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.