Theracos reports positive phase 2 results for SGLT-2 inhibitor THR1442 – March 20, 2014

Earlier this week, Marlborough, MA-based Theracos Inc. announced positive results from a 96-week phase 2 study of its SGLT-2 inhibitor THR1442 (formerly referred to as EGT0001442). Tested as a monotherapy, the drug demonstrated a 1.02% placebo-adjusted A1c reduction at week 96 (no baseline provided). The company did not see a significant difference in genital infections between the two groups (genitourinary infections have generally been seen as a class side effect for SGLT-2 inhibitors), although the number of events was small. The drug also demonstrated marked (and sustained) improvements in weight and blood pressure. The company press release states that these results have the potential to differentiate THR1442 from other SGLT-2 inhibitors. We imagine that Theracos would be, of course, looking for a partner to help bring the drug into phase 3 though it hasn’t stated this explicitly. Read on below for details on the study design and results, as well as thoughts on the partnership process.

• The phase 2 study (ClinicalTrials.gov Identifier: NCT01377844) enrolled 288 type 2 diabetes patients from sites in the US, Colombia, and Mexico. Approximately 10% of subjects were treatment-naïve. The study’s primary endpoint was A1c change at 24 weeks, although the study continued to week 96. At week 24, the THR1442 arm had achieved a placebo-adjusted A1c reduction of 0.79%, which grew to 1.02% at week 96. At week 24, 24% of patients had achieved an A1c less than 7% compared to 11% of patients on placebo; at week 96, 31% of THR1442 patients had an A1c below 7%, relative to 11% of patients on placebo. Taken as a whole, the efficacy data are fairly impressive, in terms of both durability and magnitude – pooled phase 3 data on J&J’s Invokana [canagliflozin], AZ’s Forxiga [dapagliflozin], and Lilly/BI’s empagliflozin generally show A1c reductions of 0.6-0.9%, albeit mostly in studies <96 weeks (a figure cited by Dr. Julio Rosenstock at a talk on SGLT-2 inhibitors at EASD – see page 14 of our EASD 2013 SGLT-2 Inhibitor Report).
• Interestingly, rates of genital infections between the THR1442 group (2.07%) and the placebo group (2.13%) were comparable. Granted, the number of events at play is very small: assuming that patients were randomized 1-to-1, it means that there were three patients in each group who experienced infections, which leaves plenty of room for an effect to be covered up by chance. However, if confirmed in phase 3, that finding would be a very important differentiating factor from the increasingly active SGLT-2 inhibitor field – Invokana, Forxiga, and empagliflozin are all generally associated with at least a slight increase in genitourinary infections, which (until now) have been seen as the class’ major side effect. According to the press release, THR1442 yielded durable and meaningful changes in weight and blood pressure as well, although no specific figures were listed. The incidence of hypoglycemia was comparable between groups (no severe events reported). The press release did not disclose plans for disclosure of full study results – given the timing of the company’s announcement, we imagine ADA could be a possibility (the late-breaker abstract deadline is this coming Monday).
• Given that Theracos has just received very promising results from a fairly large phase 2 trial, we wonder if THR1442 is poised to enter phase 3, which also brings up the question of partnership. Given the enormous challenges and costs associated with phase 3 testing, we cannot imagine that the company would (or could) enter phase 3 without a partner. It is unsurprising they have not commented on this yet (that we know of, publicly). The number of potential partners is relatively low if one eliminates companies that already have an SGLT-2 inhibitor on the market or in development: J&J has Invokana, AZ has Forxiga, Lilly/BI has empagliflozin, and Merck/Pfizer have ertugliflozin. That said, any of them could be looking for a next-gen candidate if the price is right.  In terms of potential options, Takeda might looking for new pipeline candidates following the discontinuation of its phase 3 GPR40 agonist TAK875 (fasiglifam), and GSK recently announced plans to build a broader cardiometabolic portfolio. Despite the promising phase 2 data, we wonder if there might be a ceiling on potential partners’ enthusiasm given how crowded the class is becoming – still, we believe this will be quite a combinable class and if, of course, renal protection emerges as a class effect, all bets are off for how big the field could become.  As background, THR1442 is not the only SGLT inhibitor looking for a partner, of course; Lexicon’s SGLT-1/2 dual inhibitor LX4211 is phase 3 ready and ready for partnership as well, and the company recently released promising phase 2 data in patients with renal impairment. BHV Pharma’s of course, is recently partnered as it was purchased last week Islet Sciences; their SGLT-2 inhibitor remogliflozin etabonate is in phase 2.

Close Concerns Questions

• Were there any imbalances in any adverse event categories?
• Might Theracos need to conduct further phase 2 testing, either to prepare for phase 3 or to appeal to potential partners?
• If further testing confirms that THR1442 has no effect in genitourinary infections, what level of impact would that have on the SGLT-2 inhibitor landscape?
• How, mechanistically, could an SGLT-2 inhibitor not increase the risk of genitourinary infections?

-- by Manu Venkat and Kelly Close