Around the globe, optimistic headlines have proclaimed safe and effective new weight-loss drugs promise ‘remarkable’ and ‘unprecedented’ results.
In a major US clinical trial, patients using one of a potential wave of new weight-loss ‘wonder’ drugs lost 11% more body weight than those undergoing an intensive diet and exercise program. That drug, marketed locally as Wegovy, was approved by Australia’s medicines regulator last year.
Its success – optimistically coupled with other news about a rapidly growing stream of anti-obesity and potential weight- loss medications – triggered a bullish January headline in The Washington Post: ‘Obesity treatments the new $40 billion pharma innovation frontier’.
Even more confidently, international news service Bloomberg quoted one Big Pharma chief executive as declaring: ‘This is a market that will grow to US$90 billion… and we are very confident on that, given the current size of the market and the current growth rates.’
Simultaneously, leading international medical newsletter medscape.com confirmed: ‘Excitement about ‘unprecedented’ weight loss associated with tirzepatide, news about other injectable medications, and updated anti-obesity recommendations (are) the top trending clinical topic.’
With equivalent enthusiasm Sydney Morning Herald and Melbourne’s The Age newspapers told their readers: ‘A new weight- loss drug is having remarkable results. Could it also change the way we talk about obesity?’
16% body weight reduction
In the Wegovy trial, scientists at the University of Pennsylvania studied 611 volunteers in a randomised clinical trial titled ‘Effect of subcutaneous semaglutide v placebo as an adjunct to intensive behavioural therapy on body weight in adults with overweight or obesity’.
In the study, published in the journal JAMA, the overweight or obese volunteers without diabetes were injected once-weekly with either 2.4mg of subcutaneous semaglutide (407 volunteers) or a placebo (204 volunteers) at 41 sites across the US for 68 weeks to determine the ‘effect on body weight when added to intensive behavioural therapy with an initial low-calorie diet’.
The intensive behavioural therapy involved: an initial 8 weeks on a supervised very low-calorie diet, followed by more than a year of a low-calorie diet; 100 minutes of exercise a week, eventually increasing to 200 minutes; and 30 visits from a dietitian.
It resulted in reductions in body weight of 16.0% (an average of 16.8kg) for those receiving once- weekly subcutaneous semaglutide as opposed to 5.7% for those similarly exercising and dieting, but receiving the placebo: the ‘difference was statistically significant’.
The authors emphasised the value of the drug semaglutide, administered via once-weekly subcutaneous injection, as an adjunct to intensive behavioural therapy and initial low-calorie diet’ to produce significantly greater weight loss than placebo over an extended period of use in overweight and obese adults.
They added: ‘Weight loss improves cardio-metabolic risk factors in people with overweight or obesity. Intensive lifestyle intervention and pharmacotherapy are the most effective non-invasive weight loss approaches.’
What is semaglutide?
Semaglutide is a glucagon-like peptide-1 (GLP-1) analogue that is approved, at doses up to 1mg administered subcutaneously (under the skin) once weekly, for the treatment of type 2 diabetes in adults and for reducing the risk of cardiovascular events in persons with type 2 diabetes and cardiovascular disease.
Wegovy mimics the natural hormone GLP-1 which slows down how fast the stomach works, making patients feel fuller for longer; it also seems to affect how the brain regulates appetite.
In an earlier study to observe the ‘effects of GLP-1 on appetite and weight’, US scientists at the Mayo Clinic explained that GLP-1 ‘is a cleavage product of the pre-proglucagon gene which is expressed in the α-cells of the pancreas, the L-cells of the intestine, and neurons located in the caudal brainstem and hypothalamus’.
They described how GLP-1 ‘is of relevance to appetite and weight maintenance because it has actions on the gastrointestinal tract as well as the direct regulation of appetite. It delays gastric emptying and gut motility in humans.
‘In addition, interventricular injections of GLP-1 inhibit food intake, independent of the presence of food in the stomach or gastric emptying.’
In addition, the Mayo scientists noted: ‘Peripherally administered GLP-1 also affects the central regulation of feeding.
‘It is therefore the synergistic actions of GLP-1 in the gut and brain, acting on both central and peripheral receptors, that seem responsible for the effects of the hormone on satiety.’
Weight-loss treatment ‘revolution’
Commenting on the University of Pennsylvania study of semaglutide, The Sydney Morning Herald declared: ‘The emergence of the new drug, marketed locally as Wegovy, promises to revolutionise weight-loss treatments.’
And international news service Bloomberg reported in January that Wegovy’s manufacturer, Danish company Novo Nordisk, is also developing CagriSema, a combination of Wegovy’s main ingredient semaglutide and another drug that targets an eating hormone.
Importantly, Bloomberg added: ‘And it’s developing a pill version of semaglutide.’
Professor Brian Oldfield, a leading obesity researcher at Monash University, told The Sydney
Morning Herald: ‘As these drugs become more effective and available, it will be harder for people to ignore them.’
Over recent decades, governments globally have poured hundreds of millions of dollars into public health campaigns to tackle obesity by encouraging healthy eating and exercise: for example, in Australia in 2004, Prime Minister John Howard instituted a $116 million initiative to pay for after- school sports and healthy-eating education for families.
But Professor Oldfield summed up bluntly: ‘While healthy eating and physical activity are vital for good health, decades of evidence suggest they simply do not lead to large amounts of weight loss.
‘They are not enough by themselves. They typically give a 3-5% reduction in body weight.’
Tiffany Petre, director of the Obesity Collective, told the Herald that she ‘hopes this drug changes conversations about obesity in society. People with obesity haven’t been able to get appropriate healthcare. Now there is something on the market.’
$40b Pharma ‘Innovation Frontier’
In mid-January, the influential Washington Post began a survey of the latest revolutionary developments in the weight-loss sector with the revelatory headline: ‘Obesity treatments the new $40 billion pharma innovation frontier’.
The newspaper explained that ‘three years ago, drugmakers and laboratories around the world responded to the pandemic with COVID-19 vaccines. Now that the urgency has faded, they’re collectively turning attention to an older ‘pandemic’: obesity.’
The survey reported that ‘companies including Eli Lilly and Pfizer are tail-gating Novo Nordisk, the first mover into the market with its highly effective Wegovy injection, which mimics a weight-related hormone called GLP-1.’
Biopharmaceutical giant Amgen was also among companies presenting at the JPMorgan Healthcare Conference in early 2023 with a potential obesity entrant.
The companies are aiming for the market with versions that either melt off more kilos, have less frequent dosing or don’t require injection.
The Washington Post survey noted that the ‘search for a safe, effective slimming drug has been long and torturous’: prescriptions for the combination of fenfluramine and phentermine (known popularly as ‘fen-phen’) soared to more than 18 million in the US in 1996 after the success of a small study, then crashed after it was linked to heart disease and deaths.
‘Now, drugmakers say, better science and promising weight- loss results from the new class of repurposed diabetes drugs are spurring a roaring comeback for medicines to treat obesity’ – with Lilly chief scientific officer Daniel Skovronsky proclaiming at the annual JPMorgan Healthcare Conference: ‘This is the beginning of a whole new therapeutic area.’
What is tirzepatide?
While Wegovy is produced by Danish company Novo Nordisk, Eli Lilly is one of its chief competitors in insulin and other diabetes treatments.
The excitement expressed by Lilly’s chief scientific officer Dr Daniel Skovronsky at January’s Morgan Conference accompanied news that Lilly is completing a second ‘late-stage’ trial of its injectable drug tirzepatide.
An initial trial last year showed ‘the drug helped patients lose more than 20% of their body weight’.
Importantly, the trial – reported by medscape.com under the headline ‘Tirzepatide Lowers Weight Across All Groups With Obesity’ – found weight loss with tirzepatide was fairly uniform across different body mass index (BMI) ranges, ages, and number of obesity-related comorbidities in patients with overweight/obesity without type 2 diabetes.
University of South Carolina’s Professor Patrick O’Neill (not involved with this research) told a session at the Obesity Week annual conference in Texas in October 2022 that these new analyses from the tirzepatide trial show that ‘regardless of BMI, regardless of age, regardless of number of obesity-related complications, there was a clear dose-related weight loss that was pretty consistent across groups.
‘The absolute levels of these weight losses are higher than we’ve seen thus far with (anti-obesity) medications.
‘Semaglutide took things up one big notch, and this is up a little notch above that.’
The trial included 2,539 adults without type 2 diabetes who had obesity (BMI ≥ 30 kg/m2) or overweight (BMI ≥ 27 kg/m2) with at least one obesity-related complication (hypertension, dyslipidemia, obstructive sleep apnea or cardiovascular disease).
The trial covered three age groups: under 50 (63% patients); 50-65 (31% patients); and 65 and over (6% patients) The trial specifically compared the ‘efficacy and safety of tirzepatide 5mg, 10mg and 15mg subcutaneous once-weekly to placebo, as an adjunct to a reduced-calorie diet and increased physical activity’.
At 72 weeks, patients taking 5mg/ week of tirzepatide lost an average 21.5% of their initial body weight; patients taking 10mg/week lost an average 20.8%; and patients taking 15mg/week lost an average 22%.
Professor Robert Kushner from Chicago’s Northwestern University summed up: ‘Tirzepatide significantly lowered total body mass versus placebo regardless of age subgroups’; and it ‘consistently lowered fat mass, lean mass, fat-mass-to-lean-mass ratio, and visceral fat mass across age subgroups.”
In addition, Dr Louis Aronne from New York’s Cornell University presented findings from a pre- specified analysis of four BMI subgroups (110 patients from the overall 2,539 group) divided into: overweight (mean initial weight 178 pounds) who recorded a mean weight reduction of 29-30 pounds; class 1 obesity (mean initial weight 198 pounds) who recorded a mean weight reduction of 33-43 pounds; class 2 obesity (mean initial weight 228 pounds) who recorded a mean weight reduction of 34-56 pounds; and class 3 obesity (mean initial weight 280 pounds) who recorded a mean weight reduction of 44-64 pounds.
Patients in the ‘class 1 obesity’ group who received the 15mg/week dose of tirzepatide had the most weight loss at 24.5%; that figure ‘is approximately what is associated with bariatric surgeries (25%)’.
The proportion of patients reaching 5% or more weight reduction was approximately 90% in all weight categories, and Dr Aronee summed up: ‘These numbers are unprecedented.’
In addition, overall 73-90% of patients receiving the 5-15mg doses of tirzepatide achieved 10% or greater body weight reduction, while 50-78% of patients receiving the drug lost 15% or more of their body weight, which Dr Aronee described as ‘something we never thought we would see’.
The trial also reported that ‘regardless of the number of comorbidities, all doses of tirzepatide resulted in a greater reduction in body weight compared with placebo.’
And at the American Heart Association Scientific Sessions 2022, a separate presentation involving another sub-study of 600 patients (from the 2,639 participants in the total tirzepatide trial group) reported ‘treatment with tirzepatide led to significant cuts in 24-hour ambulatory blood pressure’.
Mimicking natural GLP-1 biology
For years, Lilly and Novo ‘have been developing drugs targeting the receptors for incretins, first for diabetes and now for obesity’, noted The Washington Post. GLP-1 is an incretin (a hormone secreted from the gastrointestinal tract which tells the body that food has been eaten).
Lilly’s Dr Skovronsky explained that by mimicking this natural biology, the new drugs ‘appear to make people feel less hungry’; they also help reduce blood glucose levels, which can help many people with obesity and diabetes.
The Washington Post survey noted there are several types of incretins, and ‘next-generation drugs are aiming at a number of targets in hopes of helping patients shed more weight’.
Lilly’s tirzepatide, for example, mimics a second incretin along with GLP-1, as does Amgen’s experimental AMG 133 (details on next page).
Tirzepatide (sold under the brand name Mounjaro) is an anti-diabetic medication used for treatment of type 2 diabetes (by improving blood sugar control) and given by weekly subcutaneous injection (under the skin). Tirzepatide was approved for medical use (glycemic control in patients with type 2 diabetes) in the US in May 2022, in the European Union in September, in Canada in November 2022 and in Australia in December 2022.
In addition, in October 2022 the US FDA granted ‘fast-track’ status (expedited review) for tirzepatide use as an anti-obesity drug – defined as ‘for the treatment of adults with obesity, or overweight with weight- related comorbidities.
The Washington Post reported that ‘while Lilly’s tirzepatide hasn’t been specifically approved for obesity, some doctors are already recommending it for weight loss. Doctors are permitted to prescribe drugs for unapproved uses, a practice called ‘off-label prescribing’.’
Demand for Mounjaro and Ozempic (another GLP-1 drug from Novo) has already led to shortages, and Dr Skovronsky told news service Bloomberg that Lilly ‘has started a rolling submission to the US Food and Drug Administration that will allow it to quickly submit the new data to the FDA around mid-year (2023), assuming the second final-stage trial succeeded.’
Depending on when and what regulators decide, he said tirzepatide ‘could be on the market for obesity as early as the year’s end’.
Building new tirzepartide factories
Dr Skovronsky confirmed Lilly ‘is working to make sure it has enough tirzepatide on hand’ so it doesn’t repeat the supply issues that afflicted Novo.
It’s also testing the drug in ‘obesity-linked conditions such as sleep apnea and heart failure, to see if patients benefit’.
Dr Skovronsky summed up: ‘We are adding new factories and making it as quickly as we can. The potential here is large.’
The Washington Post survey concluded that with nearly 75% of US adults considered overweight or obese, Wall Street ‘has big expectations for the drug class’.
‘The overall obesity market will reach about US$30 billion (A$43 billion) by 2030, according to Cowen analysts, with Lilly’s tirzepatide notching up more than US$11bn of those sales. That would overtake the more-than US$7bn in sales estimated for Novo’s Wegovy.’
However these drugs’ high cost (Wegovy costs US$1,350 a month) and lack of insurance coverage for obesity medicines ‘present a key barrier to update’, explained Dr Marcus Schabacker, president and chief executive at international health non-profit organisation ECRI.
Dr Schabacker told Bloomberg: ‘Outdated notions and persisting misconceptions’ about the nature and seriousness of obesity stand in the way of effective use of these latest weight-loss medications.
He said the drug class ‘seems to be working, it seems to be safe, it seems to be effective’; hence ECRI ‘is appealing to insurers and politicians to change policies on paying for FDA-approved weight- loss medications’.
GLP-1 market ‘obviously exploding right now’
Elsewhere in the field, Californian-headquartered biopharmaceutical company Amgen’s AMG 133 ‘is already the focus of investor interest’, reported Bloomberg.
Patients on the highest dose ‘saw an average loss of 14.5% of their weight after 12 weeks of treatment in an early-stage trial’, according to results released in December.
Although other companies are closer to the market, Amgen’s executive vice president of research and development David Reese told Bloomberg: ‘It’s an area that’s obviously exploding right now. It’s becoming a field unto itself.’
Meanwhile, fellow American multinational pharmaceutical and biotechnology corporation Pfizer is also testing two drugs to hit the GLP-1 pathway.
Importantly, while Novo’s Wegovy is injectable, Pfizer’s drugs can be taken as a pill – which the company is betting will prove to be a crucial advantage.
Pfizer chief executive Albert Bourla told Bloomberg: ‘Clearly everybody’s excited about GLP-1. This is a market that will grow to US$90 billion altogether (the combined obesity and diabetes markets for the GLP-1 class of drugs) and we are very confident on that, given the current size of the market and the current growth rates.’
Bourla said Pfizer ‘could capture about US$10 billion of that market’.
What is BI 456906?
At the US Obesity Week 2022 conference in San Diego in November, presenters also described ‘impressive’ weight loss results associated with a ‘novel GLP-1/glucagon dual receptor agonist (BI 456906), albeit in early research’, reported medscape.com.
Patients in the study were aged 18-75 and had type 2 diabetes. At the highest tested dose of BI 456906 (1.8mg twice-weekly subcutaneous injections), 57% of patients lost 5% or more of their initial body weight and 35% lost 10% or more at 16 weeks.
Among the patients who received a 1mg semaglutide dose as a comparator, only 38% lost 5% or more of their initial body weight and only 16% lost 10% or more.
Patients had a mean initial weight of 214 pounds (97kg). After 4 months, on average, patients who received the highest tested dose of BI 456906 lost 9% of their initial weight, or roughly 19 pounds (8.7kg).
Patients who received semaglutide lost 5.4% of their initial weight, or roughly 11.5 pounds (5.2 kg). Patients who received placebo lost only 1.2% of their initial weight.
Overall, considering the current trials surrounding semaglutide, tirzepatide, AMG 133, CagriSema and BI 456906 – among numerous other potential weight-loss ‘wonder’ drugs – it’s no wonder Lilly chief scientific officer Daniel Skovronsky confidently declared at the annual JPMorgan Healthcare Conference: ‘This is the beginning of a whole new therapeutic area.’ AMP
