Genetic Engineering & Biotechnology News

MAY1 2015

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32 | MAY 1, 2015 | | Genetic Engineering & Biotechnology News TRANSLATIONAL MEDICINE to resemble the "club-and-discard" approach to seal hunting. Working with proven compounds, whose toxicity and other effects have been studied, reduces both the cost and time required for de- velopment. "The issue is making the best use of existing resources," Dr. Mucke says. Today, a number of Big Pharma and bio- pharma companies have programs in place. A new peer-reviewed journal, Drug Repur- posing, Rescue, and Repositioning (DRRR), published by Mary Ann Liebert and for which Dr. Mucke serves as editor, just started up this year, and the feld is attracting more special- ists, who are approaching repositioning from different angles. Many of them will meet at the Arrowhead conference on Drug Reposi- tioning, Repurposing, and Rescue, which will be held May 27–28 in Chicago. Several of the conference's speakers contributed their views to this article. Archetypes and Aspirants The fnancial benefts of repositioning are clear in such blockbusters as Pfzer's sildenafl (Viagra), originally developed to treat hyperten- sion. Dr. Mucke recalls some less famous ex- amples, such as the acetyl cholinesterase inhibi- tor, galantamine, the story behind which will appear in DRRR's second edition. Discovered in Bulgaria in the 1950s and sold in Eastern Europe to treat paralysis, myopathy, and brain injury, galantamine was readvanced in the 1980s once the mechanism behind Alzheimer's disease was better understood, and Janssen and Shire Pharmaceuticals launched it as Reminyl in 2000 (later rebranding it Razadyne). For repurposed drugs, the fnancial stakes are clearly high, but so are the potential ben- efts for patients. Orphan drug regulations, which offer increased funding and faster regulatory review, are driving many reposi- tioned drug research projects. Relmada Therapeutics, for example, is fo- cusing on chronic pain. "It's a major unmet medical need, and existing therapies don't work in many patients," says Elisio Salinas, M.D., the company's CSO. In addition, many exist- ing treatments are regulated substances, and the past few years have seen more cases of theft, di- version and reprocessing, and overdose. Relmada currently has four programs in Phase I, three of which will enter Phase II within the next year, says Dr. Salinas. The fourth, he says, should reach Phase II in the next 9 to 12 months. Drugs in the Relmada pipeline are: • An extended release, abuse-resistant version of Levorphenol, a strong opioid. Addicts and those who steal and sell prescription painkillers usually use basic techniques and kitchen tools to extract the API. Relmada is using different polymers and waxes to make capsules of the drug impossible to melt or crush. • d-Methadone, an N-methyl-D-aspartate (NDMA) receptor agonist. The d isomer, unlike the l isomer, is believed to have a low potential for addiction. Also, it does not cause respiratory depression. The next step will be demonstrating that the d isomer works on chronic pain. Phase I trials were successful. • An oral solid dosage form of buprenor- phine, a drug currently sold in injectable, topical patch, or sublingual forms. To prevent the drug from being fltered out by the liver, or reacting with enzymes in certain areas of the gastrointestinal (GI) tract, Relmada is using enterocoatings that would avoid problem areas in the GI tract. • A topical treatment for the neuropathy caused by HIV, as well as the post-herpetic neuralgia that affects 20% of shingles pa- tients, who continue to experience pain after the rash has gone. This project involves reformulating a local anesthetic used as an injection in dental and OB/Gyn procedures. Select Rejects Keeping track of all the potential candi- dates for repositioning is a daunting task, but a growing number of public and private databases help. Efforts are focused on har- nessing this data more effectively. H. M. Pharma Consultancy, for instance, is developing the Discontinued Drug and Candidate Database (DDCD) as a reference tool to make it easier to identify potential can- didates. The database, using publicly available data, goes back to the early 1990s, Dr. Mucke says, collating comprehensive information on pharmaceutically active compounds that have been discontinued from development, or have been pulled from the market. In addition to all identifable "hard" data (such as chemical structure, INN names and/ or research codes, pharmacological activi- ties, and key literature and patent references) for which extensive web references are to be provided, the DDCD will contain a wealth of "soft" context-based information such as de- veloper statements and analyst assessments. Currently, Dr. Mucke is using the database internally, but he will unveil it at the Chicago conference. With venture backing, and IT de- velopment and programming, he believes that it could be useful to third parties, either on a subscription basis or as an open-access tool. Ligand-Based Technology Other companies are using advanced tech- nology to mine repurposed drug data. Barce- Drug Repositioning Continued from page 1 > Myriad Diagnostic to Be Utilized in Pancreatic Cancer Collab with AstraZeneca Myriad Genetics expanded its companion diagnostic col- laboration with AstraZeneca. As part of the agreement, Myr- iad's BRACAnalysis CDx™ test will be used to prospectively identify which patients with metastatic pancreatic cancer may respond to treatment with Lynparza™ (olaparib). Lynparza is a poly-ADP ribose polymerase (PARP) inhibitor being devel- oped by AstraZeneca. BRACAnalysis CDx is an FDA-approved in vitro diagnostic device intended for the qualitative detection and classifca- tion of variants in the protein-coding regions and intron/exon boundaries of the BRCA1 and BRCA2 genes using genomic DNA obtained from whole-blood specimens. "BRACAnalysis CDx has the potential to quickly and accu- rately identify those patients who may be candidates for treat- ment with Lynparza," a capability that could bring about "bet- ter health outcomes," said Mark Capone, president of Myriad. > Ambry Genetics Acquires Progeny Software Ambry Genetics has acquired Progeny Software. Ambry said it will integrate Progeny into its own laboratory informa- tion management system to simplify its clients' workfow by using Progeny's software solutions and risk-assessment tools, while making the genetic testing process efcient, more ap- propriately ordered, and better understood. This partnership also facilitates research collaborations with institutions that are both Ambry and Progeny clients. The companies said it allows for more opportunities in population- based research and sharing data, increasing the understand- ing of inherited disorders and improving patient care. Prog- eny and Ambry both currently ofer secure, HIPAA-compliant online access to their products. > InSilixa Receives $1.5M SBIR Grant to Develop TB Diagnostic Test InSilixa received a $1.5 million Small Business Innovation Research (SBIR) grant from the National Institutes of Health for Phase II development of a cost-efcient, point-of-care (POC) molecular diagnostics test for the rapid detection and profling of antibiotic-resistant Mycobacterium tuberculosis (MDR-TB). InSilixa's sample-to-answer CMOS biochip technology enables rapid detection of pathogens (viruses and bacte- ria) in clinical samples and the simultaneous identifcation of their drug-resistance profles using a highly multiplexed targeted DNA sequencing approach. The frst generation of InSilixa's molecular diagnostic products will focus on the de- tection of infectious diseases in near-patient and POC set- tings. Applications will include the rapid detection of MDR bacteria in intensive care units, comprehensive analysis of seasonal respiratory infection outbreaks; diagnosis and drug resistance genotyping of Mycobacterium tuberculosis isolates from patients with TB; and the detection, quantif- cation, and characterization of HIV in blood samples from patients with HIV/AIDS. > Agendia Selects Rubicon's RNA Amplifcation Technology to Use with Its Breast Cancer Test Rubicon Genomics has extended its clinical supply agree- ment with Agendia for use of its TransPLEX® whole genome RNA amplifcation technology. Agendia uses Rubicon's Trans- PLEX C-WTA kits for the analysis of formalin-fxed, parafn- embedded (FFPE) patient samples for its MammaPrint® 70- gene breast cancer recurrence assay, which received 510(k) clearance from the FDA. This new three-year agreement fol- lows an earlier contract between the two companies. Agendia said its MammaPrint FFPE test uses 70 genes and a proprietary algorithm that ensures the test unambiguously diferentiates patients as "low vs. high risk" for recurrence of breast cancer. The company added that the test can provide insight into the cancer's biology. Nucleic acid extracted from FFPE samples is highly dam- aged, and the samples often contain only small amounts of usable nucleic acid. Rubicon said TransPLEX C-WTA kits are de- signed and validated to overcome these problems and deliver sufcient quantities of high-quality nucleic acids to enable ac- curate and consistent analyses from FFPE samples. The reagent formulations have been designed and optimized to yield a large library from as little as 10 ng of degraded RNA. n News MOLECULAR DIAGNOSTICS The fnancial benefts of repositioning are clear in such blockbusters as sildenafil (Viagra), originally developed to treat hypertension, and galantamine, initially used to treat paralysis, myopathy, and brain injury, and now rebranded as Razadyne, an Alzheimer's drug. / Mathier

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