Isis reports positive topline phase 2 results for insulin sensitizer ISIS-PTP1BRx – February 9, 2015

Isis reported positive topline results  from a phase 2 trial of its novel insulin sensitizer ISIS-PTP1BRx showing significantly greater mean A1c reductions (0.7% vs. 0.2%; p = 0.03; baseline = 8.6%) and weight loss (p=0.01; magnitude not disclosed) vs. placebo at 36 weeks. The double-blind trial (ClinicalTrials.gov Identifier: NCT01918865) enrolled 92 patients with type 2 diabetes who were randomized to receive once-weekly injections of 200 mg ISIS-PTP1BRx or placebo for 26 weeks on top of background therapy with metformin and/or sulfonylureas. The drug was generally well tolerated; the most common adverse events were mild injection site reactions. Although the results were positive overall, external reactions to the results were somewhat negative given a discrepancy in timing between the original primary efficacy endpoint (A1c reduction at 27 weeks) and the reported data (A1c reduction at 36 weeks). To speculate, depending on the shape of the A1c curves, it is possible that the improvement was more modest and/or was not statistically significant at 27 weeks. However, we do not see the 27 vs. 36 week differentiation as highly clinically meaningful, as longer-term efficacy is ultimately what is valuable for patients. In the same vein, we were encouraged to hear that the improvements in glycemic control and body weight increased as the trial progressed; we suspect that the full benefits of this and other insulin-sensitizing agents may only become apparent in longer-term trials (for example, head-to-head studies have shown that TZDs appear less efficacious than sulfonylureas within a short initial timeframe but ultimately produce much more durable A1c reductions). Full results from this trial will be presented at a medical meeting later this year and should offer more insight into the compound’s profile.

Isis plans to seek a partner for ISIS-PTPBRx before initiating phase 3 trials, and we are very curious to gauge the level of interest from industry. On the one hand, companies might be hesitant to invest in an injectable therapy that does not appear to offer a significant efficacy advantage over existing injectable medications, at least based on the magnitude of the A1c reductions in this trial. On the other hand, the product’s insulin-sensitizing mechanism of action (it inhibits PTP1B, a negative regulator of insulin action) offers considerable cause for excitement, as it would address the underlying pathophysiology of the disease to a greater extent than most existing drug classes. Isis has expressed hope that ISIS-PTP1BRx could help “refresh” the insulin sensitizer class, which has acquired a negative reputation in recent years due to the safety concerns associated with TZDs. We also believe the product’s unique mechanism could make it very amenable to combination therapy with other classes like GLP-1 agonists – we would love to see Isis or a future partner explore this possibility.

• Other companies developing PTP1B inhibitors include TransTech Pharma (TTP814; phase 2) and OHR Pharmaceutical (trodusquemine; phase 1). Other companies developing novel insulin sensitizers include J&J (JNJ-41443532; phase 2), Metabolic Solutions (MSDC-0160 and MSDC-0602; phase 2), Shionogi (S-707106; phase 2), and XOMA (XMetS; preclinical). Disappointingly, DiaMedica recently announced topline phase 2 results showing no significant improvements in glycemic control with its insulin sensitizer DM199.

-- by Emily Regier, Manu Venkat, and Kelly Close