June, 2017

Focus – Management of Weight Sweetly!

Weight management by approved drugs Belviq / Belviq XR (Arena/ Eisai, June 2012 & XR – July 2016; Net sales FY16A: ¥3.7bn/ ~$33.4mn), Qsymia (Vivus, July 2012; Net sales FY16A: $48.5mn), and Contrave/ Mysimba (Orexigen/ Kwang Dong Pharma/ Valeant pharma/ Laboratorios Farmacéuticos Rovi, S.A., Sept. 2014; Net sales FY16A: $33.7mn) for obesity have failed to live to their blockbuster expectations primarily due to poor compliance, safety, patient satisfaction and reimbursement issues. New treatments for obesity that are both better tolerated and more efficacious are urgently needed.

The current prevalence of 7–10% of obesity in children and adolescents; is predicted to at least double by 2025 and there is strong evidence of persistence into adulthood.  Obesity has been a “graveyard” for the drug industry in the past and to succeed in developing drugs that control body weight following surgical intervention, it appears that a new paradigm is needed.

Improvements in the understanding of peptidergic signalling of hunger and satiety from the gastrointestinal tract mediated by Ghrelin, CholeCystoKinin (CCK), Peptide YY (PYY) and Glucagon-Like Peptide-1 (GLP-1), and of homeostatic mechanisms related to leptin and its upstream pathways in the hypothalamus, have opened new possibilities.

Pharma companies appear to be adopting different strategy for controlling the growing diabetic and obese populations.  Target both glucose control and weight (marginal but stable weight loss) with a single drug or new combinations. Some combination approaches using peptides and small molecules have now reached clinical trials, although regulatory large challenges lie ahead.  However, optimism prevails and in future a poly-therapeutic strategy could possibly rival surgery in terms of efficacy, safety and sustainability of weight loss

Leading in this race is Novo Nordisk, which already has one approved GLP, Saxenda (liraglutide). Liraglutide has been FDA-approved since 2010 for diabetes and the FDA approved higher dose of liraglutide (Saxenda) for weight-loss in 2014.  Saxenda is an approved, prescription injectable medicine that, when used with a low-calorie meal plan and increased physical activity, may help some adults with excess weight who also have weight-related medical problems (such as high blood pressure, high cholesterol, or type 2 diabetes).  Novo recently presented three years data showing that liraglutide helped obese and prediabetic patients lose weight without undue risk.

Novo’s next big hope in obesity is an improved GLP-1 drug, semaglutide, that is being tested for both types of diabetes and which could reduce weight significantly more than the 5 to 10 percent seen with Saxenda.  “What will really open the obesity market? Is efficacy to get towards 15% for the market to fully open up?”

Novo is building up a portfolio of such drugs, with seven obesity compounds in clinical testing, out of 17 experimental medicines overall in trials.  Most are still in early-stage of development. Novo projects use a variety of different natural body signals to control appetite, including the first tri-agonist drug, targeting three different pathways, which recently entered initial Phase I testing.

Like Novo, several other major players in the diabetes area have recently struck collaborations to control obesity and diabetes/sugar with a similar strategy.  “Dual/Multi control” seems to be the flavour of the year!

Lilly and KeyBioscience AG have agreed to a new collaboration focused on the development of Dual Amylin Calcitonin Receptor Agonists (DACRAs), a potential new class of treatments for metabolic disorders such as type 2 diabetes.  The dual activation of calcitonin and amylin receptors is thought to improve insulin sensitivity, suppress food intake, reduce fat deposition, improve blood glucose levels and cause weight reduction.  The collaboration includes access to the DACRA platform with multiple molecules including KBP-042, KBP-089 and KBP-056.  KeyBioscience has initiated Phase 2 development with KBP-042.  Other assets included in the collaboration, engineered for differences in effect or potency, range from Phase 1 to pre-clinical.  Lilly will receive worldwide rights to develop and commercialize these molecules.  In exchange for these rights, KeyBioscience will receive an initial payment of $55mn and is eligible for additional potential development, regulatory, and commercialization milestones, as well as tiered royalty payments on future sales.

Sanofi and Exscientia, an innovative company at the forefront of Artificial Intelligence driven drug discovery, announced a strategic research collaboration (€250mn/milestones), and licence option agreement with Sanofi in the metabolic disease area.  Exscientia will apply its unique platform to identify and validate combinations of drug targets that could work synergistically and be amenable to Exscientia’s powerful bispecific-small-molecule design strategy – where a small molecule is designed to be compatible with two distinct drug targets.  Bispecific small molecules passing all these quality gates may progress to full candidate delivery projects for Sanofi.  Rapid delivery of multiple bispecific opportunities will be empowered by a pipeline of Exscientia’s capabilities driven by Artificial Intelligence and enabled automated design.

Numab AG and Intarcia Therapeutics announced a strategic collaboration for developing once- or twice-yearly mono-specific and multi-specific antibodies addressing diabetes, obesity and autoimmune indications. Collaboration combines Intarcia’s unique delivery and formulation technologies with Numab’s novel multi-specific antibody technology and will be uniquely positioned to address unmet needs.  The first results of this collaboration − a product candidate combining ITCA 650 with a proprietary antibody fragment − is expected to enter human clinical trials in 2018 for the treatment of diabetes and obesity.  Numab is eligible to receive upfront and contingent milestone payments, as well as tiered single to low double-digit royalties on any sales resulting from collaborative efforts.

Janssen Pharma partnered with the University of California San Diego School of Medicine to identify mechanisms, pathways, biomarkers, targets and gastric bypass approaches to treat obesity, NASH, chronic kidney disease (CKD) and metabolic liver disease.  The multi-project collaboration will use animal and cell models.

To control obesity, the best drug combinations will need to target more than just hunger and satiety. We believe this is just the beginning and expect more pharma companies to join the race to innovate and address the obesity epidemic in future through other novel approaches. Detailed research report follows as more drugs enter the clinic.