Drug discovery

Obesity therapeutics update

Obesity, 12th century Japan.

Obesity, 12th century Japan.

The Biopharmconsortium Blog has over the years included numerous articles about obesity, and the attempts of researchers and companies to develop treatments for this disease.

Obesity, which has historically been considered the result of “lack of willpower” or other behavioral issues, was recognized as a disease by the American Medical Association in June 2013. This followed many years of genetic, molecular biology, and physiological studies that revealed the pathobiological basis of obesity. Nevertheless, many people—including many doctors, patients, and nutritionists—persist in the believing the older view of obesity. This continues to fuel an extremely lucrative diet industry, even thought most—if not all—attempts at dieting eventually fail.

However, researchers and companies have continued in their efforts to develop approved therapies for obesity. We have followed the results of companies that had come close to obtaining FDA approval for three central nervous system (CNS)-acting antiobesity agents in 2010—only to encounter opposition due to safety concerns. However, two of their agents were approved in 2012. Now the third one was approved in September 2014.

Orexigen/Takeda’s Contrave approved by the FDA

On September 11, 2014, Orexigen Therapeutics (La Jolla, CA) and its partner, Takeda, announced that the FDA had approved their antiobesity agent, Contrave (naltrexone HCI and bupropion HCI) extended-release tablets as an adjunct to diet and exercise for chronic weight management in obese adults [body mass index (BMI) of 30 kg/m2 or greater], and in overweight adults (BMI of 27 kg/m2 or greater) who have at least one weight-related comorbid condition (e.g, high cholesterol, Type 2 diabetes, or hypertension).

However, the FDA requires Contrave’s label to carry a boxed warning of increased risk of suicidal thoughts and other psychiatric issues. The label also warns that “The effect of Contrave on cardiovascular morbidity and mortality has not been established.” Orexigen is also required to conduct several post-marketing studies, including studies in pediatric patients, and assessment of the effects of long-term treatment with Contrave on the incidence of major adverse cardiovascular (CV) events in overweight and obese subjects with CV disease or multiple CV risk factors.

The September 2014 approval of Contrave followed the February 2011 issuance by the FDA of a Complete Response Letter requiring extensive clinical studies before Contrave could be approved. In 2010 the FDA had also rejected the applications 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 all of these cases.

Nevertheless, lorcaserin (rebranded as Belviq) was approved in June 2012, and Qsymia (formerly known as Qnexa) was approved in July 2012.

Thus there are now three CNS-targeting weight-loss drugs on the U.S. market—all of which are “adjuncts to diet and exercise”, all of which work by suppressing appetite, and all of which have safety concerns that require post-marketing studies. Moreover, at least two of these drugs have levels of efficacy less than might be desired. For example, in one trial of Contrave, significant weight loss — defined as the loss of at least 5% of body weight — was achieved by 42% of Contrave-treated subjects, and 17% of subjects in the placebo group. The FDA says that patients taking Contrave should be evaluated after 12 weeks of treatment. Those who have failed to lose at least 5% of their body weight should discontinue Contrave.

Lorcaserin is the least efficacious of these drugs. Qsymia is the most efficacious, with 66.7% of patients on high-dose Qsymia losing at least 5% of body weight, as compared to 17.3% for placebo. The average weight loss in that trial was 10.9% of body weight with high-dose Qsymia and 1.2% with placebo.

A drop in weight of as little as 5% can have positive effects on risk of obesity’s comorbidities (e.g., insulin resistance, diabetes, high blood pressure, dyslipidemia, cardiovascular disease). Nevertheless, all three of these drugs are aids in management of obesity, rather than effective treatments. Moreover, their potential adverse effects are significant. It must be remembered that it was adverse effects that resulted in the withdrawal from the market of several antiobesity drugs (including sibutramine), and prevented the approval of any obesity drugs at all in 2010.

The FDA’s approval of these three drugs indicates that the agency is more willing to make antiobesity drugs available to patients than it has been previously, even in the face of continuing concerns about long-term safety. Rather than rejecting these drugs, the FDA is handling its concerns about safety via post-marketing studies, and restricted distribution of the drugs.

Liraglutide for treatment of obesity?

Meanwhile, Novo Nordisk is awaiting the FDA’s decision on the approval of its high-dose formulation of liraglutide (Saxenda) for treatment of obesity. An FDA advisory board recommended approval of the agent on September 11, 2014. The drug has an October 20 PDUFA date. The advisory board vote was based on Phase 3 results, which indicated that liraglutide produced an average 8% weight loss in obese subjects, when combined with diet and exercise. 69% of prediabetic obese individuals who were treated with liraglutide also showed no signs of prediabetes after 56 weeks, as compared to 33% for the placebo group.

We have discussed the potential use of liraglutide in treatment of obesity on this blog. A lower-dose formulation of this agent, under the trade name of Victoza, is already approved for treatment of type 2 diabetes. Liraglutide is a recombinant protein drug. It is a member of a class of drugs called incretin mimetics. An incretin is a gastrointestinal hormone that triggers 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. The major physiological incretin is glucagon-like peptide 1 (GLP-1), and incretin-mimetic drugs are peptides with homology to GLP-1 that have a longer half-life in the bloodstream than does GLP-1.

Although liraglutide does not act in the CNS, its major mechanisms of action in treatment of obesity appears to be—like CNS drugs—appetite control. Moreover, clinical trial results indicate that liraglutide is more of an aid in management of obesity than an effective treatment. Nevertheless, liraglutide’s antidiabetic effects and lack of CNS adverse effects constitute potential advantages over CNS-acting antiobesity drugs.

Sales of approved antiobesity drugs have been struggling

Despite the excitement over the approval of antiobesity drugs after so many roadblocks, sales of these drugs have fallen short of estimates. Estimates for Qsymia sales have fallen to $141 million in 2016 from the $1.2 billion projection for 2016 when the drug was approved in 2012. Eisai estimates that Belviq will generate $118 million in sales. Producers and marketers of these two drugs hope that the approval of Contrave will drive patient acceptance of all three CNS-targeting antiobesity drugs. At least one analyst projects that Contrave may achieve $740 million in sales in 2018.

If it is approved, Saxenda may have a sales advantage over the CNS-targeting drugs, since the low-dose formulation, Victoza for type 2 diabetes, is an established drug, with relationships with doctors and insurers already in place. Analysts project that liraglutide (branded as Saxenda) will generate $556 million in weight-loss sales in 2018, in addition to $3.2 billion for the antidiabetic low-dose formulation, Victoza.

A big factor in the level of sales of antiobesity drugs has been insurance reimbursement. It is estimated that some 50 percent of people with private insurance receive at least some coverage for diet drugs. However, insurers tend to classify Qsymia and Belviq as third-tier medications, requiring large patient co-payments. Moreover, Medicare and Medicaid do not pay for the drugs. Analysts hope that the approval of Contrave will result in expanded insurer coverage.

Obesity specialist company Zafgen continues to make progress

The vast majority of efforts to develop antiobesity drugs—over several decades—have been aimed at targeting the CNS. However, obesity is a complex metabolic disease that involves communication between numerous organs and tissues, notably adipose tissue (white, brown, and beige fat), skeletal muscle, the liver, the pancreas, the brain (especially the hypothalamus), the digestive system, and the endocrine system. The pathophysiology of obesity is also related to that of other major metabolic diseases, especially type 2 diabetes.

The mechanistic basis of obesity is not well understood, even though breakthroughs in understanding aspects of this disease have occurred in recent years. Thus there is great need for continuing basic research, and for novel programs aimed at development of breakthrough treatments for obesity based on non-CNS pathways.

One company that has been active in this area is Zafgen (Cambridge, MA), which we have been following on this blog. On June 24, 2014, Zafgen announced the closing of its Initial Public Offering. Zafgen is thus a young company pursuing an alternative approach to antiobesity drug discovery and development that has been able to go public.

In our May 23, 2012 article on this blog, we discussed Zafgen’s lead drug candidate, beloranib (ZGN-433). Beloranib is a methionine aminopeptidase 2 (MetAP2) inhibitor, which exerts an antiobesity effect by downregulating signal transduction pathways in the liver that are involved in the biosynthesis of fat. Animals or humans treated with beloranib oxidize fat to form ketone bodies, which can be used as energy or are excreted from the body. The result is breakdown of fat cells and weight loss. Obese individuals do not usually have the ability to form ketone bodies.

On June 22, 2013, Zafgen announced the interim results of an ongoing double blind placebo-controlled Phase 2 study of beloranib in a group of obese men and women. These results were presented in a poster session at the American Diabetes Association’s 73rd Scientific Sessions in Chicago on June 23, 2013.

Subjects had a mean age of 40.3 years, a mean weight of 101.2 kg (223.1 lbs.), and a mean BMI of 37.9 kg/m2 at the beginning of the study. 38 subjects receiving 12 weeks of treatment in the full trial were randomized to one of three doses of subcutaneous beloranib vs. placebo. The subjects were counseled not to change their usual diet and exercise patterns—this protocol thus differed from trials of the agents discussed earlier in this article. The interim analysis was of results from the first 19 subjects who completed 12 weeks of treatment.

Beloranib appeared safe and showed dose responsive weight loss. After 12 weeks, subjects on 0.6 mg, 1.2 mg, or 2.4 mg of beloranib lost an average of 3.8, 6.1 and 9.9 kg, respectively (8.4, 13.4, and 21.8 lbs.), versus 1.8 kg (4.0 lbs.) for placebo; these results were statistically significant. In addition, beloranib treated subjects showed improvements versus placebo in CV risk factors including levels of triglycerides, LDL cholesterol and C-reactive protein. Sensation of hunger also was reduced significantly.

Subcutaneous beloranib treatment over 12 weeks was generally well-tolerated. There were no major adverse events or deaths.

If later clinical trials confirm these interim Phase 2 clinical results, beloranib may have significant advantages over the three approved CNS-targeting drugs and over Saxenda, because of beloranib’s apparent benign adverse-effect profile, and major effects on weight and fat loss, even in the absence of diet and exercise advice. However, beloranib is years away from reaching the market for treatment of severe obesity with no known genetic causation.

Zafgen is attempting to develop beloranib not only as a superior alternative to “diet drugs”, but also as an alternative to bariatric surgery. In order to obtain approval for that indication, beloranib must (in late-stage, long-term clinical trials) demonstrate both the degree of weight loss and the positive metabolic effects seen in severely obese patients treated via bariatric surgery.

In addition to developing beloranib for severe obesity, Zafgen is developing this drug for treatment of the rare genetic disease Prader-Willi syndrome (PWS). Patients with PWS exhibit such symptoms as low muscle mass, short stature, incomplete sexual development, cognitive disabilities, and a chronic feeling of hunger that can result in life-threatening obesity. PWS is the most common genetic cause of life-threatening obesity. Many children with PWS become morbidly obese before age 5.

In January 2013, the FDA granted Zafgen orphan designation to treat PWS with beloranib. On July 10, 2014, the European Commission also granted orphan drug designation for beloranib for this indication. These regulatory actions were based on the initial results of Zafgen’s Phase 2a clinical trial of beloranib in PWS. This trial showed improvements in hunger-related behaviors and body composition, including reductions in body fat and preservation of lean body mass.

On October 1, 2014, Zafgen announced that it had begun a randomized, double-blind, placebo-controlled Phase 3 clinical trial of beloranib in obese adolescents and adults with PWS (clinical trial number NCT02179151). The company is also testing beloranib in Phase 2 trials in obesity due to hypothalamic injury, and is in preclinical studies with a second-generation MetAP2 inhibitor for treatment of general obesity.

Energesis Pharmaceuticals

The Biopharmconsortium Blog has also been following an earlier-stage company, Energesis Pharmaceuticals (Cambridge, MA), whose approach to developing antiobesity therapeutics is based on targeting brown fat. On June 19, 2014, FierceBiotech and Energesis announced that Janssen Pharmaceuticals and Johnson & Johnson Innovation had entered into a collaboration with Energesis, aimed at identifying agents that stimulate the formation of new brown fat in order to treat metabolic diseases.

Conclusions

The antiobesity drug field, which in 2010 was the domain of a “pall of gloom”, is now populated by three approved CNS-targeting drugs, perhaps to be soon joined by Saxenda. These drugs promise to give patients and physicians a new set of tools to aid in the management of obesity. However, the history of the CNS-targeting obesity drug field is littered with tales of the withdrawal of drug after drug due to unacceptable adverse effects. Moreover, the market—and especially payers—have not yet fully accepted the new antiobesity agents.

As readers of this blog well know, we favor approaches to treatment of obesity and its comorbidities based on targeting somatic physiological pathways that appear to be at the heart of the causation of obesity, not just the CNS. The progress of Zafgen in addressing a set of these pathways is very encouraging. However, these results must be confirmed by Phase 3 clinical trials.

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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 by phone or e-mail. We also welcome your comments on this or any other article on this blog.

Cancer Immunotherapy Report Published By CHI Insight Pharma Reports

T cells attached to tumor cell. Source: MSKCC. http://bit.ly/1uPr5nl

T cells attached to tumor cell. Source: MSKCC. http://bit.ly/1uPr5nl

 

On September 9, 2014, Cambridge Healthtech Institute’s (CHI’s) Insight Pharma Reports announced the publication of a new book-length report, Cancer Immunotherapy: Immune Checkpoint Inhibitors, Cancer Vaccines, and Adoptive T-cell Therapies, by Allan B. Haberman, Ph.D.

As attested by the torrent of recent news, cancer immunotherapy is a “hot”, fast-moving field. For example:

  • On September 5, 2014, the FDA granted accelerated approval to the PD-1 inhibitor pembrolizumab (Merck’s Keytruda, also known as MK-3475) for treatment of advanced melanoma. This approval was granted nearly two months ahead of the agency’s own deadline. Pembrolizumab is the first PD-1 inhibitor to reach the U.S. market.
  • On May 8, 2014, the New York Times published an article about a woman in her 40’s who was treated with adoptive immunotherapy with autologous T cells to treat her cancer, metastatic cholangiocarcinoma (bile-duct cancer). This deadly cancer typically kills the patient in a matter of months. However, as a result of this treatment, the patient lived for over 2 years, with good quality of life, and is still alive today.

These and other recent news articles and scientific publications attest to the rapid progress of cancer immunotherapy, a field that only a few years ago was considered to be impracticable.

Our report focuses on the three principal types of therapeutics that have become the major focuses of research and development in immuno-oncology in recent years:

  • Checkpoint inhibitors
  • Therapeutic anticancer vaccines
  • Adoptive cellular immunotherapy

The discussions of these three types of therapeutics are coupled with an in-depth introduction and history as well as data for market outlook.

Also featured in this report are exclusive interviews with the following leaders in cancer immunotherapy:

  • Adil Daud, MD, Clinical Professor, Department of Medicine (Hematology/Oncology), University of California at San Francisco (UCSF); Director, Melanoma Clinical Research, UCSF Helen Diller Family Comprehensive Cancer Center.
  • Matthew Lehman, Chief Executive Officer, Prima BioMed (a therapeutic cancer vaccine company with headquarters in Sydney, Australia).
  • Marcela Maus, MD, PhD, Director of Translational Medicine and Early Clinical Development, Translational Research Program, Abramson Cancer Center, University of Pennsylvania in Philadelphia.

The report also includes the results and an analysis of a survey of individuals working in immuno-oncology R&D, conducted by Insight Pharma Reports in conjunction with this report. The survey focuses on market outlook, and portrays industry opinions and perspectives.

Our report is an in-depth discussion of cancer immunotherapy, an important new modality of cancer treatment that may be used to treat as many as 60% of cases of advanced cancer by the late 2010s/early 2020s. It includes updated information from the 2014 ASCO (American Society of Clinical Oncology) and AACR (American Association for Cancer Research) meetings. The report is designed to enable you to understand current and future developments in immuno-oncology. It is also designed to inform the decisions of leaders in companies and in academic groups that are working in areas that relate to cancer R&D and treatment.

For more information on Cancer Immunotherapy: Immune Checkpoint Inhibitors, Cancer Vaccines, and Adoptive T-cell Therapies, or to order it, see the Insight Pharma Reports website.

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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 by phone or e-mail. We also welcome your comments on this or any other article on this blog.

Forma Therapeutics’ expanded R&D collaboration with Celgene

 

Ubiquitin pathway. Source: Rogerdodd, English language Wikipedia

Ubiquitin pathway. Source: Rogerdodd, English language Wikipedia

On April 1, 2014, Forma Therapeutics (Watertown MA) announced that it had entered into an expanded strategic collaboration with Celgene (Summit, NJ).

Under the new agreement, Forma has received an upfront cash payment of $225 million. The initial collaboration between the two companies under the new agreement will be for 3 1⁄2 years. Celgene will also have the option to enter into up to two additional collaborations with terms of two years each for additional payments totaling approximately $375 million. Depending on the success of the collaborations and if Celgene elects to enter all three collaborations, the combined duration of the three collaborations may be at least 7 1⁄2 years.

Under the terms of the new agreement, Forma will control projects from the research stage through Phase 1 clinical trials. For programs selected for licensing, Celgene will take over clinical development from Phase 2 to commercialization. Forma will retain U.S. rights to these products, and Celgene will have the rights to the products outside of the U.S. For products not licensed to Celgene, FORMA will maintain worldwide rights.

During the term of the third collaboration, Celgene will have the exclusive option to acquire Forma, including the U.S. rights to all licensed programs, and worldwide rights to other wholly owned programs within Forma at that time.

The April 2013 agreement between Forma and Celgene

The new collaboration between Forma and Celgene builds on an earlier agreement between the two companies. On April 29, 2013, the two companies entered into a collaboration aimed at discovery, development, and commercialization of drug candidates to modulate targets involved in protein homeostasis.

Protein homeostasis, also known as proteostasis, involves a tightly regulated network of pathways controlling the biogenesis, folding, transport and degradation of proteins. The ubiquitin pathway (illustrated in the figure above) is one of these pathways. We recently discussed how the ubiquitin pathway is involved in the mechanism of action of thalidomide and lenalidomide (Celgene’s Thalomid and Revlimid).

Targeting protein homeostasis has application to discovery and development of drugs for oncology, neurodegenerative disease, and other disorders. However, the April 2013 Forma/Celgene agreement focused on cancer. Under that agreement, Forma received an undisclosed upfront payment. Upon licensing of preclinical drug candidates by Celgene, Forma was to be eligible to receive up to $200 million in research and early development payments. FORMA was also to be eligible to receive $315 million in potential payments based upon development, regulatory and sales objectives for the first ex-U.S. license, as well as  up to a maximum of $430 million per program for further licensed products, in addition to post-sales royalties.

On October 8, 2013, Forma announced that it had successfully met the undisclosed first objective under its April 2013 strategic collaboration agreement with Celgene. This triggered an undisclosed payment to Forma. Progress in the April 2013 collaboration was an important basis for Celgene’s decision to enter into a new, broader collaboration with Forma a year later.

The scope of the new April 2014 Forma/Celgene collaboration

Unlike the April 2013 agreement, the April 2014 agreement between Forma and Celgene is not limited to protein homeostasis, or to oncology. The goal of the new collaboration is to “comprehensively evaluate emerging target families for which Forma’s platform has exceptional strength” over “broad areas of chemistry and biology”.  The expanded collaboration will thus involve discovery and development of compounds to address a broad range of target families and of therapeutic areas.

According to Celgene’s Thomas Daniel, M.D. (President, Global Research and Early Development), Celgene’s motivation for signing the new agreement is based not only on the early success of the existing Forma/Celgene collaboration, but also on “emerging evidence of the power of Forma’s platform to generate unique chemical matter across important emerging target families”.

According to Forma’s President and CEO, Steven Tregay, Ph.D., the new collaboration with Cegene enables Forma to maintain its autonomy in defining its research strategy and conducting discovery through early clinical development. It also aligns Forma with Celgene’s key strengths in hematology and in inflammatory diseases.

Forma Therapeutics in Haberman Associates publications

We have been following Forma on the the Biopharmconsortium Blog since July 2011. At that time, I was a speaker at Hanson Wade’s World Drug Targets Summit (Cambridge, MA). At that meeting, Mark Tebbe, Ph.D. (then Vice President, Medicinal and Computational Chemistry at Forma) was also a speaker. At the conference, Dr. Tebbe discussed FORMA’s technology platforms, which are designed to be enabling technologies for discovery of small-molecule drugs to address challenging targets such as protein-protein interactions (PPIs).

In particular, Dr. Tebbe discussed Forma’s Computational Solvent Mapping (CS-Mapping) platform, which enables company researchers to interrogate PPIs in intracellular environments, to define hot spots on the protein surfaces that might constitute targets for small-molecule drugs. FORMA has been combining CS-Mapping technology with its chemistry technologies (e.g., structure guided drug discovery, diversity orientated synthesis) for use in drug discovery.

We also discussed Forma’s earlier fundraising successes as of January 2012, and cited Forma as a “built to last” research-stage platform company in an interview for Chemical & Engineering News (C&EN).

Finally, we discussed Forma and its technology platform in our book-length report, Advances in the Discovery of Protein-Protein Interaction Modulators, published by Informa’s Scrip Insights in 2012. (See also our April 25, 2012 blog article.)

In our report, we discussed Forma as a company that employs “second-generation technologies” for the discovery of small-molecule PPI modulators. This refers to a suite of technologies designed to overcome the hurdles that stand in the way of the accelerated and systematic discovery and development of PPI modulators. Such technologies are necessary to make targeting of PPIs a viable field.

Forma’s website now has a brief explanation of its drug discovery engine, as it is applied to targeting PPIs. This includes links to web pages describing:

Our 2012 book-length report discusses technologies of these types, as applied to discovery of PPI modulators, in greater detail than the Forma website.

According to Dr. Daniel: “Progress in our existing [protein homeostasis] collaboration, coupled with emerging evidence of the power of FORMA’s platform to generate unique chemical matter across important emerging target families” led Celgene to enter into its new, expanded collaboration with Forma in April 2014. This suggests that Celgene is especially impressed by Forma’s chemistry and chemical biology platforms. it also suggests that chemistry technology platforms developed to address PPIs may be applicable to areas of drug discovery beyond PPIs as well.

Concluding remarks

Despite the enthusiasm for Forma and its drug discovery engine shown by Celgene, Forma’s other partners, and various industry experts, it must be remembered that Forma is still a research-stage company. The company has not one lone drug candidate in the clinic, let alone achieving proof-of-concept in humans. It is clinical proof-of-concept, followed by Phase 3 success and approval and marketing of the resulting drugs, that is the “proof of the pudding” of a company’s drug discovery and development efforts.

We await the achievement of such clinical milestones by Forma Therapeutics.

From a business strategy point of view, we have discussed Forma’s efforts to build a stand-alone, independent company for the long term in this blog and elsewhere. Now Forma has entered into an agreement with Celgene that might—in around 7-10 years—result in Forma’s acquisition. This would seem to contradict Forma’s “built to last” strategy.

However, in the business environment that has prevailed over the past several years, several established independent biotech companies, notably Genentech and Genzyme, have been acquired by larger companies. Even several Big Pharmas (e.g., Schering-Plough and Wyeth) have been acquired.

Nevertheless, we do not know what the business environment in the biotech/pharma industry will be like in 7-10 years, despite the efforts of strategists to predict it. And Celgene might forgo its option to acquire Forma, for any number of reasons. So the outlook for Forma’s status as an independent or an acquired company (which also depends on its success in developing drugs) is uncertain.

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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 by phone or e-mail. We also welcome your comments on this or any other article on this blog.

Neandertals, diabetes, and drug discovery

NeandFamilyIn our 2010 end-of-year blog article entitled “2010: Breakthroughs, Newsmakers, And Deals Of The Year”, we proposed an alternative nominee for the life science breakthrough of the year: the determination of the sequence of approximately two-thirds of the Neandertal genome by Svante Pääbo (Max-Planck Institute for Evolutionary Anthropology, Leipzig, Germany.) and his colleagues. We stated that this momentous achievement was “of great cultural significance, since it indicates that Neandertals contributed some 1-4 percent of the genome sequences of non-African present-day humans.” (This figure is now thought to be 1.5 to 2.1 percent.)

However, we also said that we had not blogged on this work “simply because it [had] nothing to do with drug discovery and development.” We then further stated that “perhaps someday, for example, some of the products of genes that are found in present-day humans but not in Neandertals could emerge as potential drug targets…researchers [had] begun studying some of these gene products in cell culture systems.”

Now, as of early 2014, one of the genes identified via sequencing Neandertal genomes has been implicated in a novel pathway involved in type 2 diabetes in present-day humans. However, rather than being a modern human gene not present in Neandertals, it is a haplotype that introgressed into modern humans via admixture with Neandertals.

The study that identified this gene initially had no connection with Neandertal genome studies at all. I was published by the SIGMA (Slim Initiative in Genomic Medicine for the Americas) Type 2 Diabetes Consortium in the 6 February 2014 issue of Nature. SIGMA is a joint U.S.-Mexico project funded by the Carlos Slim Foundation. It focuses on several important diseases that have particular relevance to public health in Mexico and Latin America, including type 2 diabetes and cancer. Type 2 diabetes has approximately twice the prevalence in Mexican and other Latin American populations, as compared to U.S. non-Hispanic whites.

The researchers performed a genome-wide association study (GWAS), in which they analyzed 9.2 million single nucleotide polymorphisms (SNPs) in each of 8,214 Mexicans and other Latin Americans, including 3,848 with type 2 diabetes and 4,366 non-diabetic controls. As a result of that analysis, the researchers replicated the identification of haplotypes previously associated with type 2 diabetes. They also identified a novel locus associated with type 2 diabetes at genome-wide significance.  This locus spans the genes that encode the solute carrier proteins SLC16A11 and SLC16A13. The risk haplotype carries four amino acid substitutions, all in SLC16A11.  It is present at approximately 50% frequency in Native American individuals and around 10% in East Asians, but is rare in Europeans and Africans.

Each copy of the risk newly-identified haplotype is associated with an approximately 20% increased risk of type 2 diabetes. The haplotype would thus be expected to contribute to the higher burden of type 2 diabetes in Mexican and Latin American populations. Mutations in SLC16A11 had never before been associated with type 2 diabetes. SLC16A11 thus represents a novel type 2 diabetes pathway.

The Neandertal connection

The researchers noted that the sequence of the risk haplotype is highly divergent, with an estimated time to the most recent common ancestor of both the novel haplotype and a European haplotype of 799,000 years. This is long before modern humans migrated from Africa into Eurasia. Moreover, the novel haplotype is not found in Africans and is rare in European populations. The researchers therefore hypothesized that the novel haplotype entered modern human populations via admixture with Neandertals.

At the time that this research was being conducted, the variant was not seen in published Neandertal (or Denisovan) genome sequences. However, with the help of Svante Pääbo, the researchers obtained access to a then-unpublished full-length Neandertal genome sequence from a Central Asian specimen. The Central Asian Neandertal genome sequence was homozygous across 5 killobases for the risk haplotype including all four missense SNPs in SLC16A11 . Over a span of 73 kb, the Neandertal sequence is nearly identical to that of individuals from the 1000 Genomes Project who are homozygous for the risk haplotype. The full-length Central Asian Neandertal genome has recently been published.

Moreover, the genetic length of the 73-kb risk haplotype is longer than would be expected if it had undergone recombination for the approximately 9,000 generations since the split with Neandertals. This is consistent with the hypothesis that the risk haplotype is not only similar to the Neandertal sequence, but was probably introduced into modern humans relatively recently through archaic admixture. Although this particular Neandertal-derived haplotype is common in the Americas, Native Americans and Latin Americans have the same proportion of Neandertal ancestry genome-wide as other Eurasian-derived populations. In general, although non-African populations have about the same percentage of Neandertal genes, different populations have different complements of genes derived from Neandertals.

Functional studies of SLC16A11

Although the risk haploype encodes four missense mutations in a single gene, the gene for SLC16A11, there is no formal genetic proof that SLC16A11 is responsible for increased risk of type 2 diabetes. Therefore, the researchers performed preliminary functional studies of SLC16A11.

Via immunofluorescence studies, the researchers found that SLC16A11 was expressed in the liver, the salivary glands and the thyroid. When the gene for SLC16A11 was introduced into HeLa cells, SLC16A1 was found to localize in the endoplasmic reticulum, but not in the plasma membrane, Golgi apparatus, or mitochondria. Other SLC16 family members show distinct intracellular localization pattern within the membranous structures of the cell.

SLC16A11, and other SLC16 family members, are solute carrier transporters (SLCs). We discussed SLCs and their role in transporting small-molecule nutrients and drugs across the blood-brain barrier in our 2009 book-length report, Blood-Brain Barrier: Bridging Options for Drug Discovery and Development, published by Cambridge Healthtech Institute. We also discussed SLCs in a 2009 article entitled “Strategies to Overcome Blood-Brain Barrier” in Genetic Engineering and Biotechnology News.

SLC16 family proteins are monocaboxylate transporters, which transport such compounds as lactate, pyruvate and ketone bodies, as well as thyroid hormone and aromatic amino acids, across biological membranes. As of 2008, of the 14 known members of this family, eight (including SLC16A11) had unknown functions.

The SIGMA researchers expressed SLC16A11 (or control proteins) in HeLa cells, and looked for changes in intracellular concentrations of approximately 300 polar and lipid metabolites. Expression of SLC16A11 resulted in substantial increases in intracellular triacylglycerol (triglyceride) levels, with smaller increases in intracellular diacylglycerols, and decreases in lysophosphatidylcholine, cholesteryl esters, and sphingomyelin. Since triglyceride synthesis occurs in the endoplasmic reticulum of hepatocytes, the researchers hypothesized that SLC16A11 may have a role in hepatic lipid metabolism.

Moreover, serum levels of triglycerides and accumulation of intracellular lipids are associated with insulin resistance, the metabolic syndrome, and the risk of developing type 2 diabetes. Thus, although further functional studies of SLC16A11 are needed, the researchers hypothesize that the novel risk allele for type 2 diabetes that they identified may exert its pro-diabetic effect by altering lipid metabolism in the liver.

Conclusions

This study, a GWAS in Mexican and other Latin American samples, is an illustration of how genetic mapping studies in understudied populations may identify previously undiscovered aspects of disease pathogenesis.

The risk gene identified in this study, SLC16A11, has not previously been associated with type 2 diabetes. It thus potentially represents a novel diabetes pathway, which might yield new targets for drug discovery. This new pathway might be important in type 2 diabetes not only in Native Americans and Latin Americans, but in other populations as well, even in those that lack mutations in SLC16A11.

The study initially had nothing to do with Neandertal genetics. However, the researchers noted unusual population genetics features of the risk haplotype that they identified, which led them to identify this haplotype as having entered modern human populations via introgression from Neandertals. Via the initial introgression, natural selection and/or genetic drift, the haplotype became fixed in Native Americans and some East Asians, but not in other Eurasian-derived populations such as Europeans and Euro-Americans.

It is extremely unlikely that either Neandertals, or Native Americans and Latin Americans in pre-modern times, had type 2 diabetes. However, modern diets, perhaps in concert with other risk genes, produced type 2 diabetes in carriers of the mutant SLC16A11 gene. The well-know case of the Pima Indians indicates that change from native diets and high levels of physical activity to processed foods and a more “Western” lifestyle is the major cause of the high levels of type 2 diabetes and obesity in this genetically-predisposed population. (It is not known, however, whether SLC16A11 is a factor in Pima Indians.)

As for studies of the Neandertal genome, John Hawks, Ph.D. (University of Wisconsin), an anthropologist who has been active in studies of the genetics of Neandertals and of Upper Paleolithic modern humans, believes that studies of the genomes of these ancient peoples may have relevance for the biology of present-day humans. [I took a Massive Open Online Course (MOOC) led by Dr. Hawks, entitled “Human Evolution: Past and Future” between late January and early March, 2014.]

Other researchers who study ancient genomes generally agree. As indicated by the SIGMA diabetes study, both genes for modern humans that were not present in Neandertals, and genes introgressed from Neandertals into modern humans may be relevant to modern human biology—and perhaps eventually to drug discovery.

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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 by phone or e-mail. We also welcome your comments on this or any other article on this blog.

Thalidomide, multiple myeloma, Protein-Protein interactions, and drug discovery

Ikaros. Source © Marie-Lan Nguyen / Wikimedia Commons

Ikaros. Source © Marie-Lan Nguyen / Wikimedia Commons

Thalidomide is a notorious drug that was approved in Europe in the late 1950s for use as a sedative, but was withdrawn in the early 1960s after the drug caused thousands of devastating birth defects. The FDA did not approve thalidomide at that time. However, beginning in the late 1990s, thalidomide has been repurposed and rehabilitated, provided that proper precautions are maintained to prevent its use in pregnant women and women who may become pregnant.

Currently, thalidomide (under the brand name Thalomide) is marketed by Celgene (Summit, NJ) mainly as a treatment for multiple myeloma (MM) and of a certain form of leprosy. Celgene has also been developing derivatives of thalidomide, the most important of which are lenalidomide (Celgene’s Revlimid) and pomalidomide (Celgene’s Pomalyst). All three agents are now approved in the U.S. and in Europe. Although lenalidomide and pomalidomide are more potent in treating MM and have fewer adverse effects than thalidomide, they are still teratogenic (as determined by animal studies), and are available only in a restricted distribution setting to avoid their use during pregnancy.

Celgene calls thalidomide and its derivatives “immunomodulatory drugs” (IMiDs). Until recently, their mechanism of action was poorly understood. IMiDs were found to have a wide range of activities, including antiangiogenic activity, induction of oxidative stress, upregulation of interleukin-2 (IL-2) production by activated T cells, inhibition of proinflammatory cytokines such as tumor necrosis factor alpha (TNF-α), and stimulation of natural killer (NK) cells. It is thalidomide’s antiangiogenic activity that appears to be responsible for its teratogenic effects.

However, it was the antiangiogenic activity of thalidomide that gave rise to the hypothesis that this agent might be used to treat MM. MM is a B-cell malignancy that involves the proliferation of abnormal plasma cells, which accumulate in the bone marrow.  In MM, the intimate interaction between the plasma cells and bone marrow stromal cells results in induction of the angiogenic factor vascular endothelial growth factor (VEGF) as well as the MM survival factor IL-6. Disruption of this interaction would reduce the induction of new blood vessels and of IL-6, thus decreasing tumor growth and survival. When tested against MM, thalidomide—and later lenalidomide and other IMiDs—were found to be effective in controlling MM, as predicted by the hypothesis.

However, as of 2010, researchers found that although IMiDs are indeed antiangiogenic, that is not the mechanism that explains their therapeutic effect. Now—in 2014—two papers were published in Science that expand upon that earlier effort and identify that pathway by which IMiDs work against MM. These studies were by Krönke et al. and Lu et al. The studies were led, respectively, by Benjamin L. Ebert, M.D., Ph.D. and William G. Kaelin Jr., M.D., both at the Dana-Farber Cancer Institute (Boston, MA). These two papers were accompanied by a brief Perspective by A. Keith Stewart, M.B., CH.B., of the Mayo Clinic (Scottsdale, AZ), in the same issue of Science (17 January, 2014).

The key to understanding the pathway by which lenalidomide (the drug that was used in both of the 2014 research studies) and other IMiDs work against MM is the finding that that they bind to an intracellular protein known as cereblon (CRBN). In a 2010 study, Astellas researchers and their academic collaborators demonstrated that thalidomide binds to zebrafish CRBN. Treatment of zebrafish with CRBN morpholinos or thalidomide caused fin defects, reminiscent of the limb defects seen with thalidomide in the 1960s.

As also demonstrated in the 2010 study, CRBN forms an E3 ubiquitin ligase complex with three other proteins—damaged DNA binding protein 1 (DDB1), Cullin-4A (CUL4A), and regulator of cullins 1 (Roc1). The complex is known as the CRBN-CRL4 ubiquitin ligase.

E3 ubiquitin ligases carry out the terminal step of the ubiquitin pathway—specific attachment of ubiquitin (and via repeated steps, ubiquitin chains) to substrate proteins. Attachment of ubiquitin (and especially of ubiquitin chains) to substrate proteins can tag them for destruction  by the proteasome.

Lu et al. and Krönke et al. showed that lenalidomide binding to CRBN results in the selective ubiquitination and proteasomal degradation of two lymphoid transcription factors, IKZF1 and IKZF3, by the CRBN-CRL4 ubiquitin ligase.  IKZF1 and IKZF3 are Ikaros family zinc finger proteins 1 and 3 (IKZF1 and IKZF3); they are also known, respectively as Ikaros and Aiolos.

Although IKZF1 is highly expressed in early lymphoid progenitors, studies in mice have shown that IKZF3 is required for the generation of plasma cells, which are the physiologic counterparts of MM cells. Both Krönke et al. and Lu et al. studied the roles of IKZF1 and IKZF3 via RNAi knockdown and other methods. Inhibition of IKZF1 or IKZF3 expression inhibited growth of lenalidomide-sensitive MM cell lines, but lenalidomide-insensitive cell lines were not affected. Downregulation of either IKZF protein in these cell lines led to loss of the other. Downregulation of IKZF1 and IKZF3 resulted in a decrease in interferon regulatory factor 4 (IRF4) and IRF4 mRNA, consistent with IRF4 acting downstream of IKZF1 and/or IKZF3 in lenalidomide-sepsitive MM cells. Previous studies have shown that IRF4 inhibition is toxic for MM cells.

In addition to its effects on MM cells, lenalidomide treatment also upregulates IL-2 expression in T cells. Since IKZF3 binds the IL-2 gene promoter and represses IL-2 transcription in T cells, Lu et al. and Krönke et al. investigated whether lenalidomide’s effects on IL-2 expression in T cells might work via the CRBN-CRL4 ubiquitin ligase-IKZF1/3 pathway. They found that RNAi knockdown of CRBN abrogated the effect of lenalidomide on IL-2 expression. They further found that lenalidomide treatment caused marked decreases in IKZF1 and IKZF3 protein levels In primary human T cells. Finally, they showed that RNAi knockdown of IKZF3 or IKZF1 induced IL-2 expression and repressed further response to lenalidomide. These studies thus show that lenalidomide indeed works via the CRBN-CRL4 ubiquitin ligase-IKZF1/3 pathway to upregulate IL-2 in T cells.

Thus IMiDs, working via the CRBN-CRL4 ubiquitin ligase-IKZF1/3 pathway, downregulate IRF4 in MM cells, resulting in cell death. They also upregulate IL-2 in T cells. A diagram of the pathway is given in Dr. Stewart’s Perspective.

The studies of Krönke et al. and Lu et al. have greatly advanced our understanding of the mechanism of action of IMiDs in MM. As pointed out by Krönke et al., other B cell malignancies against which lenalidomide has activity, such as mantle cell lymphoma and chronic lymphocytic leukemia, also exhibit high IKZF3 expression. Celgene is testing lenalidomide against chronic lymphocytic leukemia and other cancers in the clinic, and the drug is approved for treatment of myelodysplastic syndromes in Europe, in addition to MM. So the recent studies of the CRBN-CRL4 ubiquitin ligase-IKZF1/3 pathway may also apply to other cancers for which lenalidomide is being developed.

Nevertheless, there are still gaps in our understanding of the mechanism of action of IMiDs. For example, the proteasomal inhibitor bortezomib (Millennium’s Velcade) is used to treat MM. Combination therapies of bortezomib and lenalidomide have shown efficacy in early clinical trials, and further trials are continuing. This creates an apparent paradox, because proteasomal blockade prevents the destruction of IKZF1 and IKZF3 by lenalidomide via the CRBN-CRL4 ubiquitin ligase-IKZF1/3 pathway. Lu et al. hypothesize that since proteasomal inhibition by bortezomib is incomplete with therapeutic dosing, this might allow sufficient destruction of IKZF1 and IKZF3 while retaining bortezomib’s other therapeutic effects. Alernatively, they hypothesize that IKZF1 and IKZF2, once polyubiquitylated, may be inactive or act as dominant-negatives.

Implications for drug discovery

The most immediate implications of these findings is that they might be used to discover novel, more effective and safer modulators of the CRBN-CRL4 ubiquitin ligase-IKZF1/3 pathway as therapies for MM and other B cell malignancies. Such efforts might include finding a non-teratogenic modulator of this pathway, since thalidomide-CRBN-mediated teratogenicity may be mediated by substrates other than Ikaros family proteins in different cellular lineages.

Moreover, the 2010 zebrafish study suggested that thalidomide’s teratogenic effects are due to a loss of function of cereblon. In contrast, the 2014 studies in MM indicate that the therapeutic effects of the IMiDs reflect a cereblon gain of function. This supports the possibility of finding non-teratogenic modulators of the CRBN-CRL4 ubiquitin ligase-IKZF1/3 pathway.

The studies of Krönke et al. and Lu et al. may have wider implications for the targeting of E3 ubiquitin ligases in drug discovery for other diseases. We have discussed the possibility of targeting E3 ubiquitin ligases in our 2012 book-length report, Advances in the Discovery of Protein-Protein Interaction Modulators, published by Informa’s Scrip Insights.

The ubiquitin system is a fundamental regulatory system in all eukaryotic cells, comparable in importance to protein phosphorylation. In recent years, researchers have discovered and developed numerous important agents that modulate protein phosphorylation pathways, namely the protein kinase inhibitors. However, there as yet are very few approved and experimental drugs that modulate the ubiquitin system. Most are proteasome inhibitors, which indirectly target this system. The approved agent, bortezomib, has achieved blockbuster status despite its nonspecificity and limited field of application.

Despite the central importance of the ubiquitin system, there are only a handful of compounds that directly target it in clinical trials.

The reason that drug discovery of ubiquitin system-targeting drugs has lagged behind, for example, the discovery and development of protein kinase inhibitors is that modulating the ubiquitin system involves targeting protein-protein interactions (PPIs). Nevertheless, our 2012 report discusses novel technologies and strategies that might be applied to the discovery of PPI modulators.

As discussed in our April 25, 2012 article on this blog, there has been new interest in the discovery of PPIs by leading biotech/pharma companies in recent years, motivated by the development of these technologies and of the increasing strategic importance of PPI modulator development.

As we discussed in our 2012 report, the greatest drug discovery opportunity in the ubiquitin cascade is in targeting E3 ubiquitin ligases. That is because as one moves down the ubiquitinylation cascade, the degree of specificity of the process increases. There are over 600 E3 ubiquitin ligases encoded in the human genome, each of which targets its own specific class of proteins. Moreover, the total number of ubiquitin cascade enzymes encoded by the human genome is greater than the number of protein kinases.

As discussed by Krönke et al., their study (and that of Lu et al.) reveals that the small-molecule drug lenalidomide modulates the activity of the CRBN-CRL4 ubiquitin ligase complex to increase ubiquitination of two transcription factors, IKZF1 and IKZF3. It does so by specific binding to one component of the system, cereblon. This was found serendipitously—not by either classical or advanced technologies for discovering PPI modulators. Moreover, the targets of the CRBN-CRL4 ubiquitin ligase, IKZF1 and IKZF3, are transcription factors that act by forming PPIs. They are also involved in the complex process of chromatin remodeling, and the nature of their interactions are poorly understood. They are therefore considered “undruggable.”

Nevertheless, researchers can screen for compounds that bind cereblon, and which thus modulate the CRBN-CRL4 ubiquitin ligase. Might it also be possible to screen for compounds that modulate one component of other E3 ubiquitin ligases, and thus increase the interactions between these ligases and their specific substrates? If so, this might provide a novel means to discover drugs that modulate the ubiquitin system.

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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 by phone or e-mail. We also welcome your comments on this or any other article on this blog.

Can Merck’s R&D restructuring enable it to improve its productivity?

Simvastatin (Merck's Zocor)

Simvastatin (Merck’s Zocor)

On December 27th, 2013 the Wall Street Journal published an article by staff reporters Peter Loftus and Jonathan Rockoff about Merck’s new R&D restructuring. Fierce Biotech’s John Carroll also discussed the WSJ article in his own analysis dated December 28th, 2013.

According to these articles, Merck is in the process of cutting its internal R&D operations. This will include selling off dozens of pipeline compounds that have been under development in its labs. Merck also plans to cut its workforce by 20% over the next two years, as it had announced in October 2013. This will include reductions in its internal R&D staff.

At the same time, Merck will create new innovation hubs in Boston, the San Francisco Bay area, London and Shanghai.  The company has identified these geographic areas as having a critical mass of academic and commercial life science R&D. Merck intends to use its hubs as bases to scout for promising research that the company might license or acquire.

The overall plan is to reduce reliance on Merck’s internal R&D operations and to increase reliance on external R&D in academia and in biotech companies.

This is a similar strategy to that being followed by other Big Pharma companies, especially Johnson & Johnson and GlaxoSmithKline. All three of these companies are targeting some of the same geographic areas, especially Boston, California, London, and China.

Why are pharmaceutical companies struggling to develop new drugs?

The unveiling of Merck’s restructuring plans has triggered a wave of articles commenting on the wider implications of the move. David Shaywitz, M.D., Ph.D. (Director, Strategic and Commercial Planning at Theravance in South San Francisco, CA) writes in Forbes (12/29/2013) that pharma companies’ restructuring plans may save neither the companies carrying them out nor the pharmaceutical industry.

The reason that Merck and other pharma companies are carrying out these restructurings is that the companies are struggling to develop new drugs, and their internal labs are not producing them. The hope is that shifting from–as Dr. Shaywitz puts it–research and development to [external] search and development will produce more and better developable drugs. However, it may not do so. Outside partners may not necessarily know more about drug discovery than Merck Research Laboratories does.

The basic question then becomes why pharma companies are struggling to produce new products in the first place. One highly cited possibility is that Big Pharma companies are too bureaucratic, and thus inhibit their own ability to innovate. However, the underlying problem may well be that our understanding of biology–in health and disease–is limited.

The new President of Merck Research Laboratories, Roger M. Perlmutter, M.D., Ph.D. said, as quoted in another Forbes article:

“…if we’re discovering drugs, the problem is that we just don’t know enough. We really understand very little about human physiology. We don’t know how the machine works, so it’s not a surprise that when it’s broken, we don’t know how to fix it. The fact that we ever make a drug that gives favorable effects is a bloody miracle because it’s very difficult to understand what went wrong.”

Dr. Perlmutter then goes on to cite the example of statin drugs such as Merck’s Zocor (simvastatin) and Pfizer’s LIpitor (atorvastatin). Beginning in Merck’s own laboratories, under the company’s legendary R&D leader and CEO Roy Vagelos, statins were designed to lower blood cholesterol levels by inhibiting the enzyme HMG-CoA reductase. However, statins also appear to prevent atherosclerosis by a variety of other mechanisms (e.g., modulating inflammation). Thus their true mechanisms of action are not well understood.

How can companies carry out biology-driven R&D?

Despite the fact that our knowledge of biology is limited, we and others have noted that the most successful drug discovery and development strategy in the last two decades or so has been biology-driven R&D. For example, this is the basis of the entire R&D program of such companies as Novartis and Genentech. How is it possible to conduct reasonably successful biology-driven R&D if our knowledge of human biology is so limited?

We have discussed reasons for the success of biology-driven R&D in our book-length report Approaches to Reducing Phase II Attrition, and in our published article in Genetic Engineering and Biotechnology News “Overcoming Phase II Attrition Problem”.

Briefly, biology-driven drug discovery has often utilized academic research into pathways, disease models, and other biological systems, which have been conducted over a period of years or of decades. Targets and pathways derived from this research are usually relatively well understood and validated, with respect to their physiological functions and their roles in disease.  Examples of drugs derived from such research include most approved biologics (e.g., Genentech’s Herceptin and Biogen Idec/Genentech’s Rituxan), as well as the numerous protein kinase inhibitors for treatment of cancers. It was the successful development of the kinase inhibitor imatinib (Gleevec/Glivec) that led Novartis to adopt its pathway-based strategy in the first place.

A more recent example is the work on discovery and development of monoclonal antibody (MAb)-based immunotherapies for cancer, which we highlighted in our January 3, 2014 blog article on Science’s Breakthrough of the Year. These drugs include the approved CTLA4-targeting agent ipilimumab (Bristol-Myers Squibb’s Yervoy), and several other agents that target the PD-1/PD-L1 checkpoint pathway, including Merck’s own anti-PD-1 agent lambrolizumab.

The development of these agents was made possible by a line of academic research on T cells that was begun in the 1980s by James P Allison, Ph.D. Even after Dr. Allison’s research demonstrated in 1996 that an antibody that targeted CTLA-4 had anti-tumor activity in mice, no pharmaceutical company would agree to work on this system. However, the MAb specialist company Medarex licensed the antibody in 1999. Bristol-Myers Squibb acquired Medarex in 2009, and Yervoy was approved in 2011.

The above examples show that although we do not understand human physiology in health and decease in general, we do understand pieces of biology that are actionable for drug discovery and development. This understanding often comes after decades of effort. One strategy for a scout in a Big Pharma innovation hub might be to look for such actionable pieces of biology, and to contract with the academic lab or biotech company that developed them for licenses or partnerships. However, the case of Yervoy shows that pharmaceutical companies may not recognize these actionable areas, or may be slow to do so.

Moreover, for many diseases of great interest to physicians and patients, academic researchers, and/or companies, we may not have an actionable piece of biology that is backed by decades of research. We may only have interesting (and perhaps breakthrough) research that has been carried out over only a few years. In these cases (and even in cases based on deeper understand based on decades of research), companies will need to develop a set of “fail fast and fail cheaply” strategies. Such strategies usually reside in small biotechs rather than in Big Pharmas. Moreover, these strategies remain a work in progress.

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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 by phone or e-mail. We also welcome your comments on this or any other article on this blog.

Breakthrough of the year 2013–Cancer Immunotherapy

Happy New Year! Source: Roblespepe. http://bit.ly/1cpkyHX

Happy New Year! Source: Roblespepe. http://bit.ly/1cpkyHX

As it does every year, Science published its “Breakthrough of the Year” for 2013 in the 20 December 2013 issue of the journal.

Science chose cancer immunotherapy as its Breakthrough of the Year 2013.

In its 20 December 2013 issue, Science published an editorial by its Editor-in-Chief, Marcia McNutt, Ph.D., entitled “Cancer Immunotherapy”. The same issue has a news article  by staff writer Jennifer Couzin-Frankel, also entitled “Cancer Immunotherapy”.

As usual, the 20 December 2013 issue of Science contains a Breakthrough of the Year 2013 news section, which in addition to the Breakthrough of the Year itself, also contains articles about several interesting runners-up, ranging from genetic microsurgery using CRISPR (clustered regularly interspaced short palindromic repeat) technology to mini-organs to human cloning to vaccine design.

In the Science editorial and news article, the authors focus on the development and initial successes of two types of immunotherapy:

  • Monoclonal antibody (MAb) drugs that target T-cell regulatory molecules, including the approved CTLA4-targeting MAb ipilimumab (Bristol-Myers Squibb’s Yervoy), and the clinical-stage anti-PD-1 agents nivolumab (Bristol-Myers Squibb) and lambrolizumab (Merck).
  • Therapy with genetically engineered autologous T cells, known as chimeric antigen receptor (CAR) therapy, such as that being developed by a collaboration between the University of Pennsylvania and Novartis.

The rationale for Science’s selection of cancer immunotherapy as the breakthrough of the year is that after a decades-long process of basic biological research on T cells, immunotherapy products have emerged and–as of this year–have achieved impressive results in clinical trials. And–as pointed out by Dr. McNutt–immunotherapy would constitute a new, fourth modality for cancer treatment, together with the traditional surgery, radiation, and chemotherapy.

However, as pointed out by Dr. McNutt and Ms. Couzin-Frankel, these are still early days for cancer immunotherapy. Key needs include the discovery of biomarkers that can help predict who can benefit from a particular immunotherapy, development of combination therapies that are more potent than single-agent therapies, and that might help more patients, and means for mitigating adverse effects.

Moreover, it will take some time to determine how durable any remissions are, especially whether anti-PD1 agents give durable long-term survival. Finally, although several MAb-based immunotherapies are either approved (in the case of  ipilimumab) or well along in clinical trials, CAR T-cell therapies and other adoptive immunotherapies remain experimental.

In addition to the special Science “Breakthrough 2013″ section, Nature published a Supplement on cancer immunotherapy in its 19/26 December 2013 issue. This further highlights the growing importance of this field.

Cancer immunotherapy on the Biopharmconsortium Blog

Readers of our Biopharmconsortium Blog are no strangers to recent breakthroughs in cancer immunotherapy. In the case of MAb-based immunotherapies, we have published two summary articles, one in 2012 and the other in 2013. These articles noted that cancer immunotherapy was the “star” of the American Society of Clinical Oncology (ASCO) annual meeting in both years.

Our blog also contains articles about CAR therapy, as being developed by the University of Pennsylvania and Novartis and by bluebird bio and Celgene. Moreover, the Biopharmconsortium Blog contains articles on other types of cancer immunotherapies not covered by the Science articles, such as cancer vaccines.

We look forward to further progress in the field of cancer immunotherapy, and to the improved treatments and even cures of cancer patients that may be made possible by these developments.
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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 by phone or e-mail. We also welcome your comments on this or any other article on this blog.

Neuroscience companies sprout up in Boston

Pyramidal neurons. Source: Magnus Manske http://bit.ly/1gUo6GM

Pyramidal neurons. Source: Magnus Manske http://bit.ly/1gUo6GM

In our December 10, 2013 blog article that focused on Novartis’ new neuroscience division, we briefly mentioned two young Cambridge MA neuroscience specialty companies–Rodin Therapeutics and Sage Therapeutics.

Rodin Therapeutics

Rodin was founded by Atlas Venture and the German protein structure-focused biotech Proteros biostructures in June 2013. It is focused on applying epigenetics to discovery and development of novel therapeutics for CNS disorders, especially cognitive disorders such as Alzheimer’s disease. Rodin secured funding from Atlas and Johnson & Johnson Development Corporation (JJDC). The company plans to collaborate with the Johnson & Johnson Innovation Center in Boston and Janssen Research & Development to advance its R&D programs. In addition to several partners at Atlas (led by acting Rodin Chief Executive Officer Bruce Booth, Ph.D.), Rodin’s team includes as its Chief Scientific Officer Martin Jefson Ph.D., former head of Neuroscience Research at Pfizer.

There is little information available on Rodin, because the company is operating in stealth mode.

Sage Therapeutics

Sage was founded by venture capital firm Third Rock Ventures, and officially launched on October 2011. At the time of its launch, Third Rock provided Sage with a $35 million Series A round of financing. Third Rock founded Sage together with scientific founders Steven Paul, M.D. (formerly the Executive Vice President for science and technology and President of Lilly Research Laboratories, and a former scientific director of the National Institute of Mental Health) and Douglas Covey, Ph.D. (professor of biochemistry at the Washington University School of Medicine, St. Louis, MO).

We at Haberman Associates have known Dr. Paul mainly for his work in R&D strategy while at Lilly. We cited Dr. Paul in our 2009 book-length report, Approaches to Reducing Phase II Attrition, published by Cambridge Healthtech Institute.

In October 2013, Sage received $20 million in Series B financing from Third Rock and from ARCH Venture Partners.

Sage’s technology platform is based on targeting certain classes of neurotransmitter receptors. As we discussed in our December 10, 2013 blog article, targeting neurotransmitter receptors was a successful approach to drug discovery and development decades ago, but has proven nearly fruitless ever since.

Nevertheless, Sage is taking a novel and interesting approach to targeting neurotransmitter receptors. The company is focusing on receptors for gamma aminobutyric acid (GABA) and glutamate. GABA and glutamate are, respectively, the primary inhibitory and excitatory neurotransmitters that mediate fast synaptic transmission in the brain. Specifically, Sage is focusing on GABAreceptors (a major class of GABA receptors) and N-methyl-D-aspartic acid (NMDA) receptors (a major class of glutamate receptors).

Both GABAA receptors and NMDA receptors are ligand-gated ion channels. These multi-subunit proteins are transmembrane ion channels that open to allow ions such as Na+, K+, Ca2+, or Cl- to pass through the membrane in response to the binding of a ligand, such as a neurotransmitter. [In addition to ligand-gated ion channels, neurotransmitter receptors include members of the G-protein coupled receptor (GPCR) family. One example is the GABAB receptor.]

The GABAA receptor is a pentameric (five-subunit) chloride channel whose endogenous ligand is GABA. In addition to its binding site for GABA, this receptor has several allosteric sites that modulate its activity indirectly. Among the drugs that target an allosteric site on GABAA receptors are the benzodiazepines. Examples of benzodiazepines include the tranquilizer (anxiolytic) diazepam (Valium), and the short-term anti-insomnia drug Triazolam (Halcion).

The NMDA receptor is a heterotetrameric cation channel. It is a type of glutamate receptor. NMDA is a selective agonist that binds to NMDA receptors but not to other glutamate receptors. Calcium flux through NMDA receptors is thought to be critical for synaptic plasticity, a cellular mechanism involved in learning and memory. NMDA receptors require co-activation by two ligands: glutamate and either D-serine or glycine. (NMDA itself is a partial agonist that mimics glutamate, but is not normally found in the brain.) Among the drugs that act as NMDA receptor antagonists are the cough suppressant (antitussive) dextromethorphan and the Alzheimer’s drug memantine.

Imbalance in the levels of GABA and glutamate, or alterations in activity of their receptors can result in dysregulation of neural circuits. Such imbalance has been implicated in neuropsychiatric disorders such as epilepsy, autism, schizophrenia and pain. While GABAA receptors and NMDA receptors are considered to be validated drug targets, a major challenge has been to modulate these receptors safely and effectively. Current drugs that act at these receptors have major adverse effects (e.g., sedation, seizures, tolerance, dependence, and excitotoxicity) that strongly impair patient quality of life. For example, long-term treatment with benzodiazepines can cause tolerance and physical dependence, and dextromethorphan can act as a dissociative hallucinogen.

Sage’s proprietary technology platform is based on the identification of members of a family of small-molecule endogenous allosteric modulators, which selectively and potently modulate GABAA or NMDA receptors. Sage is developing proprietary derivatives of these compounds. The goal of Sage’s R&D is to discover and develop  positive and negative allosteric modulators of GABAA and NMDA receptors that can be used to restore the balance between GABA and glutamate receptor activity that is disrupted in several important CNS disorders. These compounds will be designed to “fine tune” GABAA and NMDA receptor activity, resulting in a greater degree of both efficacy and safety than current CNS therapeutics.

For example, in October 2013, Sage announced the publication of a research report in the October 30, 2013 issue of the Journal of Neuroscience. The report detailed the results of research at Sage, on the identification of an endogenous brain neurosteroid, the cholesterol metabolite 24(S)-hydroxycholesterol (24(S)-HC).  This compound is a potent (submicromolar), direct, and selective positive allosteric regulator of NMDA receptors. The researchers found that 24(S)-HC binds to a modulatory allosteric site that is unique to oxysterols. Subsequent drug discovery efforts resulted in the identification of several potent synthetic drug-like derivatives of 24(S)-HC that act as the same allosteric site, and serve as positive modulators of NMDA receptors. Treatment with one of these derivatives, Sage’s propriety compound SGE-301, reversed behavioral and cognitive deficits in a variety of preclinical models.

Sage’s pipeline

Sage has four pipeline drug candidates, including two compounds in the clinic. The company says that its initial pipeline focus is on “acute and orphan CNS indications with strong preclinical to clinical translation and accelerated development timelines” that enable the rapid development of important therapeutics to treat these conditions. In addition, Sage is pursuing early-stage programs that utilize the company’s PANAM platform. The goal of the early-stage programs (which target GABAA and NMDA receptors as we discussed earlier in this article) is to address “prevalent, chronic neuropsychiatric indications.”

Sage’s pipeline drug candidates include compounds in Phase 2 trials to treat status epilepticus and traumatic brain injury, and two preclinical-stage compounds–an anesthetic a treatment for patients with fragile X syndrome.

Status epilepticus (SE) is an acute life-threatening form of epilepsy, which is currently defined as a continuous seizure lasting longer than 5 minutes, or recurrent seizures without regaining consciousness between seizures for over 5 minutes. It occurs in approximately 200,000 U.S. patients each year, and has a mortality rate of nearly 20%. Refractory SE occurs in around a third of SE patients for whom first and second line treatment options are ineffective. These patients are moved to the ICU, and have little or no treatment options.

Sage’s SAGE-547, which is a proprietary positive GABAA receptor allosteric modulator, is aimed at treatment of the orphan indication of refractory SE. This compound has been selected by Elsevier Business Intelligence as one of the Top 10 Neuroscience Projects to Watch.

In addition to SAGE-547, Sage is developing next-generation treatments for SE and other forms of seizure and epilepsy. These early-stage compounds are novel positive allosteric modulators of GABAA receptors. Sage presented data on its early-stage therapeutics for SE in a poster session at the American Epilepsy Society (AES) Annual Meeting, Cambridge MA, December 9, 2013.

Sage’s drug candidate for traumatic brain injury is listed on the company’s website as “a proprietary, positive allosteric modulator”.

Sage’s preclinical anesthetic, SGE-202, is moving toward a Phase 1 clinical trial in 2014. It is an intravenous anesthetic for procedural sedation that designed to compete with the standard therapy, propofol. SGE-202 is designed to offer improved efficacy and safety as compared to propofol.

Fragile X syndrome (FSX) is an X chromosome-linked genetic syndrome that is the most widespread monogenic cause of autism and inherited cause of intellectual disability in males. FSX is an orphan condition that affects 60,000 – 80,000 people in the U.S. It causes such impairments as anxiety and social phobia, as well as cognitive deficits. There are no currently approved therapies for FXS, but patients are often prescribed treatments for anxiety, attention deficit hyperactivity disorder (ADHD) and/or epilepsy.

Sage is developing a proprietary positive GABAA receptor allosteric modulator for treatment of FSX. It is expected to provide symptomatic and potentially disease-modifying therapeutic benefits to patients with FXS, and to ameliorate anxiety and social deficits. The company is moving its FXS program toward a Phase 1 clinical trial in 2014.

EnVivo Pharmaceuticals

Sage is not the only Boston-area biotech that is developing novel classes of compounds to target specific types of neurotransmitter receptors. We discussed EnVivo Pharmaceuticals (Watertown, MA), and its program to develop agents to target subclasses of nicotinic acetylcholine receptors (nAChRs), in a November 2007 report published by Decision Resources.

nAChRs, like GABAA and NMDA receptors, are ligand-gated ion channels. In normal physiology, nAChRs are opened by the neurotransmitter acetylcholine (ACh). However, nicotine can also open these receptors. Certain subtypes of nAChRs in the brain are involved in cognitive function, and nicotine, by targeting these receptors, has long been known to improve cognitive function. However, the adverse effects of nicotine (especially its well-known addictive properties) make this drug problematic for use as a cognitive enhancer. Therefore, several companies have been working on discovering and developing subtype-specific nAChR agonists for use in such conditions as Alzheimer’s disease, schizophrenia, ADHD, and mild cognitive impairment.

EnVivo’s alpha-7 nAChR program, which targets a subtype of nChRs that have been implicated in cognitive function, has made considerable progress since 2007. Their lead compound, EVP-6124, is now in Phase 3 clinical trials for treatment of schizophrenia, and Phase 3 trials in Alzheimer’s disease are planned. This follows positive Phase 2 results in both conditions.

Outlook

Sage Therapeutics has a sophisticated approach to discovery of compounds that modulate GABAA and NMDA receptors, and has managed to both attract significant venture financing and to move compounds into the clinic rapidly. However, none of Sage’s compounds has yet achieved clinical proof of concept, so it is too early to determine whether Sage’s approach will bear fruit.

EnVivo’s alpha-7 nAChR program is based on a more straightforward technology strategy than Sage’s. It has made considerable progress since we first covered it in 2007. EnVivo’s lead compound, EVP-6124, has had successful Phase 2 clinical trials in both Alzheimer’s disease and schizophrenia. However, both of these diseases have proven very difficult for drug developers to tackle. This is particularly true for Alzheimer’s disease–we have covered several cases in which drugs failed in Phase 3 on this blog. Therefore, it is best to reserve judgment on the outlook for EnVivo’s alpha-7 nAChR program pending the results of the Phase 3 trials.

Moreover, as we discussed on this blog, many Alzheimer’s experts believe that it would be best to target very early-stage or pre-Alzheimer’s disease rather than even “mild-to-moderate” disease as in the EnVivo Phase 2 trials.

Novartis’ new neuroscience program is a foundational, early-stage biology-driven effort, and clinical compounds are not expected for five years or so. Therefore, if Sage’s and especially EnVivo’s programs bear fruit, we should know about it long before any Novartis CNS programs progress very far at all. However, it is because of the abject failure of neurotransmitter-targeting approaches to CNS drug discovery and development over several decades that Novartis is resorting to a long-term foundational CNS R&D strategy.

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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 by phone or e-mail. We also welcome your comments on this or any other article on this blog.

Will Novartis lead a pharma industry return to neuroscience R&D?

Pyramidal neurons. Source: Retama. http://bit.ly/18j9iOP

Pyramidal neurons. Source: Retama. http://bit.ly/18j9iOP

A prominent feature of pharmaceutical company strategy in recent years has been massive cuts in R&D. These cutbacks have hit especially hard in areas that have not been productive in terms of revenue-producing drugs.

Chief among the targets for R&D cuts and layoffs has been neuroscience. As outlined in a 2011 Wall Street Journal article, such companies as AstraZeneca, GlaxoSmithKline, Sanofi, and Merck have cut back on neuroscience R&D, especially in psychiatric diseases. (Neurodegenerative diseases such as Alzheimer’s, despite the frustrations of working in this area, have continued to hold some companies’ interest.)

The retreat from psychiatric disease R&D has been occurring despite the fact that mental health disorders are the most costly diseases in Western countries. For example, according to the same Wall Street Journal article, mental disorders were number one in the European Union in terms of direct and indirect health costs in recent years. In 2007, the total cost of these conditions in Europe was estimated at €295 billion ($415 billion). Indirect costs, especially lost productivity, accounted for most of these costs.

The Novartis return to neuroscience R&D

Now comes a Nature News article by Alison Abbott, Ph.D. (Nature’s Senior European Correspondent in Munich)–dated 08 October 2013, entitled “Novartis reboots brain division”.

As discussed in that article, Novartis closed its neuroscience facility at its headquarters in Basel, Switzerland in 2012. However, as was planned at the time of this closure, Novartis is now starting a new neuroscience research program at its global R&D headquarters, the Novartis Institutes for BioMedical Research (NIBR) (Cambridge, MA).

The old facility’s research was based on conventional approaches, centered on the modulation of neurotransmitters. This approach had been successful in the 1960s and 1970s, especially at Novartis’ predecessor companies. In that era, Sandoz developed clozapine, the first of the so-called “atypical antipsychotic” drugs, and Ciba developed imipramine, the first tricyclic antidepressant.

Since the development of these and other then-breakthrough psychiatric drugs, the market has become inundated with cheap generic antidepressants, antipsychotics and other psychiatric drugs. These drugs act on well-known targets–mainly neurotransmitter receptors.

Neurotransmitter receptor-based R&D has become increasingly ineffective. What has been needed are new paradigms of R&D strategy to address the lack of actionable knowledge of CNS biology. As a result of this knowledge deficit, pharmaceutical industry CNS research has become increasingly ineffective, which is the motivation for the cutbacks and layoffs in this area. Moreover, there have been no substantial improvements in therapy. For example, there are no disease-modifying drugs for autism, or for the cognitive deficits of schizophrenia.

Novartis’ return to neuroscience is based on a fresh approach to R&D strategy, based on exciting developments in academic neurobiology. This strategy is based on study of such areas as:

  • Neural circuitry, and how it may malfunction in psychiatric disease
  • The genetics of psychiatric diseases
  • The technology of optogenetics, which enables researchers to identify the neural circuits that genes involved in psychiatric disorders affect.
  • The use of induced pluripotent stem cell (iPS) technology, which enables researchers to take skin cells from patients, induce them to pluripotency, differentiate the iPS cells into neurons, and study aspects of their cell biology that may contribute to disease.

In support of this strategy, Novartis has hired an academic, Ricardo Dolmetsch, Ph.D. (Stanford University) to lead its new neuroscience division. Dr. Dolmetsch’s research has focused on the neurobiology of autism and other neurodevelopmental disorders. His laboratory has been especially interested in how electrical activity and calcium signals control brain development, and how this may be altered in children with autism spectrum disorders (ASDs).

The projects in the Dolmetsch laboratory have included:

  • Use of iPS technology–as well as mouse and Drosophila models–to study the underlying basis of ASDs.
  • Studies of calcium channels and calcium signaling in neurons, their role in development, and how they may be altered in neural diseases.
  • The development of new technologies to study neural development, and developing new pharmaceuticals that regulate calcium channels and that may be useful for treating ASDs and other diseases.

Novartis’ new approach to neuroscience is completely consistent with the company’s overall biology-driven (and more specifically pathway-driven) approach to drug discovery and development. We discussed this strategy in our July 20, 2009 article on the Biopharmconsortium Blog. We also discussed more recent development with Novartis’ overall strategy in our September 4, 2013 article on this blog.

Interestingly, the idea of hiring an academic to head Novartis’ new neuroscience division replicates the hiring of an academic–Mark Fishman, M.D. (formerly at the Massachusetts General Hospital, Harvard Medical School, Boston MA)–as the overall head of the Novartis Institutes for BioMedical Research in 2002.

Novartis’ timeline for neuroscience drug development

Novartis neuroscience program intends to work toward discovery and development of therapeutics for such neurodevelopmental conditions as ASD, schizophrenia and bipolar disorder, as well as for neurodegenerative diseases such as Parkinson’s and Alzheimer’s diseases.

All of the technologies and research strategies that Novartis plans to use in its neuroscience division are novel ones, and mainly reside in academic laboratories. Novartis therefore plans to collaborate with academia in its neuroscience research efforts–as it does in other areas.

The collaboration between Novartis and academic labs will be facilitated by accepting the norms of academic research. Research results will be published, and academic institutions will be allowed to patent targets and technologies that emerge from the research. However, Novartis will have the right to develop drugs based on the targets, and will have the right of first refusal to license the patents.

According to Dr. Dolmetsch, and to Novartis advisor Steven E. Hyman, M.D (director of the Stanley Center for Psychiatric Research at the Broad Institute, Cambridge, MA), Novartis’ new approach to neuroscience will take a long time (perhaps around 5 years) before the first drugs start entering the clinic. As with other project areas  based on Novartis’ pathway-driven drug discovery strategy, it is likely that the first clinical studies will be in rare diseases (e.g., types of autism driven by specific genetic determinants).

Is Novartis leading the way to a broader industry return to neuroscience?

An important question is whether other pharmaceutical and biotechnology companies will follow Novartis into a return to neuroscience R&D, based on biology-driven strategies. According to Alison Abbott’s article, Roche is planning such a program. However, other Big Pharmas are so far staying out.

Meanwhile, the European Commission, via its Innovative Medicines Initiative, is attempting to foster academic/pharma industry collaboration to study genetics and neural circuitry in autism, schizophrenia and depression. In the United States, the National Institutes of Health has launched the Brain Research through Advancing Innovative Neurotechnologies (BRAIN) Initiative, focused on study of neural circuitry.

Entrepreneurial start-up biotech companies, backed by leading venture capitalists, have also been exploring novel neuroscience-based approaches to drug discovery and development. For example, in Cambridge MA, there are Sage Therapeutics (backed by Third Rock Ventures and ARCH Ventures), and Rodin Therapeutics (backed by Atlas Venture). However, another Cambridge MA neuroscience company, Satori Pharmaceuticals, which had been focused on Alzheimer’s, had to close its doors in May 30, 2013, after the preclinical safety failure of its lead compound. This illustrates the risky nature of neuroscience-based drug development, especially in small biotech companies.

Nevertheless, after the decades-long failure of neurotransmitter receptor-based R&D to yield breakthrough drugs for devastating psychiatric and neurodegenerative diseases, biology-driven drug discovery R&D appears to be the way to go.

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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 by phone or e-mail. We also welcome your comments on this or any other article on this blog.

Agios Pharmaceuticals becomes a clinical-stage company!

Agios Efstratios, Greece. Source:  Christef http://bit.ly/HK636F

Agios Efstratios, Greece. Source: Christef http://bit.ly/HK636F

In a news release on September 23, 2013, Agios Pharmaceuticals (Cambridge, MA) announced that it had initiated its first clinical study. The company further discussed its early clinical and preclinical programs in its press release on its Third Quarter financial report, dated November 7, 2013.

Specifically, the company initiated a Phase 1 muticenter clinical trial of AG-221 in patients with advanced hematologic malignancies bearing an isocitrate dehydrogenase 2 (IDH2) mutation. The study is designed to evaluate the safety, pharmacokinetics, pharmacodynamics and efficacy of orally-administered AG-221 in this patient population. The first stage of the Phase 1 study is a dose-escalation phase, which is designed  to determine the maximum tolerated dose and/or the recommended dose to be used in Phase 2 studies. After the completion of this phase, several cohorts of patients will receive AG-221 to further evaluate the safety, tolerability and clinical activity of the maximum tolerated dose.

We discussed AG-221 in our June 17, 2013 article on this blog. AG-221 is an orally available, selective, potent inhibitor of the mutated IDH2 protein. It is thus a targeted (and personalized) therapy for patients with cancers with an IDH2 mutation.

As we summarized in our June 17, 2013 article, wild-type IDH1 and IDH2 catalyze the NADP+-dependent oxidative decarboxylation of isocitrate to α-ketoglutarate. Mutant forms of IDH1 and IDH2, which are found in certain human cancers, no longer catalyze this reaction, but instead catalyzes the NADPH-dependent reduction of α-ketoglutarate to R(-)-2-hydroxyglutarate (2-HG). Agios researchers hypothesized that 2HG is an oncometabolite. They further hypothesized that developing mutant-specific small molecule inhibitors of IDH1 and IDH2 might inhibit the growth or reverse the oncogenic phenotype of cancer cells that carry the mutant enzymes.

As we further discussed in our article, Agios researchers published two articles in the journal Science in May 2013 that support these hypotheses. The researchers showed that drugs that inhibit the mutant forms of IDH1 and IDH2 can reverse the oncogenic effects of the mutant enzymes in patient-derived tumor samples. These results constitute preclinical support for the hypothesis that the two mutant enzymes are driving disease, and that drugs that target the mutant forms of the enzymes can reverse their oncogenic effects.

In the results reported in one of these research articles, Agios researchers tested a mutant-IDH2 inhibitor in hematologic malignancies (including one model leukemia and one patient-derived leukemia), and showed that treatment with the inhibitor caused differentiation of the leukemic cells to normal blood cells. This preclinical study thus supports the initiation of Agios’ new Phase 1 study of AG-221 in patients with mutant-IDH2 bearing hematologic malignancies.

Additional pipeline news in Agios’ Third Quarter 2013 Report

In addition to the report of the initiation of Phase 1 studies of AG-221, Agios reported  that it had advanced AG-120, a mutant-IDH1 inhibitor, toward Investigational New Drug (IND) filing. The company plans to initiate Phase 1 clinical trials of AG-120 in early 2014, in  patients with advanced solid and hematological malignancies that carry an IDH1 mutation.

Agios also reported in their Third Quarter 2013 Report that the company had advanced AG-348 into IND-enabling studies. AG-348 is an activator of pyruvate kinase R (PKR). Germline mutation of PKR can result in pyruvate kinase deficiency (PK deficiency), a form of familial hemolytic anemia. Agios’ in vitro studies indicate that PKR activators can enhance the activity of most common PKR mutations, and suggest that these compounds may be potential treatments for PK deficiency.

Agios’ AG-348 program is part of its R&D aimed at development of treatments for inborn errors of metabolism (IEM). We discussed this program in our November 30, 2011 article on this blog.

Agios to present preclinical research at the ASH meeting in December 2013

In a second November 7, 2013 press release, Agios announced that it would present the results of the preclinical studies of its lead programs in cancer metabolism and in IEM at the 2013 American Society of Hematology (ASH) Annual Meeting, December 7-10, 2013 in New Orleans, LA.

Agios researchers will give one presentation on a study of AG-221 treatment in a primary human IDH2 mutant bearing acute myeloid leukemia (AML) xenograft model. They will also present two posters–one on a mutant-IDH1 inhibitor in combination with Ara-C (arabinofuranosyl cytidine) in a primary human IDH1 mutant bearing AML xenograft model, and another on the effects of a small molecule activation of pyruvate kinase on metabolic activity in red cells from patients with pyruvate kinase deficiency-associated hemolytic anemia.

Can Agios Pharmaceuticals become a new Genentech?

On October 13, 2013, XConomy published an article on Agios’ CEO, David Schenkein. The article is entitled “David Schenkein, Cancer Doc Turned CEO, Aims to Build New Genentech”.

As many industry experts point out, the business environment is much different from that in which Genentech (and Amgen, Genzyme and Biogen) were founded, and grew to become major companies. As one illustration of the difference between the two eras, neither Genentech nor Genzyme are independent companies today. Biogen exists as a merged company, Biogen Idec, which between 2007 and 2011 had to fend off attacks by shareholder activist Carl Icahn.

Moreover, this has been the era of the “virtual biotech company”. These are lean companies with only a very few employees that outsource most of their functions, and that are designed to be acquired by a Big Pharma or large biotech company. The virtual company strategy has been designed to deal with the inability of most young biotech companies to go public in the current financial environment. (However, there has been a surge in biotech IPOs in the past year, including Agios’ own IPO on June 11, 2013. So it is possible that the environment for young biotech companies going public is changing.)

Nevertheless, the XConomy article states that when Dr. Schenkein was in discussions with venture capitalist Third Rock on becoming the CEO of one of their portfolio companies, he stated that he wanted “a company with a vision, and investor support, to be a long-term, independent company”. As we have discussed in this blog, and also in an interview for Chemical & Engineering News (C&EN), Agios’ strategy is to build a company that can endure as an independent firm over a long period of time, and that can also demonstrate sustained performance. This strategy has been characterized (especially in the 1990s and early 2000s) as “Built to Last”, a term that I used in the interview.

Later, Agios posted a reprint of the C&EN article on its website, which it retitled “Built to Last”. This illustrates Agios’ commitment to “Built to Last”, as is more importantly shown by the company’s financial and R&D strategy.

Even if Agios cannot become the next Genentech, it–as well as a few other young platform companies mentioned in the CE&N article–might become an important biotech or pharmaceutical company like Vertex. However, all depends on the success of Agios’ products in the clinic and at regulatory agencies like the FDA, as well as the future shape of the corporate, financial and health care environment.

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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 an initial one-to-one consultation on an issue that is key to your company’s success, please contact us by phone or e-mail. We also welcome your comments on this or any other article on this blog.