Novel approaches include bifunctional peptide-based drugs
Obesity has become a devastating pandemic, with 108 million obese children and 604 million obese adults worldwide in 2015, and the problem is increasing (1). The result is an escalation in serious conditions such as type 2 diabetes mellitus (T2DM), cardiovascular disease, hypertension, dyslipidemia and several cancer forms, mainly gastrointestinal. Obesity is very difficult to treat through life style changes and surgery has become the most effective and long-lasting route to sustained weight loss, although it is only available to a small subset of individuals, and is both costly and risky. The search for more widely applicable treatment has driven the development of peptide-based pharmaceuticals that can meet key challenges of obesity, including control over satiety, blood sugar and LDL cholesterol levels.
GLP-1 provides new possibilities
One druggable route was identified through the discovery that surgical procedures such as gastric bypass, gastric banding or sleeve gastronomy, resulted in increased secretion of glucagon-like peptide 1 (GLP-1) by the intestinal L-cells after food intake. GLP-1 directly acts on the β-cells to raise glucose-stimulated insulin secretion and also through the central nervous system to lower food intake.
The role of GLP-1 in metabolic syndrome has lead to massive efforts in academic research and also pharma to map out its function and metabolism. The peptide is rapidly degraded by peptidases such as dipeptidyl peptidase-4 (DPP-4), which has driven the development of analogs that can resist attack. The activity of GLP-1 has also been improved with slow release formulations and genetic fusion with a long half-life carrier protein such as an antibody Fc or serum albumin. These efforts have resulted in the development of GLP-1 analogs such as liraglutide (Novo Nordisk) and dulaglutide (Eli Lilly) that can reduce glycated hemoglobin, lower body weight, and lower the risk of cardiovascular disease.
Dual-purpose treatment with GLP-1 fusion constructs
A more advanced approach involves fusing GLP-1 analogs with agents that address other aspects of the obese condition. The result is a broad range of polypharmacological drugs that combine the beneficial effects of several independent hormones into a single entity (2). One approach that has been pursued by a research group at MedImmune (now AstraZeneca) is the fusion of a GLP-1 analog with an antibody against a serum protein PCSK9 that binds to the LDL receptor, promoting its degradation and leading to increased LDL-C levels (3). Anti-PCSK9 antibodies such as evolocumab (Amgen) and alirocumab (Regeneron Pharmaceuticals and Sanofi) block the PCSK9–LDL receptor interaction and reduce LDL-C levels, and also have an additive effect with statin therapy to reduce the risk of cardiovascular disease.
The team at MedImmune started by constructing a panel of fusions involving a DPP-4-resistant GLP-1 analog and a series of PCSK9 antibodies and linkers, leading to the development of a candidate, MEDI4166. Challenges included improving the in vivo stability of the GLP-1 analog and balancing its activity with the anti-PCSK9 effect of its fusion partner. The activities of the fusion candidates varied greatly, probably due to steric hindrance. Pharmacokinetics studies of early fusion constructs showed that GLP-1 receptor activity decreased quickly due to peptide degradation. Designing an analog that would resist all peptidases was impractical, so the team adopted a general approach by creating a disulfide bridge between the peptide and the linker, or by adding an N-linked carbohydrate moiety. Using Gyrolab system to measure Fc concentrations in the PK studies, and to measure free PCSK9 levels in cynomolgus monkey serum, the team could show that MEDI4166 had the expected effect on T2DM mouse models and could also lower LDL-C levels in primates. The next challenge was to test MEDI4166 in humans.
Doses of MEDI4166 in the first-in-human test on patients with T2DM were based on a PK/PD model with the expectation that the suppression of PCSK9 would be similar to that achieved using alicorumab, and GLP-1 activity comparable to treatment with liraglutide and dulaglutide (4). Gyrolab system was used to measure serum levels of MEDI4166. The drug candidate was well tolerated, with immunogenicity that did not affect safety, PK or PD, and the suppression of PCSK9 was almost complete, with a sustained decrease in plasma LDL cholesterol. The problem was that an imbalance in the pharmacology that had not been predicted from the pre-clinical studies meant that the GLP-1 activity did not control glucose levels, and the clinical development had to be discontinued.
Resolving the ambiguity around GIP
Another player in the metabolic field is gastric inhibitory peptide (GIP), a physiological incretin and partner to GLP-1 that has so far failed to become a therapeutic agent. The stimulation of insulin production by GIP receptor agonism drops in modest hyperglycemia and this is reversed with improved glycemic control. This has prompted efforts to integrate agonism at both GLP-1 and GIP receptors (GLP-1R and GIPR, respectively) such that the former primes the latter to deliver a more optimal reversal of the metabolic syndrome. Two peptides, NNC0090-2746 (Novo Nordisk) and LY3298176 (Tirzepatide, Eli Lilly), with high potency dual incretin agonism have advanced to multi-dose clinical studies, with preclinical and clinical results showing improved glycemic control and reduction in body weight that exceeds what can be achieved with comparable dosing of benchmark GLP-1R specific agonists.
Despite these beneficial clinical results of combinatorial therapy, the pharmacological effect of GIP alone to lower body weight has not been adequately addressed. Researchers at Novo Nordisk therefore studied whether structurally improved GIP analogs could lower body weight of an obese mouse model through agonism or antagonism (5). To do this, they systematically studied the impact of acute and chronic treatment of non-diabetic, genetically wild type, diet-induced obese mice with peptide GIPR agonists optimized for sustained activity, and synthesized by automated Fmoc/t-Bu solid-phase synthesis using Symphony® peptide synthesizer from Gyros Protein Technologies. They found that chronic administration lead to modest weight loss, even in mice lacking GLP-1R, but not in mice lacking GIPR. Peptide-based GIP analogs designed as agonists rather than antagonists can therefore stimulate a moderate weight loss, making them promising candidates for the treatment of obesity in combination with other agonists such as GLP-1 analogs.
The search continues
The scale of the obesity problem continues to drive pharma in the search for novel approaches of treatment. Eli Lilly is focused on diabetes and diabetes-related diseases, with insulins and glucagon products, novel GLP-1 and dual-acting GLP-1 mimetics and combinations that can alleviate cardiovascular disease. MedImmune, now AstraZeneca, continues with new drug candidates, such as the oxyntomodulin-like peptide, MEDI0382, which has a novel dual targeting action. Oxyntomodulin is a peptide hormone released from the post-prandial gut that activates both the GLP-1 and glucagon receptors. The Phase IIa data looks promising for potent glucose-dependent glycemic control, marked weight loss and reduction in liver fat. Meanwhile, with more than 95 years of innovation and leadership in diabetes care, Novo Nordisk has several candidates in the pipeline, including molecule 1706, a triple full agonist of native GLP-1, GIP and glucagon receptors, and molecule 1177, a novel glucagon-GLP-1 co-agonist. The search continues.
- Health effects of overweight and obesity in 195 countries over 25 years. GBD 2015 Obesity Collaborators, Afshin A, et al. N Engl J Med. 2017 Jul 6;377(1):13-27. doi: 10.1056/NEJMoa1614362. Epub 2017 Jun 12. https://www.ncbi.nlm.nih.gov/pubmed/28604169
- Are peptide conjugates the golden therapy against obesity? Brandt SJ et al, J Endocrinol. 2018 Aug;238(2):R109-R119. doi: 10.1530/JOE-18-0264. Epub 2018 May 30. https://www.ncbi.nlm.nih.gov/pubmed/29848610
- Engineering of a GLP-1 analogue peptide/anti-PCSK9 antibody fusion for type 2 diabetes treatment. Chodorge M et al, Sci Rep. 2018 Dec 3;8(1):17545. doi: 10.1038/s41598-018-35869-4. https://www.ncbi.nlm.nih.gov/pubmed/30510163
- Randomised, phase 1, dose-finding study of MEDI4166, a PCSK9 antibody and GLP-1 analogue fusion molecule, in overweight or obese patients with type 2 diabetes mellitus. Jain M et al, 2019 Mar;62(3):373-386. doi: 10.1007/s00125-018-4789-6. Epub 2018 Dec 28. https://www.ncbi.nlm.nih.gov/pubmed/30593607
- Optimized GIP analogs promote body weight lowering in mice through GIPR agonism not antagonism. Mroz PA et al, Mol Metab. 2019 Feb;20:51-62. doi: 10.1016/j.molmet.2018.12.001. Epub 2018 Dec 5. https://www.ncbi.nlm.nih.gov/pubmed/30578168