Amyloid precursor protein (APP)

As we mentioned in our August 19, 2012 article on Alzheimer’s disease (AD), the results of Phase 3 trials of Lilly’s amyloid-targeting monoclonal antibody (MAb) drug solanezumab, had been expected soon.

On August 24 2012, Lilly announced the top-line results of the two Phase 3, double-blind, placebo-controlled EXPEDITION trials of solanezumab in patients with mild-to-moderate Alzheimer’s disease. The primary endpoints, both cognitive and functional, were not met in either of these trials.

However, a pre-specified secondary analysis of pooled data across both trials showed statistically significant slowing of cognitive decline in the overall study population, and pre-specified secondary subgroup analyses of pooled data across both studies showed a statistically significant slowing of cognitive decline in patients with mild Alzheimer’s disease, but not in patients with moderate Alzheimer’s disease.

These results were reported in a press release.  What was absent was data from the trials. However, the Alzheimer’s Disease Cooperative Study (ADCS), (an academic national research consortium) will present its independent analysis of the data from the EXPEDITION studies at the American Neurological Association (ANA) meeting in Boston on October 8, 2012, and at the Clinical Trials on Alzheimer’s Disease (CTAD) meeting in Monte Carlo, Monaco, on October 30, 2012.

Once again, an amyloid pathway-targeting drug for Alzheimer’s disease that was taken into Phase 3 trials despite Phase 2 results that showed no statistically significant efficacy has failed in Phase 3. Solanezumab joins a list of such failed drugs that includes Myriad Pharmaceuticals’ Flurizan (tarenflurbil), Neurochem’s (now Bellus Health) Alzhemed (3-amino-1-propanesulfonic acid), and as of July 2012, Pfizer/Janssen’s bapineuzumab (“bapi”). Nevertheless, as in the Phase 2 results with bapi, Lilly sees hope for the drug in the results of secondary analyses.

On the day of the Lilly announcement, August 24 2012, Lilly executives and stock analysts turned the results of these trials into something “positive”, as the result of the secondary analysis. This resulted in a one-day 3.4 percent increase in the price of Lilly stock. However, the results of the secondary analysis do not give Lilly any basis for going to the FDA with a New Drug Application (NDA) for solanezumab. Nor do they provide any realistic hope for AD patients, the physicians who treat them, or caregivers of AD patients.

At best, Lilly’s secondary analysis gives rise to a hypothesis–that solanezumab–and presumably other anti-amyloid MAbs–will be effective in treating earlier-stage AD patients, especially those who have not suffered extensive, irreversible brain damage. This is the very same hypothesis that is now being tested by Roche/Genentech in its clinical trials of its anti-amyloid MAb crenezumab, as we discussed in our August 19, 2012 article. Genentech is testing its drug candidate in a Phase 2a trial in a very special population–members of a large Colombian kindred who harbor a mutation in presenilin 1 (PS1) that causes dominant early−onset familial AD.

A News Focus article in the 17 August 2012 issue of Science, written by science writer Greg Miller, PhD, discusses three upcoming clinical trials designed to test the “treat early-stage or presymptomatic AD with anti-amyloid MAbs” hypothesis. One of these studies is the Genentech trial of crenezumab in the extended family in Colombia.

Another of these studies is being conducted in conjunction with the Dominantly Inherited Alzheimer Network (DIAN), a consortium led by researchers at Washington University School of Medicine (St. Louis, MO). This study will include people with mutations in any of the three genes linked to early-stage, dominantly-inherited AD–PS1, PS2, and amyloid precursor protein (APP).

Initial studies, published ahead of print in the July 11 issue of the New England Journal of Medicine (NEJM) looked at changes in biomarkers and in cognitive ability as a function of expected age of AD onset in people with these mutations. Concentrations of amyloid-β1–42 (Aβ42) in the cerebrospinal fluid (CSF) appeared to decline 25 years before expected symptom onset. This decrease may reflect impaired clearance of Aβ42 from the brain, which may be a factor in the amyloid plaque increase that is associated with AD. Amyloid accumulation in the brain was detected 15 years before expected symptom onset. Other biomarkers, as well as cognitive impairment, were also followed in the study published in the NEJM. In the first stage of the actual trial, three drugs (which have not yet been selected) will be tested in this population, and changes in biomarkers and cognitive performance will be followed.

The third study, known as the Anti-Amyloid Treatment of Asymptomatic Alzheimer’s (A4) trial, will involve treating adults without mutations in any of the above three genes, whose brain scans show signs of amyloid accumulation. A4 is thus designed to study prevention of sporadic AD (by far the most common form of the disease). It will enroll 500 people age 70 or older who test positive on a scan of amyloid accumulation in the brain. (This is in contrast to the two trials in subjects with gene mutations, who are typically in their 30s or 40s.) A4 will also have a control arm of 500 amyloid-negative subjects. Amyloid-positive and control subjects will be entered into a three-year double-blind clinical trial that will look at changes in cognition with drug treatment. The A4 researchers [led by  Reisa Sperling, Brigham and Women’s Hospital/Harvard University (Boston, MA), and Paul Aisen, University of California, San Diego] plan to select a drug for testing by December 2012.

If Lilly wishes to test solanezumab in early-stage (or presymptomatic) sporadic AD, it will need to follow a similar methodology to the studies outlined in the new Science article, especially with respect to the use of biomarkers to define “early-stage” AD and to track the effects of the drug. Studies such as the DIAN biomarker study published in the NEJM used the positron emission tomography (PET) ligand Pittsburgh Compound-B (PiB-C11), to image amyloid plaques. However, the use of this compound is limited by the short half-life of carbon-11 (20.4 minutes). A new PET amyloid imaging agent, Amyvid (florbetapir F18 Injection) was developed by Lilly and approved by the FDA in April 2012. This compound contains fluorine-18, which has a half-life of 109.8 minutes. A recent study indicates that Amyvid provides comparable information to PiB-C11. If Lilly wishes to conduct new studies of solanezumab in early-stage or presymptomatic sporadic AD, it may wish to use Amyvid, as suggested in a comment to an August 24, 2012 solanezumab post in Derek Lowe’s blog “In the Pipeline”. However, the FDA, in its press release announcing the approval of Amyvid, warns that increased amyloid plaque content (as detected by Amyvid or Pittsburgh Compound-B) may be present in the brains of patients with non-AD neurologic conditions, and in older people with normal cognition. Thus defining or detecting “early-stage (or presymptomatic) sporadic AD” is difficult.

In any case, for Lilly to follow up on its secondary analyses of the Phase 3 clinical trials of solanezumab will necessitate additional long and expensive clinical trials, with no assurance of success. Lilly executives will need to determine if such a course is worth the risk, or whether it should invest in other R&D efforts that might have a higher probability of success.


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


The APP processing pathway

An exciting new study on Alzheimer’s disease (AD) was published in the 2 August issue of Nature. The study was carried out by researchers at deCode Genetics (Reykjavik Iceland) and their collaborators at Genentech and several academic institutions. A News and Views article by leading AD researcher Bart De Strooper and genomics researcher Thierry Voet (both at KU Leuven, Leuven, Belgium) analyzes this study and its implications.

Amyloid plaques are a central feature of AD.  They largely consist of amyloid-β (Aβ) peptides. Aβ peptides are formed via sequential proteolytic processing of the amyloid precursor protein (APP), catalyzed by two aspartyl protease enzymes–β-secretase and γ-secretase.  The β-site APP cleaving enzyme 1 (BACE1) cleaves APP predominantly at a unique site. However, γ-secretase cleaves the resulting carboxy-terminal fragment at several sites, with preference for positions 40 and 42. This leads to formation of amyloid-β1–40 (Aβ40) and Aβ1–42 (Aβ42) peptides. APP processing to yield Aβ peptides is illustrated by the figure at the top of this article.

By studying rare, familial cases of early-onset AD, human geneticists have identified three disease genes in these conditions— genes for APP, and for two presenilins, PS1 and PS2. The presenilins are components of γ-secretase, which exists as an intramembrane protease complex. Mainly because of these genetic studies, as well as studies in animal models and postmortem studies of AD brains, the majority of AD researchers have focused on the APP processing pathway and/or on aggregation of Aβ to form plaques as intervention points for therapeutic strategies. The hypothesis that this is the central AD disease pathway is called the “amyloid hypothesis”.

Up until the publication of the new deCode report, of the 30-odd coding mutations in APP that have been found, around 25 are pathogenic, usually resulting in autosomal dominant early-onset Alzheimer’s disease. Coding mutations at or near the β- or γ-proteolytic sites have appeared to result in overproduction of either total Aβ or a shift in the Aβ40:Aβ42 ratio towards formation of Aβ42, which is the more toxic of the two Aβ peptide. Until now, mutations in APP have not been implicated in the common, late-onset form of Alzheimer’s disease.

In the new deCode study, the researchers studied coding variants in APP in a set of whole-genome sequence data from 1,795 Icelanders. They identified a single nucleotide polymorphism (SNP), designated as rs63750847. The A allele of this SNP (rs63750847-A) results in an alanine to threonine substitution at position 673 in APP (A673T). The A673T mutation was found to be significantly more common in the elderly (age 85-100) control group (i.e., those without AD) than in the AD group. The researchers therefore concluded that the mutation is protective against AD.

The researchers also found that in a cohort of individuals over 80, those who were heterozygous for the A673T mutation performed better in a test of mental capacity than did control subjects. The authors concluded that the A673T mutation not only protects against AD, but also against the mild cognitive decline that is normally associated with old age.

In cellular studies (i.e., studies in cultured cells transfected with genes coding for wild type or mutant APP) and in biochemical studies, the researchers found that APP carrying the A673T mutation undergoes about 40% less cleavage by BACE1 than does wild-type APP, resulting in 40% less production of both Aβ40 and Aβ42.

The researchers conclude that the strong protective effect of the A673T mutation against AD provides proof of principle for the hypothesis that reducing the β-cleavage of APP (e.g., by use of BACE1 inhibitors, such as those being  developed by some pharmaceutical companies) may protect against the disease. (However, success in developing BACE1 inhibitors has been elusive.) Moreover, since the A673T allele also protects against cognitive decline in elderly individuals who do not have AD, AD and age-related mild cognitive decline may be mediated through the same or similar mechanisms.

Despite this compelling genetic finding, amyloid pathway-targeting drugs have not shown efficacy in Phase 3 trials

In our January 26, 2010 blog article, we discussed Phase 2 clinical trials of bapineuzumab, a monoclonal antibody (MAb) drug that is specific for Aβ, in mild to moderate AD. In that article, we referred to the drug as “Elan/Wyeth’s bapineuzumab”, after the original developers of the drug. As the result of mergers and acquisitions, the drug is now referred to as “Pfizer/Janssen’s bapineuzumab”. Many commentators call it “bapi” for short.

As we discussed in that article, the overall result of the Phase 2 trial was that there was no difference in cognitive function between patients in the bapi-treated and the placebo groups. However, the study did not have sufficient statistical power to exclude the possibility that there was such a difference. Retrospective analysis of the data from the trial suggested that bapi-treated patients who were not carriers of the apolipoprotein E epsilon4 allele (ApoE4) showed improved cognitive function as compared to placebo treatment. Given that this conclusion was reached via retrospective analysis, the idea that the bapi was efficacious in ApoE4 noncarriers was only a hypothesis, which would require prospective clinical trials to confirm. Janssen and Pfizer had been conducted large Phase 3 trials of bapi, which they prospectively segregated into ApoE4 carrier and noncarrier groups in order to test this hypothesis.

As of the past several weeks, the results of these Phase 3 trials have come in. On July 23rd, 2012, Pfizer announced the top-line results of an 18-month Janssen-led Phase 3 study of intravenous bapi in approximately 1,100 patients with mild to moderate Alzheimer’s disease who carry at least one ApoE4 allele. The drug failed to meet its co-primary endpoints (change in cognitive and functional performance compared to placebo) in that study. On August 6, 2012, Pfizer announced the top-line results of the corresponding Phase 3 study of intravenous bapi in patients with mild-to-moderate Alzheimer’s disease who do not carry the ApoE4 genotype. Once again, the co-primary clinical endpoints were not met. Based on these results, the companies decided to discontinue all other intravenous bapi studies in patients with mild-to-moderate Alzheimer’s disease.

The bapi development program continues a history of amyloid pathway-targeting drugs that were taken into Phase 3 trials despite Phase 2 results that showed no statistically significant efficacy. For example, we cited the cases of Myriad Pharmaceuticals’ Flurizan (tarenflurbil) and Neurochem’s (now Bellus Health) Alzhemed (3-amino-1-propanesulfonic acid) in our January 26, 2010 blog article.

Leading industry commentator Matthew Herper of Forbes referred to the failure of bapi as “the latest piece of evidence of the drug industry’s strange gambling problem.” Johnson & Johnson (the parent company of Janssen) spent more than $1 billion to invest in Elan and get one-quarter of bapi, and Wyeth (later Pfizer) and Elan put the drug into Phase 3, despite the Phase 2 failure of bapi.

The temptation for pharmaceutical companies to take a chance on an AD drug such as bapi, Flurizan, and Alzhemed is driven by the complete lack of disease-modifying AD drugs, and the thinking that even a not-very-effective drug that receives FDA approval might generate billions of dollars in annual sales. In the case of bapi there was also that tantalizing suggestion that bapi might show efficacy in the subset of patients who lacked ApoE4.

In an August 16, 2012 article in Forbes, Dr. John LaMattina (the former President of Pfizer Global R&D) engages in informed speculation as to why bapi was moved into Phase 3. Dr. LaMattina (in contrast to critics like Mr. Herper, who discounted the ApoE4 retrospective analysis as “data-dredging” that was “likely to be due to chance”) referred to the efficacy signal of the Phase 2 trials as “mixed” due to the ApoE4 analysis. He stated that such “mixed results” present an “agonizing” dilemma for a pharmaceutical company.

In deciding whether to go forward Phase 3 trials of bapi, Dr. LaMattina further speculates that the decision might have been influenced by stakeholders such as AD patient advocates, and scientists who strongly believed in the science behind bapi, especially the amyloid hypothesis. Moreover, bapi had been shown to be relatively safe. In addition, dropping bapi would have caused public relations damage. Dr. LaMattina concludes, based on this analysis, “…this was a situation where these companies were in possession of a relatively safe drug, with a modest chance of success in being efficacious in what may be the biggest scourge that society will face.  How can you not make this investment?” He reminds us that pharmaceutical R&D “is a high risk, high reward business”.

Nevertheless, bapi joined Flurizan and Alzhemed on the list of high-profile amyloid-pathway failures. Now a Phase 3 trial of Lilly’s solanezumab, another MAb drug that targets Aβ, is nearing completion, with the results expected in September. Published Phase 2 results were designed to test safety, not efficacy, and 12 weeks of drug treatment gave no change in cognitive function. Although the results of the Phase 3 trial will not be known until they are reported, analysts expect the drug to fail because of its similarity to bapi.

Why don’t amyloid pathway-targeting drugs show efficacy in clinical trials, despite the compelling genetic evidence for the amyloid hypothesis?

The almost standard answer to that question given by scientists and clinicians who support the amyloid hypothesis is that we have been testing the drugs too late in the course of AD progression, after the damage to the brain has become irreversible. Roche/Genentech is testing this idea in its clinical trials of its drug candidate crenezumab (licensed from AC Immune), which is yet another MAb drug that targets Aβ. In a 5-year Phase 2a clinical trial, Genentech is testing intravenous crenezumab in 300 cognitively healthy individuals from a large Colombian kindred who harbor the Glu280Ala (codon 280 Glu to Ala substitution) PS1 mutation. This mutation causes dominant early−onset familial AD, and is associated with increased levels of Aβ42 in plasma, skin fibroblasts, and the brain. Family members with this mutation begin showing cognitive impairment around age 45, and full dementia around age 51.

Genentech is conducting this trial in collaboration with the Banner Alzheimer’s Institute and the National Institutes of Health. The company says that this trial is the first-ever AD prevention study in cognitively healthy individuals. Genentech further says that the trial may help to determine if the amyloid hypothesis is correct–more specifically, it may help to determine if a drug that works by depleting amyloid plaques can be effective in preventing and/or treating AD.

Moreover, Genentech states that there is significant unmet medical need within this Colombian population. This large extended family may have as many as 5,000 living members, and no other population in the world offers a sufficiently large number of mutation carriers close to the age of potential disease onset for a study to determine whether a prevention treatment may work. This effort by Genentech thus represents an application of a rare disease strategy to AD.

It is also possible, however that drugs that work by lowering levels of Aβ will not be efficacious in treating AD, even if administered early in the disease process. This may be true despite the findings of the new genetic study by the deCode Genetics group. For example, in their Nature News and Views article, Drs. De Strooper and Voet remind us that if the A673T mutation indeed works via lowering of Aβ levels, it works via lifelong lowering of Aβ, not lowering of Aβ in patients who already have AD, as in all clinical trials so far of anti-Aβ antibodies. (Even Genentech’s Colombian trial may involve lowering of Aβ levels relatively late in the course of exposure of patients to a disease process that will result in AD.)

Moreover, as these authors speculate on the basis of work on another mutation at the same site in the APP protein, it is possible that the protective effect of the A673T mutation may be due to changing the aggregation properties of Aβ peptides, resulting in a less-toxic form of Aβ. If true, this would mean that the protective effect of the A673T mutation is due to qualitative, rather than quantitative changes in Aβ. In that case, the finding of protection from AD by the A673T mutation might not be as predictive of the efficacy of such Aβ-lowering treatments as the use of anti-Aβ MAb drugs as drug developers might like.

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


Is beige the new brown?

This is an update to our recent discussion on targeting the physiology of brown fat [or brown adipose tissue (BAT)], in developing novel antiobesity therapies. It is based on a research article published in the July 20 2012 issue of Cell by Dr. Bruce Spiegelman (Dana-Farber Cancer Institute and Harvard Medical School, Boston MA) and his colleagues.

As we discussed in our May 23, 2012 blog article, Dr. Spiegelman, a leading metabolic disease researcher, is a founder of Ember Therapeutics. Ember is working to develop novel metabolic disease therapeutics based on Dr. Spiegelman’s work on BAT physiology and on novel insulin sensitizers.

In the work described in the new Cell article, Dr. Spiegelman and his colleagues showed that the white adipose tissue (WAT)-derived “brown fat-like cells” that they had been studying are actually a new type of cells known as “beige adipocytes”.

Other researchers had previously described a class of “brite” or “beige” adipocytes, which were induced in WAT depots that have been chronically treated with the peroxisome proliferator-activated receptor γ (PPARγ) agonist rosiglitazone. Brite/beige adipocytes expressed UCP1 (uncoupling protein 1) and had high levels of mitochondria as do brown adipocytes but lacked expression of certain characteristic brown fat-specific genes. UCP1 is the key mitochondrial protein that makes the process of thermogenesis (i.e., production of heat by oxidizing fat rather than storing it) possible. As shown previously by Dr. Spiegelman and his colleagues, BAT is derived from  a myf-5 muscle-like cell lineage, via the action of the transcriptional regulator PRDM16. However, beige cells are not.

Beige precursor cells in murine subcutaneous white fat depots

In the new Cell publication, Dr. Spiegelman and his colleagues carry these earlier studies further by cloning murine beige fat cells and describing their unique gene expression signature. They first isolated adipocyte precursors from mouse subcutaneous WAT (specifically, the inguinal fat depots). These precursors are found in the stromal-vascular fraction of the adipose tissue. The researchers immortalized stromal vascular fraction (SVF) cells from subcutaneous WAT of the 3T3 mouse by passaging them in culture, similar to the classic derivation of 3T3 fibroblast cell lines by Todaro and Green 49 years ago. They cloned the resulting immortalized cells via limiting dilution, and selected the 20-some odd cell lines that could be readily differentiated (via standard differentiation protocols) to adipocytes. For purposes of comparison, the researchers also derived multiple adipogenic clones from the SVF cells of the interscapular brown fat depot.

They then differentiated the WAT-derived adiopogenic clones to adipocytes, and treated them with forskolin [an agent that raises intracellular levels of cyclic AMP (cAMP)]–increases in cAMP levels activate expression of UCP1 in the mitochondria of brown fat cells. They then determined the gene expression pattern of the differentiated and forskolin-stimulated WAT derived clones. The clones clustered into two groups, one of which had a gene expression pattern more similar to BAT cells than the other group. These two groups appeared to represent beige and white adipocytes, respectively. Comparison of these two groups of cells to BAT cells revealed that the presumptive beige adipocytes had gene expression patterns that were similar, but not identical to, those of brown adipocytes.

Further characterization of the three types of cells indicated that beige cells have characteristics of both white and brown adipocytes. Both white and beige adipocytes have low basal levels of UCP1, while brown adipocytes have higher levels. Upon cAMP stimulation, however, the beige adipocyte lines responded with a very large induction of UCP1 gene expression, reaching similar UCP1 levels to that observed in the brown adipocyte lines. White adipocyte cell lines showed little UCPI induction. These characteristics of beige and white adipocyte cell lines also were seen in in vivo studies.

Still further characterization of the three types of cell lines revealed that beige and brown fat cells have related but distinct gene expression profiles. These include a set of beige-selective genes that can distinguish beige fat cells from both brown fat cells and white fat cells. Protein expression was highly concordant with mRNA expression. Since some of the beige-selective markers are cell surface proteins, and since antibodies to these proteins are commercially available, this allowed the researchers to use fluorescence-activated cell sorting (FACS) to isolate primary beige precursor cells from the SVF of mouse inguinal fat.

Murine beige fat precursors–not white fat or brown fat–are targets of the hormone irisin

In our May 23, 2012 blog article, we discussed the myokine hormone irisin, which was recently discovered by the Spiegelman group. As we discussed, irisin is produced by muscle cells and increases with exercise. It has little or no effect on classic brown fat found in the interscapular depot. However, It acts on subcutaneous white adipose cells in culture and in vivo to stimulate what appears to be development into brown fat-like cells. Specifically, irisin stimulates expression of UCP1 and an array of other brown fat genes, producing a thermogenic effect.

In the study reported in the July 20 2012 Cell paper, the researchers used FACS to sort primary inguinal precursor cells into white and beige preadipocytes, and studied the effects of two forms of recombinant irisin on these cells during adipogenic differentiation. All cells treated either with vehicle or irisin showed good adipocyte differentiation. Both forms of irisin, but not vehicle, induced the expression of brown fat-like genes such as UCP-1 in beige cells, but had little effect on white cells. This suggests that irisin works on white fat depots in vivo by inducing brown-like gene expression in the beige cell component of preadipocytes in these depots.

Adult human “brown fat” is really beige fat

As we discussed in our blog articles of November 17, 2010 and May 23, 2012, and as illustrated in the figures at the top of each of these articles, adult humans possess what appears to be reservoirs of brown fat in the neck region and other areas of the upper body as well as in skeletal muscle.

In the study reported in the July 20 2012 Cell paper, the researchers preformed BAT biopsies from two independent cohorts of human subjects, and analyzed their gene expression signatures based on the findings of the studies of mouse brown, beige, and white adipocytes. They found that the UCP1-positive “BAT” cells from the human biopsies had gene expression signatures that resembled those of murine beige adipocytes more closely than they resemble classic brown fat or white fat. As a result of this finding, several popular articles written about the new Cell paper are entitled “Beige is the New Brown”.


Although additional research is needed to fully characterize beige fat physiology, the picture that emerges from the above study is that beige fat cells exist in subcutaneous fat mainly in a basal, unstimulated state, in which their phenotype resembles that of white fat. Once stimulated, however, beige cells activate expression of a brown fat-like thermogenic program, including expression of levels of UCP1 similar to those of brown fat cells. Thermogenesis of beige fat cells is induced by such stimuli as 1. β-adrenergic activation; 2. the myokine irisin; and 3. other polypeptide hormones, such as fibroblast growth factor 21 (FGF21), and atrial natriuretic peptide (ANP). The role of FGF21 in inducing UCP1 and the thermogenic program in adipose tissues was elucidated by Dr. Spiegelman and his colleagues. This was described in a February 2012 report in Genes & Development.

The above scenario is mainly based on studies in mice. However, as discussed earlier, humans also have what appear to be beige cells, which may be amenable to induction by irisin or other agents, thus giving rise to a thermogenic program that might be utilized to combat obesity and type 2 diabetes. Classical interscapular brown fat in humans, however, although it is present in infants, disappears as humans mature. This it is likely that beige fat will be the target such agents as irisin, which are aimed at overcoming metabolic disease via increasing energy expenditure.

Long before researchers obtained evidence for “browning” of white fat as a potential mechanism for induction of a thermogenic program, the pharmaceutical industry had a long history of attempting to develop β3-adrenergic agonists as therapies for metabolic diseases.  Many agents were entered into clinical trials by numerous companies, but all failed, either due to lack of efficacy or to averse effects due to activation of β-adrenergic receptors in other tissues. An important underlying factor in the failure of these studies was the lack of understanding of brown (or beige) fat physiology in humans, including whether brown fat existed in adult humans at all. Of course, beige fat was completely unknown.

In our May 23, 2012 blog article, we discussed several young companies that are working to develop novel approaches to treating obesity based on brown-fat physiology and/or other non-CNS pathways involved in increasing energy expenditure. Among these companies are Ember Therapeutics. As we discussed in the May 2012 article, Ember entered into an exclusive license agreement with Dana-Farber Cancer Institute for the irisin technology, and is optimizing and developing a proprietary molecule based on this technology. This research constitutes the company’s lead BAT biology program.

More recently, Ember completed a licensing agreement with the Dana-Farber for intellectual property related to Dr. Spiegelman’s beige fat discovery. As discussed earlier, beige fat cells are specifically targeted by irisin, which induces the thermogenic program in these cells. Especially in adult humans, which appear to lack classic brown fat, beige adipocytes and/or their precursors are the true target of irisin, and any program to develop irisin-like protein drugs for metabolic disease will need to focus on the effect of such products on beige cells. Moreover, Ember’s programs to develop small molecules via screening for compounds that activate pathways specific to the “brown fat” cell lineage will need to focus specifically on pathways involved in induction of the thermogenic program in beige adipocytes.

In contrast to Ember’s R&D programs, which must focus on beige adipocytes, Energesis Pharmaceuticals’ R&D programs focus on brown fat “stem cells” from skeletal muscle. This research thus has to do with classical BAT, which is derived from a skeletal muscle-like lineage, as opposed to beige adipocytes, which are not. Thus Ember’s and Energesis’ R&D programs represent completely different approaches to developing antiobesity agents that work to increase energy expenditure. Among the other companies mentioned in our May 2012 article, Zafgen’s R&D programs represent still another completely different approach, involving targeting the liver. Acceleron Pharma’s approach, however, probably involves targeting beige fat. In fact, Dr. Spiegelman has been a collaborator in some of their research.


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

Keynote speaker, Bob Langer of MIT

2nd Annual Partnership Opportunities in Drug Delivery

October 1st and 2nd 2012

The Boston Park Plaza Hotel & Towers
50 Park Plaza at Arlington Street
Boston, MA, 02116-3912

Keynoted by Dr Robert Langer of MIT, this is a strategic level event designed with two purposes:

1. To present a strategic level event for pharma and biotech business development and external licensing professionals with a thorough overview of the latest drug delivery technologies available along with an update on deals and opportunities to enhance patients, therapies and the life cycle of a drug.

2. To provide drug delivery and specialty pharmas with a platform to present their technologies and get the latest insights from both established pharma and biotechs as well as start up companies on what the delivery and formulation needs are.

15% discount for Biopharmconsortium Blog readers with code BPCON

For more information, see

I am registered to attend this conference, and hope to see many of you there.