FDA Approves First Ever Cyclodextrin Infusion Treatment For Twin Girls Suffering From Fatal Cholesterol Disease

After months of research, document preparation, discussions with the FDA and an immense amount of stress, it’s finally official.  The FDA has approved our “compassionate use” IND request to give Addi and Cassi infusions of a non toxic sugar compound called 2-Hydroxypropyl-beta-Cyclodextrin or HPBCD.

This Wednesday, March 18, 2009, at 7:30am and 8:30am, Addi and Cassi will have medi-ports surgically placed into their chests at Children’s Hospital in Oakland, California. The placements of these medi-ports (similar to ports used to administer chemotherapy drugs) will allow our doctors to start direct infusions of 2-Hydroxypropyl-beta-Cyclodextrin directly into Addi and Cassi’s bloodstreams.  The goal of the infusions (which will take place at Renown Regional Medical Center in Reno, Nevada) is to try and move trapped cellular cholesterol out of Addi and Cassi’s spleens, livers and ultimately their brains.

From what we understand, this will be the second time in the United States that cyclodextrin alone has been used in an attempt treat a fatal disease. Over 20 years ago, cyclodextrin was used in a medical case involving a boy with severe hypervitaminosis A and cyclodextrin saved the child’s life. In Addi and Cassi’s case, we are trying to save the girls from Niemann Pick Type C disease, a fatal cholesterol metabolism disorder that is often referred to as the “Childhood Alzheimer’s.”  There is no cure for NPC and only one experimental drug treatment.

Now this promising sugar compound that is not a considered a drug provides our family with a glimmer of hope. We would like to thank the following doctors, researchers and companies for their support: Dr. Caroline Hastings, Dr. Ron Browne, Dr. Susan Sorensen, Children’s Hospital Oakland, Renown Regional Medical Center, CollabRx, Johnson & Johnson for providing critical safety data on cyclodextrin to the FDA, the FDA for approving our request, researchers Benny Liu and Steve Walkley for their amazing work on cyclodextrin and Niemann Pick Type C mouse models, cyclodextrin expert Rick Stratton at CTD, Inc. and all of our friends and family who have provided us with the emotional support to forge ahead and never give up on finding therapies for our daughters.

Cyclodextrin is made by sugar angels. The sugar angels are hard at work to bring the world more amazing medical news on cyclodextrin and Niemann Pick Type C disease.

Thank You Johnson & Johnson For Helping Sick Kids

I am happy to report to everyone that Johnson & Johnson really does care about children, especially Addi and Cassi and kids suffering from Niemann Pick Type C disease. After I posted my previous blog and contacted Johnson & Johnson’s PR department about our situation with the FDA and obtaining cyclodextrin safety data from their company, they responded over the weekend and offered to help our family. If all corporations were like Johnson & Johnson, the world would be a better place!

Johnson & Johnson’s regulatory contacts agreed to send a letter to the FDA offering to open up relevant portions of their drug master files on cyclodextrin to assist us with Addi and Cassi’s compassionate use treatment case.

They also apologized to me for the response I received from Janssen’s global clinical operations group which has restored my faith in pharmaceutical companies. The challenge now will be to get the FDA to allow us to give Addi and Cassi this potentially life-extending non-toxic sugar compound via IV that could have far reaching implications beyond Niemann Pick Type C disease.

Dear Johnson & Johnson, do kids really matter to you?

After weeks of going back and forth with the U.S. Food and Drug Administration (FDA) on our request to give Addi and Cassi hydroxypropyl-ß-cyclodextrin (HP-ß-CD) or "CYCLO" infusions, we finally have a Type A meeting scheduled on February 26, 2009, from Noon-1pm to discuss the clinical hold the FDA put on our "compassionate use" treatment request.

The FDA has requested that we change our original protocol for cyclodextrin infusions and take the dosage down to 1/50th of the amount we believe will be therapeutic.  They have asked us to provide more "safety data" on CYCLO and we now need to try and convince the FDA in person to allow us to treat our twins with higher does of cyclodextin with or without the safety data.

We know that the sugar compound cyclodextrin has been infused into the bloodstream of children and adults and there is safety data available.  There is a drug called Intravenous Intraconazole that is given to children to treat fungal infections and it contains cyclodextrin which helps solubalize the drug and deliver it more effectively in the body.   This is the same cyclodextrin we propose to infuse into Addi and Cassi.  The pharmaceutical company Janssen makes this drug and has drug master files (DMFs) which contain safety data on CYCLOs effect in animals and humans taking intraconazole.  Intravenous intraconazole could not have been approved by the FDA without some amount of safety data.

A few months ago as we were gearing up to write our cyclodextrin protocol for the FDA, I contacted Janssen to get assistance in the hopes of accessing their DMFs on cyclodextrin.   I managed to reach the drug department and spoke to the woman in charge who obviously was on a power trip.  I explain that children like Addi and Cassi are dying and have no treatments and that a simple sugar compound called cyclodextrin could possibly save their lives. She refused to help me and essentially said I was out of luck. I tried to explain that cyclodextrin is used only as a delivery agent and that I was not requesting patentable information or trade secrets on the drug. She was unsympathetic. Sarcastically, I asked her if a letter from our doctors or even the President would help. She laughed at me and said "No." After I slammed down the phone, I started to cry.   How can this be happening?   All I need is safety data on a sugar compound that is already being eaten by people in fat free butter and being used to enhance the delivery of some drugs on the market.  How hard can this be?

I found out that Janssen’s parent company is Johnson & Johnson.    Here is a quote from their website:

Your family’s health and well-being is our passion. That’s why our companies offer the world’s broadest range of health care products. Whether you have a skin blemish or sniffles or a serious medical condition, you and the health professionals you trust can turn to our companies’ products for comfort and care.

As I was giving Addi and Cassi a bath and washing their hair tonight (with Johnson & Johnson shampoo!), I decided to finish the letter I started to Johnson & Johnson’s management team and board of directors.  Will Johnson & Johnson also be unwilling to provide human safety data to us on a non toxic sugar compound? All we need from them is to provide our doctors and the FDA with more information from their files that could help save the lives of Addi and Cassi and possibly 500 children around the world afflicted with Niemann Pick Type C disease.

I guess the world will soon find how much Johnson & Johnson cares about kids who are dying. Let’s hope the values they claim are so important to their company really hold true.

World Rare Disease Day 2009 Genes Video

I made this video for World Rare Disease Day 2008 to bring global attention to the fact that Rare Disease is not so rare — it can happen to anyone or any family. Although each Rare Disease affects a small number of people, taken all together rare diseases affect millions of people in the world. The Genes video focuses on genes, which we all have, and how any of us could have a genetic disorder.

Why Rare Diseases Will Help Us Solve Common Diseases

The Key To The Closet Is The Key to the Kingdom: A Common Lesson of Rare Diseases

How can understand more about the most common diseases that affect mankind.  By looking at the rarest diseases. This story takes us back……

Nearly twenty centuries ago, the Roman poet Juvenal wrote in The Satires about “a rare bird comparable to a black swan.” The notion of rarity enticed the mind in antiquity, and continues to do so in modernity – in medicine and in our daily lives. What are the lessons of rarity and specifically of rare diseases? Let us look closer and observe.

The place was London. The date – April 24, 1657. A letter arrived at the home of Dr. William Harvey, a man whose life was distinguished by one of the greatest discoveries in the history of medicine, the discovery of the circulatory system. But, the letter to Dr. Harvey from a Dutch physician, John Vlackveld of Harlem, had nothing to do with common problems of the heart or blood or circulation. The letter invited Dr. Harvey’s attention to the case of a gentleman with an extremely rare affliction of the urinary bladder. Dr. Harvey was old and in failing health, and could not assume the challenge, but he clearly recognized the value of such a noble pursuit. He reached for a piece of parchment, dipped his pen in the inkwell, and wrote these words: “Learned Sir, your much esteemed letter reached me safely in which you not only exhibit your kind consideration of me, but display a singular zeal in the cultivation of our art. The case of the plasterer to which you refer is indeed a curious one, and might supply a text for a lengthened commentary. But, it is in vain that you apply the spur to urge me at my present age to gird myself for any new investigation.”

While unavailable, Dr. Harvey, however, was not disinterested. He continued the letter in what might arguably be one of the most prophetic passages ever written in the history of medicine:

“It is even so,” he wrote, “Nature is nowhere accustomed more openly to display her secret mysteries than in cases where she shows traces of her workings apart from the beaten path; nor is there any better way to advance the proper practice of medicine than to give our minds to the discovery of the usual law of nature by the careful investigation of cases of rarer forms of disease. For it has been found in almost all things, that what they contain of useful or of applicable nature, is hardly perceived unless we are deprived of them, or they become deranged in some way.”

Centuries later, in an address delivered to The Medical Society of London on May 21, 1928, Sir Archibald Garrod, the father of metabolic disease, cited that monumental letter from William Harvey. In an engaging essay entitled, “The Lessons of Rare Maladies,” published in The Lancet the following week, Dr. Garrod paraphrased, “The study of nature’s experiments is of special value; and many lessons which rare maladies can teach could hardly be learned in other ways.”

Francis S. Collins, M.D., Ph.D., (Former) Director of The National Human Genome Research Institute said more recently, “While many of the genes we will initially be pursuing are responsible for rare disorders, what we learn from rare disorders often has profound consequences for our understanding of more common conditions.” But, why is that so? Why are rare conditions so instructive of more common ones?

To begin, rare diseases provide robust insight into complexity in biological systems. The specificity of the rare disease often permits a causative genetic factor to be isolated in a complex regulatory network, thus identifying and defining the network itself. Such insight is often the catalyst for dissecting the structural organization and/or inter-dependent signaling networks that are influenced by common genetic variations and that lead to some of the most common diseases of mankind. Nature does not use different genes, molecules, and pathways for common conditions than it does for rare ones. Rather, it is often the rare disease that actually reveals which gene, molecule or pathways nature hijacks in its common infirmities. The key to the rare disease is often the key to the common one. The key to the closet is often the key to the kingdom.

As examples, studies of familial hypercholesterolemia, Lesch-Nyhan disease, fibrodysplasia ossificans progressiva, congenital malignant osteopetrosis, and Hutchinson-Gilford progeria, all exceedingly rare conditions, have revealed the causative genes not only for each of these rare disorders, but have also illuminated the molecular pathways for common disorders of cholesterol metabolism, uric acid metabolism, heterotopic ossification, osteoporosis, and aging respectively – diseases that in some cases affect tens of thousands of people worldwide, and in other cases, millions.

The examples, iterations and lessons of rare maladies are profound and endless. In a dazzling article on “a new grammar for drug discovery,” (Nature 437: 491-493, 2005), Mark Fishman and Jeffrey Porter discuss the value of rare diseases not only for illuminating common conditions, but also for drug discovery. “Historically pharmaceutical companies have not focused on these diseases, in some cases because the affected protein is not tractable to pharmaceutical approaches, and in others, perhaps, because the number of people affected is small. But, the powerful role of a single gene in Mendelian disease can provide insight into complex diseases where the same gene accounts for part of the phenotype. Statin therapy, for example, was initially directed to patients with a genetic predisposition to excessive levels of blood cholesterol. But after the drugs efficacy and safety had been tested, the treatment was extended to a wider population of patients who had the same condition but due to many causes.” Once again, the key to the closet is the key to the kingdom.

In the last paragraph of his essay (The Lancet; May 26, 1928), Sir Archibald Garrod states, “We may feel sure that, in the future as in the past, there will be many who will try to solve the problems of the commoner diseases, the control of which is of vital interest to the community at large. Let us hope there will always be some who will seek to guess the riddles and to learn the lessons of rare maladies.” The implication, of course, is that in doing so, one may provide the clues to solve the more common conditions as well. How ironic and fortuitous that nature would construct such a universal key and place it not in the hands of the king, but in the hands of the custodian. The key to the closet is the key to the kingdom.

And, so we will end where we began with the letter from Dr. Harvey to Dr. Vlackveld, long before the era of gene identification or molecular discovery or recombinant technology. It was almost 350 years ago in London, when Dr. Harvey wrote those words that have not been improved upon since. “It is even so. Nature is nowhere accustomed more openly to display her secret mysteries than in cases where she shows traces of her workings apart from the beaten path; nor is there any better way to advance the proper practice of medicine than to give our minds to the discovery of the usual law of nature by the careful investigation of cases of rarer forms of disease.” The key to the closet is the key to the kingdom. It is even so.

Written by Frederick S. Kaplan, M.D.

« Previous Page — Next Page »