Saxenda, originally marketed as Victoza (and prescribed to treat diabetes), is a once-daily injection for weight loss from Novo Nordisk. 

The off-the-charts obesity rate in the US is tailspinning into a reality of metabolic dysfunction. The call is out for therapies that prove efficacious and safe—and, of course, drive down costs. Thus a wider range of diabetes products are set to swarm the market, at a moment when anti-obesity drugs are aiming to establish their value.

Metabolic drug development hinges on erasing the line drawn in the sand between diabetes and obesity. Experts insist that R&D efforts in the category must mirror educational campaigns and lifestyle changes, and quickly. The number of people with diabetes in US is edging toward 30 million, with 37% of adults and 51% of seniors teetering on the edge with a pre-diabetic diagnosis.

See also: Diabetes R&D narrows in on glycemic control

The growing prevalence of obesity, according to ConscienHealth’s founder and principal Ted Kyle, is causing a cascade of chronic conditions, including diabetes, cardiovascular disease, fatty liver disease, elevated triglycerides and lipid disorder. As of 2012, the direct and indirect costs associated with diabetes reached an estimated $245 billion, with medical expenditures among people with diabetes 2.3 times higher than among those without diabetes.

Difficulty in the sector, explains Finn Partners’ managing partner of health Gil Bashe, boils down to the age-old dilemma of determining the role lifestyle and genetics each play in rates of obesity, pre-diabetes and type 2 diabetes. “Our diet and lifestyle choices are the fuel that drives this marketplace,” he says, adding that he believes challenges with payer involvement and leadership are driving a rift in the category. “Payers want healthier members and metabolic syndromes are a cost drain. Marketers need to find a way to collaborate around shared solutions.”

See also: Top 25 Metabolic Products

Eli Lilly, Novo Nordisk and Sanofi are at the helm of next-generation diabetes drug discovery. “These companies had to conquer a new high bar: efficacy and demonstrated cardiovascular safety,” Bashe says. Kyle, for his part, notes that diabetes marketers and HCPs have begun to recognize the importance of obesity as a comorbidity. As a result, drugs that cause weight gain have fallen out of favor.

On the other hand, the favorable effect of SGLT2 and GLP-1 products on body weight and long-term clinical outcomes has contributed to robust growth in the category. “Analysts have high hopes of commercial and clinical success for GLP-1/insulin combination products, but only time will tell if they live up to expectations,” Kyle says.

The newest crop of blood glucose levelers aims to slash high rates of HbA1c in at-risk patients, while also keeping weight in check. Novo Nordisk’s once-weekly semaglutide proved to reduce HbA1c levels by 1.5% and 1.6%. Sanofi’s lixisenatide is the first GLP-1 receptor agonist with long-term cardiovascular safety data in people with diabetes who have high cardiovascular risk.

The race is on

Sanofi withdrew its lixisenatide FDA application a few years ago to determine the agent’s risk of CV events. While the GLP-1 didn’t show an increase risk of CV events in patients with acute coronary syndrome, it also didn’t reveal a decrease. Jardiance, Lilly’s SGLT2 entrant with Boehringer Ingelheim, may yet give lixisenatide a run for its money. The SGLT2 slashed the combined risk of heart attack, stroke, and death from cardiovascular causes by 14% in high-risk diabetes patients.

Recently unseated as the leader in diabetes drug revenue by Novo Nordisk, Sanofi aims to reverse its fortune by inking licensing deals with Seoul-based Hanmi Pharmaceutical and Lexicon Pharmaceuticals. “These agreements aim to provide people living with diabetes with solutions ranging from oral anti-diabetic options (SGLT1/2 dual inhibitor) to other formulations of insulin delivery (once-weekly basal insulin),” explains Dr. Rachele Berria, VP and head, diabetes medical unit at Sanofi US.

Meanwhile, biosimilars are revving up to deflate insulin’s tires. Merck and Samsung Bioepis’ MK-1293 is among several insulin glargine biosimilars looking to edge in on Lantus. “The market’s ready and this factor will almost certainly add to growing price pressures,” Kyle says. “For patients, the price competition should be beneficial. For physicians, it may be more of a mixed bag.”

With Lantus (insulin glargine) feeling the pressure of the biosimilar surge, Sanofi is positioning LixiLan and Lantus follow-up agent Toujeo to defend its franchise. LixiLan, if approved, will have to compete with Novo Nordisk’s insulin/GLP-1 agonist Xultophy (insulin degludec/liraglutide), which has filed its NDA and is lined up for FDA greenlight. The once-daily, single-injection combination of Tresiba and the company’s diabetes drug Victoza is positioned to be a game-changer. 

Novo Nordisk’s Tresiba (insulin degludec) got the FDA nod for glycemic control in adults with diabetes mellitus. The firm also handed over $295 million in a deal to acquire Xoma Corp.’s type 2 diabetes treatment. Another diabetes giant, Eli Lilly, halted development of its diabetes agent basal insulin peglispro (BIL) on the heels of disappointing trial results. Lilly witnessed the 2015 approval of Synjardy (empagliflozin and metformin hydrochloride), its type 2 diabetes drug through a partnership with Boehringer Ingelheim.

Even with new diabetes solutions marching to market, generic metformin continues to enjoy sizable market share, according to Lynnette Hunter, VP/account director at AbelsonTaylor. “This shows that, overall, more patients are getting diagnosed and treated, and that the gold standard remains the first-line therapy,” she explains.

A recent JAMA study, however, found that off-label use of metformin combined with insulin to target type 1 diabetes in overweight children has backfired. The study encouraged doctors to rely on the basics in treating type 1 diabetes: Administering insulin, recommending exercise and encouraging healthy eating.

The true growth engine in the type 2 diabetes realm is meeting patient demand for oral solutions that allow them to do away with insulin or GLP-1 injections forever. The industry has responded with the option to take two to three oral medications rather than moving to insulin.

However, GA Communication Group SVP/account director Mike McCartney points to multiple studies showing once-daily therapies have higher adherence rates than therapies administered multiple times a day. “Mono-therapy regimens are adhered to better than regimens incorporating more than one therapy,” he notes.

While there are many effective approaches to managing diabetes, McCartney believes adherence and persistence continue to be significant challenges for patients struggling with glycemic control. “As many patients don’t self-monitor blood glucose, they also lack the real-time data to effectively manage their condition,” he adds. “The reality is that [in most cases] type II diabetes didn’t just show up one day. We continue to see very poor outcomes for an otherwise manageable condition because years of habits that contribute to the disease can be extremely difficult to modify.”

People with diabetes are not enthusiasts of frequent therapy, Bashe says. “Fewer injections and pills are welcome. That said, payers and formularies set the tone for market share, and those features don’t capture formulary decision-maker hearts.”

The anti-obesity business

Despite significant and rapidly increasing unmet need in the obesity market, challenges including enormous R&D expenses and high attrition run rampant. “Obesity is a complex, chronic disease that’s deeply misunderstood by the public and healthcare professionals,” Kyle says. “Poor coverage and limited options have made progress slow.”

The positive reception of Saxenda (liraglutide 3mg), the once-daily injection for weight loss from Novo Nordisk, provides Kyle with hope. Originally marketed as Victoza (and prescribed to treat diabetes), the higher dose liraglutide will gain blockbuster status in the obesity realm, analysts predict.

Novo Nordisk has made a substantial investment with its obesity-dedicated research center in Seattle. Sanofi, on the other hand, has been more cautious about investing in R&D in the wake of problems encountered with its appetite suppressant rimonabant several years ago. Then there’s Zafgen’s IND application for injectable anti-obesity therapy beloranib, placed on complete clinical hold by the FDA in December following the second death in a Phase-III trial in patients with Prader-Willi syndrome.

In the United States, 35% of adults and 17% of children are obese, according to the Centers for Disease Control. And yet still many pundits wonder why pharma isn’t jumping to cash in on what would seem to be a huge unmet need. The reasons are many, and they don’t all have to do with Orexigen Therapeutics’ Contrave trial fiasco.

Contrave continues to struggle a bit on the sales side, despite selling more scripts than Eisai/Arena Pharmaceuticals’ Belviq and Vivus’s Qsymia. “Overall patient awareness continues to remain very low for anti-obesity pills,” Hunter shrugs, adding that lack of reimbursement is the main roadblock for obesity product launches. “Until this changes, branded pharmacotherapy won’t become a widely accepted approach to weight loss at the current out-of-pocket retail cost.”

Hunter believes payers are reluctant to pull the trigger on coverage because of the fen-phen debacle. Too, they fear HCPs will prescribe medications beyond their indication and create major cost-containment issues.

The next big challenge? Encouraging HCPs to treat obesity. “Few HCPs are comfortable writing prescriptions for weight loss,” Hunter says. “When push comes to shove, we see the HCP-to-patient dialogue turn to comorbidities and not address the topic of losing weight.” Particularly with patients who haven’t requested clinical help, discussions of weight loss in the physician’s office are an emotionally charged event.

“As marketers, we need to adjust how we approach both the patient and the HCP, to better set the stage for an open conversation about pharmacotherapy and weight loss,” Hunter says.