28 Sep 23
By Jonathan Sisson
In a previous article [1], I considered progress in treatments for type 2 diabetes (T2DM) over the last 30 years. This review looks at drug treatment of obesity over the same period, mostly from a regulatory perspective and focused on the UK and EU only.
30 years ago, the licensed pharmacological options in the UK for obesity were phentermine, diethylpropion (amfepramone) fenfluramine, dexfenfluramine and methylcellulose. The latter remains licenced but has limited effectiveness and is not recommended.
Phentermine, diethylpropion, fenfluramine and dexfenfluramine are centrally acting appetite suppressants (anorectics) related to amphetamine. Even 30 years ago, when these were all licenced in the UK, there were concerns. Diethylpropion and phentermine had already been withdrawn in several countries, and multiple older drugs in the class had met the same fate. In 1992, the UK regulator (Medicines Control Agency or MCA, now MHRA) reminded UK prescribers about rare cases of pulmonary hypertension with fenfluramine and dexfenfluramine. Whilst a definite causal relationship could not be concluded, the advice was to prescribe them for no longer than 3 months [2].
In 1995, an EU referral procedure was initiated by Germany into all centrally-acting weight-loss products, following a study [3] which confirmed the relationship between some of these and primary pulmonary hypertension.
A year later, the European Medicines Evaluation agency (EMEA, now EMA) however concluded that the benefit:risk remained favourable, although with a recommended treatment duration of 4-6 weeks, and a maximum of 3 months. The indications were also restricted to an adjunctive therapy in patients with BMI of 30kg/m2 or higher who had not responded to an appropriate weight-reducing regimen. There were additional amendments to the warnings and undesirable effects labelling, including a warning that only short term efficacy had been demonstrated, with no significant data on mortality and morbidity benefits [4].
Despite this, concerns about safety and long-term effectiveness did not go away. In 1997, all EU member states suspended their national licences for dexfenfluramine and fenfluramine. This followed further cases of cardiac valve disorders, and their suspension in the US market.
By 1999, the benefit:risk evaluation for the class as a whole had turned sour, and EMEA recommended the withdrawal of diethylpropion, phentermine, dexfenfluramine and fenfluramine, as well as others in the class which were licenced in various member states [5]. The European Commission (EC) issued the enacting decisions in March 2000.
MCA complied with this, formally withdrawing the offending licences. Straight away though, there was an appeal by some licence holders. Removal of diethylpropion and phentermine in particular caused considerable difficulties for slimming clinics, leaving them with few options. MA holders were quick to point out that these agents were nationally authorised, so MCA had the ability to go against the EC decision. The UK Committee on Safety of Medicines (CSM, now CHM) were asked to consider if re-instating diethylpropion and phentermine posed a “significant public health concern”. CSM advised in April 2000 that there was limited evidence to support national withdrawal of diethylpropion and phentermine. Basically, for diethylpropion and phentermine the key evidence for the EC decision was considered to relate to the level of efficacy, there were no significant “new” safety issues for diethylpropion and phentermine; instead the cardiovascular toxicity associated with others in the class could not be excluded as a problem. In contrast – the thinking went – the decision to withdraw dexfenfluramine and fenfluramine licences was made primarily on the grounds of safety.
Similar protests and appeals were played out in Europe, and the European Court of First Instance (now the General Court) annulled the EC decision in 2002 – concluding that the conditions for withdrawal of licences were not met, and again noting the lack of authority against nationally authorised licences. The EC appealed to the higher court (European Court of Justice) in vain.
A decade later in 2022, came the latest twist in this saga – the CHMP recommended the withdrawal of diethylpropion in the EU [6]. This followed a referral by Romania, based on new cases of cardiac ADRs and persistent off-label use. The EMA Pharmacovigilance Risk Assessment Committee concluded that measures to restrict the use of diethylpropion for safety reasons had not been sufficiently effective, and that further measures would not work.
This is just a brief summary of the regulatory twists and turns related to this class of agents, and does not include the dramas around other national licences, including the huge controversy around Mediator (benfluorex) in France [7] which led to a complete reform of their medicines regulator. Despite all that has happened, some drugs in this class are still available in the UK and EU on a national basis – this reflects the continuing unmet need and the lack of wide access to newer drugs.
At the start of the millennium, more effective and safe agents were sorely needed. Several of the older, centrally acting, anorectic agents had refused to die, but had very restricted licences. The lipase inhibitor orlistat had been licenced in 1998, but it has only modest efficacy, no effects on appetite, and some unpleasant side effects.
Set against the unmet need, regulatory requirements for a new agent were becoming stricter and regulators more risk averse. The current EMA guideline on weight management requires efficacy to be evaluated over at least 1 year, setting a higher bar for minimum efficacy than the previous guideline, and has other strict criteria on assessing the degree of cardiovascular risk [8].
Two new drugs soon came along, sibutramine and rimonabant. Sibutramine (Reductil) was licenced in 2001. It has some similarities to diethylpropion but is a serotonin and noradrenaline reuptake inhibitor (plus an effect on dopamine, to a lesser extent). In addition, the cannabinoid CB1 receptor antagonist/inverse agonist rimonabant was licensed in EU in June 2006.
However, this turned out to be a false new dawn. By October 2008, reports of serious psychiatric problems led to the suspension of rimonabant. Two years later, sibutramine was suspended, following a review of cardiovascular outcomes in a long term outcome study. Also, the mean weight loss achieved with sibutramine in all clinical trials was underwhelming, decreasing bodyweight by only 2–4 kg more than placebo.
Soon after these 2 products had died in infancy, two others were dead on arrival at the EMA. Phentermine/topiramate (Qsiva) was refused because of adverse events and the perceived risk of abuse, set against only modest efficacy. As with diethylpropion in the end, it was not considered that the proposed risk management measures would be effective in practice. The centralised application for the 5HT2c receptor agonist lorcaserin (Belviq) was withdrawn during the procedure in 2013, because of modest efficacy, concerns over malignancy risk from pre-clinical tests, plus concerns about the clinical risks of psychiatric disorders and valvopathy.
Just when obesity seemed destined to become a “regulatory graveyard”, two new classes were licenced in the same month, in 2015. One was naltrexone/bupropion (Mysimba). Naltrexone acts by autoinhibition of pro-opiomelanocortin neurons in the hypothalamus, while bupropion is thought to increase the actions of dopamine at specific sites in the brain, when combined these actions are believed to reduce food craving. However, Mysimba remains subject to additional monitoring, and in the UK it is still not approved for use in the NHS, following reviews by NICE in 2017 and 2020. EMA has just started a new review of long-term cardiovascular risk and the benefit:risk of Mysimba [9].
The biggest impact by far in 2015 was the first Glucagon-Like Peptide 1 (GLP1) agonist. This class of drugs deserves a section of their own…
GLP-1 is a hormone secreted by enteroendocrine L-cells and some neurons within the brain. In T2DM it works by inhibiting glucagon secretion, promoting insulin secretion and inhibiting gastric emptying. The first GLP-1 agonist to be licenced for T2DM was exenatide (Byetta) in 2006. This was followed by liraglutide, lixisenatide, albiglutide, dulaglutide, semaglutide and tirzepatide. Albiglutide fell by the wayside for commercial reasons, but the others remain. Tirzepatide in 2022 is the most recent product to gain a licence in the EU and UK, this is actually a dual GLP-1/GIP agonist, meaning it also acts on glucose-dependent insulinotrophic polypeptide.
Early on, GLP-1 agonists were known to produce a meaningful weight loss in patients with diabetes, and to not cause hypoglycaemia in healthy volunteers. Clearly, this presented an opportunity in the management of obesity. The understanding of their weight-loss mechanism has evolved over time. Early on, gastrointestinal side effects and delay of gastric emptying were thought to be important, but now the primary effect is understood to be a direct effect in the brain, to modulate appetite and energy intake. One way to show this is to give study volunteers an unlimited buffet, and compare the active and placebo group in how heartily they get stuck in – or more scientifically to evaluate the total calories consumed and the calorie composition. As well as this measure, reduced appetite, feelings of fullness (satiety) and food cravings can be assessed in subjective rating scales.
The first GLP-1 agonist to gain an EU indication in obesity was liraglutide in 2015. Instead of adding an indication to the existing product for T2DM (Victoza) it was spun off as a separate licence, branded as Saxenda. The usual maintenance dose is 3 mg, administered as a once-daily subcutaneous injection, following dose escalation. 3 mg is significantly more than the 1.8 mg maximum recommended dose in T2DM. The pivotal data were 4 placebo-controlled phase 3 trials. After treatment with liraglutide, the mean placebo-subtracted weight loss was 5.2%. Regulators were cautious on first assessment, but as an adjunctive treatment in those with BMI ≥30 kg/m2 [or ≥27 kg/m2 to <30 kg/m2, in the presence of at least one weight-related comorbidity] the benefit:risk was considered positive. Another safeguard in the labelling is the required review after 6 months, if patients have not responded.
This was followed by the 2022 approval of semaglutide, with a similar indication to Saxenda. This was also a stand-alone licence, with the brand Wegovy to differentiate from the diabetes product (Ozempic). Again, this implemented a higher maximum dose (2.4 mg vs 1 mg) than approved in the T2DM indication – but in contrast to liraglutide, semaglutide is given once-weekly. The pivotal data were again 4 phase 3 studies. Results varied according to population but all showed a placebo-subtracted weight loss of more than 10%. Like Saxenda, the indications of Wegovy have since been extended to adolescents aged 12 and over. In August 2023, headline results from the semaglutide SELECT trial were announced [10] – indicating that the risk of major adverse cardiovascular events was reduced by 20% in overweight/obese non-diabetic adults.
There are of course caveats with Saxenda and Wegovy. The management of obesity is much more than simply prescribing a drug. Some patients respond better than others, and weight loss tends to be less when there is concomitant T2DM. As with the class, the most frequently reported adverse reactions are gastrointestinal, including nausea, diarrhoea and vomiting. These reactions are not usually severe, but they are clearly unpleasant, and a common reason for patients to stop treatment. A number of possible safety signals remain under review. A CHMP review into reports of self-harm and suicidality is ongoing for the class, expected to conclude in November 2023. It is not yet clear whether the reported cases are linked to the medicines themselves, to the patients’ underlying conditions or other factors [11].
Whilst many new drug classes are under development, in the short term it seems that further evolution of GLP-1 agonists will be important, including expansion of indications, formulation development and development of new molecules with additional useful properties.
Opportunities to widen the indication of GLP-1 agonists include metabolic-associated fatty liver disease [what used to be called non-alcoholic steatohepatitis/non-alcoholic fatty liver disease] and obstructive sleep apnoea.
On the reformulation side, a tablet form of semaglutide containing the absorption enhancer salcaprozate sodium (Rybelsus) is already approved in the treatment of T2DM, and studies in non-diabetic obese or overweight patients are ongoing, using a much higher dose. Rybelsus however requires strict dosing conditions, and newer oral GLP-1 agonists that can be taken with food are in development.
The dual GLP-1/GIP agonist tirzepatide (Mounjaro) is currently licensed in the EU only in patients with T2DM, however it has shown impressive weight loss potential in subjects without T2DM [12] and regulatory submissions are pending at the time of writing. GLP-1 mediated effects on GI motility, appetite and satiety may be complemented by GIP mediated effects on adipose tissue [13]. A comparative trial of Mounjaro against Wegovy is expected to conclude in late 2024 [14].
Another “dual-acting” product called survodutide (dual GLP-1 and glucagon receptor agonist) is currently in phase 2.
Headline phase 2 results of retatrutide, an agonist at GLP-1, GIP and glucagon receptors, look promising [15]. This has been referred to as “Triple-G”, not to be confused with Gennadiy Gennadyevich Golovkin, the outstanding Kazakhstani middleweight boxer who shares the nickname.
The last 30 years have seen significant changes. There remains considerable scope for newer agents, and the story so far reveals many lessons for their development. However, with existing drugs there is always more to learn, exploring this can provide differential advantages over competitors and extend the lifecycle. With new and established drugs, it is clear that there is no room for complacency, and potential safety signals need to be expertly evaluated and managed, with design of risk management measures that work in practice.
The story – as with all therapy areas – demonstrates the increasing demands of regulators and the growing complexity of regulatory submissions. For new and established products, tranScrip is well placed to offer deep scientific and regulatory insight, strategic expertise and operational support at every step.
The views and opinions expressed are those of the author.
Note: Current product information can be found on the EMA (https://www.ema.europa.eu/en) and MHRA (https://products.mhra.gov.uk) websites. For centrally authorised products the EMA website includes initial assessment reports and details of all post-licencing activity.
1 Sisson J. 30 Years of Progress in Type 2 Diabetes: A Brief Review. 2022. 23 February 2022 [Epub ahead of print]
2 MHRA. Current Problems Number 32: Fenfluramine (Ponderax Pacaps), Dexfenfluramine (Adifax) and Pulmonary Hypertension. In: Medicines CoS, ed.; 1992.
3 Abenhaim L, Moride Y, Brenot F et al. Appetite-suppressant drugs and the risk of primary pulmonary hypertension. International Primary Pulmonary Hypertension Study Group. N Engl J Med 1996; 335 (9): 609-616.
4 EMA. Final Opinion of the Committee for Proprietary Medicinal Products in Accordance with Article 12 of Directive 75/319/EEC as Amended. In: CPMP, ed.; 1996.
5 EMA, Bass PR, Le Courtois P. Press Release (Scientific review of anorectic agents). CPMP/2325/99. 1999.
6 EMA. EMA recommends withdrawal of marketing authorisation for amfepramone medicines. 2023. www.ema.europa.eu; 2022.
7 BBC. Mediator drug: French pharmaceutical firm fined over weight loss pill. 2023. bbc.co.uk; 2021.
8 EMA. Guideline on clinical evaluation of medicinal products used in weight management. In: CHMP, ed.; 2016.
9 EMA. EMA starts review of weight management medicine Mysimba. 2023.
10 Novo Nordisk Global. Novo Nordisk A/S: Semaglutide 2.4 mg reduces the risk of major adverse cardiovascular events by 20% in adults with overweight or obesity in the SELECT trial. 2023. 2023:Announcement.
11 EMA. EMA statement on ongoing review of GLP-1 receptor agonists. 2023. 2023.
12 Lilly Investors. Tirzepatide demonstrated significant and superior weight loss compared to placebo in two pivotal studies. 2023. investor.lilly.com; 2023.
13 EMA. Assessment report – Mounjaro (tirzepatide). In: CHMP, ed.: EMA; 2022.
14 ClinicalTrials.gov. A Study of Tirzepatide (LY3298176) in Participants With Obesity or Overweight With Weight Related Comorbidities (SURMOUNT-5). In: NCT05822830, ed.; 2023.
15 Jastreboff AM, Kaplan LM, Frías JP et al. Triple-Hormone-Receptor Agonist Retatrutide for Obesity – A Phase 2 Trial. N Engl J Med 2023; 389 (6): 514-526.
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