The idea was beautifully simple. One pill taken daily to melt away those excess pounds. The new breed of GLP-1 oral medications would be as effective as Mounjaro, it was hoped, but without the need for ‘scary’ injections.
But when pharmaceutical giant Eli Lilly released the clinical trial results for its supposedly revolutionary new pill orforglipron in August, the results weren’t as impressive as expected.
Participants on the highest dose were found to have lost 12.4 per cent of their body weight after 72 weeks. Not to be sniffed at, but markedly less than the 17 per cent some predicted, and a world away from the average 22 per cent weight loss on Mounjaro, which Eli Lilly also produces.
Not only that, but 33.7 per cent of those reported feeling nauseous, with 10.3 per cent quitting the trial altogether because of adverse events.
So much for a hassle-free solution to sugar cravings. As the news dropped, Lilly’s shares promptly plummeted by 14 per cent, knocking around £75 billion off its market value.
Such is the cut-throat nature of the GLP-1 market that Novo Nordisk, pioneer of the weight-loss movement with injectable Ozempic, watched its shares soar six per cent as a result of its rival’s misfortune.
Not that Novo has escaped the warfare unscathed either. When it was considered to be lagging behind Lilly earlier this year, its CEO was sacked, and despite submitting its own weight-loss pill for approval in April, it recently announced 11 per cent of its workforce were losing their jobs.
So what exactly is going on in the world of weight-loss tablets? Are they still worthy of our attention? Or is the truth a bitter pill to swallow?
The new breed of GLP-1 oral medications would be as effective as Mounjaro, it was hoped, but without the need for ‘scary’ injections
When pharmaceutical giant Eli Lilly released the clinical trial results for its supposedly revolutionary new pill orforglipron in August, the results weren’t as impressive as expected
The pharmaceutical companies behind the medicines appear to be holding their cards very close to their chests, citing red tape and redundancies when I press to find out more.
A spokesman for Lilly tells me they aren’t ‘doing interviews on orforglipron right now’ and when I ask Novo if I might visit its Danish HQ to see its small molecule drugs – in other words, the pills – a spokesperson implied a visit was not possible because the job losses mean ‘many roles are now uncertain’.
‘I think a lot of people got used to the whole obesity market delivering on expectations,’ says Sheena Berry, healthcare analyst at investment firm Quilter Cheviot. Orforglipron’s ‘disappointing’ results, she says, are partly why ‘the obesity story seems to have lost a bit of its shine this year’. ‘We might find the orals will take a smaller share of the US market than was initially thought. The injectables are likely to still dominate.’
Some health professionals fear the roll-out of these pills could be a disaster waiting to happen.
Dr Clare Thompson, leading the General Practice Weight Management Service at London’s Cadogan Clinic, is alarmed at the prospect of millions of people on an oral medication outside the strictly regimented confines of a clinical trial – which, if Lilly gets regulatory approval for orforglipron, could happen as soon as next year.
No study can ‘possibly’ reveal all the ways a GLP-1 pill will interact with medications the legions likely to take them could already be on, she explains.
‘Clinical trials are very much controlled,’ she adds. ‘They choose the patients. With an injectable you’ve got a much cleaner delivery into the bloodstream, whereas whenever you take oral tablets together, there are lots of times when it’s contraindicated [potentially harmful]. You’re going to have people taking lots of other things – HRT, antidepressants . . . That’s the bit that stresses me out. People will have to report side-effects as they go along.’
Then there’s the ease with which these pills are expected to be available. With no cold storage necessary or needle phobias to contend with, experts predict they are more likely to be sold directly to consumers than prescribed in medical settings.
Dr Clare Thompson, GP at the Cadogan Clinic, is alarmed at the prospect of millions of people on an oral medication outside the confines of a clinical trial
It’s already easy enough to get hold of Mounjaro and the like without meeting the minimum body mass index threshold. ‘It will be even easier to get hold of these pills,’ predicts Dr Thompson. ‘That’s my concern. It’s going to be open to abuse, isn’t it?’
Earlier this month the Daily Mail revealed a booming black market for fake jabs, while GP surgeries are reporting record waiting lists thanks to a surge in people wanting weight-loss medication.
A new report showed an astonishing 2.5 million people (one in 20) in the UK are using the jabs. Given their popularity, the prospect of a readily available pill, presented as a quick fix yet whose long-term effects we know next to nothing about, feels particularly concerning.
When Attain-1, as orforglipron’s recent phase 3 trial is called, got under way in 2023, hopes were high. Unlike Novo’s pill offering – oral semaglutide, the pill form of Ozempic, which Novo submitted to America’s FDA for approval in April – orforglipron doesn’t need to be taken on an empty stomach. That’s because it’s the first ‘small molecule’ pill that can be absorbed through the gut effectively without extra ingredients.
Some 3,120 overweight participants were enrolled in the trial and changes in body weight monitored over 72 weeks.
That nausea was reported wasn’t a surprise – it is a known side-effect of injectable weight-loss drugs, which mimic the naturally-occurring hormone glucagon-like peptide-1 (GLP-1) to slow the rate food leaves the stomach and reduce appetite. Indeed, in a Mounjaro trial, participants reported nausea levels almost as high as Attain-1, at 33.3 per cent.
However, ‘by delivering the medication directly into the bloodstream, injectables bypass the gut,’ says Dr Naveed Asif, GP at The London General Practice, which reduces the likelihood of digestive side-effects.
‘Oral weight-loss tablets must navigate through the digestive system, which often leads to more pronounced and direct gastrointestinal [and] digestive issues.’ By offering ‘a more consistent drug delivery’ he says, an injection ‘results in fewer waves of side-effects, such as nausea, which is the most common complaint’.
A new report showed an astonishing 2.5 million people (one in 20) in the UK are using weight-loss jabs
And while a trial for oral semaglutide found 6.9 per cent of participants stopped taking the drug because of ‘adverse events’ – namely unpleasant side-effects – that figure was significantly higher for those on the high dose of orforglipron at 10.3 per cent.
‘I think a lot of people got used to the whole obesity market delivering on expectations,’ says Sheena Berry, of investment firm Quilter Cheviot. ‘Injectables are likely to still dominate,’ she adds
Certainly, some on orforglipron trials who have discussed their journey anonymously on social media site Reddit seem to have been dragged through the mill. One said the drug achieved ‘slow and steady weight loss’ for six months, but after that they no longer felt the same ‘fullness’ GLP-1 agonists are known to create by mimicking satiety hormones. Another said that after five months on a ‘maintenance’ dose, they had ‘started having a lot of nausea again’.
A third said it was ‘almost like the medication stopped working’ – they didn’t say how long that took to happen – and it was constipation that had caused ‘the most pain’. Most concerningly, one says they had ‘passed out twice’ since increasing their dosage to 24mg. ‘I feel super tired, like I could just sleep all the time.’
Lilly’s chief scientific officer Daniel Skovronsky remained bullish after the trial data was released, maintaining that the drug ‘has the potential to be a more convenient alternative to injectable treatments’. He added in an interview with analysts that ‘orforglipron will bring an option that will serve the masses, will be easy to use, we can produce at scale’.
Yet orforglipron didn’t perform significantly better than Novo’s oral semaglutide, which is not a small-molecule drug but a peptide (a short chain of amino acids) too big to be efficiently absorbed from the gut into the bloodstream. It needs to be taken in a larger dose than its injectable version.
In fact, by some markers, orforglipron performed worse – 39.6 per cent of participants lost equal to or greater than 15 per cent of their body weight, with Novo’s oral semaglutide that figure was 50 per cent. ‘I do think people were hoping for better,’ says healthcare analyst Lee Brown at investor research firm Third Bridge.
Of course, not everyone needs to lose such a large proportion of their body weight. A 5 ft 6 in woman weighing 11 st, for example, need shed only around 13 per cent to reach the middle of a healthy BMI range. In this scenario, the convenience of a pill could certainly hold sway – and is perhaps the reason why pharmaceutical firms are still pursuing oral GLP-1s so aggressively.
Despite the anticlimactic results, Mr Brown doesn’t think weight-loss pills are overhyped ‘at all,’ pointing out that Lilly’s stock has recovered from its recent knock. He argues that ‘the penetration is phenomenal’ – which means, in layman’s terms, the number of untapped customers the companies stand to profit from is still vast.
But Lilly’s chief scientific officer Daniel Skovronsky maintains that the drug ‘has the potential to be a more convenient alternative to injectable treatments’
People don’t want the faff of queuing in a doctor’s surgery to get their hands on the drug, he adds. ‘They want to get online, quickly get a prescription and have the drug shipped to their home or local pharmacy.’ Whichever company can best facilitate this scenario, he believes, ‘is going to win’.
Which is precisely Dr Thompson’s concern. ‘If it’s over the counter, it could lay the path for lots of complications [and] unregulated consumption by people that should not be on it – young people that have eating disorders, body dysmorphia, those sort of issues.’
Mr Brown adds that while weight-loss pills aren’t going to be as effective as injectables, they will be ‘a lot cheaper’.
Certainly, price is a huge part of their predicted appeal, now Lilly has increased the cost of Mounjaro in the UK, with the highest dose jumping 170 per cent, from £122 to £330 a month. The company has said orforglipron’s pricing ‘will reflect the medicine’s value and aims to ensure it is accessible to those who need it’.
Novo’s new president and CEO, Mike Doustdar, explained its cull of around 9,000 jobs last month as a means to adapt to a ‘more competitive and consumer-driven’ market, and Mr Brown sees it not as a sign of defeat, but ‘a signal to the marketplace that they’re going to roll up their sleeves and fight against Eli Lilly as opposed to just getting rolled over’.
Yet it’s not just the American giant Novo has to worry about. At least two other companies have small-molecule GLP-1 pills in phase 3 trials, including CX11 (also known as VCT220) from Chinese and US-based Corxel and HRS-7535 from Chinese Jiangsu Hengrui and its collaborator, the US Kailera Therapeutics. Others are in phase 2 trials.
‘More competition is coming,’ says Ms Berry.
Whether any of them can compete with the efficacy of injections is unclear – not least because Lilly’s new fat jab, retatrutide, currently in phase 3 trials and expected to be available by 2027, appears likely to trounce all competition.
It targets three hormones involved in satiety and weight regulation, unlike the two receptors Mounjaro targets and the one targeted by Ozempic.
Early trials found participants could lose 25 per cent of their body weight in less than a year. Such is the hype that unapproved and potentially fake versions of the drug have already infiltrated the black market.
Another injectable, RES-010 from Italian company Resalis Therapeutics, claims to block genes that control how the body digests and stores fat so people don’t need to eat less food.
Animal studies found it led to 15 per cent reduction in fat mass after ten weeks, while preserving more lean mass, including muscle, than existing injectables. Human trials are under way.
Whether they live up to the hype – or flop – is anyone’s guess. But in the war over our waists, it’s still very much all to play for.
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