ADA 2015: TECOS study demonstrates Januvia’s cardiovascular safety.
CV safety data will ensure Merck & Co’s $6bn blockbuster Januvia continues its dominance over rivals Onglyza and Nesina
By Rajan Sharma, Senior Analyst
12 June 2015
I joined Datamonitor Healthcare in late in 2013 after completing a Masters in Pharmacology from the University of Oxford...
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Merck & Co presented data from its large-scale, placebo-controlled trial investigating the cardiovascular (CV) safety of its dipeptidyl peptidase-IV (DPP-IV) inhibitor Januvia (sitagliptin). The results were presented at the 75th Scientific Sessions of the American Diabetes Association (ADA), held on 8 June 2015, in a symposium titled “Results from the Trial to Evaluate Cardiovascular Outcomes after Treatment with Sitagliptin (TECOS)”. The TECOS study achieved its primary endpoint of non-inferiority on a composite of the first confirmed event of CV-related death, non-fatal myocardial infarction (MI), non-fatal stroke, or hospitalization for unstable angina compared to standard of care without Januvia. This positive outcome will allow the Januvia franchise to maintain its dominant position in the lucrative non-insulin type 2 diabetes market.
Fewer Januvia-treated patients reached the primary endpoint compared to placebo. The trial also met its secondary endpoint, thereby providing further reassurance of Januvia’s CV safety. The data were particularly favorable for Merck & Co as there was no significant increase in the rate of hospitalizations due to heart failure when compared to the cardiovascular outcomes trials (CVOTs) of rival brands.
Overview of TECOS study primary outcomes data
|Proportion of patients reaching primary composite CV outcome||11.4% (4.06 events per 100pyrs)||11.6% (4.17 events per 100pyrs)|
|Hospitalization for UA||1.5%||1.6%|
|CV = cardiovascular; MI = myocardial infarction; pyrs = patient-years; UA = unstable angina|
|Source: ADA, 2015|
TECOS is the third completed CVOT investigating a DPP-IV inhibitor. Data from the EXAMINE and SAVOR TIMI-53 studies investigating Nesina (alogliptin; Takeda) and Onglyza (saxagliptin; AstraZeneca/Otsuka) respectively have already been released and suggest an increased CV risk associated with both drugs. Although Onglyza and Nesina demonstrated non-inferiority to placebo in terms of CV-related death, non-fatal MI, and non-fatal stroke, both were associated with an increased rate of hospitalization for heart failure. Data from a fourth DPP-IV inhibitor CVOT trial investigating Tradjenta (linagliptin; Eli Lilly/Boehringer Ingelheim) are expected to be released in 2018 (ClinicalTrials.gov identifier: NCT01243424).
DPP-IV inhibitors’ cardiovascular safety compared to placebo
|Primary composite endpoint of CV death, non-fatal MI, or non-fatal stroke hazard ratio||0.98 (p=0.89)||0.96 (p=0.315)||1.00 (p=0.99)|
|MACE hazard ratio||0.99 (p=0.844)||0.96 (p=0.315)||1.00 (p=0.99)|
|Hospitalization for heart failure hazard ratio||1.00 (p=0.983)||1.19 (p=0.238)||1.27 (p=0.009)|
|CV = cardiovascular; MACE = major adverse cardiovascular event; MI = myocardial infarction|
|Source: ADA, 2015|
The data from the TECOS study are reassuring for Merck & Co and the DPP-IV inhibitor class as a whole, following some concerning data points from the EXAMINE and SAVOR TIMI-53 studies. Had the TECOS trial suggested a link between Januvia and increased CV risk, the safety of the entire drug class would have been in doubt. This would have provided the sodium-glucose cotransporter-2 (SGLT-2) inhibitor class with the opportunity to claim significant market share from the DPP-IV inhibitors. The SGLT-2 inhibitor class’s oral administration and good efficacy mean it would be the class most likely to gain from uncertainty surrounding the use of DPP-IV inhibitors. However, with the positive data from the TECOS study, Datamonitor Healthcare expects Januvia to remain the dominant second-line antidiabetic therapy after the failure of metformin.
Given Januvia’s financial importance to Merck & Co, the success of the TECOS study was of huge significance. Januvia was the company’s biggest selling brand in 2014 and the franchise contributed $6bn of combined global revenue. Unlike rival DPP-IV inhibitor developers AstraZeneca and Boehringer Ingelheim, Merck has no other marketed oral antidiabetics and its developmental SGLT-2 inhibitor, ertugliflozin, is not expected to reach the type 2 diabetes market until 2017. A negative outcome from the TECOS trial would have left the company vulnerable to any reduction in use of the class, with no alternative offerings to stymie the potential loss of revenue.
The trial data reinforce Januvia’s position as the first-choice DPP-IV inhibitor across the US, Japan, and five major EU markets (France, Germany, Italy, Spain, and the UK). Although Datamonitor Healthcare’s primary research indicates that physicians view the DPP-IV inhibitors as largely homogenous from a clinical perspective, Januvia has established a leading position due to its first-to-market status and Merck & Co’s subsequent shrewd marketing. TECOS’s positive outcome now affords Merck a point of clinical differentiation over key rivals Nesina and Onglyza, and Datamonitor Healthcare expects Januvia’s neutral CV data to strengthen its market-leading position, particularly as CV safety data for Tradjenta are not expected until 2018. CV safety is especially pertinent in the type 2 diabetes space given the strong association with CV mortality. Januvia may consequently draw share from Nesina and Onglyza as risk-averse primary care physicians move away from molecules which may increase the risk of a CV event.