AstraZeneca's CVRM Path

AstraZenca’s Joris Silon, Senior Vice President, CVRM (Cardiovascular, Renal and Metabolism), of the BioPharmaceuticals Business Unit, outlines the potential impact on type-2 diabetes and chronic kidney disease of SGLT2 inhibitors such as Forxiga.

PharmExec: Can you outline the importance and potential impact on the T2D space of the latest results for Forxiga/Farxiga?

Joris Silon

Joris Silon: The CVD-REAL 3 data recently published in The Lancet Diabetes & Endocrinology evaluated renal outcomes in patients with type-2 diabetes (T2D), and found that treatment with SGLT2 inhibitors, such as Forxiga, are associated with the prevention of chronic kidney disease (CKD) progression.¹ These new results from the CVD-REAL study are significant as they highlight the potential of SGLT2 inhibitors to treat the cardio-renal complications often faced by the estimated 425 million people worldwide living with T2D.²

In addition, previous data readouts from CVD-REAL have shown that initiation of SGLT2 inhibitor treatment was associated with a significantly lower risk of cardiovascular events, hospital admission for heart failure (HF) and death compared to other glucose-lowering drugs.^3,4

Similarly, what is the outlook for the treatment in the CKD space?

CKD is a serious, progressive condition defined by decreased kidney function that affects nearly 200 million adults globally.^5,6 The CVD-REAL 3 data recently published in Lancet Diabetes & Endocrinology provide real-world evidence that SGLT2 inhibitors, such as Forxiga, are associated with a slower rate of kidney function decline and lower risk of major kidney events compared with other glucose-lowering drugs.¹ These results build on previously reported data from three randomized controlled trials showing the benefits of SGLT2 inhibitors on preserving kidney function rates and reducing risk of major kidney events.^7-9 These findings underscore the value of SGLT2 inhibitors in slowing the progression of CKD in a contemporary population of patients with T2D and suggest that the benefits observed in clinical trials can be extended in daily clinical practice.

Are there other therapy areas where there is potential for SGTL2 inhibitors? How will SGTL2 inhibitors fit into AZ’s research/pipeline going forward?

AstraZeneca’s mission is to protect the lives of 130 million people from the often-devastating consequences of HF, cardiovascular, metabolic and renal diseases, and to evolve clinical practice to address unmet medical needs. CVRM diseases are the leading causes of death across the globe, killing more than 20 million people each year,^10,11 and we work every day to develop and grow a portfolio of medicines focused on addressing multiple risk factors or comorbidities across our disease areas under CVRM.

Forxiga has a robust programme of clinical trials that includes more than 35 completed and ongoing Phase IIb/III trials in more than 35,000 patients, as well as more than 2.5 million patient-years’ experience.

Forxiga  is already indicated as both monotherapy and as part of combination therapies to improve glycaemic control, as an adjunct to diet and exercise in adults with T2D. It is also indicated to reduce the risk of hospitalisation for HF in patients with T2D and established cardiovascular disease or multiple cardiovascular risk factors in the US.

On January 6, AstraZeneca announced that the FDA accepted a supplemental New Drug Application (sNDA) and granted Priority Review for Forxiga (known as Farxiga in the US) to reduce the risk of cardiovascular (CV) death or the worsening of HF in adults with HF with reduced ejection fraction (HFrEF), with and without type-2 diabetes (T2D). The Prescription Drug User Fee Act date, the FDA action date for this supplemental application, is scheduled for the second quarter of 2020. The FDA had previously granted Farxiga Fast Track designation in September 2019. If approved, Farxiga will be the first medicine of its kind indicated to treat patients with HF.

Forxiga is also being evaluated as a treatment option for the prevention and treatment of CKD, supported by data from the DECLARE and DAPA-HF trials. CVD-REAL 3 provides further support and continues the dialogue leading up to findings anticipated from the DAPA-CKD study in 2020.

What were the challenges of devising and coordinating a RWE study of the size of CVD-REAL?

Several cardiovascular and kidney outcome trials have shown that SGLT2 inhibitors slow progression of CKD in patients with T2D with or without CKD. The aim of this study was to assess whether these benefits extend to patients with T2D treated in routine clinical practice.

CVD-REAL 3 was a multinational observational cohort study in which new users of SGLT2 inhibitors and other glucose-lowering drugs with measurements of estimated glomerular filtration rate (eGFR) before and after (within 180 days) initiation were identified via claims, medical records and national registries. The study included data from more than 65,000 patients in Israel, Italy, Japan, Taiwan and the United Kingdom to provide truly global, real world evidence.¹

What do you aim to achieve from the “Diabetes Can Break Your Heart” national tour?

Diabetes Can Break Your Heart is a national movement with a goal to change the trajectory of HF in T2D. The initiative is designed to raise awareness, create community action and spark dialogue between those with T2D and their healthcare providers to help reduce the risk of HF-one of the earliest and most frequent cardiac complications for people living with T2D, often before heart attack or stroke, and an urgent public health issue.^12,13

The program will travel to several cities across America in 2020 to educate and activate communities around the inherent link between T2D and HF through an innovative and immersive experience. The tour will bring together national and local advocacy organizations, key community leaders and the public with the common goal of empowering the diabetes community to demand more for their future. To learn more about the Diabetes Can Break Your Heart movement, including the Airstream Local Market Tour, visit www.DiabetesHeartbreak.com.

What are your priorities for the Cardiovascular, Renal and Metabolism (CVRM) portfolio-and for Forxiga specifically-going into 2020 and beyond?

2019 has been a milestone year for AstraZeneca in CVRM, and I am excited about what lies ahead in 2020 as we continue to make even greater strides towards reaching our ambitions in each of our four disease areas within CVRM. Particularly in cardiovascular and renal, we are working hard to help provide solutions to patients that have seen little innovation, and have been lacking treatment options, for years.

• We are looking forward to the potential to offer Forxiga as a treatment option for the millions of patients with HF. If approved, Forxiga will be the first medicine of its kind indicated to treat patients with HF.

• Beyond Forxiga, we are excited about the potential of roxadustat, an oral first-in-class hypoxia-inducible factor prolyl hydroxylase inhibitor (HIF-PHI), which is under development for the treatment of anaemia from CKD.

• We also expect to see top line results early this year from the Phase III THALES trial, evaluating Brilinta (ticagrelor) for the reduced risk of a composite of stroke and death, in patients who experienced an acute ischaemic stroke or transient ischaemic attack. Brilinta is a P2Y12 inhibitor, currently indicated for the treatment of acute coronary syndromes and prevention of further coronary events in patients with high cardiovascular risk post-MI (myocardial infarction).

• Our CVRM path is grounded in our research, comprised of clinical trials and real-world evidence research, as well as grounded in industry and patient collaboration, empowering us to redefine the way these conditions are understood and treated, and ultimately providing real impact to patient outcomes. Looking at early treatment experiences, treatment patterns, treatment effectiveness and safety, as well as the quality of life for CVRM patients, we can assess the gaps in the overall patient journey and better understand what the patient is going through and how we can potentially help. We are committed to continuously expanding our portfolio, especially within existing treatments, and proactively addressing complications to improve patient outcomes. 

References

1.     Heerspink, Hiddo J L, et al. “Kidney Outcomes Associated with Use of SGLT2 Inhibitors in Real-World Clinical Practice (CVD-REAL 3): a Multinational Observational Cohort Study.” The Lancet Diabetes & Endocrinology, vol. 8, no. 1, Jan. 2020, pp. 27–35., doi:10.1016/s2213-8587(19)30384-5.

2.     Ogurtsova K, et al. IDF Diabetes Atlas: Global estimates for the prevalence of diabetes for 2015 and 2040. Diabetes Res Clin Pract. 2017;128:40–50.

3.     Birkeland KI, Jorgensen ME, Carstensen B, et al. Cardiovascular mortality and morbidity in patients with type 2 diabetes following initiation of sodium-glucose co-transporter-2 inhibitors versus other glucose-lowering drugs (CVD-REAL Nordic): a multinational observational analysis. Lancet Diabetes Endocrinol 2017; 5: 709–17.

4.     Kosiborod M, Birkeland KI, Cavender MA, et al. Rates of myocardial infarction and stroke in patients initiating treatment with SGLT2- inhibitors versus other glucose-lowering agents in real-world clinical practice: results from the CVD-REAL study. Diabetes Obes Metab 2018; 20: 1983–87.

5.     Mallappallil, M., Friedman, E. A., Delano, B. G., McFarlane, S. I., & Salifu, M. O. (2014). Chronic kidney disease in the elderly: evaluation and management. Clinical practice (London, England), 11(5), 525–535. doi:10.2217/cpr.14.46.

6.     Ojo A. Addressing the global burden of chronic kidney disease through clinical and translational research. Trans Am Clin Climatol Assoc. 2014;125:229-43; discussion 243-6.

7.     Wanner C, Inzucchi SE, Lachin JM, et al. Empagliflozin and progression of kidney disease in type 2 diabetes. N Engl J Med 2016; 375: 323–34.

8.     Perkovic V, de Zeeuw D, Mahaffey KW, et al. Canagliflozin and renal outcomes in type 2 diabetes: results from the CANVAS Program randomised clinical trials. Lancet Diabetes Endocrinol 2018; 6: 691–704.

9.     Mosenzon O, Wiviott SD, Cahn A, et al. Effects of dapagliflozin on development and progression of kidney disease in patients with type 2 diabetes: an analysis from the DECLARE-TIMI 58 randomised trial. Lancet Diabetes Endocrinol 2019; 7: 606–17.

10.  Wang H et al. Global, regional, and national life expectancy, all-cause mortality, and cause-specific mortality for 249 causes of death, 1980–2015: A systematic analysis for the Global Burden of Disease Study 2015. The Lancet 2016; 388(10053):1459–544.

11.  World Health Organization. (2019). World Heart Day. [online] Available at: https://www.who.int/cardiovascular_diseases/world-heart-day/en/ [Accessed 31 Jul. 2019].

12.  Packer, M. Heart Failure: The Most Important, Preventable, and Treatable Cardiovascular Complication of Type 2 Diabetes. Diabetes Care 2018;41(1):11-13.

13.  Shah AD et al. Type 2 diabetes and incidence of cardiovascular diseases: A cohort study in 1·9 million people. The Lancet Diabetes & Endocrinology 2015;3(2):105–13.