“That’s all, folks!” http://bit.ly/gSgL6b

As we said in our December 8, 2010 blog post, the FDA’s Endocrinologic and Metabolic Drugs Advisory Committee recommended that the FDA approve Orexigen’s Contrave (naltrexone sustained release [SR]/bupropion SR), by a vote of 13-7, for long-term use by certain obese and overweight patients.

This followed the earlier rejections in 2010 by the Advisory Committee and the FDA of two other preregistration antiobesity drugs–Vivus’  Qnexa and Arena Therapeutics’ lorcaserin (Lorqess). Also in 2010, the then-marketed antiobesity drug sibutramine (Abbott’s Meridia) was withdrawn from the market at the FDA’s request. Concern about long-term safety was the major consideration in the rejection of Qnexa and lorcaserin, and safety issues (increased risk of cardiovascular events) were the reason for the withdrawal of sibutramine. Thus the Advisory Committee’s recommendation for approval of Contrave was surprising, to us as well as to many others.

Despite the Advisory Committee’s vote to recommend approval of Contrave, it did have safety concerns. Clinical trials indicate that Contrave treatment can result in elevated blood pressure in some patients. Some panelists were also concerned about the risk of seizures, which have been seen with one of the components of Contrave, bupropion. Especially because of the adverse effect on blood pressure, some panelists expressed concern that Contrave, once approved, might suffer the same fate as sibutramine.

As a result of these safety discussions, the panel voted 11-8 to require Orexigen to conduct a long-term study of the effects of Contrave on cardiovascular health. However, they concluded that that study could be done post-marketing rather than requiring the company to conduct the study in order to gain approval.

Yesterday–January 31, 2011–was the Prescription Drug User Fee Act (PDUFA) deadline for the FDA to act on the approval of Contrave. This morning, Orexigen and its partner for Contrave commercialization, Takeda, announced that the FDA had issued a Complete Response Letter regarding the New Drug Application for Contrave.

The FDA’s Complete Response Letter stated, “before your application can be approved, you must conduct a randomized, double-blind, placebo-controlled trial of sufficient size and duration to demonstrate that the risk of major adverse cardiovascular events in overweight and obese subjects treated with naltrexone/bupropion does not adversely affect the drug’s benefit-risk profile.”  Essentially, the FDA required Orexigen and Takeda to conduct the cardiovascular safety trial of Contrave prior to marketing approval, not post-marketing as recommended by the Advisory Committee. The safety trial required by the FDA will be neither fast nor inexpensive.

As a result of the FDA ruling, what we called “the pall of gloom” descended once again on the antiobesity drug field. Forbes’ Matthew Herper, for example, declared the antiobesity drug field “effectively dead”. Herper further said, “The clear lesson is that weight-loss medicines simply do not have enough of a benefit to justify any risk – and that this makes getting them approved just about impossible.”

If you click on the “metabolic diseases” category on the right-hand panel of this blog, you will see that we have quite a number of blog articles on obesity, usually in the more holistic context of metabolic diseases–obesity, type 2 diabetes, and metabolic syndrome (which is a major risk factor for cardiovascular disease). In these articles, you will see that we are not negative about antiobesity drug development. However, we are–and have been for some time–quite negative about developing appetite suppressant drugs that address common neurotransmitter receptors in the CNS.  Such agents might be expected to have significant adverse effects, since their targets are involved in multiple CNS and/or peripheral tissue pathways. They also tend to have low efficacy.

If you read our articles, you will see that there are several companies that have strategies to develop antiobesity agents that are not appetite suppressants, and that are being–or can be–developed for diabetes and/or metabolic syndrome in addition to obesity.  A common strategy is to develop diabetes/obesity drugs first for diabetes, resulting in easier FDA approval. Such drugs may later also be developed for obesity, after they prove to be safe and to induce weight loss in diabetes trials. For example, Novo Nordisk is following this strategy with the development of liraglutide (Victoza), which is already approved for treatment of type 2 diabetes.

Other established companies are pursuing different strategies, such as Amylin/Takeda’s development of pramlintide/metreleptin for obesity. This is really a metabolic syndrome-based approach to obesity. Indeed, Amylin (whose assets have passed on to AstraZeneca as of early 2014) had been developing metreleptin as a single agent for treatment of diabetes and high triglycerides in patients with lipodystrophy.

Then there are several young companies covered in this blog that are developing antiobesity treatments via innovative biology-driven strategies. Two of these companies, Energesis and Acceleron, are developing antiobesity therapies that target brown fat. Such an approach is really a metabolic syndrome-based one, and might also be applied to various diabetes and/or cardiovascular indications for easier regulatory approval.

Meanwhile, a News and Analysis article in the January 2011 issue of Nature Reviews Drug Discovery lists several agents not covered in our blog. One agent, tesamorelin (Theratechnologies/Merck KGaA’s Egrifta) was approved by the FDA in November 2010 as the first and only treatment indicated to reduce excess abdominal fat in HIV-infected patients with lipodystrophy. Tesamorelin is a synthetic analogue of growth hormone–releasing factor — a hypothalamic peptide that acts on the pituitary to stimulate production and release of human growth hormone. This drug is now in a Phase 2 clinical study for treatment of human growth hormone deficiency associated with abdominal obesity. This represents a potential personalized medicine approach for treatment of a specific population of obese patients. Such an approach may be looked at more favorably by regulatory agencies than a “diet pill” for the general obese population.

As we also discussed in another article, John C. Lechleiter, Ph.D., the chairman, president and CEO of Lilly, outlined the need for “public policies that enable and reward medical innovation”, especially in the metabolic syndrome/diabetes/obesity therapeutic area. This includes “creation of a systematic and transparent regulatory approach to assessing the benefits and risks of new medicines.” Dr. Lechleiter noted the ongoing discussions with the FDA on the PDUFA, which is up for reauthorization in 2012. He sees these discussions as offering an opportunity for negotiation between industry and the FDA to achieve these ends.

We hope that industry and the FDA can work toward a more favorable environment for the approval of safe and efficacious antiobesity drugs. And Dr. John Jenkins, director of the FDA office of new drugs, said that the FDA was “committed to working toward approval” of new obesity drugs, “so long as they are safe and effective for the population for which they are intended.” Nevertheless, we do not see the FDA approving a minimally-efficacious CNS-acting appetite suppressor for the general obese population any time in the foreseeable future.

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As the producers of this blog, and as consultants to the biotechnology and pharmaceutical industry, Haberman Associates would like to hear from you. If you are in a biotech or pharmaceutical company, and would like a 15-20-minute, no-obligation telephone discussion of issues raised by this or other blog articles, or of other issues that are important to  your company, please click here. We also welcome your comments on this or any other article on this blog.

Naltrexone

Bupropion

As many of you know, this blog has been covering the review of preregistration antiobesity drugs by the FDA’s Endocrinologic and Metabolic Drugs Advisory Committee and by the FDA itself. 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 FDA review this year. This follows a long hiatus, since the FDA has approved no antiobesity drug since 1999.

So far, the Advisory Committee–and later the FDA itself–has rejected approval of two of these drugs–Qnexa and lorcaserin. At the same time, the marketed antiobesity drug sibutramine (Abbott’s Meridia) was withdrawn from the market at the FDA’s request.

The third preregistration antiobesity drug, Orexigen’s Contrave, was scheduled for review by the Endocrinologic and Metabolic Drugs Advisory Committee in December 2010, and the review was held on December 7th. Most industry experts expected that the Advisory Committee would reject Contrave as well. But, surprisingly, the Committee recommended that the FDA approve Contrave (naltrexone sustained release [SR]/bupropion SR), by a vote of 13-7, for long-term use by certain obese and overweight patients.

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

Contrave is a combination of long-acting formulations of two FDA-approved drugs–naltrexone and bupropion. Orexigen designed Contrave to have a dual effect on pathways within the hypothalamus of the brain that control energy balance–increasing anorexia and inhibiting the reward effects of food. The company also believes that Contrave may block the body’s compensation for weight loss–i.e., decreased energy use and increased feeding. For additional details, see our 2008 book-length obesity report, published by Cambridge Healthtech Institute.

The Advisory Committee, although they voted positively, did not do so with much enthusiasm, since Contrave just barely met the FDA’s criteria for efficacy. The drug enabled a majority of patients to lose about 5% of their body weight. Despite the drug’s minimal efficacy, a 5% loss in body weight can have significant health effects, such as helping patients to prevent diabetes and heart disease and to control their blood pressure. Some panelists were concerned that there is no data on the drug’s efficacy or safety beyond one year of treatment. Obesity is a long-term condition, and most patients would probably require long-term treatment with Contrave if it is approved.

However, as in the previous reviews by the Advisory Committee of Qnexa and lorcaserin, the main emphasis of the discussion was on safety. Clinical trials indicate that Contrave treatment can result in elevated blood pressure in some patients. Some panelists were also concerned about the risk of seizures, which have been seen with one of the components of Contrave, bupropion. Especially because of the adverse effect on blood pressure, some panelists expressed concern that Contrave, once approved, might suffer the same fate as Meridia, which at the time of its approval was also known to cause elevated blood pressure in some patients. The reason for this year’s withdrawal of Meridia was its increased risk of cardiovascular events.

As a result of these safety discussions, the panel voted 11-8 to require Orexigen to conduct a long-term study of the effects of Contrave on cardiovascular health. However, they concluded that that study could be done post-marketing rather than requiring the company to conduct the study in order to gain approval.

Overall, the Advisory Committee concluded that physicians and patients need additional options to treat obesity, and that the risk-to-benefit ratio for Contrave falls on the side of benefits. Although that was the general conclusion of the panel, some members did not agree.

When the FDA conducts its own review of Contrave, it not only must decide on whether to approve the drug, but also on the drug’s label and on requirements for post-marketing studies. FDA action is expected by the end of January 2011.

As we discussed in a previous blog post, Takeda is Orexigen’s commercialization partner for Contrave. Under their agreement, 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. Takeda will also share the costs of further development of these drugs, presumably including any post-marketing studies.

As we also discussed in the same article, Takeda also has an agreement with Amylin to develop earlier-stage antiobesity drugs, with the potential for greater efficacy than drugs that address appetite-control pathways in the CNS that involve common neurotransmitters.

The approval of Contrave (if the FDA goes along with its Advisory Committee’s recommendations) may affect the strategy of Vivus and Arena as they work with the FDA to obtain reconsideration for approval of Qnexa and lorcaserin, respectively. And it might restart research on early-stage antiobesity drugs, which has been largely on hold as the pharmaceutical/biotechnology industry and the medical and financial communities awaited approval of one or more of the three drugs being reviewed by the FDA in 2010. And–by lifting the “pall of gloom” over the antiobesity drug field–it might improve funding and partnering prospects for such early-stage obesity specialist companies as Zafgen and Energesis, which we discussed in an earlier blog post.

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As the producers of this blog, and as consultants to the biotechnology and pharmaceutical industry, Haberman Associates would like to hear from you. If you are in a biotech or pharmaceutical company, and would like a 15-20-minute, no-obligation telephone discussion of issues raised by this or other blog articles, or of other issues that are important to  your company, please click here. We also welcome your comments on this or any other article on this blog.

Resveratrol

In statements to Fierce Biotech and to the Myeloma Beacon, GlaxoSmihtKline (GSK) said that it has stopped all development of its proprietary resveratrol formulation SRT501. Thanks also to the “In the Pipeline” blog for the information on the Myeloma Beacon statement.

As you all may recall, GSK acquired the sirtuin-pathway specialty company Sirtris (Cambridge, MA) for $720 million in June 2008. This gave GSK ownership of Sirtris’ sirtuin modulator drugs, including SRT501. GSK also appointed Christoph Westphal, then CEO of Sirtris, as the Senior Vice President of GSK’s Centre of Excellence in External Drug Discovery (CEEDD), and Michelle Dipp, then vice president of business development at Sirtris, as Vice President and the head of the US CEEDD at GSK.

According to the Fierce Biotech article, the precipitating factor in GSK’s decision to halt development of SRT501 was the result of a Phase 2a study of the drug in advanced multiple myeloma. The company suspended the study after several patients developed kidney failure. GSK said that in its analysis, the company concluded that SRT501 “may only offer minimal efficacy while having a potential to indirectly exacerbate a renal complication common in this patient population.” It then said that the company has “no further plans to develop SRT501.”

Instead, GSK intends to focus on development of Sirtris’ non-resveratrol synthetic selective sirtuin 1 (SIRT1) activators, which in addition to their greater potency, have more favorably drug-like properties. In its statement to the Myeloma Beacon, GSK in particular mentioned SRT2104 and SRT2379 as the focus of its continuing activity. According to the Sirtris website, SRT2104 is in Phase 2 studies in metabolic and cardiovascular disease, and SRT2379 is in Phase 1 studies in healthy volunteers. Neither compound is currently being tested in cancer.

We discussed Sirtris’ SIRT1 activators in the context of the anti-aging biology field, in a February 10, 2010 blog post. In summary, the mechanism of action of reseveratrol and of Sirtris/GSK’s sirtuin activators is unclear. They apparently activate multiple targets, and they may not be direct SIRT1 activators at all. Nevertheless, Sirtris’ studies of these compounds in mice indicate that they have efficacy in treatment of metabolic diseases. The Phase 2 clinical trials in humans are still ongoing.

To complicate matters further, a study published in the journal Diabetes in March 2010 by NIH researcher Jay H. Chung and his colleagues indicates that resveratrol works indirectly, via the energy sensor AMP-activated protein kinase (AMPK), to activate sirtuins. Since activation of AMPK increases fatty acid oxidation and upregulates mitochondrial biogenesis, the effect of resveratrol on AMPK may be more important than its more indirect activation of sirtuins, at least in the case of metabolic diseases.

Thus Sirtris/GSK’s “sirtuin activators” are under a cloud.

However, as we discussed in our blog posts of November 8, 2009 and February 10, 2010, basic research on anti-aging biology has yielded ample material for drug discovery which may eventually lead to novel treatments for metabolic diseases, and perhaps for other conditions such as various cancers. For example, several companies are developing AMPK activator drugs. Thus there are other avenues for harnessing basic research on anti-aging pathways to discover and develop novel drugs for multiple conditions, even if the Sirtris compounds prove to be a dead end.

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As the producers of this blog, and as consultants to the biotechnology and pharmaceutical industry, Haberman Associates would like to hear from you. If you are in a biotech or pharmaceutical company, and would like a 15-20-minute, no-obligation telephone discussion of issues raised by this or other blog articles, or of other issues that are important to  your company, please click here. We also welcome your comments on this or any other article on this blog.

Brown fat deposits in a young woman. Source: Hellerhoff. http://bit.ly/9RNG69

As we said in our November 3, 2010 blog post, “The withdrawal of Meridia from the market, coupled with the FDA rejections of lorcaserin and Qnexa, has cast a pall of gloom on the obesity drug market. Some commentators have declared the field to be dead….”

Nevertheless, a few hardy entrepreneurs and venture capitalists continue to found and fund start-ups, whose goal is to discover and develop truly innovative classes of drugs for obesity and metabolic disease.

A November 3, 2010 Xconomy article focused on the Cambridge, MA startup biotech firm Energesis Pharmaceuticals. Energesis was confounded by Olivier Boss, PhD (formerly of Sirtris Pharmaceuticals), Brian Freeman, MD (former Venture Partner at GreatPoint Ventures), and Jean-Paul Giacobino, MD (Professor Emeritus, University of Geneva Medical School, Switzerland). Dr. Boss serves as Energesis’ Chief Scientific Officer, and Dr. Freeman as its Chief Operating Officer.

Energesis focuses on the discovery and development of drugs for the treatment of obesity, diabetes, and related metabolic diseases. The company plans to develop therapeutics that work by increasing energy expenditure, rather than the usual approaches of decreasing appetite or blocking absorption of fat in the gut. Energesis researchers intend to discover and develop drugs that increase the amount and/or activity of brown adipose tissue (BAT) to combat obesity and other metabolic diseases. BAT is a type of mitochondria-rich adipose tissue that burns fat and dissipates the energy as heat rather than storing it. The mitochondrial protein UCP1 (uncoupling protein 1) is the key biomolecule that makes this process possible. BAT has long been known to be central to non-shivering thermogenesis in rodents, for example to maintain body temperature when they are exposed to cold.

Until recently, researchers believed that in humans, significant populations of BAT cells were found only in infants. However, in recent years researchers found that adult humans possess reservoirs of brown fat in the neck region and other areas of the upper body as well as in skeletal muscle. (See the figure above.) Adult human BAT can be stimulated by acute exposure to cold and via the sympathetic nervous system, and by various pharmacological agents. Energesis’ drug discovery technology is based on the use of brown fat stem cells. The company has provided few details on its technology in published sources.

In October 2010, Energesis was named as one of the winners of the 2010 MassChallenge Global Startup Competition, where it was the top life sciences company. In that competition, Energesis was also one of the top 111 entrants that were invited to participate in a 3-month accelerator program. This provided intensive mentoring, and access to such resources as office space, legal counsel, and introductions to funding sources. Energesis, which has temporary office space in the Cambridge MA incubator Dogpatch Labs (created by venture capital firm Polaris Ventures), is now seeking additional seed-stage funding.

Brian Freeman is key to Energesis’ financing strategy. As a Venture Partner at GreatPoint Ventures, Dr. Freeman cofounded another Cambridge MA company that focuses on obesity, Zafgen. Zafgen was founded in 2005. We discussed Zafgen briefly in an earlier blog post. Zafgen’s drug discovery and development profile is based on targeting the vasculature of adipose tissue, similarly to targeting tumor angiogenesis. Zafgen already has a compound, ZGN-433 (which is a methionine aminopeptidase inhibitor), in Phase I development, and is working on earlier-stage compounds. Thus, like Energesis, Zafgen targets a novel weight-control mechanism that does not involve appetite control in the CNS or fat absorption in the gut.

Zafgen has venture funding not only from GreatPoint, but also from Atlas Ventures and Third Rock Ventures. It was named as one of the “Fierce 15” leading biotechnology companies of 2009 by FierceBiotech.

Meanwhile, another Cambridge MA biotech company, Acceleron Pharma, discovered a compound, ACE-435, which targets BAT.  ACE-435 inhibits signaling of members of the TGF-beta protein superfamily. in preclinical studies in obese animals, ACE-435 increased brown fat, decreased white fat, increased skeletal muscle, and dramatically lowered serum cholesterol and triglyceride levels. Acceleron is developing ACE-435 for treatment of metabolic diseases. The company was named as one of the “Fierce 15” biotech companies in 2010.

Acceleron, which was founded in 2004 and has three products in the clinic, has raised three rounds of venture capital, and has a major corporate alliance with Celgene. In September 2010, it also signed a $498 million agreement with Shire to develop muscular dystrophy drugs. Acceleron is thus a more mature company than Zafgen or Energesis. Unlike Zafgen and Energesis, Acceleron works in several therapeutic areas, not just obesity and metabolic diseases.

The entrepreneurs who founded obesity specialists Zafgen and Energesis–as well as the venture capitalists who funded Zafgen, and the executives and researchers at Acceleron who have been developing ACE-435–are working on obesity drug development despite the pall of gloom caused by the failures of nearly every antiobesity drug, and the increasing currency among leaders of health insurance companies and health care providers of the old idea that obesity is entirely the fault of the obese, due to “lack of personal responsibility” or “food addiction”. This is despite the abundant evidence that obesity is a complex disease with a large genetic component. Health care leaders, as well as obese people themselves, are frustrated with the lack of solutions to the growing obesity problem, and thus may be tempted to fall back on old, discredited explanations.

The entrepreneurs, researchers, and venture capitalists behind Energesis, Zafgen, and Accleron, however, see the failure of most antiobesity drugs as an opportunity. The failed drugs target common neurotransmitter receptors in the CNS, and thus would be expected to have serious adverse effects, since these receptors are involved in multiple physiological processes in the CNS and elsewhere in the body. Drugs that target physiological pathways other than appetite control in the CNS, and which are based on superior biology-driven drug discovery strategies, may avoid the safety problems of the CNS-acting drugs, as well as exhibiting much greater efficacy. Such drugs may fulfill the major unmet medical need in the obesity area, where there are currently no good solutions.

The founding of Zafgen and Energesis also flies in the face of the current negative situation in the venture capital and credit markets, and in the economy in general.  Small companies (especially including startups) continue to find it difficult to raise cash. More established biotech companies, as well as pharmaceutical companies, also feel the need to cut budgets and especially to cut their workforces to save cash. In the Boston area, Big Biotechs Genzyme (which has been facing a hostile takeover from Sanofi Aventis, and which is in discussions to sell itself to Takeda) and Biogen Idec have slashed workforces and budgets, as has contract research firm and animal model supplier Charles River Laboratories. Acceleron also cut its workforce in November 2010.

Nevertheless, both Acceleron and Zafgen (the latter under the leadership of Brian Freeman) have managed to raise significant amounts of venture capital in this tough market. In the case of Zafgen, this is despite the generally gloomy prospects for antiobesity drugs, which are its dedicated focus. We hope that Energesis, in Dr. Freeman’s capable hands, will also be able to bring in Series A venture funding.

The type of entrepreneurial innovation shown by Energesis, Zafgen, and Acceleron has implications beyond the obesity area. In a recent speech, the CEO of Lilly, John C. Lechleiter, Ph.D. outlined the components of an environment that supports medical innovation. (We citied Dr. Lechleiter’s speech in an earlier blog post on the obesity drug market.) Among these components is what Dr. Lechleiter called “a larger ‘ecosystem’ that allows innovation to flourish”.  Such an ecosystem would include an “atmosphere” that allows innovation to thrive, “nutrients” in the form of monetary investments, and the “seeds” of human talent in relevant scientific disciplines.

The development of Zafgen and Energesis illustrates the importance of the Boston area biotech and pharmaceutical innovation hub in fostering the initiation and growth of biotech companies with innovative strategies that are potentially game-changing, by providing such an ecosystem. This has included entrepreneurial researchers with innovative ideas and intellectual property, lead venture capitalists willing to back their ideas (and, as in the case of Brian Freeman, to leave their venture capital firms and to join with the researchers in a start-up), universities such as Harvard, MIT, Tufts, and Boston University, the large numbers of biotech companies, both large and small, in greater Boston, the presence of Big Pharma facilities including Novartis’ R&D world headquarters, incubators such as Dogpatch Labs, and entrepreneurship competitions such as the MassChallenge and the MIT Enterprise Forum’s 100K competition.

The United States has other biotech/pharma innovation hubs as well, most notably the San Francisco Bay area and greater San Diego. As shown by the example of ZymoGenetics (see our November 11, 2010 blog post), Greater Seattle has been such an innovation hub, although biotech leaders in Seattle are afraid that their hub has been eroded by acquisitions such as that of ZymoGenetics by Bristol-Myers Squibb and the earlier Amgen-Immunex merger, with the resulting substantial layoffs. Other major U.S. biotech/pharma hubs include the Research Triangle Park area of North Carolina and greater New York/New Jersey/Philadelphia. Canada and several Western European countries also have biotech/pharma innovation hubs.

Various other cities and states in the U.S., as well as cities and countries in Europe and South and East Asia, are working to build new biotech hubs to bolster their economies. Big Pharma companies, with their massive need to acquire or partner for new, innovative drugs, must also develop strategies to foster ecosystems for innovation, both within their own organizations and in seedbeds for potential partners such as existing and emerging biotech hubs. The example of the role of the greater Boston area in spawning such companies as Energesis, Zafgen, Acceleron, and several others that have been covered in this blog may provide case studies to help Big Pharmas in formulating new strategies to foster innovation.

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As the producers of this blog, and as consultants to the biotechnology and pharmaceutical industry, Haberman Associates would like to hear from you. If you are in a biotech or pharmaceutical company, and would like a 15-20-minute, no-obligation telephone discussion of issues raised by this or other blog articles, or of other issues that are important to  your company, please contact us. We also welcome your comments on this or any other article on this blog.

sibutramine

As we reported in several earlier blog posts, 2010 has been a very busy year for FDA review of antiobesity drugs. At the same time, as we also reported, sibutramine (Abbott’s Meridia/ Reductil), one of the only two antiobesity agents on the market, had been under review by regulatory agencies because of cardiovascular safety concerns. In January 2010, sibutramine was suspended from the market in Europe. Early in 2010, the FDA also issued a warning that sibutramine posed an increased risk of heart attack and stroke in patients with a history of cardiovascular disease. This resulted in an additional contraindication on the drug’s label.

On October 8, 2010, at the FDA’s request, Abbott voluntarily withdrew Meridia from the U.S. market. This leaves only one approved antiobesity drug–orlistat (Roche’s Xenical–also marketed as a low-dose over the counter formulation, GlaxoSmithKline’s alli)–on the market. Orlistat’s adverse effects are unacceptable to many patients, and its efficacy is minimal.

The FDA’s request to withdraw Meridia from the market was based mainly on the results of the SCOUT (Sibutramine Cardiovascular OUTcome Trial) study. This was a 10,744 patient, 6-year study designed to evaluate cardiovascular safety of sibutramine in obese patients over age 55 with preexisting cardiovascular disease, diabetes, or both. Most of these patients had underlying cardiovascular disease, which made them ineligible to receive sibutramine under its then current labeling. The study had been requested of Abbott by European regulatory authorities as a post-marketing commitment. The SCOUT study showed that patients with a preexisting cardiovascular condition receiving long-term treatment with sibutramine had an increased risk of nonfatal myocardial infarction and nonfatal stroke, but not of cardiovascular death or death from any cause.

According to Abbott, the great majority of studies of sibutramine (46 controlled clinical trials and over 6 million patient years of use in the 13 years since the drug’s entry onto the market) in patents in the on-label population showed no such excess cardiovascular risk as in the SCOUT study. Abbott therefore believes that Meridia has a positive risk/benefit profile in the approved patient population. However, the FDA was concerned that patients with undiagnosed cardiovascular disease might be harmed by the drug, and that since the efficacy of the drug was minimal, the risk/benefit ratio was unfavorable. Therefore, the FDA requested that Meridia be withdrawn, and Abbott, despite its objections, complied.

Also in October 2010, in accord with the recommendation of its Endocrinologic and Metabolic Drugs Advisory Committee, the FDA issued a Complete Response Letter to Arena Pharmaceuticals regarding its New Drug Application for lorcaserin (Lorqess). (See our discussion of the advisory committee’s recommendations. The FDA requested additional data from Arena regarding studies of tumor formation in rats receiving lorcaserin, and regarding final study data from a clinical study of lorcaserin in patients with type 2 diabetes.

In the same month, and also in accord with the recommendation of its Endocrinologic and Metabolic Drugs Advisory Committee, the FDA issued a Complete Response Letter to Vivus Pharmaceuticals regarding its New Drug Application for Qnexa (phentermine/topiramate). (See our discussion of the advisory committee’s recommendations. The FDA requested additional data from Vivus regarding the results of an extension study of Qnexa in patients who had already completed a previously-reported trial, as well as an assessment of topiramate and phentermine/topiramate’s teratogenic potential. The agency also requested evidence that the elevation in heart rate associated with Qnexa does not increase the risk of major cardiovascular events.

A third preregistration-stage antiobesity drug, Contrave, (bupropion/naltrexone) is up for review by the Endocrinologic and Metabolic Drugs Advisory Committee in December 2010.

The withdrawal of Meridia from the market, coupled with the FDA rejections of lorcaserin and Qnexa, has cast a pall of gloom on the obesity drug market. Some commentators have declared the field to be dead, and have stated that the FDA’s safety standards require antiobesity drugs to have safety profiles comparable to diet and exercise. However, John Jenkins, M.D., director of the FDA’s Office of New Drugs, Center for Drug Evaluation and Research (CDER), said in an interview that the FDA was “committed to working toward approval” of new obesity drugs, “so long as they are safe and effective for the population for which they are intended.”

Meanwhile, on September 21, 2010, the Lasker Foundation announced that its 2010 Lasker Award for Basic Medical Research was given to Drs. Douglas Coleman (Jackson Laboratory) and Jeffrey M. Friedman (Rockefeller University) for “the discovery of leptin, a hormone that regulates appetite and body weight—a breakthrough that opened obesity research to molecular exploration.”

Mouse researcher Coleman, working with obese diabetic mouse strains in the 1960s, showed that an appetite-suppressing substance (encoded by the ob gene) circulates in the bloodstream and signals a second molecule (encoded by the db gene) to curb hunger. Molecular geneticist Friedman, in the 1990s, showed that the ob gene encoded a hormone called leptin. The db gene encodes the leptin receptor. Leptin is produced by fat cells and is released into the circulation, and signals via leptin receptors in the hypothalamus of the brain to curb appetite and control fat mass. Although obese humans have elevated levels of leptin, these high levels of leptin fail to control fat mass. Obese humans are therefore said to be leptin resistant.

Leptin resistance caused the clinical failure of Amgen’s recombinant leptin product metreleptin, although this product does help humans with a rare familial type of morbid obesity that is caused by a loss-of-function mutation in the human homologue of the mouse ob gene. So far, researchers have not been able to unravel the mechanisms of leptin resistance in humans.

The Lasker Award-winning research on leptin showed once and for all that obesity is a complex disease which results from both genetic and environmental factors. Subsequent research has abundantly confirmed this picture. Most recently, a large genome-wide association study (GWAS) of body-mass index confirmed 14 known obesity susceptibility loci, and identified 18 new loci, including one copy number variant. These results add to the picture of obesity as a complex disease, and genes in some of the new loci may provide new insights into body weight regulation in humans. This research may also provide new leads for drug discovery and development.

The development of the three preregistration drugs that have been up for review by the FDA–lorcaserin, Qnexa, and Contrave–owe very little to the basic research on the genetics of obesity begun by Drs. Coleman and Friedman. The discovery and development of these drugs has been based on the same strategy as the development of such antiobesity drugs as phentermine, dexfenfluramine, and sibutramine–target common receptors in the CNS that are involved in (or deemed to be involved In) appetite control.

The only way that this strategy benefits from the study of the genetics of obesity is that that work demonstrated that obesity is indeed a disease, not just due to a failure of willpower. Therefore, there is a rationale to develop drugs to treat obesity. Nevertheless, so far the appetite-suppressant strategy has been a failure, leading to clinical attrition or expensive postmarketing safety failures, with the resulting product withdrawals and lawsuits.

As we discussed in previous blog posts, appetite suppressant drugs that address common neurotransmitter receptors might be expected to have significant adverse effects, since their targets are involved in multiple CNS and/or peripheral tissue pathways. They also tend to have low efficacy, as is true for all of these drugs so far except for Qnexa.

The drug candidate that is specifically based on the Lasker Award-winning discovery of leptin by Drs. Coleman and Friedman is Amylin/Takeda’s combination product pramlintide/metreleptin. We discussed this drug in an earlier blog post. A proof-of-concept study of pramalintide/metreleptin showed that this product was well tolerated, and gave a 12.7% mean weight loss in patients treated for 24 weeks. This appears to be superior to the efficacy of any antiobesity drug that is or ever has been on the market, as well as to lorcaserin and Contrave.  Amylin and Takeda are moving to enter pramlintide/metreleptin into Phase III clinical trials.

We also discussed other drug discovery and development programs that are based on alternative strategies to CNS-targeting appetite suppressants in an earlier blog post.

The recent Advisory Panel and FDA reviews of antiobesity drugs in 2010 not only highlight the inadequacy of the CNS-targeting appetite suppressant strategy, but also the importance of regulatory policy in fostering development of innovative drugs that address unmet medical needs. In a  Nov. 3, 2010 speech at the Cleveland Clinic Medical Innovation Summit, John C. Lechleiter, Ph.D., the chairman, president and CEO Lilly outlined the need for new, innovative drugs to address the epidemic of type 2 diabetes, in the United States and in the world. Dr. Lechleiter considers diabetes to be part of a network of complex conditions, including not only diabetes, but also obesity and metabolic syndrome.

In addition to the development of novel research and clinical trial strategies in academia, biotech companies, and pharmaceutical companies, Dr. Lechleiter sees the need for “public policies that enable and reward medical innovation.” Dr. Lechleiter said, “To sustain progress against diabetes, public policies – including benefit/risk assessments, reimbursement decisions, and prescribing guidelines – must enable and foster true medical innovation.”

This includes “creation of a systematic and transparent regulatory approach to assessing the benefits and risks of new medicines.” Dr. Lechleiter noted the ongoing discussions with the FDA on the Prescription Drug User Fee Act, which is up for reauthorization in 2012. He sees these discussions as offering an opportunity for a “real victory for innovation and for patients.”

In the area of obesity–which is a major risk factor for type 2 diabetes and cardiovascular disease (CVD)–there is a need for both innovative strategies to develop a new generation of safe and efficacious drugs (especially for obese patients who have–or are at high risk of developing–diabetes and/or CVD), and a regulatory environment that fosters successful development and marketing of such innovative drugs. This will require negotiation between industry and the FDA, as well as other stakeholders involved in policy decisions that affect the development, approval, reimbursement, and market acceptance of innovative drugs for obesity and its complications.

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