Articles: oligonucleotides.
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Isis and Merck are developing an antisense oligonucleotide for the potential treatment of hepatitis C virus (HCV) infection [305306]. As of March 2000, the lead from this program, ISI-14803, was being studied in a phase I/II trial where it was administered in three weekly 2-h infusions for 4 weeks [327913], [357823]. ⋯ In January 2000, Isis signed a binding letter of agreement with Elan to form a new subsidiary of Isis to develop ISIS-14803 [351881], [362727]. In October 2001, Isis reported that it had earned a $1.5 million research milestone payment from Merck for progress in this collaboration [426015].
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Loris Therapeutics (formerly GeneSense Therapeutics) is developing the antisense oligonucleotide GTI-2040, directed against the R2 component of ribonucleotide reductase, for the potential treatment of cancer [348194]. It is in phase I/II trials [353796] and Lorus had anticipated phase II trials would be initiated in July 2001. By August 2001, GTI-2040 was undergoing a phase II trial as a monotherapy for the potential treatment of renal cell carcinoma, and was about to enter a phase II combination study for this indication with capecitabine (Hoffmann-La Roche). ⋯ Lorus has entered into a strategic supply alliance with Proligo to provide the higher volumes of drug product required for the planned multiple phase II trials [385976]. In February 1998, Genesense (now Lorus) received patent WO-09805769. Loris also received a patent (subsequently identified as WO-00047733) from the USPTO in January 2000, entitled 'Antitumor antisense sequences directed against components of ribonucleotide reductase' covering the design and use of unique antisense anticancer drugs, including GTI-2040 and GTI-2501 [353538].
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Abnormal expression of Ras proteins frequently is found with oncogenic transformation making ras a promising therapeutic target. ISIS 2503 is a 20-base antisense phosphorothioate oligodeoxyribonucleotide that specifically downregulates H-ras expression and inhibits tumor cell growth in preclinical studies. Here, the authors report an initial clinical study of the safety and tolerability of an intravenous infusion of ISIS 2503 in patients with advanced cancer. ⋯ ISIS 2503, an antisense oligonucleotide against H-ras, was well tolerated as a single agent at doses up to 10.0 mg/kg/day by 14-day continuous intravenous infusion. Several patients had stabilization of disease, suggesting that ISIS 2503 had some tumor growth inhibitory effects and future trials of ISIS 2503 in combination with chemotherapy should be considered.
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Fomivirsen (ISIS-2922, Vitravene) is an antisense 21 mer phosphorothioate oligonucleotide with sequence complementarity to the coding region of the major immediate-early gene of human cytomegalovirus (CMV). Developed by Isis Pharmaceuticals Inc, fomivirsen is the first antisense oligonucleotide to receive approval for licensing and is marketed by Novartis' CIBA Vision. Fomivirsen is administered by intravitreal injection to AIDS patients for the treatment of CMV-induced retinitis. In August 1998, the FDA approved the marketing of Vitravene for the local treatment of CMV retinitis [296420], [296780], and both European and Brazilian registration approval followed in the summer of 1999 [335238].