SP-333 is the d-amino acid version of plecanatide and being developed for inflammatory bowel disease. Originally (2009), plecanatide was to be developed for IBD but instead, plecanatide was deveoped for IBS with the same indications as linaclotide (Ironwood). While plecanatide is released in the duodenum, SP-333 is released in the distal small intestine and colon by the enteric coating used in the formulation. The issue is that the pH optimum for SP-333 is no different from plecanatide and this type of delivery provides lack of optimal performance for SP-333. The additional problem for SP-333 is that the reducing conditions in the intestine due to bacteria present there cause the molecule to lose disulfide bonding and hence lose activity. The dose for IBD is likely to be much higher for this reason.
The issue with SP-333 is likely to be lack of effectiveness for IBD. The current multi-dose P1 trial is not being done in patients with IBD (ulcerative colitis selected for SP-333) but in healthy volunteers. Here should the drug show a sign of efficacy, there will be more diahrrea seen in the SP-333 arm vs. placebo. It is likely that the performance has been poor in this trial. Overall, SP-333 is a dud.
Synergy's lead proprietary drug candidate, plecanatide, is a synthetic analog of the human gastrointestinal hormone uroguanylin, and functions by activating the guanylate cyclase C receptor on epithelial cells of the GI tract. Synergy completed a positive Phase I study of plecanatide in healthy volunteers, and positive Phase IIa and Phase IIb/III clinical trials in patients with chronic idiopathic constipation (CIC). Detailed positive findings from a recently completed 951 patient CIC clinical trial will be presented at a major scientific meeting this year.
Synergy is also developing plecanatide for the treatment of irritable bowel syndrome with constipation (IBS-C), having initiated the first trial in IBS-C patients in late 2012. Synergy's second GC-C agonist, SP-333, is in clinical development to treat inflammatory bowel diseases, and has recently completed its first Phase I trial in healthy volunteers.