Therapeutic focus - After Contrave few green shoots of recovery for obesity research

Analysis

Obesity drug development has suffered the regulatory version of a wildfire – a massive destruction of most late-stage hopes and one already-marketed product because of safety concerns (FDA wipes obesity slate clean with rejection of Orexigen's Contrave, February 1, 2011). Now those who work in the space are crawling out of the ashes, dusting themselves off and surveying the landscape.

What they see is not pretty. In phase III are just two drugs – Novo Nordisk’s diabetes drug Victoza and the Norgine-Takeda partnership on cetilistat, which so far is only being tested late-stage in diabetics with high cholesterol. Novel therapies are further up the pipeline – and given the regulators’ safety concerns remain high-risk bets. Meanwhile, some companies are delaying development or diverting promising candidates into lower-risk niche indications.

As if to underscore the risks, at the same time as Novo is forging ahead with its phase III trials of Victoza in obesity, last week it pulled the plug on novel obesity product NN9161. Likewise, after promising phase II trials of tesofensine, fellow Danish group NeuroSearch has put on hold plans to move into phase III following the withdrawal of Meridia, which like tesofensine inhibits reuptake of serotonin and norepinephrine (Meridia adcom leaves obesity space clear as mud, September 16, 2010).

Outlook

Demonstrating what is at stake in obesity drug development, Orexigen, developer of Contrave, the last of the current generation of obesity drugs to be stiffed-armed by the FDA, announced this week it would be sacking 23 of its 58 employees to save money.

A look at EvaluatePharma data demonstrates how the safety worries that have dogged the space have led to limited opportunities (see table). Analysts have attached obesity sales forecasts to only two candidates in development, Victoza, at $315m, and Orexigen’s Empatic, at $100m. The Empatic forecast should be taken as chancy at best; it is a combination therapy of anti-seizure medication zonisamide and antidepressant bupropion, the latter of which raised safety concerns in the Contrave review.

Given the focus on safety – an obesity drug could be prescribed for long-term use to a large proportion of the population in the US and Europe – it is not surprising that the Novo GLP-1 agonist appears the most promising candidate. It has a known safety profile and will be taken chronically by a large patient population, and thus has already leaped many of the hurdles that regulators would be likely to erect.

As a commercial product, however, Victoza might have some limitations: Would such a large population, obese but otherwise healthy, be willing to take an injectable product, even if just once a day? Will the well-known nausea and diarrhoea side effects put such target patients off using Victoza?

Novo’s phase III Scale trial plans on enrolling 3,600 patients starting this summer, with final data expected to be collected in March 2013. Thus, filing would likely not happen until late 2013 or early 2014. As the leading edge of the broad obesity pipeline, it appears there will be a long wait before any new products hit the market.

Selected Phase III/II obesity candidates
Phase Product Company Pharmacological Class
III Cetilistat Norgine/Takeda Lipase inhibitor
Victoza Novo Nordisk Glucagon-like peptide 1 (GLP-1) agonist
II PYY3-36 Marina Biotech/Pfizer Peptide YY (PYY) 3-36
Tesofensine (NS2330) NeuroSearch Noradrenaline & dopamine reuptake inhibitor
Empatic Orexigen Therapeutics  Noradrenaline & dopamine reuptake inhibitor & sulphonamide
JNJ16269110 Johnson & Johnson Microsomal triglyceride transfer protein (MTP) inhibitor
Empatic Orexigen Therapeutics Noradrenaline & dopamine reuptake inhibitor & sulphonamide
AC137-164594 Amylin Pharmaceuticals Leptin & amylin receptor agonist
Byetta Amylin Pharmaceuticals/Eli Lilly Glucagon-like peptide 1 (GLP-1) agonist
Canagliflozin Depomed/Johnson & Johnson/Mitsubishi Tanabe Pharma SGLT2 inhibitor
Symlin Amylin Pharmaceuticals Amylin receptor agonist
Nutropin Roche Growth hormone

The diabetes approach

Fellow GLP-1 Byetta is also being tested in obesity. As the class increases pancreatic insulin secretion and slows gastric motility, it is believed they might also be broadly effective weight-loss tools. Given that obesity, metabolic disorders and diabetes are closely intertwined, it is a logical area of research.

Interestingly, Byetta partners Eli Lilly and Amylin Pharmaceuticals have taken the weight-loss hypothesis only through phase II in non-diabetics, but the US National Institutes of Health has embarked on a phase III test of Byetta and its effects on energy expenditure and weight loss in non-diabetic obese patients.

Amylin has set itself up with more than one shot on goal in the obesity space. It also has partnered AC137-164594, a combination of its synthetic metabolic hormone Symlin and metreleptin, with Takeda. The partnership came in November 2009 after a successful phase II trial, but the two companies are now recruiting for a new phase II trial of 200, expected to be completed next year.

Symlin represents its third shot on goal, with a phase IV trial in drug-induced obesity in schizophrenic patients following several completed phase II studies in a broader population.

Not to be outdone, the sodium-glucose transporter-2 inhibitor (SGLT-2) class has a representative in the obesity space – Depomed, Johnson & Johnson and Mitsubishi Tanabe Pharma’s canagliflozin, in phase II. The SGLT-2 class enables greater excretion of glucose in the urine, which is the hypothesis behind the research into it as a means to control blood sugar.

Novel mechanisms

An interesting entry in the mid-stage race is the Marina Biotech/Pfizer intranasal spray PYY3-36. The peptide is believed to suppress appetite by slowing gastric motility and increasing absorption of water and nutrients.

Another similarly interesting novel approach is J&J's JNJ16269110, a microsomal triglyceride transfer protein (MTP) inhibitor, a class of drugs being tested mostly in patients with severe lipid disorders (Aegerion takes a 'haircut' to prove MTP doubters wrong, October 25, 2010). J&J's phase II trials in obesity were completed in 2008 and no news has been heard since.

In phase I, Amylin has its own PYY3-36 candidate, along with Emisphere Technologies, while Compellis Pharmaceuticals is testing another nasal spray medication that blocks smell and is hoped will reduce patients’ interest in food.

There is no shortage of candidates listed in Phase I: 44 in all, from biotechs and big pharma alike, signifying a recognition that obesity is a serious and growing condition in developed and developing countries. The usual caveats about R&D attrition apply here, though, perhaps more than in many development areas because of the high regulatory barriers.

The first company to break through with a relatively safe and effective medication has a likely blockbuster on its hands. The question is how many will take that chance.

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