Antisense drugs stop making sense?
again proved a disappointment after one drug in development was
refused approval and another was scrapped.
Genta, US, has announced that the lead compound in their antisense programme failed to win approval from the US Food and Drug Administration (FDA). Genasense was to be given alongside chemotherapy in the treatment of chronic lymphocytic leukaemia (CLL). "We are keenly disappointed by this decision," said Dr Raymond Warrell, Genta's chief executive. "We believe that Genasense has amply demonstrated its efficacy and safety in patients with relapsed and refractory CLL in a carefully designed and executed randomized clinical trial. "As we decide on next steps with this application, we will continue working to seek worldwide approval of Genasense for patients who have advanced cancer." Genasense inhibits production of Bcl-2, a protein made by cancer cells that prevents cell death. By reducing the production of Bcl-2, it was hoped that Genasense would increase the effectiveness of other cancer treatments. This is not the first time Genta have suffered disappointment with Genasense. The drug was also refused approval as a melanoma treatment in 2004, a decision that prompted Sanofi-Aventis (then Aventis) to pull out of a possible $480m (€366m) collaboration deal. The announcement is just another in a series of antisense drug flops. At the same time, the Canadian pharmaceutical company Methylgene, in conjunction with US company MGI Pharma, have stopped developing MG98, a second-generation antisense compound that targeted DNA methyltranseferase. The two companies will seek alternative development partners or arrangements for the MG98 programme. When DNA methyltranseferase is over produced, some tumour suppression genes are 'switched off.' At the end of Phase I trials into MG98, Methylgene commented that 'MG98 was reasonably well tolerated in these studies and, in general, adverse effects were reversible.' Typically, small molecule drugs work by binding to a target protein and either preventing it from functioning or ensuring it functions better or at different times. Antisense drugs hoped to do the job of these inhibitors but by preventing the protein targets from ever being produced. DNA is made up of an antisense and a sense strand. During transcription, the antisense strand is used as a template to make messenger RNA (mRNA). This can leave the cell nucleus and travel to the ribosome where it is used to produce proteins during translation. Antisense drugs are DNA-like strands of nucleotides that bind to specific areas of mRNA, called oligonucleotides. This section of RNA is then degraded and the corresponding protein is never produced. These types of drugs were heralded as a major breakthrough for the pharmaceutical industry as they are highly specific. They discriminate between protein targets based on genetic information, as opposed to small molecule drugs that often bind to several proteins with similar structures. The more specific a drug, the fewer side effects can be expected. Also, as they are all made of nucleotides, antisense drugs should have predictable metabolism mechanisms, which should lead to shortened development times and a reduced number of failures in the early stage of development. However, this has not proved to be the case. According to Isis, which has heavily invested in antisense development (the majority of their pipeline are antisense drugs), there are at least 12 different ways that mRNA is destroyed and these mechanisms are not fully understood. Affinitak was another antisense let-down. Developed by Isis and Eli Lilly, it failed its Phase III trials for lung cancer. Isis have suffered another Phase III failure with Alicaforsen. This drug was targeted against Crohn's disease. Only one antisense drug has ever been approved, in 1998. This was Isis Pharmaceuticals' Vitravene (fomivirsen), a treatment for cytomegalovirus retinitis (CMV) in immunocompromised patients, such as those with AIDS. There is at least one upside to antisense technology though. The ability of antisense molecules to prevent the production of certain proteins means it can also be used as a method of target validation. Other antisense-like technologies use double stranded oligonucleotides to bind to mRNA, an approach known as RNA interference. Drugs based on this RNAi technology are still in their infancy but might have more promising results. Alnylam Pharmaceuticals is developing ALN-RSV01 , a drug for respiratory syncytial virus (RSV) infection and Merck have bought into the sector by acquiring Sirna Therapeutics for $1.1bn (€830m). Sirna were developing Sirna-027, a drug for age-related macular degeneration (AMD).
