Welcome to the session, FDA Updates on Endocrinology, Diabetes, and Obesity. My name is Mata Bnyadi. I'll be serving as your moderator today. You'll be hearing talks from Drs. Naomi Laue, Laura Higginbotham, and myself. Following the talks, Drs. Brisa Kehoe and Lisa Yanov will join us for a Q&A and panel discussion, during which we'll take your questions. Before we move on, I would like to briefly introduce our speakers and panelists. Dr. Naomi Laue is a Deputy Director of the Division of General Endocrinology within the Office of New Drugs under the Center for Drug Evaluation and Research, or CDER, at FDA. Prior to her current role, she served as a Deputy Director in the Division of Anesthesiology, Addiction Medicine, and Pain Medicine. Dr. Laue is an adult endocrinologist and completed her fellowship in endocrinology, diabetes, and metabolism at New York University. Dr. Laura Higginbotham is a physician in FDA's Division of Diabetes, Lipid Disorders, and Obesity within CDER's Office of New Drugs and is involved in the clinical review of products intended to treat obesity and hyperlipidemia. She received her medical degree from the University of Virginia and completed a preventive medicine residency at the University of North Carolina. She's board certified in public health and general preventive medicine. Dr. Lisa Yanov is the Director of the Division of Diabetes, Lipid Disorders, and Obesity, and Dr. Teresa Kehoe is the Director of Division of General Endocrinology. Both divisions are within the Office of Cardiology, Hematology, Endocrinology, and Nephrology under CDER's Office of New Drugs. Both will join us during the panel discussion. Now we'll go ahead with the presentations. Thank you. Good evening. My name is Mata Abnyadi. I'm a physician in the Division of Diabetes, Lipid Disorders, and Obesity at the FDA. I perform clinical reviews for the diabetes group. I thank you for this opportunity to present today. In this talk, I'm going to briefly discuss some of our recent approvals in the past year, which include new indications for some of the GLP-1 agonists and new approvals for insulin and antihyperglycine products. First, I'll discuss the new indications for a couple of GLP-1 agonists, Lozempic and Trulicity. Lozempic, which is the brand name for semaglutide injection, was first approved in 2017 as an adjunct to diet and exercise to improve glycemic control in adults with type 2 diabetes. In 2020, it was approved to reduce the risk of major adverse cardiovascular events, or MACE, in adults with type 2 diabetes and established cardiovascular disease. In the next couple of slides, I'll discuss the study design and results of SUSTAIN-6, the cardiovascular outcome trial in which the approval for the new indication was based. SUSTAIN-6 was a randomized, double-blind, placebo-controlled cardiovascular outcomes trial comparing the risk of MACE between Lozempic and placebo when these were added to standard of care treatment. Over 3,000 patients were randomized to Lozempic or placebo, administered subcutaneously once a week. Over 80% of the patients enrolled in the study had a history of established cardiovascular disease, while only 17% were at high risk but without known cardiovascular disease. The primary endpoint, the three-point MACE composite, was a time to first occurrence of cardiovascular death, nonfatal MI, or nonfatal stroke. After a median follow-up time of about two years, 6.6% versus 8.9% of the Lozempic and placebo groups, respectively, contributed an event with a hazard ratio of 0.74 and upper bound with a confidence interval of 0.95. These results provided sufficient evidence to support approval of Lozempic to reduce MACE in adults with type 2 diabetes and established cardiovascular disease. Tulicity or dulacotype, another GLP-1 agonist, was first approved in 2017 as an adjunct to diet and exercise to improve glycemic control in adults with type 2 diabetes. In 2020, Tulicity was approved to reduce the risk of MACE in adults with type 2 diabetes with or without established cardiovascular disease. The approval was based on the REWIND outcome trial, which I'll briefly discuss next. Of note, Tulicity is the first antihyperglycemic product approved to reduce cardiovascular events in adults with or without established cardiovascular disease. The REWIND trial was a randomized, placebo-controlled, double-blind trial. Over 9,000 adult patients with type 2 diabetes and established cardiovascular disease or multiple cardiovascular risk factors were randomized to Tulicity 1.5 mg or placebo administered subcutaneously once a week, both added to standard of care. The primary outcome was the first occurrence of the composite endpoint of nonfatal MI, nonfatal stroke, or death from cardiovascular causes. After a median follow-up duration of 5.4 years, the primary composite outcome occurred in 12% and 13.4% of the patients treated with Tulicity and placebo, respectively. Tulicity significantly reduced the risk of first occurrence of the primary composite endpoint with a hazard ratio of 0.88 and upper bound of 0.99 in the overall population. About 63% of the randomized patients had multiple cardiovascular risk factors or without established cardiovascular disease. Now I'll switch to the recently approved insulin products. Semgli is an insulin-enlarging product, a long-acting insulin analog. It has similar labeling to Lantus, and it's approved to improve glycemic control in adults and pediatric patients with type 1 diabetes and in adults with type 2 diabetes. It's important to note that Semgli is not considered a biosimilar insulin. Rather, a follow-on insulin product that relied on FDA's findings of safety and effectiveness for Lantus for its approval. Lumja is a new formulation of insulin Lispro. This product is formulated with insulin Lispro, but also has two excipients that accelerate the absorption of insulin Lispro from the injection site, resulting in a faster insulin type action profile compared to Humalox. Next, I'll touch upon some of the newly approved glucagon and glucagon analog products. Zegalog, a glucagon analog, was approved as rescue for treatment of severe hypoglycemia in diabetic patients. Gvoke and Voxamy, both are glucagon products, approved as rescue for treatment of severe hypoglycemia in diabetic patients. All three products are ready-to-use formulations that don't require reconstitution prior to injection, unlike the older marketed glucagon products. Next, my colleague, Dr. Higginbotham, will present the recently approved products for lipid disorders. Hello, I'm Laura Higginbotham, a physician within FDA's Division of Diabetes Control Hello, I'm Laura Higginbotham, a physician within FDA's Division of Diabetes, Lipid Disorders, and Obesity. During my session, I will provide several updates on notable approvals and withdrawals of drugs intended to treat lipid disorders and obesity. Next slide. During the previous year, notable lipid-lowering approvals included an oral non-statin drug for LDL-C reduction, a treatment for homozygous familial hypercholesterolemia, or HOFH, that utilizes a novel mechanism of action. Next slide. And an expanded indication for a previously approved PCSK9 inhibitor. I will discuss these approvals further in the subsequent slides. Next slide. Next slide. Bempidoic acid is a first-in-class ACL inhibitor that is administered orally. It is indicated as an add-on treatment to maximally tolerated statins in adults with HEFH or established cardiovascular disease who require additional LDL-C reduction. Next slide. In two 52-week randomized controlled trials, Bempidoic acid, as add-on therapy to maximally tolerated statins, reduced LDL by an additional 17% to 18% compared to placebo. The most common adverse reactions associated with Bempidoic acid include upper respiratory tract infections, muscle spasms, and increased uric acid. In clinical trials, Bempidoic acid was also associated with tendon rupture, gout, and changes in multiple lab parameters, including increased BUN and creatinine, decreased hemoglobin and anemia, elevated liver enzymes, and increased CK. Next slide. Evanocumab is a recombinant human monoclonal antibody administered by IV infusion. It is approved for patients 12 years and older with HOFH, a genetic condition that causes severely high cholesterol and often results in premature cardiovascular disease. Evanocumab reduces LDL by a novel mechanism of action that is independent of the LDL receptor. This new mechanism may be important for HOFH patients who do not often respond to lipid lowering therapies that reduce LDL through upregulation of the LDL receptor, such as statins or PCSK9 inhibitors. This is because HOFH patients typically lack a functional LDL receptor. Next slide. In a single 24-week double-blind trial in 87 patients with HOFH, Evanocumab reduced LDL by 49% compared to placebo. The most common adverse reactions associated with Evanocumab include nasal pharyngitis, influenza-like illness, and dizziness. Evanocumab is also associated with serious hypersensitivity reactions, including anaphylaxis, and is likely teratogenic based on data from animal studies. Females of reproductive potential should consider pregnancy testing prior to treatment initiation and should use contraception throughout treatment. Next slide. Lastly, Alirocumab is a PCSK9 inhibitor already approved in adults for the treatment of primary hyperlipidemia and CV risk reduction. During the last year, Alirocumab received a new indication for the treatment of adults with HOFH. The recommended dose for treatment of HOFH patients is 150 milligrams every two weeks. Next slide. Next, I'll provide updates on drugs for the treatment of obesity. Notable approvals include the first drug approval for pediatric obesity since Orlistat and approval of the first weight management treatment for patients with certain rare genetic conditions. Over the next several slides, I will discuss these approvals. Next slide. Next slide. Loraglutide is a GLP-1 agonist previously approved for chronic weight management in adults as Bexsenda and for type 2 diabetes and CV risk reduction as Victoza. In December, Loraglutide was also approved for chronic weight management in pediatric patients 12 years and older. Next slide. In a 56-week trial, Loraglutide reduced body weight by 5% compared to placebo. Additionally, over 40% of pediatric patients experienced a reduction in baseline BMI of 5% or more. The adverse reaction profile of Loraglutide in pediatrics was generally similar to that in adults. The most common adverse reactions experienced in the pediatric population include nausea, vomiting, diarrhea, and hypoglycemia. Next slide. Cetmelanotide is an MC4R agonist that was approved for weight management in patients with genetically induced obesity due to deficiencies in POMC, PCSK1, or LEPR. Cetmelanotide safety and efficacy were evaluated in two one-year open-label trials. At one year, 10 patients with POMC or PCSK1 mutations experienced a mean reduction in baseline weight of 23%, and 11 patients with LEPR mutations experienced a mean reduction in baseline weight of 10%. Cetmelanotide is associated with disturbances in sexual arousal, depression and suicidal ideation, and increased skin pigmentation. Next slide. Finally, one obesity drug, lopathrin, was voluntarily withdrawn at FDA's request in February 2020 due to an imbalance in cancers observed in a large cardiovascular outcomes trial. During the five-year trial, 7.7% of patients treated with lopathrin were diagnosed with cancer, compared to 7.1% of patients treated with placebo. Various cancer types were reported, and pancreatic, colorectal, and lung cancer occurred more frequently in the lopathrin treatment arm. Patients who were taking lopathrin do not require special cancer screening, but should follow standard cancer screening recommendations, as with any individual patient. Next slide. That concludes my brief overview of notable new approvals and withdrawals of drugs for the treatment of lipid reduction and weight management. Thank you for watching, and I look forward to answering your questions during the live Q&A session. Hello, my name is Naomi Lowy, and I am the Deputy Director in the Division of General Endocrinology, which I'll also refer to as DGE. I am an adult endocrinologist, and have spent the better part of my career at FDA regulating drugs for endocrine diseases. Thank you for inviting us to share an update on our activities in our division. Today in my brief talk, I will describe the recent formation of our division, and will lead you through some notable actions that we have taken this year, both for general endocrine conditions, as well as bone disease. The Office of New Drugs in the Center for Drugs at FDA has recently undergone a reorganization, and our division was formed just about one year ago. The division was stood up by combining the general endocrinology team from the former Division of Metabolism and Endocrinology Products, known as DMEP, and the bone team from the former Division of Bone, Reproductive, and Urology Products. Here is a figure that shows how the former Division of Metabolism and Endocrinology Products split into our division, general endocrinology, and the Division of Diabetes, Lipids, and Obesity, or DDLO. Not shown in the slide, but there is also a new division of urology, obstetrics, and gynecology that retains the products for reproductive, gynecologic, and urologic health. One of the purposes of the reorganization was to group related therapeutic areas in the same office, so we are now one of four divisions within this office, with the Division of Cardiology and Nephrology, the Division of Nonmalignant Hematology, and the Division of Diabetes, Lipids, and Obesity, and you'll be hearing next from my colleagues in DDLO. This is our current leadership team in the Division of General Endocrinology. Teresa Kehoe is our very knowledgeable and committed director, and we have two outstanding team leads, Marina Zemskova and Shannon Sullivan, all endocrinologists who have worked and trained in the D.C. area for many years. Our division also has a strong multidisciplinary team of other clinicians, clinical pharmacologists, pharmacologists, toxicologists, statisticians, project managers, and other disciplines who all collaborate to do the important work the public interests us with. Our goals in DGE are to facilitate drug development to treat general endocrinology and bone disorders, to ensure that treatments for endocrinology and bone disorders are safe, effective, and available, and to communicate clearly with professional and patient communities and the general public. These are the areas we regulate, and apart from the general endocrine disorders and bone diseases, our division regulates cachexia, geriatric frailty, and sarcopenia, as well as vitamin deficiencies. And now, as of this year, our division reviews investigational new drugs for chronic, nonspecific, post-COVID-19 symptoms. Now, we'll go through some recent notable approvals and labeling changes for the drugs that we regulate. Starting in the acromegaly space, last year saw the first approval for an oral octreotide. Our division also approved the first weekly growth hormone for adults. And for patients with Cushing's disease, we approved the first drug to specifically affect cortisol synthesis as a lidrostat. And a little more about this drug. It is an inhibitor of cortisol synthesis via inhibition of 11-beta-hydroxylase. It is given orally. As a lidrostat is indicated for patients who either cannot undergo pituitary gland surgery or who have undergone surgery but still have the disease. The drug was evaluated in a 24-week open-label study followed by a randomized withdrawal period. The safety and efficacy of this drug was supported by a 48-week study which included patients with Cushing's disease who had persistent or recurrent disease despite pituitary surgery. The study also enrolled de novo patients for whom surgery was not indicated or who had refused surgery. There were 137 patients who entered an open-label period in which doses could be titrated and were then maintained on that dose. At the end of the 24-week open-label period, about half of the subjects had normal cortisol levels. And at this point, 71 patients who did not require further dose increases and who tolerated the drug endured an 8-week randomized withdrawal period in which they continued to either receive drug or were switched to placebo. This table from the drug label summarizes the results of the primary efficacy endpoint, which was the complete responder rate at the end of the 8-week randomized withdrawal period. You can see that 86% of those patients receiving drug continue to maintain cortisol levels within normal limits compared to 30% of patients taking placebo. Here are some other approvals that are notable, not because they are novel in their mechanisms, but their approvals and availability represent formulations that are of particular benefit for the pediatric population. First, for the treatment of pediatric patients with central precocious puberty, we approve Luprolide for deposed suspension for subcutaneous use. This is the standard of care treatment, but with less frequent dosing every six months and avoidance of intramuscular injection. For adrenocortical insufficiency, we approve the first pediatric formulation that also allows delivery of lower doses that this population requires. This drug is approved as immediate release oral granules in doses of 0.5 milligram, 1 milligram, 2 milligram, and 5 milligrams contained in capsules. Now, I'll shift to some important labeling changes that we've approved recently, starting with thyrogen. In this label, we remove the previous limitation of use that stated that the effect of thyrogen on long-term thyroid cancer outcomes has not been determined. This change followed submission and review of data from two long-term trials that compared thyroid cancer recurrence rates after radioactive iodine ablation with thyrogen compared to thyroid hormone withdrawal. Based on those data, the current limitation of use now reads the effect of thyrogen on thyroid cancer recurrence rate recurrence greater than five years post remnant ablation has not been evaluated. Moving to notable approvals in the bone disease space, let's start with borosimab for the treatment of hypophosphatemia in tumor-induced osteomalacia. This drug was first approved in 2018 for the treatment of X-linked hypophosphatemia. Now, this is the second indication added for this drug. This approval is specifically for the treatment of FGF23-related hypophosphatemia in tumor-induced osteomalacia associated with phosphaturic mesenchymal tumors that cannot be curatively resected or localized in adult and pediatric patients two years of age and older. The approval of this indication was based on two open-label studies in a total of 27 patients. For the first study, half of patients achieved normal phosphate levels through week 24 and maintained normal or near-normal phosphate levels through week 144. In the second study, 69 percent of participants achieved normal phosphate levels through week 24 and maintained normal or near-normal phosphate levels through week 88. The results of bone scans for patients in the first study also suggested healing of the bone lesions related to osteomalacia. Here is a figure from the label looking at mean phosphorus levels, which clearly normalized over the course of the study. Moving to labeling changes, the Forteo label has a couple of notable recent changes. The first involves the boxed warning, often referred to outside of FDA as the black box, that described the risk of osteosarcoma. The language in the box was removed, but is still described in the warnings and precautions section of the label. There were many data that supported the box removal. There were two case series studies that did not identify a safety concern for osteosarcoma. In addition, there has been a patient registry in place since approval, which enrolled over 71,000 teriparatide users. The findings from this registry did not suggest a risk for osteosarcoma. Finally, we have post-marketing safety surveillance in a population of nearly two and a half million patients who have been treated with teriparatide. The number of spontaneous reports of confirmed osteosarcoma for patients who took teriparatide did not appear to exceed the predicted background incidence. In addition, the previous label recommended that the duration of use should not exceed two years. This limitation dates back to the original trials being limited to two years, when an osteosarcoma signal became evident in rat studies. The current label now reads that use of Forteo for more than two years during a patient's lifetime should only be considered if a patient remains at or has returned to having a high risk for fracture. This change was supported by the post-marketing safety data, which did not suggest an increased risk of osteosarcoma associated with teriparatide use up to two years. Although the safety data were critical to supporting the change, we also considered efficacy data to understand if there is continued benefit. Therefore, the change was also supported by data from a phase three clinical trial that showed a continued increase in lumbar spine bone mineral density compared to baseline in patients treated with teriparatide 20 micrograms daily up to 36 months. Finally, the label for denosumab has been updated to reflect reports of vertebral fracture following discontinuation of the drug. This language is now in the warnings and precautions section of the label. Multiple vertebral fractures have been reported following prolia discontinuation. Patients should be transitioned to another antiresorptive agent if prolia is discontinued. Those are our specific regulatory updates, and I hope they are informative and useful to you. Now that I've taken you through some of the highlights from the past year, I'd like to leave you with a few thoughts about the present and the future and some of the things we're working on in the regulatory space to support drug development for much needed areas. These include work that we've been doing to validate bone mineral density as a surrogate endpoint for fracture for osteoporosis therapeutic trials. We've also been actively working on refining endpoints for cachexia and sarcopenia indications. And finally, we will continue to provide advice and review development programs for treatment of chronic post-COVID symptoms. I thank you for your attention, and we look forward to future interaction, discussion, and collaboration. Thank you. Thank you to all our presenters on this very informative topic. We'll go ahead and open the floor for Q&A. Please type your questions into the chat if you have any. If there are no questions, then I'm going to thank on behalf of the FDA for everyone who has participated. We appreciate your participation in this session, and I think this is all the time we have for today's session. Thank you. Thank you. Thank you. So, I see that some questions are rolling in. One of the questions I see is, if you stop Prolea because of renal failure, what would be the replacement? If Dr. Kehoe or Dr. Lowey would like to chime in. Sure. This is Teresa Kehoe. So, Prolea would be the main anti-resorptive medication in the setting of renal failure. For the bisphosphonate medications, there is a concern of renal toxicity, especially with zoledronic acid or Reclast. With the other oral bisphosphonates, they have recommendations not to use with a creatinine clearance of 30 or 35. However, that's mainly because they have not been studied. So, I think for patients with renal failure and osteoporosis that you would have to start thinking about whether an anabolic agent may be beneficial, such as Corteo or Abaloperatide or even Romazosumab. Thanks a lot. We have another question about Cahexia. What are the chances that something will be available to treat Cahexia? For Cahexia? Was that the question? Yes. So, certainly this is a very hot topic, mostly in the space of cancer Cahexia. I can't give you a date of when things might happen. What I can tell you is that it is a very active area of research and from regulatory submissions. So, there is hope in the horizon that there will be agents available for Cahexia. I will also add that it's a particular area of interest to the division. So, we are paying a lot of attention to it. It's important to us. So, stay tuned, but it's very much on our radar. Another question is, are you able to comment on HCG availability? I had to get back to that screen. So, unfortunately, HCG is not something that is regulated by the endocrine divisions. It is regulated by the reproductive and neurologic divisions. So, we cannot really comment because we don't deal in that space very often. Looks like there's another one for you, Teresa. Any idea about approval timeline for modified release hydrocortisone in the U.S.? So, certainly, again, this is a space that's active. I would never assume to try to give information about timelines. Certainly, there are companies that are looking into this. So, we would expect to get applications in the future, but I really can't really say much about timeline. I think one of the things that our colleagues have to recognize for FDA is there are a lot of things like that that we cannot necessarily talk about because of confidentiality, that we cannot talk about specific drug products under review or in development. We can talk in general terms, but we really can't talk about specific products. Okay. I don't see any other questions. There's one that's a nice question. It's not about FDA, but does anyone know if there's an age limit on going back to do an endocrine fellowship? I'm not aware. I don't think there's an age limit. Yeah, I guess if they accept you, then you're in. Not up to us, though. Well, I think that's all the time we have for today's session. Again, thank you for participating, and we appreciate you. There's one more that just popped in. Oh, it did. And it's again for general endocrinology. It says that the question I would like to know, would Forteo be considered in CKD patients with osteoporosis, despite that they may have secondary hyperparathyroidism? I think that's a good question, and you'd have to look at the CDC. I think that's a good question, and you'd have to look at the CDC. I think that's a good question, and you'd have to look at the specific patient and exactly what the situation, how well-controlled their kidney disease is. Forteo and the PTH1 receptor agonist, like also a valoperatide, which is PTHRP and is not PTH, they can cause hypercalcemia, but it's a very short-acting. The half-life of the product is short-acting. So I think you have to look at the patient and what the status is of that patient in considering whether to give a PTH1 agonist to the patient. It's a good question, but I don't have a great answer for you. Okay, I don't see any additional questions. We have a few minutes left, but if there are no additional questions, then I guess this is the time we have for today's session. So thank you again for participating.

FDA

endocrinology

diabetes

obesity

GLP-1 agonists

lipid-lowering drugs

insulin products