AZ releases positive topline phase 3 data on saxagliptin/dapagliflozin fixed-dose combination and announces phase 3 trial for Forxiga/Farxiga in type 1 diabetes patients – May 13, 2014

Earlier today, AZ announced positive topline phase 3 results from a 24-week study investigating AZ’s SGLT-2 inhibitor/DPP-4 inhibitor fixed dose combination (FDC), saxagliptin/dapagliflozin compared to each of its individual components: the SGLT-2 inhibitor Forxiga (known as Farxiga in the US; dapagliflozin) and the DPP-4 inhibitor Onglyza (saxagliptin). The trial enrolled 534 type 2 diabetes patients on background metformin and randomized them 1:1:1 to saxa/dapa, dapagliflozin, or saxagliptin.

Saxa/dapa yielded a mean A1c reduction of just under 1.5%, which was significantly greater than the mean reductions of 1.20% with Forxiga/Farxiga monotherapy and 0.88% with Onglyza monotherapy, although fell short of being additive or synergistic as had once been hoped could be the case (more details below). Although no baseline A1c was provided, the study enrollment A1c window was 8.0-12.0%, which suggests the mean baseline A1c was probably on the higher side. Significantly more patients on saxa/dapa achieved an A1c of less than 7% (41%) than patients on monotherapy with Forxiga (22%) or Onglyza (18%). The combination yielded a significant decrease in two-hour postprandial glucose (PPG) relative to Onglyza, but not relative to Forxiga. A similar pattern was seen with fasting plasma glucose (FPG), where the mean reduction seen with saxa/dapa (38 mg/dl) was significantly greater than the reduction seen with Onglyza (14 mg/dl) and more comparable to the reduction seen with Forxiga/Farxiga (32 mg/dl). The press release mentions that the saxa/dapa group experienced weight loss, although it is not clear how that reduction compared to any body weight changes seen in the monotherapy arms.

On the safety side, the overall incidence of adverse events (including hypoglycemia) was similar between treatment groups, with most events being mild to moderate in intensity. The press release did not discuss specific adverse events. While one theoretical benefit of some fixed-dose combinations is a more balanced side effect profile that stems from a lower dose of each medicine being used in the combination product. That may not be the case with saxa/dapa, as the combination dosages are the same as the monotherapy dosages (5 mg Onglyza and 10 mg Forxiga); we will be interested to learn more about this. From our view, even if the combination is not officially additive or synergistic, patients would certainly prefer the 1.5% vs. 1.2% A1c drop with the fixed dose combination vs. Forxiga/Farxiga monotherapy.

Based on previous company guidance, we expect to see full results presented at ADA. During AZ’s 1Q14 update, management guided for US and EU regulatory filings in 4Q14. We are excited to be moving toward seeing more FDC therapy, and wonder if several years from now, oral agent monotherapy will be used very widely.

There is enormous enthusiasm, of course, regarding fixed dose combinations’ ability to improve adherence and reduce patient co-pays. SGLT-2/DPP-4 inhibitor combination is particularly attractive, due to the combination of insulin-dependent and insulin-independent modes of action that yield weight loss and a low risk of hypoglycemia or other side effects. Indeed, the results shown here suggest that saxa/dapa’s efficacy is on par with that of GLP-1 agonists, yet it does not require injections and probably is not associated with nausea as GLP-1 agonists are.

Excitingly, we learned from a note at the bottom of the press release that AZ plans to initiate a phase 3 trial on Forxiga/Farxiga monotherapy in type 1 diabetes patients in 2014. Just last year at ADA 2013, BMS/AZ presented results of a phase 2 pilot study for this indication showing that dapagliflozin reduced total daily insulin dose. At this point, AZ is leading the race to get a selective SGLT-2 inhibitor approved for type 1 diabetes (Lexicon could initiate phase 3 testing of its SGLT-1/2 dual inhibitor LX4211 in type 1 diabetes in 2014 – read our Lexicon 1Q14 Report for more details). SGLT-2 inhibition holds great promise for type 1 diabetes patients due to the oral class’ insulin-independent mode of action.

• Saxa/dapa’s demonstrated A1c lowering efficacy of 1.47% was certainly impressive, but it did not quite represent an additive effect of its individual components (1.2% on Forxiga and 0.88% on Onglyza sums to about 2.1%). As such, it was certainly not synergistic (as has been proposed for the combination of DPP-4 inhibition and SGLT-2 inhibition). Additive effects were theoretically expected given that the combination brings together insulin-dependent and insulin-independent mechanisms of action. Additionally, SGLT-2 inhibitors’ efficacy has been shown to be blunted by a paradoxical rise in hepatic glucose production, which a paired DPP-4 inhibitor could counter (since incretins inhibit glucagon production), raising the possibility of synergistic additional efficacy. Of course, this incremental additional efficacy in one oral pill is still be valuable if it comes with no additional safety or tolerability issues. We also wonder if the arithmetic may have been skewed by an aberrantly high performance from the dapagliflozin arm; in dapagliflozin’s phase 3 program, we generally saw A1c reductions more on the order of 0.8-0.9%. However, the relatively high efficacy seen with Forxiga/Farxiga in this trial could also have been due to high baseline A1c levels.
• Lilly/BI’s “empa/lina” (empagliflozin/linagliptin) FDC is AZ’s most direct competitor in the development of a DPP-4/SGLT-2 inhibitor FDC. Empa/lina is ahead of saxa/dapa in the US but behind in the EU: it was filed in the US earlier this year and should be submitted in Europe in 2015 (read our report on the compound’s FDA submission), while AZ plans to submit saxa/dapa in both the US and EU in 4Q14. In the future, Merck and Pfizer plan to combine their partnered phase 3 SGLT-2 inhibitor ertugliflozin and Merck’s market-leading DPP-4 inhibitor Januvia (sitagliptin), although this might be complicated somewhat by Pfizer’s quest to acquire AZ. If that acquisition to occur, we wonder which fixed-dose combination would come out on top – at this point, it is anyone’s guess. We would presume that Novartis and Takeda, the other major DPP-4 inhibitor manufacturers, might be looking to partner with an SGLT-2 inhibitor and get into the SGLT-2 inhibitor/DPP-4 inhibitor FDC game as well. At the moment, J&J’s Invokana (canagliflozin) is the only broadly approved SGLT-2 inhibitor without a paired DPP-4 inhibitor prospect, as of yet.
• Earlier this year, AZ’s other major Forxiga-related FDC, Xigduo (dapagliflozin/metformin IR), was approved in Europe – read our report on the approval for more details. Currently, Xigduo is available as a twice-daily tablet (metformin extended-release is not available in Europe); AZ expects a regulatory decision from the FDA in 4Q14 on a once-daily dapagliflozin/metformin XR formulation. J&J’s Vokanamet (canagliflozin/metformin) was approved in Europe in April (read our report); the combination received a Complete Response Letter from the FDA in November requesting additional data, but J&J re-filed the drug earlier this year. 

Close Concerns’ Questions

• Why might saxa/dapa have a much-less-than additive glycemic effect than each individual component when they operate by independent mechanisms?
• Was weight loss on saxa/dapa greater than weight loss on either agent alone?
• What will be the primary endpoint of the phase 3 type 1 diabetes trial for Forxiga? We presume that something like reduction in daily insulin requirement would make sense.
• Will the type 1 diabetes trial investigate measure of glycemic variability?
• Will this phase 3 type 1 diabetes trial serve as the single registrational trial for this indication or are other studies planned?

--by Manu Venkat, Jessica Dong, and Kelly Close