Memorandum

FDA grants first-in-class hospitalization for heart failure indication to AZ’s SGLT-2 inhibitor Farxiga – October 21, 2019

See updated label here; Reduction in hHF for patients with established CVD or multiple risk factors; Decision comes ahead of predicted 1Q20 date

AZ announced today that FDA has granted a first-of-its-kind indication to SGLT-2 inhibitor Farxiga (dapagliflozin) for the reduction of hospitalization of heart failure (hHF) in patients with type 2 diabetes and established CVD or with multiple CV risk factors. See the updated label here.

The new indication comes considerably sooner than the previously expected 1Q20 date, and we salute both FDA and AZ for expediting this updated label which represents a huge win for patients and the entire diabetes community. Considering that patients with type 2 diabetes are at a 2.5-times greater risk of developing heart failure compared to background populations, the approval potential is hugely exciting and could significantly impact current paradigms of care. On this note, we’re thrilled to see AZ’s continued commitment to earlier intervention, particularly at a time when translation isn’t altogether straightforward, especially in the US. In the company’s press release accompanying this news, Mr. Ruud Dobber, Executive Vice President of AZ’s Biopharmaceuticals Business Unit, commented, “Farxiga now offers the opportunity for physicians to act sooner and reduce the risk of hospitalization for heart failure.”

Approval was based off of positive results from the DECLARE-TIMI 58 CVOT, which demonstrated a 17% relative risk reduction (RRR) on the co-primary endpoint of hHF and CV death vs. placebo (HR=0.83, 95% CI: 0.73-0.95, p=0.005 for superiority). Benefit on hHF was the primary driver of superiority, with a substantial 27% RRR (HR=0.73, 95% CI: 0.61-0.88), explaining the FDA’s selective approval of hHF rather than a dual CV death/hHF indication. Notably, ~60% of total DECLARE trial enrollees were in the primary prevention cohort, making it one of the most generalizable SGLT inhibitor CVOTs to date. It’s likely that this broader population (and Farxiga’s consistent effect on hHF in primary and secondary prevention populations in DECLARE) led to FDA expanding Farxiga’s CV indication to people with multiple CV risk factors as well (not just established CVD) – a first for an SGLT-2 inhibitor. See our comparison table below for more.

The news comes on the heels of a more comprehensive EU label expansion this past August to add CV and renal data from DECLARE to the Forxiga label, following a positive CHMP opinion in July. Though renal benefits were not included in today’s new FDA approval, dapagliflozin was recently given Fast Track designation in August as a treatment to slow the progression of renal failure and prevent CV and renal death in patients with chronic kidney disease (CKD) based on the ongoing DAPA-CKD trial, which is expected to complete in November 2020. The drug also received Fast Track designation to reduce the risk of CV death, or the worsening of HF, in adults with HF with reduced ejection fraction (HFrEF) or preserved ejection fraction (HFpEF) in September, backed by landmark positive results from the DAPA-HF trial. Farxiga is also currently under regulatory review in China with a decision expected 1H20.

  • In an interview with our team, Ms. Kiersten Combs, Vice President of US Cardiovascular & Metabolic Disease, highlighted Farxiga’s future as an expansive treatment option for a variety of type 2 co-morbidities. She explained, “for us, this is the beginning of an exciting time for Farxiga. As you know, we’re anticipating the DAPA-HF indication sometime next year, we have data in DAPA-CKD reading out in the near future, and we have dapagliflozin being studied in HFpEF. So, this is the beginning of a new paradigm for Farxiga, not only to treat diabetes differently, but also the possibility of treating conditions like CKD and HF in the future. It truly could be a gamechanger.” Ms. Combs pointed out that while the current indication only applies to prevention rather than treatment of HF, which will be addressed with DAPA-HF in the future, the label update gives “the opportunity to talk to PCPs, cardiologists, endocrinologists, about how they are treating patients with diabetes and how they are lowering A1c.”

SGLT-2 Inhibitors CV Indications Comparison

  • Although a class effect for SGLT-2 inhibitors in reducing cardiovascular complications appears to be fairly well-cemented, the CV labels for the class are quite heterogeneous. Reflecting the unique study designs and populations of each therapy’s respective CVOT, each member of the class has garnered a different CV indication from FDA. While our sense is that HCPs view members of the class as somewhat interchangeable in terms of benefits derived for patients (some doctors reference certain ones prompting more weight loss is one smaller difference we’ve seen), we are uncertain to what degree, if any, this differential labelling may influence payer discussions and formulary positioning, along with patient impressions of the class. We are also not sure to what extent there may be more questions surrounding the complexity. Ultimately, we believe the field is thrilled to see three SGLT-2 inhibitors on the market now with approved CV indications – what a huge win for patients and the entire community.

SGLT-2 Inhibitor CV Indications

Drug

CV Indication Language by FDA

Date Granted

Jardiance (Lilly/BI’s empagliflozin)

Reduce CV death in people with type 2 diabetes and established CVD

December 2016

Invokana (J&J’s canagliflozin)

Reduce MACE (heart attack, stroke, and CV death) in people with type 2 diabetes and established CVD

(Invokana also has its novel renal indication)

October 2018

Farxiga (AZ’s dapagliflozin)

Reduce hospitalization for heart failure in people with type 2 diabetes and established CVD or multiple CV risk factors

October 2019

SGLT-2 Inhibitors in Heart Failure Landscape

  • Looking at the overall SGLT-2 landscape, multiple companies have an array of heart failure trials in progress. Most recently, the FDA granted Fast Track designation to Lilly/BI’s Jardiance (empagliflozin) in June for chronic heart failure in patients with or without diabetes and a similar designation to Farxiga in September.

Ongoing SGLT-2 Inhibitor Heart Failure Clinical Trials 

Drug

Sponsor

Trial Name

Population

Expected Completion Date

Jardiance (empagliflozin)

Lilly/BI

EMPEROR HF-Preserved

Heart failure with preserved ejection fraction (n=5,250)

 

June 2021

Jardiance (empagliflozin)

Lilly/BI

EMPEROR HF-Reduced

Heart failure with reduced ejection fraction (n=3,600)

 

June 2021

Jardiance (empagliflozin)

Lilly/BI

EMPERIAL-PRESERVED

Heart failure with preserved ejection fraction (n=300); walk test

June 2020

Jardiance (empagliflozin)

Lilly/BI

EMPERIAL-REDUCED

Heart failure with reduced ejection fraction (n=300); walk test

June 2020

Farxiga (dapagliflozin)

AZ

DAPA-HF

Chronic heart failure with reduced ejection fraction (n=4,744)

Completed

Farxiga (dapagliflozin)

AZ

DEFINE-HF

Chronic heart failure with reduced ejection fraction (n=263)

Completed

Farxiga (dapagliflozin)

AZ

DELIVER

Heart failure with preserved ejection fraction (n=4,700)

June 2021

Farxiga (dapagliflozin)

AZ

DETERMINE-PRESERVED

Heart failure with preserved ejection fraction (n=400); walk test

February 2020

Farxiga (dapagliflozin)

AZ

DETERMINE-REDUCED

Heart failure with reduced ejection fraction (n=300); walk test

January 2020

Zynquista (sotagliflozin)

Sanofi/Lexicon

SOLOIST-WHF

Type 2 diabetes and heart failure (n=4,000), with prespecified subpopulation examination of those with type 2 and heart failure with LVEF <50% after admission for worsening heart failure

January 2021

Close Concerns Questions

  • When should Farxiga be prescribed to provide maximum hHF benefit?

  • Are any efforts being made to include CV death on an indication?

  • How does this indication complement or contrast from that intended for DAPA-HF in HFrEF?

  • What work is being done on translating FDA labels to ensure awareness and use by endocrinologists, cardiologists, nephrologists, PCPs, internists, family practitioners, pharmacists, nurses, patient advocates, and patients? What work should be done with each population?

  • How to best show ROI on improved outcomes from health economics perspective?

 

--by Rhea Teng, Martin Kurian, and Kelly Close