Cancer cachexia contender enters first pivotal trial

Cancer dominates the drug development pipeline, but industry has paid little attention over the years to cancer cachexia — the complex weight-loss syndrome that accounts for 20–30% of cancer deaths. Two GDF15-targeted antibodies are now approaching phase II/III trials, however. Pfizer is gearing up to soon start recruiting patients into a pivotal trial of its ponsegromab, and CatalYm is set to start a similar trial of its visugromab in early 2026.

“It’s a cachexia moment,” says Vickie Baracos, a cachexia expert at the University of Alberta. “A positive phase III result would be amazing. We’ve been waiting for this for a long time,” adds Baracos, who has consulted for Pfizer.

Patients have few supportive care options right now for cancer-associated cachexia, a metabolic syndrome that commonly develops during advanced cancer. Cachexia results in decreased appetite and the loss of skeletal muscle and fat, as well as fatigue, weakness and declining quality of life. It also reduces the ability of patients to handle the toxicities of cancer drugs, and chemotherapies can exacerbate the effects. But although the resulting weight loss is linked with poorer survival rates, drug developers have turned up few pharmacological interventions for the disease.

GDF15 blockers — the first new drugs to enter industry-sponsored pivotal cachexia trials in over a decade — could turn things around. “This is really the first time that there has been proof-of-principle clinical data to show that cachexia isn’t hopeless,” says Daniel Marks, CMO and CSO of Endevica Bio, a biotech that is working on another cancer cachexia target.

A pleiotropic cytokine

Researchers started down the path to ponsegromab and visugromab with the discovery of a new member of the TGF-beta superfamily of cytokines in the late 1990s. The protein was found in different places, and with different functions, and so was given five different names: growth differentiation factor-15 (GDF15), macrophage inhibitory cytokine-1 (MIC-1), prostate-derived factor (PDF), placental bone morphogenetic protein (PLAB) and nonsteroidal anti-inflammatory drug-activated gene (NAG-1). Researchers quickly got to work at understanding its pleiotropic effects.

By 2006, evidence started to emerge to show that GDF15 could modulate body weight: mice that over-expressed the protein were smaller than wild-type controls. Then in 2007, St. Vincent’s Hospital’s Samuel Breit and colleagues linked it directly to cancer-induced weight loss. After noticing that blood levels of GDF15 sometimes rose by 10–100-fold in people with cancer, his team showed that cancer-carrying xenograft mice that over-expressed GDF15 rapidly lost weight. An antibody against the protein could reverse this effect, they also found.

Drug developers picked up the trail. Researchers from Novo Nordisk, Eli Lilly and Janssen reported for example in three separate papers in Nature Medicine in 2017 that GDF15 binds the GFRAL receptor in the hindbrain to regulate appetite.

“Appetite regulation through that receptor is what we understand best,” says John Groarke, executive director of cardiometabolic clinical R&D at Pfizer. “But we keep an open mind as to whether or not there are additional mechanisms beyond appetite regulation that we have yet to fully understand.”

Most big pharma companies tried to harness the appetite suppressing effects of GDF15 mimetics for the treatment of obesity. These have mostly now been discontinued. Pfizer went against the big pharma flow, and is now leading a small pack of companies in pursuit of GDF15 blockers (Table 1). By mopping up GDF15 in the blood, their goal is to prevent the cytokine from binding its receptor — de-suppressing appetite and helping cancer patients maintain or gain body weight.

Last year, mid-stage clinical data highlighted the potential. Pfizer’s phase II trial of ponsegromab recruited 187 patients with cancer cachexia and high GDF15 levels for treatment with placebo or one of three doses of ponsegromab. Researchers reported a dose-dependent effect on weight loss in the New England Journal of Medicine, with a 2.81 kg placebo-adjusted benefit for patients on the highest dose of the antibody after 12 weeks.

The antibody also boosted appetite, helped with cachexia symptoms and led to increased levels of physical activity.

It was well tolerated, with similar rates of adverse events between treatment and placebo. The most common side effects were diarrhoea, cancer progression, anaemia, hypokalaemia, nausea, vomiting and pyrexia.

Pfizer’s upcoming phase II/III trial could now start to pave a path for a first regulatory approval for a cachexia drug in the US and Europe. It is set to recruit over 980 patients with metastatic pancreatic cancer for treatment with systemic chemotherapy plus either ponsegromab or placebo.

“I think it’s a great trial,” says Rutgers University’s cancer biologist Eileen White, who co-leads the CANCAN cancer cachexia network. “The results, no matter what they are, will be very interesting.”

Whereas Pfizer’s phase II trial of ponsegromab only recruited patients with elevated GDF15 levels, its pivotal trial drops this inclusion criterion.

This decision was driven by the phase II trial results, notes Groarke. While screening for patients in that trial, they found that 94% of cancer patients with pre-existing cachexia had GDF15 levels above the entry criteria. The trial results also showed that baseline GDF15 levels did not seem to impact the effect of the antibody on body weight.

“There was a bit of a blind spot about the natural history of GDF15 in patients with cachexia that we have been able to address with the data that has emerged from our studies,” says Groarke. “There’s an opportunity to help a lot of patients without requiring GDF15 for inclusion into the trial.”

Endpoint evolution

To assess efficacy, Pfizer’s trial will look at two co-primary endpoints: per cent change from baseline in body weight at 12 weeks, to assess if the drug is slowing wasting; and change from baseline in the Functional Assessment of Anorexia/Cachexia Therapy (FAACT) 5-item Anorexia Symptom Scale Score, a patient quality of life tool that measures changes in appetite.

“In our work with patients, loss of appetite was a very impactful symptom that kept coming up,” says Groarke. “We heard from patients that they were frustrated by wanting to eat, wanting to sit down and enjoy dinner with their family, and not being able to because they either had no appetite or they had really early satiety. That was the impetus for us to really invest in an endpoint that could be used to understand whether or not we could move the needle on appetite.”

This is a change from cachexia precedent.

The last industry-sponsored appetite-enhancing drug candidate to make it to phase III cancer cachexia trials was anamorelin, a ghrelin receptor agonist. In 2011, Helsinn Healthcare launched pivotal trials of that candidate, using the co-primary endpoints of change in lean body mass and handgrip strength. The trials hit the body mass endpoint, showing 0.75–1.10 kg gains on treatment versus 0.44–0.96 kg losses on placebo, researchers reported in 2015. But it missed on handgrip strength.

Helsinn secured an approval for anamorelin in Japan in 2020, but never filed it for FDA approval.

For Marks, the handgrip endpoint was a poor choice as a proxy for physical function. There is just too much variability in the handgrip readout, he argues, because it depends on how patients feel on any given day, how motivated they are to perform, and how well they are instructed by a clinical investigator.

“It was kind of a hopeless measure to begin with,” says Marks.

Baracos thinks that Pfizer’s decision to instead go with a patient-reported assessment of appetite is solid. “If the drug works, people regain appetite. If they regain appetite, they eat more food. And if they eat more food, just at that point there is a benefit,” she says. “This represents a shift in thinking in the field.”

For Aditi Saxena, vice president of internal medicine clinical research at Pfizer, it is still too early to say how Pfizer or the field would interpret mixed results on its co-primary endpoints. But Marks argues that even a success on a body mass endpoint alone should be enough for approval, because of the relationship between involuntary weight loss and mortality in patients with cancer. “The regulatory landscape is changing,” he says. “Regulatory agencies are coming to understand that weight maintenance or weight gain is an approvable endpoint unto itself,” he says.

There is no consensus on this yet, adds Baracos. “If you asked every clinical investigator and all the regulatory authorities around the world about endpoints, you’d get different answers,” says Baracos.

A lifeline for patients?

Pfizer hopes, however, that the antibody will also help people to live longer. If cachexia and weight-loss can be addressed, the theory goes, patients should have hardier immune systems and be better able to withstand the toxicities of cancer-killing drugs.

To test this possibility, Pfizer is powering its trial to look at overall survival as a secondary endpoint.

“Our broader goal is to improve the way people feel, function and survive, and we’re trying to capture that with the design of this study,” says Saxena. “We do realize that this secondary endpoint is a much higher bar. We’re forging new ground here.”

A win on this endpoint would be massive, adds Baracos. “A survival benefit would change the way we think about things. It would be a quantum jump,” she says.

The effect of GDF15 blockers on overall survival “is the key question that’s on my mind all the time,” agrees White. While she hopes that patients will gain time, there may be an outside chance that these drugs could shorten lives if the cancer cells can hijack any increased energy availability to prioritize their own growth. “I don’t think that that’s going to be the case, but until someone does the experiment we don’t know,” she says.

Pfizer will be monitoring tumour responses over the course of the trial, in part to rule out this risk. “We did not see any concerning signal for tumour response in the phase II trial,” adds Groarke. “But it will be evaluated further in the phase II/III study.”

Baracos is not concerned about this risk. A massive body of evidence shows that “getting people to eat more food is beneficial to them, and is not considered to be beneficial to the tumour,” she explains.

Marks, too, pushes back against fears that tumours might thrive with cachexia drugs. “I think that notion is nonsense,” he says.

In a recent study of Endevica’s cachexia drug in rats with colorectal cancer, his team showed that it is possible to stabilize body weight without changing a cancer’s growth rate. “The odds that you’re going to change the kinetics of tumour growth are extraordinarily small,” he says.

But while Marks hopes that cachexia drugs will offer an overall survival advantage, he won’t be surprised if Pfizer’s ponsegromab misses this goal in its first phase II/III trial. Patients with pancreatic cancer can suffer from malabsorption of nutrients from the gut, which might contribute to cachexia independently from the effects of GDF15. Pancreatic cancer is also a fast and lethal disease, leaving patients with little time to benefit from treatment. And the patients Pfizer is recruiting, with pre-existing cachexia, are already in a fragile and sick state. “It’s hard to pull out of that,” he adds.

But Pfizer’s published phase II trial results showed promise in pancreatic cancer, counters Groarke. “We had a really robust weight gain signal in the pancreatic cancer patients,” he says.

The chances of overall survival success may be better in other populations, especially if the drugs are used earlier in the course of disease, says Marks. Rather than focusing on rescuing patients with established cachexia, his team at Endevica Bio is running a trial to look at the prevention of weight loss before it even starts in patients with metastatic colorectal cancer.

“Our clinical trial is designed to test the hypothesis that the initiation of a drug can prevent involuntary weight loss,” says Marks. This will allow patients to have a better quality of life through their cancer journey, and to tolerate more chemotherapy from the get go as well. “An ounce of prevention is a pound of cure,” he says.

For Groarke, prevention is “an area of interest” for Pfizer. But more data is needed to determine the path forward for GDF15 blockers here, including a better understanding of the role of GDF15 in pre-cachexia. “This is a space with tremendous unmet need, and certainly it’s something that we’re giving a lot of consideration to.”

Pfizer’s future trials could also look at the effect of the antibody in other cancers, including colorectal and non-small-cell lung cancer (NSCLC), adds Saxena. Pfizer’s phase II trial of ponsegromab showed activity in both of these settings.

Immunotherapeutic opportunity

GDF15 blockers might also harness the immune system more directly to help patients to fend of cancer, say some researchers.

When GDF15 was first discovered in the late 1990s, one team found it in the placenta — an immune-privileged organ. Its expression by this organ has been linked to nausea and vomiting associated with pregnancy, but some researchers wondered whether it might also help to keep the immune system in check in pregnant women. Decades on, researchers have established that GDF15 can indeed act as a “T cell repellent” — blocking the recruitment, infiltration and activation of T cells into a microenvironment.

“Our understanding is that GDF15 really is a signalling shutdown mechanism for various different immune cells,” says Christine Schuberth-Wagner, former CSO at CatalYm.

If cancers co-opt this effect, GDF15 blockers could neutralize it. The drugs seem to have mild immune-enhancing activity when used as monotherapy in mice with cancer, she adds, but really shine when used in combination with PD1 blockers to enhance T-cell recruitment into tumours.

Clinical data bear this out, says Eugen Leo, former CMO at CatalYm.

CatalYm recently completed a phase I/II trial of its GDF15-blocker visugromab in combination with nivolumab in patients with advanced solid cancers that were refractory to anti-PD1 or anti-PDL1 therapy. Initial results show response rates of around 15–19%. “That may not sound very impressive, but remember that immunotherapies in last-line patients barely work at all,” says Leo. Historical data suggest that the response rate with retreatment with a PD1 blocker would be in the 0–3% range, he adds.

The trial data also show that visugromab plus nivolumab drove T cells into the tumour microenvironment, induced T cell proliferation in situ in the tumour microenvironment, bolstered granzyme B production and triggered the adaptive immune system’s interferon gamma response signature.

“This is very nice, early proof of concept and proof of mechanism,” says Leo.

“The results are very suggestive that there is activity in the heavily pre-treated checkpoint inhibitor refractory patients,” agrees Ignacio Melero, a cancer immunologist at the Cima Universidad de Navarra and investigator in the phase I trial of CatalYm’s GDF15-blocker visugromab.

Additional trials of the antibody as part of a combination therapy are ongoing in patients with NSCLC and bladder cancer. “We really need to document and expand the knowledge we have about this,” adds Melero.

The idea that GDF15 might act as an immunotherapy is “certainly an interesting hypothesis,” says Saxena. But the sample sizes that CatalYm has reported on to date are relatively small, she cautions.

CatalYm meanwhile is also expanding its scope to look at its antibody in cancer cachexia. “The opportunities are intertwined,” says Schuberth-Wagner. “There’s no ‘either/or’, there’s just an ‘and’.”

The company plans to start recruiting 500 patients into a phase II/III trial of visugromab as a monotherapy in cancer patients with cachexia in 2026.

AstraZeneca was also developing the GDF15-blocker AZD8853 as an immunotherapy, but officially discontinued it in 2023 due to “strategic portfolio prioritization”. A year later, they reported that the antibody did not elicit any treatment responses in its phase I trial. It was tested as a monotherapy, and in a different patient population than visugromab. AZD8853’s GDF15-blocking effects were also only transient, the company reported.

A commercial conundrum

If Pfizer and CatalYm can run the regulatory gauntlet with their drugs, patients with cancer could at last have access to FDA-approved cachexia therapies. The companies could then have to contend with the commercial challenge of cheaper, off-label alternatives.

Faced with little industry interest in cachexia drug development, cachexia specialists have long been exploring repurposing opportunities for their patients. In 2023, they finally hit on a viable option: olanzapine, an atypical antipsychotic that induces weight gain as one of its side effects. A trial in 124 patients with chemotherapy-related anorexia showed that a low dose of the drug helped 60% of treated patients to gain greater than 5% of their body mass, compared with only 9% of placebo recipients. After 12 weeks olanzapine recipients had gained on average 2.7 kg, while placebo recipients had lost on average 1.9 kg. The drug also restored appetite, improved quality of life measures and mitigated chemotoxicity.

The incidence of other side effects typically associated with olanzapine, such as drowsiness, was also low, potentially because the trial used a low dose of the drug.

The American Society of Clinical Oncology (ASCO) subsequently updated its guidelines to recommend low-dose olanzapine as a pharmacologic option for patients with advanced cancer.

Olanzapine is thought to both suppress nausea and to stimulate appetite by modulating dopamine and serotonin receptors. It was first approved by the FDA in 1996 for psychotic disorders, and generic versions of the drug can cost just a few dollars a month.

This could prove problematic for the commercialization of future cachexia drugs. “Another battle that is emergent in all of this is the cost–benefit to payers,” says Baracos. “That is uncharted territory.”

But Keld Fosgerau, CEO of Pephexia Therapeutics, is optimistic that the market is there. The unmet need in cancer cachexia is massive, he explains, and patients are likely to need multiple treatment options. If GDF15 blockers can stave off weight loss and improve quality of life, they should still be able to command “a fair price”. And if they can improve overall survival as well, “that would up the price they can charge”.

Analyst at Stifel have meanwhile estimated that the cancer cachexia market could be worth up to US$100 billion. That forecast doesn’t include cachexia associated with other diseases, such as heart failure and chronic obstructive pulmonary disease.

Commercial success for the GDF15 blockers could consequently be transformative for the community. “Maybe you’ll have a frenzy in cachexia, just like we’ve seen in obesity,” says Fosgerau, who worked in that space when it too was largely overlooked by large pharmaceutical firms.

Beyond GDF15

To prepare for this possibility, a handful of companies are persevering with other cachexia targets (Table 2).

At Pephexia, for example, the focus is on the biology of neuropeptide Y (NPY).

NPY was discovered in 1982 and subsequently attracted the attention of cachexia researchers because of its role in food intake and energy balance, until researchers reported in the mid 1990s that repeated injections of NPY did not increase food intake significantly in rats with cancer.

A deeper understanding of NPY biology and its receptor system is now bringing it back. Researchers now know that NPY acts through four different receptors (Y1, Y2, Y4 and Y5), explains Fosgerau, with some of these receptors driving opposing effects. In Fosgerau’s hands, Y5 has the strongest effect on appetite and resting energy expenditure. Enter Pephexia’s selective Y5 agonist PEP-366.

“We have now shown in three different models of cachexia that our Y5 specific agonist increases appetite and decreases energy expenditure,” says Fosgerau.

PEP-366 is now in preclinical toxicity and safety studies, and the company is raising funding for a potential phase I trial of the drug next year.

“It helps a lot that Pfizer is advancing ponsegromab into phase III, with CatalYm as a fast follower,” says Fosgerau. “The whole perception of the cachexia field has changed in the past year, and banks and investors have started to put money on it,” he adds.

Marks and his colleagues at Endevica are similarly rebooting interest in an established appetite target — the melanocortin receptors. The melanocortin type 3 (MC3R) and type 4 (MC4R) receptors in particular are expressed in the same region of the brain as Y5R, though by a different population of neurons, and have long drawn interest because of their dampening effect on appetite.

Researchers and drug developers alike have consequently looked to drug melanocortin receptors with both agonists, for weight loss, and with antagonists, for cachexia. But most of the early programmes “were relatively crude and unsophisticated by today’s standards,” says Marks. First-generation small molecule and peptide-based approaches alike were set back by off-target activity, he adds. But better insights of the drivers of this off-target activity, and improved understanding of how to get molecules across the blood–brain barrier, has led to a new crop of agents.

“Neuroscience has come a long way,” says Marks.

Endevica’s TCMCB07, also known as mifomelatide, is a brain-penetrant cyclic peptide that blocks both MC3R and MC4R to boost appetite.

“We have created a drug that is extraordinarily safe and effective, and we’re really excited about being able to offer it in clinical trials to patients,” says Marks. Endevica advanced the drug into a phase II trial earlier this year, and hopes to start a phase III trial by 2027.

“The field is highly energized right now,” adds Marks. “We have some sophisticated shots on goal that come from modern neuroscience.”

Researchers are also working to find new targets for the field. White and colleagues recently reported in bioRxiv that the CCL2 cytokine pathway could be in play.

“I think it’s another reasonable target,” says White.

There are probably different molecular subtypes of cancer cachexia, she adds, prompting the need for deeper understanding of which mechanisms are driving the syndrome in which patients. “You could have the best drug in the world, but if you use it in the wrong patient population you’re going to get a bad result,” she adds.

For Baracos, however, the target space needs to be rethought entirely. Baracos and colleagues recently reported in Nature on the molecular signatures that develop in the muscles of people with cachexia, and concluded that the syndrome is a “muscle disorder of daunting complexity” marked by entrenched inflammation and dramatic regulatory changes.

Appetite stimulants alone are unlikely to be enough, she suspects, and the same is likely true for any anti-inflammatory that takes out only a single node in a vast and interconnected inflammatory network.

“We need to look into the developing area of therapeutics for cytokine storms and cellular inflammatory cascades,” says Baracos.

“The real positive here is evolution,” she adds. “The therapeutics are evolving, the investigators are evolving, the regulators are evolving and the targets are evolving. Nobody’s stuck.”