Intellect Neurosciences Inc. (OTCBB: ILNS) is a biopharmaceutical company engaged in the discovery and development of a new breed of innovative "disease-modifying" therapeutic drugs that are designed to slow, arrest and ultimately prevent Alzheimer's disease and other serious neurodegenerative disorders.
Intellect is focused on neurodegenerative conditions collectively known as proteinopathies such as Alzheimer's, Parkinson's and Huntington disease. Proteinopathies are caused by amyloidogenic proteins, such as amyloid beta, tau, alpha synuclein and Huntingtin. Intellect is the first company to develop antibody drug conjugates (ADCs) in which amyloid clearing antibodies are empowered by chemically linking them to molecules that offer neuroprotection, creating a single drug. The use of ADCs is one way in which Intellect is developing more effective drugs with the recognition that monotherapy may not be effective enough in treating the complex nature of proteinopathies.
A second approach being pioneered by Intellect, also based on this idea and specifically focused on Alzheimer's disease, is a bi-specific vaccine that targets both beta amyloid and a pathogenic form of tau protein. In contrast to antibodies that only target beta amyloid and have not yet proven their ability to treat mild to moderate Alzheimer's disease, the dual target vaccine being developed by Intellect has the potential to be used both prophylactically in presymptomatic patients and therapeutically in patients that are symptomatic.
Intellect Neurosciences has its origins in some of the earliest pioneering work that stimulated the development of the potential disease-modifying monoclonal antibodies that several global pharmaceutical companies have been testing as treatments for Alzheimer's disease. The intellectual property resulting from the discovery of how such antibodies could be used as treatments predates competitive strategies such that the pharmaceutical companies developing those drugs, purchased licenses to the technology from Intellect. The company remains ahead of the curve with respect to next-generation therapies, as it has developed multiple distinctive platform technologies that are generating drug candidates for a wide variety of diseases.
The company developed OX1, a multimodal antioxidant molecule, through preclinical and human safety trials before licensing the program to ViroPharma. ViroPharma has said it plans to enter Phase 2 clinical trials in patients with Friedreich's Ataxia, an orphan indication, in 2013. Intellect could receive in excess of $100 million in milestone payments from ViroPharma and, if approved, royalties from sales over many years.
Intellect's preclinical R&D pipeline is based on two proprietary platform technologies, CONJUMAB-A and RECALL-VAX and includes the following drug candidates:
CONJUMAB-A: Empowered Antibodies for the Treatment of Proteinopathies
N01-OX2 is a first-in-class ADC. It is a humanized monoclonal antibody specific for beta amyloid protein that is empowered to deliver on-site neuroprotection by its conjugation to melatonin. The goal of N01-OX2 is to reduce the oxidative stress that leads to cellular inflammation and damage. N01-OX2 is being developed for the treatment of age-related macular degeneration (AMD), the leading cause of blindness in people over the age of 55. AMD therapies generate $4 billion annually, even though the few approved treatments don't cure the disease and offer only modest improvements in vision for most patients. N01-OX2 also has potential applications for diabetic retinopathy, glaucoma, traumatic brain injury and Alzheimer's disease.
T01-OX2 is an ADC comprised of a monoclonal antibody selective for oligomeric toxic forms of tau protein and is empowered with neuroprotection by its conjugation to melatonin. T01-OX2 is expected to reduce tau pathology and has potential for the treatment of Alzheimer's disease, Frontotemporal dementia and also has potential applications to treat ophthalmology indications.
RECALL VAX: A chimeric peptide vaccine comprised of a human B cell epitope linked to a bacterial T cell epitope to produce highly specific vaccines against one or more amyloidogenic proteins.
RV03 is a first-in-class bi-specific vaccine targeting both beta amyloid and delta tau. Delta tau is a shorter form of the tau protein. It is especially toxic to nerve cells and precedes the formation of neurofibrillary tangles. RV03 has potential for the treatment of Alzheimer's disease and Frontotemporal dementia. http://www.intellectns.com/
Intellect's preclinical R&D pipeline is based on four proprietary platform technologies: ANTISENILINÒ, CONJUMAB™, OLIGOTOPE™ and RECALL-VAX™
ANTISENILIN®: Free-end Specific Amyloid Beta Antibodies for Treatment of AD
IN-N01 is a humanized a high-affinity, stabilized, IgG4 therapeutic antibody that binds the amino terminus of amyloid beta without binding to the amyloid precursor protein (APP).
Antibodies exist in several isoforms; IgG1 antibodies have the strongest potential to induce inflammation while IgG4 has the lowest potential. IN-N01 is designed to promote the clearance of monomeric, oligomeric and plaque forms of amyloid beta, which accumulate in the brains of Alzheimer's patients or following traumatic brain injury and in the retina of the eye in patients with age-related macular degeneration, diabetic neuropathy and glaucoma.
CONJUMAB™: Empowered Antibodies for the Treatment of Proteinopathies
CONJUMAB-A is a first-in-class antibody drug conjugate for treatment of proteinopathies. IN-N01 has been empowered to deliver on-site neuroprotection by its conjugation to melatonin. Melatonin is a potent free radical scavenger and is an inhibitor of beta amyloid aggregation and previously shown to counteract the neurotoxicity associated with amyloid beta. Compounds based upon CONJUMAB-A are designed to reduce the oxidative stress and promote clearance of beta amyloid that is central to cellular inflammation and damage.
CONJUMAB-A is being developed for the treatment of age-related macular degeneration (AMD), the leading cause of blindness in people over the age of 55. CONJUMAB-A also has potential applications for diabetic retinopathy, glaucoma, traumatic brain injury, and Alzheimer's disease.
OLIGOTOPE™: Protein oligomer selective antibodies and methods of making them using chemically cross-linked stabilized aggregates as immunogens
TOC-1, our first compound utilizing the OLIOGOTOPE platform, is a murine monoclonal antibody selective for neurotoxic tau oligomers or aggregates considered to be the earliest pathogenic form of tau. Intellect plans to test TOC-01 as potential therapeutic for Alzheimer's disease and other tauopathies such as Frontotemporal dementia.
TauC3 specifically targets the neoepitope that is formed following cleavage of intact tau protein by proteolytic enzymes known as "executioner" caspases. This pathological process is stimulated by an accumulation of amyloid beta in the brain of Alzheimer's patients. It is believed that the smaller cleaved tau, referred to as delta tau, is especially toxic and prone to form tangles inside nerve cells and occurs early in the pathogenesis of the disease so antibody-mediated removal of delta tau would be expected to prevent the irreversible damage to nerve cells.
RECALL VAX™: Chimeric peptide vaccine platform incorporating bacterial and human epitopes to target neoepitopes in pathological proteins
RV03, our first compound generated on the RECALL-VAX platform, is a first-in-class bi-specific vaccine targeting both beta amyloid and delta tau. Delta tau is a shorter form of the tau protein. It is especially toxic to nerve cells and precedes the formation of neurofibrillary tangles. RV03 has potential for the treatment of Alzheimer's disease and Frontotemporal dementias.
Intellect Neurosciences has two preclinical programs it is developing internally.
One program under the RECALL-VAX platform has yielded two AD vaccine drug candidates, RV01 and RV02. RECALL-VAX™ has the potential to delay or prevent the development of Alzheimer's in those who are at risk by stimulating patients' immune systems to produce antibodies that clear amyloid betas and prevent further accumulation and deposition. Many view a vaccine of this nature, which is analogous to a flu shot, as the ultimate quest in Alzheimer's research.
Additionally, CONJUMAB-A is Intellect's newly introduced platform technology for a novel class of therapeutics for treatment of Alzheimer's disease and other proteinopathies based on antibody-drug conjugates (ADCs). The new ADC- based technology has the potential to improve on current methods of passive immunotherapy by increasing clearance of amyloid proteins while delivering potent cytoprotective molecules to sites of damage in the brain and other organs. CONJUMAB-A is designed to reduce inflammation caused by amyloidosis while avoiding vasogenic edema, a side effect of plaque dissolution that occurs in some patients. The company's lead CONJUMAB-A candidate is IN-N01-OX2, a non-activating, stabilized IgG4 humanized antibody specific for beta amyloid protein conjugated to melatonin, which is a naturally occurring molecule with potent anti-oxidant and anti-fibrillogenic properties.
The Company has applied for a patent for its CONJUMAB-A technology. Intellect has the exclusively license to certain patents granted by the USPTO to NYU School of Medicine and the University of South Alabama Research Foundation specifically covering the use of melatonin for the treatment of Alzheimer's disease and other types of amyloidosis. The CONJUMAB-A platform is applicable to a broad range of diseases including, Alzheimer's, Parkinson's, Huntington's, Age-Related Macular Degeneration, Glaucoma, Cerebral Angiopathy, Frontotemporal Dementia, Progressive Supranuclear Palsy, Pick's disease, Cortical Basal Degeneration and Peripheral Amyloidosis.
SHP622:Shire will continue to analyze these results and determine an optimal path forward for this program.
"SHP622 for the treatment of FA SHP622 is in development for the treatment of Friedreich’s Ataxia and was acquired as part of the acquisition of ViroPharma. This product is a naturally occurring small molecular weight compound (indole-3-propionic acid) that prevents oxidative stress OX1 by a combination of hydroxyl radical scavenging activity and metal chelation. Phase 1 studies in healthy adults were completed in 2010. The drug was found to be generally well tolerated, and the pharmacokinetics revealed that the drug was rapidly absorbed and distributed in the body after oral administration. A Phase 1b trial to evaluate the safety, tolerability, pharmacokinetics, and pharmacodynamics of SHP622 in adults with FA has been completed. SHP622 was generally safe and well tolerated when administered as single and multiple PO doses. There were no severe treatment emergent adverse events (“TEAEs”) or deaths reported in either the single or multiple dose groups, and the majority of TEAEs were of mild severity. However, one subject in the multiple dose group was discontinued due to a possibly related treatment emergent of angina pectoris. Overall, there were no clinically meaningful differences between SHP622 and placebo or between the single and multiple dose groups. The mean terminal elimination half-life ranged between 7.36 and 10.33 hours across all dose groups. Intersubject variability appeared to be low to moderate. Shire will continue to analyze these results and determine an optimal path forward for this program. " Page 42: http://api40.10kwizard.com/cgi/convert/pdf/Shireplc-20160504-10Q-20160331.pdf?ipage=10913903&xml=1&quest=1&rid=23§ion=1&sequence=-1&pdf=1&dn=1
New Peer Reviewed Article Describes Role of TauC3 in AD Transgenic Mice
TauC3 Mice Showed Drastic Learning and Spatial Memory Deficits and Reduced Synaptic Density at a Young Age (2-3 months); First Published Study Describing Role of TauC3 in Vivo; Study Independently Conducted by Scientists at School of Biological Sciences, Seoul National University, Seoul, Republic of Korea
January 07, 2016: 08:36 AM ET
Intellect Neurosciences, Inc. (OTCQB: ILNS) ("Company" or "Intellect"), a biopharmaceutical company engaged in the discovery and development of disease-modifying therapeutic agents for the treatment and prevention of rare neurodegenerative conditions, today announced the publication of a scientific study of the role of TauC3 in transgenic mice in the prominent, peer-reviewed journal, Neurobiology of Disease [2015, 87:19-28]. The paper, titled "Caspase-cleaved tau exhibits rapid memory impairment associated with tau oligomers in a transgenic mouse model," describes the findings of a recent preclinical study of caspase-cleaved tau in a transgenic mouse model. The study marks the first published study indicating that the expression of caspase-cleaved tau (TauC3) in mice induces early memory deficit and reduced synaptic density. In addition, the study demonstrated that hyperphosphorylated tau oligomers and aggregates appear in TauC3 mice showing memory deficit and that aggregation blocker or rapamycin rescues memory impairment and reduces tau oligomers in TauC3 mice. The TauC3 mouse in the study is an Alzheimer's disease (AD) model used elucidate tau oligomer-associated pathogenesis and to evaluate therapeutic drug options. The paper was co-authored by scientists at the Global Research Laboratory, School of Biological Sciences, Seoul National University, Seoul, and the Department of Neurology and Neuroscience & Cell Biology, University of Texas, Galveston, Texas.
As described in the Abstract of the article, in neurodegenerative diseases like AD, tau forms neurofibrillary tangles, composed of tau protein. In the AD brain, activated caspases cleave tau at the 421th Asp, generating a caspase-cleaved form of tau, TauC3. Although TauC3 is known to assemble rapidly into filaments in vitro, the role of TauC3 in vivo remains unclear. In the study, scientists generated a transgenic mouse expressing human TauC3 using a neuron-specific promoter. The researchers found that human TauC3 was expressed in the hippocampus and cortex. Interestingly, the TauC3 mice showed drastic learning and spatial memory deficits and reduced synaptic density at a young age (2-3months). Notably, tau oligomers as well as tau aggregates were found in TauC3 mice showing memory deficits. These results suggest that TauC3 facilitates early memory impairment in transgenic mice accompanied with tau oligomer formation, providing insight into the role of TauC3 in the AD pathogenesis associated with tau oligomers and a useful AD model to test drug candidates.
Dr. Troy Rohn, Professor, Department of Biological Sciences, Boise State University, Boise, Idaho, Intellect's lead scientific advisor, commented, "This study is exciting because it provides proof-of-concept data regarding the role of TauC3 in various tauopathies. It is well known that the generation of the TauC3 fragment by caspases occurs in numerous neurodegenerative diseases and may facilitate the pathology associated with these disorders. However, to date, whether the TauC3 fragment itself can lead to behavioral deficits has been lacking. This in vivo study confirms that hypothesis and strongly supports targeting the TauC3 fragment as a therapeutic strategy in various diseases in which the fragment is produced."
In 2012, Intellect licensed a unique TauC3 antibody from Northwestern University, acquiring exclusive global rights to develop and commercialize the antibody. In January 2014, the Company announced top line data showing initial proof of concept in a preclinical Alzheimer's model, indicating the antibody's potential to be disease modifying. The study was conducted in collaboration with Dr. Frank LaFerla, University of California, Irvine, Chancellor's Professor and Chair, Neurobiology and Behavior School of Biological Sciences, Director, Institute for Memory Impairments and Neurological Disorders. The data showed that the TauC3 monoclonal antibody effectively engaged the target and reduced certain phosphorylated pathological forms of tau, indicating that the treatment with the peripherally administered antibody had an effect in the brain and potentially is disease modifying. In 2015, Intellect sponsored a research collaboration with Professor Bradley T. Hyman MD, PhD, Director, Massachusetts Alzheimer's Disease Research Center & Co-Director, Massachusetts General Hospital Memory Disorders Unit and John B. Penney Jr. Professor of Neurology, Harvard Medical School. The research project was designed to examine the detailed molecular mechanism affecting propagation of tau pathology and was aimed at developing a novel treatment for Alzheimer's disease and other tauopathies. The research yielded important data regarding target engagement, which the Company plans to use to strengthen its proprietary position in the TauC3 antibody. Intellect is planning to test its TauC3 monoclonal antibody in several orphan disease preclinical models in early 2016.
Jan. 16, 2014, 3:20 a.m. EST
Intellect Neurosciences, Inc. Announces Positive Top Line Data Showing Proof of Concept in a Preclinical Alzheimer's Model for Its TauC3 Monoclonal Antibody Indicating its Potential to be Disease Modifying
Study indicates potential for TauC3 to be disease-modifying.
ENGLEWOOD CLIFFS, N.J., Jan 16, 2014 (GLOBE NEWSWIRE via COMTEX) -- via PRWEB - Intellect Neurosciences, Inc. ILNS +1.37% , a biopharmaceutical company engaged in the discovery and development of disease-modifying therapeutic and diagnostic agents for the treatment of Alzheimer's and other neurological diseases, today announced it obtained proof of concept in a preclinical Alzheimer's model for its TauC3 monoclonal antibody indicating its potential to be disease modifying. The study was conducted in collaboration with University of California, Irvine's Dr. Frank LaFerla, Chancellor's Professor and Chair, Neurobiology and Behavior School of Biological Sciences, Director, Institute for Memory Impairments and Neurological Disorders as well as Dr. Kim Green and his team. The data showed that the TauC3 antibody effectively engaged the target and reduced certain phosphorylated pathological forms of Tau indicating that the treatment with the peripherally administered antibody had an effect in the brain and is able to be disease modifying. The investigators aim to publish the full data in a peer-reviewed scientific journal.
TauC3 specifically targets a fragment of Tau protein that is believed to result from beta-amyloid ("Aβ") induced cleavage of full length Tau by apoptotic caspase enzymes, early in the disease process leading to neuronal loss. The truncated tau ("delta tau", aka "TauC3" fragment) displays increased rates and extents of polymerization in vitro compared with wild-type full-length tau, suggesting a role for tau truncation in neurofibrillary tangle formation. Recently Professor Bradley Hyman's laboratory at Harvard Medical School also showed a critical role of this fragment in oligomeric Aβ-induced synaptic loss near Aβ plaques in the AD brain providing a mechanistic link between oligomeric Aβ and tau in AD (Polydoro et al., AAIC 2013, P2-048).
"We are gratified by this compelling proof of concept data independently generated by our collaborators at the University of California, Irvine." said Mr. Elliot Maza, a director of Intellect Neurosciences. "These important new data and growing strength of our revitalized patent portfolio, including the recent patent Allowance from the USPTO in relation to the TOC-1 monoclonal antibody targeting oligomeric tau, underscore our leadership in this area and should attract significant renewed interest from the pharmaceutical industry".
Intellect Neurosciences holds worldwide development and commercialization rights to TauC3 under an exclusive license agreement with Northwestern University. Also, Intellect owns pending patent applications relating to antibodies targeting fragments of Tau in the brain for treatment of Alzheimer's and other tauopathies (e.g. Chain, 2011: Treatment of Tauopathies, WO 2012/106363 published November 15, 2012).
About Intellect Neurosciences
Intellect Neurosciences, Inc. develops innovative approaches aimed at arresting or preventing Alzheimer's disease and other neurodegenerative diseases, with a specific focus on proteinopathies. Intellect's pipeline includes, antibodies and neuroprotective antibody drug conjugates. For more information, please visit http://www.intellectns.com .
Safe Harbor Statements Regarding Forward Looking Statements
The statements in this release and oral statements made by representatives of Intellect Neurosciences relating to matters that are not historical facts (including, without limitation, those regarding future performance or financial results, the timing or potential outcomes of research collaborations or clinical trials, any market that might develop for any of Intellect's product candidates and the sufficiency of Intellect's cash and other capital resources) are forward-looking statements that involve risks and uncertainties, including, but not limited to, the likelihood that actual performance or results could materially differ, that future research will prove successful, the likelihood that any product in the research pipeline will receive regulatory approval in the United States or abroad, or Intellect's ability to fund such efforts with or without partners. Intellect undertakes no obligation to update any of these statements. Readers are cautioned not to place undue reliance on these forward-looking statements, which speak only as to the date hereof. Accordingly, any forward-looking statements should be read in conjunction with the additional risks and uncertainties detailed in Intellect's filings with the Securities and Exchange Commission, including those discussed in Intellect's Annual Report on Form 10-K (file no. 333-128226) filed on October 15, 2013 and Quarterly Report on Form 10-Q (file no. 333-128226), filed on November 19, 2013.
This article was originally distributed on PRWeb. For the original version including any supplementary images or video, visithttp://www.prweb.com/releases/2014/1/prweb11489644.htm
Intellect Neurosciences Obtains Patent Allowance From the United States Patent and Trademark Office in Relation to Its TOC-1 Monoclonal Antibody Selective for Pre-Fibrillar Tau Aggregates
Published: November 14, 2013
NEW YORK, Nov. 14, 2013 (GLOBE NEWSWIRE) -- Intellect Neurosciences, Inc.(OTCBB:ILNS), a biopharmaceutical company engaged in the discovery and development of disease-modifying therapeutic and diagnostic agents for the treatment of Alzheimer's and other neurological diseases, today announced it obtained a Notice of Allowance from the United States Patent and Trademark Office (USPTO). The patent allowance is in relation to TOC-1, a monoclonal antibody that selectively binds neurotoxic pre-fibrillar tau aggregates which are important pathological components in Alzheimer's disease (AD) and other neurodegenerative tauopathies. Intellect previously obtained development and commercialization rights to TOC-1 under an exclusive license agreement withNorthwestern University.
New findings regarding the antibody were recently published in the Journal of Alzheimer's Disease in a paper titled, "TOC1: Characterization of a Selective Oligomeric Tau Antibody" written by Lester Binder, Ph.D., the Abbott Laboratories, Duane and Susan Burnham Research Professor of Genetic and Molecular Medicine, at Northwestern University. These data underscore its potential as a powerful biochemical tool that can be used to better investigate the involvement of tau in neurodegenerative diseases.
"The new patent allowance from the USPTO awarded to Intellect Neurosciences is of particular significance in view of the considerable attention being given to the important role of pre-fibrillar aggregated forms of tau in the pathogenesis of AD and other tauopathies such as cortico-basal ganglia degeneration and progressive supranuclear palsy," said Professor Moses V. Chao, Molecular Neurobiology Program Skirball Institute of Biomolecular Medicine NYU School of Medicine. "TOC-1 reacts with brain pathology in each of these types of diseases and is undoubtedly an important biochemical tool that will be extremely helpful to academic and industry researchers".
The Company is exploring ways to commercialize TOC-1, initially as an essential tool which is required for research, but also for further development clinically.
About Intellect Neurosciences
Intellect Neurosciences, Inc. develops innovative approaches aimed at arresting or preventing Alzheimer's disease and other neurodegenerative diseases, with a specific focus on proteinopathies. Intellect's pipeline includes therapeutic vaccines, antibodies and neuroprotective antibody drug conjugates. For more information, please visitwww.intellectns.com.
Study Evaluating the Safety,Tolerability and Efficacy of PF-04360365 in Adults With Probable Cerebral Amyloid Angiopathy
This study is ongoing, but not recruiting participants.
Information provided by (Responsible Party):
First received: March 4, 2013
Last updated: May 14, 2015
Last verified: May 2015
Indolepropionic acid - ViroPharma
Alternative Names: Indole-3-propionic acid; IPA - ViroPharma; OX-1; Oxigon; SHP622; VP-20629
Latest Information Update: 28 Aug 2015
At a glance
- OriginatorNew York University; University of South Alabama
DeveloperIntellect Neurosciences; Shire ViroPharma
ClassAntidementias; Indoles; Neuroprotectants; Propionic acids; Small molecules
Mechanism of ActionAmyloid inhibitors; Antioxidants; Chelating agents; Free radical scavengers; Protein aggregation inhibitors
- Orphan Drug StatusNo
On Fast trackNo
New Molecular EntityYes
Highest Development Phases
- Phase IFriedreich's ataxia
No development reportedAlzheimer's disease
Most Recent Events
- 01 Jul 2015Shire ViroPharma completes a phase I trial in Friedreich's ataxia in USA (NCT01898884)
11 Mar 2014ViroPharma is now called Shire ViroPharma
24 Jan 2014ViroPharma has been acquired by Shire
STATEMENT ON A NONPROPRIETARY NAME ADOPTED BY THE USAN COUNCIL
PRONUNCIATION poe nez' oo mab
THERAPEUTIC CLAIM Treatment of Alzheimer’s disease
1. Immunoglobulin G2, anti-(human ß-amyloid) (human-mouse monoclonal PF-04360365
clone 9TL heavy chain), disulfide with human-mouse monoclonal PF-04360365
clone 9TL light chain, dimer
2. Immunoglobulin G2, anti-(human amyloid beta A4 protein (Alzheimer disease amyloid
protein, ABPP, APPI, preA4, protease nexin-II)); humanized mouse monoclonal
PF-04360365 clone 9TL des-442-lysine(CH3107-K)-[325-serine(CH299A>S),326-
serine(CH2100P>S)]?2 heavy chain (130-219')-disulfide with humanized mouse
monoclonal PF-04360365 clone 9TL ? light chain, dimer (218-218'':219-219'':222-
MOLECULAR FORMULA C6552H10158N1730O2090S52
MOLECULAR WEIGHT 148.3 kDa
TRADEMARK None as yet
MANUFACTURER Pfizer, Inc.
CODE DESIGNATION PF-04360365, RN-1219
CAS REGISTRY NUMBER 1178862-65-1
ILNS Security Details
| ||Market Value1 ||$456,497 ||a/o Jan 26, 2016 |
| ||Authorized Shares ||2,000,000,000 ||a/o Nov 04, 2015 |
| ||Outstanding Shares ||5,567,037 ||a/o Nov 04, 2015 |
| ||-Restricted ||Not Available |
| ||-Unrestricted ||Not Available |
| ||Held at DTC ||Not Available |
| ||Float ||4,717,663 ||a/o Nov 04, 2015 |
| ||Par Value ||Not Available |
Capital Change=shs decreased by 1 for 50 split Pay date=04/12/2011.
Capital Change=shs decreased by 1 for 250 split. Pay date=02/11/2015.