Biopharmconsortium Blog

Ivacaftor

In our January 24, 2013 article on this blog, we discussed the cases of two genetic diseases, sickle cell disease (SCD) and cystic fibrosis (CF). In both cases, the genetic cause of the disease was identified decades ago. However, no disease-modifying drugs for SCD have yet been developed.

In the case of CF, small-molecule disease-modifying drugs have only recently entered the pipeline. In one case, such a drug–ivacaftor (Vertex’ Kalydeco), was approved both in the U.S. and in Europe in 2012.

In this article, we discuss the development of small-molecule drugs for CF.

Cystic fibrosis

As we discussed in our earlier article, CF causes a number of symptoms, which affect the skin, the lungs and sinuses, and the digestive, endocrine, and reproductive systems. Notably, people with CF accumulate thick, sticky mucus in the lungs, resulting in clogging of the airways due to mucus build-up. This leads to inflammation and bacterial infections. Ultimately, lung transplantation is often necessary as the disease worsens. With proper management, patients can live into their late 30s or 40s.

The affected gene in CF and the most common mutation that causes the disease (called ΔF508 or F508del) were identified by Francis S Collins, M.D., Ph.D. (then at the Howard Hughes Medical Institute and Departments of Internal Medicine and Human Genetics, University of Michigan, Ann Arbor, MI) and his colleagues in 1989. (Dr. Collins was subsequently the leader of the publicly-funded Human Genome Project and is now the Director of the National Institutes of Health, Bethesda, MD.)

The gene that is affected in cystic fibrosis encodes a protein known as the cystic fibrosis transmembrane conductance regulator (CFTR).  CFTR regulates the movement of chloride and sodium ions across epithelial membranes, including the epithelia of lung alveoli. CF is an autosomal recessive disease, which is most common in Caucasians; one in 2000–3000 newborns in the European Union is found to be affected by CF. ΔF508 is a deletion of three nucleotides that causes the loss of the amino acid phenylalanine at position 508 of the CFTR protein. The ΔF508 mutation accounts for approximately two-thirds of CF cases worldwide and 90% of cases in the United States. However, there are over 1500 other mutations that can cause CF.

CFTR is an ion channel–specifically a chloride channel.  Ion channels constitute an important class of drug targets, which are targeted by numerous currently marketed drugs, e.g., calcium channel blockers such as amlodipine (Pfizer’s Norvasc; generics) and diltiazem (Valeant’s Cardizem; generics). These compounds were mainly developed empirically by traditional pharmacology before knowing anything about the molecular nature of their targets.

However, discovery of novel ion channel modulators via modern molecular methods has proven to be challenging, mainly because of the difficulty in developing assays suitable for drug screening. In addition, development of suitable assays for assaying chloride channel function has lagged behind the development of assays for the function of cation channels (e.g., sodium and calcium channels).

Moreover the most common CFTR mutation that causes CF, ΔF508, results in defective cellular processing, and the mutant CTFR protein is retained in the endoplasmic reticulum. In the case of some other mutant forms of CTFR (accounting for a small percentage of CF patients), the mutant proteins reach the cell membrane, but are ineffective in chloride-channel function.

Vertex’ program for the development of small molecule CF drugs

Efforts aimed at the discovery of small-molecule drugs for CF began in 1998, when the nonprofit Cystic Fibrosis Foundation (CFF) established its Therapeutics Development Program. This included a drug discovery unit, through which CFF would support both academic and industrial research. An early recipient of CFF funding via this program was a small biotech company, Aurora Biosciences (San Diego, CA).  Aurora had developed technology for ultra-high-throughput screening in cellular assays, which they were applying to the discovery of small-molecule drugs for CF. In 2001, Vertex Pharmaceuticals (Cambridge, MA) acquired Aurora. Vertex then incorporated Aurora’s technology into its drug discovery programs, including its CF program. Vertex’ CF program received continuing support from CFF.

Vertex researchers screened thousands of drug-like and lead-like synthetic compounds in recombinant mouse cells expressing mutant human CFTR. Positive hits that met criteria for developability were further tested in a rat epithelial cell line that expressed the mutant CFTR. Compounds selected for further study were also tested for rescue of CFTR activity in cultured primary human lung airway epithelial cells from CF patients, which expressed the same mutant CFTRs studied in the recombinant cell assays. Performing the latter studies required isolating the epithelial cells from lung tissue of CF patients. The thick mucus found in CF lungs made this isolation very challenging. According to Vertex researcher and project head Fred Van Goor, researchers had to use tweezers to extract the mucus, in order to isolate the cells. It reportedly took all of 2003 to develop cellular assays (both in primary and recombinant cells) to conduct the drug discovery studies.

Vertex’ high-throughput screening studies resulted in the identifications of two types of lead compounds:

• CFTR potentiators, which potentiate the chloride channel activity of mutant CFTR molecules at the cell surface;
• CFTR correctors, which partially correct the folding and/or trafficking defect of such mutant CFTRs as ΔF508, thus facilitating exit from the endoplasmic reticulum and deposition of a portion of the mutant CFTR in the cell membrane.

Vertex’ ivacaftor, a CFTR potentiator

The Vertex screening studies discussed in the previous section, published in 2006, resulted in clinical candidates in both the potentiator and corrector classes. The company pursued development of one potentiator compound, ivacaftor (formerly known as VX-770) (Vertex’ Kalydeco). Ivacaftor is indicated only in patients with the G551D (Gly551Asp) mutation in CFTR, which only accounts for around 4% of CF patients.

Ivacaftor was discovered via high-throughput screening as described in the previous section, followed by lead optimization. The compound increased chloride channel function both in recombinant cells carrying mutant CFTR, and in cultured primary human lung airway epithelial cells from CF patients. Ivacaftor was found to be efficacious in opening both CFTR G551D and CFTR ΔF508 present in the cell membranes of recombinant cells. However, because of the retention of  CFTR ΔF508 in the endoplasmic reticulum in human lung airway epithelial cells, this compound is not efficacious in treating CF patients carrying this mutation. The lack of efficacy in patients homozygous for CFTR ΔF508 was confirmed in a subsequent clinical trial.

On February 23, 2011, the CFF and Vertex announced that a Phase 3 trial of ivacaftor (then called VX-770) showed marked improvement in lung function in CF patients carrying the CFTR G551D mutation. Treated patients also had significant weight gain, showed reduced sweat chloride (a CF biomarker), and were less likely to have a pulmonary exacerbation. The results of this Phase 3 trial were published in the New England Journal of Medicine. Also in 2011, Vertex submitted a New Drug Application (NDA) for ivacaftor.  In January 2012, the FDA approved ivacaftor for treatment of CF patients carrying the CFTR G551D mutation. In July 2012, Vertex received European approval for this drug.

Vertex’ lumacaftor (VX-809) and VX-661, CFTR correctors

Vertex is currently developing the CFTR corrector lumacaftor (VX-809). The company has completed Phase 2 studies of a combination of ivacaftor and lumacaftor/VX-809 in CF patients who are homozygous for the CFTR ΔF508 mutation. It is now planning pivotal phase 3 trials of the combination therapy in this patient population. The rationale for the combination treatment is that VX-809 potentates the deposition of CFTR ΔF508 in the cell membrane, and invacaftor potentiates the function of cell-surface CFTR ΔF508.

Vertex is also conducting Phase 2 trials of another CTFR corrector, VX-661, alone and in combination with ivacaftor/VX-770 in CF patients homozygous for CFTR ΔF508.

The Cystic Fibrosis Foundation’s collaboration with Pfizer

The CFF has also been collaborating with Pfizer to discover drugs to treat patients carrying the the CFTR ΔF508 mutation. This collaboration began after the 2010 acquisition by Pfizer of FoldRX (Cambridge, MA). In November 2012, the CFF and Pfizer expanded their collaboration.

The Pfizer/CFF collaboration builds on FoldRx’s cystic fibrosis research program in collaboration with the CFF, which started in 2007. FoldRX (now a wholly-owned subsidiary of Pfizer) specializes in discovering and developing drugs to treat diseases of protein misfolding. The correction of protein misfolding clearly applies to CFTR ΔF508 protein.

Under the expanded six-year CFF/Pfizer collaboration, the CFF will invest up to $58 million to support and accelerate the discovery and development of disease-modifying therapies for CFTR ΔF508 CF. The goal of the collaboration is to advance one or more drug candidates into the clinic by the end of the six-year period. The CFF will provide scientific as well as financial support to help advance this discovery program.

Ataluren, for treatment of patients with CFTR nonsense mutations

Ataluren (formerly known as PTC124), is being developed by PTC Therapeutics for various genetic diseases caused by nonsense mutations in critical genes. The drug is currently being investigated for use in patients with nonsense mutation Duchenne/Becker muscular dystrophy (DBMD) and cystic fibrosis (CF). PTC Therapeutics’ efforts in CF are supported by a grant from the CFF.

Ribosomes normally translate messenger RNAs (mRNAs) into protein until arriving at a normal stop codon in the mRNA, at which point the ribosome stops translation, resulting in a functional protein. Nonsense mutations, however, create a premature stop signal in the mRNA coding sequence. This causes the ribosome to stop translation before a functioning protein is generated, creating a truncated, nonfunctional protein. This can result in disease.

Ataluren is designed to allow the ribosome to ignore the premature stop signal and continue translation of the mRNA, resulting in formation of a functioning protein. Ataluren does not cause the ribosome to read through the normal stop signal.

The results of clinical trials of ataluren in pediatric (Phase 2a) and adult (Phase 2) patients with nonsense-mutation CF showed that the drug resulted in production of functional CFTR protein and statistically significant improvements in CFTR chloride channel function. Ataluren treatment was also associated with significant reductions in cough frequency and trends toward improvement in pulmonary function tests.

Conclusions

As we discussed in our January 24, 2013 article on this blog, the 1989 identification of the genetic cause of CF did not immediately lead to the development of disease-modifying drugs. Bottlenecks in the pathway from genetic research to small-molecule drugs included understanding the different ways (e.g., deficiencies in chloride channel function, deficiencies in protein processing, blockages in protein translation due to nonsense mutations) in which the many mutations that can cause CF act, and the need to develop effective assays for use in drug discovery.

The 2012 approval of the CFTR potentiator ivacaftor (Vertex’ Kalydeco) in the U.S. and Europe represents a real milestone in CF drug development. Vertex and the CFF should be congratulated on their breakthrough CF R&D program, which required the willingness to pursue a long pathway to development.

Other compounds that target CFTR are in Phase 2 development. All indications suggest that treatment for CF will represent a case of “personalized medicine”, as befits a disease that is caused by multiple mutations that act at different levels of protein synthesis, processing, and function.

As is typical for personalized medicines that target rare diseases, Kalydeco is expensive. The drug reportedly costs upwards of $294,000 for a year’s supply. Vertex says that it will supply Kalydeco free to U.S. patients with no insurance and a household income of under $150,000.

With the interest of pharmaceutical and biotechnology companies in developing targeted therapies and therapies for rare diseases, the story of the development of small-molecule drugs for CF represents an important case study in drug discovery and development in the 2010s. According to the FDA, the emphasis on targeted drugs and rare diseases has also resulted in the the recent increase in FDA drug approvals; the agency approved 39 new drugs in 2012, which represents a 16-year high.
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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.

NBD1 of human CFTR. Source: PDBbot http://bit.ly/11UmpkS

A major objective of research in genomics is to identify mutations that cause genetic diseases. However, doing so does not necessarily directly enable researchers to discover and develop drugs to treat these diseases.

Two examples of genetic diseases whose causes were identified decades ago, without directly enabling the development of any disease-modifying drug, are sickle cell disease (SCD) (also known as sickle cell anemia) and cystic fibrosis (CF).

Sickle cell disease

The causative mutation of SCD was identified by protein researchers, decades before the era of genomics. Vernon M. Ingram, Ph.D. showed in 1957 that a glutamic acid to valine mutation at position 6 of the β-chain of hemoglobin was the sole abnormality in SCD. For this discovery, Dr. Ingram has been called The Father of Molecular Medicine. Dr. Ingram’s work was made possible by a 1949 study by Linus Pauling and his colleagues, which showed that SCD hemoglobin had a different electrophoretic mobility than normal hemoglobin. Thus the sickle cell trait was likely to be due to a mutation in the β-hemoglobin gene that changed its amino acid composition, as confirmed by Dr. Ingram.

Yet to this day, although SCD (which occurs in individuals who are homozygous for the sickle-cell mutation) can be managed by various treatments (such as hydroxyurea and blood transfusions and bone marrow transplants) that can result in survival into one’s fifties, there is no mechanism-based therapy for this disease. Thus the identification of the causative mutation of SCD has not led to any treatments.

The reason why discovery and development of drugs for SCD has been so very difficult is that the mutation that causes this disease affects an intracellular protein, hemoglobin, which is neither a receptor nor an enzyme. Unlike secreted proteins such as insulin, it is not possible to develop protein drugs to replace missing or defective hemoglobin. It is also not possible to replace the missing function of normal hemoglobin by treatment with a small molecule drug.

Diseases such as SCD–in which the function of an essential intracellular protein is defective or missing–have often been cited as candidates for gene therapy.

However, as we discussed in our October 11, 2012 and our November 8, 2012 Biopharmconsortium Blog articles, it is only this past fall that the first gene therapy was approved for marketing in a regulated market. As we discussed in the first of these articles, gene therapy has a history going back to at least the early 1970s. However, gene therapy has displayed the characteristics of a premature technology. Several notable failures, including some that caused the deaths of patients, put a severe damper on the gene therapy field. Only recently–between around 2003 and 2012–have researchers been developing more advanced gene therapy technologies and conducting clinical studies, with some success. Entrepreneurs have also been building gene therapy specialty companies to commercialize this research.

As also we discussed in our October 11, 2012 article, among the many companies that are developing gene therapies, bluebird bio (Cambridge, MA) has been singled our for special attention lately. Among the diseases being targeted by bluebird bio are SCD, and beta-thalassemias, which are also genetic diseases that affect hemoglobin. bluebird bio is in Phase 1/2 trials for its beta-thalassemia therapy, and in Phase 1 for its SCD program.

Cystic fibrosis

CF causes a number of symptoms, which affect the skin, the lungs and sinuses, and the digestive, endocrine, and reproductive systems. Notably, people with CF accumulate thick, sticky mucus in the lungs, resulting in clogging of the airways due to mucus build-up. This leads to inflammation and bacterial infections. Ultimately, lung transplantation is often necessary as the disease worsens. With proper management, patients can live into their late 30s or 40s.

The affected gene in CF and the most common mutation that causes the disease (called ΔF508 or F508del) were identified by Francis S Collins, M.D., Ph.D. (then at the Howard Hughes Medical Institute and Departments of Internal Medicine and Human Genetics, University of Michigan, Ann Arbor, MI) and his colleagues in 1989. Dr. Collins was subsequently the leader of the publicly-funded Human Genome Project and is now the Director of the U.S. National Institutes of Health, Bethesda, MD.

The gene that is affected in cystic fibrosis encodes a protein known as the cystic fibrosis transmembrane conductance regulator (CFTR).  CFTR regulates the movement of chloride and sodium ions across epithelial membranes, including the epithelia of lung alveoli. CF is an autosomal recessive disease, which is most common in Caucasians; one in 2000–3000 newborns in the European Union is found to be affected by CF. ΔF508 is a deletion of three nucleotides that causes the loss of the amino acid phenylalanine at position 508 of the CFTR protein. The ΔF508 mutation accounts for approximately two-thirds of CF cases worldwide and 90% of cases in the United States. However, there are over 1500 other mutations that can cause CF.

In the case of CF, the affected protein, CFTR, is an ion channel–specifically a chloride channel.

Ion channels constitute an important class of drug targets, which are targeted by numerous currently marketed drugs, e.g., calcium channel blockers such as amlodipine (Pfizer’s Norvasc; generics) and diltiazem (Valeant’s Cardizem; generics). These compounds were mainly developed empirically by traditional pharmacology before knowing anything about the molecular nature of their targets. However, discovery of novel ion channel modulators via modern molecular methods has proven to be challenging, mainly because of the difficulty in developing assays suitable for drug screening. In addition, development of suitable assays for assaying chloride channel function has lagged behind the development of assays for the function of cation channels (e.g., sodium and calcium channels).

Moreover the most common CFTR mutation that causes CF, ΔF508, results in defective cellular processing, and the mutant CTFR protein is retained in the endoplasmic reticulum. In the case of some other mutant forms of CTFR (accounting for perhaps 5% of CF patients), the mutant proteins reach the cell membrane, but are ineffective in chloride-channel function.

Given these difficulties, researchers first attempted to develop gene therapies for CF. Genzyme (a Sanofi company since 2011) has been a leader in developing gene therapy for CF, and has been conducting research in this area since the 1990s. However, as with most gene therapies, development of treatments capable of reaching the market has been elusive.

Genzyme is still researching gene therapies for CF, as are others. An academic group in the U.K., known as the U.K. Cystic Fibrosis Gene Therapy Consortium is working to develop CF gene therapies, using Genzyme’s nonviral cationic lipid vector GL67 (Genzyme lipid 67) as the delivery vehicle. GL67 is the current “gold-standard” for in vivo lung gene transfer. Recently, the Consortium received funding from the U.K. Medical Research Council and National Institute of Health Research to continue its Phase 2B trial of its CF gene therapy product,GL67A/pGM169. This is a combination of GL67 and plasmid DNA expressing CFTR (pGM169).

Very recently, R&D on disease-modifying small-molecule drugs for CF has begun to bear fruit. In January 2012, the FDA approved the first such drug, ivacaftor (Vertex’ Kalydeco.) In July 2012, Vertex received European approval for this drug. Ivacaftor only works in patients with the G551D  (Gly551Asp) mutation in CFTR, which only accounts for around 4% of CF patients. Vertex and other companies–including Genzyme–are working on development of other small-molecule disease-modifying drugs with the potential to treat greater numbers of CF patients.

We shall discuss the new wave of disease-modifying CF drugs, including ivacaftor, in a later post on this blog.

Conclusions

SCD and CF are two examples of cases in which the identification of the genetic or molecular cause of a disease did not directly lead to new treatments. In the case of SCD, even though over 55 years have elapsed since the identification of the genetic cause of the disease, no therapy had yet emerged from this discovery. In the case of CF, it took over two decades from the identification of the molecular cause of the disease to the approval of the first disease-modifying drug.

Many other cases in which molecular targets involved in disease have been identified also lack disease-modifying treatments because the targets are “undruggable”. This especially applies to protein-protein interactions (PPIs). However, PPIs have assumed increasing strategic importance in drug discovery and development in recent years, and researchers and companies have been developing new technologies and strategies to discover  developable drugs that address PPIs.

Back in the early 2000s, researchers and commentators hailed the sequencing of the human genome as heralding a new era in drug discovery and development. However, the “industrialized biology” approach that grew out of the genomics of that era gave very few successes in terms of drug development. Now–a decade later–we have next-generation sequencing and  are approaching the “$1000 genome.” Once again, at least some commentators are expecting immediate breakthroughs in therapeutic development to come out of these breakthroughs in sequencing technology. Others, such as CFTR gene discoverer Francis Collins, believe that we can “speed the development of genetic advances into treatments” by more rapidly weeding out “what turn out to be..nonviable compounds.”

However, in the case of CF there were barriers to drug discovery, such as limited understanding of disease biology and difficulties in assay development, that were the true causes of lack of progress in developing disease-modifying genes. Moreover, once they had good assays, researchers needed to come up with effective strategies to develop small-molecule drugs for CF. In the case of SCD, because of the nature of the target, only gene therapy–with its manifold difficulties–had any hope of addressing the disease. In the case of PPIs, there was the need to discover new breakthrough strategies to address these “undruggable” targets.

Thus, despite breakthroughs in sequencing technologies, determining of disease-related sequences is likely to only be the first step in effective discovery of disease-modifying drugs. And there may continue to be a considerable time lag between sequence determination and drug development.

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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.

Agios Germanos, Greece. Source: http://bit.ly/YRDIBJ

I was quoted in an article in the November 19, 2012 issue of Chemical & Engineering News (C&EN) by senior editor Lisa M Jarvis. The article is entitled “Agios Takes A Long View In Cell Metabolism.”

The article focuses on Agios Pharmaceuticals’ (Cambridge, MA) strategy for building a company that can endure as an independent firm over a long period of time, and that can also demonstrate sustained performance.

This contrasts with the recent trend toward “virtual biotech companies”–lean companies with only a very few employees that outsource most of their functions, and that are designed for early acquisition by a Big Pharma or large biotech company. The virtual company strategy is designed to deal with the inability of most young biotech companies to go public in the current financial environment. Without the ability to go public, young companies cannot provide early-stage venture capital investors with a profitable exit within a few years after launching the company. Virtual companies typically have a few assets, such as molecules that are ready for preclinical studies or early clinical trials. The goal is to obtain enough evidence that their compounds can become drugs to interest a Big Pharma.

In contrast, there are a few young  “platform companies” that are built on a broad technology platform, which aim to address important areas of biology and potentially to develop numerous products with the potential to address important areas of unmet medical need. One of these is Agios.

“Built to Last” in the current biotech ecosystem

In the C&EN article, I was quoted as saying that only a few platform companies have been launched in recent years. In the Boston area, in addition to Agios, such companies include Forma Therapeutics and Aileron Therapeutics. I was further quoted as saying “These companies are built to last.”

That brings up the old business paradigm from the 1990s and early 2000s–“Built to Last” versus “Built to Flip”. Those involved in building virtual biotech companies–especially venture capitalists and angel investors–do not like the use of “Built to Flip” to characterize their companies. And there are some fine virtual biotechs–some, such as Energesis and Zafgen–which we have covered in our blog.

(Plexxikon, the developer of targeted melanoma drug vemurafenib, also operated as a virtual company. However, it had a technology platform, and had the potential to become an independent biotech with marketed products. Thus Plexxikon did not fit the usual “virtual biotech model”. Nevertheless, it was acquired by Daiichi Sankyo in 2011.)

However, some industry commentators believe that “Built to Flip” is an appropriate designation for virtual biotech companies, and that the virtual model is likely to be detrimental to drug discovery and to the biotech/pharma industry as a whole.

Meanwhile, the 2012 BIO International Convention in Boston had a session entitled “Moving the Goal Posts: How to Build a Free-Standing Biotech from Scratch in Today’s Environment.” This session focused on how to build the “next Vertex or even the next Genentech” (i.e., a “Built to Last” biotech company) in today’s environment. John Evans, the Vice President of Business Development & Operations of Agios was a speaker at that session. The session was moderated by Bruce Booth of Atlas Ventures. Thus, despite the preference for lean virtual biotech companies in the current funding environment, there is an interest in the entrepreneurial and venture capital communities for how free-standing biotechs might emerge under current conditions.

How to build a young platform biotech company

The Biopharmconsortium Blog has included three articles about Agios:

• Cancer metabolism as a target for drug discovery: Agios Pharmaceuticals (December 31, 2009)
• Agios Pharmaceuticals partners with Celgene (April 23, 2010)
• Cancer metabolism specialist Agios Pharmaceuticals continues its spectacular fundraising success (November 30, 2011)

These articles, as well as the November 19 2012 C&EN article, outline how Agios has been building a free-standing biotech in today’s unfavorable environment. Agios’ strategy is based on three elements:

• A stellar group of scientific founders–Drs. Craig B. Thompson, Tak W. Mak, and Lewis C. Cantley.
• A strong proprietary technology platform based on cancer metabolism
• A financing strategy that includes both venture capital and partnerships with established companies. In the case of Agios, their partner is Celgene. The Agios/Celgene partnership provides Agios with $150 million, and allows Agios to maintain control over the direction of its early stage research.

As stated in the C&EN article, the financial security gained via Agios’ funding by its venture investors and by Celgene enables Agios to work on multiple potential targets, with the goal of dominating the field of cancer metabolism. Agios focuses on two types of targets: metabolic enzyme species that are found only in cancer cells, and enzyme species on which a cancer cell has become dependent. Agios researchers intend to develop drugs against targets for which their are predictive biomarkers that identify the right patients for clinical studies.

New developments outlined in the November 19, 2012 C&EN article

Both the November 19, 2012 C&EN article and our Bipharmconsortium Blog articles outline Agios’ program to target a mutated form of isocitrate dehydrogenase 1 (IDH1), which together with mutated IDH2 has been implicated in 70% of human brain cancers. As stated in the C&EN article, Agios researchers have recently reported a series of compounds that selectively inhibit the mutant form of IDH1. This research had been carried out in collaboration with researchers from Ember Therapeutics (Watertown, MA). As we stated in another Biopharmconsortium Blog article, Ember specializes in targeting beige adipocytes for treatment of metabolic diseases.

As we noted in our November 30, 2011 Biopharmconsortium Blog article, Agios had slated a portion of the $78 million that it raised in its Series C financing to expand its R&D efforts into inborn errors of metabolism (IEMs). IEMs comprise a large class of inherited disorders of metabolism, most of which are defects in single genes that code for metabolic enzymes. These rare metabolic diseases have a high level of unmet medical need.

As outlined in the C&EN article, Agios’ work with mutant IDH1 and IDH2 is serving as a bridge to the company’s programs in IEMs. IDH2 mutations have been found in a class of children with 2-hydroxyglutaric aciduria, a rare inherited neurometabolic disorder that can cause developmental delay, epilepsy, and a set of other pathologies.

According to the C&EN article, IEMs are of special strategic interest to Agios. Agios CEO David Schenkein stated that expanding the company’s R&D efforts into IEMs helps the company to manage the risk profile of its portfolio. In the case of cancer, Agios researchers must identify and validate targets involved in the pathobiology of these diseases, and then to find drugs that modulate these targets. In the case of IEMs, disease biology is already validated by genetics.

Moreover, IEMs have small patient populations. Thus only small clinical trials are needed to bring a drug to market. Agios therefore believes that it can bring drugs for these diseases to market on its own, without the need for a larger partner such as Celgene or a Big Pharma.

As we discussed in a Biopharmconsortium Blog article on improving the clinical trial system, although rare diseases only require small clinical trials, finding and recruiting patients for the trials is made more difficult because of the very small number of patients with a particular disease. One solution is to work with patient advocates and “disease organizations”, some of which have patient registries. In the case of 2-hydroxyglutaric aciduria and other organic acidemias, a “disease organization” exists–the Organic Acidemia Association (OAA). Perhaps Agios will find it fruitful to work with the OAA in its patient recruitment efforts.

Currently, Agios is focused on getting compounds into the clinic–both for IEMs and for cancer. Looking down the road, the company’s $180 million war chest should enable Agios to put several compounds through proof-of-concept studies, according to Dr. Schenkein. (This is besides any cancer drug candidates that are licensed by Celgene.) Despite Agios’ strategy of conducting small trials for IEM drug candidates, Dr. Schenkein said that the company will eventually need to go public to achieve its strategic goal of dominating the cancer metabolism field.

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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

A few weeks ago, I attended a presentation that was produced by another consulting firm, which we shall call Company X. They began their presentation with a discussion of “what is Company X?” Then they went on the the substance of their presentation.

In the same vein, as the producers of the Biopharmconsortium Blog, this article is entitled “What is Haberman Associates?” After we have posted this article, we also shall go on to our usual subject matter.

Haberman Associates is a Boston-based consulting firm, founded in 1993, that specializes in science and technology strategy for life science companies–principally pharmaceutical, biotechnology, diagnostics, and research products companies, and other companies (e.g., life science publishers, venture capitalists, angel investors, etc.) that serve the industry.

The focus of our company is new product development and commercialization. This includes new products developed via internal R&D and through partnering. In internal R&D, our usual focus is toward the early end of the process–drug discovery and early development.

Clients have used our consulting services to help them:

• discover and develop new drugs, diagnostics, and research products
• improve their drug pipelines
• identify and evaluate potential partners
• develop new applications for their technologies
• penetrate new markets

Haberman Associates is a member the Boston-based Biopharmaceutical Consortium (BPC) and an Affiliate of the North Carolina-based consulting consortium Innovalyst. Our relationship with Innovalyst began after one of our BPC partners moved to North Carolina, and eventually became a Principal of Innovalyst. Between BPC and Innovalyst, we have nearly 90 senior consultants on our team.

We have worked on consulting engagements with both BPC and Innovalyst consultants.  Our relationship with these consortia enables us to take on larger projects, as well as projects requiring multiple types of expertise.

One of my Innovalyst colleagues referred to the Haberman Associates/Innovalyst combination as a “virtual drug discovery and development organization”. Another way to look at the Haberman Associates/Innovalyst combination is as having to power of a single office of a large consulting firm, but one dedicated to helping pharmaceutical and biotechnology clients to increase their effectiveness in the difficult areas of drug discovery and development.

In one case last year, a prospective client asked me whether Haberman Associates could take on a consulting engagement involving GMP services. I know little about that subject, other than where it fits into the process of developing a drug. I also know people who work in that area. So I handed the engagement over to another project leader in Innovalyst. He formed a team that included himself, several domain experts (one of whom knows the Chinese GMP services market), and me.  Although I knew little about GMP services, I used my research and interviewing skills, and made a material contribution to the project. Our team delivered a result that exceeded client expectations.

We always aim to exceed client expectations, whatever the project.

In addition to consulting, Haberman Associates has produced numerous publications–ranging from articles to book-length reports–which have been published by leading life science industry publishers. A list of recent publications is now available on my public LinkedIn profile.

As for the Biopharmconsortium Blog, it is the blog for our consulting group, not a journalistic blog. Despite the diversity of subjects covered by the blog, the focus is on effective drug discovery and development, and on company strategies designed to facilitate effective new product development. We have more good content available than we can possibly blog about, and do not accept requests to blog about content that is irrelevant to our focus.

We hope that the diverse community of our readers will benefit from the discussions on our blog. We also hope that potential clients in the life science industry will get a feeling for how we approach issues in drug discovery and development and company strategies.

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Lomitapide

Mid-October 2012 was a busy time for the FDA’s Endocrinologic and Metabolic Drugs Advisory Committee. On October 17, 2012, the panel voted 13-2 to recommend approval of Aegerion’s lomitapide for treatment of homozygous familial hypercholesterolemia. The next day, October 18, 2012, the same panel voted 9-6 to recommend approval of Isis/Sanofi/Genzyme’s mipomersen for the same condition.

Familial hypercholesterolemia (FH) is a rare genetic condition characterized by very high levels of low-density lipoprotein (LDL, or “bad cholesterol”), in the blood and early cardiovascular disease. Most patients with FH have mutations in either the LDL receptor (which functions to remove LDL from the circulation), or in apolipoprotein B (ApoB) (the protein moiety of LDL, which binds to the LDL receptor).

Patients who are heterozygous for an FH mutation (but have one normal copy of the affected gene) may have premature cardiovascular disease in their thirties. Patients who are homozygous for an FH mutation may have severe cardiovascular disease in childhood. Heterozygous FH is a common genetic disease, which is inherited in an autosomal dominant pattern, and occurs in one out of 500 people. Homozygous FH, however, occurs in about 1 in a million births. Homozygous FH thus qualifies as a “rare disease”.

Physicians generally treat heterozygous FH with statins, bile acid sequestrants or other lipid-lowering agents that lower cholesterol levels. Homozygous FH often does not respond to these drugs. It may require chronic treatment via LDL apheresis (removal of LDL in a method similar to dialysis) and in some cases liver transplantation.

Aegerion (Cambridge, MA), the developer of lomitapide, is a publicly-traded biotech company that seeks to “change the way that rare, genetic lipid disorders are treated”. It is currently focused on the development of lomitapide, a small-molecule compound (pictured above).

Lomitapide inhibits the microsomal triglyceride transfer protein (MTTP) which is necessary for very low-density lipoprotein (VLDL) assembly and secretion in the liver. A 2007 article in the New England Journal of Medicine (NEJM) concluded that inhibition of MTTP by lomitapide (then known as BMS-201038) resulted in the reduction of LDL cholesterol levels in patients with homozygous FH. BMS-201038/lomitapide was originally developed by Bristol-Myers Squibb (BMS), donated to the University of Pennsylvania in 2003 and licensed to Aegerion in 2006. BMS had abandoned development of the compound after early Phase 1 and Phase 2 trials had found increases in heptatic fat content and gastrointestinal disturbances. The NEJM study (conducted by Penn researchers in collaboration with other academic researchers and with BMS) also found that therapy with the compound was associated with elevated liver aminotransferase levels and hepatic fat accumulation.

78-week data from Aegerion’s pivotal Phase 3 study of lomitapide in adults patients with homozygous FH were published in the online version of The Lancet on November 2, 2012.

Mipomersen (which will be called Kynamro if and when it is commercialized) is an antisense oligonucleotide that targets the messenger RNA for apolipoprotein B. We discussed mipomersen in our August 21, 2009 blog article on oligonucleotide therapeutics. Mipomersen represents the most advanced oligonucleotide drug in development that is capable of systemic delivery. (The only two marketed oligonucleotide drugs both treat ophthalmologic diseases and are delivered locally.) Mipomersen targets the liver, without the need for a delivery vehicle. Thus mipomersen–potentially the first systemically-delivered oligonucleotide drug to reach the market–represents the “great hope” for proof-of-concept for oligonucleotide drugs, including antisense and  RNAi-based drugs.

Patients treated with mipomersen, as with lomitapide, exhibit liver-related adverse effects, especially hepatic fat accumulation and elevated liver aminotransferase levels. Moreover, unlike lomitapide, which is an orally-delivered compound, mipomersen, which is delivered via subcutaneous injection, can cause injection site reactions and flu-like symptoms. Moreoever, mipomersen has a much longer half-life than lomitapide (30 days versus 20 hours).

Industry commentators, and well as the FDA Advisory Committee, generally favor lomitapide over mipomersen, because lomitapide appears to be the more efficacious drug in lowering LDL-cholesterol, and also because lomitapide is an oral drug. However, most of the FDA panelists, as well as other industry commentators believe that not all patients with homozygous FH would be likely to benefit from only one drug. Thus having two alternative drugs may well be better in treating this disease.

Both lomitapide and mipomersen have potentially serious adverse effects. A finding of elevated liver aminotransferase levels is enough to stop development of most drugs. However, the FDA and its Advisory Panel believe that a risk evaluation and mitigation strategy (REMS) would support appropriate use of these drugs in patients with homozygous FH, because of their life threatening disease, and because they have limited therapeutic options. Both Aegerion and Genzyme are proposing that their compounds be approved with REMS programs, including an education program for physicians and active monitoring of patients. The REMS program would also include monitoring to ensure that only adult homozygous FH patients would be treated with the drugs. However, Aegerion plans to conduct clinical trials of the use of lomitapide in pediatric homozygous FH patients, as well as patients with another rare disease, familial chylomicronemia. Genzyme has already tested mipomersen in a small number of pediatric patients.

Companies developing therapeutics for rare diseases whose mechanisms are related to those of more common diseases often attempt to first get their drugs approved for the rare disease, and then perform additional clinical trials to expand the drug’s indications to larger populations. We discussed this strategy in an earlier article on this blog. Homozygous FH is mechanistically related to not only heterozygous FH, but also to cases of severe hypercholesterolemia that are poorly controlled by statins. Both companies have shown interest in treating patients with homozygous FH and severe hypercholesterolemia, since they have preformed clinical trials that included patients with these conditions. However, the adverse effects of these drugs may limit their use to homozygous FH, at least in the near future.

Aegerion intends to market lomitapide on its own, and is ramping up its marketing and sales organization in anticipation of approval. Mipomersen, if approved, would have the benefit of the Sanofi marketing organization behind it. However, industry commentators expect lomitapide to have a large advantage over mipomersen, if both are approved. That is because of the greater efficacy of lomitapide, its oral dosing, and other factors related to injection site reactions for mipomersen and the half-lives of the compounds.

We await FDA action in the next several weeks on the approval of lomitapide and mipomersen.

Meanwhile, researchers and companies are working on potential drugs for severe hypercholesterolemia that act via an entirely different mechanism–PCSK9 (proprotein convertase subtilisin/kexin 9) inhibition. These drugs are in an earlier stage of development than lomitapide and mipomersen. However, they might eventually provide strong competition to these drugs, or replace them altogether.

For oligonucleotide drug developers and enthusiasts, the case of mipomersen–considered the “great hope” for proof-of-concept for oligonucleotide drugs by many in the field–provides several lessons. 1. At the end of the day, oligonucleotide drugs must meet the same standards of safety and efficacy as other drugs. 2. Oligonucleotide drugs may encounter competition from drugs in other classes, such as small molecules or monoclonal antibodies.

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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.

Source: Madprime http://bit.ly/RLmMqL

On October 11, 2012 we published an article entitled “Is gene therapy emerging from technological prematurity?” on the Biopharmconsortium Blog. The centerpiece of that article was the July 20, 2012 ruling by the European Medicines Agency’s Committee for Medicinal Products for Human Use (CHMP) that recommended marketing uniQure’s Glybera. Glybera (alipogene tiparvovec) is a gene therapy for the ultra-rare genetic disease lipoprotein lipase deficiency (LPLD).

On November 2, 2012, the European Commission approved Glybera, which now becomes the first gene therapy approved in a regulated market. This was announced by uniQure, and covered by BioWorld Today and Reuters, among others.

Now that Glybera is approved in Europe, uniQure is exploring registration of Glybera in North America, and is developing its strategy for interaction with relevant regulators, especially the FDA. uniQure is aiming for a U.S. launch of Glybera in 2014.

According to uniQure, the commercial roll-out of Glybera will begin in the second half of 2013. uniQure estimates that there are 400 to 500 patients in Europe eligible to receive the therapy.

uniQure also says that the approval of Glybera validates the company’s  adeno-associated virus (AAV) vector-based gene therapy platform. In that connection, uniQure is planning to develop four other gene therapies that utilize its platform–treatments for hemophilia B, for acute intermittent porphyria, for Parkinson’s disease, and for Sanfilippo B, a rare liposomal storage disorder. These four gene therapy products have approval to enter clinical trials within the next nine months.

uniQure faces a short-term funding gap until revenues from Glybera start coming in. It is seeking to raise €20 million (US$26.7 million) in investment over the next five months.

uniQure’s ability to successfully commercialize Glybera depends on the pricing for the therapy allowed by payers. The company is now negotiating with payers to set prices. uniQure is basing its pricing for Glybera for the prices of enzyme replacement products for treating lysosomal storage disorders, such as those developed by Genzyme. For example, Genzyme’s Cerezyme (imiglucerase), a treatment for Gaucher’s disease, cost $200,000 per year in the United States in 2009. However, unlike Genzyme’s enzyme replacement therapies, Glybera, being a gene therapy, is a one-time treatment designed to restore a natural body function rather than providing short-term amelioration of a genetic disease.

According to the Reuters article, Glybera is expected to cost approximately €1.2 million ($1.6 million) per patient. This would be a new record for expensive modern therapeutics. Jörn Aldag, uniQure’s CEO, believes that the high price is justified by the long-term benefit provided by a gene therapy, as opposed to the classic protein replacement strategy in which the drug must be administered repeatedly for life.

Different European countries prefer different payment schemes for Glybera. Some favor charging an annual price for the therapy, while others prefer a single up-front charge, based on multiplying the annual cost of treating a similar disease (e.g., Gaucher’s disease) by the number of years Glybera is known to have an effect. Currently, that is five years.

For an in-depth discussion of the prospects for the gene therapy field, and the implications of the approval of Glybera for the future of gene therapy, see our October 11, 2012 article on this blog.

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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.

The idea of gene therapy has been around since at least the early 1970s. In 1972, an article by Theodore Friedmann and Richard Roblin advanced the concept of treating genetic diseases by replacing defective endogenous DNA with exogenous “good” DNA. However, these authors concluded that it was premature to begin gene therapy studies in humans because of lack of basic knowledge of genetic regulation and of genetic diseases, and for ethical reasons. They did, however, propose that studies in cell cultures and in animal models aimed at development of gene therapies be undertaken. Such studies–as well as abortive gene therapy studies in humans–had already begun as of 1972.

In the 1970s and 1980s, researchers applied such technologies as recombinant DNA and development of viral vectors for transfer of genes to cells and animals to the study and development of gene therapies. In the 1990s, several research groups conducted FDA-approved human studies of gene therapies, based on this technological development and increased knowledge of genetic diseases. However, several notable failures put a damper on development of gene therapies.

The most notorious case was the 1999 death of 18-year-old Jesse Gelsinger, who had ornithine transcarbamylase deficiency. In a clinical trial at the University of Pennsylvania, he was injected with an adenoviral vector carrying a corrected gene to test the safety of use of this procedure. He suffered a massive immune response triggered by the use of the viral vector, and died four days later. As a result of this incident, the FDA suspended several gene therapy clinical trials pending review of ethical and scientific/medical practices.

This incident, as well as the failure of other clinical studies put a severe damper on the gene therapy field, especially attempts at commercialization of gene therapies and of building biotech companies specializing in this field. Nevertheless, between 2003 and 2012, researchers have been quietly developing more advanced gene therapy technologies and conducting clinical studies, with some success. Entrepreneurs have also been building gene therapy specialty companies to commercialize this research.

Now comes the July 20, 2012 ruling by the European Medicines Agency’s Committee for Medicinal Products for Human Use (CHMP) that recommends marketing of a gene therapy known as Glybera (alipogene tiparvovec) as a treatment for the ultra-rare genetic disease lipoprotein lipase deficiency (LPLD) under exceptional circumstances. LPLD affects no more than two people per million in the general population. People with LPLD cannot break down fat, and must manage their disease with a restricted diet. However, dietary management is difficult, and a high proportion of patients suffer life-threatening pancreatitis.

Glybera is being developed by a small Dutch biotech called uniQure biopharma. Glybera consists of an adeno-associated virus (AAV) vector that carries the gene for LPL. Therapy consist of multiple intramuscular injections of the product, resulting in the delivery of functional LPL genes to muscle cells.

The European Commission (EC) generally follows the recommendations of the CHMP. At the time of the CHMP ruling, uniQure expected initial approval from the EC within 3 months of that decision. Articles published in Nature and Nature Biotechnology in the late September/early October 2012 period anticipate EC approval in a mater of days or a week or two.

If it is approved in the European Union (EU) as expected, that approval will require that Glybera be offered through dedicated centers of excellence with expertise in treating LPLD, and by specially trained doctors to ensure ongoing safety of the therapy. uniQure is now preparing to apply for approval in the U.S., Canada, and other markets.

uniQure is also using its AAVvector platform as the basis of a series of gene therapies for other rare diseases, including porphyria and Sanfilippo B, as well as what it calls “disruptive innovation” products for such diseases with established treatments as Parkinson’s disease and Hemophilia B.

Does the expected approval of Glybera herald the beginning of a new era of gene therapy?

Jörn Aldag, the CEO of uniQure, believes that “just like antibodies, gene therapy will one day be a mainstay in clinical practice.” Although uniQure is concentrating its development efforts in the area of rare diseases, Mr Aldag believes that “the potential of gene therapy stretches far beyond rare diseases.” He cites a December 2011 publication in the New England Journal of Medicine, which describes a study in which 6 patients with hemophilia B were treated (via peripheral-vein infusion) with an AAV vector carrying a proprietary (codon-optimized) human factor IX (FIX) transgene. This treatment resulted in FIX transgene expression at levels sufficient to improve the bleeding phenotype, with few side effects, all of which were easily treatable. Hemophilia B, the second most common form of hemophilia, is nowhere as rare as the ultra-rare disease LPLD. Some of the patients treated with this gene therapy were able to discontinue prophylactic treatment with FIX. uniQure’s program in gene therapy for Parkinson’s disease exemplifies the companies efforts to move beyond the rare disease area.

However, others are not so sure that the approval of Glybera will usher in a new era of gene therapy, at least not in the near future. In particular, Fulvio Mavilio, Ph.D., Scientific Director of Genethon (Evry, France) (a non-profit center for development of gene therapies), does not believe that a large number of patients will be treated with gene therapies in the near future.

Dr. Mavilio cites the “relatively rich pipeline of gene therapy candidates already in human trials,” which  “suggests there may be a surge in the number of gene therapies approved over the next few years.” However, most of the gene therapy clinical candidates are for ultra-rare single Mendelian genetic deficiencies, with similar frequencies in the population to LPLD. The hemophilias (hemophilia A, 1 in every 5,000 male babies diagnosed per year in the US; hemophilia B, 1 in every 30,000 male babies per year) are the most common diseases to be addressed by gene therapies now in clinical development, according to Dr. Mavilio’s article. Moreover, Dr. Mavilio–as well as others–expects safety issues to thwart or slow the development of at least some gene therapies, which will also face competition from existing enzyme replacement therapies similar to those developed by Genzyme.

No gene therapy has yet been approved in the U.S. However, the FDA has established a system that facilitates faster reporting of adverse events in human gene transfer trials and that tracks such trials that are taking place. And uniQure has been planning to work with the FDA to seek U.S. approval of Glybera.

Gene therapy as a “premature technology”

Gene therapy fits the model of a “premature technology”. A field of biomedical science is said to be scientifically or technologically premature when despite the great science and exciting potential of the field, any practicable therapeutic applications are in the distant future, due to difficult hurdles in applying the technology. Moving a premature technology up the development curve requires the development of enabling technologies that can allow researchers and product developers to overcome the hurdles.

The classic case of a premature technology that has moved up the development curve and become successful is the field of therapeutic monoclonal antibodies (MAbs). We discussed the history of MAbs in detail in our September 28, 2009 blog article. The first ever MAb to enter the market, Johnson & Johnson’s Orthoclone OKT3 was approved in 1986 for use in transplant rejection. However, this drug can only be used once in a patient due to its immunogenicity. There were not any further approvals of MAb drugs until 1994. The numerous MAbs that have entered the market since then were made possible by the development of enabling technologies that overcame the immunogenicity problem. Several of these products are highly successful, and there is a rich pipeline of MAb therapeutics now in development.

Commentators on recent developments in gene therapies, including the ones we cited earlier, compare Glybera to Orthoclone OKT3. Given the limited number of patients for whom Glybera is appropriate, and especially given the exceptional circumstances under which Glybera may be prescribed and used, they are likely to be right.

bluebird bio

Among the many companies that are developing gene therapies, one has been singled our for special attention lately. That is bluebird bio (Cambridge, MA). On September 19, 2012, bluebird bio was named to FierceBiotech’s 2012 “Fierce 15″. By naming bluebird bio to the Fierce 15, FierceBiotech is designating the company as “one of the most promising private biotechnology companies in the industry”. “The Fierce 15 celebrates the spirit of being ‘fierce’ – championing innovation and creativity, even in the face of intense competition.” bluebird bio was formerly known as Genetix Pharmaceuticals.

bluebird bio has developed a novel gene therapy platform, in which a wild-type version of a patient’s disease-causing gene, carried in a lentiviral vector, is inserted into autologous CD34+ bone marrow-derived stem cells. These transformed autologous stem cells are then transfused into the patient. This eliminates potential complications associated with donor cell transplantation, or with systemic administration of gene therapy vectors.

bluebird bio’s platform thus represents both a gene therapy technology and an adoptive cellular transfer (ACT) technology. We have discussed ACT technologies (in this case, for immunotherapy for cancer) in the previous article on this blog. Since some of these technologies involve genetically-engineered autologous T cells, they may also be thought of as representing both ACT and a kind gene therapy. (However, the “gene therapy” in these cases is not directed toward repairing a genetic disease, as  in classic gene therapy.)

For a list of links to bluebird bio publications using this and other gene therapy technologies, see the publications page of the company’s website.

bluebird bio is preparing a pivotal Phase 2/Phase 3 study of its lead treatment, for childhood cerebral adrenoleukodystrophy (ALD). The company is also in Phase 1/2 trials for its beta-thalassemia therapy, and in Phase 1 for its sickle cell disease program.

ALD is a rare, inherited neurological disorder that affects one in every 21,000 boys worldwide. It can cause damage to neural myelin sheaths in the brain, and progressive dysfunction of the adrenal glands. ALD is the disease that was featured in the 1992 movie Lorenzo’s Oil. Beta-thalassemias affect one in every 100,000 people throughout the world, with the greatest prevalence in the Mediterranean basin and in South Asia. Sickle cell disease mainly affects sub-Saharan Africans and their decedents, as well as residents of other areas with a high prevalence of malaria. Its prevalence in the U.S. is around 1 in 5,000, in France one in 2,415, and in the U.K. 1 in 2,000.

Thus the diseases that constitute the current focus of bluebird bio are much more common than is LPLD, the target of Glybera. The prevalence of the diseases that are the current targets of bluebird bio resemble the prevalence of “rare diseases” targeted by current Genzyme therapies–Gaucher’s disease (1 in 40,000 in the U.S.), and lysosomal storage disorders (individual diseases, an incidence of less than 1:100,000; total lysosomal storage diseases, an incidence of about 1 in 5,000 to 1 in 10,000).

bluebird bio’s business thus lies in the intersection between gene therapy and the “rare diseases” that are the main targets of an increasing number of biotechs and Big Pharmas.

bluebird bio is backed by several venture capital firms, notably TVM Capital, Third Rock Ventures, and Forbion Capital Partners, as well as by Genzyme (which is now part of Sanofi) and Shire. According to the Fierce 15 press release, bluebird bio is also “exploring a potential set of partnerships”.

Conclusions

In the long history of gene therapy, the expected approval in Europe of Glybera represents a key milestone–if indeed the EC approves the therapy as expected. However, given the very limited number of patients for whom Glybera is appropriate, and the exceptional circumstances under which Glybera may be prescribed and used, this milestone may be analogous to the approval of Orthoclone OKT3. Thus there may be a lag between the approval of the first gene therapy and the beginning of a more steady stream of gene therapy approvals.

However, bluebird bio’s cellular approach may enable it to circumvent many of the pitfalls of gene therapy. Other gene therapy companies may also possess enabling technologies that can help drive the gene therapy field up the technology development curve.

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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.

Tumor infiltrating lymphocytes (TILs) in a colorectal carcinoma. Source: Nephron. http://bit.ly/QdusBi

On April 27, 2011 we published an article on this blog entitled “Adoptive immunotherapy for metastatic melanoma?” This blog post, which was in part based on an article in the April 2011 issue of The Scientist, described a treatment for metastatic melanoma known as adoptive cell transfer (ACT), or adoptive immunotherapy. ACT is the only type of therapy that has resulted in high percentages of durable compete responses in metastatic melanoma. A durable complete response, which is tantamount to a cure, is the real desire of every cancer patient, and of their loved ones, and of caring physicians who treat them.

In ACT, a physician/researcher extracts a patient’s antigen-specific immune cells, which are usually found in tumor tissue. Such cells are known as “tumor infiltrating lymphocytes” (TILs). He or she then expands the numbers of the antitumor T lymphocytes in cell culture, using the T-cell growth factor, IL-2. The physician/researcher then infuses the cells, plus IL-2, intravenously into the patient. The infused T cells traffic to tumors and can mediate their destruction. Prior to TIL infusion, the patient may have his or her immune system temporarily ablated via “preparative lymphodepletion” with chemotherapy and sometimes also total-body irradiation. The preparative lymphodepletion treatment is associated with enhanced persistence of the transferred TILs.

In a clinical study of ACT published in 2011, the treatment resulted in the disappearance of all tumors in 20/93 patients (21.5%) with advanced metastatic melanoma. For 19 of these 20 patients (95%), the complete responses have been durable and long-lasting, in some cases lasting for over 7 years. (See also the Faculty of 1000 evaluation.)

Research on the mechanistic basis of adoptive immunotherapy, as well as on means to improve ACT technologies, is ongoing, so there is the potential to improve the durable complete response rate further. We featured a December 2012 Nature cancer immunotherapy review article that included a discussion of ways to improve ACT in the 2011 end-of-year article on our Biopharmconsortium Blog.

Despite the fact that ACT is the only type of therapy that has resulted in high percentages of durable compete responses in metastatic melanoma, it is not widely available. ACT is only available in a small number of cancer canters worldwide, and there has been little commercial interest in developing ACT.

Adoptive immunotherapies are still considered experimental, are not FDA-approved, and are not covered by third party payers. Thus only a handful of locations can bear the financial burden of administering adoptive immunotherapy. If a cancer center has a cell production facility with the required staff, the cost of producing a single dose of T-cells for adoptive transfer is approximately $20,000. ACT treatment also entails factoring in the cost of hospitalization. However, most patients only require a single dose.

The cost of ACT is, however, much lower than a full course of other immunotherapies, such as the dendritic cell vaccine Provenge (which is not indicated for melanoma) or the immunotheraputic MAb drug ipilimumab, both of which cost approximately $120,000. The total cost of a 6-month treatment with the targeted kinase drug vemurafenib is $56,400. None of these treatments result in durable complete responses, except in a very small number of patients.

The main problem with increasing the availability of ACT is the lack of a viable business model for its commercialization. Adoptive immunotherapies lack a clearly defined claim to intellectual property (IP), since the patient’s own cells are not a “drug” to be patented. It would be difficult for a private company to pursue clinical trials for FDA approval and commercialization of ACT. To conduct such trials, a company would need to build a specialized cell processing and treatment facility, with a highly trained and competent staff. If the therapies cannot be protected as IP, and would therefore not be considered proprietary, it would not be worth the effort and expense to commercialize them.

The Novartis/Penn agreement

Now comes an agreement (announced on August 6, 2012) between Novartis and the University of Pennsylvania (Penn) aimed at commercializing adoptive cellular immunotherapy.

The agreement is based on one of the improvements to ACT discussed in the December 2011 Nature cancer immunotherapy review, in which autologous T cells isolated from patient blood (not from tumors) are engineered with retroviral vectors carrying chimeric antigen receptors (CARs). This technology allows physician researchers to extend ACT beyond patients from whom TILs can be isolated and expanded. It also enables them to extend ACT beyond melanoma to include other types of solid tumors and leukemias and lymphomas. Unlike TILs, CAR-bearing T cells do not recognize surface antigens on tumor cells [presented by major histocompatibility complex (MHC) proteins] via their T-cell receptors. They instead recognize surface proteins on tumor cells via the affinity domain on the engineered CAR. This also expands the kinds of tumor cells that can be recognized, as compared to TILs.

In the Penn studies, led by David L. Porter, M.D. at the Perelman School of Medicine of the University of Pennsylvania, the researchers used this technology to treat patients with chronic lymphocytic leukemia (CLL). They designed a lentiviral vector expressing a chimeric antigen receptor with specificity for the B-cell antigen CD19, coupled with the T cell costimulatory receptor CD137 and CD3-zeta (a signal-transduction component of the T-cell antigen receptor) signaling domains. They used this vector to engineer autologous T cells, and infused the engineered cells into the patient after preparative lymphodepletion with chemotherapy. In a pilot study with one patient with refractory chronic lymphocytic leukemia (CLL), the infused cells exhibited in vivo expansion and anti-leukemia activity. The treatment resulted in complete remission, which was ongoing 10 months after initiation.

In a later study, the researchers treated three more patients with autologous engineered CAR T cells. The T cells expanded over 1000-fold in vivo, trafficked to bone marrow, and continued to express CARs at high levels for at least six months. The CAR T-cells showed anti-leukemia activity, with each engineered T cell eliminating approximately 1000 CLL cells. A CD19-specific immune response was demonstrated in the blood and bone marrow of two of three patients; these patents showed complete remission. Some of the cells in these patients persisted as memory CAR T cells and retained anti-CD19 effector activity. These results suggested that this technology has the potential to effectively treat B cell malignancies, and to induce durable complete remissions in at least a portion of patients.

As reported in August 2012, of the three patients who showed positive results with the anti-CD19 immunotherapy, two were still in complete remission over a year into the CART-19 trial, and the third patient maintained partial remission for more than seven months. An immune deficiency resulting from the treatment known as hypogammaglobulinemia, an expected chronic toxic effect of anti-B cell therapy, was corrected with infusions of intravenous immune globulin. Patients were also treated for symptoms associated with tumor lysis syndrome, an effect of tumor breakdown.

Under the agreement, Novartis acquired exclusive rights from Penn to CART-19, the investigational CAR immunotherapy that was the focus of the studies discussed earlier. The target of CART-19, CD19, is associated with several B-cell malignancies, including CLL, B-cell acute lymphocytic leukemia and diffuse large B-cell lymphoma. Novartis expects to initiate a Phase II clinical trial with CART-19 in collaboration with Penn during the fourth quarter of 2012.

To facilitate the discovery and development of additional types of CAR immunotherapy, Novartis and Penn will build the Center for Advanced Cellular Therapies (CACT) at Penn. This center will be established specifically to develop and manufacture adoptive T-cell immunotherapies under the research collaboration between Penn and Novartis.

Penn also granted Novartis an exclusive worldwide license to CARs developed through the collaboration for all indications, in addition to CART-19. In return, Novartis will provide an up-front payment, research funding, funding for the establishment of the CACT and milestone payments for the achievement of certain clinical, regulatory and commercial milestones as well as and royalties on any sales.

Business implications of the Novartis/Penn agreement

The feasibility of developing and commercializing CAR T-cell-based immunotherapy is based on the ability of Penn to patent and license its CAR technology. Such an approach in principle would apply to immunotherapies based on other types of engineered T cells, such as those engineered with retroviral vectors carrying cloned T-cell receptors, as discussed in the December 2011 Nature review article.

As discussed earlier, adoptive immunotherapies with engineered T cells would also address patients with a variety of types of cancer (not just melanoma) and from who TILs cannot be isolated. However, whether any therapies with engineered T cells can give the percentages of durable complete responses seen with TIL-based therapy of melanoma remains to be demonstrated in clinical trials.

The Novartis/Penn agreement represents an example of Novartis’ willingness to take risks, in order to “bring innovative therapies to patients”, as stated by Hervé Hoppenot, President, Novartis Oncology. Mark Fishman, President of the Novartis Institutes for BioMedical Research, sees cancer immunotherapy as “one of the exciting frontiers in cancer research,” and the CAR technology as showing “early promise as a new way for treating cancer.”

Novartis thus has not built a viable business model for TIL-based ACT. However, it is developing a parallel technology that is more protectable than TILs, which might result in bringing adoptive cellular immunotherapy to a much larger number of patients.

BiTE immunotherapy

Meanwhile another type of T-cell-based immunotherapy technology (also discussed in the Nature review) is now under development. This is bi-specific T-cell engager (BiTE) technology, originally developed by the German-American biotech company Micromet. Amgen acquired Micromet in April 2012, and is now developing the first BiTE agent, blinatumomab. Blinatumomab is a bispecific MAb that binds to CD19 on target B-cell malignancies and to CD3 (an invariant component of the T-cell receptor) on T cells. This results in the activation of the T cell to exert cytotoxic activity on the target cell. BiTE immunotherapy does not require isolation and culture of autologous T cells, and BITE technology and therapeutics derived from it are patentable as with other drugs.

In May 2012, Amgen reported that blinatumomab treatment gave a high rate (72 percent) of complete responses in a Phase 2 study in patients with relapsed or refractory B-precursor acute lymphoblastic leukemia (ALL). The rate of remission seen in this trial was a great improvement over the current standard of care. However, no durable complete responses were seen; median survival was 9 months.

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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.

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.

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

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