An Endocrine News roundup of the week’s pharmaceutical news, breakthroughs, and general information. *
Results from AMGEN’S Phase 2 Obesity Study OF Monthly MariTide Presented at The American Diabetes Association 85th Scientific Sessions
MariTide, the First Monthly or Less Frequently Dosed Obesity Treatment, Demonstrated Up to ~20% Average Weight Loss Without a Weight Loss Plateau, and Delivered Significant Cardiometabolic Improvements at 52 Weeks
In People Living With Obesity With Type 2 Diabetes, MariTide Demonstrated Up to ~17% Average Weight Loss and Robust HbA1c Improvements
Dose Escalation With Lower Starting Doses Substantially Improved Gastrointestinal Tolerability, Without Compromising Efficacy
The MARITIME Phase 3 Chronic Weight Management Studies are Actively Enrolling, and Phase 3 Studies in People Living With Atherosclerotic Cardiovascular Disease, Heart Failure and Obstructive Sleep Apnea Will be Initiated in 2025
Amgen this past week announced full results from Part 1 of the Phase 2 study of MariTide (maridebart cafraglutide, formerly AMG 133), a long-acting, peptide-antibody conjugate subcutaneously administered monthly or less frequently. In addition to these data, complete results from the primary analysis of the Phase 1 pharmacokinetics low dose initiation (PK-LDI) study evaluating lower starting doses of MariTide were presented as part of an expert-led Symposium at the 85th American Diabetes Association (ADA) 85th Scientific Sessions and simultaneously published in The New England Journal of Medicine.
In the Phase 2 study, MariTide demonstrated up to ~20% average weight loss in people living with obesity without Type 2 diabetes (T2D) compared with 2.6% in the placebo arm, and up to ~17% average weight loss in people living with obesity with T2D, compared with 1.4% in the placebo arm, per the efficacy estimand.1 Weight loss had not plateaued by 52 weeks, indicating the potential for further weight reduction. In addition to meaningful weight loss, MariTide demonstrated a robust and sustained reduction in hemoglobin A1c (HbA1c) of up to 2.2%1 in people living with obesity and T2D. Weight loss with MariTide was also accompanied by improvements across pre-specified cardiometabolic measures, including waist circumference, blood pressure, high-sensitivity C-reactive protein (hs-CRP) and select lipid parameters.
“MariTide delivered strong efficacy, including sustained weight loss without a plateau in the 52-week Phase 2 study and meaningful improvements in cardiometabolic risk factors, representing a defining advance for the obesity field,” says Jay Bradner, MD, executive vice president of Research and Development at Amgen. “These results, alongside the Phase 1 Pharmacokinetics Low Dose Initiation data, have shaped our Phase 3 MARITIME program. MariTide’s monthly or less frequent dosing has the potential to improve adherence and long-term weight control, providing the opportunity to optimize health outcomes for people living with obesity, Type 2 diabetes and related conditions.”
No new safety signals were identified in the Phase 2 study and tolerability was consistent with the GLP-1 class. The most frequently reported adverse events (AEs) were gastrointestinal (GI) related, and most were mild to moderate. The study employed a rigorous daily patient reporting tool known as the MINVR (modified index of nausea/vomiting/retching) to actively solicit the presence of select GI symptoms in addition to standard unsolicited AE reporting. Gastrointestinal events were predominantly limited to initial dosing and less frequent when dose escalation was used without compromising efficacy. Discontinuation rates of MariTide due to GI AEs in the dose escalation arms (up to 7.8%) were lower than non-dose escalation arms.
“In this Phase 2 study, participants living with obesity treated with MariTide had substantial weight reduction at 52 weeks without reaching a weight plateau,” says Ania Jastreboff, MD, PhD, professor at Yale School of Medicine and director of the Y-Weight Yale Obesity Research Center. “Additionally, robust improvements in HbA1c were observed in participants who had Type 2 diabetes and obesity. These data demonstrate the potential for once monthly or less frequent dosing and are particularly encouraging as we seek sustainable, long-term treatments for people living with obesity, with and without Type 2 diabetes.”
The Phase 1 PK-LDI study assessed PK and also used the MINVR reporting tool to assess different dose escalation schedules of MariTide. The complete primary analysis showed participants that received 21 mg/70 mg/350 mg had an overall incidence of vomiting of 24.4% and participants that received 35 mg/70 mg/350 mg had an overall incidence of vomiting of 22.5%. There were no discontinuations due to GI AEs at any time during the study.
Data from the Phase 2 and Phase 1 PK-LDI MariTide studies informed the Phase 3 MARITIME program. The recently initiated Phase 3, 72-week chronic weight management studies will evaluate the safety, efficacy and tolerability of MariTide in participants living with obesity or overweight with and without Type 2 diabetes. Participants will be randomized to one of three target doses, each with an initial starting dose of 21 mg, followed by 35 mg and then 70 mg, over a further optimized eight-week dose escalation period. Amgen also expects to initiate Phase 3 clinical outcomes studies for atherosclerotic cardiovascular disease (ASCVD) and heart failure (HF), as well as a Phase 3 study for obstructive sleep apnea (OSA) in 2025.
Sana Biotechnology Announces Positive Six-Month Clinical Results from Type 1 Diabetes Study of Islet Cell Transplantation Without Immunosuppression
Groundbreaking First-in-Human Study Establishes Potential to Treat Type 1 Diabetes by Transplanting Insulin-Secreting Cells Without Immunosuppression
Six-Month Patient Follow-up Results Demonstrate that Sana’s Transplanted Pancreatic Islet Cells Modified with its Hypoimmune (HIP) Technology are Safe and Well-tolerated, Survive, Evade Detection by the Immune System, and Continue to Produce Insulin in the Patient
Function and Persistence of Pancreatic Islets Were Detectable by Production of Consistent Levels of Circulating C-Peptide, a Marker of Insulin Production, and Increased C-Peptide Levels with a Mixed Meal Tolerance Test (MMTT)
MRI Show Signals Consistent with Graft Survival Six Months after Transplantation
Study Continues to Evaluate Safety, Survival, and Function of Transplanted Cells
Data Shared at an Invited Presentation at the 85th Annual American Diabetes Association (ADA) Scientific Sessions Today
Sana is Incorporating the Tested Immune Evasion Technology to Develop SC451, a HIP-modified, Stem Cell-Derived Therapy as a One-Time Treatment for Patients with Type 1 Diabetes, with a Goal of Normal Blood Glucose, with No Insulin and No Immunosuppression
Sana Biotechnology, Inc. this past week announced six-month follow-up results from an investigator-sponsored, first-in-human study transplanting UP421, an allogeneic primary islet cell therapy engineered with Sana’s hypoimmune (HIP) technology, into a patient with type 1 diabetes without any immunosuppression. The study is being conducted in partnership with Uppsala University Hospital. The results are consistent with and build upon the previously reported four-week and 12-week clinical results. Results of the study at six months after cell transplantation demonstrate the survival and function of pancreatic beta cells as measured by the presence of circulating C-peptide, a biomarker indicating that transplanted beta cells are producing insulin. C-peptide levels also increase with a mixed meal tolerance test (MMTT), consistent with insulin secretion in response to a meal. 12-week PET-MRI scanning also demonstrated islet cells at the transplant site, a forearm muscle. The study identified no safety issues, and the HIP-modified islet cells evaded immune responses.
“As an endocrinologist who has dedicated my career to improving outcomes for patients with type 1 diabetes, I am pleased to share these exciting results. Consistent with the previously reported four-week and 12-week data, we believe today’s six-month update continues to suggest that a functional cure for type 1 diabetes without immunosuppression is possible,” says Per-Ola Carlsson, MD, study principal investigator, senior physician and professor at the Clinic for Endocrinology and Diabetology at Uppsala University Hospital. “These groundbreaking results build upon the extensive preclinical and translational studies of Dr. Sonja Schrepfer and the team at Sana and provide hope for a cure. We look forward to continued follow-up, with study results submitted for publication in a peer-reviewed journal.”
“Durable survival, function, and immune evasion of transplanted allogeneic pancreatic islet cells with no immunosuppressive medicines, particularly in the context of a pre-existing autoimmune response to these cells, represents a transformative and necessary step to making cellular and transplant medicine more accessible,” says Steve Harr, MD, Sana’s president and CEO. “Type 1 diabetes currently impacts over nine million people globally, and there have been relatively few transformational advances in this disease since the discovery of insulin over 100 years ago. The data presented today bring our vision—treating diabetes with a broadly available therapy leading to normal blood glucose control without either insulin or immunosuppression—closer to reality. We are incorporating the immune evasion learnings and technology from the current UP421 trial to develop SC451, a HIP-modified, stem cell-derived islet cell therapy, for which we intend to file an investigational new drug application (IND) as soon as next year.”
Aaron J. Kowalski, PhD, CEO of Breakthrough T1D (previously known as JDRF), adds, “A paradigm shift in the treatment of diabetes is long overdue. For more than a century, exogenous insulin administration has remained the only therapy for this chronic disease. Significant improvements in insulin therapy, like automated insulin delivery systems, have improved outcomes for many living with this disease. Yet, most people with type 1 diabetes are still unable to achieve ideal glucose levels, heightening the risk of many complications, including cardiovascular disease, kidney disease, and more. The prospect of administering insulin-producing cells into people with this disease—enabling stable glycemic control without lifelong injections, drugs that suppress their immune system, or constant daily management—represents a transformative and potentially life-changing breakthrough. We are extremely grateful for the collaborative efforts of the research teams at Sana, Uppsala University Hospital, and all those involved, for their dedication to this work. The entire team at Breakthrough T1D looks forward to working with Sana and others to ensure all members of the T1D community can benefit from these life-changing breakthroughs.”
Primary islet cell transplantation with immunosuppression is an established procedure in type 1 diabetes in which allogeneic pancreatic islet cells are isolated from a deceased donor’s pancreas and transplanted into a patient with a goal of normal blood glucose control and insulin independence. As with whole-organ transplants, suppression of the recipient’s immune system has historically been required to prevent immune rejection of the allogeneic transplanted cells and resurgence of the inciting autoimmune attack. Sana’s HIP technology is designed to overcome immunologic rejection of allogeneic cells, and in type 1 diabetes, to evade the autoimmune rejection of pancreatic beta cells as well. UP421 cells were transplanted with no immunosuppression, and the survival of those islet cells provides evidence that they evade both allogeneic and autoimmune detection.
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