Preregistration antiobesity drugs: two down, one to go

By |2010-09-23T00:00:00+00:00September 23, 2010|Drug Development, Metabolic diseases, Strategy and Consulting|

Lorcaserin

As we stated in our August 4, 2010 blog post, 2010 was supposed to be the year in which one or more new obesity drugs would be approved by the FDA and reach the market. Three new drugs developed by small California companies–Vivus Pharmaceuticals’ Qnexa, Orexigen Therapeutics’ Contrave, and Arena Therapeutics’ lorcaserin, were up for review by the FDA. This followed a long hiatus, since the FDA has approved no anti-obesity drug since 1999.

On July 15, 2010, the FDA’s Endocrinologic and Metabolic Drugs Advisory Committee voted against FDA approval of the first of these three drugs to be reviewed, Vivus’ Qnexa (phentermine/topiramate). On September 16, 2010, the same Advisory Committee voted 9 to 5 against approval of the second drug up for review, lorcaserin (expected trade name, Lorqess).

The FDA usually follows the advice of its advisory panels, but does not always do so.

Lorcaserin is a selective serotonin receptor agonist, which is specific for the 5-HT2C serotonin receptor. This contrasts with the nonselective serotonin reuptake inhibitor and serotonin-releasing agents, fenfluramine and dexfenfluramine, which are notorious for their association with heart valve abnormalities. Lorcaserin is designed to be a more selective agent that works by a similar mechanism to dexfenfluramine or fenfluramine. The anorectic effect of fenfluramine/dexfenfluramine is due to their activity on 5-HT2C, but the adverse effects of these agents appears to be due to their activity on 5-HT2B. Therefore, lorcaserin is expected to be a safer agent that fenfluramine/dexfenfluramine.

However, like fenfluramine and dexfenfluramine, the efficacy of lorcaserin appears to be minimal. Pivotal Phase III clinical trials showed an average weight loss of 5.8% among subjects taking lorcaserin, as compared to 2.5% for the placebo group.

A Phase III clinical trial published in the New England Journal of Medicine (NEJM) in July 2010 showed that the drug caused significant weight loss and improved maintenance of weight loss as compared to placebo,  in a generally healthy obese population. Lorcaserin also improved values for such biomarkers as lipid levels, insulin resistance, inflammatory markers and blood pressure. A commentary by Arne Astrup, M.D. (University of Copenhagen, Denmark) published in the same issue of the NEJM concluded that lorcaserin appeared to have efficacy that was less than or equivalent to that of the two marketed antiobesity drugs, orlistat (Roche’s Xenical) and sibutramine (Abbott’s Meridia/Reductil). However, lorcaserin appeared to be safer than either of the two marketed drugs. (The clinical trials did not compare the drugs directly.) This it appeared to Dr. Astrup that lorcaserin might have a place in the management of obesity. However, he said that where the drug would fit in obesity management remained to be seen, and that it will be necessary to be “doubly sure” about the safety of lorcaserin, given the history of the obesity drug field.

The Advisory Committee noted that lorcaserin, although its efficacy was not great, met FDA efficacy criteria for approvable antiobesity drugs. However, some panelists thought that the study population consisted mainly of healthy obese individuals, and that in populations containing more patients with comorbidities (e.g., diabetes, cardiovascular disease) there might be a lesser degree of efficacy and/or additional safety issues. There is an ongoing study of lorcaserin in obese diabetics, which is expected to be reported by the end of 2010. However, some panelists thought that the trial population (600 patients) is too small to give meaningful results. This could mean that Arena–a company with limited resources–might need to rerun its Phase III trials in a patient population that includes more people with comorbidities.

Advisory Committee members also had various safety concerns. Animal studies indicated the potential for an increased risk of cancer, especially brain and breast tumors. A few panel members were concerned about the potential of lorcaserin to cause valvular heart disease, despite Arena’s efforts to avoid that problem via the design of the drug. Most panelists, however, saw no evidence of such a risk.

The induction of cancer in animals by a drug does not necessarily mean that the drug will cause tumors in humans. However, the animal results left many panelists uneasy. Some said that if the drug were approved, there would need to be an active surveillance program to look for possible brain and breast cancer in patients taking lorcaserin. Other panelists thought that there would need to be follow-up echocardiograms to check for valvular disease if the drug was marketed.

Many panelists felt that lorcaserin was a promising drug, but that the evidence that this drug’s benefits outweigh its risk was not there yet. Thus, as with Qnexa, lorcaserin might eventually be approved, if Arena can present additional data that can overcome Advisory Committee and FDA doubts.

The third preregistration antiobesity drug, Contrave (bupropion/naltrexone) is up for review by the same Advisory Committee in December 2010.

On September 15, 2010 (the day before it recommended against approval of lorcaserin), the Endocrinologic and Metabolic Drugs Advisory Committee voted 8 to 8 on whether sibutramine  should be allowed to remain on the market. This reflects the continuing controversies with sibutramine–the drug’s modest efficacy coupled with an increased risk of cardiovascular adverse effects, as discussed in our August 4 blog post. The eight panelists who recommended that sibutramine remain on the market stipulated that the drug’s label should carry additional warnings, and restrictions on who can prescribe the drug.

Sibutramine has already been withdraw from the market in Europe as of January 2010. The Advisory Panel recommendations on sibutamine not only put the drug’s future in doubt, but constitute an additional blow to the antiobesity drug market as a whole. The loss of sibutramine from the market–in the absence of any new antiobesity drug approvals–would leave only orlistat (Roche’s Xenical), a modestly efficacious drug with adverse effects that are unacceptable to many if not most patients.

Meanwhile, Gil Van Bokkelen, Ph.D., the Chairman and CEO of the biotech company Athersys (Cleveland, OH), told Fierce Biotech that the advisory panel’s rejection of lorcaserin should not affect the prospects for Athersys’ development of an antiobesity drug that is also a selective 5-HT2C receptor agonist. Dr. Van Bokkelen stated that he believes that the advisory panel decision was the result of some compound-specific issues with lorcaserin, and the approach that Arena took in developing that drug. He believes that these issues should not apply to Athersys’ preclinical 5-HT2C receptor agonist, which has shown more selectivity for the receptor. Moreover, he says that preclinical studies suggest that the Athersys drug may be more efficacious than lorcaserin.

An interesting strategic issue in the development and commercialization of late-stage antiobesty drugs is the role of Big Pharma. Both Arena’s lorcaserin and Orexigen’s Contrave have attracted Big Pharma commercialization partners–Eisai for lorcaserin and Takeda for Contrave. The two deals are similar. Arena granted Eisai exclusive rights to commercialize lorcaserin in the United States. Eisai paid Arena $50 million upfront, and is to pay Arena up to an additional $90 million in milestone payments, depending on FDA approval and sales of the drug. Similarly, Orexigen granted Takeda North American (U.S, Mexico, and Canada) marketing rights for Contrave; Orexigen retains copromotion rights in the United States. Takeda paid Orexigen $50 million upfront, and will pay (upon FDA approval) tiered double-digit royalties (starting at 20% and increasing to 35%) on any net sales of Contrave. The deal is estimated to be worth a potential $1 billion. In both cases, the Big Pharma partner will also share the costs of further development of these drugs.

In both agreements, the Japanese Big Pharma companies pay their biotech partners a relatively small upfront fee, and in turn receive U.S. (in the case of Contrave, North American) marketing rights. Substantial payments to the biotechs depend on FDA approval and on the drugs doing well in the market. Eisai and Takeda are thus making small initial payments for the right to market products with a high risk of failing to gain approval, but a high prospect of reward in terms of sales should they gain approval. The biotech partners gain financial support for further development of the drug, the credibility of having a Big Pharma partner, and upon approval, the strength of a partner with the resources necessary to market a primary care drug in the U.S./North America.

The Contrave deal is not Takeda’s only obesity partnership. In November 2009, Takeda entered into a worldwide agreement to codevelop and commercialize antiobesity drugs with Amylin (San Diego, CA). The agreement included Amylin’s Phase II agents, pramlintide/metreleptin and davalintide, as well as other, earlier-stage compounds from both companies’ obesity programs. Amylin received an upfront payment of $75 million, and is eligible to receive development, commercialization, and sales-based milestone payments that could exceed $1 billion. Amylin may also receive tiered, double-digit royalties on any future sales. Under the agreement, Amylin will be responsible for leading development through Phase II in the U.S., and Takeda will lead later-stage U.S. development and all development outside of the U.S. The companies will share the costs of development according to an agreed-upon formula.

In February 2010, Amylin and Takeda decided to halt development of davalintide, a second-generation amylin mimetic. In a Phase II study, the weight loss efficacy and tolerability profile of davalintide was not improved over pramlintide, Amylin’s first-generation amylin mimetic that is marketed as Symlin for treatment of diabetes. Amylin is a natural pancreatic peptide hormone that slows gastric emptying and promotes satiety. (Amylin the company was named after amylin the hormone.) Symlin is indicated to help diabetics who take insulin to improve their post-meal glycemic control; it can also help these patients to lose weight.

Also in February 2010, Amylin and Takeda announced that they had selected pramlintide/metreleptin for advancement toward Phase III development. This is a combination product containing pramlintide and metreleptin. Metreleptin is the recombinant methionine human leptin originally developed by Amgen as an antiobesity treatment. However, Amgen’s metreleptin program failed in Phase II trials because of leptin resistance. In 2006, Amgen licensed its leptin franchise to Amylin.

In 2008, Amylin researchers published a report containing evidence that administration of amylin to leptin-resistant diet-induced obese rats can restore leptin responsiveness to these leptin-resistant animals. Co-administration of amylin and metreleptin resulted in decreased feeding and increased weight loss, and that the combination treatment reduced feeding and weight to a greater extent than amylin treatment alone. The combination of amylin and leptin also resulted in increased energy expenditure.

In the same publication, the researchers also reported the results of a proof-of-concept study of pramlintide/metreleptin. In this 24-week randomized, double-blind, clinical trial in overweight/obese subjects, administration of the combination of metreleptin and pramlintide resulted in 12.7% mean weight loss (an average loss of 25 pounds), significantly more than was seen with either drug administered as a single agent.

Amylin later reported (on its website) the results of a 28-week Phase IIb study completed in late 2009 followed by a extension study to 52 weeks. Patients who continued treatment with pramlintide/metreleptin for the full 52 weeks exhibited sustained weight loss, whereas those who received placebo during the extension study regained almost all of their weight. The combination therapy appeared to be generally well tolerated.

Takeda’s obesity strategy thus combines a short-term “bet” on the approval of Orexigen’s Contrave, with the longer-term development of potentially more effective agents in collaboration with Amylin.

Now the immediate focus in the obesity drug area will be on the FDA Endocrinologic and Metabolic Drugs Advisory Committee meeting on Contrave in December, as well as what the FDA will do with the panel’s recommendations on sibutramine.

Meanwhile, as we stated in earlier blog posts, many companies have adopted the strategy of developing drugs that treat both diabetes and obesity, and developing the drugs for diabetes first. As the drugs prove themselves in the clinic, with respect to safety, antidiabetic efficacy, and effects on weight loss, companies may later develop them for obesity. Liraglutide (Novo Nordisk’s Victoza) is one such drug that has been approved for treatment of type 2 diabetes in both the United States and Europe. Novo Nordisk is now also developing the drug for obesity. However, most dual diabetes/obesity drugs are in early-stage development for diabetes. Early stage obesity drug development is mainly on hold, awaiting the regulatory approval of the three late-stage drugs now nearing NDA submission.

The apparent lack of regulatory success of Qnexa and lorcaserin will therefore be expected to keep development of most early-stage drugs for obesity on hold.

A notable exception is Zafgen’s ZGN-433, a methionine aminopeptidase inhibitor now in Phase I development, which targets the vasculature of adipose tissue. Zafgen (Cambridge, MA) goes against the conventional wisdom by dedicating itself to the development of novel antiobesity medicines, in the face of all the negativity surrounding that field. However, as we implied in our blog post on Qnexa, this negativity is mainly due to the relatively poor prospects for drugs that address appetite-control pathways in the CNS that involve common neurotransmitters. Such drugs often have unacceptable adverse effects, and may also have a low degree of efficacy due to the complex and redundant nature of CNS weight control pathways. Instead, we believe that drugs that address metabolic pathways involved in both obesity and diabetes may have a better chance of success. Zafgen’s R&D strategy involves targeting adipose tissue directly, rather than CNS appetite-control pathways.

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