Since the approval of the first SGLT2 canagliflozin by FDA as an anti-diabetic drug in 2013, the battle for supremacy in drugs used for glycemic control only got more heated. The battle ground was earlier dominated by the DPP4 inhibitors and GLP1 agonists. While the DPP4 agonist benefits from being an oral drug, the injectable GLP1 reined in potential benefits in obese or overweight type 2 diabetes (T2D) patients. With Novo Nordisk recently scoring FDA approval for the first oral GLP1 with semaglutide, interesting times lie ahead on potential reshaping of the market composition.
SGLT2 inhibitors have long gained from potential benefit in cardiovascular risk reduction in Type 2 diabetes (T2D) patients. Beyond the perceived benefit driving use for glycemic control, formal FDA support with clinical data backing came through in December 2016 when Boehringer Ingelheim and Eli Lily’s Jardiance (empagliflozin) gained the stamp of FDA approval for reduction of cardiovascular death in Type 2 diabetic patients with established cardiovascular disease. The approval was based on data from the EMPA-REG OUTCOME trial that demonstrated a 14% reduction in the combined primary endpoint of cardiovascular death, non-fatal heart attack or non-fatal stroke versus placebo and a 38% reduction in the risk of cardiovascular death versus placebo. This triggered investments from other SGLT2 developers as well to pursue claims around cardiovascular benefits. The last few months are significant for additional developments that establish use of SGLT2 inhibitors in cardiovascular indications and break new ground in indication expansion. Developments in May and June 2020 lay the foundation for the three FDA approved SGLT2 inhibitors to address unmet clinical need in cardiovascular indications and also provide substantial fillip to revenue potential.
One of the three FDA approved SGLT2 inhibitors, AstraZeneca’s Farxiga (dapagliflozin) has now been approved for cardiovascular indications even in patients who are not diabetic. Earlier in May this year, Farxiga was approved by FDA to treat patients with heart failure with a reduced ejection fraction (HFrEF) (LVEF ≤ 40%) and reduce risk of cardiovascular death and hospitalization for heart failure (Hhf) with and without type-2 Diabetes. Farxiga’s May approval was based on two Phase III trials DAPA-HF and DELIVER showing that Farxiga lowered the risk of worsening heart failure or death from cardiovascular causes by 26% over standard-of-care among those who received dapagliflozin compared to those who received placebo in patients with heart failure and a reduced ejection fraction regardless of whether they were diabetic or not.
Now in July 2020, Farxiga has received FDA’s Fast Track Designation to add yet another cardiovascular indication for the drug as it aims to investigate Farxiga in reducing the risk of hospitalization for heart failure and cardiovascular death in adults following an acute myocardial infarction or heart attack. The designation has been granted on the basis of phase III DAPA-MI (DAPAgliflozin Myopcardial Infraction) trial which has also been granted Special Protocol Assessment (SPA), a rare approval granted for a study design confirming that it is acceptable for a marketing application in the future. This trial will be the first indication-seeking registry-based randomised controlled trial that will provide quicker access to data and reduce recruitment time and cost, thereby minimising burden on patient and investigator. This trial will involve 6400 patients from 50 sites in Sweden and 50 in U.K. and will be in collaboration with U.K.’s Uppsala Clinical Research Centre and Myocardial Ischaemia National Audit Project, it expects to begin recruiting patients in the fourth quarter of 2020.
Similarly, in June 2019, the FDA had also granted breakthrough designation for empagliflozin to be evaluated for reduction of cardiovascular death/ hospitalization for heart failure for patients with chronic heart failure. July has been doubly beneficial for SGLT2 inhibitors and cardiovascular treatment possibilities. Boehringer Ingelheim and Eli Lilly have inched closer to approval with the announcement of positive top line results from the EMPEROR-Reduced phase III trials for empagliflozin. The trails covered 3,730 patients for investigating safety and efficacy of Jardiance in patients with heart failure with reduced ejection fraction and 5990 patients with heart failure with preserved ejection fraction. While trial outcomes are yet to be published, the companies have reported that primary endpoint has been met demonstrating benefit of Jardiance® in reducing risk of cardiovascular death or hospitalization due to heart failure. This sets the stage for another SGLT2 inhibitor soon gaining approval for cardiovascular conditions in non-diabetic patients.
The expansion of the SGLT2 inhibitors provides much needed life cycle extension in the context of impending genericization. FDA has granted tentative approval to multiple generics for dapagliflozin; and the first drug substance patent as well as exclusivity for use in Type-2 diabetes expire in 2020. With the May 2020 approval for cardiovascular conditions, while no additional patents have been filed, exclusivity now extends until 2023. These indication expansions are great benchmarks for rigorous data driven efforts to address meaningful clinical unmet needs in an area of high perceived benefit.