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.

Alzheimer’s Patients Presenilin 1 Gene Defect Causes A Lysosomal Storage Disorder

A research paper by Dr. Ralph Nixon, director of the Center of Excellence on Brain Aging and the Silberstein Alzheimer’s Institute at NYU Langone Medical Center, was published today in the journal Cell reporting that Alzheimer’s patients with genetic mutations in the presenilin 1 gene have disruptions in the cellular protein recycling process mechanisms in their lysosomes.

The paper abstract is: Lysosomal Proteolysis and Autophagy Require Presenilin 1 and Are Disrupted by Alzheimer-Related PS1 Mutations.

Dr. Nixon’s amazing research work indicates that Alzheimer’s disease has a major lysosomal component and could be a  lysosomal storage disease.  Alzheimer’s patients presenilin 1 gene disruptions cause toxic proteins to accumulate in the internal cell structure  – the lysosome. The failure results in a clump of proteins known as beta-amyloids to form in the brain and also leads to neuronal cell death.

I imagine the hits on the Wikipedia lysosomal storage disease page are through the roof today because most people (including Alzheimer’s researchers!)  connect lysosomal storage diseases with ultra rare diseases.

There are approximately 50 rare inherited metabolic disorders that result from defects in lysosomal function. It appears from this paper that lysosomal storage diseases are not so rare after all!  Apparently, the groundbreaking research has generated lots of interest with drug companies.

Alzheimer’s is very similar to Niemann Pick Type C disease (NPC), a well characterized lysosomal storage disease where cholesterol accumulates in the lysosome causing neurons to die.  My six year old identical twins, Addi and Cassi, have the fatal dementia condition and have increases in beta amyloid, tau, hypometabolism developing in their brains, elevated oxysterols – many of the same symptoms seen in Alzheimer’s patients!

Maybe my prediction that cyclodextrin could also help Alzheimer’s patients will turn out to be true?

Orphan Drug Act – A Collosal Failure Considering Rare Disease Drug Statistics

For the past week, I have been obsessing over rare disease statistics ever since it was published that 80% of all rare diseases are ‘ultra orphans’ – affecting 6,000 people per disease state or less – and only 15% of all rare disease drug applications filed with the FDA are for ‘ultra orphans.’

Yesterday, I posted a blog with some extremely alarming statistics I worked out on paper. For example, if 80% of all rare diseases are ‘ultra orphans’ (affecting 6,000 people or less) and there are 7,000 rare diseases, approximately 5,600 different rare diseases would fall into the ‘ultra orphan’ category.

This morning, I went on the FDA Orphan Drug Database to run some other estimates. Of course, these numbers are estimates but I am sure I am not very far off with my projections.

Fact: Since the Orphan Drug Act was enacted in 1983 to present, there have been 2,182 orphan applications that have officially received the orphan drug designation from the FDA. Of all of the designations submitted, 347 have been approved as drugs by the FDA which works out to about 16%.

Estimate: If approximatley15% of all the rare disease applications submitted to the FDA are for ‘ultra orphans’, then approximately 327 of the total pool of 2,182 designations over the past 25 years would have been given to ‘ultra orphan” diseases.

Estimate: If we know that 16% of the applications eventually receive FDA drug approval, then of the estimated 327 ‘ultra orphan’ designations that have been in the pipeline over the past 25 years, approximately 52 would have moved forward to become FDA approved drugs.  This estimate is for all ‘ultra orphan’ diseases combined. Another way to look at this statistic — over the past 25 years, on average about 2 drugs per year have been approved by the FDA for 5,600 different ‘ultra orphan’ diseases.

Some people have actually tried to look at me with a straight face to tell me that the Orphan Drug Act of 1983 has been a success. A success?  How can anyone claim this drug development system for rare diseases is working for millions of Americans with ‘ultra orphan’ diseases?  The Orphan Drug Act of 1983 is a collosal failure on multiple dimensions. There are no novel incentives in place for Pharma or BioTech companies to develop products for thousands and thousands of ‘ultra orphan’ diseases.

I am planning to contact the National Organization of Rare Disorders (NORD) and the FDAs Office of Orphan Products Development (OOPD) to see if I can confirm if the ‘ultra orphan’ estimates I have worked out are accurate or not.  The last time I contacted NORD, they were unable able to provide me with any relevant statistics or facts on this drug development issue.

I recently found a very interesting budget document from the FDA’s Office of Orphan Products Development online which summarizes the budget program requirements that justify a $22 million request for FY 2011. We’re going to need a lot more than $22 million to deal with a healthcare crisis of this magnitude.  This is why I am in support of a new FDA Rare Disease division being proposed by the Kakkis Every Life Foundation to the U.S. House Appropriations Committee.

The statistic that continues to remain elusive is how many people fall into the  ‘ultra orphan’ category?  By using 500 people as an average for every ‘ultra orphan’ disease that exists, this works out to about 2.8 million people (500 people x 5600 ‘ultra orphan’ diseases).  The number of people could be much higher depending on what the average number turns out to be (or it could be lower), but this estimated number needs to be published to fully understand the scope of the problem.

New FDA ‘Rare Disease’ Division Being Proposed to U.S. House Committee on Appropriations

The Kakkis Every Life Foundation is leading the effort to request $10 million in the fiscal year 2011 Ag-Rural Development-FDA Appropriations bill directing the U.S. Food and Drug Administration to establish a new review division for Biochemical and Genetic Diseases within the Center for Drug Evaluation Research (CDER), Office of New Drugs.

A letter from a number of rare disease foundations and advocates was sent to Chairman David Obey and Jerry Lewis and Chairwoman Rosa DeLauro, and Ranking Member Jack Kingston requesting the funds for the new FDA division. This would allow the Food and Drug Administration to build the human and scientific resources necessary to create a more specialized drug review by experts who understand rare diseases and the issues facing rare and ‘ultra orphan’ diseases.

Here is why a new FDA division is needed.  Have you ever tried to find some compelling statistics on Rare Disease on the Internet?  Try a Google or Bing search and see what comes up. It’s pretty frightening given that 30 million people, or 10% of the U.S. population, are living with rare disease.  Where’s the data for all these people?  It does not exist.

Since receiving our orphan drug designation for cyclodextrin last week from FDA, I have been thinking about the statistics that were published in the Wall Street Journal.  The Wall Street Journal referenced statistics from the Kakkis Every Life Foundation and BioMedical Insights in a blog post about our FDA approval:

Last year (2009), only 160 applications — out of 250 requests – received an orphan drug designation from the FDA. “Ultra orphans” make up less than 15% of orphan drug designations even though they represent more than 80% of identified rare diseases, according to data prepared by the Kakkis EveryLife Foundation and BioMedical Insights.

Ok, let’s do some math based on the data from the Journal and what we currently know about Rare Disease.  We’ll end up with even more shocking statistics!

Reasons Why New FDA Rare Disease Division is Needed Now

There are approximately 7000 identified rare diseases afflicting about 30 million American’s or 10% of the U.S. population. If 80% of identified rare diseases are ‘ultra orphans’ — affecting fewer than 6,000 patients in the U.S. per disease state — this means approximately 5,600 different rare diseases are ‘ultra orphans’. 5,600!

We know that in 2009, only 160 applications — out of 250 requests – received an orphan drug designation from the FDA. If only 15% of these designations are for ‘ultra orphan’ diseases, this means the FDA approved an application for approximately 24 ‘ultra orphan’ diseases out of 5,600 that exist.  It’s clear that pharmaceutical and biotech companies are simply not developing ‘ultra orphan’ drugs for people. If this is not a crisis situation, I don’t know what is.

According to the FDA, between 16-17% of drugs that receive an orphan drug designation will eventually make it through the pipeline and receive an approval at some point down the line. If you take 2009 as an example, of the 24 ‘ultra orphan’ designations handed out by the FDA, only about 4 or less will eventually become FDA approved drugs to treat people.  Less than 4 approved drugs a year on average to treat 5,600 different ‘ultra orphan’ diseases.

Statistics show that between 50%-75% of people afflicted with rare diseases are children. If 30 million American’s have rare disease,  between 15 and 22 million are children.  What we don’t know is how many of the 15-22 million children diagnosed with rare diseases are actually afflicted with ‘ultra orphan’ diseases where almost no drug development is happening.  The numbers must be in the  multi-millions.  Obviously, the Orphan Drug Act incentives are not working to encourage Pharma or Biotech companies to develop drugs for diseases that impact 6,000 people or less per disease state!

Given that most ‘ultra orphan’ diseases are fatal, life threatening or chronic, an economist needs to calculate the total financial burden of rare diseases on the U.S. healthcare system. This is what the savvy people in the Alzheimer’s community are finally doing to get the nation to pay attention to the dementia crisis.

With rare diseases and ‘ultra orphan’ rare diseases, we’re talking billions and billions of dollars in health care costs to care for children who have no treatments or drugs even entering the pipeline to help them. Very few people except for the folks at the Kakkis Every Life Foundation seem to understand the gravity of the situation facing the nation.

In my mind, establishing a new FDA division for rare diseases is a baby step but we must start somewhere because where things stand today is simply not acceptable for millions of families and children. It’s time the U.S. House Committee on Appropriations makes rare disease a priority and grants the money for this new FDA division.

It’s also time that the government passes new laws to give pharmaceutical companies and biotechs novel incentives to develop drugs for ‘ultra orphan’ rare diseases.

Kids Living With Dementia Diagnosis – 4 Year Old Johnathan Spenser’s Story

  Johnathan Spencer has Niemann Pick Type C disease like Addi and Cassi.

Embracing every moment

Thursday, April 29, 2010

By Sara Suddes (ssuddes@gilroydispatch.com):  Photo by: Lora Schraft, Staff Photographer, Gilroy Dispatch  

Every morning, Johnathan Spencer’s mother dissolves the contents of a pill containing an experimental drug into a cup of water, draws the solution into a syringe and squirts the foul tasting liquid into her 4-year-old son’s mouth. With little more than a wince, he swallows the medication, hops down from his stool and resumes playtime.

“Look at him. Does it look like he has a terminal illness?” asked Patty Spencer as she watched her grandson blow bubbles with his cousin, Landon, in her backyard. The boys swatted at a few stray blue and black balloons and streamers, the remnants of Johnathan’s birthday party. Other than a couple inches, few differences separated the two. Johnathan tugged open the sliding glass door and poked his head into the living room.

“Can we swing?” he asked his grandmother.

Doctors at Lucile Packard Children’s Hospital recently diagnosed Johnathan with Niemann-Pick Type C, a genetic disease so rare there are only about 500 known cases worldwide. The disease attacks the body’s ability to properly metabolize cholesterol and other lipids within the cell, causing excessive amounts of cholesterol to accumulate within the liver and spleen and excessive amounts of other lipids – or fatty tissue – to accumulate in the brain.

Sometimes referred to as “childhood Alzheimer’s” because it causes neurological impairment so severe it often renders children bedridden, Niemann-Pick Type C is always fatal, according to the National Niemann-Pick Disease Foundation. It typically claims its victims’ lives by the time they turn 20.

The day Rebecca Merrill Spencer received the news that her son is one of about 150 people in the country with the disease is seared in her memory.

“I swear I relive this phone call so many times a day,” she said.

The geneticist that tested her son warned her not to look up Niemann-Pick – a disease doctors hoped to rule out after drawing a blank on the cause of Johnathan’s chronically enlarged liver and spleen, a mysterious condition he’s had since birth.

“‘We’re 99 percent sure he doesn’t have it,’” Rebecca remembered the geneticist telling her.

After the doctors ran the test, “I forgot all about it,” she said.

“No you didn’t,” her sister, Kim, interrupted. By reading everything she can get her hands on, Kim is working to organize what little information is available about Niemann-Pick into a website telling Johnathan’s story. Sitting on Patty’s couch, the two sisters rehashed “the day we will never forget” – as they refer to March 9, 2010.

The phone rang about 4 p.m. that day. As a blood technician who works nights, Rebecca was sleeping when her nephew woke her up to take the phone call.

“‘Rebecca, it’s not good news,’” Rebecca remembered hearing over the line.

“And I just started screaming,” she said. “I couldn’t breathe.”

Shortly after Johnathan’s birth, he landed back in the hospital with what doctors thought was jaundice. Test results showed that the level of his bilirubin – a brownish yellow substance excreted in bile and urine that is responsible for the yellow color of bruises, urine and the yellow discoloration of jaundice – were more than 10 times normal levels. After a month of needle pricks from daily blood draws, four platelet transfusions and a spinal tap, Rebecca and Johnathan’s father, Keith Spencer, took their infant son home with many unanswered questions. His liver and spleen remained larger than normal, a telltale symptom of Niemann-Pick, but doctors told his parents, “‘Oh, it’s nothing,’” Rebecca remembers. “‘He’ll grow into it.’”

“He was convinced he had a baby in his belly,” said Patty, remembering how her grandson would mimic his aunt, who was pregnant at the time. “We played into it so that he would be careful.”

Other than the enlarged organs, Johnathan’s life returned to normal as the ailments that plagued his infancy faded into little more than a memory.

When Rebecca started a new job at Dominican Hospital in Santa Cruz, her insurance bumped them over to doctors at Lucile Packard who took another stab at identifying the source of Johnathan’s swollen liver and spleen.

Last July, Johnathan underwent a liver biopsy and the geneticist who later informed Rebecca of her son’s disease pushed to run that one final test.

“Looking back, everything makes sense now,” Rebecca said.

Not able to sit still for long after receiving the diagnosis, Rebecca started making phone calls and landed an appointment at the National Institute of Health in Bethesda, Md. One week later, she, Keith and their son were on a plane.

“Johnathan’s blood is like gold,” Kim said, explaining how her nephew’s case is so unique because of how early doctors detected it – before he started showing neurological symptoms.

“The doctors are blunt with us,” Rebecca said. “It’s in his brain. He might not show neurological symptoms at this point, but it’s there.”

Keith and Rebecca aren’t sure their son will live to see his 15th birthday.

“We live every day in hope,” Kim said. “We have to live partially in hope and partially in denial. And occasionally, you fall on the floor. But we can’t spend too much time crying on the floor because we have a 4-year-old to raise.”

Despite the uncertainly and $2,000 in weekly expenditures for Jonathan’s medication, Johnathan’s family is hoping he’ll lead as normal a life as possible. They catch themselves sometimes from searching for symptoms or mistaking his typical childhood clumsiness for the disease. Rebecca held back tears when her son told her about how he wants to become a pilot when he grows up.

“You worry and are nervous about every step he takes,” Keith said. “But you try not to let on to him.”

“All he knows is that he’s got an owie in his tummy,” Rebecca said.

“Well, he knows something serious is going on,” Kim added.

“Because Mommy cries all the time,” Rebecca said, finishing her sister’s sentence.

An outpouring of support from the community and talking to other parents of children with Niemann-Pick helps Johnathan’s parents move forward. The two are divorced but remain best friends and lean on each other in times of need.

“I have my moments,” Keith said. “Sometimes I just lose it. But I’m trying to stay as strong as I can for Becca and Johnathan.”

Family members have dedicated themselves to raising money to put toward research and, one day, hopefully finding a cure.

“We don’t know what tomorrow’s going to bring,” Rebecca said. “We don’t have a timeline. But we do have hope that he’s going to survive, and every prayer counts.”

Visit www.johnathanspencer.org

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