Pipeline Pulse: A look at tirzepatide, ziltivekimab and obicetrapib
Click Here to Manage Email Alerts
The field of cardiology has seen stunning advances in the past several years: HF, dyslipidemia and cardiomyopathy are just three of the disorders in which there have been recent practice-changing therapeutic innovations.
Unfortunately, many cardiologists find themselves inadequately prepared when novel treatments hit the market. Nonetheless, physicians are routinely asked to immediately and seamlessly incorporate new modalities into our clinical approach. Absent meaningful forewarning, this can be impossible.
Consequently, adoption lag times for important new treatments have become unacceptable. As of 2020, for example, cardiologists were responsible for only 1.5% and 0.4% of SGLT2 inhibitor and GLP-1 receptor agonist prescriptions, respectively, even though these therapies carry important FDA CV indications. A major cause for our slow medication adoption is simply our unawareness of potential emerging therapies. As noted above, physicians usually do not develop a solid understanding of new drugs until after they have entered the market. And that is the reason for this new column.
Introducing Pipeline Pulse
The Pipeline Pulse column will succinctly highlight several therapies in development, describing mechanisms of action, current pertinent clinical trials and their potential future place in the therapeutic armamentaria.
As cardiologists, having your finger on the pulse of drug development will put you in a better position to accelerate your adoption of newly approved therapies and promptly provide them to your patients in need.
This first column reviews three drugs in development: tirzepatide (Mounjaro, Eli Lilly) for HF with preserved ejection fraction, ziltivekimab (Novo Nordisk) for inflammation in CVD and chronic kidney disease (CKD), and obicetrapib (NewAmsterdam Pharma) for hypercholesterolemia in high-risk patients.
Tirzepatide
Tirzepatide is a glucose-dependent insulinotropic polypeptide (GIP) and GLP-1 dual agonist currently being evaluated in multiple phase 3 studies in patients with diabetes, obesity and HFpEF. Together, through both central and peripheral effects, these two agonists decrease appetite, delay gastric emptying, improve insulin sensitivity, decrease BP, and diminish fibrosis and inflammation.
In 2022, tirzepatide was approved for the treatment of type 2 diabetes. Remarkably, it was also shown to cause unprecedented, sustained weight loss of up to 20% in people without diabetes.
Specific attributes of tirzepatide that have led to its consideration in HFpEF include anti-inflammatory, antifibrotic, weight loss, epicardial fat loss and volume contraction. As HFpEF is a complex clinical syndrome with significant inflammatory and fibrotic components, impacting mostly patients with overweight or obesity, there is a clear scientific rationale for studying tirzepatide in this setting. Nearly 50% of Americans have obesity, and HFpEF is increasing in prevalence in parallel with obesity. It is not hyperbole to predict an HFpEF epidemic in the near future. Thus, we need to find targeted solutions to obesity-related HF.
SUMMIT, a randomized, double-blind, placebo-controlled, phase 3 study comparing efficacy and safety of tirzepatide vs. placebo in patients with HFpEF and obesity, is assessing functional and symptomatic endpoints as well as clinical HF outcomes. By reducing body weight, epicardial fat, volume overload, fibrosis and inflammation, tirzepatide addresses the key elements in obesity-related HFpEF that could lead to significant improvement. Should SUMMIT succeed, it may lead to a unique therapeutic option to treat the increasingly prevalent disorder of obesity-related HFpEF.
Ziltivekimab
Ziltivekimab, an anti-inflammatory fully human monoclonal antibody to interleukin (IL)-6, is being studied in ZEUS, a phase 3 CV outcomes trial.
Based on multiple lines of evidence, we now understand that inflammation plays a critical role in atherosclerotic CVD. Studies such as CANTOS and COLCOT have paved the way for ZEUS by producing promising results.
CANTOS evaluated canakinumab, a monoclonal antibody that reduces IL-beta, the cytokine upstream of IL-6. In a prespecified analysis, patients with the greatest reduction in inflammation — largest decrease in C-reactive protein and IL-6 — achieved the most significant reductions in CV endpoints. Importantly, those with moderate CKD experienced even greater benefit. This stands to reason as CKD is a highly inflammatory state, one that greatly increases the risk for ASCVD events.
COLCOT and LoDoCo2 studied the effects of colchicine, an anti-inflammatory drug that works through the disruption of neutrophil microtubules. In patients with recent MI, colchicine led to a significant reduction in recurrent CV events. Importantly, colchicine was not only effective, but it also had an excellent safety profile.
In ZEUS, IL-6, the cytokine central to the inflammatory response and a key driver of inflammatory conditions as well as the release of CRP, is targeted by ziltivekimab. The patient population being studied has been highly enriched for risk: Established ASCVD, moderate CKD and an elevated CRP are all inclusion criteria. Thus, event rates should be high in this study, yielding informative results. Should ZEUS be positive, anti-inflammation will likely become commonplace in the management of ASCVD, the persistent worldwide leading cause of death.
Obicetrapib
Obicetrapib, a cholesteryl ester transfer protein (CETP) inhibitor, is being studied in two pivotal phase 3 trials, PREVAIL and BROADWAY.
It has been firmly established that decreasing LDL reduces CV events in a linear fashion. Each 40 mg reduction in LDL yields an approximately 21% RR reduction in CV events. And, the greater a patient population’s CV risk, the greater their absolute risk reduction will be. For this reason, these studies are evaluating high-risk patients with persistently elevated LDL, established ASCVD and/or heterozygous familial hypercholesterolemia.
When we think of CETP inhibitors, however, we often consider just their HDL-augmenting properties, and we remember their prior failed CV outcome trials. It is important to note, though, that not all CETP inhibitors are created equal. In addition to its significant HDL-raising effect, obicetrapib has a uniquely powerful LDL-reducing effect, decreasing LDL by 50% in phase 2 studies. Principally circulating on HDL particles, CETP facilitates the exchange of cholesteryl esters for triglycerides between HDL and the apolipoprotein B-containing (atherogenic) lipoprotein particles LDL and VLDL. Inhibition of this transfer decreases LDL and ApoB-containing lipoprotein particles while increasing HDL. Although the history of CETP inhibitor CV outcome trials has been uninspiring, it is important to recognize that issues with prior trials included significant off-target adverse effects.
The focus in prior CETP studies was to increase HDL; LDL was not a primary target. Though we learned from these prior studies that increasing HDL does not reduce the risk for CV events, we also learned from REVEAL, which evaluated anacetrapib, that a mere 17% reduction in LDL was linked with a significant reduction in CV events. This further reinforced our knowledge that LDL reduction predictably diminishes CV events.
Thus, in the case of obicetrapib, with its 50% decrease in LDL, this CETP inhibitor may finally become the first in its class to achieve meaningful reductions in CV events. Of course, in this case, as in that of the other aforementioned drugs in development, we will have to wait for the results before declaring victory.
I hope you enjoyed this first Pipeline Pulse and look forward to sharing more exciting information with you.
Editor’s note: Information in this article was up to date as of the time of publication.
References:
- Adhikari R, et al. J Am Heart Assoc. 2022;doi:10.1161/JAHA.121.023811.
- Clinicaltrials.gov. clinicaltrials.gov/ct2/show/NCT04847557. Published April 19, 2021. Accessed Oct. 24, 2022.
- Clinicaltrials.gov. clinicaltrials.gov/ct2/show/NCT05021835. Published Aug. 26, 2021. Accessed Oct. 24, 2022.
- Clinicaltrials.gov. clinicaltrials.gov/ct2/show/NCT05142722. Published Dec. 3, 2021. Accessed Oct. 24, 2022.
- Clinicaltrials.gov. clinicaltrials.gov/ct2/show/NCT05202509. Published Jan. 21, 2022. Accessed Oct. 24, 2022.
- The HPS3/TIMI55–REVEAL Collaborative Group. N Engl J Med. 2017;doi:10.1056/NEJMoa1706444.
- Nidorf SM, et al. N Engl J Med. 2020;doi:10.1056/NEJMoa2021372.
- Ridker PM, et al. N Engl J Med. 2017;doi:10.1056/NEJMoa1707914.
- Tardif JC, et al. N Engl J Med. 2019;doi:10.1056/NEJMoa1912388.
For more information:
Seth J. Baum, MD, is chief scientific officer at Flourish Research and clinical affiliate professor of cardiology at the Florida Atlantic University Charles E. Schmidt College of Medicine. He is also a member of the Cardiology Today Editorial Board. Baum can be reached at sjbaum@fpim.org; Twitter: @sethjbaummd.
Collapse
Read more about
Click Here to Manage Email Alerts