FDA logo for illustration purposes only.

On September 23, 2010, the FDA made its decision on  what to do about the antidiabetic drug rosiglitazone (GlaxoSmithKline’s [GSK’s] Avandia), based largely on the July 15, 2010 recommendations of the agency’s Endocrinologic and Metabolic Drugs Advisory Committee. That committee had voted to keep Avandia on the market with some new restrictions, because of cardiovascular safety concerns with the drug. But the committee was deeply divided with respect to the specifics of these restrictions, and whether Avandia should remain on the market at all.

The FDA decided to restrict access to Avandia by requiring GSK to submit a Risk Evaluation and Mitigation Strategy (REMS). After implementation of the REMS, Avandia will be available to patients not already taking it only if they are unable to achieve glycemic control using other drugs and, who decide not to take pioglitazone (Takeda’s Actos) for medical reasons in consultation with their physician. Patients now on Avandia will be able to continue using the drug if they appear to be benefiting from it and they acknowledge that they understand the drug’s risks. Doctors will have to attest to and document their patients’ eligibility; patients will have to review statements describing the cardiovascular safety concerns. These new restrictions should significantly limit the use of Avandia, whose use has already declined precipitously.

FDA officials Drs. Janet Woodcock, Joshua Sharfstein, and Margaret Hamburg (who is the FDA Commissioner) published the reasoning behind their decision in the New England Journal of Medicine.

On September 23, 2010, the European Medicines Agency (EMA) also took regulatory action on rosiglitazone. This agency recommended that the drug, marketed as Avandia, Avandamet and Avaglim in Europe, be taken off the market. These drugs will no longer be available in Europe within the next few months. The EMA published a question and answer document on its action.

During August and September 2010, we published a series of three articles on this blog on the safety issues with rosiglitazone and the other marketed drug of the insulin sensitizing thiazolidinedione (TZD) class pioglitazone, as well as how the biotechnology/pharmaceutical industry might develop improved, safer, and more efficacious insulin sensitizers. These articles are:

• “Avandia squeaks through an FDA Advisory Panel. But can the pharmaceutical/biotechnology industry develop better insulin sensitizers?”

• “Can the pharmaceutical/biotechnology industry develop better insulin sensitizers? A breakthrough result in the biochemistry of PPARγ.”

• “How might the pharmaceutical/biotechnology industry develop better insulin sensitizers?”

Please read these articles if you have not already done so.

Because of the key importance of insulin resistance in the pathogenesis of type 2 diabetes, and because of the major unmet needs in treatment of this disease, we believe that it is important to work to develop novel, innovative insulin sensitizers that can overcome the deficiencies of the TZDs and hopefully fill at least some of these unmet needs. These articles outline ways in which the industry might be able to accomplish this objective.

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.

PPAR complex coactivator interaction

This is part 3 of a three-part series on insulin sensitizers for treatment of type 2 diabetes.

In part 1 of the series (posted August 23, 2010), we focused on safety issues with the two marketed thiazolidinedione (TZD) peroxisome proliferator-activated receptor gamma (PPARγ) agonists–rosiglitazone and pioglitazone (Takeda’s Actos). Both of these insulin sensitizing, antidiabetic agents induce weight gain, and carry an increased risk of edema and heart failure. In addition, rosiglitazone carries an increased risk of myocardial infarction. Because of the latter risk, some critics would like to see it removed from the market. However, on July 15, 2010, by a close vote the FDA’s Endocrinologic and Metabolic Drugs Advisory Committee voted to leave rosiglitazone on the market, with some new restrictions.

In part 2 of the series (posted on August 29, 2010, we discussed a breakthrough discovery by Bruce Spiegelman (Dana-Farber Cancer Institute and Harvard Medical School, Boston MA) and his colleagues, published in the 22 July issue of Nature. It was the Spiegelman group that originally identified PPARγ as the master regulator of adipocyte biology and differentiation, which eventual led to the development of the TZD drugs.

In the new research, the Spiegelman group found evidence that the insulin sensitizing and antidiabetic effects of PPARγ agonists may not be due to the agonistic effects of these compounds on PPARγ, but to their ability to inhibit phosphorylation (at Ser 273) of PPARγ by the enzyme cyclin-dependent kinase 5 (CDK5). A weak PPARγ agonist, the benzoyl 2-methyl indole (non-TZD) MRL24, inhibits CDK5 phosphorylation of PPARγ as well as rosiglitazone, and also has very good antidiabetic activity. MRL24 had been discovered by Merck in 2005.

CDK5 phosphorylation of PPARγ does not change the ability of PPARγ to upregulate transcription of genes involved in adipocyte differentiation. However, it inhibits the ability of PPARγ to upregulate transcription of a set of genes, including the gene for the adipokine adiponectin, that induce insulin sensitivity and resistance to obesity. Although both rosiglitazone and MRL24 inhibit CDK5 phosphorylation of PPARγ, treatment with the strong agonist rosiglitazone results in upregulation of both the adipogenic and the pro-insulin resistance sets of genes, while treatment with MRL24 results only in upregulation of the pro-insulin resistance set.

The Spiegelman group’s research indicates that the difference between the action of rosiglitazone and MRL24 is due to the different conformational changes induced in the PPARγ protein molecule by binding of the two compounds. The researchers hypothesized that these two different conformational changes may change the way in which PPARγ interacts with coregulator proteins. Nuclear receptors work together with coregulators (i.e., coactivators and corepressors) to regulate specific sets of genes. Different ligands (natural or synthetic) that modulate nuclear receptor interactions with its coregulators can give different results in terms of which genes are unregulated or downregulated.

Researchers hypothesize that it is the upregulation of the adipogenic gene set that is responsible for the adverse effects of strong agonists of PPARγ–weight gain, edema, and the risk of heart failure. In contrast, the upregulation of adiponectin and the other members of the pro-insulin resistance gene set is thought to be responsible for the desirable, antidiabetic effect of PPARγ agonists. If researchers could develop synthetic PPARγ ligands that would induce PPARγ upregulation of the pro-insulin resistance gene set but not the adiopgenic gene set, these compounds might constitute improved, second-generation insulin sensitizers that would have the desirable effects of the TZDs with fewer adverse effects.

In the 22 July 2010 issue of Nature, there are two essays that discuss using the new breakthrough results of the Spiegelman group to discover and develop such improved insulin sensitizers. These are a News and Views article by metabolic disease researchers Riekelt Houtkooper and Johan Auwerx (Ecole Polytechnique Federale de Lausanne [EPFL] in Switzerland), and a Nature News article by Boston-based journalist Heidi Ledford, Ph.D. of Nature.

In the Houtkooper and Auwerx article, the authors advocate changing screening strategies for PPARγ-modulating drugs, to look for those that inhibit CDK5 phosporylation of PPARγ rather than those that are strong PPARγ agonists. Potential PPARγ-modulating drugs would also induce conformational changes in the PPARγ protein that support its recruitment of coregulators that have favorable effects on metabolism (e.g., induce insulin sensitivity and/or protect against obesity). Specifically, these authors suggest that researchers determine whether CDK5-mediated PPARγ phosphorylation enhances recruitment of coactivators such as TIF2/SRC-2 and RIP140 (which unfavorably affect metabolism), and inhibits recruitment of coactivators such as SRC-1 and PGC-1, which have a favorable effect on metabolism. If this is true, drugs that inhibit CDK5 phosporylation of PPARγ should shift the balance toward recruitment of cofactors that favorably affect metabolism (i.e., promote insulin sensitivity and resistance to obesity).

Houtkooper and Auwerx also advocate biochemical and genetic research on the multiple roles of CDK5 and its upstream regulators in metabolic pathways and disorders, as well as research to identify a PPARγ phosphatase that reverses the effects of CDK5 on PPARγ. These authors do not advocate screening for CDK5 inhibitors. (Several already exist, such as roscovitine, which also inhibits several CDKs that are involved in the cell cycle, and is being developed as the anticancer drug Seliciclib by Cyclacel).  CDK5 inhibitors would interfere with CDK5’s other functions, including in the central nervous system. Instead, drug discovery researchers should focus on discovering compounds that specifically change the conformation of PPARγ so that CDK5 phosphorylation of that molecule is inhibited.

In Heidi Ledford’s News article, she also advocates that pharmaceutical companies screen for inhibition of PPARγ phosphorylation, rather than strong activation of PPARγ. She also reviews the rocky history of the “glitazone” class of drugs (i.e., TZDs and related compounds), many of which have exhibited various safety problems that have kept them from the market or removed them from it. (You can see our take on this history in two 2006 articles on our website [here and here). Some commentators therefore believe that companies are unlikely to perform any new screens to identify PPARγ modulators, given the recent conflicts over Avandia and the checkered history of the glitazones. Other commentators counter that because of the large and growing type 2 diabetes market ($20.2 billion in 2008 and a projected $37.9 billion in 2018), companies will be tempted to try some new drug discovery efforts based on the new Spiegelman research. However, others counter that the new Spiegelman results are only preliminary. In any case, if drug developers would start the new screens now, it would take around 10-15 years for any new drugs to appear on the market.

But some companies may not need to start from scratch, by screening for novel compounds that inhibit CDK5 phosphorylation of PPARγ. These companies already have potential second generation insulin sensitizers in clinical development. In our published 2006 article “Safety Issues Hamper Dual PPAR Agonists Is Partial Antagonism the Solution?”, we discussed safety issues both with PPARγ agonists, and with two PPARγ/PPARα dual agonists that were in late-stage development but were discontinued in 2006 because of adverse cardiovascular events. (PPARα is another PPAR nuclear receptor that is involved in control of lipid metabolism, especially of serum triglycerides and high density lipoprotein [HDL].) We proposed that development of what we called “partial agonists” of PPARs might be a solution to these safety problems. “Partial agonists” of PPARγ and of other PPARs are also called “selective PPAR modulators”. In the case of PPARγ, selective modulators are compounds that are less active in activating pathways that result in adipogenesis than strong agonists such as rosiglitzone and pioglitazone, while still upregulating pathways involved in insulin resistance.

In our 2006 article, we especially focused on a compound then called metaglidasen, which was being developed by Metabolex (Hayward, CA) and Johnson & Johnson (JNJ). This non-TZD drug is now called MBX-102/JNJ39659100. Metabolex and JNJ had tested MBX-102 for treatment of type 2 diabetes in eight Phase I and four Phase II clinical studies. However, according to the Metabolex website, the companies have repurposed the drug to treat gout, after discovering that MBX-102 is an effective uricosuric agent (i.e., it increases the excretion of uric acid in the urine).

MBX-102 is a single optical isomer of halofenate, a compound that had been studied in the 1970’s by Merck as a lipid-lowering agent. Halofenate was serendipitously found to be an insulin sensitizer; Metabolex produced a form of the drug that contained only the active optical isomer, and developed it as MBX-102.

in a 2009 paper, researchers showed that MBX-102 had insulin sensitizing and serum glucose-lowering effects in diabetic rat models (but with much lower potency than rosiglitazone), without the weight gain seen with TZDs. In vitro, MBX-102 did not drive human and mouse adipocyte differentiation, unlike TZDs. Moreover, MBX-102 had a greatly reduced ability to recruit PPARγ coactivators. MBX-102’s ability to recruit coactivators that favorably affect metabolism (SRC-1 and PGC-1) was significantly greater than its ability to recruit coactivators that unfavorably affect metabolism (such as TIF2/SRC2). MBX-102 also potently mediated transrepression of proinflammatory genes in vitro and in vivo. Earlier preclinical studies, discussed in our 2006 article, indicated that MBX-102 produced less cardiac hypertrophy in animals than rosglitazone, and also preserved the function of pancreatic beta cells.

Metabolex had also been developing a second selective PPARγ modulator, MBX-2044, a more potent follow-on compound to MBX-102, which reached Phase II of development. However, due to the company’s limited resources, it cannot conduct Phase III clinical trials without partners, especially the large Phase III trials required for diabetes. Therefore, Metabolex has shelved MBX-2044 for now, and has repurposed MBX-102 for gout, in partnership with JNJ. In a June 23 news release, Metabolex characterized itself as “a research-based company…not a commercial company” However, Metabolex is likely to seek to retain co-promotion rights in any commercialization agreement with pharmaceutical companies.

Meanwhile, another biotech company, InteKrin Therapeutics (Los Altos, CA) is developing another selective non-TZD PPARγ modulator, INT131. InteKrin had licensed the drug (formerly known as AMG131 and originally discovered by Tularik) from Amgen in January 2007. Unlike MBX-102, INT131 was purposefully designed to be a selective PPARγ modulator. INT131 has been in Phase II clinical trials for treatment of type 2 diabetes. in a 2009 paper, Amgen researchers showed that INT131 exhibited a different pattern of PPARγ coregulator recruitment from TZDs. in adipocytes, INT131 only minimally activated genes involved in adipogenesis, and exhibited a greater degrees of activation of genes involved in mediating insulin sensitivity. In a diabetic rat model, INT131 had a similar effect on glucose metabolism to rosiglitazone, with similar potency. But unlike rosigliatazone, INT131 did not induce weight gain, cardiac hypertrophy, or edema, in both rodents and nonhuman primates. In Phase IIa clinical trials (as published by InteKrin in 2010, INT131 showed potent glucose lowering (even at the low, 1 mg dose), without weight gain and fluid retention. High-dose (10 mg) INT131 provided apparently greater benefit to glucose metabolism than maximal-dose TZDs, without weight gain and fluid retention. InteKrin has tested INT131 in Phase IIb clinical trials, in which the drug gave comparable glycemic control to pioglitazone, but without edema and with minimal weight gain. The company has completed an End-of-Phase II meeting with the FDA, and is moving INT131 into Phase III clinical trials.

In order to “close the loop” in comparing studies of such compounds as MBX-102, MBX-2044, and INT131 with the new Spiegelman studies of the mechanism of insulin sensitization by PPARγ modulators, researchers would need to test these compounds for inhibition of phosphorylation of PPARγ by CDK5. Such studies have not yet been done.

While we were completing preparation of this three-part series of articles for our blog, a two-page “News and Analysis” article on selective PPAR (including PPARγ and the two other human PPARs) modulators was published in this month’s (September 2010) issue of Nature Reviews Drug Discovery (NRD). As with our blog posts, this article discussed (in a briefer format) the July 2005 FDA Advisory Committee recommendations on Avandia, the recently published Spiegelman article on the effects of insulin sensitizers on PPARγ phosphorylation by CDK5, and the prospects for selective PPARγ modulators as therapeutics for type 2 diabetes.

The NRD article not only discusses selective PPARγ modulators developed by InteKrin and Metabolex (with the latter company’s PPARγ modulators only being listed in a table), but also selective agonists of other PPARs, including single compounds that address multiple PPARs. Among these compounds is Metabolex’ selective PPARδ agonist MBX-8025 (formerly RWJ-800025, in-licensed from Janssen Pharmaceutica). PPARδ regulates genes involved in multiple aspects of the metabolic syndrome, including lipid storage and transport, fatty acid oxidation, and insulin sensitivity. MBX-8025 is being developed for treatment of mixed dyslipidemia and metabolic syndrome. In late 2008, MBX-8025 completed a Phase II proof-of-concept clinical trial, in which the compound was found to substantially reduce serum triglycerides, increase HDL, lower low-density lipoprotein (LDL), and improve insulin sensitivity in obese patients with metabolic syndrome. The effects of MBX-8025 are complementary to the LDL-lowering effects of statins such as atorvastatin (Pfizer’s Lipitor).

Another compound discussed in the NRD article is Roche’s rationally designed balanced dual PPARα/PPARγ activator aleglitazar, which is in Phase III development for treatment of patients with type 2 diabetes who have experienced a recent acute coronary syndrome.  This compound is designed to combine the improvements in insulin sensitivity associated with activation of PPARγ with the amelioration of dyslipidemia associated with activation of PPARα. Roche believes that aleglitazar will avoid the adverse cardiovascular effects seen with earlier dual PPARα/PPARγ activators, or “glitazars”, as discussed in our 2006 article. A 2009 clinical trialshowed that aleglitazar had a positive effect on lipid and glucose metabolism, with no induction of edema or congestive heart failure, and less weight gain than for pioglitazone, over a 16-week treatment period. These short-term results are encouraging, but must be confirmed by the results of ongoing Phase III trials.

Meanwhile, other companies, including Merck, the discoverer of MRL24, have been continuing to develop selective PPARγ modulators for treatment of type 2 diabetes.

In conclusion, the development of selective PPARγ agonists for type 2 diabetes, as we postulated in our 2006 article, is a promising approach to overcoming the issues with current PPARγ agonists, especially rosiglitazone/Avandia. However, it will be important to overcome the cloud that hangs over PPAR modulators, as the result of safety issues with such drug classes as TZDs and glitazars. Encouraging data from ongoing trials of second-generation, selective modulators will hopefully overcome these doubts, enabling companies to develop them and regulators to review them without prejudgment.

It will also be important to “close the loop” with the recent Spiegelman studies, by looking at the effects of these agents on PPARγ phosphorylation by CDK5. Moreover, screening of compounds for their effects on PPARγ phosphorylation may lead to the development of even better agents, especially if agents now in the clinic fail or give less than optimal results in late-stage trials. However, we hope that agents now in development (especially InteKrin’s INT131 and/or the two Metabolex agents if that company can find the resources from partners to complete development for diabetes) will prove to be safe and effective in clinical studies. In the longer term, it will be important to confirm that any new insulin sensitizers work to preserve beta-cell function (which would prevent progression of type 2 diabetes), and to determine if they lower the incidence of cardiovascular complications of diabetes. These are major unmet needs in treatment of type 2 diabetes.

PPARgamma

In part 1 of this three-part series (posted August 24, 2010), we discussed the recent action of the  Endocrinologic and Metabolic Drugs Advisory Committee regarding rosiglitazone (GlaxoSmithKline’s Avandia). The advisory committee, by a close vote, recommended to the FDA that it leave the drug on the market, with new restrictions (e.g., closer supervision and new label warnings).

Avandia and pioglitazone (Takeda’s Actos) are the only marketed members of the thiazolidinedione (TZD) class of peroxisome proliferator-activated receptor gamma (PPARγ) agonists. PPARγ is a nuclear receptor that controls glucose metabolism and adipocyte differentiation. In treatment of type 2 diabetes, TZD modulation of PPARγ results in decreased insulin resistance, thus enabling tissues such as muscle and fat to utilize insulin more efficiently for the uptake of glucose. Agents that work by decreasing insulin resistance are known as “insulin sensitizers”.

As discussed in our August 23 article, clinical evidence indicates that both Avandia and Actos induce weight gain in type 2 diabetics (who are usually obese to begin with), and carry an increased risk of edema and heart failure. Avandia also carries a significantly increased risk of myocardial infarction (MI). Critics of Avandia who want the drug removed from the market cite the increased risk of MI, and the availability of a safer TZD, Actos.

Despite the major safety issues with TZDs, there is both animal model and human evidence that these agents may work to preserve and/or enhance beta-cell function, and thus to help prevent progression of type 2 diabetes. Moreover, insulin resistance is a major factor in the pathogenesis of the disease. We therefore asked whether it might be possible to discover and develop better, safer insulin sensitizers that would have the desirable properties of the TZDs with fewer adverse effects. In this article, which is part 2 of the series, we discuss a recent breakthrough in the biochemistry of PPARγ that may enable companies to develop better insulin sensitizers. In part 3 of this series, we shall look at how companies might develop such compounds.

It was Bruce Spiegelman (Dana-Farber Cancer Institute and Harvard Medical School, Boston MA) and his colleagues who identified PPARγ as the master regulator of adipocyte biology and differentiation back in 1994. This eventually led to the discovery and development of TZDs such as Avandia and Actos, which are synthetic compounds that are strong agonists of PPARγ. These compounds act as potent insulin sensitizers, and are thus used in the treatment of type 2 diabetes. However, the mechanism of their insulin sensitizing activity is not clear. Administration of  TZDs result in decreased expression in adipose tissue of insulin-resistance inducing hormones such as tumor necrosis factor-alpha (TNF-α), interleukin-1 (IL-1) and resistin. They also induce increased expression of adiponectin, an adipose-derived hormone or adipokine (a member of a class of cytokines that are secreted by adipocytes) that acts as a natural insulin sensitizer.

In a July 2010 research article published in Nature, the Spiegelman group noted that the action of insulin-sensitizing PPARγ agonists does not make biological sense. Obese people and people with insulin resistance (including type 2 diabetics) have no deficiency in PPARγ or PPARγ activity. Therefore, why do synthetic activators of PPARγ have such dramatic insulin sensitizing and antidiabetic activity? Since PPARγ controls adipocyte differentiation, it makes good biological sense that PPARγ agonists can induce weight gain, however. But why do these inducers of weight gain also act as insulin sensitizers, while excessive weight is generally associated with increased insulin resistance? Finally, although the strong PPARγ agonists rosiglitazone and pioglitazone are insulin sensitizing and antidiabetic, some selective PPARγ modulators with poor agonist activity, such as the (non-TZD) benzoyl 2-methyl indole MRL24 (discovered by Merck Research Laboratories) have very good antidiabetic activity.

The Spiegelman group found that the enzyme cyclin-dependent kinase 5 (CDK5) phosphorylates PPARγ at serine 273 (Ser 273). There are no other CDK5 phosphorylation sites on PPARγ. Unlike other members of the CDK family, CDK5 is not a cell-cycle kinase that is regulated by a cyclin, but instead is regulated by p35/25, which are targets of numerous cytokines and other proinflammatory signals. Specifically, cytoplasmic p35, possibly in response to proinflammatory signals, is cleaved to form p25. p25 can then enter the nucleus, where it associates with and activates CDK5. The activated CDK5 can then phosphorylate PPARγ at Ser 273.

Treatment of adipocytes with proinflammatory cytokines or free fatty acids results in enhanced formation of p25, and enhanced phosphorylation of PPARγ at Ser 273. The same results occur in vivo, in mice that are fed a high-fat diet over a prolonged period of time, and thus become obese. It is well known that both free fatty acids and proinflammatory cytokines are elevated in obesity.

The researchers also found that phosphorylation of PPARγ at Ser 273 does not change the ability of PPARγ to upregulate transcription of genes involved in adipocyte differentiation. However, it inhibits the ability of PPARγ to upregulate transcription of certain other genes, including adiponectin. The insulin-sensitizing synthetic compounds rosiglitazone (a strong PPARγ agonist) and MRL24 (a weak PPARγ agonist) both inhibited phosphorylation of PPARγ at Ser 273 in adipocytes. However, treatment of adipocytes with these two compounds gave different results in terms of their effects on PPARγ-regulated genes. Treatment of fat cells with rosiglitazone resulted in upregulation of adiponectin and other genes that are downregulated by Ser 273 phosphorylation. But rosiglitazone treatment also resulted in upregualtion of PPARγ-regulated genes involved in adipogenesis. In contrast, treatment of adipocytes with MRL24 did not upregulate the genes involved in adipogenesis. But it did upregulate the gene set (including adiponectin) that was downregulated by phosphorylation of PPARγ at Ser 273.

Mass spectrometry studies indicated that both rosiglitazone and MRL24 changed the conformation of PPARγ in such a way as to make this protein less favorable for phosphorylation by CDK5. However, rosiglitazone and MRL24 binding results in different conformational changes. The researchers hypothesized that these conformational changes may change the way in which PPARγ interacts with coregulator proteins. Nuclear receptors work together with coregulators to regulate specific sets of genes. Different ligands (natural or synthetic) that modulate nuclear receptor interactions with its coregulators can give different results in terms of which genes are unregulated or downregulated.

The researchers then studied the action of roslglitazone and of MRL24 on phosphorylation of PPARγ at Ser 273 and on modulation of PPARγ-regulated genes in vivo. In mouse models, these two compounds inhibited PPARγ Ser 273 phosphorylation in adipose tissue, and caused similar changes in PPARγ-regulated gene expression as they do in adipose cells in vitro. Moreover, human diabetes patients treated with rosiglitazone usually exhibited decreased phosphorylation of PPARγ at Ser 273 in biopsied subcutaneous fat. However, in some cases, no such decreased phosphorylation was seen. Improvements in insulin sensitivity in these patients correlated with decreased phosphorylation of PPARγ at Ser 273.

On the basis of these results, the researchers concluded that the insulin sensitizing and antidiabetic effects of PPARγ agonists may not be due to the agonistic effects of these compounds on PPARγ, but on their ability to inhibit CDK5 phosphorylation of PPARγ.

In a News and Views article in the same issue of Nature, Riekelt Houtkooper and Johan Auwerx (Ecole Polytechnique Federale de Lausanne [EPFL] in Switzerland) postulate that the new findings of the Spiegelman group may be used to develop PPARγ modulating drugs that lack full agonist activity, but still inhibit CDK5 phosphorylation of PPARγ. Such compounds (of which MRL24 may be a starting point) would not upregulate adipogenic genes, but would upregulate insulin sensitizing genes such as adiponectin. These authors postulate that these novel compounds may thus have strong insulin sensitizing and antidiabetic effects, but would lack such adverse effects as weight gain, edema, and the risk of heart failure.

We shall discuss strategies for developing improved insulin sensitizers in greater depth in Part 3 of this series.

Avandia (rosiglitazone)

On July 15, 2010, the FDA’s Endocrinologic and Metabolic Drugs Advisory Committee voted to leave the diabetes drug rosiglitazone  (GlaxoSmithKline’s  Avandia) on the market, with some new restrictions (e.g., closer supervision and new label warnings). This is the same committee that voted against FDA approval of Vivus’ anti-obesity drug Qnexa on the same day, as discussed in our August 4 blog post. (Some commentators believe that the Qnexa rejection is connected to the decision on Avandia. We shall reserve judgment on that question.)

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

Of the 33-member panel, 10 voted to keep Avandia on the market under close supervision, seven voted to keep it on the market but with stronger label warnings, and three voted to keep the drug on the market with no new restrictions. Twelve voted to remove Avandia from the market. One member abstained.

One factor in the recommendations of several panelists to add restrictions or to eliminate Avanida from the market altogether is that a competing drug of the same thiazolidinedione (TZD) class, pioglitazone (Takeda’s Actos), appears to have similar efficacy to Avandia, but fewer adverse effects.

The panel members’ decisions were based on their analysis of large amounts (18 presentations worth) of contradictory data.

TZDs are agonists of peroxisome proliferator-activated receptor gamma (PPARγ), a nuclear receptor that controls glucose metabolism and adipocyte differentiation. In treatment of type 2 diabetes, TZD modulation of PPARγ results in decreased insulin resistance. (Insulin resistance is the inability of tissues such as muscle and fat to utilize insulin efficiently for the uptake of glucose.) Thus treatment with these drugs can result in decreased levels of serum glucose, and amelioration of diabetes. Agents that work by decreasing insulin resistance are known as “insulin sensitizers”.

We have been following safety issues with agonists of PPAR receptors for quite some time. For example, there are two articles (here and here) published in 2006 (and available on our website) that include discussion of PPAR agonist safety.

As discussed in these two articles, Steven Nissen, M.D. (now Chairman of the Robert and Suzanne Tomsich Department of Cardiovascular Medicine, Cleveland Clinic, Cleveland, OH) has been a leading critic of Avandia’s cardiac safety. This began with his 2007 meta-analysis of clinical studies of the drug, published in the New England Journal of Medicine. This meta-analysis indicated that treatment with Avandia was associated with a significant increase in the risk of myocardial infarction (MI), and an increase in the risk of cardiovascular death that had borderline significance. A 2010 meta-analysis by Dr. Nissen and his colleagues (published online ahead of print in the Archives of Internal Medicine on June 28) indicated that treatment with Avandia was associated with a significant increase in the risk of MI, but no increased risk of cardiovascular death or all-cause mortality. The results also suggest an unfavorable benefit to risk ratio for Avandia.

A retrospective study by FDA researchers of Medicare recipients published in the Journal of the American Medical Association in July 2010 indicated that Avandia treatment is associated with an increased risk of the composite of AMI, stroke, heart failure, and all-cause mortality as compared with Actos, in patients 65 years or older.

The consensus of multiple studies is that both Avandia and Actos induce weight gain, and carry an increased risk of edema and heart failure as compared with placebo, but that Avandia has a higher risk of MI than Actos. (Few studies directly compared the two drugs, however. The 2010 FDA study is an exception). However, some studies presented to the FDA Advisory Committee indicated that the risk of cardiovascular events were comparable between Avandia, Actos, and diabetes medications of other classes.

The panel’s decision was a compromise, based not only on the contradictory nature of the evidence, but also on the contention that Avandia may be a better choice than Actos (or other diabetes drugs) for certain groups of patients, but not others. However, the continuing bad publicity about Avandia’s risks have significantly reduced its sales.

The continuing unfavorable safety findings for Avandia, as well as the findings that both Avandia and Actos induce weight gain in type 2 diabetics (who are usually obese to begin with), and carry an increased risk of edema and heart failure, have given new ammunition to critics who believe that physicians treating diabetes should stick to combinations of the older, cheaper drugs–insulin, metformin, and sulfonylureas, and avoid using not only TZDs, but also newer agents. This point of view also suggests that there is no need to discover and develop new antidiabetic agents.

However, the arguments in our 2008 Genetic Engineering News (GEN) article on diabetes (available on our website) still apply. There are still major unmet needs in type 2 diabetes, especially the need to prevent weight gain in diabetes treatment (and even to promote weight loss), and the need to prevent long-term loss of pancreatic beta-cell function. It is the loss of beta-cell function that results in the progression of type 2 diabetes, such that patients who initially succeed in reaching glycemic goals even with multidrug treatment with older antidiabetics eventually experience poor glycemic control on the same regimens.

As we discussed in earlier blog posts, some of the newer antidiabetics, namely the incretin mimetic exenatide (Amylin/Lilly’s Byetta) and liraglutide (Novo Nordisk’s Victoza), may give increased glycemic control while promoting weight loss. There is also evidence from animal studies that these drugs might help to preserve beta-cell function.

Ironically, despite the major safety issues with TZDs, there is both animal model and human evidence that these agents may work to preserve and/or enhance beta-cell function. Moreover, insulin resistance is a major factor in the pathogenesis of type 2 diabetes. Therefore, it would be very advantageous, and perhaps essential, for physicians and patients to have access to safer insulin sensitizers, especially if they work to prevent diabetes progression by preserving and enhancing beta-cell function.

Might it be possible to discover and develop better, safer insulin sensitizers than the TZDs? We shall discuss this question in Part 2 and Part 3 of this series.