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Is the pipeline for obesity therapies set to expand with waistlines
- 1. ANDREW FROST SENIOR ANALYST, CARDIOVASCULAR AND METABOLIC Wishful shrinking: Is the pipeline for obesity therapies set to expand with waistlines?
- 2. 2 Introduction During their Annual Meeting in 2013, the American Medical Association (AMA) voted to officially recognise obesity as a disease, necessitating the development of novel medical interventions to treat this major US health issue1 . In the same year, the prevalence of obesity in US adults stood at 33.3% for males and 35.9% for females, while prevalence in under-18s was 18.6% for males and 19.3% in females2 . In 2012, a study from Cornell University estimated that the cost to the US healthcare system of treating obesity exceeded $190 billion, equating to approximately 21% of all health expenditure. This is over double previous projections of $86 billion (or 9% of total spend)3 . Current interventions for treating obesity fall into 3 major categories, namely: Behavioural (i.e. change to diet and physical activity), Surgical, or Pharmacological Management. Although lifestyle changes (i.e. achieving a negative energy balance by decreasing food intake whilst subsequently increasing physical activity) are an effective and relatively risk free means of weight loss, difficulties with patients sustaining these modifications long term have increased interest in pharmacotherapies. Using Pharmaprojects® data, we review here past and present as well as pipeline pharmacotherapies for obesity to discuss possible future treatments. 1. http://www.ama-assn.org/ama/pub/news/news/2013/2013-06-18-new-ama-policies-annual-meeting.page 2. Datamonitor Healthcare®, 2015, Informa 3. Cawley J, Meyerhoefer C. J Health Econ. 2012 Jan;31(1):219-30. doi: 10.1016/j.jhealeco.2011.10.003. Epub 2011 Oct 20. 2
- 3. Obesity pharmacotherapies: failures from history Historically, anti-obesity pharmacotherapies focused on targeting the central nervous system (CNS), typically by modulating endogenous catecholamines (i.e. dopamine, adrenaline and noradrenaline). Through prolonged use, it became apparent that these centrally acting drugs were associated with modest efficacy and serious safety issues. The safety issues and prolonged legal ramifications may indeed have deterred subsequent drug development efforts. Fenfluramine, a serotonin releasing agent, was released to the US market in 1973, but failed to become a blockbuster due to only providing temporary weight loss whilst causing negative side effects such as nausea and anxiety. In the early 1990s, fenfluramine was released in combination with the phenethylamine drug, phentermine, which was commonly referred to as ‘Fen-Phen’. Fen-Phen rapidly became the most widely prescribed weight loss therapy in the US but swiftly fell from grace due to potentially fatal pulmonary hypertension and heart valve dysfunction related to fenfluramine. Other failures include the cannabinoid-1 (CB-1) inverse agonist, rimonabant, and the serotonin/noradrenaline/dopamine reuptake inhibitor, sibutramine. Both compounds were previously available to the EU and US markets, respectively, until they were linked to serious safety concerns. Rimonabant was unable to reach the US market with the FDA voting against the drug in 2007 due to concerns over psychiatric issues associated with use, namely depression and increased incidence of suicidal thoughts4 . Given these examples it is clear that the pharmaceutical industry needed to move away from centrally acting, catecholamine targeting pharmacotherapies in order to produce efficacious compounds that do not put patients at undue risk of potentially life threatening side effects. Current options in marketed therapies During the first half of the current decade, a number of branded compounds were launched in the US market for the treatment of obesity, comprised of both centrally and peripherally acting compounds (Table 1). Despite issues that have been observed in the past, the majority of these centrally acting drugs still target catecholamine systems, albeit in the absence of the major side effects previously observed. Also, the efficacy of these centrally acting compounds is relatively modest as observed weight loss in pivotal trials was around 4-9% of total body weight (data not shown). Further to these centrally acting treatments, there are now also a few peripherally acting agents accessible to the US population, namely orlistat and liraglutide. Orlistat is a pancreatic lipase inhibitor that aids weight loss by decreasing calorific intake and inhibiting fat absorption in the gastrointestinal 4. By 1997, the FDA announced the withdrawal of combinations containing fenfluramine (or its related compound, dexfenfluramine) and phentermine from the market. Since toxicity was believed to be related to the fenfluramine component alone, phentermine was not withdrawn for use; indeed, it is still available in a number of branded compounds for obesity treatment. The European Medicines Agency (EMA) withdrew rimonabant’s licensing authority in 2008 after it was proven that the drug was capable of doubling the risk of the aforementioned psychiatric disorders. In 2010 the FDA released a statement to medical professionals that the serotonin/noradrenaline/dopamine reuptake inhibitor, sibutramine, should no longer be made available to patients due to clinical evidence that the compound increased the risk of cardiovascular events such as myocardial infarction and stroke. 3
- 4. tract. Originally developed as a prescription medication by Roche, orlistat is now available as the popular over-the-counter medication ‘Alli’, which is associated with modest weight loss (on average, 3kg compared to placebo) and a number of unpleasant, but relatively harmless, side effects including flatulence and faecal incontinence (data not shown). Liraglutide, Novo Nordisk’s glucagon-like peptide 1 (GLP-1) agonist, was initially approved for the treatment of type 2 diabetes in 2009. The drug was subsequently approved and launched onto the US as Saxenda as an ‘adjunct to a reduced-calorie diet and increased physical activity for chronic weight management in adults with obesity (BMI >30 kg/m2 ) or who are overweight (BMI >27 kg/m2 ) in the presence of at least one weight-related comorbid condition’ (i.e. diabetes, hyperlipidaemia etc.). Phase III trials showed that 9/10 obese adults lost an average of 9.2% of their body weight (when compared to 3.5% observed in placebo group) following administration of 3mg liraglutide5 . 5 http://www.novo-pi.com/saxenda.pdf Table 1: Marketed therapies for the treatment of obesity DRUG NAME ORIGINATOR LAUNCH YEAR MECHANISM OF ACTION CENTRALLY ACTING COMPOUNDS Phentermine HCL Citius 2012 Dopamine/5-HT/adrenergic uptake inhibitor Phentermine/Topiramate Vivus 2012 GABA receptor agonist; gluamate antagonist; voltage-gated sodium channel antagonist Lorcaserin Arena 2013 5-HT2C receptor agonist Buproprion/Naltrexone Orexigen 2014 Dopamine reuptake inhibitor, adrenergic transmitter uptake inhibitor, κ/μ opioid receptor antagonist, Norepinephrine/ dopamine dual reuptake inhibitor PERIPHERALLY ACTING COMPOUNDS Liraglutide Novo Nordisk 2015 Glucagon-like peptide 1 agonist Insulin secretagogue Incretin mimetic Orlistat Roche 1998 Lipase inhibitor Source: Citeline’s Pharmaprojects®, October 2015 Although prescribers and consumers now have a choice of both peripherally and centrally acting drugs for the treatment of obesity, it should be noted that in terms of efficacy, both sets of compounds still only deliver a fairly modest weight loss when compared to placebo. Evidently, new approaches need to be considered when developing the next generation of anti-obesity therapeutics. 4
- 5. Is there any hope for the future for obesity therapeutics? Figure 1 shows the number of preclinical through registered obesity therapies in each phase of development by disease status and looking at this graph, there is clearly a high rate of attrition between phases. Drug counts decrease by 80% between preclinical and Phase I, 33% between Phase I and Phase II, and 83% between Phase II and Phase III. As of October 2015, there are no pre-registration drugs and only one currently registered compound awaits launch: Takeda/Norgine’s pancreatic lipase inhibitor, cetilistat. Cetilistat was first approved in Japan in 2013, but is yet to be launched onto the Japanese market. (Pharmaprojects analysts have recently been in touch with Takeda/Norgine and both companies were unable to provide a timeline on when this product may be launched). Source: Citeline’s Pharmaprojects®, October 2015 Phase III There are currently two Phase III compounds for the treatment of obesity. Firstly, Angiolab’s ALS-L1023, derived from the herb Melissa officinalis, acts as an angiogenesis and matrix metalloproteinase (MMP) inhibitor that targets adipose tissue. In May 2015, Angiolab’s partner, Hanmi Pharma, announced that they had ceased development but Angiolab confirmed to Pharmaprojects that they will continue to pursue ALS-L1023 for treating obesity in additional to age-related macular degeneration. Secondly, BTI-320 is Boston Therapeutics’ carbohydrate hydrolysing inhibitor. Boston has stated that their Phase III trial is expected to complete its Phase III trial by the end of 2015. BTI-320 is already commercially available as an over-the-counter dietary supplement, Sugardown® , to support healthy blood glucose levels, and Boston aims to file the compound for obesity in January 2016 (data not shown). Figure 1. Number of compounds under development for the treatment of obesity by disease status 0 10 20 30 40 50 60 70 80 90 100 Pre-clinical Phase I Phase II Phase III Pre-registration Registered NumberofCompounds Stage of Development 92 18 12 2 0 1 5
- 6. Phase II Table 2 shows the 12 compounds currently in Phase II studies for the treatment of obesity, most of which act peripherally rather than centrally. Of these peripherally acting compounds, there is mix of familiar mechanisms of action (i.e. SGLT-2 inhibitors and GLP-1 agonists) and those which we have not previously seen in launched obesity therapeutics (i.e. melanocortin MC-4 receptor agonists, methionine aminopeptidase-2 inhibitors, AMPK stimulants and fibroblast growth factor receptor 4 antagonists). In a trend that is repeated across almost all phases of obesity drug development, you will notice that a number of these therapies have been approved or investigated to treat other indications and were serendipitously found to cause weight loss as a side effect. The following 4 of 12 phase II compounds have now been repurposed for treating obesity: I. canagliflozin: approved for Type 2 Diabetes II. fluticasone + salmeterol: approved for allergies /asthma III. bupropion + zonisamide: individual components approved for depression (bupropion) and convulsions (zonisamide) IV. tesofensine: originally investigated for the treatment of Alzheimer’s and Parkinson’s disease Given that most of these compounds have previously been approved and launched for the treatment of other indications, it should be hoped that safety issues previously seen during derailed development efforts of novel anti-obesity compounds should not be an issue here. Table 2: Phase II compounds under development for the treatment of obesity DRUG NAME COMPANY MECHANISM OF ACTION PERIPHERALLY ACTING COMPOUNDS canagliflozin Mitsubishi Tanabe Pharma/ Johnson Johnson Sodium/glucose co-transporter 2 inhibitor beloranib Zafgen Methionine aminopeptidase-2 inhibitor Angiogenesis inhibitor setmelanotide Rhythm Pharmaceuticals Melanocortin MC-4 receptor agonist Melanocyte stimulating hormone receptor agonist MB-11055 KTG Life Sciences AMPK stimulant langlenatide Hanmi Glucagon-like peptide 1 agonist Insulin secretagogue Incretin mimetic Oral HDV biotin, Diasome Diasome Unidentified pharmacological activity 6
- 7. Source: Citeline’s Pharmaprojects®, October 2015 Preclinical – Phase 1 Of the 92 compounds currently listed as preclinical for obesity, only 49 (53%) have a disclosed mechanism of action (MOA), perhaps suggesting a move towards novel approaches for the treatment of obesity, or a reluctance to expose a lack of innovation. A marginally higher proportion of drugs in Phase I (11 of the 18 drugs; 63%) currently have disclosed MOAs. Research at Phase I seems to focus on GLP-1/glucagon receptor dual agonists, as 3 of the 11 compounds with disclosed MOAs targeting these two receptors (Zealand Pharma’s ZP-2929, Medimmune’s MEDI-0382 and Hanmi’s HM-12525A). Overall, there are 6 dual GLP-1/glucagon receptor agonist compounds in preclinical and Phase I development (data not shown). In addition to these more familiar targets, there are also numerous preclinical compounds with MOAs that have not been previously seen in obesity therapies (indeed, there are too many to discuss fully DRUG NAME COMPANY MECHANISM OF ACTION Semaglutide (injectable) Novo Nordisk Glucagon-like peptide 1 agonist Insulin secretagogue Incretin mimetic ISIS-FGFR4Rx Isis Pharmaceuticals Fibroblast growth factor receptor 4 antagonist CENTRALLY ACTING COMPOUNDS S-237648 Shionogi Neuropeptide Y5 receptor antagonist bupropion + zonisamide SR Orexigen Dopamine reuptake inhibitor Adrenergic transmitter uptake inhibitor GABA receptor agonist Norepinephrine/dopamine dual reuptake inhibitor tesofensine Saniona Dopamine reuptake inhibitor Adrenergic transmitter uptake inhibitor 5 Hydroxytryptamine uptake inhibitor Serotonin-norepinephrine- dopamine reuptake inhibitor PERIPHERALLY + CENTRALLY ACTING COMPOUNDS fluticasone propionate + salmeterol xinafoate Neothetics Glucocorticoid agonist Lipocortin synthesis stimulant Long-acting beta 2 adrenoceptor (LABA) agonist Beta 2 adrenoreceptor agonist 7
- 8. here). In a departure from the typical small molecule approach to tackling obesity, there are currently numerous biological compounds in early stage development including BioRestorative Therapies adult-derived brown fat stem cell therapy, (ThermoStem), a preadipocytes MAb from Abeome and a reverse vaccines (using a viral gene delivery platform) from Amarna. Figure 2 shows the top 10 targets of drugs in Preclinical/Phase 1 development (the vast majority of Preclinical/Phase I compounds still have unspecified targets. This grouping has not been included in Figure 2 below). Overwhelmingly, we can see here that the peripheral targets seem to be favoured here (9 peripheral targets vs 1 central target). Of the 9 peripheral targets, we can see that the industry seems to be focusing mainly on receptor targets (i.e. the GLP-1, glucagon, leptin and growth hormone secretagogue receptors) in addition to a number of regulatory enzyme/proteins (i.e. tyrosine-protein phosphatase non-receptor type 1 (PTPN1), monoacylglycerol O-acyltransferase 2 (MOGAT2), methionine aminopeptidase 2 (METAP2), diglyceride acyltransferase 1 (DGAT1) and bone morphogenetic protein 7 (BMP7)). Source: Citeline’s Pharmaprojects®, October 2015 0 2 4 6 8 10 12 14 16 18 5HT2C receptor BMP7 DGAT1 growth hormone secretagogue receptor leptin receptor METAP2 MOGAT2 PTPN1 glucagon receptor GLP-1 receptor Number of Compounds Target Figure 2. Top 10 targets for preclinical and phase I obesity therapeutics 16 6 2 2 2 2 2 2 2 2 8
- 9. Conclusions Despite obesity being a major health issue for the US, there has yet to be a blockbuster pharmacotherapy to offer significant weight loss without life-threatening side effects, which historically necessitated the withdrawal of compounds from the market. The current launched therapies are mostly centrally acting compounds targeting the catecholamine system; although given the mechanism of actions and targets of drugs in Preclinical, Phase I and Phase II, there is a suggestion that industry is finally moving away from these centrally acting compounds. There are still a relatively high number of drugs in later-stage clinical development which are repurposed drugs that previously were investigated (or in some cases, launched) for different indications and found to cause weight loss as a side effect. There is a more heterogeneous mix of compounds in early-stage development, however the high attrition rates of compounds at these phases make it extremely difficult to predict which (if any) will make it to market in the future. Further research is needed into the mechanisms underlying obesity in order to develop more focused and efficacious compounds. Will the classification of obesity as a disease lead to the development of these novel therapies? Only time will tell. 9
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