Biopharmaceutical Report II
• Superiority to standard therapy bodes well for approvals
• Regulators may require dropout explanation
• Good potential for first line and combination use
Novartis’ (VTX:NOVN) LCZ696 will likely secure EMA and FDA approval after showing Phase III superior efficacy over generic comparator enalapril in chronic heart failure (CHF), experts said. Reducing cardiovascular (CV) deaths and hospitalisations will likely be looked at favourably by regulators, they added.
The PARADIGM-HF study enrolled 8,436 HF with reduced ejection fraction (HF-REF) patients to evaluate the efficacy and safety of LCZ696 versus standard of care angiotensin-convertingenzyme (ACE) inhibitor enalapril.
At the third interim analysis of PARADIGM-HF, the Data Monitoring Committee (DMC) confirmed the primary composite endpoint had been met, showing LCZ696 delayed CV death and reduced HF hospitalizations versus enalapril, according to a 31 March press release. The analysis also confirmed significance on reduction of CV death against enalapril independently, according to a Novartis spokesperson.
The PARADIGM-HF data is likely to show at least 15% reduction in the composite primary endpoint with LCZ696 use over enalapril and the full data set will be presented at the European Society of Cardiology meeting in August and submitted to the New England Journal of Medicine, this news service recently reported.
LCZ696 twice-daily pill, is an Angiotensin Receptor Neprilysin Inhibitor (ARNI) thought to reduce the strain on the failing heart, promoting the ability of the heart muscle to recover, according to Novartis’ website.
A 20% or above reduction in the risk of mortality would be extremely useful and show a clear additional benefit for LCZ696 over standard of care
Added mortality benefit sufficient for approval
Phase II data and an early trial closure after an interim analysis, shows the clear clinical treatment benefit of LCZ696 and a potential mortality benefit which will be looked at favourably by regulators, said Dr. Miguel Camafort-Babkowski, cardiologist, IDIBAPS Hospital Clinic, Barcelona, Spain. A 20% or above reduction in the risk of mortality would be extremely useful and show a clear additional benefit for LCZ696 over standard of care, agreed Shelby Reed, Assistant Professor, Duke Clinical Research Institute, Durham, North Carolina.
The early trial closure provides unequivocal evidence for superiority of LCZ696 over enalapril which should be sufficient for approval in HFREF, an investigator agreed. The combined endpoint of CV death and hospitalizations is difficult to meet in such a large HF trial, a second investigator said, adding if it met statistical significance as expected, this should be sufficient for FDA and EMA approval.
LCZ696 is likely to exceed the bar for approval if there is a clear mortality benefit, agreed Reed, adding even if the mortality benefit is not statistically significant, approval chances are high because CV death and hospitalizations are both important and rigorous endpoints. All-cause mortality is a secondary endpoint, according to ClinicalTrials.gov.
Given the number of approved treatments for HF-REF, the regulatory agencies are likely to scrutinize LCZ696 data to ensure superior safety and efficacy over standard of care, CamafortBabkowski said.
This head-to-head trial design with gold standard 10mg enalapril twice daily is important to clearly show superiority and avoid skepticism, a third investigator said. Clear efficacy on top of optimal background care will be looked at favorably in the eyes of regulators, Reed said.
Safety an unlikely hurdle though dropouts need clarification
Although efficacy is clear, LCZ696 has a number of hoops to go through before approval, including quantitative evidence that it is well tolerated and safe, a fourth investigator said, though agreed that based on safety data he had seen, approval is achievable.
It is unlikely that there will be significant safety signals based on Phase II data, Reed and Camafort-Babkowski agreed. However, because of its dual mechanism of action and targeting beta amyloid metabolism, there is a theoretical possibility that this could contribute to development of Alzheimer’s disease or other cognitive impairments with long term use, Camafort-Babkowski added, though this may not be evident in PARADIGM-HF.
The dropout rate in PARADIGM-HF is as expected in a CHF trial of this size and investigators estimated 15%-20% dropout, this news service recently reported. This rate may be too high for regulators and could hold up an approval as the company will need to explain the reasons for such a high dropout rate, CamafortBabkowski said. Feedback from the FDA and EMA during Novo Nordisk’s (NYSE:NVO) Victoza (liraglutide) for diabetes said a threshold of up to 15% dropout was tolerable, and CV indications are assessed similarly, he added.
All experts agreed that LCZ696 has good potential for use in combination to standard of care and drug interactions should be tested in future studies.
Many factors contribute to a high dropout rate and a 15%-20% dropout will not necessarily hinder approval, Reed said. Dropout rates can be a result of trial location, conduct or individual patient differences rather than a negative reflection of the drug’s safety profile, she said, but agreed regulators will require explanations for these high rates.
No apparent safety concerns have been noted by the DMC after three interim analyses and multiple safety reviews of the data, according to the spokesperson.
First-line treatment as it trumps best ACE inhibitor
Despite numerous options for HF-REF, there is a persistently high mortality rate in these patients, the third investigator said. All experts agreed there has been a plateau in CHF treatments and regulators are well aware of the clinical need for options with added benefits over the standard of care. Enalapril and other ACE inhibitors have dominated the CHF market since the first approval 27 years ago and very few drugs have changed the treatment paradigm, the third investigator said. LCZ696 has potential to be a first-line treatment in HF-REF because of its superiority to enalapril, the first and fourth investigators said.
LCZ696 has peak sales forecast of USD 3bn, according to an analyst report.
Regulators may ask for further studies to assess LCZ696’s safety in combination with standard therapies including ACE inhibitors, angiotensin II receptor blockers (ARBs) and beta blockers because in clinical practice it is likely to be used in combination regimens, CamafortBabkowski said, though noted this would not be a requirement for approval.
All experts agreed that LCZ696 has good potential for use in combination to standard of care and drug interactions should be tested in future studies
Subsequent trials will need to assess LCZ696’s efficacy in other CHF patients subgroups for a broader label, the fourth investigator and Camafort-Babkowski said. CHF with preserved ejection fraction is where the biggest clinical need is, the first investigator agreed, adding this is the next step for Novartis as the Phase III PARAGON-HF trial (NCT01920711) will start recruitment soon.
Novartis has a market cap of CHF 196.8bn (EUR 161.2bn).
Jinan was a freelance journalist before joining BioPharm Insight, writing for numerous magazines and websites covering health and science stories. She has a BSc in Physiology from King’s College London and an MA in Science Journalism from City University London.