What does a new study say about the safety and efficacy of deferiprone?

Deferiprone is a medication that chelates, or binds, iron and removes excess amounts from the body. Unlike previous chelator drugs, deferiprone can enter the brain, remove iron from places where it is high, and “redistribute” it. It has been used for treatment of various diseases since 1994 in Europe and Asia. Deferiprone was approved by the FDA for treatment of thalassemia in 2011. It has not yet been approved for treatment of NBIA disorders.

When deferiprone first came out, it sounded like a miracle drug for individuals with NBIA. Unlike iron chelating drugs available in the past, deferiprone was able to get into the brain and could potentially remove accumulated iron. Patients and scientists both hoped that if deferiprone was able to flush out some of the excess brain iron, it could improve the symptoms of NBIA. However, like all the other iron chelating agents, there was also a possibility that deferiprone’s side effects could cause problems before it showed any benefits.

Previous deferiprone studies

So, what do we know about deferiprone in NBIA? Not very much yet! Two small studies have looked at the safety and effectiveness of deferiprone. The first was a pilot study that tested the medication in 6 individuals with NBIA. The second was another small study that tested the medication in 10 PKAN patients. There is a larger, international trial going on right now, but we don’t have the results yet.

Both of these small studies showed that deferiprone was safe and well-tolerated during the trial. They also showed that deferiprone was able to decrease the level of iron in the brain in some cases. How did they prove this? By using specialized MRI technology to measure the iron over time. However, these trials were very limited and they did not answer the biggest question of all: does deferiprone improve the symptoms of NBIA?

It is important to answer this question because even if deferiprone is able to remove iron from the brain, this may not matter if it cannot change a person’s symptoms. Many people believe that iron is the problem in NBIA, but what if it’s not? There may be brain tissue damage or other changes happening before the iron moves in that are causing most of the problems.

New long-term deferiprone study

One of the major criticisms of the previous deferiprone studies has been that they only followed patients for one year. A potential medication needs to be tested for a much longer period of time to get an idea of its safety and effectiveness.

There are still many unanswered questions about deferiprone:

  • Deferiprone may be well-tolerated if only taken for a year, but will the side effects get worse the longer it is taken?
  • How long does deferiprone need to be taken before it shows any improvement of symptoms?
  • Can deferiprone actually improve symptoms at all?
  • Are there only some NBIA symptoms that can improve due to deferiprone?
  • Will the side effects of deferiprone cause too many problems before we are able to see any clear benefits of the medication?

The research team that conducted the first pilot study has now published a follow-up trial. The new study followed the patients from the original trial for an additional 3 years. So, they were able to report on the safety and performance of deferiprone over a 4-year period.

Out of the 6 patients who were in the previous pilot study, only 5 agreed to participate in this new long-term study. Therefore, 1 new patient was added at the start of the follow-up study. By the end of the study, 5 participants had taken deferiprone for 4 years and one participant had taken it for only 3 years.

Did deferiprone have any serious side effects?

The dosage of deferiprone used during the trial was well-tolerated and safe for continued use up to 4 years. Their medication dosage was determined by their weight. The deferiprone was taken by mouth twice a day. By the end of the study, the participants had no serious side effects.

Can deferiprone reduce iron levels in the brain?

Deferiprone was able to reduce the levels of brain iron in most cases. However, it was not effective in ALL cases. Of 6 patients studied, 4 showed reduced levels of iron, 1 patient’s brain iron levels stayed the same, and 1 patient’s brain iron levels increased.

More research is needed to understand why deferiprone can reduce brain iron levels in some individuals but not in others.

Can deferiprone improve the symptoms of NBIA?

Although deferiprone may be safe, and it appears to reduce brain iron levels in some cases, we still need to decide if it has any effect on the symptoms of NBIA. In this new long-term study, the researchers used a combination of two methods to evaluate if the symptoms had improved.

First, a group of neurologists who were experts in movement disorders used two rating scales to measure the severity of the patients’ symptoms. One was a general dystonia scale and the other was a scale used commonly for Parkinson’s disease. Both scales were used to measure symptoms every 12 months. It is important to keep in mind that these scales were developed for patients with Parkinson’s disease and general dystonia. Although some NBIA patients have symptoms that overlap with Parkinson’s disease and dystonia, these scales are not specific to NBIA.

Second, a different neurologist rated patient videos and gave brief overall assessments such as “unchanged,” “worsened,” or “improved moderately.” This method is less scientific and very subjective since it only includes the observations of a single neurologist.

By the end of this 4-year study, 3 out of the 6 patients had symptoms that improved or stabilized according to both the clinical rating scales and the video rating. Two of the patients were said to have mildly worse symptoms by the video rater, but their clinical rating scales were unchanged or mildly improved. One patient had worse symptoms according to both the clinical rating scores and the video evaluation. However, it is important to note that 1 of the patients in the “improved or stabilized” category was the patient who took deferiprone for only 3 years. By the end of the three years, this patient’s clinical ratings were starting to mildly worsen. Therefore, it is unclear whether this patient would have continued to worsen or ended up stabilize/improved if she had taken deferiprone for 4 years like the other patients in the study.

The patient who worsened while on deferiprone had developed NBIA symptoms at the youngest age (11 yrs) out of the group and was one of the most disabled at the beginning of the study. Patients who develop symptoms at an earlier age tend to have more severe symptoms and may progress at a faster rate. It is possible that this patient did not respond as well to deferiprone because she was more severely affected. The research team used this patient’s results to suggest that deferiprone may be most effective if it is started right after diagnosis, when symptoms are less severe. However, there is no additional data to back-up this suggestion, and more research needs to be done.

While this new study is an improvement compared to previous studies of deferiprone, it still has several problems.

What did this clinical trial do right?

1.) Long-term follow up

The biggest improvement in this new trial is that the researchers followed the patients for an additional three years. By analyzing the effects of deferiprone for a longer period of time, the results provide a clearer picture of how the medication affects patients.

2.) Two methods of symptom evaluation

The use of two different methods to evaluate symptoms is important because it gives a broader picture of how the patient is doing.

What were the limitations?

1.) Small number of patients

Since the study only evaluated 6 patients, it is impossible to predict if the NBIA population in general would have similar results. A larger group of patients needs to be studied.

2.) Including one participant who took deferiprone for a shorter amount of time

This patient’s results were used to draw conclusions about the effectiveness of deferiprone, even though she had taken it for less time than everyone else in the study. It is unknown if the patient’s results might have changed if she had been evaluated after taking deferiprone for another year.

3.) Using clinical rating scales that are not specific to NBIA

The researchers used general dystonia and Parkinson’s disease scales to evaluate symptoms of NBIA. Although some patients with NBIA have parkinsonism and many have dystonia, others do not. Also, many patients with NBIA have other symptoms, like spasticity or motor tics, which can make it difficult to use these scales accurately.

4.) Not all of the 6 patients were confirmed to have PKAN

In this study, only 5 out of the 6 patients had their PKAN diagnosis confirmed by genetic testing. One individual had idiopathic NBIA (idiopathic means a genetic change known to cause NBIA was not found, but the individual has symptoms consistent with NBIA). Non-PKAN results should not be grouped together with those from PKAN patients. What if individuals with different forms of NBIA react differently to deferiprone?

Implications and a new upcoming study

Deferiprone continues to be well-tolerated among patients after 4 years of use, and it is able to reduce levels of brain iron in some individuals. However, the ability of deferiprone to improve NBIA symptoms is still unknown.

A new study underway since 2012 may provide the answer to this question. This new study was funded by the European Commission and is currently being carried out in five centers around the world: Munich (Germany), Warsaw (Poland), Milan (Italy), Newcastle (United Kingdom) and Oakland, California (USA). The study is placebo-controlled, randomized, and double-blinded. This means that some of the patients in the study will be taking a placebo* instead of deferiprone. In order to make it randomized, a computer program selects at random which patients receive the placebo and which receive deferiprone. Since it is double-blinded, neither the patients nor the study investigators will know which individuals received the placebo and which ones received deferiprone until after the study is completed.

Some of the improvements in this new study compared to previous studies include:

  • A larger group of patients (90 total)
  • Patient follow-up for 18 months (with a possibility for continuation)
  • All patients are genetically confirmed to have PKAN
  • Patients will range from ages 4 to adult
  • Randomized, placebo-controlled, double-blinded analysis

*A placebo is something that looks exactly like the medication being tested in the study but it does not contain the same main ingredient(s) as the real medication. A placebo is sometimes called a “sugar pill” because it contains nothing useful but also nothing harmful. A placebo is used to create a patient group that can be compared to the group taking the medication being tested.


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