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rom total obscurity in 1999 to first-ever clinical drug trials starting in 2007, PRF is leading the charge in the quest to discover treatments and the cure.
In just 13 years, since we founded PRF and there were no resources for these children, we have gone from gene finding to the first clinical trials in Progeria, to a first-ever treatment- a pace virtually unheard of in the scientific community. And while helping this handful of children, the connection of Progeria to common heart disease and aging has tremendous implications for us all.
To date, PRF has funded and co-coordinated three clinical trials: the first, involving a single drug lonafarnib, began in 2007 and proved successful; the second was a 1-month “mini trial” in March 2009 to determine if adding 2 more drugs was safe to move forward with a larger population (which it was); and the third, the “Triple Trial” began August 2009 and is ongoing. Most recently, the Triple Trial protocol has changed in 3 ways:
Read all about the historic treatment discovery here, and below is the history of these trials.
“The two Megans”, both
6 years old, were the first
to enroll in the clinical
trial in May 2007.
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 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 lengthy 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
The Progeria Clinical Research Drug Trial: Who, Where, When, How and How Much…
The clinical trial is led by Mark Kieran MD, PhD, Director, 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. The clinical trial is a collaborative effort. The children were seen by physicians at Children’s Hospital Boston, 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 trial 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 lonafarnib. Click here for more details on the research.
How do researchers think this drug will 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.
Progeria cells become normalized when FTIs are applied. Capell et al., PNAS, 2005
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, including clinical testing, translators, staff, travel, food and lodging expenses for the 28 families from 16 countries who came to Boston every four months for two years. 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. And in May 2014, further study revealed lonafarnib (and possibly the other 2 drugs tested in the Triple Trial – see below) increases estimated lifespan 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 study, and here for details on the 2014 findings.
The Progeria Research Foundation and Children’s Hospital Boston are once again partnering to conduct a new clinical trial for children with Progeria. This much larger trial includes 45 children from 24 different countries!
Summary: Researchers have 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 with lonafarnib.
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 will work as partners, to complement each other so that the progerin protein is affected more by combining the three drugs.
Who is Enrolled In The Triple Drug Trial?
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 has moved ahead to the larger efficacy trial.
The Efficacy Trial: 45 children have enrolled in this trial, from 24 different countries, speaking 17 different languages. This includes children participating in the FTI-only trial, the 5 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.
The Treatment/Progeria Relationship
How did we get from gene discovery to drug therapy for children with Progeria? Finding the gene for Progeria was the key. This gene is called LMNA, and it normally encodes a protein called prelamin A (this protein is further processed and becomes lamin A). Children with Progeria have a mutation in LMNA which leads to the production of an abnormal form of prelamin A called “progerin.” Many years’ worth of basic research on prelamin A and lamin A gave us the ability to understand that the drugs administered in this trial may affect disease in Progeria. Over the past six years, research has focused on systematically testing these drugs on Progeria cells and Progeria mice.
The Clinical Trial Team
Since May 2007, a 28-member team has treated children with Progeria from around the globe. Members of the team have expertise not only in Progeria, but also in the three drugs administered in this trial.
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, MarÄ±a F. Suarez, Pierre Cau, Juan Cadinanos, Fernando G. Osorio, Nicolas Foray, Juan Cobo, Felix de Carlos, Nicolas Levy, Jose MP Freije and Carlos Lopez-OtÄ±n. Nature Medicine, 2008. 14(7): p. 767-72.
The new generation of children PRF is helping…
In March 2009, five children, ages 2-3, participated in the one-month feasibility study to determine if the side effects of the three drugs taken together were tolerable. The results were positive, paving the way for the full Triple Drug Trial to (initially) enroll up to 45 children with Progeria. Hats off to these amazing families! Here is what some of them had to say:
“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”.
“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,”
Cam and his dad learn how to mix the FTI drug with a sweetener.
Where are we now?
The “Triple Trial” has been extended for 2 years, and expanded to include up to 80 children, so that every child can have access to treatment that could give them longer and healthier lives. However, during this last trial phase, all children will be taking lonafarnib alone while the trial team analyzes the many thousands of data elements (each child underwent over 100 tests per visit!) on the three-drug therapy phase of the trial. The triple therapy trial was pre-designed to include lonafarnib, pravastatin, and zoledronate. The hope is that adding two additional drugs to lonafarnib will boost the beneficial effects of the single drug therapy. While we know that lonafarnib is helping the children, it is still too early to tell if the other two are boosting the benefit. Usually, clinical trials run their course and the patients are taken off all the drugs until the data is analyzed to see if it helps; this could take years. PRF and the Boston Children’s Hospital team have made the important decision to add two years of lonafarnib treatment for several crucial reasons. This extension and expansion allows additional time for the trial team to explore other potential benefits and track any long-term side effects of lonafarnib, including lifespan. Moreover, it allows us to continue exploring additional treatment options while giving all known children living with Progeria today the opportunity to participate in a clinical trial.
We are grateful and excited to start the clinical trial, and waiting for the day Yusi can meet more children like her.
- Mother of Yusally, 13 years old, from Brazil, who plans to come to Boston for the first time during the summer of 2014.
We are very happy with the visit…To know that we will have a better quality of life for my baby makes me feel amazing, as my wife says he is a "Warrior of Life ".
- Father of Angel, 3 years old, from Mexico, scheduled to arrive in Boston for his initial clinical clinical trial visit in August 2014
In October 2009, PRF, Children’s Hospital Boston and Dana-Farber Cancer Institute received the highly competitive and prestigious NIH “Grand Opportunities” grant, funded by the American Recovery and Reinvestment Act and sponsored by the National Heart, Lung and Blood Institute. This exciting grant provided $3.1 million in funding for the the majority of the Triple Trial expenses through June 2013, when the grant ended; PRF contributed approximately $1 million during that time. PRF is responsible for all trial expenses from June 2013 on - estimated to be an additional $3 million. Thanks to our many supporters, as of July 2014 we have raised $1.5 million. Please help us raise the rest – donate today!