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.

FDA Grants Orphan Drug Status For Cyclodextrin Compound To Treat Fatal Genetic Cholesterol Disease

Drum roll, please! Dr. Caroline Hastings at Children’s Hospital Oakland and Research Center received a call on Friday afternoon from the U.S. Food and Drug Administration regarding the orphan drug submission we made at the end of February.

While we have not received the official letter by mail (probably next week), it appears our Orphan Drug application for hydroxy propel beta cyclodextrin (HPBCD Trappsol® brand from CTD Holdings, Inc.) for the treatment of Niemann Pick Type C disease has been approved!  Who would ever in a million years think that a sugar compound could actually be a very powerful pharmacologic agent against cholesterol?

For those of you reading my blog for the first time, Niemann Pick Type C disease is a rare and fatal genetic cholesterol disease that is often referred to as as the ‘childhood Alzheimer’s’ because it causes severe dementia in children. The Niemann Pick Type C genes control human cholesterol metabolism at the cellular level and people born with double mutations on this critical gene are afflicted with a horrible progressive neurological condition.

Orphan drug designation is granted by the FDA Office of Orphan Products Development to novel drugs or biologics that treat a rare disease or condition affecting fewer than 200,000 patients in the U.S.

Receiving a formal orphan drug designation from the FDA is a major milestone. To put this designation in perspective, in 2009, approximately 250 requests for orphan drug designation were filed with the FDA, and 160 received it. The 160 approvals were given for all rare diseases combined (7,000 different rare disease that affect approximately 30 million Americans).

Over the past 25 years, it is my understanding that very few applications have  been filed for ultra rare diseases like Niemann Pick Type C that impact less than 1000 people worldwide. Certainly very few applications have been filed and received approval by non biotech or pharma companies.

This is only the second time in history that a drug/compound for treating Niemann Pick Type C disease has been given an Orphan drug designation by the FDA. The first one was Zavesca made by Actelion Corporation (it still only has a designation and no approval in the United States).

Moving forward, our orphan drug designation makes us eligible to receive special tax credits that will apply to qualified human clinical trial and research expenses and possibly grant funding for Phase I and II clinical trials. We are currently looking into these benefits now and how we can maximize them.

One of our goals now is to take our application and re-purpose it and submit it in other countries (specifically to the the EMA). When we file our annual report with the FDA in the United States, I have been told we can automatically submit the same annual report to the EMA with all of Addi and Cassi’s human clinical data that we have been gathering for over a year.  By submitting this human clinical data to different agencies worldwide, we could speed up the ability for Niemann Pick Type C families around the world to be able to conduct cyclodextrin treatments on their children in their own countries.

While we have managed to cross a very large hurdle, the next hurdle awaits us in the coming weeks. We are pursuing another major filing with the FDA requesting the ability to deliver cyclodextrin intratehcally to Addi and Cassi.  This is the filing that I believe will give us the real opportunity to save Addi and Cassi’s lives.

SeizureTracker – Great Tool For Tracking and Recording Seizures

This week I started using an online program called SeizureTracker. Over the past few months, Addi and Cassi have been having seizure episodes and we have been dosing them up and down on different medications.

SeizureTracker was created by Rob and Lisa Moss, parents with a son named Evan who suffers from a severe seizure disorder called Tuberous Sclerosis (TSC). Their personal story is incredibly inspirational because the Moss family has turned their hardship and frustration in tracking Evan’s seizures into a web based program to help everyone afflicted with seizures.

The video about their journey with Evan won the American Academy of Neurology 2010 Neuro Film Festival award.  Please take a moment to watch this video as it’s one of the most compelling videos I have seen.

Seizure Tracker is very easy-to-use and has terrific graphs and reports.  The website even has printable logs enabling you can track seizures when you are on the go, at the hospital, or even when kids are in school.  Currently, I log Addi and Cassi’s seizures each day on paper and then sit down and do the data entry at the end of the week.  You can also access your account on any web enabled mobile phone and soon users will have the capability of recording rescue medication usage and daily notes through the mobile site.

Seizure Tracker also allows you to share epilepsy and seizure related data and trends with your doctor. I feel this is the biggest benefit of all of the SeizureTracker program. I must admit it was hard to enter in all the seizures and see the number tallying higher and higher.  But at the same time Seizure Tracker’s trend charts will allow us to make better decisions on medications for Addi and Cassi and to know if a seizure medicine is actually working or not.

Thank you to the Moss family for the amount of time an energy you have put into creating this website and program for all of us. You have made a difference in our daily lives. I hope and pray someday our twins can reach a seizure free state.

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