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Geron gets green light for human trial of ES in brief cell–derived product Alnylam dealt blow The European Patent Office (EPO) has revoked a patent covering RNA interference (RNAi) After an eight-month delay, on 23 January, technology from Alnylam Pharmaceuticals. The ‘945 patent (EP 1214945), which belongs to the US Food and Drug Administration (FDA) the Kreutzer-Limmer patent family, protects approved the first human trials of embryonic the use of small interfering RNAs 15–49 stem (hES) cells, a surprise decision that came nucleotides long. Alnylam’s claim was disputed on the eve of President Barack Obama’s expected by London-based Silence Therapeutics, policy change concerning hES cell research. Abbott Park, Illinois–based Abbott and San Francisco–based Sirna, owned by Merck. The This summer, Geron Corporation of Menlo ruling—made in part because the patent was Park, California, will begin treating ten patients deemed too broad—is not final and will be who have suffered a complete thoracic-level spi- appealed. “In an area like this, companies nal cord injury in a phase 1 multicenter trial. The don’t expect to get their patents through pioneering therapy is Geron’s ‘GRNOPC1 prod- unobjected to,” says patent lawyer Simon uct’, which contains hES cell–derived oligoden- Cohen, of Taylor Wessing, a European law firm. “They start off with broad claims and they drocyte progenitor cells that have demonstrated realize they have to narrow down their scope.” remyelinating and nerve growth–stimulating Cambridge, Massachusetts–based Alnylam had properties. another of its Kreutzer-Limmer patents revoked For a company that held its ground during by the EPO last December. A spokesman the Bush administration’s assault on hES cell for Silence Therapeutics says the whole Kreutzer–Limmer patent series may eventually research, the FDA’s clearance is part triumph, Inc. Researchers, Photo / Cavallini James fall, creating space for other companies who part vindication for sticking with the Sisyphean want to work with RNAi. This is “very much the Embryonic stem cells. Companies are rapidly task of preparing a gargantuan 22,000-plus page start of litigation and opposition, rather than gearing up to follow in Geron’s footsteps, as the last phase of it,” Cohen stresses. In the Investigational New Drug (IND) application the firm receives the first approval to carry out US, Alnylam received recent FDA approval for for their product. “There was plenty of crying embryonic stem cell work in humans. going on here when we received notification phase 1 trials of an RNAi-based treatment for liver cancer. Asher Mullard that the FDA had cleared our IND,” says Thomas Thomson and John Gearhart before leaving Okarma, Geron’s president and CEO. the company in 1998 and then ran Worcester, Although they may not have shed tears of joy, Massachusetts–based stem cell company C-Path sets diagnostics many players in the budding regenerative medi- Advanced Cell Technology (ACT) until 2007, standard cine sector sounded a note of relief, and even says there’s also a sense of unease with Geron’s A newly launched diagnostics evaluation optimism. “I’ve been talking to my colleagues planned trial. “While we all want [the clinical tri- service for companies could help standardize in this field, and the overall feeling is that this is als] to work, there’s a concern among many of us tests and ease their transition to market. an important milestone because it means that that some of these patients will develop ectopic The United States Diagnostic Standards (USDS), a nonprofit organization set up by the FDA will approve clinical trials using human growths, and that would be a disaster.”

© All rights reserved. 2009 Inc. Nature America, Critical Path Institute (C-Path), will provide embryonic stem cells, and that, in fact, there is Ectopic growths, also known as teratomas, independent test evaluations, effectively [regulatory] support for developing therapies are encapsulated, usually benign tumors that functioning as a voluntary “Underwriters based on embryonic stem cells,” says Michael may grow from residual hES cells. They can Labs” for diagnostics companies, says Jeffrey West, CEO of BioTime and Embryome Sciences, occur naturally, but the fear, based on some Cossman, chief scientific officer at C-Path, both in Emeryville, California, who cofounded animal studies, is that some proportion of the of Rockville, Maryland. Analytic evaluations performed by the new entity will take place Geron in 1990. cells derived from hES cells injected into the at carefully selected neutral sites. Under Other CEOs of stem cell firms are also upbeat: body could stray from their intended develop- USDS policy, the clinical samples (e.g., “Clearly, this opens the door not only for Geron, mental pathway. Last month, a group of Israeli blood, tumor tissue) used as standards in but other companies that develop strong IND researchers reported that a boy with ataxia the evaluation of diagnostic assays must packages for stem cell–based therapeutics. And telangiectasia who had received several fetal be approved by an independent, outside panel of experts. In some instances, well- given the compelling evidence that there’s a neural stem cell transplants developed terato- established clinical samples may serve reasonable chance for clinical success, this is a mas in his brain and spinal cord four years after as standards so that assays from different very positive development for the regenerative treatment (PLoS Med. 6, e1000029).“Concerns suppliers can be compared. Although the medicine field,” says Richard Garr, president and about tumorigenicity are bang on,” says Melissa group has no regulatory authority, diagnostic CEO of Rockville, Maryland–based Neuralstem, Carpenter, a San Diego–based independent test manufacturers can use evaluation results which in December filed an IND to use human consultant on stem cell therapeutics. “Yes, to support an application for FDA approval. Alternatively, as one of its many services, the neural stem cells for treating amyotrophic Geron and others have done extensive testing USDS will certify a Laboratory Developed Test lateral sclerosis. On the same day, StemCells, in rodents that show that teratomas don’t form (LDT) and ensure its performance. As Cossman Inc. received approval to begin clinical trials from their preparations, but a rat’s lifespan is explains, “The information [USDS provides] of a purified human neural stem cell to treat short. What we really don’t know is how these would be useful for [insurance] payers, clinical Pelizaeus-Merzbacher disease—a fatal brain cells will behave in a human that might live pathology laboratories, providers, as well as for regulators such as FDA, [and] might help with disorder that affects children. 10–50 years after receiving treatment.” reimbursement decisions, as well as approval But West, who spurred Geron’s support for Although acknowledging that teratoma for- or assurance that an LDT (not evaluated by the research of human stem cell pioneers James mation might be a concern, Geron’s Okarma FDA) performs as labeled.” Jim Roberts

nature biotechnology volume 27 number 3 march 2009 213