key: cord-0039882-gyeovc06
authors: Lou, Kai-Jye; Parmley, Stephen; Zipkin, Mark
title: Translational tidbits
date: 2014
journal: nan
DOI: 10.1038/scibx.2014.1282
sha: aecac50f2c8dc8e629bf0f6c15646aa5f30f8eb8
doc_id: 39882
cord_uid: gyeovc06

Merck KGaA enters the tankyrase race; Pluristem joins with Case Western to test its new cell therapy; Astellas' AIM unit targets Boston for innovation; the White House clamps down on gain-of-function studies; a round-up of public-private partnerships.

With a few pharmas entering the search for tankyrase inhibitors for cancer, Merck KGaA is hedging its bets by joining forces with The Institute of Cancer Research and the Wellcome Trust to accelerate development of selective inhibitors of the enzymes.

The two tankyrases-tankyrase TRF1-interacting ankyrin-related ADP-ribose polymerase (TNKS) and TNKS2-are members of the poly(ADP-ribose) polymerase (PARP) family of enzymes that transfer ADP-ribose groups to a range of cellular proteins and are upregulated in a variety of cancers.

Last year, several groups identified selective compounds that inhibited tankyrases but not other PARPs, including teams at the University of Oslo, Novartis AG's Novartis Institutes for BioMedical Research and Roche's Genentech Inc. unit. 1, 2 However, Genentech's program is no longer active, and the current development status of the University of Oslo and Novartis compounds was unavailable at press time.

Under the terms of the Merck KGaA deal, the pharma's Merck Serono unit and the team at the Institute of Cancer Research (ICR) will initially focus on translating existing leads from both groups into the clinic and identifying backup compounds. Merck Serono will make milestone payments to ICR and Wellcome-which originally funded the program at ICR-based on regulatory and sales goals, plus royalty payments on net sales of future products discovered or developed under the agreement.

The partners will combine their portfolios of tankyrase inhibitors, continue parallel screening efforts and work together on biomarker identification and animal studies.

The ICR team is led by Alan Ashworth, a professor of molecular biology at ICR, and Chris Lord, team leader and reader in cancer biology and therapeutics at ICR. The two have experience with small molecule inhibitors of PARP.

Andree Blaukat, head of translational innovation platform oncology at Merck Serono, told SciBX that both partners have confirmed the selectivity of their initial leads and that studies are under way to profile the therapeutic window of the compounds. "Our tankyrase inhibitors are also very selective, so they do not inhibit other PARPs at all, " he said.

Blaukat added that biomarker identification was also one of the key goals. "We will only move programs forward if we have biomarkers either preclinically validated or a very solid hypothesis for additional markers, " he said.

Although Merck declined to disclose funding details, Blaukat said that both Merck and ICR are contributing resources to the collaboration.

He added that each partner will contribute scientifically based on its particular strengths-for example, by performing animal models or biophysical analyses that are well established at the respective institutions.

Case for Pluristem Pluristem Therapeutics Inc. is wasting little time in advancing its second cell therapy product-PLX-RAD-toward the clinic. A week after the biotech said that it was ready to begin large-scale GMP manufacturing of PLX-RAD for a planned Phase I study in 2016, it announced a new research collaboration with Case Western Reserve University to test the cell therapy in preclinical models of human umbilical cord blood transplantation. Chairman and CEO Zami Aberman said that the company will begin GLP toxicology studies on PLX-RAD early next year.

The biotech's first cell therapy, PLX-PAD, is in Phase II or earlier testing to treat multiple cardiovascular, musculoskeletal and pulmonary disorders. Both PLX-RAD and PLX-PAD are composed of expanded populations of placenta-derived stromal cells, but the majority of cells in PLX-RAD are of fetal origin, whereas cells in PLX-PAD are mainly of maternal origin.

Under the collaboration, Pluristem will provide PLX-RAD to researchers at Case Western for preclinical studies to evaluate whether the cells can increase the speed of engraftment and the efficiency of new blood cell formation in mice receiving a human umbilical cord blood transplant. The partners will split research costs evenly.

Umbilical cord blood is an alternative to bone marrow for hematopoietic stem cell transplants and carries a lower risk for graftversus-host disease (GvHD) than bone marrow. Cord blood transplants require less stringent matching but take longer to engraft. That lag leaves recipients highly vulnerable to infections for longer periods of time.

Earlier results from compassionate use cases suggested that PLX-PAD can restore the ability to produce hematopoietic cells and improve survival in patients who have failed a hematopoietic stem cell transplantation. However, Aberman said that the company decided to study PLX-RAD for this indication based on mouse data that showed it had a more pronounced benefit than Pluristem's first product.

A 2012 study from researchers at Hadassah Medical Center and Pluristem showed that in lethally irradiated mice, intramuscular injection of PLX-RAD resulted in a 98% survival rate versus 27% for vehicle or 67% for PLX cells of maternal origin that are similar to PLX-PAD. 3 Astellas takes AIM at Boston After launching an external innovation strategy last year, Astellas Pharma Inc. is bringing the initiative stateside with two new Bostonbased academic collaborations. The pharma is partnering with Harvard Medical School to find new treatments for ophthalmologic diseases and with Dana-Farber Cancer Institute to discover small molecule inhibitors of the K-RAS (KRAS) oncogene.

Under the terms of both deals, Astellas will fund the academic partners for up to three years and has the option for exclusive licenses from the respective institutions to develop any therapies obtained from the research collaborations. If Astellas exercises an option, it will develop and commercialize the compounds.

TranslaTional noTes 

The collaboration with Harvard Medical School will be led by Constance Cepko, a professor of genetics and ophthalmology at Harvard, and will focus on identifying and validating gene therapies to prolong vision in individuals with retinitis pigmentosa-an inherited retinal degenerative disease characterized by loss of peripheral, night and color vision that leads to complete blindness. The partners hope that any resulting therapies might also be effective in other ocular diseases such as age-related macular degeneration (AMD) or glaucoma.

The collaboration with Dana-Farber will be led by Nathanael Gray, a professor of biological chemistry and molecular pharmacology at Harvard Medical School. Gray's group previously identified a K-RAS inhibitor that covalently binds the enzyme's catalytic site and confirmed the interaction with crystal structure studies. 4 The partnership will support optimization of the compound and additional screening for druggable leads.

Kenji Yasukawa, SVP and chief strategy officer at Astellas, told SciBX that both of these partnerships are being managed by the Astellas Innovation Management (AIM) unit, which was established last year as part of a reshaping initiative. He said that the pharma is looking for new opportunities in drug discovery through external innovations.

"AIM is interested in platform technologies and new molecular entities in preclinical stages in the areas of oncology, emerging biology and therapeutic areas where unmet medical need exists, " said Yasukawa. "AIM is looking to flexibly collaborate with various partners such as startup biotech companies, academia and venture capital groups around the world. "

After recent revelations about biosafety incidents in U.S. governmentrun labs and criticism of the White House's handling of the Ebola response in the U.S., the Office of Science and Technology Policy announced in October a funding pause for new gain-of-function studies. The office also requested a voluntary freeze at labs with other funding sources.

Gain-of-function experiments confer new attributes to existing organisms and have been used to study how dangerous mutations affect the function of known pathogens. But safety concerns have led some researchers to question whether the risks inherent in this type of study outweigh the benefits.

Over the next year, the NIH's National Science Advisory Board for Biosecurity (NSABB) and the National Research Council of the National Academies (NRC) will work in tandem to generate a new policy framework covering gain-of-function studies on influenza, Middle East respiratory syndrome (MERS) and severe acute respiratory syndrome (SARS) viruses.

The policy will fill a gap left in rules issued in September covering dual-use research of concern, which is research conducted for legitimate purposes that could be misapplied for harmful uses that pose a significant threat to public health and safety. The NSABB will review the risks and potential benefits of this type of research and draft a set of recommendations, and it is considering widening the funding pause to other pathogens.

NIH spokesperson Renate Myles told SciBX that the pause will affect 1 planned intramural project, 7 contracts and 10 grants on enhanced pathogenicity or respiratory transmissibility in mammals.

"The pause is a responsible step to take while the period of deliberation is under way, " said Andrew Hebbeler, assistant director for biological and chemical threats at the Office of Science and Technology Policy. "The deliberative process will enable the life sciences community to assess the risks and benefits of gain-of-function studies and will result in the adoption of a U.S. government policy to guide future federal investments in this area of research. "

Once the NSABB creates a set of draft recommendations governing approval and conduct of gain-of-function experiments, the NRC will hold a conference to review the recommendations with the scientific community. Final recommendations should be complete within 6 months, and the new policy is expected before the end of 2015.

Public-private partnership round-up The quartet of new research alliances seeded with funds from the amyotrophic lateral sclerosis (ALS) ice bucket challenge 5 and a stream of new R&D collaborations announced by multiple pharmas and large biotechs drove the bulk of public-private partnership activity in October (see Table 1 , "Selected public-private partnerships for October 2014").

Johnson & Johnson's J&J Innovation unit coupled the official opening of its Asia Pacific Innovation Center in Shanghai with the announcement of four new collaborations between various subsidiaries of the pharma and research institutes in the region, the extension of an ongoing collaboration and a new partnering office at Suzhou Industrial Park Biotech Development Co. Ltd., a life sciences incubator. 6 Also in October, the GPCR Consortium was launched with the goal of defining the structures of at least 200 of the 826 known human GPCRs to aid drug development. The initial disease areas of focus are diabetes, cancer and mental disorders. Research outputs of the not-for-profit Planned research under the consortium will be carried out at various academic centers including the iHuman Institute at ShanghaiTech University, Shanghai Institute of Materia Medica and the University of Southern California. The consortium was started by Raymond Stevens, a professor of molecular biology and chemistry at The Scripps Research Institute and founding director of the iHuman Institute.

The consortium's founding industry members are Amgen Inc., Ono Pharmaceutical Co. Ltd. and Sanofi. It aims to recruit up to five additional industry members.

In addition, the Regeneron Genetics Center unit of Regeneron Pharmaceuticals Inc. announced research collaborations in October with Columbia University Medical Center, the Clinic for Special Children and the Baylor College of Medicine to study inherited genetic diseases.

The Columbia collaboration will focus on cardiometabolic diseases, familial cancer predisposition and rare genetic diseases; the Clinic for Special Children collaboration will study early onset and familial forms of pediatric disorders in Amish and Mennonite populations; and the Baylor collaboration will study the function of Mendelian disease genes discovered at the college.

Regeneron opened its Regeneron Genetics Center unit in January to enhance the biotech's in-house commitments to genomics-guided drug discovery. 7 The center is tasked with analyzing the genomes of at least 100,000 Geisinger Health System patients over the next 5 years.

COMPANIES AND INSTITUTIONS MENTIONED Amgen Inc. (NASDAQ:AMGN)

Pluristem Therapeutics Inc. (NASDAQ:PSTI; Tel Aviv:PSTI)