Entresto Overview

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Part
01

Entresto Drug: Challenges

Insights around the challenges of regulatory approvals for the Entresto drug include the presence of a lengthy regulatory approval process of drugs in the United States and the strict considerations put on clinical trial results before approval is granted. These two challenges were evident in the research analysis conducted on Entresto's use in the two major types of chronic heart failure disease i.e. heart failure with reduced ejection fraction (HFrEF) and heart failure with preserved ejection fraction (HFpEF). A detailed look at these insights follows below.

LENGTHY REGULATORY APPROVAL PROCESS

STRICT CONSIDERATION OF CLINICAL TRIAL RESULTS BEFORE APPROVAL




Part
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Part
02

Entresto Drug:

Entresto is available through health insurance and is distributed in hospitals, physicians' practices, and other medical institutions, in both European Union and the UK.

Entresto in the UK

  • Entresto entered the UK market in 2015 via the Early Access to Medicines Scheme (EAMS), which is a scheme used to introduce medicine into the market before it gets full marketing approval.
  • The drug is distributed through Novartis' network and was the first drug not intended to treat cancer, but has been recognized under the EAMS.
  • It is available to patients covered by the National Healthcare System (NHS). As such, it is distributed in hospitals, physicians' practices, and other medical institutions, and is covered (or partly covered) by health insurance.
  • According to NHS guidance, it can be distributed to treat adults with "symptomatic chronic heart failure (fitting the New York Heart Association’s class 11 to 1V), a left ventricular ejection fraction of 35% or less, and who are on a stable dose of ACE inhibitors or ARBs."
  • The NYHA classes are designed to cover most patients with heart failure symptoms, but do not cover those with class 1 symptoms, meaning those who have no limitations to "physical activity and ordinary physical activity does not cause undue fatigue, palpitation and shortness of breath."

Entresto in Europe

  • According to the European Medicines Agency, in the European Union, Entresto is available only as tablets (24 mg sacubitril / 26 mg valsartan, 49 mg sacubitril / 51 mg valsartan, and 97 mg sacubitril / 103 mg valsartan) and only with a prescription.
  • As with the UK, it is distributed in hospitals, physicians' practices, and other medical institutions, and is covered (or partly covered) by health insurance.
  • Novartis is the exclusive distributor in Europe. According to the company's records, although specific distribution patterns vary in Europe by country, Novartis sells its prescription drugs mainly to "wholesale and retail drug distributors, hospitals, clinics, government agencies and managed healthcare providers."
  • Last month, Novartis announced positive results for Entresto regarding both pre-operative and post-operative care to the European Commission. So far, it has been distributed only for post-operative care but the positive results are an indicator that the drug will soon be distributed for pre-operative care as well.




Part
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Part
03

Entresto Drug: Instances of Approvals

The FDA's initial approval of Entresto, and more recent approval of the drug for use in a pediatric setting, appears to have been motivated by different factors. While the drug's initial approval for use with adults required a robust trial and statistically significant benefits, Entresto's subsequent approval for use in a younger cohort was expedited given the drugs previously demonstrated results as well as the downside risk of delaying access to Entresto for additional populations.

ADULT TRIALS HELP SUBSTANTIATE PEDIATRIC APPROVAL

  • This October of 2019, the FDA approved Entresto for use in pediatric patients based on the initial, 12-week results of a larger 52-week PANORAMA-HF trial for pediatric patients with heart failure resulting from systemic left ventricular dysfunction.
  • Although the drug trial findings were based on a limited time series of data, the FDA decided to approve the expanded use of Entresto within the pediatric population given that the preliminary results for this younger cohort were consistent with the more complete trials of the drug in adult populations.
  • This decision to approve a pediatric application of Entresto based, in part, on trials with adult groups was similar to the approval process for several other medicines currently in use to managed pediatric systolic heart failure, in that these drugs were also approved by the FDA "based mostly" on the findings from adult studies.
  • Meanwhile, in parallel with the FDA's approval, Novartis affirmed its commitment to completing 52-week follow-up assessments for the entire pediatric population currently engaged in the PANORAMA-HF trial.

RISKS WITHOUT TREATMENT MOTIVATES APPROVAL

  • Another insight related to the FDA's recent approval of the use of Entresto in pediatric applications is that the decision appeared to be motivated by the high risk or cost of not providing such treatment as quickly as possible to younger patients.
  • Specifically, the high risks associated with not treating pediatric patients with relevant conditions is reflected in the fact that approximately half of children with systolic heart failure require a heart transplant before the age of five years, and approximately one third die or require a transplant within another year.
  • Additionally, despite the consequences of heart failure in children, there remains a "significant unmet need" for such treatments that are both safe and effective.
  • As such, the risks and lack of available related treatment protocols likely served as additional motivation for the FDA's quick approval of Entresto for the pediatric population.

CLEAR, COMPARATIVE DRUG SUPERIORITY

  • In July of 2015, the FDA first approved Entresto for use in adult patients based on the full results of a 52-week, multinational, randomized, double-blind PARADIGM-HF trial comparing Entresto and enalapril in 8,442 adults with symptomatic chronic heart failure and systolic dysfunction.
  • Notably, the trial demonstrated that Entresto was superior to a RAS inhibitor alone in reducing the risk of the combined endpoint of cardiovascular death or hospitalization for heart failure, in that those who received Entresto treatments clearly saw a reduction in both negative consequences as well as improved survival rates.
  • In this instances, the robust design of the Entresto trial, the statistically significant benefits of the drug and its comparative superiority over existing medications collectively motivated the FDA's approval of Entresto.
Part
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Part
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Entresto Drug: Competitors

Three competitors of Entresto that are already in the market are Prinivil, Qbrelis and Zestril.

PRINIVIL

QBRELIS

  • Qbrelis (lisinopril) is an ACE inhibitor that is used to treat hypertension in pediatric patients above the age of 6 and adult patients. It is also used to treat congestive heart failure and reduce mortality after heart attacks.
  • The link to the website can be found here.

ZESTRIL

RESEARCH STRATEGY

In order to provide information on competitors of Entresto, we sought to understand what type of drug Entresto is. According to information on the Entresto website, Entresto is taken in place of an ACE inhibitor. Furthermore, an article by The New York Times stated that Entresto would be competing with ACE inhibitors which are relatively inexpensive.

With this information in mind, we went on to look for information on ACE inhibitors and picked three of these as Entresto's competitors.

Part
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Part
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Entresto Drug: Licensing Agreements

Entresto drug as a specific combination of sacubitril and valsartan, was approved by US FDA in 2015 as a treatment for heart failure. It was launched to the market by Novartis in the same year. It achieved a major breakthrough in 2018 when the sales doubled compared to the previous year.

REGISTRATION AND LICENSE APPROVALS

LAUNCHING AND SALES GROWTH

  • Entresto production was launched in third season of 2015, released to US market and was sold USD 21 million.
  • The product sales grew steadily in 2016 which was about USD 170 million.
  • Entresto sale grew more strongly in the following years which was USD 507 million and about USD 1.0 billion, respectively.

RESEARCH STRATEGY

Direct Research Approach

In order to conduct this research, I first began by looking for direct data and insights regarding licensing agreements of the Entresto drug in United States. To do so, first, I checked all the related US FDA files from 2015 to the present. Also, I have an overall look on US patents and there was no sacubitril/valsartan formulation or production that has an applicant name but Novartis. Therefore, I wasn’t able to locate any direct insights about licensing agreements of the drug.

Triangulation Attempt 1

Since a direct answer for this part of the request was lacking, I instead attempted to triangulate an answer to this question. For my first triangulation attempt, I tried to find data that show any license agreement for producing heart failure treatment drugs in Novartis annual reports from 2015 to the present. There were several licensing agreements mentioned in those files but none of them were in the heart failure category. Hence, this attempt to triangulate failed as there were no data reported in this case.

Triangulation Attempt 2

Since my first triangulation attempt failed, my next strategy to gain insight on other companies that might share a part in production of the drug, I checked all the producer of sacubitril/valsartan, sacubitril and valsartan or sacubitril;valsartan in United States by searching in FDA website, seeking for another producers submitting this drug. I was unable to find any related product in America which has another producer or another brand name. I assume that there is no licensing agreements and Novartis company has kept the drug production exclusively.




Part
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Part
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Entresto Drug: Insights

Entresto is used to treat heart failures in conjunction with other heart failure therapies. It has potentially mortal effects on pregnant women and their fetus' health. It may cause side effects such as Angioedema, hypotension, and a decrease in renal functionality.

Overview of Entresto Drug




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