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Posts Tagged ‘Roche Holding’

Proteins that control neurotransmitter release

Author & Curator: Larry H. Bernstein, MD, FCAP

Richard H. Scheller, PhD

The sec6/8 Complex Is Located at Neurite Outgrowth and Axonal Synapse-Assembly Domains

Christopher D. Hazuka, Davide L. Foletti, Shu-Chan Hsu, Yun Kee, F. Woodward Hopf, and Richard H. Scheller
Department of Molecular and Cellular Physiology, Howard Hughes Medical Institute, Stanford University School of Medicine, Stanford, California 94305-5428

The Journal of Neuroscience, February 15, 1999, 19(4):1324–1334   http://www.jneurosci.org/content/19/4/1324.full.pdf

The molecules that specify domains on the neuronal plasma membrane for the delivery and accumulation of vesicles during neurite outgrowth and synapse formation are unknown. We investigated the role of the sec6/8 complex, a set of proteins that specifies vesicle targeting sites in yeast and epithelial cells, in neuronal membrane trafficking. This complex was found in layers of developing rat brain undergoing synaptogenesis. In cultured hippocampal neurons, the sec6/8 complex was present in regions of ongoing membrane addition: the tips of growing neurites, filopodia, and growth cones. In young axons, the sec6/8 complex was also confined to periodic domains of the plasma membrane. The distribution of synaptotagmin, synapsin1, sec6, and FM1–43 labeling in cultured neurons suggested that the plasma membrane localization of the sec6/8 complex preceded the arrival of synaptic markers and was downregulated in mature synapses. We propose that the sec6/8 complex specifies sites for targeting vesicles at domains of neurite outgrowth and potential active zones during synaptogenesis. Key words: synaptogenesis; neurotransmission; secretion; exocytosis; synaptic vesicle; vesicle targeting

Targeting of vesicles to synaptic sites during development may use similar mechanisms as those involved in vesicle fusion underlying membrane outgrowth. Before contact with a postsynaptic target, axons possess mobile vesicle clusters bearing synaptotagmin, which fuse with the plasma membrane after stimulation (Matteoli et al., 1992; Kraszewski et al., 1995; Dai and Peng, 1996). Thus, growing axons must contain the molecular machinery required for constitutive exocytosis, endocytosis, and activitydependent vesicle release. However, it is unclear how vesicles become clustered at synapses. Although vesicle fusion in axons might occur anywhere along the plasma membrane, there must be membrane targets that signal the clustering of vesicles for synapse formation. Furthermore, it is unclear how sites of vesicle exocytosis are modified as the neuron forms stable contacts with postsynaptic partners.

Identification of a Novel Rab11/25 Binding Domain Present in Eferin and Rip Proteins

Rytis Prekeris*, Jason M. Davies*, and Richard H. Scheller#
JBC Papers in Press. Published on July 31, 2001 as Manuscript M106133200
http://www.jbc.org/content/early/2001/07/31/jbc.M106133200.full.pdf

Rab11, a low molecular weight GTP binding protein, has been shown to play a key role in a variety of cellular processes, including endosomal recycling, phagocytosis, and transport of secretory proteins from the TGN. In this study we describe a novel Rab11 effector, EF hands containing Rab11 interacting protein (eferin). In addition, we identify a 20 amino acid domain that is present at the C-terminus of eferin and other Rab11/25 interacting proteins, such as Rip11 and nRip11. Using biochemical techniques we demonstrate that this domain is necessary and sufficient for Rab11 binding in vitro and that it is required for localization of Rab11 effector proteins in vivo. The data suggest that various Rab effectors compete with each other for the binding to Rab11/25 possibly accounting for the diversity of Rab11 functions.

Members of the Rab/Ypt GTPase family have emerged as important regulators of vesicular trafficking (1). Rab proteins have been proposed to mediate a variety of functions, including vesicle translocation and docking at a specific fusion sites. Like all small GTPases, Rabs cycle between active (GTP bound) and inactive (GDP bound) conformations (2). In the GTP bound state, Rab proteins can bind a variety of downstream effector proteins, while GTP hydrolysis leads to a conformational change in the “switch” region that renders the Rab GTPase unrecognizable to its effector proteins (3,4). A key question in understanding the interactions between Rabs and their effectors concerns the mechanisms by which Rab GTPases specifically bind a diverse spectrum of effectors and how this is regulated by the common structural motif used as a GTP switch. Biochemical and genetic studies have identified several hypervariable regions that might be involved in determining Rab specificity, including N- and C-termini, as well as α3/β5 by guest on September 6, 2015 http://www.jbc.org/ Downloaded from loop (5,6). Indeed, the recently reported structure of Rab3a bound to a putative effector, rabphillin-3a, revealed that Rab3a/rabphillin-3a complex interacts through two main regions (7). The first consists of conformationally sensitive “switch” regions of Rab3a bound to the a1 helix and the C-terminal part of rabphillin-3a. The second involves the SGAWFF domain of rabphillin-3a which fits into a pocket formed by the three hypervariable complementary determining regions (CDRs) of Rab3a, corresponding to the N- and C-termini and α3/β5 loop. Thus, it appears that the hypervariable RabCDR are involved in determining the specificity of effector binding, while the conserved “switch” regions impart GTP dependency and binding. It remains to be determined, however, whether this paradigm also applies to other Rab/effector complexes. Rab11a, -11b, and -25 are closely related members of Rab GTPase family that have been implicated in regulating a variety of different post-Golgi trafficking pathways, such as protein recycling (8), phagocytosis (9), insulin-stimulated Glut4 insertion in the plasma membrane (10), and membrane trafficking from early endosomes to the transGolgi network (11). During the last few years several Rab11/25 interacting proteins have been identified, including Rab11BP/Rabphilin-11, Rip11, nRip11, and myosin Vb (12- 15). However, the mechanisms of their function, as well as molecular aspects of their interactions with Rab11, remain to be fully understood. In the present study, we report the identification of EF-hands containing Rab11/25 interacting protein (eferin). Furthermore, we characterized a Rab binding domain (RBD11) which is present at the Cterminus of eferin as well as other Rab11/25 binding proteins, such as Rip11 and nRip11. Using biochemical techniques we demonstrated that RBD11 is the region which encodes the specificity for Rab11/25, but is distinct from the region interacting with Rab “switch” domain, since its interactions with the Rab11/25 are not GTP-dependent.

The functional significance of the differences in Rip and eferin interactions with Rab11/25 remains to be determined. One possibility is that additional cellular factors can regulate the affinity of Rab11/25 binding to its effectors. Indeed, the recombinant full length Rip11 binds poorly to Rab11a in pull down and yeast-two hybrid assays as compared to full length endogenous Rip11 from cellular TX-100 extracts (data not shown). Furthermore, it has been previously shown that Rip11 can also interact with γSNAP and cytoskeleton (13,24). Thus, the interactions of Rips and eferin with different factors could be used as a means of differentially regulating Rab11/25 binding. Alternatively, the Rab11/25 binding motif in eferin and Rip11 might be conformationlly hidden and require activation before binding to Rab11/25. We have previously demonstrated that phosphorylation of Rip11 plays an important role in its trafficking (13). Thus, differential phosphorylation on Rab11/25 binding motifs could also play a role in regulating the binding of Rip11 and eferin to Rab GTPases. Despite to recent progress in understanding the roles of Rabs and their effectors in regulating membrane trafficking, we are only beginning to unravel the structural determinants of their function. Identification and characterization of the Rab11/25 binding regions in Rip and Eferin proteins will be of a crucial importance in understanding the molecular mechanisms involved in differential regulation of the variety of Rab11-dependent trafficking pathways.

J. Immunol. Methods
J Immunol Methods 2008 Mar 14;332(1-2):41-52. Epub 2008 Jan 14.
Genentech Inc., 1DNA Way, South San Francisco, California, 94080, United States. jagath@gene.com
Cysteines with reactive thiol groups are attractive tools for site-specific labeling of proteins. Engineering a reactive cysteine residue into proteins with multiple disulfide bonds is often a challenging task as it may interfere with structural and functional properties of the protein. Here we developed a phage display-based biochemical assay, PHESELECTOR (Phage ELISA for Selection of Reactive Thiols) to rapidly screen reactive thiol groups on antibody fragments without interfering with their antigen binding, using trastuzumab-Fab (hu4D5Fab) as a model system

Antibody-drug conjugates enhance the antitumor effects of antibodies and reduce adverse systemic effects of potent cytotoxic drugs. However, conventional drug conjugation strategies yield heterogenous conjugates with relatively narrow therapeutic index (maximum tolerated dose/curative dose). Using leads from our previously described phage display-based method to predict suitable conjugation sites, we engineered cysteine substitutions at positions on light and heavy chains that provide reactive thiol groups and do not perturb immunoglobulin folding and assembly, or alter antigen binding.

Neuron
Neuron 2008 Nov;60(3):400-1

Antibody drug conjugates (ADCs) combine the ideal properties of both antibodies and cytotoxic drugs by targeting potent drugs to the antigen-expressing tumor cells, thereby enhancing their antitumor activity. Successful ADC development for a given target antigen depends on optimization of antibody selection, linker stability, cytotoxic drug potency, and mode of linker-drug conjugation to the antibody. Here, we systematically examined the in vitro potency as well as in vivo preclinical efficacy and safety profiles of a heterogeneous preparation of conventional trastuzumab-mcc-DM1 (TMAb-mcc-DM1) ADC with that of a homogeneous engineered thio-trastuzumab-mpeo-DM1 (thioTMAb-mpeo-DM1) conjugate.

Sensory and signaling pathways are exquisitely organized in primary cilia. Bardet-Biedl syndrome (BBS) patients have compromised cilia and signaling. BBS proteins form the BBSome, which binds Rabin8, a guanine nucleotide exchange factor (GEF) activating the Rab8 GTPase, required for ciliary assembly.

The reactive thiol in cysteine is used for coupling maleimide linkers in the generation of antibody conjugates. To assess the impact of the conjugation site, we engineered cysteines into a therapeutic HER2/neu antibody at three sites differing in solvent accessibility and local charge. The highly solvent-accessible site rapidly lost conjugated thiol-reactive linkers in plasma owing to maleimide exchange with reactive thiols in albumin, free cysteine or glutathione.

The intracellular pathogenic bacterium Salmonella enterica serovar typhimurium (Salmonella) relies on acidification of the Salmonella-containing vacuole (SCV) for survival inside host cells. The transport and fusion of membrane-bound compartments in a cell is regulated by small GTPases, including Rac and members of the Rab GTPase family, and their effector proteins. However, the role of these components in survival of intracellular pathogens is not completely understood.

Nat. Med.
Nat Med 2013 Oct;19(10):1232-5
Genentech Research and Early Development, 1 DNA Way, San Francisco, California, USA.
MAbs
MAbs 2014 Jan-Feb;6(1):95-107
Multi-transmembrane proteins are especially difficult targets for antibody generation largely due to the challenge of producing a protein that maintains its native conformation in the absence of a stabilizing membrane. Here, we describe an immunization strategy that successfully resulted in the identification of monoclonal antibodies that bind specifically to extracellular epitopes of a 12 transmembrane protein, multi-drug resistant protein 4 (MRP4). These monoclonal antibodies were developed following hydrodynamic tail vein immunization with a cytomegalovirus (CMV) promoter-based plasmid expressing MRP4 cDNA and were characterized by flow cytometry.

Antibody-drug conjugates (ADCs) have a significant impact toward the treatment of cancer, as evidenced by the clinical activity of the recently approved ADCs, brentuximab vedotin for Hodgkin lymphoma and ado-trastuzumab emtansine (trastuzumab-MCC-DM1) for metastatic HER2+ breast cancer. DM1 is an analog of the natural product maytansine, a microtubule inhibitor that by itself has limited clinical activity and high systemic toxicity. However, by conjugation of DM1 to trastuzumab, the safety was improved and clinical activity was demonstrated.

Richard H Scheller, PhD

Published on 16 Sep 2014

The Keck School of Medicine of USC is the first medical school in the nation to host the Lasker Lectures, featuring recipients of the prestigious 2013 Albert Lasker Basic Medical Research Award. In this installment, Richard H. Scheller, PhD, executive vice president of Genentech research and early development, discusses breakthoughs in drug development that are turning the tide in the war against cancer.

https://www.youtube.com/watch?v=Fx54EVJMcxM

Kavli Prize 2015

Xenon Pharmaceuticals Appoints Dr. Richard H. Scheller to Its Board of Directors

Biopharmaceutical company Xenon Pharmaceuticals (NasdaqGM:XENE) reported on Monday the addition of Richard H. Scheller, PhD to its board of directors.

Most recently, Dr Scheller has served as chief science officer and head of Therapeutics at 23andMe.

Previously Dr Scheller was the executive vice president at Genentech Research and Early Development & a member of the Roche Corporate Executive Committee; chief scientific officer, executive vice president of Research and senior vice president of Research at Genentech; as well as a professor of Molecular and Cellular Physiology and of Biological Sciences at Stanford University Medical Center and an investigator of the Howard Hughes Medical Institute.

Dr Scheller is currently an adjunct professor in the Department of Biochemistry and Biophysics, School of Medicine at the University of California, San Francisco.

He has been a Director at Xenon Pharmaceuticals Inc. since March 16, 2015 and Medrio, Inc. since November 2012. He serves as a Member of the Medical and Scientific Review Board of Evotec (US), Inc. (Renovis Inc.). In 2014, he was named a trustee of Caltech. He served as a Member of Scientific Advisory Board of Intra-Cellular Therapies, Inc. and Rinat Neuroscience Corporation.

He served on numerous advisory boards including the National Advisory Mental Health Council of the National Institutes of Health. Dr. Scheller served as chairman of the Genentech Foundation’s board of directors. He is a globally recognized leader in biomedical research.

He has published over 200 papers in scientific journals, and worked in cell biology. He has received several additional awards for his work elucidating the molecular mechanisms governing neurotransmitter release, including the 2013 Albert Lasker Basic Medical Research Award, the 2014 California Institute of Technology’s Caltech Distinguished Alumni Award, the 2010 Kavli Prize in Neuroscience, and the 1997 U.S. National Academy of Sciences Award in Molecular Biology. He is a Fellow of the American Academy of Arts and Sciences. Dr. Scheller holds a Doctorate in Chemistry from the California Institute of Technology in 1980, where he was also a Postdoctoral Fellow, Division of Biology. He was also a Postdoctoral Fellow at Columbia University, College of Physicians & Surgeons. He has Bachelor’s Degree in Biochemistry in 1975 at the University of Wisconsin, Madison.

Education: 1971-1975 University of Wisconsin-Madison B.S. – Biochemistry with Honors 1975-1980 California Institute of Technology Ph.D. – Chemistry – Advisor: Eric H. Davidson 1980-1981 California Institute of Technology Postdoctoral Fellow-Division of Biology Advisor: Eric H. Davidson 1981-1982 Columbia University-College of Physicians & Surgeons Postdoctoral Fellow-Molecular Neurobiology Advisors: Richard Axel and Eric R. Kandel Industry Positions: 2001-2003 Senior Vice President – Research Genentech, Inc. 2003-2009 Executive Vice President – Research Genentech, Inc. 2008-2009 Chief Scientific Officer and Executive Vice President – Research Genentech, Inc. 2009- Executive Vice President – Genentech Research and Early Development (gRED) and Member of the Enlarged Roche Corporate Executive Committee Academic Appointments: 1982-1987 Assistant Professor, Department of Biological Sciences, Stanford University 1987-1990 Associate Professor, Department of Biological Sciences, Stanford University 1990-1993 Associate Professor, Department of Molecular and Cellular Physiology, Stanford University Associate Professor (by courtesy), Department of Biological Sciences, Stanford University

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Reporter: Aviva Lev-Ari, PhD, RN

During Investor Day, Roche Highlights Personalized Medicine as Key Area for Future Growth

September 12, 2012

As regulators and payors around the world are demanding more evidence that healthcare products improve patient outcomes and save money, Roche this week attempted to reassure investors that its strategy to develop innovative products — with a strong focus on molecularly guided personalized medicines — will place it ahead of competitors.

Through several presentations during an investor day in London, Roche officials highlighted a number of drugs for cancer, neuropsychiatric conditions, and autoimmune diseases for which the company is investigating biomarkers that can help target treatment to specific groups of patients. The company said that more than 60 percent of the compounds in its drug pipeline are currently paired with a companion diagnostic and that it has more than 200 companion diagnostic projects underway across its pharma and diagnostic business groups.

Personalized medicines are not only a major part of Roche’s plan for future growth, but they also represent a way for the company to differentiate its products from competitors. By setting its drugs apart from other me-too treatments in the marketplace, the company is hoping that its products won’t be as heavily affected by the pricing pressures currently plaguing the pharma and biotech sectors.

“Yes, regulators are very stringent. But if I look back at our most recent launches, particularly in the US, if you have true medical innovation, then regulators are very willing to bring those medicines and novel diagnostics to the market,” Roche CEO Severin Schwan said during the investor conference. He highlighted that the US Food and Drug Administration reviewed and approved the BRAF inhibitor Zelboraf for metastatic melanoma and its companion diagnostic in record time and that the recent approval of the HER2-targeted breast cancer drug Perjeta also occurred ahead of schedule (PGx Reporter 8/17/2011 and 6/13/2012).

“Likewise, if you look at the payors, there is cost pressure,” Schwan reflected, but he noted that the “innovative nature” of its portfolio helps it to “negotiate better prices with payors.”

Despite this optimistic forecast, Roche has experienced some pushback from cost-conscious national payors in Europe. For example, in June the UK’s National Institute for Health and Clinical Excellence deemed Zelboraf, which costs more than $82,000 for a seven-month treatment, too pricey. Zelboraf, which Roche launched in the US market last year and in European countries earlier this year, netted the company around $97 million in revenue for the six months ended June 30.

In an effort to battle pushback from national payors, Roche is in discussions with European governments about value-based pricing schemes for several of its products. In this regard, high priced personalized medicine drugs are well suited to these types of arrangements. David Loew, chief marketing officer at Roche, told investors that governments are increasingly developing registries to track how individual patients are doing on various treatments. This information will help governments move from a volume-based pricing model for drugs to paying for them based on the drug’s indication.

He noted that in Germany, for example, Roche has developed a payment scheme where in colorectal cancer, patients pay a certain amount for up to 10 grams of the oncologic Avastin, receive it for free for up to 12 months, and then the scheme repeats. For personalized medicines, such as Herceptin, Perjeta, T-DM1, and Zelboraf, “we will have to think about different ways of pricing those new combinations,” Loew said.

Schwan highlighted that one of the major advantages for Roche in this difficult environment is that it has both drug and diagnostic capabilities in house. This, according to Schwan, enables Roche to have significant internal capabilities in early-phase research, and makes the company attractive for partnerships, as well. Roche currently has more than 70 new molecular entities in clinical development and since 2011 there have been 25 late-stage clinical trials that have yielded positive results. The firm plans to bring three more products into late-stage clinical trials by the end of the year and would like to move 10 products into late-stage development in 2013.

On the diagnostics side, newly hired chief operating officer Roland Diggelmann said that Roche is aiming to grow its presence in the testing market by becoming “the partner of choice” for developing companion assays and collaborating internally with Roche pharma to advance personalized medicine.

“We need to make sure that science translates into great medicines by designing trials that take smart risk into account, that really focus on ensuring that the molecules are being developed in the right diseases; to make sure we have the right dose; to make sure, whenever possible, we have the … companion diagnostic strategies,” Chief Medical Officer Hal Barron said at the meeting. “This whole strategy needs to result in a higher probability of success so that the return on investment is above the cost of capital and an important driver for our business.”

While Roche plans on identifying new product opportunities through a mix of its internal capabilities and external collaborations, growth through large mergers and acquisitions – a strategy that other large pharmaceutical companies have readily utilized to expand product portfolios – doesn’t seem to be a priority at the company. Noting that there may be opportunities for smaller M&A deals, Alan Hippe, chief financial and information technology officer, noted that at Roche, “we are not big fans of big mergers and big M&A.”

Targeting Cancer

A large portion of Roche’s personalized medicine strategy will be directed toward oncology, where the company has allocated 50 percent of its research and development budget.

In June, the FDA approved Perjeta in combination with Herceptin and decetaxel chemotherapy as a treatment for metastatic breast cancer patients whose tumors overexpress the HER2 protein. The agency simultaneously also approved two companion tests that can help doctors discern best responders to the treatment (PGx Reporter 6/13/2012).

Herceptin (trastuzumab), approved in 1998, still comprises a big chunk of Roche’s therapeutics business, contributing 11 percent of the $18.2 billion the firm netted in overall drug sales in the first half of the year. Roche is hoping to preserve earnings from this blockbuster drug — often hailed as the first personalized medicine success story — by combining it with Perjeta and linking it with a derivative of the chemotherapy maytansine, DM1.

Recently, Roche announced data from a late-stage clinical trial called EMILIA that showed that advanced breast cancer patients receiving the antibody drug conjugate trastuzumab emtansine, or T-DM1, lived “significantly” longer than those treated with a combination of Genentech’s Xeloda (capecitabine) and GlaxoSmithKline’s Tykerb (lapatinib). The patients in EMILIA had to have progressed after initial treatment with Herceptin and taxane chemotherapy.

According to Loew, the company is currently conducting a study looking at T-DM1 as a potential option for first-line metastatic breast cancer patients. In addition, Roche is also studying T-DM1 as an adjuvant treatment in early-stage breast cancer patients with residual disease; comparing T-DM1 plus Perjeta against Herceptin plus Perjeta in the adjuvant early-stage breast cancer setting; and looking at T-DM1-based chemotherapy in the neoadjuvant setting.

“So if we are successfully delivering those results, I think the HER2-positive breast cancer space has been completely changed and redefined,” Loew told investors.

At the end of the year, another study, called the Protocol of Herceptin Adjuvant with Reduced Exposure, or PHARE, is slated to report results, and the outcome could have a negative impact on Herceptin sales. PHARE is comparing whether patients given Herceptin for 12 months, which is currently the standard of care in the US, fare better than those given the drug for six months.

Industry observers have projected that Perjeta and T-DM1 could be a sufficient buffer against a scenario in which six months of Herceptin is found to be non-inferior to a year of the drug.

Barron noted that Roche is readily applying the strategy behind antibody-drug conjugates such as T-DM1 – where antibodies to attach to antigens on the surface of cancer cells to localize chemotherapy delivery and reduce adverse reactions – in 25 projects across its portfolio. He added that antibody-drug conjugates offer a promising mechanism for personalizing treatments.

In non-small cell lung cancer, Roche is studying MetMab (onartuzumab) in combination with Tarceva in patients with tumors that overexpress the Met protein. Data from this Phase III trial, called METLUNG, is expected in 2014. Data from a Phase II study looking at MetMab and Tarceva as a second-line NSCLC treatment yielded negative results when all comers were considered. However, the subgroup of patients who over-expressed Met had a “doubling” of progression-free survival and a “pronounced” effect on overall survival compared to the low-Met group.

Roche is also investigating MetMab in metastatic gastric cancer (Phase III), triple-negative breast cancer, (Phase II), metastatic colorectal cancer (Phase II), glioblastoma (Phase II), as well as in combination with Avastin in various cancer indications.

Other Areas of Personalization

Outside of oncology, Roche is exploring biomarker strategies to personalize drugs for Alzheimer’s disease and schizophrenia. Phase I data from a study involving gantenerumab, a IgG1 monoclonal antibody, suggest that the drug could potentially reduce amyloid plaque in Alzheimer’s patients’ brains.

Investigational drugs targeting beta-amyloid, which many researchers believe to be involved in the pathogenesis of Alzheimer’s disease, haven’t fared well in clinical trials. Most recently, Johnson & Johnson/Pfizer’s drug bapineuzumab, which also targeted the β-amyloid protein, failed to benefit Alzheimer’s patients who were non-carriers of APOE4 gene variations.

Wall Street analysts are hoping that Roche’s biomarker-driven strategy for gantenerumab will help it avoid a similar fate. The company is currently conducting a 770-patient trial called Scarlet Road, in which researchers will measure Tau/Aβ levels in study participants’ spinal fluid to identify early onset or prodormal Alzheimer’s patients and treat them with gantenerumab. Roche is developing a companion test to gauge Tau/Aβ levels in trial participants. Results from Scarlet Road are expected in 2015.

Roche subsidiary Genentech is testing another compound, crenezumab, to see if it can prevent Alzheimer’s in a population genetically predisposed to getting the disease. Genentech, in collaboration with Banner Alzheimer’s Institute and the National Institutes of Health, is conducting a Phase II trial investigating crenezumab in the residents of Medellin, Colombia, where people share a common ancestor and have a high prevalence of mutations in the presenelin 1 gene. Those harboring the dominant gene mutation will start to lose their memory in their mid-40s and their cognitive functions will deteriorate by age 50.

The five-year study will involve approximately 300 participants, of whom approximately 100 mutation carriers will receive crenezumab and another 100 mutation carriers will receive a placebo. In a third arm, approximately 100 participants who don’t carry the mutations will receive a placebo. Study investigators will begin recruiting patients for this study next year.

In schizophrenia, Roche is exploring bitopertin, a glycine reuptake inhibitor, in six Phase III studies slated for completion next year. Three of these studies are looking at the drug’s ability to control negative symptoms in schizophrenia, while the other three trials are studying the drug’s impact on sub-optimally controlled disease symptoms. “A companion diagnostics assay is in development to validate the hypothesis for an exploratory biomarker predicting response to therapy with bitopertin,” Roche said in a statement.

For lupus, Roche is conducting a proof of concept Phase II trial involving rontalizumab, an anti-interferon-alpha antibody, in which researchers are using a biomarker to identify patients most likely to respond to the drug. Data from this trial will be presented at a medical conference later this year.

Growing Role of Diagnostics

Daniel O’Day, who served as CEO of Roche Molecular Diagnostics until last week when he was appointed chief operating officer of the company’s pharma division, valued the worldwide diagnostics market at $53 billion. “We represent 20 percent of that, or around 10 billion Swiss francs ($11 billion),” he said in his investor day presentation.

While molecular diagnostics promise to be a growing part of Roche’s business in the coming years, these products currently only represent a single-digit percent of Roche’s overall diagnostics business. For the first half of this year, molecular diagnostics comprised around 6 percent of Roche’s diagnostics sales of $5.3 billion.

Roche’s Ventana Medical Systems subsidiary will likely play a large role in advancing Roche’s presence in the companion diagnostics space. This year, Ventana announced it was developing companion tests for a number of drug makers, including Aeterna Zentaris, Syndax Pharmaceuticals, Pfizer, and Bayer (PGx Reporter 1/18/2012).

In addition to these external collaborations, Roche officials highlighted the company’s internal diagnostics capabilities as particularly advantageous for expanding its presence in the personalized medicine space. For example, Roche developed the BRAF companion test for Zelboraf. The company is also developing a companion EGFR-mutation test for its non-small cell lung cancer drug Tarceva in the first-line setting, and a test to gauge so-called “super-responders” to the investigational asthma drug lebrikizumab being developed by Genentech.

In terms of molecular diagnostics, O’Day highlighted a test that gauges the overexpression of the p16 gene in cervical Pap test samples to gauge whether women have precancerous lesions.

Additionally, the FDA this year approved the use of Ventana’s INFORM HER2 Dual ISH DNA Probe cocktail on the BenchMark ULTRA automated slide staining platform, which allows labs to analyze fluorescent in situ hybridization and immunohistochemistry samples in one assay. According to O’Day, this test has been more successful than standard FISH tests in identifying HER2 status in difficult-to-diagnose patients. The company will be publishing data on this test soon, showing that it can “identify about 4 percent more [HER2-postiive patients] than FISH alone.”

When it comes to molecular technologies, Roche, like other pharma and biotech players, appear to be sticking to tried and tested technologies, such as IHC, FISH, and PCR, and reserving whole-genome sequencing for research use. “Today, sequencing is predominantly a research tool. And it’s a very valuable research tool in the future,” O’Day said, estimating that sequencing-based tests will “go into the clinic” in the next half decade.

Turna Ray is the editor of GenomeWeb’s Pharmacogenomics Reporter. She covers pharmacogenomics, personalized medicine, and companion diagnostics. E-mail her here or follow her GenomeWeb Twitter account at @PGxReporter.

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