Walgreen’s Support Allows Our Twins with Niemann Pick Type C To Receive Cyclodextrin Treatments At Home

We are sorry for the lack of posts in recent months! Hugh and I have been extremely busy with rare disease initiatives for Solution Therapeutics, our virtual biotech, as well as helping the Global Genes Project with a number of community based rare disease projects.

We would like to report that after three years of receiving intravenous cyclodextrin infusions (IV Cyclo) in a hospital setting, we have received both hospital Institutional Review Board (IRB) approval and what is considered the “green light” from the FDA to begin our IV Cyclo at home.

We can’t begin to express what this means to our entire family to begin IV Cyclo treatments at home.  Since April 2009, we have been making bi-weekly, and then weekly, visits to our local hospital in order for the twins to receive IV Cyclo.  Their weekly infusion lasts eight hours. By the time we leave our house, initiate the infusion, disconnect the tubing and get home, we’re dealing with a 10+ hour day.

We estimate we have done about 225 IV Cyclo infusions (x2) since we started on this journey to treat Addi and Cassi with Hydroxypropyl Beta Cyclodextrin (HPβCD)– that works out to 2250 hours in the hospital and this does not include our bi-monthly intrathecal cyclodextrin (IT Cyclo) treatments so that HPβCD can reach the twins’ brains.

Why has it taken over three years to get cyclodextrin started in a home setting?  Very good question!

First, we had to contend with the FDA. Our original treatment protocol called for many procedures such as blood pressure checks and having special equipment in place in the event the twins experienced anaphylactic shock from the compound.  Since the twins were the first in the United States to receive this type of treatment, the safety protocol that needed to be in place with the FDA was incredibly strict.   We had to prove the compound was safe and with limited side effects.  (Note: we have not had one reported side effect to FDA in over three years since starting treatment.)

Next, we had issues with how the cyclodextrin was produced from a powder into a sterile liquid form that could be put into Addi and Cassi’s bodies. Our hospital pharmacy was creating our liquid cyclodextrin compound from scratch each week using extensive filters.  This is not a drug you can purchase from a pharmaceutical company, although we are trying to work on an agreement with Johnson & Johnson to provide us with a cyclodextrin solution since they already use it in another drug. Until that agreement in place, we have had to spent tens of thousands of dollars to have it made from scratch and in sterile form.

In order to get an IV Cyclo formula created outside of the hospital, we searched to find a pharmacist and organization willing to help us move to our home. This is where Walgreen’s stepped up to the plate. Ron Vaught, our local Walgreen’s Infusion Services pharmacist, is amazing.  After reviewing our case and meeting with our hospital pharmacist to understand the methods to make the liquid cyclodextrin, Ron contacted Walgreen’s corporate offices to see if the company would allow him to make this formula for our twins.  It was a “long shot” due to corporate liability issue (this seems to be the first thing that comes up before someone can decide to help us) but Walgreen’s was willing to work with us and we are so grateful!

After receiving Walgreen’s commitment to make the IV cyclodextrin formula, we had to alter our treatment protocol for the FDA to allow for home based infusions using Walgreen’s Infusions Services and nurses.  We then submitted the new protocol to the FDA and Children’s Hospital Oakland IRB.  Our protocol called for a “transition period” where the twins would receive their treatments in a clinic setting at the Children’s Specialty Center of Nevada with the formula mixed by Ron at Walgreen’s Infusion Services.  We have been doing that for the past 3-4 months and all has been well.

Critical Care Systems of Reno, NV, worked with Walgreen’s Infusion Services and Dr. Caroline Hastings to get our insurance approval to do these treatments in our home.

This Tuesday, July 17, at 9:30am, two Critical Care Systems nurses will arrive at our home to connect Addi and Cassi’s IV Mediports (which are installed in their chest). With them will be the cyclodextrin solution made by Ron at Walgreen’s and a new portable pump.  The nurses are not allowed to push the “start” button on the home infusion system — that will be left to Hugh and I due to “liability” issues.  We will also be trained on how to “de-access” the ports, which means we will flush them and take the needles out.

After watching the procedure 225 times (x2), I am pretty sure I can de-access the port in my sleep!  And after three years in the hospital, I seriously can’t wait to push that pump button!

 

 

FDA Approves Request For New Cyclodextrin Treatment For Niemann Pick Type C

FDA Approval Received!

Children’s Hospital Oakland Receives FDA Clearance to Begin World’s First Cyclodextrin Administration Into the Brains of Twins with Rare and Deadly Cholesterol Disease

Sugar Molecule Used In Common Food and Household Products Like Febreze® Fabric Refresher Called Hydroxypropyl Beta Cyclodextrin (HPßCD) Will be Delivered into Twins’ Central Nervous System in an Attempt to Stop Neurological Progression of Niemann Pick Type C Disease

September 23, 2010 – Oakland, Calif. – Children’s Hospital & Research Center Oakland announced today that the US Food and Drug Administration (FDA) has granted clearance of an Investigational New Drug (IND) application to introduce Trappsol® Cyclo™ (Hydroxypropyl Beta Cyclodextrin or HPßCD) into the brains of six year old identical twin girls dying of a rare brain-destroying cholesterol disease called Niemann Pick Type C (NPC). Known as “childhood Alzheimer’s,” NPC is a deadly progressive neurological condition that causes severe dementia and other debilitating symptoms in children. The FDAs approved use of Trappsol® Cyclo™ marks the first time in medical history that HPßCD will be delivered directly into the brain of a human being in an attempt to arrest a progressive and fatal neurological condition.

Within days, Addison and Cassidy Hempel will travel from their home in Reno, Nev., to Children’s Hospital Oakland to start ongoing injections of Hydroxypropyl Beta Cyclodextrin (HPßCD) into their central nervous systems. Initially, the twins will receive six cyclodextrin treatments of Trappsol® Cyclo™ via lumbar injection over a 12-week period. If Trappsol® Cyclo™ is well tolerated and no adverse side effects occur, the twins are then expected to undergo brain surgery to implant access ports allowing HPßCD to be delivered into the brain’s ventricle system.

HPßCD is a ring of seven sugar molecules known as a cyclic oligosaccharide that is derived from starch. Derivatized cyclodextrins are used extensively in research labs to remove cholesterol from cultured cells and are well known in the pharmaceutical industry for their ability to solubilize drugs. Underivatized cyclodextrins are used throughout the food industry to make cholesterol-free products, such as fat-free butter, eggs and milk products. HPßCD is recognized as a GRAS (Generally Recognized As Safe) material for use in food products in Asian and European countries and is being considered for similar certification in the United States. Hydroxypropyl Beta Cyclodextrin, the chemical compound that will be administered into the twins’ central nervous system, is also an active ingredient found in Procter & Gamble’s Febreze® Fabric Refresher and is used to help eliminate odors from fabrics. Millions of people worldwide are exposed to small amounts of cyclodextrin compounds every day in food, cosmetics and household products.

“It is remarkable to be in position to try a genuine medical intervention that may retard or restore neurological function in children suffering from Niemann Pick Type C disease,” said Caroline Hastings, MD, the Children’s Hospital Oakland pediatric hematologist/oncologist who diagnosed the twins. Dr. Hastings also manages the satellite hematology/oncology clinic at Renown Regional Medical Center in Reno where the girls receive much of their treatment. “This family’s tremendous courage to move forward with this groundbreaking treatment to deliver cyclodextrin into the brains of their twins provides real hope for all children afflicted by this mind-robbing condition and possibly others suffering from cholesterol and lipid related disorders.”

In April 2009, the FDA approved an Investigational New Drug protocol that allowed Addison and Cassidy Hempel to undergo weekly intravenous infusions of Hydroxypropyl Beta Cyclodextrin into their bloodstreams through a Medi-Port catheter implanted in their chest walls. However, research conducted by David Begley, PhD, a leading blood-brain barrier expert at Kings College London, discovered that Hydroxypropyl Beta Cyclodextrin does not cross from the bloodstream into the brain. While the Hempel twins have shown improvements with ataxia and have less difficulty swallowing following intravenous intervention with HPßCD, they continue to decline neurologically and there are no other treatment options available to save their lives. The twins have lost most of their ability to speak and are experiencing intermittent seizures and dementia; however, the girls can still walk, see, and communicate to their parents with a range of sounds and gestures.

On June 13, 2010, Dr. Hastings filed a revised protocol to the Hempel twins’ Investigational New Drug applications with the FDA requesting permission to deliver Trappsol® Cyclo™ directly into the central nervous system of the twins in order to bypass the blood-brain barrier. Researchers studying Niemann Pick Type C afflicted cats and mice have discovered that when HPßCD is delivered directly into the brains of these animals, HPßCD has a remarkable life extending effect and appears to arrest the progression of this deadly neurological condition. It is currently unknown exactly how HPßCD is working to achieve these astonishing neurological effects in NPC animals or if it will have the same effect in humans.

For Chris Hempel, mother of the twins, the start of cyclodextrin treatments into the central nervous system of her twins “creates new hope that was unimaginable even a few years ago for an ultra rare disease with a certain death sentence.” Since receiving the NPC diagnosis in October 2007, Ms. Hempel has worked tirelessly with doctors and researchers around the world to search for a lifesaving treatment for her twin daughters. In May 2010, she worked with Dr. Hastings to receive one of the few orphan drug designations granted by the FDA for the compound Trappsol® Cyclo™.

“It’s extraordinary to think that a sugar compound used in common products found in my refrigerator and laundry room could have such a profound effect on human cholesterol metabolism and may actually save our daughters lives,” said Hempel. “We are incredibly grateful for the support we have received from the medical, regulatory, pharmaceutical, and academic communities who have worked to help us bridge the scientific gap and turn a treatment idea into a treatment reality.”

Approximately 500 children worldwide have been diagnosed with double genetic mutations on the Niemann Pick Type C cholesterol gene, yet what scientists learn about these children may have implications that reach far beyond this ultra rare genetic cholesterol disease. Recent published research reports of the role for the NPC1 gene in Alzheimer’s disease and human immunodeficiency virus infection (HIV) make Niemann Pick Type C disease and gene research relevant to millions of people worldwide.

Cyclodextrins – Recipes To Make Edible Nanostructures and CD MOFs To LifeSaving Drug Treatments

Kenneth Chang of the New York Times reports on researchers creating edible nanostructures with gamma cyclodextrin which researchers are calling edible CD MOF (metal-organic frameworks). Of course, another amazing discovery with cyclodextrin that was found by accident!

Potential applications with this gamma cyclodextrin (CD MOF) could include storing hydrogen in future fuel cells in cars. Interestingly, the article mentioned “drug delivery” which I am already working on with hydroxy propel beta cyclodextrin (Trappsol brand). I wonder if HPBCD could be turned into nanoparticles and cross the blood brain barrier? I wonder if this new gamma cyclodextrin nanoparticle crosses the blood brain barrier?

One of the articles quotes a researcher who made the discovery as saying, “With our accidental discovery, chemistry in the kitchen has taken on a whole new meaning!”  This statement is something I can relate to as I’ve mixed up cyclodextrin into juice and with curcumin to try and get better absorption.

The article also gives a ‘recipe” on how to make edible cyclodextrin nanostructures which I found interesting. We have our own cyclodextin recipe that I am hoping the United States Food and Drug Administration will approve within the next few weeks.  Our doctor is trying to use cyclodextrin to save the lives of my identical twin six year old girls who suffer from Niemann Pick Type C, a rare and fatal genetic cholesterol disease that causes dementia in children.

When cyclodextrin is given intrathecally into cats and mice suffering from Niemann Pick Type C disease, hydroxy propel beta cyclodextrin arrests the neurological progression of the disease! When was the last time you heard of a compound or drug arresting the neurological progression of a disease like Alzheimer’s, Parkinson’s or ALS?

Here is the simple recipe we have proposed to the FDA:

Cyclodextrin To Stop Brain Neurodegeneration In Fatal Cholesterol Disorder

1. Dissolve 175 mg of hydroxy propel beta cyclodextrin (Trappsol brand) into 6 ml sterile saline

2. Put into sterile tube

3.  Inject via lumbar puncture into central nervous system

4. Repeat with dose escalations by adding 17.5 mg of HPBCD every two weeks until concentrations of 5 mM are achieved

5. Test central spinal fluid for reductions in A-beta levels, total T-Tau levels and other biomarkers such as the oxysterol called 7 ketocholesterol

6. Conduct neurological assessments on twins to see if speech returns, seizures and gelastic cataplexy reduce, etc.

7. For complete FDA filing with full instructions, contact me: chris@hempelfamily.com

IND Application Filed With FDA To Bring Cyclodextrin Into The Brain To Treat Fatal Childhood Cholesterol Disease

After months and months of work and input by doctors and researchers, Dr. Caroline Hastings at Children’s Hospital Research Center Oakland filed our second Investigational New Drug application (IND) with the FDA on July 14, 2010.

The 200+ page IND filing details our request to deliver hydroxy-propel-beta-cyclodextrin (HPBCD or CYCLO) directly into Addi and Cassi’s central nervous system and ultimately their brains.

Addi and Cassi suffer from Niemann Pick Type C, a ultra rare and fatal genetic cholesterol disease that causes progressive neurological deterioration and has been callled the “childhood Alzheimer’s” as it causes dementia in children.

While only approximately 500 children in the world have double genetic defects on the Niemann Pick Type C gene, everyone is born with the NPC gene, and the gene regulates human cholesterol metabolism. Studying children like Addi and Cassi may lead to breakthroughs in more common diseases such as Alzheimer’s and heart disease where disrupted lipids and cholesterol are implicated.

For the past year, we have been treating Addi and Cassi with weekly intravenous infusions of cyclodextrin but we learned from leading blood brain barrier researchers that cyclodextrin does not readily cross from the bloodstream into the brain. However, when cyclodextrin is delivered directly into the brains of NPC animals (cats/mice), this compound is creating a remarkable effect and arresting the neurological condition.

Here is some data from the NIH and NINDS meeting last month from Dr. John Dietschy, one of world’s leading lipid and sterol researchers, at UT Southwestern. Dr. Dietschy’s data shows that cyclodextrin delivered into the central nervous system of NPC mice prevents neurodegeneration.

Mechanism of action of cyclodextrins in reversing cholesterol transport defects in Niemann-Pick type C disease
John M. Dietschy, M.D., Professor Department of Internal Medicine
University of Texas Southwestern Medical Center Dallas

Niemann-Pick type C (NPC) disease is one of a number of disorders in which the underlying metabolic defect is abnormal accumulation of either cholesterol (C) or cholesteryl esters (CEs). The severity of the disease in organs like liver, lung, and CNS is proportional to the amount of sterol that accumulates in that particular tissue, and interventions that prevent this accumulation prevent the disease. Administration of cyclodextrin (CYCLO) rapidly overcomes the C transport defect seen in NPC1 and NPC2 disease and allows the sterol to move to the cytosolic compartment of cells, to be transported to the liver, and ultimately to be excreted from the body as bile acid. The ED50 for this effect equals ~300 mg/kg in most organs. However, the value in kidney, which is only ~30 mg/kg, is much higher in the CNS. The ED50 value for the lung is infinitely high. This ED50 value for the CNS is much lower when the CYCLO is administered directly into the brain. The acute or continuous administration of cyclodextrin into the CNS normalizes cholesterol metabolism and prevents neurodegeneration. To bring about these changes, the particular CYCLO must interact with C, but it need not bring about solubilization into the bulk-water phase. After administration of appropriate doses at appropriate intervals, the pools of C in nearly every organ are maintained at normal levels and disease is prevented. Only in lung is the abnormal C metabolism resistant to CYCLO therapy. Consequently, whereas liver and CNS disease can be prevented, pulmonary disease progresses.

Besides thanking Dr. Caroline Hastings, Dr. Ron Browne and Karen Barca for helping get this second IND submitted, there are countless others to thank for their generous assistance and strategic guidance:

• NPC researcher Dr. Charles Vite worked closely with Dr. Steven Silber and the Johnson & Johnson team, who donated their time and critical expertise and knowledge to help conduct PK experiments on Addi and Cassi and the NPC cats
• Alzheimer’s biomarker expert (Dr. Kaj Blennow) conducted important CSF biomarker experiments and has also offered to continue testing the twins’ CSF when we get approval from the FDA to move forward
• Dr. Steve Walkley, Dr. John Dietschy, Dr. Jean Vance and Dr. David Begley provided critical research data on NPC animals in advance of publishing  which helped accelerate this process
• Rick Stratton and Dr. Lajos Szente, cyclodextrin experts, provided needed references and strategic advice
• Dr. Peter Penchev, the “godfather of NPC disease” for his support and strategic guidance
• Dr. Tony Yaksh at UCSD and Dr. Patti Dickson at UCLA provided relevant intratehcal and cyclodextrin data
• Dr. Joe Madsen in the department of neurosurgery at Children’s Boston and Dr. Peter Sun at CHRCO offered advice on the feasibility of delivering cyclodextrin into the CNS
• Dr. Emil Kakkis, founder of BioMarin and the Kakkis EveryLife Foundation provided toxicity and safety advice as well as overall encouragement
• Dr. Harrry Chugani at Children’s Hospital of Michigan provided cutting edge PET imaging which helped support our case to move in this new treatment direction

Countless others offered to read our protocol and provided a tip here and there which all adds up to a comprehensive FDA filing. We simply can’t thank all the people who donated their time to helping us make it this far.

The FDA apparently has 30 days to respond to our intrathecal cyclodextrin filing. We are praying that the FDA does not require unrealistic toxicity studies that we can’t afford or throws out some other hurdle that can’t be easily crossed. Addi and Cassi’s seizures are getting a lot worse and their disease is progressing with hypometabolsim spreading to many regions of their brains.

Intrathecal cyclodextrin treatment is our only hope to try and save their brains from dementia and save their lives.

The Road to Building a New Orphan Drug – Am I Mad?

On February 25-26, 2010, I will be attending the inaugural FDA Build-an-Orphan-Drug-Workshop hosted by the Center for Rare Disease Therapies at Keck Graduate Institute (KGI) in Claremont, Calif.  FDA agency experts will be on hand to provide guidance on applying for orphan drug designation.

I will be attending the workshop with Dr. Ron Browne, hired to help us write the orphan drug application for hydroxy propel beta cyclodextrin (HPBCD).  Children’s Hospital Oakland Research Institute (CHORI) is sponsoring our orphan application as we do not have a pharmaceutical or biotechnology sponsor (a rare event in itself!). Our application is already drafted and we are attending the workshop to get final input and advice. Applications will be submitted at the close of the workshop. Perfect timing as this is the Friday before World Rare Disease Day 2010 (Feb. 28).

According to recent FDA statistics, over the past 25 years there have been 2,100 orphan designated drugs to treat rare diseases (of which 344 have become approved products). That works out to about 16.4%, which does not seem like a high percentage considering that rare conditions affect between 25-30 million Americans.  As of Feb. 8, 2010, a searchable database located on the FDA website has the number at 347/2131 which takes the percentage slightly lower.

For the most part, academics, pharmaceutical firms and biotechnology companies will be at KGI trying to find ways to move their drugs forward. Amidst all of these wonderful scientists, I (a “Mom” without a science degree) will presenting our case for a seven ring sugar molecule called cyclodextrin. Cyclodextrin has never been considered a “drug” yet this compound could save the lives of our six year old identical twins who suffer from perhaps the worst cholesterol disease on the planet.  I wonder what they are going to print on my badge?  Mom? SugarNut? More than likely “Lunatic” because I must be insane to embark on trying to get into the 16% club.

Orphan drugs are either drug or biologic products used to treat rare conditions affecting fewer than 200,000 people in the United States. Since there are only 250 children in the United States with Niemann Pick Type C disease, I think we will qualify! I am really not worried about qualifying because the science on cyclodextrin backs up our application. I am worried about how to move development forward on this compound.

I have a number of key goals:

Submit an exceptionally strong application for cyclodextrin

Determine how cyclodexrin can make it into the 16 percent club, despite the fact we only have 250 patients in US/500 Worldwide

Find out if the government/FDA can help us move the development of cyclodextrin forward — what kind of grants can we get for this sugar compound? Maybe some nice biotech executive with a cholesterol issue or a parent with Alzheimer’s might invest in us?

Determine what kind of safety and efficacy studies are reasonable for an ultra rare disease like Niemann Pick Type C.  We don’t have $800 million and 12 years to invest in moving a therapy forward when there are only a few hundred patients (many without insurance to pay for expensive drugs)

Understand more about animal studies that can help bolster our chances to make it into the club

Clarify how to move this compound forward while we are under “compassionate use” INDs with another FDA division.  How do we maximize getting data from Addi and Cassi’s treatment since they are already receiving IV cyclodextrin infusions 2x per week

What kind of new incentives can the government put in place for individuals like us?

By the time the two day workshop is finished, it will cost $4,000 dollars for Dr. Browne and I to attend (air, hotel, conference fee). We could really use $4,000 for an animal dosing safety study.  Every second and every penny counts when you’re trying to save your kids from a fatal childhood illness on a shoestring budget compared to the hundreds of millions of dollars of investment it takes to move a drug forward.

I hope the meeting is useful and we actually leave having filed an orphan drug application for cyclodextrin. I also hope that the FDA can learn something from a parent like me.  I may be crazy but what if I am right?

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