Simvastatin (Merck’s Zocor)

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

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

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

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

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

Why are pharmaceutical companies struggling to develop new drugs?

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

Rodin Therapeutics

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

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

Sage Therapeutics

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

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

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

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

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

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

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

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

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

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

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

Sage’s pipeline

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

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

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

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

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

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

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

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

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

EnVivo Pharmaceuticals

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

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

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

Outlook

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

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

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

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

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

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

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

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

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

The Novartis return to neuroscience R&D

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

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

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

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

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

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

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

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

The projects in the Dolmetsch laboratory have included:

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

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

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

Novartis’ timeline for neuroscience drug development

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

Additional pipeline news in Agios’ Third Quarter 2013 Report

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

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

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

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

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

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

Can Agios Pharmaceuticals become a new Genentech?

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

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

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

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

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

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

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.

CXCR-1 N-terminal peptide bound to IL-8

In our October 31, 2013 blog article, we discussed recent structural studies of the chemokine receptors CCR5 and CXCR4. We discussed the implications of these studies for the treatment of HIV/AIDS, especially using the CCR5 inhibitor maraviroc (Pfizer’s Selzentry/Celsentri). As discussed in the article, researchers are utilizing the structural studies of CCR5 and CXCR4 to develop improved HIV entry inhibitors that target these chemokine receptors.

Meanwhile, other researchers have been studying the role of chemokine receptors in cancer biology, and the potential use of chemokine receptor antagonists in cancer treatment.

CCR5 antagonists as potential treatments for metastatic breast cancer

One group of researchers, led by Richard G. Pestell, M.D., Ph.D. (Thomas Jefferson University, Philadelphia, PA) has been studying expression of CCR5 and its ligand CCL5 (also known as RANTES) and their role in breast cancer biology and pathogenesis. Their report of this study was published in the August 1, 2012 issue of Cancer Research.

These researchers first studied the combined expression of CCL5 and CCR5 in various subtypes of breast cancer, by analyzing a microarray database of over 2,000 human breast cancer samples. (The database was compiled from 27 independent studies). They found that CCL5/CCR5 expression was preferentially expressed in the basal and HER-2 positive subpopulations of human breast cancer.

Because of the high level of unmet medical need in treatment of basal breast cancer, the authors chose to focus their study on this breast cancer subtype. As the researchers point out, patients with basal breast cancer have increased risk of metastasis and low survival rates. Basal tumors in most cases do not express either androgen receptors, estrogen receptors (ERs), or HER-2. They thus cannot be treated with such standard receptor-targeting breast cancer therapeutics as tamoxifen, aromatase inhibitors, or trastuzumab. The only treatment options are cytotoxic chemotherapy, radiation, and/or surgery. However, these treatments typically results in early relapse and metastasis.

The basal breast cancer subpopulation shows a high degree of overlap with triple-negative (TN) breast cancer. We discussed TN breast cancer, and research aimed at defining subtypes and driver signaling pathways, in our August 2, 2011 article on this blog. In that article, we noted that TN breast cancers include two basal-like subtypes, at least according to one study. Other researchers found that 71% of TN breast cancers are of basal-like subtype, and that 77% of basal-like tumors are TN. A good part of the problem is that there is no accepted definition of basal-like breast cancers, and how best to define such tumors is controversial. However, both the TN and the basal subpopulations are very difficult to treat and have poor prognoses. It is thus crucial to find novel treatment strategies for these subpopulations of breast cancer.

Dr. Pestell and his colleagues therefore investigated the role of CCL5/CCR5 signaling in three human basal breast cancer cell lines that express CCR5. They found that CCL5 promoted intracellular calcium (Ca2+) signaling in these cells. The researchers then determined the effects of CCL5/CCR5 signaling in promoting in vitro cell invasion in a 3-dimensional invasion assay. For this assay, the researchers assessed the ability of cells to move from the bottom well of a Transwell chamber, across a membrane and through a collagen plug, in response to CCL5 as a chemoattractant. The researchers found that CCR5-positive cells, but not CCR5-negative cells, showed CCL5-dependent invasion.

The researchers then studied the ability of CCR5 inhibitors to block calcium signaling and in vitro invasion. The agents that they investigated were maraviroc and vicriviroc. Maraviroc (Pfizer’s Selzentry/Celsentri) is the marketed HIV-1 entry inhibitor that we discussed in our October 31, 2013 article.  Vicriviroc is an experimental HIV-1 inhibitor originally developed by Schering-Plough. Schering-Plough was acquired by Merck in 2009. Merck discontinued development of vicriviroc because the drug failed to meet primary efficacy endpoints in late stage trials.

Pestell et al. found that maraviroc and vicriviroc inhibited calcium responses by 65% and 90%, respectively in one of their CCR5-positive basal cell breast cancer lines, and gave similar results in another cell line. The researchers then found that  in two different CCR5-positive basal breast cancer cell lines, both maraviroc and vicriviroc inhibited in vitro invasion.

The researchers then studied the effect of maraviroc in blocking in vivo metastasis of a CCR5-positive basal cell breast cancer line, which had been genetically labeled with a fluorescent marker to facilitate noninvasive visualization by in vivo bioluminescence imaging (BLI). They used a standard in vivo lung metastasis assay, in which cells were injected into the tail veins of immunodeficient mice, and mice were treated by oral administration with either maraviroc or vehicle. The researchers then looked for lung metastases. They found that maraviroc-treated mice showed a significant reduction in both the number and the size of lung metastases, as compared to vehicle-treated mice.

In both in vitro and in vivo studies, the researchers showed that maraviroc did not affect cell viability or proliferation. In mice with established lung metastases, maraviroc did not affect tumor growth. Maraviroc inhibits only metastasis and homing of CCR5-positive basal cell breast cancer cells, but not their viability or proliferation.

As the result of their study, the researchers propose that CCR5 antagonists such as maraviroc and vicriviroc may be useful as adjuvant antimetastatic therapies for breast basal tumors with CCR5 overexpression.  They may also be useful as adjuvant antimetastatic treatments for other tumor types where CCR5 promotes metastasis, such as prostate and gastric cancer.

As usual, it must be emphasized that although this study is promising, it is only a preclinical proof-of-principle study in mice, which must be confirmed by human clinical trials.

In an October 25, 2013 Reuters news story, it was revealed that Citi analysts believe that Merck will take vicriviroc into the clinic  in cancer patients in 2014. Citi said that it expected vicriviroc to be tested in combination with “a Merck cancer immunotherapy” across multiple cancer types, including melanoma, colorectal, breast, prostate and liver cancer. (We discussed Merck’s promising cancer immunotherapy agent lambrolizumab/MK-3475 in our June 25, 2013 blog article. But the Merck agent to be tested together with vicriviroc was not disclosed in the Reuters news story.)

Despite this news story, Merck said that it had not disclosed any plans for clinical trials of vicriviroc in cancer.

The CXCR1 antagonist reparixin as a potential treatment for breast cancer

In our In April 2012 book-length report, “Advances in the Discovery of Protein-Protein Interaction Modulators” (published by Informa’s Scrip Insights), we discussed the case of the allosteric chemokine receptor antagonist reparixin (formerly known as repertaxin). Reparixin has been under developed by Dompé Farmaceutici (Milan, Italy). This agent targets both CXCR1 and CXCR2, which are receptors for interleukin-8 (IL-8). IL-8 is a well-known proinflammatory chemokine that is a major mediator of inflammation. As we discussed in our report, reparixin had been in Phase 2 development for the prevention of primary graft dysfunction after lung and kidney transplantation. However, it failed in clinical trials.

Meanwhile, researchers at the University of Michigan (led by Max S. Wicha, M.D., the Director of the University of Michigan Comprehensive Cancer Center) and at the Institut National de la Santé et de la Recherche Médicale (INSERM) in France were working to define a breast cancer stem cell signature using gene expression profiling. They found that CXCR1 was among the genes almost exclusively expressed in breast cancer stem cells, as compared with its expression in the bulk tumor.

IL-8 promoted invasion by the cancer stem cells, as demonstrated in an in vitro invasion assay. The CXCR1-positive, IL-8 sensitive cancer stem cell population was also found to give rise to many more metastases in mice than non-stem cell breast tumor cells isolate from the same cell line. This suggested the hypothesis that a CXCR1 inhibitor such as reparixin might be used as an anti-stem cell, antimetastatic agent in the treatment of breast cancer.

Dr. Wicha and his colleagues then studied the effects of blockade of CXCR1 by either reparixin or a CXCR1-specific blocking antibody on  bulk tumor and cancer stem cells in two breast cancer cell lines. The researchers found in in vitro studies that treatment with either of these two CXCR1 antagonists selectively depleted the cell lines of cancer stem cells (which represented 2% of the tumor cell population in both cell lines).

This depletion was followed by the induction of massive apoptosis of the bulk, non-stem tumor cells. This was mediated via a bystander effect, in which CXCR1-inhibited stem cells produce the soluble death mediator FASL (FAS ligand). FASL binds to FAS receptors on the bulk tumor cells, and induces an apoptotic pathway in these cells that results in their death.

In in vivo breast cancer xenograft models, the researchers treated tumor-bearing mice with either the cytotoxic agent docetaxel, reparixin, or a combination of both agents. Docetaxel treatment–with or without reparixin–resulted in a significant inhibition of tumor growth, while reparixin alone gave only a modest reduction in tumor growth. However, treatment with docetaxel alone gave no reduction (or an increase) in the percentage of stem cells in the tumors, while reparixin–either alone or in combination with docetaxel–gave a 75% reduction in the percentage of cancer stem cells. Moreover, in in vivo metastasis studies in mice, reparixin treatment gave a major reduction in systemic metastases. These results suggest that reparixin may be useful in eliminating breast cancer stem cells and in inhibiting metastasis and thus preventing recurrence of cancer in patients treated with chemotherapy.

As we discussed in our 2012 report, Dr. Wicha’s research on reperixin might represent an opportunity for Dompé to repurpose reperixin for cancer treatment. Since the publication of the 2012 report, Dompé has been carrying out a Phase 2 pilot study of reparixin in patients diagnosed with early, operable breast cancer, prior to their treatment via surgery. The goal of this study is to investigate if cancer stem cells decrease in two early breast cancer subgroups (estrogen receptor-positive and/or progesterone receptor positive/HER-2-negative, and estrogen receptor negative/progesterone receptor negative/HER-2-negative). The goal is to compare any differences between the two subgroups in order to better identify a target population.

Dompé has thus begun the process of clinical evaluation of reparixin for the new indication–treatment of breast cancer in order to inhibit metastasis and prevent recurrence.

Conclusions

Researchers have found promising evidence that at least two chemokine/chemokine receptor combinations may be involved in cancer stem cell biology and thus in the processes of metastasis and cancer recurrence. In at least one case–and perhaps both–companies are in the early stages of developing small-molecule chemokine receptor antagonists for inhibiting breast cancer metastasis and recurrence. Such a strategy might be applicable to other types of cancer as well.

As discussed by Wicha et al., in immune and inflammatory processes, chemokines serve to facilitate the homing and migration of immune cells. In the case of cancer, chemokines may act as “stemokines”, by facilitating the homing of cancer stem cells in the process of metastasis. Other chemokines and their receptors than those discussed in this article may be involved in other types of cancer, and may carry out similar “stemokine” functions.

Since around 90% of cancer deaths are due to metastasis, and since effective treatments for metastatic cancers are few, this is a potentially important area of cancer research and drug development.

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