Alpha-helix

On November 27, 2009, we posted an article on this blog about the use of stapled peptides in targeting intracellular pathways. This technology was originally developed by Dr. Gregory Verdine (Department of Chemical Biology, Harvard University, Cambridge MA, and the Dana-Farber Cancer Institute, Boston MA) and his colleagues. A biotechnology company, Aileron Therapeutics (Cambridge, MA) was founded (with Dr. Verdine among its founders) in 2005 to develop and commercialize stapled peptide drugs. Aileron’s most advanced compounds, which are being developed for the treatment of solid and hematological tumors, are only in the preclinical stage.

On August 24, 2010, Aileron and Roche announced that they had entered into a collaboration to discover, develop, and commercialize stapled peptide drugs designed to address up to five undisclosed targets. These targets are selected from Roche’s key therapeutic areas of interest–oncology, viral diseases, inflammation, metabolic diseases, and central nervous system diseases.

Under the agreement, Roche will provide Aileron guaranteed funding of at least $25 million in R&D support and technology access fees. Aileron will also be eligible to receive up to $1.1 billion in discovery, development, regulatory, and commercialization milestone payments, if drug candidates are developed against all five targets. Aileron will also receive royalties on any future sales of marketed products that result from the collaboration.

In our November 2009 article, we discussed the design of stapled peptides, in which hydrocarbon moieties are used to constrain, or “staple” peptide sequences into an α-helical conformation. These sequences are designed to mimic key binding domains of proteins that are involved in intracellular signaling pathways. We gave two examples of pathways that were addressed by specific stapled peptides: the Notch pathway and a Bcl-2-related apoptotic pathway. In both cases, the stapled peptides modulated protein-protein interactions that are considered “undruggable” by conventional small-molecule drugs.

According to Roche, It is “as yet intractable” intracellular protein-protein interactions that are of special interest to the company in collaborating with Aileron.

According to Aileron, the new alliance with Roche validates the broad potential of their stapled peptide technology platform across multiple therapeutic areas and classes of targets. The alliance also provides Aileron with capital to advance its internal R&D.

The Roche agreement represents Aileron’s first Big Pharma strategic alliance. However, a venture capital consortium that included GlaxoSmithKline, Novartis, Roche, and Lilly invested $40 million in Aileron in June 2009.

As we said in our November 2009 article, stapled peptides represent an exciting and innovative technology with the potential to address “undruggable” protein-protein interactions, even though the therapeutic value of stapled peptides has not yet been confirmed in the clinic. (We have discussed several other means of addressing protein-protein interactions in various articles in this blog–these targets represent an area of opportunity for companies that are innovative enough to pursue it.) And as we discussed in a more recent article, Roche is one of the Big Pharma companies that continues to be focused on innovative drug discovery and development, in an era of Big Pharma R&D retrenchment. The Aileron-Roche partnership therefore appears to be an ideal match.

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.

Topiramate

Phentermine

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 follows 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 Vivus’ Qnexa (phentermine/topiramate), with six votes in favor and 10 against. The FDA usually follows the advice of its advisory panels, but does not always do so.

The advisory committee agreed that the drug caused significant weight loss, with patients who took the highest doses of the drug having lost over 10 percent of their weight in a year. But many panelists questioned the lack of long-term data on efficacy, since the real issue with weight loss regimens (whether diet and exercise alone or with drug treatments) is the inability of patients to keep weight off once it has been lost.

But above all, panelists had concerns about Qnexa’s safety. Major concerns included the potential for fetal exposure during pregnancy and birth defects, depression, cognitive issues, and increases in heart rate. Most panelists who voted no were not strongly against approval, but they had lingering concerns, especially since the drug if approved would be given to large numbers of essentially healthy people over a long period of time–perhaps a lifetime.

Vivus said that it would work with the FDA to address the panelists concerns. For example, the company expects to have longer-term safety data on the drug in the next several months.

Qnexa is a low-dose, controlled release formulation of two FDA-approved drugs: phentermine and topiramate. Qnexa is designed to both suppress appetite (phentermine) and promote satiety (topiramate). Phentermine, an amphetamine, is prescribed as a weight-loss aid that is used short-term. It was the “phen” half of the notorious “Fen-Phen” combination. The “fen” part, fenfluramine (Pondimin) or dexfenfluramine (Redux), were serotonin modulators that caused cardiovascular side-effects. Topiramate is an anticonvulsant. As separate agents, phentermine and topiramate have minimal effects on weight loss. However, according to Vivus’ studies, the two drugs appear to have a synergistic effect, even at low doses, that results in significant weight loss. Vivus’ studies also indicate that the two drugs mitigate each other’s side effects; the low does and controlled release is also designed to reduce side effects.

Side effects of phentermine may include increase in blood pressure and heart palpitations, as well as gastrointestinal side effects. Side effects of topirmate may include cognitive issues, lack of coordination, aggressiveness, changes in ability to taste food and loss of appetite, cardiovascular side effects, and others. The risk of birth defects with ether of these drugs is unknown. However, there is preliminary evidence that topiramate might cause birth defects.

Lorcaserin is up for FDA Advisory Panel review in September 2010 and Contrave is tentatively scheduled for review in December 2010. Lorcaserin is a selective serotonin receptor agonist, which is specific for the 5-HT2C receptor. This contrasts with the nonselective serotonin reuptake inhibitor and serotonin-releasing agents, fenfluramine and dexfenfluramine. Lorcaserin is thus designed to be a more selective agent that works by a similar mechanism to dexfenfluramine or fenfluramine. Since the anorectic effects 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, lorcaserin may be a safer agent that fenfluramine/dexfenfluramine. But like fenfluramine and dexfenfluramine, the efficacy of lorcaserin appears to be minimal.

Contrave, like Qnexa, is a combination of long-acting formulations of two FDA-approved drugs–bupropion and naltrexone. 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 Endocrinologic and Metabolic Drugs Advisory Committee’s recommendation against Qnexa casts a cloud on the upcoming reviews by the same committee of the other two drugs. However, the jury is still out on lorcaserin and Contrave. And approval of Qnexa may (or may not) be reconsidered as Vivus presents additional data.

However, antiobesity drugs that work via the CNS to control appetite by modulating the activity of common neurotransmitter pathways have a generally poor record. First was the fenfluramine/dexfenfluramine/Fen-Phen debacle, in which fenfluramine and dexfenfluramine (Interneuron/Wyeth) were found in the postmarking period to cause heart valve damage, leading to market withdrawal in 1997 and a host of lawsuits. Sanofi Aventis’ rimonabant never reached the U.S. market–in 2007 the FDA rejected the drug due to neurologic and psychological adverse effects. Rimonabant was also suspended from use in Europe in 2008. A related Merck drug, taranabant, was never submitted to the FDA, since it had similar adverse effects to rimonabant. And despite a growing understanding of pathways (involving neurotransmitters and neuropeptides) in the hypothalamus that control appetite, and despite a large number of promising leads that emerged from that research, not one drug derived from this research has yet emerged from early clinical trials.

In many cases, drugs that were designed to address these pathways had unacceptable adverse effects, since the neurotransmitter or neuropeptide receptors that they addressed are also involved in other CNS and/or peripheral tissue pathways that do not control body weight or energy balance. This is also the problem with appetite control drugs that have reached the IND or post-marketing stage. Such drugs as fenfluramine/dexfenfluramine and sibutramine target receptors for such common neurotransmitters as serotonin and noradrenaline, which are involved in many pathways within the CNS and peripheral tissues. Rimonabant is an antagonist of the CB1 cannabinoid receptor, which is widely expressed in the brain and in other tissues and modulates multiple pathways.

Sibutramine (Abbott’s Meridia/ Reductil) is an approved and marketed appetite-control drug that works via the CNS. It is a serotonin–norepinephrine reuptake inhibitor. Sibutramine causes increases in blood pressure and heart rate. Therefore, the drug is contraindicated in patients with uncontrolled blood pressure and certain other conditions.

There is also concern that sibutramine may cause more serious cardiovascular conditions. Early in 2010, the FDA issued a warning that the drug 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. And a few patients taking sibutramine may experience psychological adverse effects. Because of concerns about sibutramine’s safety, the drug has recently been suspended from use in the U.K. and the E.U. Sibutramine is also under continued review by the FDA.

Sibutramine and the other approved antiobesity drug, orlistat (Roche’s Xenical–also marketed as a low-dose over the counter formulation, GlaxoSmithKline’s alli) have only marginal efficacy. And orlistat, which works not in the CNS, but in the gut to block fat absorption, has unpleasant gastrointestinal adverse effects. Therefore there is a need for safer, more efficacious antiobesity drugs.

Nevertheless, the history of failure of antiobesity drugs, especially appetite-control drugs that work via the CNS and modulate neurotransmitter receptors that are involved in multiple pathways, continues, with the decision of the FDA Advisory Committee on Qnexa being the latest episode.

Perhaps companies will have more success developing antiobesity drugs that primarily address metabolic pathways involved in both obesity and diabetes, rather than being directed at appetite-control pathways in the CNS that involve common neurotransmitters. We discussed this strategy in two earlier articles on this blog, dated October 25, 2009 and January 28, 2010. These articles focused on the incretin mimetics, especially liraglutide (Novo Nordisk’s Victoza). Incretin mimetics [which also include exenatide (Amylin/Lilly’s Byetta)] trigger an increase in insulin secretion by the pancreas, and also reduces gastric emptying. The latter effect slows nutrient release into the bloodstream and appears to increase satiety and thus reduce food intake.

Part of the mechanisms of action of the natural incretin glucagon-like peptide-1 (GLP-1) and of incretin mimetics involves activity in the CNS. However, GLP-1 receptors in the brain appear to be more specific in their activity than receptors for common neurotransmitters like serotonin and norepinephrine. The main adverse effect that has been seen with the incretin mimetics exenatide and liraglutide is a transient nausea. Thus incretin mimetics do not appear to cause the psychological and neurological side effects seen with such drugs as sibutramine, rimonabant, and phentermine, and presumably Qnexa.

Nevertheless, acute pancreatitis has been seen in some patients taking exenatide (which resulted in a warning on the label that patients with a history of pancreatitis should not take the drug, and that the drug should be discontinued if symptoms suggesting pancreatitis should develop). Rodents receiving either exenatide or liraglutide have developed thyroid C-cell focal hyperplasia and C-cell tumors. There is no evidence that humans develop thyroid tumors as the result of taking ether drug, however. Nevertheless, the label for liraglutide carries a “back box” warning highlighting the thyroid tumor results in rodents, and including a contraindicating the use of the drug in patents with a history of medullary thyroid carcinoma.

Companies usually develop dual diabetes/obesity drugs first for diabetes, since the regulatory pathway for that disease is easier than for obesity. This has been the case for both exenatide and liraglutide. However, Novo Nordisk announced on June 22, 2010, that following the FDA approval of liraglutide for treatment of type 2 diabetes, it was restarting Phase III clinical trials of the drug in obesity.

As we noted in our October 25, 2009 article, there are at least several companies with early stage dual diabetes/obesity drugs, which they are developing for diabetes. Early-stage obesity drug development has been mainly on hold, awaiting the regulatory approval of Qnexa, Contrave, and/or lorcaserin. Now the results of the regulatory reviews of these three drugs are starting to come in. If none of the three is approved, than early-stage obesity drug development may remain on hold indefinitely.

1. Continuing Controversy

In our blog post on 10 February 2010, we discussed the controversy over Sirtris/GlaxoSmithKline’s reseveratrol formulation, and its second-generation sirtuin-1 (SIRT1) activators. Researchers at Amgen and Pfizer found that the apparent in vitro activation of SIRT1 by these compounds was an artifact of the experimental method used by Sirtris researchers. The Amgen group found that the fluorescent SIRT1 peptide substrate used in the Sirtris assay is a substrate for SIRT1, but in the absence of the covalently linked fluorophore, the peptide is not a SIRT1 substrate. Although resveratrol appears to be an activator of SIRT1 if the artificial fluorophore-conjugated substrate is used, resveratrol does not activate SIRT1 in vitro as determined by assays using two other non-fluorescently-labeled substrates.

Last month, I attended two meetings at which this controversy was discussed. One was the Bio-IT World Conference & Expo in Boston. At that conference, Christoph Westphal (then CEO of Sirtris) gave a keynote address. In that presentation, Mr. Wesphal stuck with the story that Sirtis’ compounds and its assays are valid. The day after his presentation, Mr. Westphal resigned as Sirtris’ CEO, and now is the head of GSK’s SR One venture fund. He and other Sirtris and Vertex founders also started the Longwood Founders Fund in February of this year.

At the other meeting (which was Harvard-related), one of the most respected leaders of the longevity-related pathway field (whose name I am withholding) stated that the whole resveratrol/sirtuin-activator story is nonsense. He did, however, concur with our views on anti-aging pathways as expressed in our November 8, 2009 article on this blog. We do not go as far as calling the resveratrol story nonsense, but remain unconvinced of the mechanistic basis for resveratrol action pending further evidence.

Meanwhile, Derek Lowe’s “In the Pipeline” blog has a discussion of Mr. Wesphal’s talk at the Bio-IT conference.

In its 25 March 2010 issue, Nature also has a News Feature centered upon the controversy. This article (written by Cambridge MA-based Nature reporter Heidi Ledford) basically says that the controversy remains unsettled, but that several laboratories are working to resolve the assay issue. These include corporate researchers at Sirtris, Leonard Guarente of MIT (another leader in the longevity-related pathway field, who is co-chair of Sirtris’ scientific advisory board), and Anthony Sauve of Weill Cornell Medical School (also a member of Sirtris’ scientific advisory board).

2. Opportunity

There was a review of longevity-related pathways in the 16 April 2010 issue of Science. It covers all the bases of anti-aging research in yeast, worms, flies, and mammals, with an emphasis on the TOR and insulin-like growth factor-1 (IGF-1) pathways. Sirtuins and resveratrol rate a minimal mention in the review.

Cynthia Kenyon, another leader in the longevity pathway field, published a review on the genetics of aging in a special Nature Insight section on aging in the 25 March 2010 issue. In this review, Dr. Kenyon discussed the panoply of aging-related pathways in worms, flies, and mice, especially the insulin/IGF-1 and TOR pathways, as well as several other biomolecules and biological processes. Dr. Kenyon discusses sirtuins, but notes the unknowns in aging-related mechanisms involving sirtuins, especially in mammals. She also notes the difficulties in interpreting results with resveratrol. In addition to the issue with the assays involving the fluorescent substrate, she notes that although (in studies conducted by Sirtris researchers and their academic colleagues) resveratrol has been found to extend the lifespan of mice fed a high-fat diet, it did not extend the lifespan of mice fed a normal diet. Dr. Kenyon also cited the results of studies with resveratrol in yeast, worms, and flies that are not consistent with the hypothesis that resveratrol extends lifespan by acting as a sirtuin activator.

The bottom line of the discussion in the two reviews in Science and Nature is that lifespan is controlled by sets of complex, interacting pathways. Sirtuins represent only one control point in these pathways, which might not be the most important one. Thus no one company “owns” the anti-aging field in terms of drug discovery and development, and there is a lot of opportunity out there. Even Mr. Westphal stated as much in his Bio-IT World presentation.

Interestingly, Dr Kenyon notes that different closely related animals can have large differences in lifespan. For example, rats live for three years, but squirrels for 25. She speculates that differences in longevity might be easily evolvable, and mechanisms by which lifespan changes during evolution (perhaps involving mutations in regulatory genes or that affect rates of respiration) might constitute novel intervention points.

3. Good News

Now for some good news about aging. In an article in the 25 March 2010 Nature Insight section by James W Vaupel (Max Planck Institute for Demographic Research, Rostock, Germany, University of Southern Denmark, Odense, and Duke University), the author presents evidence that human senescence (i.e., deterioration with age)—at least in advanced countries—has been postponed by a decade. This process, first noted in 1994, is continuing. The factors that are making this possible are prosperity (which promotes good health) and medicine (including medical and surgical interventions to prevent or treat disability, and public health efforts). These two factors enable people to reach old age in better health, as well as promoting better health in older people.

This ongoing postponement of senescence and mortality provides a foundation for ongoing anti-aging research and eventual treatments based on that research. (One must remember, however, that regulatory agencies as well as the practical considerations of drug development will not permit researchers and companies to utilize mortality as an endpoint in clinical trials. Companies must therefore develop putative “anti-aging drugs” for specific diseases associated with aging, such as diabetes, cancer, various cardiovascular indications, and dementia.) The postponement of senescence also has profound implications for how one lives one’s life, as well as for social policy and the practice of medicine.

On December 31, 2009, we posted an article on this blog about Agios Pharmaceuticals (Cambridge, MA). Agios is a private research-stage biotech company that is developing a pipeline of oncology drugs based on targeting metabolic pathways in cancer cells. In our article, we focused on Agios’ research on mutations in the metabolic enzyme cytosolic isocitrate dehydrogenase (IDH1) as a causative factor in gliomas and glioblastomas. We also mentioned Agios’ research on pyruvate kinase M2 (PKM2) and aerobic glycolysis in cancer.

On April 15, 2010, it was announced that Agios and Celgene Corporation (Summit, NJ), a public biotechnology company with marketed products, had formed a strategic collaboration in the area of cancer metabolism.

Celgene markets Thalomid (thalidomide), which is approved by the FDA for treatment of multiple myeloma (MM). Thalidomide was notorious for causing birth defects in the late 1950s and early 1960s. However, beginning in the late 1990s, this drug has undergone a rehabilitation, provided that proper precautions are maintained to prevent its use in pregnant women and women who may become pregnant. Celgene has also been developing a class of thalidomide-derivative immunomodulatory drugs (IMiDs), which are designed to have greater efficacy against cancer and lesser toxicity than thalidomide. Of these drugs, Revlimid (lenalidomide) is approved by the FDA for treatment of MM and myelodysplastic syndromes (MDS) (life-threatening diseases of the bone marrow in which abnormally functioning immature hematopoietic cells are made; MDS can progress to acute myeloid leukemia in a substantial percentage of patients.) Celgene is researching additional indications for lenalidomide, and is also developing other IMiDs for various indications in cancer and inflammatory and neurodegenerative diseases.

Celgene’s Vidaza (azacitidine), a nucleoside metabolic inhibitor, is also indicated for the treatment of MDS. Celgene acquired Vidaza via its 2007 acquisition of Pharmion (Boulder, CO), which had developed the drug. Vidaza is an inhibitor of DNA methyltransferases (DNMT), which are enzymes that methylate DNA at specific sites and are important in epigenetic regulation. It was the first approved drug that works via an epigenetic mechanism. (Epigenetics is the study of heritable changes in gene function that do not involve changes in the nucleotide sequence of DNA. Major epigenetic processes include DNA methylation, modification of histones in chromatin, and RNA interference.)

Since Vidaza’s approval in 2004, two histone deacetylase (HDAC) inhibitors, which also modulate epigenetic regulation, have been approved. In late 2009, Celgene acquired the HDAC inhibitor romidepsin (Istodax) [approved in 2009 for the treatment of cutaneous T-cell lymphoma (CTCL)], via its acquisition of Gloucester Pharmaceuticals (Cambridge MA).

Celgene is also developing several other anti-inflammatory drugs and kinase inhibitors.

The goal of the Agios/Celgene collaboration is to discover, develop, and commercialize novel oncology therapeutics based on Agios’ innovative cancer metabolism platform. Celgene sees the potential for early drug development opportunities in Agios’ IDH1 and PKM2 programs, as well as future opportunities based on new targets expected from Agios research programs. Celgene also sees opportunities to harness Agios’ R&D to expand its own pipeline in cancer and other diseases.

Under the terms of the agreement, Agios will receive a $130 million upfront payment, including equity. In return, Celgene will receives an initial period during which it will have the exclusive option to develop any drugs resulting from the Agios cancer metabolism platform. Celgene may also extend this exclusivity period through additional funding. Agios will lead discovery and early development for all cancer metabolism programs. During the period of exclusivity, Celgene will have an exclusive option to license any clinical candidates at the end of Phase I, and will lead and fund global development and commercialization of licensed programs. On each program, Agios may receive up to $120 million in milestones as well as royalties, and may also participate in the development and commercialization of certain products in the United States.

The Celgene collaboration continues Agios’ record of success in fundraising, and in gaining the recognition of the scientific and corporate communities. Despite the generally unfavorable financial environment for young biotech companies, Agios has raised, through alliances and investments, over $163 million in less than two years. This is despite the fact that the company has not one drug in the clinic. Agios expects to have a lead compound in the clinic some time in 2010, however. As is always the case, the validation of Agios’ innovative biology-driven platform awaits the results of human clinical trials and the attainment of regulatory approval.