FDA Panel Votes to Recommend New Iron Replacement Treatment

A US Food and Drug Administration (FDA) advisory committee voted 8 to 3 to recommend marketing approval of soluble ferric pyrophosphate (SFP; Triferic, Rockland Medical) as a parenteral iron agent to treat iron loss or iron deficiency and to maintain hemoglobin in adults with hemodialysis-dependent chronic kidney disease.

However, members of the Oncologic Drugs Advisory Committee also recommended to FDA staff members that Rockland Medical, based in Wixom, Minnesota, conduct postapproval studies, should the FDA go along with the committee’s recommendation, into the safety and efficacy of the agent during prolonged use.

SFP is delivered during hemodialysis through a 5-mL ampule containing 27.2 mg elemental iron added to water for injection. Rockland Medical said that Triferic, delivered three to four times a week during hemodialysis, can compensate for an estimated 5 mg of iron loss from dialysis-related blood losses.

The company submitted evidence in its application for approval that included results from two identical phase 3 trials in which investigators tested SFP against placebo. In both studies, according to the company, patients in the SFP group experienced a statistically significant and clinically meaningful difference of 0.36 g/dL over the placebo group between baseline and end of treatment (P = .011 for both studies), with a safety similar to placebo.

Data Questioned

FDA staff members called into question, however, the reliability of the company’s data. Staff members pointed out that although treatment duration was planned for up to 48 weeks, only 18% of patients went that long in the trial, and 44% completed only 24 weeks. The various time values make it difficult to draw inferences, they said.

FDA staff members also pointed out that twice the number of deaths occurred in the SFP treatment group than in the placebo group (12 vs 6).

However, after a long discussion involving minute details of the study results, most committee members chose to support the recommendation to approve marketing Triferic, with advice that the research continue.

Lakhmir Chawla, MD, chief of intensive care medicine at the Veterans Affairs Medical Center in Washington, DC, who voted yes, said, “I compliment the sponsor for putting together a very difficult-to-do study…and I do think that these initial results are interesting and the mechanism is interesting. But I am concerned about the ability to dose properly.”

“I’m excited about the possibility of maintaining the iron level,” said Michael Flessner, MD, PhD, director of inflammatory renal diseases at the National Institute of Diabetes and Digestive and Kidney Diseases in Bethesda, Maryland, who voted yes. “I think that this study was well conducted, although complicated. I had to read it over about five times to understand it, but I do think in this case the applicants did show that this was an effective method of maintaining iron.”

Tito Fojo, MD, PhD, senior oncology investigator at the National Cancer Institute in Bethesda, said he voted no because he was not comfortable with the study and its results. “I thought the study was not all that well designed.”

Bernard F. Cole, PhD, a statistician and professor at the University of Vermont, Burlington, who voted no, said, “It was not a strong ‘no.’ I felt that the data show clearly that Triferic is active vs placebo….We have proof of principle, but in terms of clinical practice, I would have liked to see [the] study in a more realistic clinical setting.”

“I think the study as it was designed showed a benefit to the patients who received the treatment,” said panel Chair Deborah K. Armstrong, MD, professor of oncology at Johns Hopkins University School of Medicine, Baltimore, Maryland, who voted yes. “My concern is that the actual use of the drug will be quite different than it is from the data that was presented…. There needs to be some safety and potential efficacy studies looking into the prolonged use of the agent.”

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Novel agent outperforms ACE inhibitor in large HF trial

The investigational agent LCZ696, an angiotensin receptor-neprilysin inhibitor (ARNI), has demonstrated superior efficacy to a widely used ACE inhibitor in the treatment of patients with chronic heart failure, according to a study presented at the recent European Society of Cardiology (ESC) Congress in Barcelona, Spain.

In the PARADIGM-HF* trial, LCZ696, a combination of the ARB valsartan and neprilysin inhibitor sacubitril, showed a significant 20 percent greater effect over enalapril 20 mg/day in reducing cardiovascular death or hospitalization for heart failure (21.8 vs 26.5 percent; p=0.0000002). [N Engl J Med 2014, e-pub 30 Aug, DOI: 10.1056/NEJMoa1409077]

When components of the composite primary endpoint were analyzed separately, LCZ696 demonstrated a 20 percent greater reduction in cardiovascular death (13.3 vs 16.5 percent; p=0.00004) and a 21 percent greater reduction in hospitalization for heart failure (12.8 vs 15.6 percent; p=0.0004) compared with enalapril.

“The trial was stopped early in April, after a median follow-up of 27 months, for an overwhelming benefit of LCZ696 on cardiovascular mortality,” said co-principal investigator Dr. Milton Packer of the Southwestern Medical Center in Dallas, Texas, US.

The ARNI also reduced all-cause mortality, a secondary endpoint of the trial, by an incremental 16 percent compared with enalapril (17 vs 19.8 percent; p<0.0001).

Symptoms and physical limitations of heart failure, measured on the Kansas City Cardiomyopathy Questionnaire (KCCQ) at 8 months, significantly improved in patients receiving LCZ696 vs enalapril (KCCQ score, -2.99 vs -4.63; p=0.001).

“Enalapril 20 mg/day is the current gold-standard therapy in CHF. Results of the PARADIGM-HF trial provide compelling evidence that LCZ696 should replace current use of ACEIs and ARBs in the management of patients with mild to moderately severe CHF,” said Packer.

“The major benefit of LCZ696 is that it changes the natural course of CHF,” he pointed out. “It doubles the benefit of current cornerstone treatment with ACEIs, which reduce cardiovascular death by 18 percent vs placebo.”

The PARADIGM-HF trial included 8,399 patients with class II to IV heart failure and an ejection fraction of 40 percent or below. The patients were randomized to receive LCZ696 200 mg twice daily (n=4,187) or enalapril 10 mg twice daily (n=4,212), in addition to recommended therapy.

“LCZ696 was better tolerated than enalapril,” reported Packer. “It was less likely than enalapril to cause cough, hyperkalemia or renal impairment, and less likely to be discontinued due to an adverse event.”

“Although more symptomatic hypotension was reported with LCZ696, this rarely required treatment discontinuation,” he continued. “Importantly, LCZ696 was not associated with an increased risk of serious angioedema, which was the main safety concern observed with a related medication known as omapatrilat in another trial.”

The survival advantage demonstrated in the trial has prompted the US FDA to grant Fast Track status to LCZ696. Its developer Novartis expects the FDA review to be completed by the end of 2014.

*PARADIGM-HF: Prospective Comparison of ARNI with ACEI to Determine Impact on Global Mortality and Morbidity in Heart Failure.

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FDA approves first combination pill to treat hepatitis C

The U.S. Food and Drug Administration today approved Harvoni (ledipasvir and sofosbuvir) to treat chronic hepatitis C virus (HCV) genotype 1 infection.

Harvoni is the first combination pill approved to treat chronic HCV genotype 1 infection. It is also the first approved regimen that does not require administration with interferon or ribavirin, two FDA-approved drugs also used to treat HCV infection.

Both drugs in Harvoni interfere with the enzymes needed by HCV to multiply. Sofosbuvir is a previously approved HCV drug marketed under the brand name Sovaldi. Harvoni also contains a new drug called ledipasvir.

“With the development and approval of new treatments for hepatitis C virus, we are changing the treatment paradigm for Americans living with the disease,” said Edward Cox, M.D., M.P.H., director of the Office of Antimicrobial Products in the FDA’s Center for Drug Evaluation and Research. “Until last year, the only available treatments for hepatitis C virus required administration with interferon and ribavirin. Now, patients and health care professionals have multiple treatment options, including a combination pill to help simplify treatment regimens.”

Harvoni is the third drug approved by the FDA in the past year to treat chronic HCV infection. The FDA approved Olysio (simeprevir) in November 2013 and Sovaldi in December 2013.

Hepatitis C is a viral disease that causes inflammation of the liver that can lead to diminished liver function or liver failure. Most people infected with HCV have no symptoms of the disease until liver damage becomes apparent, which may take decades.

Some people with chronic HCV infection develop scarring and poor liver function (cirrhosis) over many years, which can lead to complications such as bleeding, jaundice (yellowish eyes or skin), fluid accumulation in the abdomen, infections and liver cancer. According to the Centers for Disease Control and Prevention, about 3.2 million Americans are infected with HCV, and without proper treatment, 15-30 percent of these people will go on to develop cirrhosis.

Harvoni’s efficacy was evaluated in three clinical trials enrolling 1,518 participants who had not previously received treatment for their infection (treatment-naive) or had not responded to previous treatment (treatment-experienced), including participants with cirrhosis. Participants were randomly assigned to receive Harvoni with or without ribavirin. The trials were designed to measure whether the hepatitis C virus was no longer detected in the blood at least 12 weeks after finishing treatment (sustained virologic response, or SVR), indicating that a participant’s HCV infection has been cured.

In the first trial, comprised of treatment-naive participants, 94 percent of those who received Harvoni for eight weeks and 96 percent of those who received Harvoni for 12 weeks achieved SVR. The second trial showed 99 percent of such participants with and without cirrhosis achieved SVR after 12 weeks. And in the third trial, which examined Harvoni’s efficacy in treatment-experienced participants with and without cirrhosis, 94 percent of those who received Harvoni for 12 weeks and 99 percent of those who received Harvoni for 24 weeks achieved SVR. In all trials, ribavirin did not increase response rates in the participants.

The most common side effects reported in clinical trial participants were fatigue and headache.

Harvoni is the seventh new drug with breakthrough therapy designation to receive FDA approval. The FDA can designate a drug as a breakthrough therapy at the request of the sponsor if preliminary clinical evidence indicates the drug may demonstrate a substantial improvement over available therapies for patients with serious or life-threatening diseases. Harvoni was reviewed under the FDA’s priority review program, which provides for an expedited review of drugs that treat serious conditions and, if approved, would provide significant improvement in safety or effectiveness.

Harvoni and Sovaldi are marketed by Gilead, based in Foster City, California. Olysio is marketed by Janssen Pharmaceutical based in Raritan, New Jersey.

The FDA, an agency within the U.S. Department of Health and Human Services, protects the public health by assuring the safety, effectiveness, and security of human and veterinary drugs, vaccines and other biological products for human use, and medical devices. The agency also is responsible for the safety and security of our nation’s food supply, cosmetics, dietary supplements, products that give off electronic radiation, and for regulating tobacco products.

Source : FDA News Release

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