What Would It Take To Develop A Chiari Drug?

February 20, 2006 - Current medications used to treat Chiari are not particularly effective. There are no disease modifying drugs for Chiari and drugs used to treat symptoms are usually only modestly beneficial. There is also a school of thought that drugs which mask the symptoms and pain of Chiari could also do more harm than good by masking the progression of the syndrome and delaying the need for surgery to relieve hindbrain compression. I would like to address in this first article of my column what it would take to discover and develop a breakthrough disease modifying drug for Chiari.

However, before I discuss Chiari, I want to talk about what it took to find a treatment for osteoporosis as lessons can be learned from that experience. In 1984, I headed a research team looking for a new drug to treat osteoporosis. At that time, osteoporosis was poorly understood. In many countries/cultures, osteoporosis wasn't even considered a disease. It was considered a natural consequence of aging. Early diagnosis was a problem; bone-scanning machines were not yet standardized and used almost exclusively for research. Treatment options were also very limited. Parathyroid hormone, or PTH, was known to stimulate bone formation but its use was limited because it required frequent injections and was expensive. In some countries, oral fluoride was used because fluoride increases bone density quickly and dramatically; however, concern existed about the quality of new bone tissue that it produced, and it was later shown in clinical studies conducted in the late 1980's and early 1990's to actually increase fracture risk.

My team focused on new agents that prevented the loss or resorption of bone and discovered a novel potent bisphosphonate. We first synthesized the drug in 1984 and evaluated it in animals for both efficacy and safety in 1985/86. Clinical human studies were initiated in late 1987. After testing the molecule in over 15,000 women and men, our data were submitted in 1998 to the FDA requesting approval. Approval was granted in 2000 and today the drug is prescribed to protect millions of women with annual worldwide sales approaching nearly $ 2 billion.

Along the way, we had to overcome many challenges, working with hundreds of academic investigators. We worked with instrument companies to develop diagnostic tests. We helped form appropriate medical societies. We sponsored hundreds of conferences and seminars to educate health care providers. The research team, which I was appointed to lead in 1984 actually had been in place since the late 1970's; it took about 20 years to discover and develop a drug for this major disease. We probably spent a billion dollars in the process, and a couple of other drug companies followed our lead and spent similar amounts of money.

Chiari today, is where osteoporosis was 25 years ago. A key difference, however, is that Chiari is 100 times less prevalent than osteoporosis. As a result, it is not on the radar screen of any drug company as a disease of interest because the cost of discovering and developing a drug to effectively treat it will not be readily recovered in sales.

Drug companies will continue to develop new drugs for other diseases that will have application to Chiari for treating symptoms, like pain or numbness; however, discovering a treatment that halts the progression of the syndrome, or better, prevents the malformation in the first place is another story.

To find a new effective treatment for Chiari, the pathogenesis of the disease must be better understood. By pathogenesis I simply mean the origin and development of the disease. I have spent the last couple of months looking into what is known about the pathogenesis of Chiari. I have read over 3000 medical paper titles, a couple hundred abstracts and about 30 full papers. This may sound like a lot of papers but actually it isn't. Searches on diseases for which even a modest understanding exists will typically yield hundreds of papers on pathogenesis. Relevant to the pathogenesis of Chiari, there are two key questions: How or why does the malformation form in the first place? And, what changes occur that bring on the emergence of symptoms later in life? There is more in the medical literature germane to the first question than the second.

There are a couple of theories on how the malformation forms during fetal development but most of the literature converges on a theory involving differential growth rates of the skull and hindbrain. Observations and measurements on fetuses, infants, and young children support the theory that the skull begins to grow first but does not grow to its full volume, forcing the later growing hindbrain to grow downward and through the foramen magnum (large opening at the base of the skull)1. It has been suggested that in the more severe instance of Chiari II, this may be related to differential pressures between the skull and spine; either as a result of a defect in the unfolding or closure of the developing fetal tissue2. Why such a defect occurs in the first place is unknown. Defects in developing tissue can be caused by any number of mechanisms including genetic miscoding, chemical/microbiological offenders, or dietary deficiencies. Interestingly, animal models exist in which Chiari malformations have been induced using the mumps virus, vitamin A over-dosing, and surgical trauma. Basic academic research is needed to determine why incomplete mesoderm closure during fetal development occurs. If it is due to a chemical or biological offender, then a cure may be as simple as removing the offender. If it is due to a dietary deficiency, then a simple supplement may represent the solution. A genetic defect would represent a more difficult challenge to find a cure.

Another approach is to find out what changes take place later in life to trigger symptoms. Turning again to the literature, there are at least three theories, but one in particular has been the focus of most of the research. This theory holds that symptoms are a result of increased pressure to the hind brain as a consequence of the malformation blocking the flow of cerebrospinal fluid (CSF). This is the basis of using Cine MRI for diagnosis as Cine MRI can determine if CSF flow is compromised at the foramen magnum3. However, the malformation is present prior to the onset of symptoms and CSF flow blockage. So, exactly what changes occur with respect to the malformation? With the spinal cord and the cerebellar tonsils both occupying the foramen magnum, little space exists for CSF drainage in the first place. As a result, only a small change needs to take place to further restrict that space and block CSF flow.

A few theories have been offered with respect to small anatomical changes that choke off CSF flow at the foramen magnum; understanding these changes in greater depth could unlock the secret to finding a breakthrough treatment. The first has to due with the thickening of the dural band. The dural band is a relatively thick band of tissue lining the dura around the foramen magnum. It is often observed during surgery to be thickened, fibrous, and even ossified (calcified like bone) in many patients. Understanding why these changes in the dural band occur and then finding a drug to inhibit them would be one approach to look for a treatment that prevents the onset of symptoms- provided dural band-thickening is the culprit.

The second has to do with the formation of intradural adhesions. Dissection of such adhesions is often performed during decompression surgery as it is believed that releasing these adhesions promotes CSF flow from the fourth ventricle to the spinal canal. It is not understood, however, why these adhesions form in the first place. One theory I have heard is that they may form in a natural attempt by the body to stabilize the herniated tonsils from the forces associated with the turning of the head. An understanding of the role of adhesions in CSF blockage and the biochemistry which regulates their generation and subsequent growth could lead to new ideas for preventing their formation.

The third has to do with craniocervical junction compression or "settling". It is well known that we all lose height as we grow older. This is due to the compression of spinal column discs over several decades of life. The skull also settles to some extent on the spine over time as well. This craniocervical settling may result in pushing the tonsils further down into the spinal canal to cause CSF blockage and symptom onset. To what extent this process may contribute to the progression of the syndrome could also be further explored. However, since the average age at which symptoms emerge in patients is only 25, this factor seems less likely.

It is important to realize that basic research to understand the pathogenesis only represents the very first step. Discovering a new class of drugs to intervene in the disease process would be the next major hurdle, followed by an extensive search for a specific molecule that is not only effective--but safe. If that weren't enough of a challenge, there would remain the challenge of screening and diagnosing people at risk before any drug treatment could be effectively utilized. At present, most Chiari patients are only diagnosed after prominent symptoms emerge, and it is not practical nor within the financial means of the healthcare system to provide MRI scans on everyone. Net, some affordable and effective means for identifying patients with Chiari malformations who are at risk of developing symptoms would be needed.

Regardless of the approach taken, a great deal of research (costing hundreds of millions of dollars) will ultimately be needed to discover and develop a truly new effective pharmacologic treatment for Chiari. The first step is to gain a better understanding of the basic pathogenesis of Chiari as discussed previously. Since the potential market for treating Chiari is too small to attract the attention of traditional pharmaceutical companies, this first research step is best taken by academic and government investigators. Once the biological target for intervention is better understood, the quest for discovering and developing novel therapeutic agents is likely to be taken up by small entrepreneurial biotech companies, as these companies often enter the pharmaceutical industry by conquering less prevalent diseases.

The potential to conquer Chiari clearly exists. Interest and awareness amongst academic and government researchers must be increased as a first step. This often initially occurs by non-profit organizations providing seed funds for basic research. Success in basic research will attract larger government grants and eventually small industry.

Non-profit organizations are highly dependant on those of us afflicted with Chiari (and our friends and relatives) to provide support; this is true for many other diseases. Our support can come in many ways, from simply increasing awareness in others to making significant monetary donations. The one thing we can not afford to do is to sit back and let Chiari conquer us.

1 Griffiths et al, Acta Radiol. 2004 Apr;45(2):236-42.
2 McLone and Naidich, AJNR Am J Neuroradiol. 1992 Mar-Apr;13(2):463-82.
3 Quigley et al, Radiology. 2004 Jul;232(1):229-36.

Ed. Note:The opinions expressed above are solely those of the author. They do not represent the opinions of the editor, publisher, or this publication. Anyone with a medical problem is strongly encouraged to seek professional medical care.