LCZ696 and Other Investigational Congestive Heart Failure Medications | Rachael Olsufka, PharmD | RxEconsult

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LCZ696 and Other Congestive Heart Failure Medications in Development Category: Heart Disease by - September 12, 2014 | Views: 26309 | Likes: 1 | Comment: 0  

Congestive Heart failure medications
Congestive heart failure (CHF) or heart failure is a condition characterized by the heart’s inability to properly pump blood throughout the body. It is estimated that 26 million people worldwide suffer from heart failure and this number is expected to grow. Congestive heart failure is the number one cause of hospitalization for persons over the age of 65 and estimated to account for 108 billion dollars in health care costs each year. Unfortunately hospitalizations and costs will likely continue to rise since currently available therapy is limited to treatment of associated conditions and symptoms. This gap in treatment challenged researchers and pharmaceutical companies to think outside the box and develop a groundbreaking new treatment for congestive heart failure patients. The data from a recent clinical trial of a new heart failure therapy under investigation called LCZ696 appears promising that a new blockbuster drug may have been uncovered and will soon be available for patients. Other novel compounds are being investigated for the treatment of congestive heart failure.
What is heart failure?
The heart is a muscle and acts as a pump to circulate oxygen rich blood throughout the body. Injury to the heart muscle tissue can compromise the pumping action and reduce the ability of the heart to efficiently circulate blood. Injury can be from a heart attack, chronic high blood pressure, uncontrolled diabetes, an irregular heartbeat, high cholesterol, inflammation caused by smoking, excessive alcohol, or a damaged heart valve. Generally the combination of several of these factors leads to the development of heart failure.
Ejection fraction is the percentage of blood the heart is able to pump from the left ventricle and it is used for diagnosing heart failure. Injury to the heart reduces the amount of blood the heart is able to pump out and therefore reduces the ejection fraction. The heart, being a muscle, attempts to compensate for this reduced output by filling with more blood and pumping harder to push it out of the ventricle. Eventually the heart becomes stiff because and over time will push less and less blood out of the ventricle (as seen by the progressive decline in ejection fraction).
What are the symptoms of congestive heart failure?
  • The symptoms of heart failure correlate with the stage of the disease. Heart failure symptoms can include:
  • Fatigue
  • Shortness of breath
  • Fluid overload in the extremities or lungs
  • Difficulty breathing while laying down (orthopnea)
Fluid overload is the cause of most symptoms reported by hospitalized  patients with congestive heart failure. It requires diuretic medications. As heart failure progresses, symptoms worsen to the point where a person will have difficult breathing even while laying down.
Medications used for congestive heart failure treatment?
There is no cure for heart failure and therapy is targeted at relief of symptoms. The management is complex and specific to each individual based on the duration of the disease, symptoms, and other co-morbidities. Options for treating congestive heart failure include ACE inhibitors, beta-blockers, ARBs, loop diuretics, angiotensin receptor blockers, lanoxin (Digoxin), and aldosterone antagonists.
Congestive heart failure medications in development
LCZ696 is an angiotensin receptor antagonist and neprilysin inhibitor. It is a new medication being developed by Novartis for treatment of congestive heart failure. It works by simultaneously inhibiting the angiotensin receptor and neprilysin, two different targets implicated in heart failure. Because of its novel mechanism it is classified as a new category of medications called angiotensin receptor antagonists neprilysin inhibitors (ARNIs). Blocking the angiotensin receptor improves blood flow and reduces workload of the heart by inhibition of the renin angiotensin aldosterone system. Neprilysin, on the other hand, has positive effects for patients with heart failure; therefore, preventing the breakdown of this molecule potentiates its positive effects. Dual inhibition may be synergistic and provides more benefit than an ACE or ARB alone.
A large clinical study of LCZ696 was recently published in the New England Journal of Medicine. The study included 8,442 patients with mostly moderate to advanced stage heart failure from 1043 treatment centers across 47 countries. Of the patients who successfully completing the study, 4212 received the ACE inhibitor enalapril and 4187 received LCZ696. The two study groups were compared for all cause mortality and hospitalization rate. The group that received the LCZ696 achieved the pre-defined endpoints before the completion of the study. There was a 21% reduction in hospitalization for heart failure compared to the group that received enalapril. Additionally, 21.8 percent of patients died from cardiovascular causes on treatment with LCZ696 compared to 26.5 percent treated with enalapril. The trends were in favor of LCZ696 in subgroup analysis of age, sex, race, kidney function, and comorbid conditions. 
The most common side effects observed were low blood pressure (14% for LCZ696 versus 9.2% for enalapril), increases in potassium in the blood (16.1% for LCZ696 versus 17.3 for enalapril), and cough (11.3% for LCZ696 versus 14.3 percent for enalapril). Of the patients with low blood pressure, 36 from the LCZ696 group and 29 from the enalapril had to stop the study early.
As previously mentioned, researchers and pharmaceutical companies have been working to develop new therapy options for patients with heart failure. Many of the medications in development exhibit a new mechanism of action or will target a new process in the body. The following list represents some of the promising new therapies in development for heart failure.
Other investigational drugs for heart failure
Mydicar is a specific gene therapy being developed by the Celladon Corporation. It works by using gene therapy to restore function in the SERCA2A enzyme and improves the ability of the heart to pump blood. In April 2014 the company received breakthrough status designation from the FDA, meaning the approval process will be streamlined for this medication.
Other gene therapies are in development. A company called uniQure recently acquired another company called InoCard that was developing a gene therapy for heart failure. This medication is in preclinical stages. It works by expression of the calcium-binding protein S100A1, a protein deficient in heart failure patients. Restoring this protein in animal models has shown it can improve the contractility, rhythm and energy supply to the heart which increases the overall function of the heart.
Seralaxin (RLX030) is a recombinant form of the naturally occurring hormone, relaxin, and works as a relaxin receptor agonist. In the body, the relaxin hormone relaxes blood vessels and prevents fluid buildup. Novartis is developing the medication for treatment of acute heart failure and has submitted licensing materials to the FDA. In May 2014, the FDA responded to Novartis stating more data about the effectiveness of seralaxin would be required before granting approval.
As the population continues to age, and comorbidities that contribute to the development of congestive heart failure rise, the number of persons afflicted with the condition will also increase. This will lead to more hospitalizations and significant increases in health care costs. LCZ696 may offer patients a new option for reducing complications and death from heart failure. Available clinical data for LCZ696 exceeds expectations and suggests that LCZ696 may be an important new treatment option for congestive heart failure patients. Other novel heart failure treatments are being developed. Hopefully, in the near future there will be more effective treatments for congestive heart failure.
McMurray JJ, Packer M, Desai AS, Gong J, Lefkowitz MP, Rizkala AR, Rouleau JL, Shi VC, Solomon SD, Swedberg K, et al. Angiotensin-neprilysin inhibition versus enalapril in heart failure. N Engl J Med. 2014 Sep 11; 371(11):993-1004. Epub 2014 Aug 30.
Langenickel TH, et al. Angiotensin receptor-neprilysin inhibition with LCZ696: a novel approach for the treatment of heart failure.
Jessup, M. Neprilysin inhibition--a novel therapy for heart failure. N Engl J Med. 2014 Sep 11;371(11):1062-4. doi: 10.1056/NEJMe1409898. Epub 2014 Aug 30.
Lueder TG, et al. Current role of neprilysin inhibitors in hypertension and heart failure. Pharmacol Ther. 2014 Oct;144(1):41-9. doi: 10.1016/j.pharmthera.2014.05.002. Epub 2014 May 14.

Novartis Heart Failure Backgrounder April 20

Celladon Press Release

uniQure Press Release

Novartis Seralaxin Press Release

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