Indoleamine 2,3-dioxygenase 1

Indoleamine 2,3-dioxygenase 1

On October 20, 2014, New Link Genetics Corporation (Ames, IA) announced that it had entered into an exclusive worldwide license agreement with Genentech/Roche for the development of NLG919, an IDO (indoleamine-pyrrole 2,3-dioxygenase) inhibitor under development by NewLink. The two companies also initiated a research collaboration for the discovery of next generation IDO/TDO (tryptophan-2,3-dioxygenase) inhibitors.

Under the terms of the agreement, NewLink will receive an upfront payment of $150 million, and may receive up to over $1 billion in milestone payments, as well as royalties on any sales of drugs developed under the agreement. Genentech will also provide research funding to NewLink in support of the collaboration. Other details of the agreement are outlined in NewLink’s October 20, 2014 press release.

The target of NewLink’s iDO/TDO program, and of its collaboration with Genentech, is cancer immunotherapy. As we discussed in our September 2014 report, Cancer Immunotherapy: Immune Checkpoint Inhibitors, Cancer Vaccines, and Adoptive T-cell Therapies (published by Cambridge Healthtech Institute), Genentech is developing the PD-L1 inhibitor MPDL3280A, which is in Phase 2 trials in renal cell carcinoma and urothelial bladder cancer, and in Phase 1 trials in several other types of cancer. PD-L1 inhibitors such as MPDL3280A constitute an alternative means to PD-1 inhibitors of blocking The PD-1/PD-L1 immune checkpoint pathway.

Two PD-1 inhibitors, pembrolizumab (Merck’s Keytruda) and nivolumab (Medarex/Bristol-Myers Squibb’s Opdivo) are in a more advanced stage of development than MPDL3280A and other PD-L1 inhibitors. The FDA approved pembrolizumab for treatment of advanced melanoma in September 2014, and nivolumab was approved in Japan in July 2014, also for treatment of advanced melanoma.

MPDL3280A, pembrolizumab, and nivolumab are monoclonal antibody (MAb) drugs. Another MAb immune checkpoint inhibitor, ipilimumab (Medarex/BMS’s Yervoy) was approved for treatment of advanced melanoma in 2011. Ipilimumab, which was the first checkpoint inhibitor to gain regulatory approval, targets CTLA-4.

As summarized in the October 20, 2014 New Link press release, IDO pathway inhibitors constitute another class of immune checkpoint inhibitors. However, they are small-molecule drugs. The IDO pathway is active in many types of cancer both within tumor cells and within antigen presenting cells (APCs) in tumor draining lymph nodes. This pathway can suppress T-cell activation within tumors, and also promote peripheral tolerance to tumor associated antigens. Via both of these mechanisms, the IDO pathway may enable the survival, growth, invasion and metastasis of malignant cells by preventing their recognition and destruction by the immune system.

As also summarized in this press release, NewLink has several active IDO inhibitor discovery and development programs, and has also discovered novel tryptophan-2,3-dioxygenase (TDO) inhibitors. As with IDO, TDO is expressed in a significant proportion of human tumors, and also functions in immunosuppression. TDO inhibitors are thus potential anti-cancer compounds that might be used alone or in combination with IDO inhibitors.

The kynurenine pathway and its role in tumor immunity and in neurodegenerative diseases

IDO and TDO are enzymes that catalyze the first and rate-limiting step of tryptophan catabolism through the kynurenine pathway (KP). The resulting depletion of tryptophan, an essential amino acid, inhibits T-cell proliferation. Moreover, the tryptophan metabolite kynurenine can induce development of immunosuppressive regulatory T cells (Tregs), as well as causing apoptosis of effector T cells, especially Th1 cells.

A 2014 review by Joanne Lysaght Ph.D. and her colleagues on the role of metabolic pathways in tumor immunity, and the potential to target these pathways in cancer immunotherapy also highlights the role of IDO and kynurenine in upregulation of Tregs and in the phenomenon of T-cell exhaustion, in which T cells chronically exposed to antigen become inactivated or anergic.

In our cancer immunotherapy report, we discuss the role of Tregs and T-cell exhaustion in immune suppression in tumors, and the role of anti-PD-1 agents in overcoming these immune blockades. Targeting the IDO and TDO-mediated tryptophan degradation pathway may thus complement the use of anti-PD-1 (and/or anti-PD-L1) MAb drugs, and potentially lead to the development of combination therapies.

We have discussed the kynurenine pathway of tryptophan catabolism in another context in our July 11, 2011 article on this blog. This article discusses the potential role of kynurenine pathway metabolites in such neurodegenerative diseases as Alzheimer’s disease (AD) and Huntington’s disease (HD).

As discussed in that article, HD and AD patients have elevated levels of two metabolites in the KP–quinolinic acid (QUIN) and 3-hydroxykynurenine (3-HK)–in their blood and brains. Both of these metabolites have been implicated in pathophysiological processes in the brain. In contrast, kynurenic acid (KYNA), which is formed in a side arm of the KP by conversion of kynurenine by the enzyme kynurenine aminotransferase, appears to be neuroprotective.

Researchers have been targeting kynurenine 3-monooxygenase (KMO) in order to induce a more favorable ratio of KYNA to QUIN. As a result, they have discovered a drug candidate, JM6. They proposed to first conduct clinical trials in HD, since the cause of HD is much better understood than for AD, and disease progression in placebo controls is better characterized than for AD. Moreover, clinical trials in AD are notoriously long and expensive.

A 2014 review of targets for future clinical trials in HD lists JM6 as a “current priority preclinical therapeutic targets in Huntington’s disease”. It also contains an updated discussion of the mechanism of action of JM6.

NewLink’s IDO inhibitor development program

NewLink presented progress posters on its IDO inhibitor development program at the American Society for Clinical Oncology (ASCO) 2014 annual meeting. These described trials in progress, which did not yet have any results. As described in these presentations, NewLink’s most advanced IDO inhibitor, indoximod is in:

  • a Phase 1/2 clinical trial in combination with ipilimumab in advanced melanoma
  • a Phase 1/2 study in combination with the alkylating agent temozolomide (Merck’s Temodar) in primary malignant brain tumors
  • a Phase 2 study in combination with the antimitotic agent docetaxel (Sanofi’s Taxotere) in metastatic breast cancer
  • a Phase 2 study in which indoximod is given subsequent to the anticancer vaccine sipuleucel-T (Dendreon’s Provenge) in metastatic castration-resistant prostate cancer.

The company also presented a progress poster on a first-in-humans Phase 1 study of NLG919, in solid tumors. NLG919, the focus of NewLink’s alliance with Genentech, is the second product candidate from NewLink’s IDO pathway inhibitor technology platform.

The major theme of NewLink’s ASCO meeting presentations is thus the development of the company’s IDO inhibitors as elements of combination immuno-oncology therapies with MAb immune checkpoint inhibitors, cancer vaccines, and cytotoxic chemotherapies.

In this connection, NewLink also hosted a panel discussion on combination therapies entitled “Points to Consider in Future Cancer Treatment: Chemotherapy, Checkpoint Inhibitors and Novel Synergistic Combinations” at the ASCO meeting. The collaboration of NewLink with Genentech will provide the opportunity for the two companies to test combinations of IDO inhibitors with Genentech’s PD-L1 inhibitor MPDL3280A.

Might targeting T-cell metabolism be used to enhance cancer immunotherapy?

In their 2014 review, Dr. Lysaght and her colleagues outline changes in metabolism as T-cells become activated, and differences in metabolism between various T-cell subsets (e.g., effector T cells, Tregs, exhausted or anergic T cells, and memory T cells). These researchers propose devising means to modulate T-cell metabolism in order to enhance anti-tumor immunity. However more research needs to be done in order to make such approaches a reality. In the meantime, development of IDO and TDO inhibitors is already in the clinic, providing the possibility of a metabolic approach to cancer immunotherapy.

________________________________

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.

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

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

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

Rodin Therapeutics

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

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

Sage Therapeutics

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

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

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

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

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

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

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

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

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

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

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

Sage’s pipeline

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

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

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

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

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

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

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

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

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

EnVivo Pharmaceuticals

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

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

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

Outlook

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

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

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

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

__________________________________________

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

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.

Hypothalamic nuclei on one side of the hypothalamus, in 3-D. Source: Was a bee. http://bit.ly/13o91HU

Hypothalamic nuclei on one side of the hypothalamus, in 3-D. Source: Was a bee. http://bit.ly/13o91HU

The Biopharmconsortium Blog has been following novel developments in anti-aging medicine and biology for several years. Much of the interest in this field has centered around sirtuins and potential drugs that modulate these protein deacetylase enzymes. Recently–on May 29, 2013–we published our latest blog article on sirtuins.

However, we have long been aware that studies in the biology of aging reveal that lifespan is controlled by sets of complex, interacting pathways. Sirtuins represent only one control point in these pathways, which might not be the most important one.

Now comes a research article in the 9 May 2013 issue of Nature, on the role of inflammatory pathways in the hypothalamus of the brain in the control of systemic aging. This article (Zhang et al.) was authored by Dongsheng Cai, M.D., Ph.D. of the Albert Einstein College of Medicine (Bronx, NY) and his colleagues. The same issue of Nature contains a News and Views mini-review of Zhang et al., authored by Dana Gabuzda, M.D. and Bruce A. Yankner, M.D., Ph.D. (Harvard Medical School).

The role of the neuroendocrine system–and other tissues–in the regulation of lifespan

The News and Views review begins with the statement that classic studies of aging-related pathways in Caenorhabditis elegans by such pioneering researchers as Cynthia Kenyon and Leonard Guarente, as well as later studies in Drosophila suggested that genetic changes that affect the function of nutrient-sensing and environmental-stress-sensing neurons can regulate aging of the entire organism.

In our May 11, 2010 Biopharmconsortium Blog article that reviewed the aging field, we focused on biochemical pathways that may affect lifespan, not the specific tissues in which they act. That article included a link to a 25 March 2010 review in Nature by Dr. Kenyon, entitled “The genetics of ageing”. As we said in our article, that review “discussed the panoply of aging-related pathways in worms, flies, and mice, especially the insulin/insulin-like growth factor-1 (IGF-1) and TOR pathways, as well as several other biomolecules and biological processes”. However, Dr. Kenyon’s article, and several of the references she cites, also deal with the tissues in which these pathways act.

Numerous leading researchers have found evidence that IGF signaling in the C. elegans nervous system regulates longevity. A 2008 article by Laurent Kappeler (INSERM U893, Hopital Saint-Antoine, Paris, France) and his colleagues referenced in the Kenyon review also found evidence that IGF-1 receptors in the brain control lifespan and growth in mice via a neuroendocrine mechanism.

Nevertheless, there is evidence that the insulin pathway in such tissues as the intestine of C. elegans can also regulate lifespan in a non-cell autonomous manner. These studies indicate that changes in insulin pathway gene expression in one tissue–perhaps with certain tissues (the neuroendocrine system, endoderm, adipose tissue) being especially important–results in coordinated changes in insulin pathway activity among all the relevant tissues of the organism. These studies complicate the determination that the neuroendocrine system is the locus of longevity regulation by the insulin pathway and other aging-related pathways.

The potential role of the hypothalamus in the regulation of mammalian aging

Based on the results of studies of neural regulation of lifespan in C. elegans and Drosophila, Zhang et al. asked whether the hypothalamus may have a fundamental role in the process of aging and in regulation of lifespan. The hypothalamus is a region of the brain that is critically involved in regulating such functions as growth, reproduction and metabolism. An important function of the hypothalamus is to link the nervous system to the endocrine system via the pituitary gland, an endocrine gland that is intimately associated with the hypothalamus, and is the master regulator of the endocrine system. According to the Gabuzda and Yankner News and Views article, the mammalian hypothalamus has similar functions to the nutrient-sensing and environmental-stress-sensing neurons of C. elegans and Drosophila that have been implicated in regulation of aging in those organisms.

Zhang et al. studied the increase in NF-κB (nuclear factor kappa-light-chain-enhancer of activated B cells) in the hypothalamus of mice as a function of aging. NF-κB is a transcriptional regulator that is involved in cellular responses to stress, and in particular mediates inflammatory responses; it has also been implicated as a driver of aging-related gene expression in mice. The researchers found that the numbers of microglia (central nervous system cells that functionally resemble macrophages) in the hypothalamus increased as the mice aged. These microglia exhibited inflammatory function, expressing activated NF-κB and overproducing tumor necrosis factor alpha (TNFα). In turn, secretion of TNF-α (an inflammatory cell-signaling molecule) stimulated NF-κB-mediated signaling in hypothalamic neurons.

Zhang et al. showed–via using genetic models such as specific gene knockouts–that activation of the NF-κB pathway in hypothalamic neurons accelerated the aging process and shortened lifespan. Conversely, inhibiting the NF-κB pathway resulting in delayed aging and increased lifespan. They further showed that activation of neural NF-κB signaling resulted in declines in gonadotropin-releasing hormone (GnRH) levels. Since GnRH stimulates adult neurogenesis in the hypothalamus and hippocampus, decline in GnRH secretion suppressed neurogenesis. Conversely, hypothalamic administration of GnRH reversed aging-associated declines in neurogenesis.

The researchers also treated old mice with GnRH peripherally (i.e., via subcutaneous injection, rather than via hypothalamic administration). Such treatment with GnRH resulted in amelioration of aging-related changes in muscle, skin, and the brain. Notably, GnRH treatment resulted in amelioration of  aging-related cognitive decline. The researchers hypothesize that peripherally-administered GnRH (a neurohormone that is secreted by specific neurons in the hypothalamus) exerts its anti-aging effects via its action on one or more of the GnRH-responsive brain regions that lack a blood–brain barrier, such as the median eminence, subfornical organ and area postrema.

As pointed out by Gabuzda and Yankner in their News and Views article, a 2011 study showed that dendrites of hypothalamic GnRH-producing neurons extend through the blood–brain barrier. These dendrites are able to sense inflammatory and metabolic signals in the blood. Gabuzda and Yankner hypothesize that inflammatory signals in the periphery (which are known to be associated with aging, and such aging-related conditions as insulin resistance, obesity, and cardiovascular disease) may feed back via these dendrites to downregulate GnRH production in the hypothalamus. Such a feedback loop might be analogous to the coordination between peripheral and neural tissues of aging-related pathways seen in C. elegans by Dr. Kenyon and other researchers.

Despite these hypotheses (as pointed out by Zhang et al.), the mechanisms by which GnRH (especially peripherally-administered GnRH) exerts its anti-aging effects are not well-understood, and need further investigation. The researchers conclude, however, that the hypothalamus can integrate NF-κB-directed immunity and the GnRH-driven neuroendocrine system to program development of aging.

With respect to anti-aging therapy, the study of Zhang et al. suggests two potential therapeutic strategies–inhibition of inflammatory microglia in the hypothalamus, and restoration of levels of GnRH. Given the difficulties of specific targeting of microglia in the hypothalamus (across the blood-brain barrier), the second of these alternatives seems to be the more feasible of these strategies.

The GnRH receptor agonist leuprolide as a potential therapy for Alzheimer’s disease

GnRH has a short half-life in the human body, and thus cannot be used as a medication unless it is delivered via infusion pumps. However, the GnRH receptor agonist leuprolide acetate (AbbVie’s Lupron, Sanofi’s Eligard) has been approved by the FDA since 1985. It is available as a slow-release implant (AbbVie’s Lupron Depot) or a formulation delivered via subcutaneous/intramuscular injection. Leuprolide is approved for treatment of prostate cancer, endometriosis, fibroids, and several other conditions. Although leuprolide is the largest-selling GnRH agonist, there are other approved nanopeptide GnRH agonists, such as goserelin (AstraZeneca’s Zoladex) and histrelin (Endo’s Supprelin and Vantas).

As discussed in a 2007 review by Wilson et al., leuprolide acetate has also been under investigation as a therapeutic for Alzheimer’s disease (AD). Studies in mice indicated that leuprolide modulated such markers of AD as amyloid-β (Aβ) and tau phosphorylation, and prevented AD-related cognitive decline. For example, in a 2006 study in a classic mouse model of AD (Tg2576 amyloid precursor protein transgenic mice carrying the Swedish mutation) by Casadesus et al., the researchers demonstrated that leuprolide acetate halted Aβ deposition and improved cognitive performance.

Although Casadesus et al. attributed the efficacy of leuprolide to its suppression of the production of luteinizing hormone, Wilson et al. speculated that it might be possible that leuprolide works directly via GnRH receptors in the brain. Those receptors had only been identified in 2006 by the first author of the review, Andrea Wilson, and her colleagues at the University of Wisconsin. The direct action of leuprolide on GnRH receptors in the brain to ameliorate aging-related cognitive decline–and perhaps AD itself–is consistent with the 2013 findings of Zhang et al.

Development of a leuprolide-based Alzheimer’s disease treatment by Voyager Pharmaceuticals

As discussed in the review of Wilson et al., a Phase 2 clinical trial in women with mild-to-moderate AD receiving acetylcholinesterase inhibitors and implanted subcutaneously with leuprolide acetate showed a stabilization in cognitive decline at 48 weeks. A subsequent study in men (clinical trial number NCT00076440) was documented on ClinicalTrials.gov between 2004 and 2007. However, no results of this trial were ever posted.

The clinical development of a formulation of leuprolide (known as Memryte) as a treatment for AD had been carried our by a small Durham, NC biotech company called Voyager Pharmaceutical Corporation. Memryte was a biodegradable implant filled with leuprolide acetate, designed to treat mild to moderate AD.

After struggling to develop their treatment for nearly a decade, Voyager ran out of money, and stopped its R&D operations in 2007. In 2009, Voyager acquired a new set of investors, and changed its name to Curaxis. In 2010, Curaxis did a reverse stock merger, which enabled it to become a publicly traded company. Also in 2010, Curaxis attracted $25 million from a Connecticut investment firm. Nevertheless, Curaxis noted in its SEC filing that it would need “at least $48 million through 2014” to complete development of Memryte and file a New Drug Application (NDA) with the FDA.

However, Curaxis failed to find the needed funding and/or a partner to complete its development plans. In July 2012, the company filed for bankruptcy.

The failure of Voyager/Curaxis as a company does not necessarily mean that leuprolide may not be a viable treatment for AD. However, as we noted in earlier Biopharmconsortium Blog articles, development of an AD therapy is an enormously long, expensive, and risky proposition, which is beyond the capacity of a small biotech (such as Voyager/Curaxis) unless it attracts a Big Pharma partner. Moreover, treating AD once it reaches the “mild to moderate” stage is unlikely to work.

As we discussed in our April 5, 2013 article, the FDA has been working with industry and academia to develop guidelines for clinical trials of agents to treat the very earliest stages of AD, before the development of extensive irreversible brain damage. If another company endeavors to develop a formulation of leuprolide (or another GnRH pathway activator) for AD, it would probably do best to aim to treat very early-stage disease using the new proposed FDA guidelines.

Conclusions

Why should drug discovery and development researchers and executives be interested in anti-aging research? No pharmaceutical company will be able to run a clinical trial with longevity as an endpoint. However, the hope is that an “anti-aging” drug approved for treatment of one disease of aging will have pleiotropic effects on multiple diseases of aging, and will ultimately be found to increase lifespan or “healthspan” (the length of a person’s life in which he/she is generally healthy and not debilitated by chronic diseases). Numerous pharmaceutical and biotechnology companies have been working on discovery and development of treatments for major aging-related diseases, such as type 2 diabetes and AD. It would be truly spectacular if a new drug for (for example) type 2 diabetes would also be effective against AD.

Moreover, their are also major aging-related conditions, such as sarcopenia (aging-related loss of muscle mass, quality, and strength) that are not normally targets for drug development, but are major causes of disability and death. It would also be amazing if an anti-aging drug aimed at (for example) AD would be effective against sarcopenia as well. Note that Zhang et al. showed that GnRH treatment ameliorated aging-related changes in muscle in their mouse models. (Update: The statement that sarcopenia is “not normally a target for drug development” is no longer true. See our September 4, 2013 article on this blog, “Novartis’ Breakthrough Therapy For A Rare Muscle-Wasting Disease”.)

The study of Zhang et al. constitutes a new approach to anti-aging biology and target and drug discovery. However, aging biology is complex and not well-understood. Researchers will need to study many aspects of aging-related pathways for anyone to be able to discover and develop successful anti-aging drugs. This includes, of course, the sirtuin field, as well as the role of mitochondria in aging related metabolic imbalance, as exemplified by a recent paper in Cell.  As discussed in our other Biopharmconsortium Blog articles on anti-aging biology and medicine, there are many other avenues for investigation as well.

__________________________________________

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.

Pittsburgh compound B staining in AD. Source: National Institute on Aging/NIH.

Pittsburgh compound B staining in AD. Source: National Institute on Aging/NIH.

In our February 28, 2013 article on the Biopharmconsortium Blog, we discussed the FDA’s February 7, 2013 Draft Guidance for Industry entitled “Alzheimer’s Disease: Developing Drugs for the Treatment of Early Stage Disease”.

This document had been distributed for comment purposes only, and the FDA has been seeking public comment on the draft guidance for 60 days following publication.

As we discussed, by issuing this Draft Guidance, the FDA added its voice to that of an ever-increasing segment of the scientific community that calls for a new focus on conducting clinical trials in early-stage Alzheimer’s disease (AD). This is in order to  focus industry R&D on developing treatments for patients whose disease is in a stage prior to the development of extensive irreversible brain damage. It is in this early stage of disease in which researchers believe that new drugs have the best chance of providing benefits to patients, by preventing further damage to the brain.

In our February 28, 2013 article, we also discussed several clinical trials being carried out by industry and academic researchers in early-stage AD. These trials should allow the scientific and medical community to answer the question as to whether treating patients with pre-AD or very early-stage AD with anti-amyloid MAb drugs can have a positive effect on the course of the disease, and slow or prevent cognitive decline.

Readers of our article may have noticed that the February 7, 2013 Draft Guidance was somewhat vague or confused. That is because there is currently no evidence-based consensus as to which biomarkers might be appropriate to support clinical findings in trials in early AD. Moreover, in “pre-AD” or very early-stage AD (i.e., before the onset of overt dementia) disease-related impairments are extremely challenging to assess accurately. Thus both measuring clinical outcomes and assessment via biomarkers in very early-stage AD are fraught with difficulty, making determination of drug efficacy very difficult.

In issuing the Draft Guidance, The FDA appeared to be seeking guidance from industry and from the academic community on how these issues might be resolved. As we said in our article, the early-stage AD trials now in progress might help the scientific and medical community, and the FDA, with issues of evaluation of biomarkers and clinical outcome measures in determining disease prognosis and the efficacy of drug treatments.

More recently–on March 13, 2013–the FDA proposed a further modification of its proposed guidelines for regulation of early-stage AD therapeutics. This was published online in an article in the New England Journal of Medicine (NEJM), entitled “Regulatory Innovation and Drug Development for Early-Stage Alzheimer’s Disease”, by Nicholas Kozauer, M.D. and Russell Katz, M.D. (As we stated in our earlier article, Dr.Katz is the director of the Division of Neurology Products in the FDA’s Center for Drug Evaluation and Research. Dr. Kozauer is a Clinical Team Lead in the same division of the FDA.)

The new proposal attempts to deal with some of the apparent confusion in the February 7, 2013 Draft Guidance, and to facilitate the development and approval of new drugs for early-stage AD. The NEJM article notes that traditional measures of AD drug efficacy at the FDA had included assessment both of improved cognition and improvements in function. Specifically, as stated by a New York Times article discussing the new FDA proposal, “cognition” refers to such mental processes as memory and reasoning (as assessed by various tests), and “function” refers to performing such day-to-day activities as cooking, dressing or bathing.

In the FDA’s March 13, 2013 NEJM article, the authors note that researchers and regulatory agencies “simply do not yet have drug-development tools that are validated to provide measures of function in patients with Alzheimer’s disease before the onset of overt dementia”. Thus, although one can test early-stage AD patients for improvements in cognition with the appropriate tests, testing for deficits and improvements in function is extremely difficult.

The authors of the NEJM article therefore suggest that it might be feasible that a drug for treating early-stage AD be approved via the FDA’s accelerated approval pathway, on the basis of assessment of cognitive outcome alone. The agency’s accelerated-approval pathway allows drugs that address an unmet medical need to be approved on the basis of a surrogate or an intermediate clinical endpoint–in this case, a sensitive measure of improvement in cognition. Drugs approved via “accelerated approval” must be subjected to postmarketing studies to verify the clinical benefit. This regulatory pathway might facilitate the approval of treatments that appear to be effective in early AD, when patients might be expected to derive a greatest benefit than after the development of overt dementia.

With respect to selection of patients for trials in early-stage AD, the authors of the NEJM article suggest that (based on “the consensus emerging within the AD research community”) clinical diagnosis of early cognitive impairment be combined with appropriate biomarkers. These biomarkers might include brain amyloid load [as measured by positron-emission tomography (PET)] and cerebrospinal fluid levels of β-amyloid and tau proteins. The FDA places a high priority on efforts by the researchers to qualify such biomarkers in clinical trial design in early-stage AD.

The author of the New York Times article, veteran science and medicine reporter Gina Kolata, says that the FDA’s new proposal could “help millions of people at risk of developing [AD] by speeding the development and approval of drugs that might slow or prevent it.”

She also says that the proposal could be a boon for the pharmaceutical industry and AD researchers. They have often been hampered by regulations that left them uncertain of how to get drugs tested and approved for early-stage AD. Not only might anti-AD therapies provide greater benefit to patients with early-stage AD than with later stage disease, but clinical trials in early-stage AD would have a greater potential for success–provided that researchers had appropriate means of determining efficacy in early-stage AD. The new FDA proposal may increase the likelihood of identifying such appropriate means.

As pointed out in the Times article, several leading AD researchers agree, with some important caveats. For example, AD researcher P. Murali Doraiswamy, M.D. (Duke University School of Medicine) said that the new proposed regulations would lead to more clinical trials, and more motivation now to invest in the AD field. However, many companies never manage to do postmarking studies required for drugs given accelerated approval, and such studies might not be randomized clinical trials as required in gaining approval of the drugs in the first place.

Sean Bohen, M.D., Ph.D. (Senior Vice President for Early Development at Genentech) was very positive about the proposed new FDA policy, but wondered how researchers could develop appropriate tests to identify subtle cognitive changes in early AD or pre-AD. Nevertheless, he said, “We have to start somewhere.”

Thus clinical trials in early-stage AD, and development of regulatory frameworks for approval and postmarketing studies of agents that emerge from these trials, 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 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.