Neuren's Breakthrough Therapy Status Recent Update: What does it mean?

by Dr. Steve Kaminsky, Chief Science Officer and Janice Ascano, Grants and Research Manager

 

Breakthrough Therapy Status is a premier designation that is difficult to achieve, especially for potential new medicines that are early in development.  In this instance, it does not change anything in regard to the path forward.  If Neuren was granted Breakthrough Therapy status, it could have afforded more attention at the FDA but not necessarily improved response time.  So it would have been excellent to have Breakthrough, in addition to Orphan Drug and Fast Track, but it is not truly necessary in regard to the continued development of trofinetide as a potential new treatment for Rett syndrome.

Breakthrough Therapy Status for Trofinetide to treat Rett syndrome was not given by the U.S. Food and Drug Administration.  What does this mean?

Today Neuren Pharmaceuticals announced that the U.S. Food and Drug Administration responded to their request for Breakthrough Therapy Status, one of several programs at the FDA for drug development. While Breakthrough Therapy Status was not granted for trofinetide to treat Rett syndrome, Neuren Pharmaceuticals will continue to proceed as planned under the Fast Track and Orphan drug designation statuses they already acquired.  Neuren will be meeting with the FDA to review their Phase II trial results and to define the next steps to move forward with the development of trofinetide as a potential new treatment for Rett syndrome.

So what does this mean for all of us who have been following the clinical trials with Trofinetide? 

First, let me say that being granted Breakthrough Status is a tough hill to climb with approximately only a 30% success rate for all the drugs that apply for this status.  Going into the application for this status, Neuren understood how tough it is to be granted this status.  In the Phase II clinical trial with trofinetide, Neuren introduced a statistical analysis that is different from traditional methods that may focus on a single outcome measure, such as assessment of changes in breathing.  It is our understanding that the analytical approach that was used by Neuren, which simultaneously evaluated several outcome measures relative to Rett syndrome that assess benefit had never been presented to the FDA for a neurological disorder (while it has been used for other types of clinical trials in therapeutic areas such as heart disease).  It is likely that the FDA group reviewing this application had an initial response that the statistical analysis was new for a neurologic disorder, and they were conservative in their decision to grant Breakthrough Therapy Status.  

Second, please remember trofinetide has already been granted Fast Track Status and Orphan Drug Status. These are important designations for this drug moving forward as a potential new treatment for Rett syndrome.  By not getting Breakthrough Status, it only changes the scope of the FDA participants in a meeting and the level of guidance during this early phase of the development of trofinetide as a potential new medicine.  It does not alter the FDA’s response time since the program already has Fast Track designation.

We at Rettsyndrome.org want to thank the donors and families who helped fund and participated in the trofinetide Phase II trial.  Our excitement is not diminished by the FDA decision because it only changes the nature of the interactions with the FDA.  This Phase II trial and future trials with trofinetide bring us closer to developing a drug and to improving the lives of women and girls and boys with Rett syndrome.

More about Breakthrough Therapy Status. 

On July 9, 2012 the Food and Drug Administration Safety and Innovation Act (FDASIA) was signed.  FDASIA Section 902 provides for a new designation - Breakthrough Therapy Designation.  A breakthrough therapy is a drug:

  • Intended alone or in combination with one or more other drugs to treat a serious or life threatening disease or condition and
  • Preliminary clinical evidence indicates that the drug may demonstrate substantial improvement over existing therapies on one or more clinically significant endpoints, such as substantial treatment effects observed early in clinical development.

A drug that receives Breakthrough Therapy designation is eligible for the following:

  • All Fast Track designation features
  • Intensive guidance on an efficient drug development program, beginning as early as Phase 1
  • Organizational commitment involving senior managers


If a drug is designated as Breakthrough Therapy, FDA will endeavor to expedite the development and review of such drug. 

So what are the differences between the Breakthrough Therapy designation and the Fast Track designation? 

Although Breakthrough Therapy and Fast Track designation programs have many similarities, as they both are intended to expedite the development and review of new medicines for serious or life-threatening conditions, there are differences in what needs to be demonstrated to qualify for the programs.

A Breakthrough Therapy program is for a potential new medicine that treats a serious or life-threatening condition and preliminary clinical evidence indicates that the drug may demonstrate substantial improvement on a clinically significant endpoint(s) over available therapies.

In contrast, a Fast Track program is for a medicine that has the potential to treat a serious or life-threatening condition, and preclinical data demonstrate the potential to address unmet medical need.  Both Breakthrough Therapy and Fast Track designation are intended to streamline the drug development process.

Fast Track and Breakthrough Therapy are just a couple approaches of the FDA that are intended to make potential new medicines available at an earlier time.  It is important to note that standards for the safety and effectiveness of such drugs that become available through these processes are not compromised.  Trofinetide is the first drug granted Fast Track Status for Rett syndrome, and Neuren Pharmaceuticals continues to have an open dialogue with those at the FDA.  We hope that more compounds that come to the end of the drug discovery pipeline will have enough preclinical and/or clinical evidence to be given either of these designations. Rettsyndrome.org will continue to participate in such discussions with the academic labs, biotech and pharmaceutical companies, and the FDA to expedite drug development and review for Rett syndrome. 

I would urge everyone to remember what two Rett syndrome clinical researchers have said about the trofinetide phase II trial.  Walter Kaufmann MD, Professor of Neurology at Harvard Medical School and Director of the Rett Syndrome Program at the Boston Children’s Hospital, who was not involved in the trial, commented: “The outcome of this trial is very promising in terms of both safety and clinical improvement. It was a challenging study since the older age of the cohort and the short duration of the trial made it less likely to show a positive effect. It opens not only the possibility of successful treatment of adults with Rett syndrome, but also of early interventions modifying the course of the disease.”

Alan Percy MD, Professor of Pediatric Neurology at the University of Alabama was one of the trial investigators. He commented: “The results of this trial suggest a very promising proof of concept as we continue on the pathway to develop a disease-altering treatment for girls and women with Rett syndrome. Not only was this short-term trial managed successfully, but also the data analyses were conducted in a very robust fashion.”

In conclusion, Breakthrough Therapy Status is a premier designation that is difficult to achieve, especially for potential new medicines that are early in development.  In this instance, it does not change anything in regard to the path forward.  If Neuren was granted Breakthrough Therapy status, it could have affected the level of attention at the FDA but not necessarily their response time.  So it is excellent to have, but not truly necessary in regard to the continued development of trofinetide as a potential new treatment for Rett syndrome.