S-arrestin

Chakravarthy gets asked “all the time” whether Roche left it too late to jump into the obesity race, but insists “the answer is categorically no.” Roche is holding out hopes that its injectable obesity prospect could eventually demonstrate 25% weight loss in late-stage trials, the pharma’s head of metabolism R&D has told Fierce Biotech.The Swiss Big Pharma imported a pipeline of three molecules as part of its $2.7 billion acquisition of Carmot Therapeutics at the end of last year, including an injectable dual GLP-1/GIP receptor agonist dubbed CT-388.The candidate has already demonstrated average placebo-adjusted weight loss of 18.8% over 24 weeks in a phase 1b study, and Roche is using the European Association for the Study of Diabetes Annual Meeting in Madrid, Spain this week to take a deeper dive into the data.Talking to Fierce from the sidelines of the conference, Manu Chakravarthy, M.D., Ph.D., Roche’s Global Head of Cardiovascular, Renal and Metabolism Product Development, said the pharma has ambitions to demonstrate even greater weight loss in later-stage studies. “If we continue to see the trajectories that we're seeing in our ongoing studies, we could be looking at roughly 20, 25% body weight loss, which is going to be in line with what bariatric surgery does,” Chakravarthy said in the interview.For comparison, Novo Nordisk’s blockbuster GLP-1 agonist Wegovy achieved 14.9% average weight reduction in the 68-week STEP-1 phase 3 trial, while another study called OASIS showed 15% weight loss over the same period. Meanwhile, Eli Lilly’s dual GIP/GLP-1 agonist Zepbound was shown to induce 22.9% weight loss over the far longer time frame of 176 weeks.Roche already moved CT-388 into a phase 2 study in July, but Chakravarthy stressed that even if the company can eventually demonstrate 25% weight loss, this wouldn’t be seen until a phase 3 trial due to the longer time frame involved.“With the high dose option with the right patient population we can, in fact, aspire to a 25% or more weight loss,” he said. Because if you're on the trajectory from close to 19% in six months —most obesity trials run for 72 weeks, sometimes up to 100 weeks.”“So we have a lot of room here that we have to explore,” Chakravarthy added. “But the trajectory is very encouraging for us.”With the injectable obesity market currently dominated by Novo and Lilly, does Roche really think it can carve out its own space?While acknowledging it’s “a fair question,” Chakravarthy pointed to CT-388’s “signaling bias” as setting it apart from the competition.“It is the only molecule today that we are aware of that is dually biased, meaning it is signaling for [cyclic AMP] without ß-arrestin on both the GLP-1 receptor and the GIP receptor,” he explained. “We think that's a very unique attribute.” The approach is intended to achieve greater weight loss and glycaemic control plus a more favorable tolerability profile—leading Roche to continue to tout CT-388 as “potentially best-in-class.”“What was reassuring is that we're seeing that level of efficacy, while the safety and the tolerability is no worse than anything else that's out there,” Chakravarthy explained about the data shared at this week’s conference. “An integrated approach”At the same event, Roche is presenting additional data from a phase 1 trial of CT-996, an oral GLP-1 that also originated at Carmot. In July, the pharma announced 7.3% weight loss from the trial after four weeks.More broadly, Roche also thinks it can stand out from the obesity crowd with an “integrated approach” that takes account of these molecules in development and offers patients digital health support, Chakravarthy said.“When we actually go out into the market space, we're actually offering a comprehensive suite of solutions, not just a one-off ‘Oh, here's an injectable, here's an oral, go figure it out’ kind of thing,” he said. “We are looking at it in a very long-term view.” “We can also bring in the oral [drug] as a maintenance directly for those that have finished their injectable induction phase, right? So there is multiple ways of mixing and matching,” he said.This integrated strategy also encompasses the planned kick-off of a phase 2 trial next year of CT-388 in combination with Roche’s anti-myostatin antibody, RO7204239, to see if together they can reduce the muscle loss typically associated with losing weight.Chakravarthy admitted he gets asked “all the time” whether Roche left it too late to jump into the obesity race, but insisted “the answer is categorically no.”“We have, like, four billion people in the world that are going to become overweight or obese in the next half a decade or so,” Chakravarthy added. “Fundamentally, I just don't think that two companies currently can supply the world's medicines for all those people.”

An additional cohort from the same trial will now evaluate obese patients with Type 2 diabetes. Roche’s incursion into the obesity space seems to be paying off so far based on the first clinical readout since the drugmaker scooped up Carmot Therapeutics for $2.7 billion. The biotech caught the attention of the Swiss pharma based on its pipeline of three molecules that could potentially challenge market leaders Eli Lilly and Novo Nordisk in the booming obesity and diabetes space. Chief among those acquired assets was CT-388, an injectable dual GLP-1/GIP receptor agonist that was already in a phase 1b trial when Roche bought Carmot in December. Now, Roche has released 24-week data from the study showing CT-388 produced average placebo-adjusted weight loss of 18.8%. All participants who received the therapy achieved weight loss of more than 5%, Roche noted, with 85% seeing weight loss of more than 10% and 45% achieving over 20% loss. The results suggest that CT-388 can more than hold its own in an increasingly crowded field. While trial-to-trial comparisons should always be treated with caution, Novo Nordisk’s blockbuster Wegovy achieved 14.9% average weight reduction in STEP-1, a 68-week phase 3 trial of nondiabetic patients with obesity or who were overweight and had at least one weight-related comorbidity. Another study called OASIS showed 15% weight loss after 68 weeks of treatment, with 34% seeing a 20% drop in their weight. Meanwhile, Novo’s next-gen obesity bet CagriSema has shown 17.1% average weight loss in a 20-week phase 1 obesity trial, compared to 9.8% for Wegovy. The readout appeared to be enough to enthuse investors, who sent Roche’s shares up 4% to 236.60 Swiss francs as of 11:25 a.m. local time. Roche noted in this morning’s release that CT-388 was well tolerated with “mild to moderate gastrointestinal-related adverse events being the most common, consistent with the incretin class of medicines that CT-388 belongs to.” When Roche drilled down into a subgroup of participants identified as “pre-diabetes,” the company noted that their blood sugar levels all reached normal levels after 24 weeks of receiving CT-388, while the levels of those who received placebo “remained largely unchanged.” An additional cohort from the same trial will now evaluate obese patients with Type 2 diabetes over 12 weeks of treatment, with data set to read out in the second half of the year. “We are very pleased to see the significant and clinically meaningful weight loss in people treated with CT-388,” Roche’s chief medical officer and head of global product development Levi Garraway, M.D., Ph.D., said in the release. “The results are highly encouraging for further development of CT-388 for both obesity and type 2 diabetes and underscore its potential to become a best-in-class therapy with durable weight loss and glucose control.” Carmot’s attempt to differentiate its candidates from the competition rests on “biased signaling” that is designed to minimize recruitment of ß-arrestin. The approach is intended to achieve greater weight loss and glycemic control plus a more favorable tolerability profile. Today’s results are focused on CT-388’s use as a monotherapy, but part of the attraction of the Carmot deal is the potential of allying the biotech's obesity assets with an anti-myostatin antibody that’s already in Roche’s pipeline. The antibody, dubbed RO7204239, is being studied for its potential to strengthen the muscles of people with spinal muscular atrophy. The hope is that adding RO7204239 to the mix means that Roche has its own answer to the next holy grail of obesity medicine: weight loss without muscle loss. “We know that incretins may have applicability into other disease areas,” Roche Pharmaceuticals CEO Teresa Graham told analysts on a call in February. “We would be looking at the assets that we acquired as part of the Carmot deal really as a backbone for future plays across cardiometabolism, but also potentially other disease areas as well.”

Over 24 weeks, a once-weekly subcutaneous injection of CT-388 achieved a clinically meaningful and statistically significant mean placebo-adjusted weight loss of 18.8% (p < 0.001) At week 24, 100% of CT-388 treated participants achieved >5% weight loss, 70% achieved >15% and 45% achieved >20% weight loss In a subgroup with pre-diabetes at baseline, CT-388 treatment normalised glycemia in all patients, indicating its strong impact on glucose homeostasisNo new or unexpected safety signals were detected. Overall, CT-388 demonstrated a safety and tolerability profile consistent with its drug class Basel, 16 May 2024 - Roche (SIX: RO, ROG; OTCQX: RHHBY) announced today positive results from the Phase I clinical trial of CT-388, a dual GLP-1/GIP receptor agonist being developed for the treatment of obesity and type 2 diabetes. The study found that a once-weekly subcutaneous injection of CT-388 over 24 weeks resulted in significant weight loss in healthy adults with obesity compared to placebo. The weight loss achieved with CT-388 was clinically meaningful, with a mean placebo-adjusted weight loss of 18.8% (p-value < 0.001). At week 24, 100% of CT-388 treated participants achieved a weight loss of >5%, 85% achieved >10%, 70% achieved >15%, and 45% achieved >20%. The treatment was well tolerated, with mild to moderate gastrointestinal-related adverse events being the most common, consistent with the incretin class of medicines that CT-388 belongs to. All participants with a pre-diabetes status at baseline became normoglycemic after 24 weeks of CT-388 treatment, whereas glycemic status of participants treated with placebo remained largely unchanged during this period. “We are very pleased to see the significant and clinically meaningful weight loss in people treated with CT-388,” said Levi Garraway, M.D., Ph.D., Roche’s Chief Medical Officer and Head of Global Product Development. “The results are highly encouraging for further development of CT-388 for both obesity and type 2 diabetes and underscore its potential to become a best-in-class therapy with durable weight loss and glucose control.” Obesity is one of the most urgent health challenges in the world with extensive comorbidities, such as type 2 diabetes, cardiovascular diseases, steatohepatitis and chronic kidney disease. Over four billion people - about 50% of the world’s population - are estimated to be impacted by obesity or being overweight by 2035. The growing number puts an incredible strain on societies and healthcare systems around the world. CT-388 belongs to the class of incretin-based medicines that aim to regulate blood sugar and reduce appetite. It selectively targets and activates two specific receptors in the body, known as GLP-1 and GIP, which integrate nutrient-derived signals to control food intake, energy absorption and assimilation. It is hypothesised that the dual targeting effect of CT-388 could result in a meaningful durable glucose reduction and weight loss, in addition to a favourable safety profile. An additional cohort from the ongoing placebo-controlled Phase I trial of CT-388 will evaluate obese patients (BMI>30 kg/m2) with type 2 diabetes over a 12-week treatment duration. Roche expects data from this additional cohort in the second half of 2024. About the CT-388 studyThe CT-388-101 trial is a multi-arm, multi-cohort Phase I randomised, double-blind, placebo-controlled study designed to evaluate the safety, tolerability, pharmacokinetics and pharmacodynamics of CT-388 in otherwise-healthy adult participants with overweight or obesity and in participants with obesity and type-2 diabetes mellitus. The primary endpoint of the trial is safety and tolerability of CT-388; secondary endpoints include its effect on body weight and glucose homeostasis. Pharmacokinetics and other pharmacodynamic effects of CT-388 were also assessed. About CT-388CT-388 is a once-weekly subcutaneous injectable, dual GLP-1/GIP receptor agonist being developed for the treatment of obesity and type 2 diabetes (T2D). CT-388 was designed to have potent activity on both the GLP-1 and GIP receptors but with minimal to no ß-arrestin recruitment on either receptor. This biased signalling significantly minimises receptor internalisation and consequent desensitisation, which is expected to lead to prolonged pharmacological activity. It is currently being studied in a multi-part, multi-cohort Phase 1 clinical trial in people with overweight/obesity with and without T2D.About Roche Founded in 1896 in Basel, Switzerland, as one of the first industrial manufacturers of branded medicines, Roche has grown into the world’s largest biotechnology company and the global leader in in-vitro diagnostics. The company pursues scientific excellence to discover and develop medicines and diagnostics for improving and saving the lives of people around the world. We are a pioneer in personalised healthcare and want to further transform how healthcare is delivered to have an even greater impact. To provide the best care for each person we partner with many stakeholders and combine our strengths in Diagnostics and Pharma with data insights from the clinical practice. In recognising our endeavour to pursue a long-term perspective in all we do, Roche has been named one of the most sustainable companies in the pharmaceuticals industry by the Dow Jones Sustainability Indices for the fifteenth consecutive year. This distinction also reflects our efforts to improve access to healthcare together with local partners in every country we work. Genentech, in the United States, is a wholly owned member of the Roche Group. Roche is the majority shareholder in Chugai Pharmaceutical, Japan. For more information, please visit www.roche.com. All trademarks used or mentioned in this release are protected by law. Roche Global Media RelationsPhone: +41 61 688 8888 / e-mail: media.relations@roche.com Hans Trees, PhDPhone: +41 79 407 72 58 Sileia UrechPhone: +41 79 935 81 48 Nathalie AltermattPhone: +41 79 771 05 25 Simon GoldsboroughPhone: +44 797 32 72 915 Karsten KleinePhone: +41 79 461 86 83 Nina MählitzPhone: +41 79 327 54 74 Kirti PandeyPhone: +49 172 6367262 Yvette PetillonPhone: +41 79 961 92 50 Dr. Rebekka SchnellPhone: +41 79 205 27 03 Roche Investor Relations Dr. Bruno EschliPhone: +41 61 68-75284e-mail: bruno.eschli@roche.com Dr. Sabine BorngräberPhone: +41 61 68-88027 e-mail: sabine.borngraeber@roche.com Dr. Birgit MasjostPhone: +41 61 68-84814e-mail: birgit.masjost@roche.com Investor Relations North America Loren Kalm Phone: +1 650 225 3217 e-mail: kalm.loren@gene.com Attachment 16052024_MR_GLP-1_GIP receptor agonist CT-388_en