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Glucagon-like peptide 1 (GLP-1) is a hormone that triggers the release of insulin, inhibits the secretion of glucagon to prevent blood sugar levels rising, slows the emptying of the stomach and increases satiety.
GLP-1 agonist drugs such as semaglutide (OzempicTM and WegovyTM) and tirzepatide (MounjaroTM) were initially developed to mimic this hormone and treat type 2 diabetes (T2D). In recent years, these drugs have gained significant attention for their weight loss effects.
Today, there are numerous GLP-1 agonists being developed and trialed for the treatment of obesity. Injectable and oral formulations are available and both have become popular options. However, as results from the first two-year follow-up studies start to be released for these drugs, Jon Rees, CEO of MitoRx Therapeutics, believes that alternative treatments for obesity are still needed.
To overcome issues such as poor adherence to dosing, muscle mass loss and other known side effects associated with GLP-1s, Rees and the team at MitoRx are pursuing a completely different method of action – one that moves away from targeting food intake, instead aiming to modify the metabolism.
Technology Networks recently spoke with Rees to learn more about the landscape for GLP-1 drugs, their limitations, and what this could mean for the next generation of obesity treatment.
Can you break down why there is such a push for making oral GLP-1s agonists?
Currently, the pharma industry does appear to have convinced itself that oral weight loss medicines are going to be really important. However, at the moment, Novo Nordisk’s orally formulated GLP-1 drug (“RybelsusTM” semaglutide), which is on the market, has only achieved a six percent market share.
Although many patients may prefer pills to injections prior to therapy, a once-weekly or once-monthly injection using an autoinjector pen may be easier. This is because of dosing rules with oral GLP-1 drugs (e.g., empty stomach, 30 mins before food and other medications). In addition, intermittent dosing may be less likely to make the person living with obesity feel “medicalized” by removing the ritual of daily medication. This might be why studies can show higher satisfaction and adherence with injectables than daily oral diabetes meds; patient surveys like the REVISE study showed that preference for a once-daily oral weight loss pill over a once-weekly injectable was lost after watching videos explaining the actual administration process.
Given that orally formulated GLP-1 agonists have lower efficacy than injectables, small molecule GLP-1 mimics are expected to make more headway. Put simply, oral GLP-1 mimics are expected to be most attractive to those new patients who may at present be resistant to injections. Conversely, patients who have tried injectables may be socialized to their convenience. Hence, oral GLP-1 drugs are a way for the industry to expand the market for GLP-1 agonists through an additional route of administration, albeit a route that may be attractive to people earlier in their disease journey.
While the pharma industry attempts to expand the “improved GLP-1 drug” market, including orals, the generics industry will grow its GLP-1 agonist foothold, making cheaper and less efficacious injectable GLP-1 drugs much more widely available, rapidly growing the number of patients comfortable with self-injection for weight loss.
The industry also has its eye on a range of alternative approaches to GLP-1 receptor agonism. These include oral small molecule approaches that can drive fat loss, cause little or no lean mass loss and may have a less severe gastrointestinal side effect profile. The industry is also trialing a variety of largely biologic muscle protective approaches to use in combination with GLP-1 drugs, which might act as a “sticking plaster” to extend the duration of the GLP-1 market opportunity for longer by countering the extent of GLP-1 muscle loss, which is the equivalent of 20 years of age-related muscle loss.
Ultimately, the obesity market will likely develop in a complex and unpredictable way, which will likely include both subcutaneous and oral products and combinations, with patients seeking cleaner side-effect profiles and becoming more averse to the ever-more publicized risks.
How do the outcomes of current oral GLP-1 drugs compare to injectable GLP-1 drugs, in terms of efficacy and side effects?
The latest data for orforglipron, a daily oral small molecule GLP-1 mimic developed by Lilly for weight management and T2D, showed around 10.5% weight loss in the ATTAIN-2 clinical trial in diabetic patients, compared to 2.2% weight loss for those on placebo. In the ATTAIN-1 trial, non-diabetic patients’ weight loss was on average 12.4%. This is about half as effective as injectable GLP-1 peptides, but with broadly the same side-effect profile.
We already know from two-year follow-up studies of patients who have taken injectable GLP-1 drugs for at least six months that net weight loss in the real world is as little as 4.7% for many reasons, including poor adherence as a result of side effects, supply and affordability. It is not unreasonable, then, to make a best guess that real-world weight loss at a two-year follow-up with a less efficacious oral GLP-1 mimic will be even lower.
The health economic case for GLP-1 drugs for self-funding patient and health insurers, as well as single-payer state health systems, is weakened by incidences of chronic and acute pancreatitis. In addition, the willingness of patients to take GLP-1 therapies is eroded by reports, such as those that appeared in the British Medical Journal earlier this year, reporting 82 deaths linked to adverse reactions in the United Kingdom.
More and more articles have appeared highlighting the “stomach-churning side effects” of GLP-1 drugs in the press, as well as wider societal chatter about the apparent accelerated aging, such as the dreaded “Ozempic face”. This has joined industry criticism from heavyweights like George Yancopoulos, a co-founder of Regeneron, who suggested that blockbuster weight-loss drugs could cause “more harm than good” in the Financial Times last October. As a result, it is clear that the industry expects to provide better alternatives than GLP-1 drugs in the foreseeable future.
If oral GLP-1 drugs have reached their ceiling, what alternative options are out there for tackling obesity?
Our view is that MitoRx’s approach is the best alternative option, but there are others – both oral and not. One option is long-acting amylins, including Petrelintide, an acylated peptide which Zealand Pharma is developing with Roche.
Another option is the myostatin blockers like bimagrumab, trevogrumab and apitegromab. Some of these myostatin blockers have demonstrated impressive lean mass protection in the clinic. However, that success is partially stemming from lean mass loss driven by GLP-1, rather than the prevention of lean mass loss. Bimagrumab was invented in the 2000s and repurposed for obesity, and though it can grow muscle mass as a monotherapy, there is a question about whether that amounts to a functional strength benefit for patients. These biologic approaches are more difficult and expensive to manufacture and aren’t amenable to oral delivery.
Another approach is oral mitochondrial uncouplers, such as the molecules being developed by OrsoBio, Energesis and also Rivus. These approaches are based on the unusual observation that workers exposed to a chemical called 2,4-dinitrophenol (DNP), which was being used in French munitions factories, lost weight, felt fatigued, sweated excessively and exhibited elevated body temperature (hyperthermia). Sadly, many deaths occurred before safety measures were introduced. The mechanism of action was later discovered to be chemically-mediated mitochondrial uncoupling – put very simply, chemicals knock holes in the mitochondrial membrane and force the mitochondria to work really hard to reverse the dissipation of membrane potential, which generates heat and reduces weight.
DNP was later studied at Stanford in the 1930s, where scientists warned of the dangers of DNP alongside reports of its effectiveness in weight loss. Over 100,000 people took DNP in the 1930s through drug stores without a prescription and many deaths occurred, resulting in the designation of DNP as extremely dangerous and not fit for human consumption in 1938.
Rivus Pharma is developing a DNP pro-drug called HU6, which is claimed to have an improved safety profile. However, flushing in individuals treated by HU6 was flagged in The Lancet last year as a possible harbinger of a safety concern, while palpitations were also reported in its clinical trial results. Eolo Pharma has an alternative approach to thermogenesis, which is also being explored in the clinic.
As you can see, there are a variety of other approaches. However, MitoRx is unique in developing a small molecule approach that addresses a known impairment in metabolism: restoring sulfide-signaling.
MitoRx Therapeutics is pursuing a metabolism-modifying approach rather than appetite suppression. Can you explain how this works?
The fundamental difference we are taking is that where GLP-1 drugs slow down the gut and suppress appetite, our lead therapy, Myo4, works directly on metabolism.
There is a known metabolic defect in cardiometabolic disease – this was highlighted most recently by Lefer et al., who showed that an impairment in the sulfurome is a hallmark feature of cardiometabolic disease. Sulfide signaling is impaired in obesity, diabetes and heart failure with preserved ejection fraction (HFpEF).
Myo4 directly addresses that by restoring cysteine post-translational modification for a small number of key proteins that regulate metabolism. As a result, we are developing root-cause treatments, rather than modifying food intake. This has the huge advantage that, in patients whose behavior around food might not be modifiable with the health and wellness resources available to them, Myo4 is expected to still help them lose fat mass, regardless of whether they exercise or reduce calorie intake.
