Biopharmconsortium Blog

Expert commentary from Haberman Associates biotechnology and pharmaceutical consulting.

Posts filed under: Neurodegenerative diseases

“Our Promise to Nicholas”, Batten disease, and gene therapy

 

Wayland MA Source: http://bit.ly/1N1TyRk

Wayland MA Source: http://bit.ly/1N1TyRk

Russell’s Garden Center, on Route 20, a family-owned business established in 1876, is a unique Wayland MA institution. When you shop at Russell’s and approach the check-out counter with your plants, flowers, or other purchases, you will see a donation box for a rare-disease charity called “Our Promise to Nicholas Foundation”.

This charity is named for Nicholas R. Dainiak, a Bedford MA boy who died on his 11th birthday in 2014, after “a courageous six year battle with Batten’s disease”. The primary mission of the foundation is to raise funds and create partnerships aimed at promoting awareness, providing education, and developing translational research in Batten disease.

One of the events that the Foundation sponsors in order to raise funds and awareness is the John Tanner Memorial 5-K Run and Walk, which this year took place on October 4, 2015 in Wayland. This event memorializes both Nicholas and John Tanner. John Tanner was a competitive runner who devoted all of his races over 5 years to raising awareness about Nicholas and Batten disease. He was also a long-time employee of Russell’s Garden Center—hence the Russell’s and Wayland connection to the Foundation. John Tanner died unexpectedly while running the NYC half marathon in the spring of 2013.

Batten disease

Batten disease is a very rare, fatal, autosomal recessive neurodegenerative disorder that usually begins in childhood. Juvenile Batten disease is one of a group of disorders known as neuronal ceroid lipofuscinoses (NCLs). NCLs may be caused by one of over 400 different mutations. They affect the nervous system with vision loss, seizures, movement disorders, slow learning, altered thought processes, and cognitive decline.

Although Batten disease was originally used to describe only the juvenile form of NCL the term “Batten disease” is now widely used to refer to all forms of NCL, including adult-onset disease. Juvenile NCL, the most prevalent form of Batten disease, has been linked to mutations in the CLN3 gene. Late infantile NCL has been linked to mutations in NCL2.

Batten disease is a type of lysosomal storage disease. The CLN3 gene codes for a protein called battenin, which is found principally in lysosomes and in endosomes. The protein’s function is currently unknown. The CLN2 gene codes for a lysosomal enzyme called tripeptidyl peptidase 1 (TPP1), which is an acid protease.

Mutations in CLN2, CLN3, and other Batten disease genes result in the accumulation of lipofuscins in the tissues of the body. Lipofuscins are lipoproteins that form autofluorescent ceroid (i.e., waxy) deposits throughout the body of Batten disease patients.  Lipopfuscin deposits can sometimes be detected visually in the back of the eye. As the disease progresses, the deposits in the retina appear more pronounced, and ophthalmologists see circular bands of different shades of pink and orange in the patient’s optic nerve and retina. Ceroid lipofuscins are a hallmark of Batten disease, and appear to cause disease symptoms.

Juvenile Batten disease has an estimated incidence between 0.5 – 8 per 100,000 live births, with an average of 1.2. Despite its rarity, juvenile Batten disease appears to be the most common form of pediatric neurodegenerative disease. In addition to Batten disease patients, there are approximately 440,000 asymptomatic people in the United States who are carriers of juvenile Batten disease who have one copy of a mutated version of the CLN3 gene.

As with other rare diseases, a typical Batten disease patient may visit 8 physicians and receives 2 to 3 misdiagnoses before being correctly diagnosed. This may take many years. In the case of Nicholas, he had several misdiagnoses and mis-treatments over the early course of his disease, from age 4 to age 5. It was a ophthalmologist who finally correctly diagnosed Nicholas with Batten disease.

Relationship between Batten disease and more common neurodegenerative diseases

The written material next to the donation box for “Our Promise to Nicholas” in Russell’s Garden Center claims that study of Batten disease may lead to a greater understanding of such neurodegenerative diseases of aging as Alzheimer’s and Parkinson’s disease. Some of the symptoms and consequences of Batten disease resemble those of Alzheimer’s and Parkinson’s. Nevertheless, Batten disease is classified as a lysosomal storage disease, while Alzheimer’s and Parkinson’s are thought to be caused via other mechanisms.

However, some researchers see common mechanisms in the pathobiology of neurodegenerative lysosomal storage diseases such as Batten and of other neurodegenerative diseases such as Alzheimer’s and Parkinson’s. Specifically, these include impairment of autophagy and increase in cytoplasmic protein aggregation. For example, some researchers have found relationships between mutations in the Alzheimer’s disease-related protein presenilin 1 and lysosomal dysfunction.

Since clinical trials of drugs for Alzheimer’s disease have so far been unsuccessful, study of alternative mechanisms for the pathogenesis of Alzheimer’s may be useful in developing new ways of addressing drug discovery for this devastating and all-too-common disease.

Discovery and development of gene therapies for Batten disease

The “Our Promise to Nicholas” website has a page entitled “Where your donations go”. According to that Web page, Nicholas’ disease was caused by a splice mutation in CLN2, which blocked production of TPP1. This is the most common mutation in children with the late infantile subtype of Batten Disease.

The same Web page discusses a gene therapy program led by Beverly Davidson, Ph.D. (then at the University of Iowa, Iowa City, IA), which had been supported by Our Promise To Nicholas Foundation. As of April 2014, Dr. Davidson joined the Children’s Hospital of Philadelphia (CHOP). At that time, Dr. Davidson became the director of CHOP’s Center for Cellular and Molecular Therapeutics. She has also continued her research on gene therapy for neurodegenerative diseases, including Batten disease, other neurologic lysosomal storage disorders, Huntington’s and Alzheimer’s diseases, and others.

While at Iowa, and continuing at CHOP, Dr. Davidson and her colleagues were investigating the use of adeno-associated virus (AAV) vectors carrying a functional TPP1 gene in treatment of late infantile Batten disease in animal models.

On November 11, 2015, Spark Therapeutics (Philadelphia, PA) announced that its first gene therapy program targeting a central nervous system (CNS) disease will target late infantile Batten disease. In that press release, it also announced that a report published in the 11 November issue of Science Translational Medicine provides preclinical proof of principle for Spark’s gene therapy, known as SPK-TPP1. The preclinical study, in a naturally occurring dog model, was led by Dr. Davidson at CHOP.

The study demonstrated the potential of a one-time administration of SPK-TPP1 to delay onset and progression of Batten disease in the dog model. SPK-TPP1 consists of Spark’s AAV2 vector carrying a functional TPP1 gene. The preclinical study showed that one-time administration of SPK-TPP1 to the ependymal cells of the brain ventricular system produced steady expression of the enzyme in the cerebrospinal fluid, and throughout the CNS. It also resulted in delayed onset of clinical symptoms and disease progression, protection from cognitive decline and extension of lifespan, as compared to untreated controls.

Based on these results, Spark plans to initiate Investigational New Drug Application (IND)-enabling studies in 2015.

Our November 2015 book-length report, Gene Therapy: Moving Toward Commercialization (published by Cambridge Healthtech Institute), contains a discussion of gene therapy vectors, including AAV. It also highlights Spark Therapeutics as a leader in AAV-based gene therapy and in gene-therapy treatments for retinal diseases. Spark’s technology platform had been developed over a 20-year period at CHOP.

As also discussed in our November 16, 2015 article on this blog, Spark has recently completed a Phase 3 pivotal trial of SPK-RPE65, a gene therapy for treatment of inherited retinal diseases (IRDs) caused by mutations in the gene for RPE65. SPK-TPP1 uses the same AAV2 vector as SPK-RPE65, and will utilize the same manufacturing processes. AAV2 has a neural tropism. Since the retina is an extension of the brain, researchers can utilize AAV2 vectors to target both tissues.

Conclusions

On the Web page “Where your donations go”, Dr. Davidson says that funding from “family foundations such as Our Promise to Nicholas Foundation” has provided much needed support. Their donations have allowed cutting-edge research to be conducted in a timely manner, rather than months or years after researchers develop the ideas for these studies. Moreover, interacting with Batten disease families is especially motivating, and the advisory role of scientists who review grant proposals for family foundations is valuable as well.

Our Promise to Nicholas is far from the only Batten disease “family foundation”. Other families of patients with juvenile and adult-onset Batten disease have formed foundations to fund research and awareness. For example, there are Nathan’s Battle Foundation and the Batten Disease Support and Research Association (BDSRA). Our Promise to Nicholas participated in the 2015 BDSRA Annual Conference, and worked together with other Batten disease family foundations to provide nursing care and childcare for the event. Thus when Dr. Davidson refers to “family foundations”, she is referring to several such organizations.

Dr. Davidson also pointed out that grant funding from the National Institutes of Health (NIH) has dramatically decreased in recent years due to Federal budget constraints. This has especially affected research on rare diseases such as Batten disease. Dr. Davidson believes that “family foundation support is being increasingly relied upon to fill a growing void in NIH funding”.

Funding of Dr. Davidson’s research by Our Promise to Nicholas Foundation and other family foundations has resulted in a gene therapy R&D program that has been adopted by one of the world’s leading gene therapy companies, Spark Therapeutics. Spark (in collaboration with Dr. Davidson’s group at CHOP) is taking its Batten disease program into the clinic, and intends to commercialize SPK-TPP1. Spark is also using its Batten disease program as the basis for its larger neurodegenerative disease program. Thus Our Promise to Nicholas Foundation has much to be proud of.

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

The Genentech/NewLink alliance, the IDO/TDO pathway, and targeting metabolism for immuno-oncology

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.

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

Neuroscience companies sprout up in Boston

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.

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

Will Novartis lead a pharma industry return to neuroscience R&D?

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.

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

Does inflammation in the brain cause aging?

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.

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

FDA proposes accelerated approval of early-stage Alzheimer’s drugs based on cognitive improvement alone

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.

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

FDA publishes Draft Guidance on developing drugs for early stages of Alzheimer’s disease

 

Normal and Alzheimer's brains compared.

Normal and Alzheimer’s brains compared.

Once again, approaches to improving clinical trials for candidate disease-modifying drugs for Alzheimer’s disease (AD) are in the news. On February 7, 2013, the FDA issued a Draft Guidance for Industry entitled “Alzheimer’s Disease: Developing Drugs for the Treatment of Early Stage Disease”.

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

The wording of the Draft Guidance illustrates the extreme difficulty of defining populations with pre-AD or very early-stage AD, and of demonstrating the efficacy of a drug in ameliorating early-stage disease, and/or in preventing its progression to later-stage disease. The document states that the FDA is “open to considering the argument that a positive biomarker result (generally included as a secondary outcome measure in a trial) in combination with a positive finding on a primary clinical outcome measure may support a claim of disease modification in AD.”

However,  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) mild 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 extremely difficult. The FDA thus appears to be seeking guidance from industry and from the academic community on how these knotty problems might be solved.

The move toward conducting clinical trials in early-stage AD patients

By issuing the Draft Guidance, the FDA adds 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 AD. We discussed this trend in our August 19, 2012 and August 28, 2012 articles on the Biopharmconsortium Blog.

As we discussed, this trend is driven in part by the Phase 3 failures of Pfizer/Janssen’s bapineuzumab and Lilly’s solanezumab in 2012. Now–in February 2013–Russell Katz, M.D. (director of the Division of Neurology Products in the FDA’s Center for Drug Evaluation and Research) says, “The scientific community and the FDA believe that it is critical to identify and study patients with very early Alzheimer’s disease before there is too much irreversible injury to the brain. It is in this population that most researchers believe that new drugs have the best chance of providing meaningful benefit to patients.”  In line with this statement, the FDA refused to entertain Lilly’s  secondary analysis of early stage patients in the solanezumab study that we discussed in our August 28, 2012 blog article. Instead, the FDA mandated that Lilly conduct a new Phase 3 trial that will exclude the moderate-stage patients who hadn’t responded, and focus only on early-stage patients.

Recent news on clinical trials in early-stage AD

Despite the difficulties highlighted in the Draft Guidance in conducting clinical trials in early-stage AD patients, three research groups are actually conducting such trials. We outlined these studies in our August 28, 2012 blog article, and discussed one of these studies, the one begin carried out by Genentech, in greater detail in our August 19 2012 article.

The three studies are:

  • Roche/Genentech’s Phase 2a trial of its its anti-amyloid MAb crenezumab, in presymptomatic members of a large Colombian kindred who harbor a mutation in presenilin 1 (PS1) that causes dominant early−onset familial AD.
  • Studies conducted in conjunction with the Dominantly Inherited Alzheimer Network (DIAN), a consortium led by researchers at Washington University School of Medicine (St. Louis, MO). This study will include people with mutations in any of the three genes linked to early-stage, dominantly-inherited AD–PS1, PS2, and amyloid precursor protein (APP). Initial studies focused on changes in biomarkers and in cognitive ability as a function of expected age of AD onset in people with these mutations. These included changes in concentrations of amyloid-β1–42 (Aβ42) in cerebrospinal fluid (CSF), and amyloid accumulation in the brain. In the first stage of the actual trial, three drugs (which have not yet been selected) will be tested in this population, and changes in biomarkers and cognitive performance will be followed.
  • The Anti-Amyloid Treatment of Asymptomatic Alzheimer’s (A4) trial, will involve treating adults without mutations in any of the above three genes, whose brain scans show signs of amyloid accumulation. A4 is thus designed to study prevention of sporadic AD (by far the most common form of the disease). It will enroll 500 people age 70 or older who test positive on a scan of amyloid accumulation in the brain. (This is in contrast to the two trials in subjects with gene mutations, who are typically in their 30s or 40s.) A4 will also have a control arm of 500 amyloid-negative subjects. Amyloid-positive and control subjects will be entered into a three-year double-blind clinical trial that will look at changes in cognition with drug treatment. The A4 researchers [led by Reisa Sperling, Brigham and Women’s Hospital/Harvard University (Boston, MA), and Paul Aisen, University of California, San Diego] planned to select a drug for testing by December 2012.

Now there is more recent news on two of these trials.

1. On December 13, 2012, the Los Angeles Times reported that Genentech and its collaborators [affiliated with the University of Antioquia medical school (Medellin, Colombia), the University of California at Los Angeles (UCLA), and the Banner Alzheimer’s Institute (Phoenix, AZ)] will begin their $100 million clinical trial of crenezumab with 100 Colombians who carry the PS1 mutation in the spring of 2013. Genentech is contributing $65 million of the study’s $100-million cost. The NIH and the Banner Alzheimer’s Institute (Phoenix, AZ) are financing the remainder.

This story was also reported on December 14, 2012 by Fierce Biotech.

The design of the trial calls for 100 additional patients in Colombia with the same Alzheimer’s-related gene to receive a placebo, and an equal number of other at-risk patients without the gene to take crenezumab.  A branch of the trial will include U.S. patients as well. A “branch study” will also be conducted at UCLA, where researchers have discovered a similar genetic disposition among members of an extended family from Jalisco, Mexico. Some 30 individuals from this family who have immigrated to Southern California could participate. Around 150 other U.S. patients with similar mutations will also participate in the trial.

The trial is designed to provide evidence that targeting amyloid with crenezumab at an early stage or even before patients show signs of dementia can have a positive effect on the course of disease.

2. On January 18, 2013, Fierce Biotech reported that the researchers conducting the A4 study have chosen Lilly’s solanezumab as as the first therapeutic drug candidate to be evaluated in the trial. The A4 trial’s principal investigator, Reisa Sperling said that the researchers chose solanezumab (after considering a number of anti-amyloid drugs) because the compound has a good safety profile, and appeared to show a modest clinical benefit in the mild AD patients in Lilly’s Phase 3 trial. The A4 researchers’ confidence in solanezumab grew when this was confirmed via an independent academic analysis by the Alzheimer’s Disease Cooperative Study (ADCS), a consortium of academic Alzheimer’s disease clinical trial centers. The ADCS, which was established by NIH, will help facilitate the A4 trial.

The A4 researchers hope that starting treatment with solanezumab before symptoms are present, as well as treating for a longer period of time, will slow cognitive decline and ultimately prevent AD dementia.

After the failure of solanezumab in Lilly’s own Phase 3 studies, and the FDA’s rebuff of the company’s secondary analysis of early stage patients, the A4 study’s choice of solanezumab gives the drug a new lease on life. Meanwhile, Lilly will be continuing its own clinical trial program for solanezumab.

Conclusions

The three clinical trials discussed in this article 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. The studies may also 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. Given the large size and rapid growth of the at-risk population, finding safe and efficacious disease-modifying preventives and treatments for AD is of increasing urgency.

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

Identification of a novel Alzheimer’s disease pathway provides potential new avenues for drug discovery

 

Neurofibrillary tangle.

Neurofibrillary tangle.

In August and September of 2012, we published three articles on Alzheimer’s disease on the Biopharmconsortium Blog:

Subsequent to the publication of our articles–on 21 November, 2012–the Wellcome Trust announced the identification of a novel pathway involved in the pathogenesis of Alzheimer’s disease (AD). This research was led by Professor Simon Lovestone and Dr Richard Killick (Kings College, London U.K.), and was published in the online edition of Molecular Psychiatry on 20 November 2012. The Wellcome Trust helped to fund the research.

As we have discussed in earlier articles on this blog, the dominant paradigm among AD researchers and drug developers is that the disease is caused by aberrant metabolism of amyloid-β (Aβ) peptide, resulting in accumulation of neurotoxic Aβ plaques. This paradigm is known as the “amyloid hypothesis”. AD is also associated with neurofibrillary tangles (NFTs) which are intracellular aggregates of hyperphosphorylated tau protein. In contrast to the amyloid hypothesis, some AD researchers have postulated that NFT formation is the true cause of AD. The new research links amyloid toxicity to the formation of NFTs, and identifies potential new drug targets.

The new study is based on the discovery of the role of clusterin–an extracellular chaperone protein–in sporadic (i.e., late-onset, non-familial) AD. The gene for clusterin, CLU, has been identified as a genetic risk factor for sporadic AD via a genome-wide association study published in 2009. Clusterin protein levels are also increased in the brains of transgenic mouse models of AD that express mutant forms of amyloid precursor protein (APP), as well as in the serum of humans with early stage AD.

The researchers first studied the relationship between Aβ and clusterin in mouse neuronal cells in culture. Aβ rapidly increases intracellular concentrations of clusterin in these cells. Aβ-induced increases in clusterin drives transcription of a set of genes that are involved in the induction of tau phosphorylation and of Aβ-mediated neurotoxicity. This pathway is dependent on the action of a protein known as Dickkopf-1 (Dkk1), which is an antagonist of the cell-surface signaling protein wnt. The transcriptional effects of Aβ, clusterin, and Dkk1 are mediated by activation of the wnt-planar cell polarity (PCP) pathway. Among the target genes in the clusterin-induced DKK1-WNT pathway that were identified by the researchers are EGR1 (early growth response-1), KLF10 (Krüppel-like factor-10) and NAB2 (Ngfi-A-binding protein-2)–all of these are transcriptional regulators. These genes are necessary mediators of Aβ-driven neurotoxicity and tau phosphorylation.

The researchers went on to show that transgenic mice that express mutant amyloid display the transcriptional signature of the DKK1-WNT pathway, in an age-dependent manner, as do postmortem human AD and Down syndrome hippocampus. (Most people with Down syndrome who survive into their 40s or 50s suffer from AD.) However, animal models of non-AD tauopathies (non-AD neurodegenerative diseases associated with pathological aggregation of tau, and formation of NFTs, but no amyloid plaques) do not display upregulation of transcription of genes involved in the DKK1-WNT pathway, nor does postmortem brain tissue of humans with these diseases.

The Kings College London researchers concluded that the clusterin-induced DKK1-WNT pathway may be involved in the pathogenesis of AD in humans. They also hypothesize that such strategies as blocking the effect of Aβ on clusterin or blocking the ability of Dkk1 to drive Wnt–PCP signaling might be fruitful avenues for AD drug discovery. According to the Wellcome Trust’s 21 November 2012 press release, Professor Lovestone and his colleagues have shown that they can block the toxic effects of amyloid by inhibiting DKK1-WNT signaling in cultured neuronal cells. Based on these studies, the researchers have begun a drug discovery program, and are at a stage where potential compounds are coming back to them for further testing.

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

Alzheimer’s disease–where do we go from here?

 

New Alzheimer’s disease model, the CVN mouse

Our August 19, 2012 and our August 28, 2012 articles on this blog focused on the latest developments in Alzheimer’s disease (AD) drug development. To summarize the conclusions of the articles:

  • The results of a new genetic study by DeCode Genetics and its collaborators strongly support the amyloid hypothesis of AD, and especially the hypothesis that reducing the β-cleavage of APP [e.g., by use of an inhibitor of β-secretase (also known as the β-site APP cleaving enzyme 1, or BACE1)] may protect against the disease.
  • Nevertheless, in Phase 3 trials of two anti-amyloid monoclonal antibody (MAb) drugs in patients with mild to moderate AD–Pfizer/Janssen’s bapineuzumab (often called “bapi” for short) and Lilly’s solanezumab–the drugs failed their primary cognitive and functional endpoints.
  • Roche/Genentech, as well as two academic consortia, have begun clinical trials of anti-amyloid MAb drugs in asymptomatic patients with mutations that predispose them to develop AD, or in asymptomatic patients with amyloid accumulation. These studies are based on the hypothesis that the reason for the failure of anti-amyloid MAb drugs in clinical trials has been that the patients being treated had suffered extensive, irreversible brain damage. Treating patients at a much earlier stage of disease with these agents might therefore be expected to be more successful.

Analyses of the data from the Phase 3 studies of both bapi and solanezumab will be presented in scientific meetings in October 2012. An academic research consortium will present its independent analysis of the data from the EXPEDITION studies of solanezumab at the American Neurological Association (ANA) meeting in Boston on October 8, 2012, and at the Clinical Trials on Alzheimer’s Disease (CTAD) meeting in Monte Carlo, Monaco, on October 30, 2012.

According to a September 11, 2012 news article in Drug Discovery & Development, researchers who conducted the Phase 3 trials of bapi found evidence that the drug stabilized amyloid plaque in the brain and may have ameliorated further nerve damage in patients treated with the drug. This finding is among the results to be presented in the October meetings.

Development of BACE1 inhibitors

Strictly speaking, the results of the DeCode Genetics study most strongly support the development of BACE1 inhibitors. In our August 28, 2012 article, we link to a 2010 review that includes a discussion of companies developing BACE1 inhibitors. However, we also note that the development of BACE1 inhibitors has been elusive. This is because of medicinal chemistry considerations. Specifically, it has been difficult to design a specific, high-affinity inhibitor of the BACE1 active site that can cross the blood-brain barrier and which has good drug-like ADME (absorption, distribution, metabolism and excretion) properties. Nevertheless, recently progress has been made in developing such compounds, and several companies are developing BACE1 inhibitors and have entered them into early-stage clinical trials.

Among the companies developing BACE1 inhibitors, as listed in a recent post on Derek Lowe’s In The Pipeline blog are CoMentis/Astellas, Merck, Lilly, and Takeda.

Satori Pharmaceuticals was developing γ-secretase inhibitors, but ran into safety problems

Developing γ-secretase inhibitors has been abandoned by the vast majority of companies, because of the essential role of these enzymes in the Notch pathway and other pathways involved in normal physiology. As a result, development of γ-secretase inhibitors for AD has not progressed beyond the preclinical stage.

Nevertheless, Satori Pharmaceuticals, a Cambridge, MA venture capital-backed biotech company, had been actively involved in developing γ-secretase inhibitors. Satori’s γ-secretase inhibitors were based on a proprietary scaffold derived from a compound isolated from the black cohosh plant (Actaea racemosa). The company utilized modern synthetic and medicinal chemistry to derive compounds based on this scaffold that they believed was suitable for long-term oral therapy for AD in humans. Satori’s lead compound, SPI-1865, was a potent γ-secretase modulator that decreased levels of the amyloidogenic Aβ42 peptide as well as Aβ38, increased levels of Aβ37 and Aβ39, but did not affect Aβ40. Researchers believe that decreasing Aβ42 levels in favor of shorter, less amyloidgenic A-beta forms is beneficial in treatment of AD. SPI-1865 was also selective for Aβ42 lowering over the inhibition of Notch processing, and appeared to be free of any other off-target activities.

In animal models [e.g., wild type mice and rats, and transgenic mice (Tg2576) that overexpress APP and thus have high levels of Aβ peptides] orally-administered SPI-1865 has been found to lower brain Aβ42. SPI-1865 has good brain penetration in these models, and a long half-life that should permit once a day dosing in humans.

SPI-1865 was in the preclinical stage. Satori planned to file an Investigational New Drug (IND) Application with the FDA in late 2012 with the goal of enabling initial human testing to begin in the early part of 2013.

However, in late 2012, a study in monkeys showed that Satori’s lead compound–as well as its backup compounds–disrupted adrenal function. This adverse effect was completely unexpected, and unrelated to the gamma secretase target.  As of May 30, 2013, Satori closed its doors.

Meanwhile, other companies, including Envivo Pharmaceuticals (Watertown, MA), Bristol-Myers Squibb, and Eisai continue with their R&D efforts in gamma secretase modulators for treatment of AD.

A new mouse model for AD

As Derek Lowe says in an August 31, 2012 post on “In the Pipeline” with respect to Lilly’s AD drugs, anti-amyloid MAbs, BACE1 inhibitors, and γ-secretase inhibitors are “some of the best ideas that anyone has for Alzheimer’s therapy”. Given the APP processing pathway as illustrated in the figure at the top of our August 28, 2012 article, these are the “sensible” and “logical” alternatives.

Nevertheless, there is the nagging feeling among many AD researchers that we do not understand the causes of AD, especially sporadic AD, which represents around 95% of all cases of the disease. Sporadic AD occurs in aging individuals who have normal genes for the components of the APP processing pathway. Not only do we not understand the pathobiology of sporadic AD, but we have little understanding of the normal physiological function of APP and of APP processing. Processes that may be involved in the initiation of sporadic AD may include not only those involved in Aβ production, but also those involved in Aβ clearance.

An important tool in understanding the pathobiology of AD, and potentially in developing novel therapies for the disease, would be an animal model that recapitulates the human disease as closely as possible. We published an article on AD mouse models that were designed to more closely recapitulate human AD than the most commonly used models in the September 15, 2004 issue of Genetic Engineering News. However, since the publication of our article, Carol A Colton, Ph.D. (Duke University Medical Center, Durham, NC) and her colleagues have published on their research aimed at producing an even better mouse model, known as the CVN mouse. They published their research in two articles, one in PNAS in 2006 and the other in the Journal of Neuroscience in 2008.

Charles River Laboratories (CRL) (Wilmington, MA) now offers the CVN mouse to researchers who might wish to employ it in their AD research. CRL has also recently produced a webinar (with the participation of Dr. Colton) on the CVN mouse, entitled “CVN Mouse: A More Translatable Alzheimer’s Efficacy Model”. You may access this webinar by registering at http://www.criver.com/thesource.

Genome-wide association studies (GWAS) in humans, as well as various functional studies, have implicated variants in genes involved in inflammation and immune responses in susceptibility to late-onset, sporadic AD in humans. The Colton group, noting that commonly-used mouse models of AD recapitulated human disease very poorly, looked for differences between mice and humans in innate immunity. The biggest difference they found was that expression of nitric oxide synthase 2 (NOS2) the inducible form of nitric oxide synthase, is high in mice and low in humans. NOS2 is an enzyme that produces nitric oxide (NO), a highly reactive oxidant that can serve in signal transduction, neurotransmission and in cell killing by macrophages. Microglia, the macrophages of the brain, express NOS2 and NO. The Colton group has been studying the role of microglia and oxidants and antioxidants in microglia that can produce oxidative stress in the brain in normal aging and in AD.

Because of the striking difference in NOS2 expression between mice and humans, the Colton group created a transgenic mouse AD model by crossing mice that  expressed a mutant form of human APP known as APPSwDI (APP Swedish Dutch Iowa) with NOS2 knockout (NOS2 -/-) mice. The APPSwDI transgenic mouse, a well-characterized standard AD mouse model, was chosen because it expresses low levels of APP and high levels of Aβ peptides in the brain. The APPSwDI/NOS2 -/- mouse is the CVN mouse that is available from CRL.

Unlike APPSwDI mice and other standard AD mouse models, the CVN mouse recapitulates many features of human AD as the animals age, including AD-like amyloid pathology (starting at 6 weeks of age, which is early), perivascular deposition of amyloid, AD-like tau pathology (including aggregated hyperphosphoryated tau), AD-like neuronal loss, and reduction in interneuron numbers (including NPY interneurons). Age-related cognitive (learning and memory) loss (as assessed by the radial arm water maze test) was also seen. The researchers also saw increases in immune activation and inflammation (e.g., microglial activation) over the course of the disease; this appeared to be dependent on increases in Aβ and in tau.

The researchers also used the mouse to study changes in immune-related proteins over the course of the disease. Several protein that are encoded by genes that have been associated with sporadic AD via GWAS change over time in this mouse model, including APOE (which has been known to be important in AD for a long time) and BIN1. Other proteins that change over the course of disease include the complement component C1QB, and the centrosomal protein ninein. Immune activation genes such as those that encode IL-1α and TGF-β also show changes over the course of disease in these mice. The Colton group will soon publish their work on changes in these proteins and genes in the CVN mouse in a peer-reviewed journal.

In summary, the CVN mouse more faithfully models AD-like progression than other mouse models that have been used to study AD, including those that have been used in preclinical studies of such failed drug candidates as solanezumab, bapineuzumab, Flurizan (tarenflurbil), and Alzhemed (3-amino-1-propanesulfonic acid). It also allows researchers to study the role of genes and proteins such as those identified in GWAS studies in AD, and especially in sporadic AD. (However since the CVN mouse expresses a mutant form of APP, it can not be used to study all aspects of the pathophysiology of sporadic AD, especially the initiation of the disease process.) The CVN mouse can also be used in drug discovery and preclinical studies.

One example of such drug discovery studies is being carried out by the Colton group. They have recently been studying small APOE mimetic peptides in CVN mice. The subcutaneously administered APOE mimetics were reported to significantly improve behavior, while decreasing the inflammatory cytokine IL-6, as well as decreasing neurofibrillary tangle-like and amyloid plaque-like structures. These improvements are associated with apoE mimetic-mediated increases in protein phosphatase 2A (PP2A) activity. [Decreased PP2A levels in AD may be involved in formation of neurofibrillary tangles (NFTs) which are aggregates of hyperphosphorylated tau; PP2A may also be involved in the production of Aβ peptides. The APOE mimetic are thus potential AD therapeutics.

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

Here we go again–Lilly’s Alzheimer’s drug solanezumab fails to show efficacy in Phase 3, but company is “encouraged” by secondary analysis

 

Amyloid precursor protein (APP)

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

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

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

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

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

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

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

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

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

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

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

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

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

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