ARTICLE IN BRIEF
A new paper finding that adrenocorticotropic hormone and prednisolone were equally effective in managing infantile spasms has contributed to a growing debate about why the more expensive ACTH is being used for therapy.
In a single randomized trial of 97 infants with West syndrome — a disorder characterized by epileptic/infantile spasms, hypsarrhythmia, and intellectual disability — synthetic adrenocorticotropic hormone (ACTH) and prednisolone were found to be equally effective at controlling seizures at one year, a team of investigators at the University of Colombo in Sri Lanka reported in the August 14 online edition of Pediatric Neurology.
The findings come on the heels of a longstanding debate among pediatric neurologists about which therapy is most cost effective. The question, they say, is this: If the two drugs are similarly effective in controlling seizures, why use the much more expensive treatment?
“The whole issue of infantile spasms therapy is controversial,” said E. Steven Roach, FAAN, chief of neurology at Nationwide Children's Hospital in Columbus, OH, and editor-in-chief of Pediatric Neurology, who was not involved with the study. “This is partly because of the shifting science and partly because Questcor bought the rights to ACTH and dramatically increased its price. We have traditionally recommended ACTH injections in the US, but it is extremely costly, and outside of the US people tend to use the cheaper prednisolone alternative. We are talking something on the order of $150,000 per treatment course [for ACTH] versus $200 [for prednisolone].”
“The Sri Lanka study is something we could not easily do here,” Dr. Roach acknowledged. “It would be too expensive to purchase natural ACTH for a study.”
But it was not always so expensive. The ACTH agent, Acthar, cost $40 a vial when it was first licensed by Questcor Pharmaceuticals in 2001, and over the years, the price hiked, in large part, according to the Federal Trade Commission (FTC), because the company bought the rights to competitive products, monopolizing the market, stifling competition, and keeping prices high.
In January, Mallinckrodt Pharmaceuticals, which acquired Questcor in 2014, agreed to pay $100 million to settle the lawsuit by the FTC and several state attorneys general, alleging that the company had violated antitrust laws in regard to Acthar. (For more on this story, see the sidebar, “The High Price of Acthar: The Back Story.”)
Acthar, after several attempts by Questcor, was approved by the Food and Drug Administration (FDA) for infantile spasms in 2010.
STUDY METHODS, FINDINGS
Sri Lanka, where the trial was conducted, has limited access to ACTH, the study author Jithangi Wanigasinghe, MD, a pediatric neurologist at the University of Colombo, told Neurology Today. Dr. Wanigasinghe said she assesses and treats two children a month with infantile spasms and has always treated them with prednisolone. But she wants to compare synthetic ACTH and prednisolone. The study was partly funded by the Sri Lanka Medical Association.
“We were not trying to find that one was superior to the other but whether they were similar in efficacy,” said Dr. Wanigasinghe.
The investigators randomized half of the 97 infants with untreated West syndrome to intramuscular long-acting synthetic ACTH (40 to 60 IU every other day) and half to 14 days of oral prednisolone (40 to 60 mg/day). Both groups received a subsequent three-week taper with prednisolone. The children were evaluated at three, six, and 12 months. Everyone completed the protocol but some were lost to follow-up. They examined 85 children at three months; 82 at six months; and 76 at one year.
The children were always evaluated by the same pediatric neurologist who was blinded to the treatment arm. A spasm-free period was determined by parental reports over the preceding week at each testing period, which the scientists said was a limitation of the study. They also did not have extensive electroencephalogram (EEG) data for every visit.
The investigators reported that 64.6 percent of those on prednisolone were seizure-free at three months compared to 39 percent of patients who had received ACTH (p=0.01). By six months and at one year, there was no statistical difference between the control of spasms in either treatment arm: 58.3 percent were seizure-free on prednisolone versus 44.9 percent for ACTH at six months (p=0.19) and 56.2 percent versus 40.8 percent with ACTH, respectively, at twelve months (p=0.13).
Also, the rate of relapse during the year was equivalent in both groups. Dr. Wanigasinghe said that there were 28 in the prednisolone group who went into remission by day 14 of the treatment and 18 in the ACTH group. The total number who relapsed at least one time during the 12-month follow up period was 14 (30 percent) – six from the prednisolone group and eight from ACTH group.
Children who relapsed were re-treated with the same hormonal therapy if it was at least two months after the first treatment ended. Other alternative oral anticonvulsants were used if the child relapsed earlier. Thirty percent of the children who had gone into remission by day 14 would go on to have at least one relapse by the one-year assessment.
There were eleven deaths during the 12 months of follow up, all occurring after the completion of the initial treatment and related to other systemic diseases, Dr. Wanigasinghe said.
“Our clinical trial provided additional evidence that first-line high-dose oral prednisolone may be superior to ACTH for short-term spasm control,” she said.
“The current follow-up data show that the long-term control of spasms is similar for the two treatments, with a statistically insignificant trend favoring prednisolone therapy,” the authors wrote in the paper. “Given the substantially higher cost of ACTH versus prednisolone, even similar efficacy between the two drugs would seemingly favor the use of prednisolone.”
In a phone interview, the investigator added that it is frustrating “that the field has not reached a consensus on the optimal therapy.” Among the reasons, she contends, are that different types of ACTH have been used in the various studies. Clinicians outside of the United States use a synthetic version that contains 24 amino-acids in the ACTH peptide. Synthetic ACTH is not approved by the US Food and Drug Administration (FDA) and is rarely used in the US. Mallinckrodt's H.P. Acthar Gel is the only natural ACTH substance available in the US. It contains the full 39 amino acid peptide.
The current study did not use the H.P. Acthar Gel, which is used in the US. Dr. Wanigasinghe noted that it is difficult to make sense of the conflicting results because of varying types, doses, and treatment durations of ACTH and the oral steroids. Most of the studies have had very small numbers of patients, she pointed out.
EXPERTS WEIGH IN
Commenting on the study, Dr. Roach agreed that “no one in this country has ever done an adequate comparison of ACTH and prednisolone for the treatment of infantile spasms. And that is why this study is so lovely. They did it. There is increasing evidence that prednisolone is just as good, yet a lot of people in the US persist in an almost fanatical preference for the injections.”
Dr. Roach, who has not received research funding related to the treatments, said that some centers are using prednisolone first and if that doesn't work to stop seizures in two weeks they will order ACTH.
The American Academy of Neurology and the Child Neurology Society developed guidelines in 2004 on treating infantile spasms, which were updated in 2012, when an advisory panel reviewed 26 articles. They concluded that there was “insufficient evidence to determine whether other forms of corticosteroids are as effective as adrenocorticotropic hormone (ACTH) for short-term treatment of infantile spasms. However, low-dose ACTH is probably as effective as high-dose ACTH.”
The sooner treatment starts, the better it could be for the long-term development of the child, the guideline concluded.
“I don't think adequate evidence was ever there,” said Dr. Roach. He noted that the guidelines were devised before the results of the Sri Lanka study and the United Kingdom Infantile Spasms Study (UKISS) were available. UKISS compared hormone treatment with vigabatrin on developmental and epilepsy outcomes to age 14 months. This multicenter randomized trial was not designed to compare the differences between ACTH and prednisolone, but a secondary analysis, published in The Lancet Neurology in 2005, showed similar results. Another study – the International Collaborative Infantile Spasm Study (ICISS) – published in the Lancet Neurology this past January also found a combination therapy to be more effective than either drug used alone.
“Some neurologists believe that ACTH is the optimal treatment for infantile spasms,” said John R. Mytinger, MD, a child neurologist at Nationwide Children's Hospital and assistant professor of clinical pediatrics and neurology at the Ohio State University College of Medicine.
“But since the price increase in the US, and with additional data, there has been more interest in using high-dose oral prednisolone as a first-line option. Prednisolone is not FDA-approved for the treatment of infantile spasms. However, there would be no incentive for a pharmaceutical company to pursue FDA approval for such an inexpensive medication.”
“Consistent with the 2013 Cochrane Database of Systematic Reviews on infantile spasms, I believe that ACTH, vigabatrin, and high-dose oral prednisolone are all reasonable first-line treatments for infantile spasms,” said Dr. Mytinger, who has not received research funding for either drug.
“Practice varies between and within centers,” Dr. Mytinger added. “What is critical is that we diagnose early and use first-line therapy. ACTH is one of our few first-line treatments; it can be very effective and some patients may require it to achieve remission. I just wish it was not so expensive.”
Shaun Hussain, MD, a pediatric neurologist the University of California, Los Angeles (UCLA) Medical Center, also agreed that there is insufficient evidence that ACTH is superior to prednisolone “because the ideal clinical study has not been done.” And that study would be: ACTH 150 U/m2/day compared to oral prednisolone 4-8 mg/kg/day, he said.
“I believe high doses of prednisolone are effective but I am not sure that it is as effective as ACTH,” said Dr. Hussain, who is on the speaker's bureau for Mallinckrodt, which manufactures the ACTH used in the US.
“ACTH is expensive but the price tag is dwarfed by the monetary and intellectual costs of not treating these children,” Dr. Hussain said. The problem, he said, is that it is very expensive and many centers order it when the child arrives in the emergency room with seizures. Timing is critically important. UCLA's protocol is to begin with prednisolone and vigabatrin and switch to ACTH within two weeks if the combination isn't working.
Mary Zupanc, MD, division chief of pediatric neurology and director of the Pediatric Comprehensive Epilepsy Program at the Children's Hospital of Orange County in Southern California and the University of California, Irvine, said the issue is complex. “I have reviewed virtually all of the literature on ACTH, prednisolone, and other therapies in the treatment of infantile spasms. I have always fallen into the ACTH camp — partly due to training, but primarily due to my review of the literature and clinical experience. I have never seen prednisone be as effective as high-dose ACTH — and this is supported by the current literature.” said Dr. Zupanc, who has served on the speaker's bureau for Questcor, which had held licensing rights to the drug prior to the company being acquired by Mallinckrodt.
“The only way to resolve this debate is to do the right clinical study – a prospective, randomized trial comparing high-dose ACTH to high-dose prednisolone,” she said.
“There have been many neurologists looking for alternatives, even before the price increase, due to side effects of ACTH,” said Eric H. Kossoff, MD, professor of neurology and pediatrics and medical director of the Ketogenic Diet Center at Johns Hopkins Hospital. “We don't use ACTH here any longer. We did a study of our experience using oral prednisolone and ACTH [in Epilepsy & Behavior in 2009] and found that both were effective. Prednisolone is a fraction of the cost and doesn't involve injections or hospitalizations. Even if the price decreased, I'm not sure we'd use ACTH again.”
Tallie Z. Baram MD, PhD, now a professor of pediatrics, anatomy & neurobiology, neurology and physiology & biophysics at the University of California Irvine, conducted the original controlled study on high-dose natural ACTH.
In 1996, she and her colleagues reported in Pediatrics findings from a trial comparing high-dose ACTH – 150 U/m2/day — to a low dose of oral prednisone (2 mg/kg once a day) for two weeks with a subsequent taper. They randomized 29 children who were admitted to the hospital with infantile spasms to receive either the high dose of ACTH or prednisone. Dr. Baram said that 13 of the 15 patients receiving the high dose of ACTH had no more seizures within the two-week testing period. Their EEGs also returned to normal. By comparison, four of the 14 patients on prednisone (28.6 percent) had a similar response.
Dr. Baram said that her group had evidence that it was the very high dose of ACTH that led to the results. Further work showed that such high doses get into the brain and work on a completely different mechanism to stop seizure activity. Specifically, whereas the mechanism of ACTH in stopping seizures is considered only to involve releasing the baby's endogenous cortisol (the natural equivalent of prednisone or prednisolone) from the adrenal gland, or perhaps exert mild anti-inflammatory effects, high-dose ACTH got into the brain and had additional actions that prednisolone and low-dose ACTH did not. Dr. Baram indicated that ACTH targets melanocortin receptors in the brain and this shuts down a natural pro-seizure molecule, corticotropin-releasing hormone.
She added that “lower doses of ACTH may not work any better than prednisolone, because they mainly function by releasing the body's own prednisolone-like molecules.” Dr. Baram never received money from the pharmaceutical companies during the implementation of the study or afterwards.
THE HIGH PRICE OF ACTHAR: THE BACK STORY
Mallinckrodt agreed to pay $100 million in January of this year to settle charges by the Federal Trade Commission (FTC) that the company violated antitrust laws when its division, Questcor, acquired the US rights to develop a competing drug to Acthar, Synacthen Depot. The FTC alleged that the acquisition effectively stifled competition by preventing any other company from using Synacthen assets to develop a synthetic ACTH drug, preserving Questcor's monopoly and allowing it to maintain extremely high prices for Acthar.
In a statement about the settlement, FTC Chairwoman Edith Ramirez, wrote: “Questcor took advantage of its monopoly to repeatedly raise the price of Acthar, from $40 per vial in 2001 to more than $34,000 per vial today — an 85,000 percent increase. We charge that, to maintain its monopoly pricing, it acquired the rights to its greatest competitive threat, a synthetic version of Acthar, to forestall future competition. This is precisely the kind of conduct the antitrust laws prohibit.”
When asked to respond to the controversy, a spokesperson for Mallinckrodt, Rhonda Sciarra, said: “Mallinckrodt has made only modest adjustments to the price of the drug since acquiring it in 2014. Mallinckrodt discounts this list price to both public and private payers.”