Shire is developing DP-VPA, a prodrug of valproic acid (VPA) licensed from D-Pharm, for the potential treatment of severe forms of epilepsy, including status epilepticus, acute repetitive seizures in children and possibly manic depression and migraine [242649], [385958]; the drug is also being developed for bipolar disorder and migraine prophylaxis [385862]. By March 2000, phase I trials had been completed [359581], [373232] and in October 2000, the compound entered phase II trials for the treatment of epilepsy, bipolar disorder and migraine [385862]; these trials were ongoing in November 2001 [429470]. In October 2001, Shire initiated multicenter, multinational phase II trials of SPD-421 as add-on therapy in the treatment of complex partial seizures [425660]. In February 2002, Shire reported that it planned to make a decision regarding the future of the compound by the second half of 2002 [441819]. DP-VPA is based on D-Pharm's regulation activation of prodrugs (RAP) technology, which designs drugs to be internalized within cells and to be activated only when the tissue becomes diseased. In the case of DP-VPA, the pathological epilepsy process activates it on demand [342433]. RAP-prodrugs are composed of the active drug moiety attached via a chemical linkage to a hydrophobic molecule which allows the agent to penetrate into the cell [182806]. In October 2000, D-Pharrm received patent US-06077837 from the USPTO covering novel 'Prodrugs with enhanced penetration into cells'. This patent claims prodrugs, comprising a pharmacologically active compound covalently linked to an intracellular transporter by a bond which is preferentially cleaved by disease-associated supranormal enzyme activity [385507]. In April 2000, Lehman Brothers predicted the launch of DP-VPA during 2003 [365103]. In December 2001, Lehman Brothers suggested that the product would be approved in 2004. The analysts estimated a 25% probability of the drug reaching the market, and envisaged peak sales of $200 million [434768]. Analysts at Schroder Salomon Smith Barney predicted in March 2002, that sales for Shire of DP-VPA would reach US $9.5 million in 2005, rising to US $31 million in 2006 [449087].