Committee for Medicinal Products for Human Use (CHMP) endorsed the combination for licensure as an obesity medication when used alongside diet and exercise.  Approval was granted in late March 2015.

In May 2015, Orexigen ended a safety study of its diet drug earlier than planned, because an independent panel of experts says the drug maker “inappropriately” compromised the trial by prematurely releasing interim data.  The early data release reported a reduction in heart attacks that was no longer observed when a more complete view of the data was analyzed

Saxenda (liraglutide)/
Novo Nordisk
First approved by the FDA in 2010. See summary article correlating with weight loss. 

Novo Nordisk partnering with other ventures for obesity research. 

See academic review of liraglutide linked to NCBI/NIH. 

 

 

According to Dr. Lee Kaplan, director of Massachusetts Hospital Weight Center, “we now have six FDA approved drugs, but that is a tiny percentage of the number available to treat hypertension and other chronic diseases, so we need even more options to treat obesity most effectively.”  According to a recent publication with NCBI, liraglutide (Novo Nordisk Saxenda) performs better than orlistat or lorcaserin but may be slightly outperformed by phentermine/topiramate.  Saxenda does include additional cardiovascular benefits however current impediments include gastrointestinal side effects, high-cost and need for injection.

What Direction?

Referring again to the Managed HealthCare Executive article, research and development for obesity drugs has been less than stellar or “lackluster—and medications recently approved aren’t providing significant improvements in reduction of long-term primary outcomes (i.e. prevention of diabetes, heart attack, stroke, etc.).”  Recent experts in the field challenge the ultimate premise of weight loss drugs such as a recent article in Pharmaceutical Journal by David Katz, who argues that they (drugs) may not be the ultimate solution. 

Others articulate that new treatments will make it into the market, such as beloranib (Zafgen), and are being studied for obesity therapy.  Payers continue to be concerned about covering obesity drugs due to safety and cost concerns. 

Present Obesity Drug Pipeline Analysis

We reviewed Obesity Drug candidates currently recruiting, or active and across phases.  We found eight trials dominated by Danish commercial sponsor Novo Nordisk.  What follows is a summary of relevant clinical trials.  It is apparent that only one global biopharmaceutical companies commits substantial ongoing R&D investment in obesity targets.

Novo Nordisk

One Novo Nordisk Phase I trial focuses on patients with overweight or obesity diagnosis.  The study is testing a new medicine for weight control in people who are overweight or have obesity.  The aim of the study is to find out how safe the study medicine is and how it works in the body.  Participants will either get NNC9204-1706 (the new study medicine) or placebo (a dummy medicine).  Which treatment participants get is decided by chance.  NNC9204-1706 is a new medicine which cannot be prescribed by doctors.  Participants will get an injection under the skin of participants’ stomach each morning for 10 weeks.  A medical tool called NovoPen®4 will be used for the injection. Participants must change the part of the pen including the medicine (the cartridge) each day.  The study will last for about 16 weeks, during which, participants will have at least 17 clinic visits and 10 phone calls with the study doctor. At certain times during the study, participants will have blood drawn and three various kinds of heart tests (electrocardiograms).  Study doctors will ask participants to answer mental health surveys.

With this study arises the question: what is NNC9204-1706?  It is a Novo Nordisk developed drug candidate in early clinical study (Phase I) Mechanism of Action: it is a gastric inhibitor polypeptide receptor agonist; Glucagon like peptide 1 receptor agonists; Glucagen receptor agonists.

Novo Nordisk is a sponsor of another phase I obesity study currently not recruiting and apparently ongoing, where the commercial sponsor will look at a new study medicine for weight management in people with obesity or are overweight.  The sponsor’s objectives are to find out how safe and tolerable the study medicine is.  The new investigational drug is known as NNC92-4-1177.

According to the sponsor’s description in Clinicaltrials.gov, participants will either get NNC9204-1177 (the new study medicine) or placebo (a formula that looks like the study medicine but does not have active ingredients).  Which treatment participants get will be decided by chance. NNC9204-1177 has not been approved by the United States Food and Drug Administration and its use in this study is experimental.  Participants will get one or more injections into the skin of the stomach area once each week for 12 weeks, and the study will last for about five months.  Participants will have 19 clinic visits with the study doctor, and at certain times during the study, participants will have blood draws and three different kinds of electrocardiograms.  Participants will answer mental health questionnaires.  Women: Women cannot take part if pregnant, breast-feeding or plan to become pregnant during the study period.

A different Novo Nordisk Phase I study focuses on NNC0194-0499, an investigational treatment that is an experimental obesity therapy with mechanism of action involving fibroblast growth factor modulators.  According to the sponsor’s ClinicalTrials.gov description:

This study looks at a new study medicine for weight control in people with overweight or obesity.  The aim of this study is to see if the study medicine is safe for people to take.  The study also looks at how fast the body removes the study medicine.  The participants will either get NNC0194-0499 (the study medicine) or placebo (a formula that looks like the medicine but does not have active ingredients).  Which treatment the participants get is decided by chance.  The participants will get one or more injections into the skin of stomach area once each week for 12 weeks.  The study will last for about four to five months.  The participants will have 18 visits to the clinic. 

Additionally, sponsor Novo Nordisk, is running a Phase III trial with an existing drug (Liraglutide) and the effect of that drug for weight management in pubertal adolescent subjects with obesity. 

From equity and business perspective, investment analyst website Seeking Alpha recent suggested that despite recent stock decline (due in part to competitor Lilly news), Novo Nordisk will move back up in price due to its market position with diabetes and obesity drugs.  In the summer, they suggested a buy based on growing obesity epidemic.  

Other Obesity-focused Clinical Trials

In China, The Affiliated Nanjing Drum Tower Hospital of Nanjing University Medical School sponsors a Phase IV Trial studying the effect and safety of Benaglutide or Metformin in patients with simple obesity who have inadequate weight control.  The Chinese study with 60 patients, started in 2017 and is scheduled to be completed in 2019.  

What is Benaglutide?  It is a product invested by Chinese biopharmaceutical company, Shanghai Benemae Pharmaceutical.  It falls in the drug class of Antihyperglycaemics; Peptides and its mechanism of action is Glucagon like peptide one receptor agonists.  According to the listing, the drug is only being investigated in China. They study includes two groups (Benaglutide or Metformin)—the latter marketed under the trade name Glucophage (marketed by Bristol-Myers Squibb).

Johnson & Johnson’s Janssen partnered with South Korea’s Hanmi Pharmaceutical to evaluate the safety and efficacy of their JNJ-64565111 drug in non-diabetic, severely obese patients. The partnership was announced in the Korean Herald in 2018. 

Another commercial sponsor example is Swiss-based Novartis running a safety study of its LL580 drug in obese volunteers. 

Phase IV trial in Korea represents a pilot study exploring the efficacy and safety of herbal medicine on Korean obese women with metabolic syndrome risk factors.  Sponsored by Gachon University South Korea, it investigates the following herbal treatment:

The sponsor, Gachon University Gil Oriental Medical Hospital lists Yun-Kyung Song, KMD as Principal Investigator. 


Summary

All evidence points to a mounting global obesity crisis.  Direct and indirect costs to health systems can only grow, barring heretofore unanticipated changes to human behavior across developing and emerging economies.  Although it should be well known that diet, activity and behavior play a key role in the initial onslaught, it is apparent that that knowledge is not correlating to any material improvements in the chronic diseases’ growth.  

This author believes strongly that as societal wealth grows so do the opportunities for the prevalence of certain health conditions including obesity. Undoubtedly, depending on the individual, setting, treatment provider and other factors, there are well-known standards of care.  

Based on TrialSite News research, it is apparent that in addition to a dynamic push for food, dietary and lifestyle changes, payers (commercial insurance, managed care, Medicare & Medicaid, et al) in the United States need to consider more pervasive coverage for obesity and not just its comorbidity diagnoses (e.g. cardiovascular disease, diabetes, etc.).  Considering the magnitude and severity of the crisis worldwide, the researchers were surprised by the dearth of concentrated commercial investment involved with obesity drug research.  Based on our active research criteria, only a handful of biopharmaceutical companies have reported trials in Clinicaltrials.gov.

Although we did uncover a range of activities, and even a Korean study focusing on select herbal remedies, we did not have time to research this approach or its validity.  However, there are other established biotech ventures commercializing obesity drugs including Orexigen, Arena Pharmaceuticals and Vivus Inc. to name some examples.  Moreover, when the search was expanded to include obesity beyond “obesity drugs,” other sponsors such as Rhythm Pharmaceuticals, Inc., Medimmune (AstraZeneca), Boehringer Ingelheim, Janssen and Novartis as well as others have some active obesity pipeline activity.  

Undoubtedly, there are other ventures and activities, but only one company appears to have worldwide focus on obesity as measured by considerable R&D investment.  That company would be Novo Nordisk of Denmark.

 

TrialSite News

Daniel O’Connor

 

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