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?

Family of Twins with Rare and Fatal Cholesterol Disease To Seek FDA Approval To Deliver Cyclodextrin Into the Brain

The tagline of the new movie, Extraordinary Measures, about John Crowley’s fight to save his children from the rare and fatal Pompe disease is….Don’t Hope For a Miracle – Make One!

We are now working on making our own miracle  – a new compassionate use investigational new drug (IND) protocol and application that we plan to submit to the FDA by April 2010. We are seeking to add intrathecal and/or intraventricular cyclodextrin delivery into Addi and Cassi’s brains to treat Niemann Pick Type C disease.

We realize this sounds radical to some people but we believe that based on the data and the twins’ cyclodextrin treatment throughout 2009, we can show the FDA that doctors can administer cyclodextrin into the brain safely and that the treatment could be life-saving.

Our efforts to alter our treatment protocol from bloodstream to brain may create some amount of debate. We are prepared to fight the next set of roadblocks in our efforts to save Addi and Cassi and other children suffering from this fatal cholesterol disorder.

Addi and Cassi have been receiving cyclodextrin intravenous treatment (IV into bloodstream) for the past nine months. In September 2009, we stopped our weekly dose escalations and remain constant at a dose of 2500mg/kg, 8 hour treatments two times per week via IV.

Since putting cyclodextrin into the brain in humans has never been attempted before, it’s going to take a monumental effort to pull together the IND application. We remain hopeful that with the world-class team of experts we are assembling to write the protocol, we can administer cyclodextrin safely into Addi and Cassi’s brains.

Research funded by The Addi and Cassi Fund and Hadley Hope Fund with Dr. David Begley of Kings College of London has shown that cyclodextrin does not cross the blood brain barrier (which was under debate). However, Dr. Begley has found that cyclodextrin does not cross it may bind to the blood brain barrier which could be a key clue into how it is working. Dr. Begley will be presenting data at the Lysosomal Disease Network World Conference being held in Miami Feb 10-12, 2010.

The bottom line is that cyclodextrin is not getting into the brain.  However, cyclodextrin’s ability to possibly bind to the blood brain barrier or it’s impact in teh bloodstream may be causing the positive effects we are seeing in pur twins such as:

Reduction in the size of their lysosomes

Reduction of plasma oxysterols which appear to be a new biomarker for Niemann Pick Type C disease

Improved balance and stability, less ataxia and better head control

Improved mood and stronger emotions (happier, smiling and laughing more)

Much more affectionate, better eye contact

Increased appetite (better swallowing and chewing with Cassi in particular!)

More overall awareness to their surroundings, less “flat” and distant

Making more sounds and more volume to sounds

Increased concentration and ability to sit for longer periods

Not as floppy and jello-like, seem to have more muscle strength

Following directions better, seem to understand more what we’re saying even if they can’t talk

Improved general health status

We do not see any visible outward side effects – no vomiting, hair loss, skin rashes, dizziness – nothing. The most concerning and serious side effect with cyclodextrin appears to be pulmonary issues based on the animal studies conducted on NPC cats and mice. Apparently, in cats and mice they see increase macrophage development in the lungs but researchers do not know why.

We are keeping a close eye on Addi and Cassi’s pulmonary function. Last month, the twins underwent bronchoscopes at Children’s Hospital Oakland to look inside their lungs. I have posted the lung procedures on Vimeo for anyone to view (Addi – Cassi).

According to our pulmonologist, the girls have slight scattered nodules in their lungs. Doctors believe these nodules may be xanthomas. Xanthomas can occur in people with high blood lipids but usually appear on the elbows, joints, tendons, knees, hands, feet or buttocks.

Xanthomas are not a common feature of Niemann Pick Type C disease, however, there has been a case of suspected xanthomas with a child with NPC mutations. If the nodules are xanthomas, they are either as result of Addi and Cassi’s rare and private mutations or from the cyclodextrin IV treatment.  Since the girls are identical twins, the only logical conclusion is genetic or cyclodextrin. Interestingly, researchers do not see xanthoma development in the lungs of cyclodextrin treated mice or cats.

In addition, we had CT scans done on Addi and Cassi’s spleens and livers and there was no change in size. We are told by experts that this does not mean that the cyclodextrin is not benefiting their organs. On the other hand, we may not be achieving the right concentrations of cyclodextrin in the plasma. We are still trying to develop the pharmacokinetics around cyclodextrin.  They don’t exist and we have to create everything from scratch.

We have been in contact with top metabolic doctors in Japan and they are treating little girl with cyclodextrin.  The good news is they have seen a reduction in the child’s liver and spleen size. Her liver and spleen size were 4-5cm and 7cm below the coastal margin before cyclodextrin treatment and today are 1cm and 3-4cm below the coastal margin. She showed some improvement on her EEG and has not had any adverse effects with the IV treatment.  However, she is progressed and they are not seeing major neurological benefits.

It is clear that we must design further treatment options with cyclodextrin to try and improve neurological function. This means delivering cyclodextrin into the brain through the intrethecal and/or intraventricular route of administration. We will never know if cyclodextrin can save our girls unless we try.

Miracles do happen.  Please help Addi and Cassi as we try and make our miracle.

Instructions On How Cyclodextrin Solution Is Made For Addi and Cassi’s Intravenous Cyclodextrin Therapy

A number of people from around the world who have children diagnosed with the fatal cholesterol disease called Niemann Pick Type C  have asked me how our we prepare our cyclodextrin solution for Addi and Cassi’s bi-weekly IV infusions of the compound.

I asked our pharmacist at Renown Hospital in Reno, Nevada, to provide me with step-by-step instructions on how he makes the sterile solution for the twins. You can read his instructions here.

All hydroxy propel beta cyclodextrin (HPBCD) is not the same. It’s very important that you make sure that the cyclodextrin that is purchased is endotoxin controlled and does not have propylene glycol in it or other impurities. Essentially propylene glycol is anti-freeze – not exactly what you want to put into kids!

We purchase our cyclodextrin from CTD, Inc., which is located in High Springs, Florida. The owner of CTD is extremely knowledgable when it comes to cyclodextrins and sells many different types of cyclodextrin products.  The cost for his HPBCD is about $5 USD per gram.

I am still working to try and make a solution that can be bottled and sent worldwide. As you can imagine, this takes time since we have no pharmaceutical company helping us with this effort.

When the girls receive their infusions, there is a basic filter that the cyclodextrin funnels through (this is simply as a precaution).  The filter is attached to the infusion line and as the cyclodextrin drips through the plastic line it goes through this little blue filter. I will try and find out the name of the filter we use.

We are currently looking at different ways to get cyclodextrin into the body — possibly through regular subcutaneous injections as well as intrathecal methods to get cyclodextrin directly into the brain through the spinal canal.  We are actively pursuing both ideas now on how this would be possible for Addi and Cassi.

I continue to be very happy with how the infusions are going.  The most difficult part so far has not been giving them cyclodextrin — it is being at the hospital for 2x a week all day long just sitting there watching cartoons. I am hoping the FDA will approve us to do infusions in a home setting (hopefully at night when they are sleeping) as we have not experienced any side effects.  We are at 2500 (yes, 2500) mg per Kg BW and the infusion lasts 8 hours.

Addi and Cassi seem to be a lot more alert and aware and have better balance and head control!   I pray we can speed up research on cyclodextrin and determine the mechanism for how it’s working.

For more information on Addi and Cassi’s cyclodexrin protocol, you can view our FDA compassionate use filings here.

Parents To Seek FDA Orphan Drug Designation For Cyclodextrin To Treat Rare and Fatal Cholesterol Disease

On Tuesday morning at 11am, Addi and Cassi are going to undergo volumetric CT scans of their livers and spleens.  The tests are being conducted by doctors to determine if the cyclodextrin IV infusion treatment the twins are receiving under compassionate use INDs approved by the FDA are reducing the size of their enlarged cholesterol filled organs.

UT Southwestern scientists have shown that Niemann Pick Type C mice organs can be restored to normal size through cyclodextrin treatment.  We are soon to find out whether the same is true for children who are afflicted with this rare and fatal cholesterol disease.

In all previous tests conducted on Addi and Cassi’s swollen abdomens, their spleens have measured about 12 centimeters. We are very excited and hopeful that they have reduced in size since starting the cyclodextrin infusions about 5 months ago.

We also received preliminary results this week that cholesterol is being excreted in Addi and Cassi’s urine and their lysosomes are getting smaller!  All positive signs and so far no negative side effects from the cyclodextrin treatment.  We are now infusing 2800 mg/kg over 8 hours 2x per week — we are getting into some significant doses.

Currently, my husband and I are working with a small core team of doctors and NPC parents to apply for Orphan Drug Designation for cyclodextrin (HPBCD). We intend to file our documents with the FDA in February 2010 and we are trying to get a pharmaceutical sponsor to help us.  If we are unable to secure a sponsor, we will sponsor the Orphan Drug Designation filing ourselves as private citizens.

Since no pharmaceutical company makes a sterile cyclodextrin infusion formulation, Adam our hospital pharmacist has to make Addi and Cassi’s formulation from scratch.  For the past few months, I have been working with a cyclodextrin manufacturer in Hungary and a US based cyclodextrin supplier who can help me make an endotoxin controlled cyclodextrin formulation that can be distributed to patients worldwide.  I hope to have a sterile compound available in 2010 for patients if all goes well.

Just for fun, I mocked up a little bottle (using Genzyme’s Cerezyme drug bottle) with a label.  We might be able to put our cyclodextrin into a plastic bag — essentially it would look like a bag of saline only it would have cyclodextrin in it.

Dysfunctional cholesterol metabolism has been implicated in the etiology of many diseases from  Alzheimer’s to Coronary Artery Disease.  It’s amazing to think that a non toxic food additive that is also the main ingredient in Febreze fabric freshener could be the next miracle drug and might be able to save my girls lives or give them more time with us.

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