Retatrutide

Tucked into its latest earnings report, Eli Lilly disclosed that it has removed from its research pipeline an experimental drug for pain.The drug, which Lilly in-licensed several years ago, works by inhibiting a protein called P2X7. This protein helps regulate molecules that trigger inflammation and amplify pain signals. Blocking P2X7, Lilly had hoped, would be an effective way to treat conditions like osteoarthritis, chronic lower back pain and the nerve pain that often accompanies diabetes.However, data from mid-stage tests did not meet our high internal bar for success, according to Lilly spokesperson Ashley Hennessey. While the company is assessing next steps for the program, including possible additional indications, for now, the drug is out of its pain pipeline.Its at least the second Lilly pain program to get axed this year. A drug named mazisotine, designed to boost a pain-relieving protein known as SSTR4, was shelved this summer.These cuts underscore just how incredibly difficult pain drug research continues to be, even for deep-pocketed companies with extensive experience studying the nervous system. Lillys biggest rival in pain, Vertex Pharmaceuticals, lost billions of dollars in market value a few months ago, after reporting a potential successor to its pioneering pain medicine Journavx had failed a key mid-stage trial.Alongside that disclosure, Vertex said it would not start a late-stage study of Journavx in a form of sciatica, derailing plans to expand use of the drug into peripheral neuropathic pain.Despite such setbacks, the immense number of people suffering from pain has encouraged some companies to keep pushing forward. Lilly, for one, has gradually deepened its investments over the past few years. In May, it wagered up to $1 billion on an acquisition of SiteOne Therapeutics, a private biotechnology company working on new, non-opioid pain medicines that may one day compete with Journavx.Lilly has had a persistent interest in pain in recent years ... but with little tangible success, Carter Gould, an analyst at the investment firm Cantor Fitzgerald, wrote in a note to clients shortly after the acquisition was announced. Given the deal terms and the clear strategic interest, this seems like a reasonable move, even with the outstanding commercial and clinical questions for the class of drugs SiteOne specializes in.That deal handed Lilly a drug which had already gone through Phase 1 testing and, like Vertexs molecule, targets a type of cellular signaling channel known as Nav1.8.Beyond that program, Lilly has a another non-opioid, early-stage candidate targeting a protein, AT2R, tied to neuropathic pain.And on the more advanced end, Lilly is evaluating whether an antibody that impedes the epiregulin protein can be a treatment for chronic pain. The company is also seeing if two of its most closely watched experimental therapies for diabetes and weight loss orforglipron and retatrutide could also be useful against osteoarthritis or chronic lower back pain. '

Skye Bioscience’s obesity shot has failed in a mid-stage trial, adding to the evidence that cannabinoid receptor 1 inhibitors have little effect in the disease. Nimacimab, as Skye’s antibody is known, did not improve weight loss over placebo in the Phase 2a study when used as a monotherapy, the company said Monday. Patients taking the drug lost just 1.5% of their body weight at 26 weeks (just over six months). Those given a placebo lost even less (0.3%), but the difference was not statistically significant. Speaking at an investor conference in September, Skye’s CEO Punit Dhillon said the company had guided towards weight loss of 5% to 8% at 26 weeks, adding that the company was “very confident about that.” On Monday, though, Skye said that a pharmacokinetic analysis showed lower-than-expected drug exposure, suggesting that the 200 mg weekly dose used in the trial was “suboptimal.” The company’s share price $SKYE fell more than 60% before the opening bell. The trial, named Cbeyond, also had an arm testing nimacimab in combination with Novo Nordisk’s Wegovy. This regimen cut patients’ weight by 13.2% at week 26, but did not reach statistical significance versus the control arm of Wegovy monotherapy, which yielded weight loss of 10.3%. Skye called the additional weight loss in the combination arm “clinically meaningful.” It added that patients in the combo arm had a significantly better ratio of lean mass to fat mass versus both the placebo and Wegovy monotherapy groups. The biotech claimed that this finding “supports potential further studies to evaluate combinations of nimacimab and incretin-based therapies.” Nimacimab had “placebo-like tolerability,” with 27% of subjects taking the drug having gastrointestinal adverse events, compared with 29.5% on placebo. GI events were seen in 57.1% of those in the Wegovy combination cohort, versus 66.7% with Wegovy alone. No neuropsychiatric concerns were raised, with no increase in anxiety, insomnia or depression among nimacimab recipients. The study had an overall discontinuation rate of 27%, with 3.7% of patients quitting due to side effects. Most of those who left the trial due to side effects had been given placebo. Skye said it would look at dosing the drug higher in “potential future clinical trials.” But cross-trial efficacy comparisons with other obesity therapies show that nimacimab is a long way behind competing drugs. Novo Nordisk’s cannabinoid receptor 1 (CB1) blocker pill monlunabant was much more effective than nimacimab in Phase 2, with patients losing 6.4% of their weight after four months. Even so, the readout was seen as a disappointment . The drug remains in Novo’s pipeline, but no active studies are listed in the federal clinical trials register. Another small biotech, Corbus Pharmaceuticals, is investigating this mechanism in obesity. Corbus kicked off a Phase 1 study of its pill, named CRB-913, in March, and early data could come this year. The only other CB1 drug used for obesity was Sanofi’s Acomplia, which was approved in Europe nearly 20 years ago. However, Sanofi had to pull Acomplia from the market in 2008 after it was linked with serious psychiatric disorders. But if CB1 drugs reach market again, they won’t just compete with each other — they’ll also have to go up against the much more effective class of GLP-1-based drugs. Weight loss at 26 weeks was around 10% and 15% on the pivotal trials of Wegovy and Eli Lilly’s Zepbound, respectively. Investigational products like Lilly’s triple agonist retatrutide and Roche’s GLP-1/GIP agonist CT-388 have demonstrated weight loss of around 18% to 19% at 24 weeks. So far, no CB1 inhibitor has got near this level of efficacy, and it is not clear that there is demand for a GLP-1/CB1 combination that is only marginally more effective. Editor’s note: This article was updated to note Skye Bioscience’s share price drop.