Clinical Trials

Progeria clinical drug trials are the best hope for children with Progeria, testing potential treatments that may enable them to live longer, healthier lives. These trials are the culmination of years of research focused on what drug or combination of drugs will treat and cure the children.

Since 1999 when we founded PRF and there were no resources for these children, we have soared from total obscurity, to gene finding, to the first Progeria clinical trials, to a first-ever treatment called lonafarnib – all at a pace virtually unheard of in the scientific community. And while helping this handful of children, Progeria’s connection to common heart disease and aging has tremendous implications for us all.

Trials history at-a-glance:

To date, PRF has funded and co-coordinated three clinical trials (two of which had two parts, phases 1 and 2). PRF is and always has been responsible for all trial expenses, including testing, travel, food, lodging, translators and staff.   Each new trial is more expensive than the last, as more children enroll for a chance at longer, healthier lives. Please help us fund these vital trials –  DONATE TODAY!

What’s happening TODAY with the Progeria clinical trials? 

The current trial involves 2 drugs: the treatment lonafarnib and a new drug everolimus.  Phase 1, to determine the safe and appropriate dosage of everolimus, began in April 2016 and was successfully completed in June 2017. Phase 2, which is testing the effectiveness of the 2-drug combination, began in July 2017.  Sixty children from 27 countries have enrolled!  We expect the trial visits to end in October 2020, followed by several months of data analysis and eventual publication of results in a peer-reviewed, scientific publication.

Everolimus is a form of the drug rapamycin; everolimus can be more easily given to children with Progeria because it requires fewer blood draws to measure drug levels.  While lonafarnib may block the toxic progerin from developing, rapamycin appears to allow cells to more rapidly clear out progerin.  Thus with rapamycin targeting a different pathway than lonafarnib, the combination may prove to be a “one-two punch” to Progeria – hopefully a better treatment than lonafarnib on its own.

The science behind the addition of this second drug: Rapamycin is an FDA-approved drug that has previously been shown to extend the lives of non-Progeria mouse models.  A study* by researchers at the NIH in Bethesda, MD and Massachusetts General Hospital in Boston demonstrates that rapamycin decreases the amount of the disease-causing protein progerin by 50%, improves the abnormal nuclear shape, and extends the lifespan of Progeria cells in the laboratory.

Rapamycin is known for its anti-aging properties in mice. These findings are part of a growing list of studies that help to validate the theory that finding the cure for Progeria may also benefit the entire aging population.

* K.  Cao, J.  J.  Graziotto, C.  D.  Blair, J.  R.  Mazzulli, M.  R.  Erdos, D.  Krainc, F.  S.  Collins, “Rapamycin Reverses Cellular Phenotypes and Enhances Mutant Protein Clearance in Hutchinson-Gilford Progeria Syndrome Cells.” Sci.  Transl.  Med.  3, 89ra58 (2011).

The Progeria Research Foundation provided cells for this project from the PRF Cell & Tissue Bank and helped fund the research through our grants program – more proof that PRF’s research-related programs are essential to advancements toward the cure.

This 2-drug trial is a collaborative effort that will build upon the knowledge gained from the previous Progeria trials. The children are being seen by virtually the same team of physicians from Boston Children’s Hospital and Brigham and Women’s Hospital, all of whom now have world-renowned expertise in Progeria as well as the drugs involved.

8-year-old Ana Clara shares a special moment with her mother while taking a break from testing at Boston Children’s Hospital.
Ana is enrolled in phase 2 of the Progeria 2-drug trial. Travel from her remote town in Brazil included a 10-hour bus ride to the airport.

Details on the prior trials:  

#1 involved a single drug lonafarnib, began in 2007, and proved successful.  Read all about the historic treatment discovery here.

#2, the “Triple Trial” involved 3 drugs (lonafarnib, pravastatin and zoledronate).  This began with  a 1-month, phase 1 “mini trial” in March 2009 to determine if adding 2 more drugs to the lonafarnib regimen was safe to move forward with a larger population (which it was). Phase 2 began August 2009.  Its protocol changed over the course of 5 years, switching back to just lonafarnib and re-opening enrollment so more children could participate.

May 7, 2007: The Start of the First-Ever Progeria Clinical Drug Trial Marks Historic Moment in Progeria Research History!

In 2006, researchers identified a potential drug treatment for children with Progeria, called FTIs. For the first time, we had in front of us a possible treatment for children with Progeria. Exciting times!  The Progeria clinical drug trial began on May 7th, 2007 with two children – Meghan and Megan – arriving at Boston Children’s Hospital in Boston, MA for their first of seven visits over a 2-year period. At this first visit, they were given extensive tests and their first doses of the drug. An average of two families traveled to Boston each week thereafter, through December 2009, followed by a period of time in which the trial team analyzed the many thousands of data elements (each child underwent over 100 tests per visit!)and sought publication of the results.

“I know of no other rare genetic disease that has gone from gene discovery to clinical trial in under four years – a phenomenal testament to the hard work of The Progeria Research Foundation.”  Francis Collins, MD, PhD, Director of the National Human Genome Research Institute that mapped the human genome, workshop speaker and co-discoverer of the Progeria gene.

Twenty-eight (28) children from sixteen countries participated, ages 3 to 15 years. Children returned to Children’s Hospital Boston every four months, for testing and to receive new drug supply, and stayed in Boston for 4-8 days each visit.  While at home, their doctors kept a close watch over the children and submitted periodic health reports to the Boston research team.  For the duration of the trial, an average of 2 children per week traveled to Boston to participate.

Children in the first clinical trial originated from the following countries: Argentina, Belgium, Canada, Denmark, England, India, Israel, Italy, Japan, Mexico, Pakistan, Poland, Portugal, Romania, USA, Venezuela

Who, Where, When, How and How Much…
The first three clinical trials were led by Mark Kieran MD, PhDDirector, Pediatric Medical Neuro-Oncology, Dana-Farber Cancer Institute and Children’s Hospital Boston; Assistant Professor, Departments of Pediatrics and Hematology/Oncology, Harvard Medical School. Dr. Kieran is a pediatric oncologist with extensive experience with the drug under study (farnesyltransferase, or FTI) in children.  In 2017, he left his position at Dana Farber to work in the private sector. Co-Chairs were Monica Kleinman, MD, Director of Medical-Surgical Intensive Care Unit, Sr. Associate in Critical Care Medicine at BCH, Assistant Prof. at Harvard Medical School; and Leslie Gordon, MD, PhD, Medical Director of PRF, Lecturer at BCH and Harvard Medical School, Professor of Pediatrics at Hasbro Children’s Hospital and Brown University in Providence, RI.  Dr. Kleinman has assumed the lead role of Principal Investigator.

The clinical trials are a collaborative effort, involving physicians at Boston Children’s Hospital, Dana-Farber Cancer Institute, and Brigham and Women’s Hospital, all Harvard University institutions. In addition, physicians and scientists from The Warren Alpert Medical School at Brown University and NIH helped to make this first and the other trials a success.

How did we get to this point?
In 2003, The Progeria Research Foundation’s collaborative research team  discovered the Progeria gene. This discovery not only led to further understanding of Progeria, but scientists now know that studying Progeria can help us learn more about heart disease and the normal aging process that affects us all.   Since the gene discovery, the support of researchers, clinicians, families of children with Progeria and people like YOU brought us to another crossroads in the search for a treatment. Researchers began an intense study of this enemy protein called progerin, and in 2006 they identified a potential drug treatment for children with Progeria, called farnesyltransferase inhibitors (FTIs), and conducted studies in the lab that supported a human trial with the drug. The FTI chosen is supplied by Merck and called lonafarnibClick here for more details on the research.

Why did researchers think this drug would work in Progeria?
The protein that we believe is responsible for Progeria is called progerin. In order to block normal cell function and cause Progeria, a molecule called a “farnesyl group” must be attached to the progerin protein. FTIs act by blocking (inhibiting) the attachment of the farnesyl group onto progerin.  So if the FTI drug can block this farnesyl group attachment in children with Progeria, then progerin may be “paralyzed” and Progeria improved.  Click here for more information on FTIs.

Normal cell, Progeria cell, Progeria cell after being treated with FTI

Normal cell, Progeria cell, Progeria cell after being treated with FTI.

How did PRF fund the trial?
Thanks to the support of thousands, we were able to raise all the funds necessary to cover the trial costs.  Our heartfelt gratitude goes out to everyone who contributed their “time, talents and treasure” to make this incredible achievement possible, and of course to all the courageous families who participated.

All of the children received trophies at their final, 2-year visit for the first-ever Progeria clinical drug trial.
Here, Mateo, Milagros and Jesper are thrilled to get their awards
.

The FTI lonafarnib is now a proven treatment for Progeria. In 2012 the study results were published, demonstrating that every child experienced improvement in one or more areas, including the vital cardiovascular system.  In May 2014, a study showed one or more of 3 drugs – including lonafarnib – being tested in PRF-funded clinical trials extended lifespan; it was unclear which drug had this positive life-changing impact.  However, in April 2018 a study published in The Journal of the American Medical Association (JAMA) reported that lonafarnib alone extended survival in children with Progeria by at least 1.6 years (time will tell if that number increases – it just hasn’t been long enough to determine). Click here for details on the 2012 historic treatment discovery study, here for details on the 2014 findings, and here for details on the 2018 study.

Here is what some of the courageous families have said:
“EVERYONE has been so wonderful. To us you are ALL GOD SENT and we APPRECIATE all that you do for these little angels. Our family is so overwhelmed with excitement and all sorts of emotions with Adalia’s trip to Boston this weekend, I can’t even begin to type the words of how we are feeling.”

Cam and his dad learn how to mix the FTI drug with a sweetener.

“This new medication for Zach gives us a renewed hope that his heart will be stronger, his smile will be brighter and his life will be longer. This new drug trial is an answer to our prayers. Thank you to everyone involved with PRF who made this happen…the doctors, the researchers and the staff. You are our heroes!”

“On behalf of Cam and our family, thank you all at PRF so much for all you have done! We would have been lost in a world of confusion and grief without you. Instead, we live in a world of hope and purpose. Thank you again and again! With much love and respect,” 

 

Always Moving Forward: The Progeria Triple Drug Trial Begins August 2009

Hayley from England and Michiel from Belgium are all smiles as they pose with their trophies for completing the first-ever Progeria clinical drug trial in August, 2009.
They also, along with Michiel’s sister Amber (right), completed their first visit for the triple drug trial that week.

Summary: Researchers identified two additional drugs that, when used in combination with the current FTI drug being tested (lonafarnib), may provide an even more effective treatment for children with Progeria than FTI’s alone. Pravastatin and zoledronate were added to the current treatment lonafarnib. This much larger trial included 45 children from 24 different countries!

Strategy: All three drugs target different points along the pathway leading to production of the disease-causing progerin. In exciting laboratory studies presented by Dr. Carlos Lopez-Otin of Spain at the 2007 Progeria Research Foundation Scientific Workshop, the two new drugs improved disease in Progeria cells and extended lifespan in mouse models of Progeria.

Goal: If the three drugs administered in this trial can effectively block this farnesyl group attachment, then progerin may be “paralyzed” and Progeria may be improved even more than it is with the lonafarnib alone. The hope is that the drugs would work as partners, to complement each other so that the progerin protein is affected more by combining the three drugs.

The Feasibility Trial: The team conducted a mini-trial for 5 children with Progeria. The short, one-month “feasibility” trial asked whether the three-drug combination would be well-tolerated, prior to embarking on a larger international trial. Side effects were acceptable, and the team moved ahead to the larger efficacy trial.  

The Efficacy Trial: 45 children enrolled in this trial, from 24 countries, speaking 17 languages. This includes children that participated in the FTI-only trial, the participants in the feasibility trial, and other children that were either too young to participate in the first trial or children that we discovered during the first clinical trial (after enrollment had ended). Children enrolled in the FTI-only trial had the opportunity to enroll in the triple trial when they participated in their last visit for the current trial. This allowed those children to continue taking FTI without any missed doses.

Trial Medications at a Glance
Pravastatin (marketed as Pravachol or Selektine) is a member of the drug class of statins. It is usually used for lowering cholesterol and preventing cardiovascular disease.
Zoledronic acid is a bisphosphonate, usually used as a bone drug for improving osteoporosis, and to prevent skeletal fractures in people suffering from some forms of cancer.
Lonafarnib is an FTI (Farnesyltransferase inhibitor), a drug that can reverse an abnormality in Progeria cells in the laboratory, and has improved disease in Progeria mice.
All 3 drugs block the production of the farnesyl molecule that is needed for progerin to create disease in Progeria.

* “Combined treatment with statins and aminobisphosphonates extends longevity in a mouse model of human premature aging, by Ignacio Varela, Sandrine Pereira, Alejandro P. Ugalde, Claire L. Navarro, Marıa F. Suarez, Pierre Cau, Juan Cadinanos, Fernando G. Osorio, Nicolas Foray, Juan Cobo, Felix de Carlos, Nicolas Levy, Jose MP Freije and Carlos Lopez-Otın. Nature Medicine, 2008. 14(7): p. 767-72.

In July a study ** was published that showed no significant improvements were found over and above the lonafarnib single therapy. **Gordon, et. al., Clinical Trial of Protein Farnesylation Inhibitors Lonafarnib, Pravastatin and Zoledronic Acid in Children with Hutchinson-Gilford Progeria Syndrome, Circulation,    10.1161/CIRCULATIONAHA.116.022188

However, the “Triple Trial” was extended beyond its original 2-3-year timeframe, and expanded to include up to 80 children, so that every child could have access to lonafarnib alone because we know that it is helping the children. Usually, clinical trials run their course and the patients are taken off all the drugs until FDA approval; this could take years.  PRF has ensured that the children continue to take the one known treatment, while they and their research partners continue exploring additional treatment options (such as everolimus that is currently being tested).

Our quest for the cure continues…

Everolimus is a drug that gives us even more hope for children with Progeria.   Our trial will determine if it has benefits which exceed those derived from lonafarnib.  With your help, PRF can continue to move forward as quickly as possible toward the most effective treatments and the cure.