CPX, ein neues Medikament in der Erprobung

Im folgenden Text gibt Adam Davis seine Notizen und Eindrücke von einem Vortrag betreffend CPX wieder. Der Text ist leider nicht ganz einfach zu lesen, aber selbst derjenige dessen Englisch nicht sooo toll ist, kann m.E. die wesentlichen Dinge verstehen. Adam Davis ist KEIN Mediziner, seine Aufzeichnungen sind aber trotzdem nicht minder interessant.

Hi there everyone... I came home from the lecture on CPX last night quite excited, although I know there is many a slip twixt the cup and the lip. It is a very exciting drug, folks, which could theoretically provide a cure for the basic chloride transport problem in CF. We will know more at the conclusion of the Phase I trials, in 12 to 15 months.

There are clearly reasons to be skeptical of slam dunk results too, however. The studies "in vitro" (in the lab) which indicate that CPX works were not all done on epithelial tissue. One test which was done on epithelial tissue (in North Carolina, I believe) did not show good results.

However, the whole line of research clearly derives from a deeper understanding of the disease process and the disease physiology than existed just a few years ago. Apparantly the drug is extremely safe. In the animal toxicology studies (done on rats and dogs), Sci Clone reports that they could literally not give a high enough dose to cause side effects. Other good news is that because the drug would be given in capsule form (and thus be carried throughout the blood stream) it would affect all epithelial tissue; presumably this could affect other CF problem areas apart from the lung such as pancreatic ducts, vas deferens, etc.

Anyway, here are my notes from last night. Please don’t take these notes as any kind of final authority; I am not an MD or a scientist, just an interested layperson and father of a beautiful little 2 year old girl with CF.

Notes From Stanford Lecture On CPX

Dr. Richard Moss, Director of the CF Clinic at Stanford

In 1989, the CF gene was cloned, and a 3-dimensional model of the protein it creates was predicted. The model has stood up very well since then under the light of further research. This protein, the CFTR, has three sections:

1. the transmembrane domains, which attach the protein to the lipid layer which forms the cell membrane
2. two nucleotide binding domains (NBD1 and NBD2) which attach to molcules like ATP and give the protein energy to perform its function, and;
3. an "R" domain, which performs the "opening and closing" function, which we can think of as "pumping" the chloride ion out of the cell.

The Delta F508 mutation is on NBD1, one of the domains which binds ATP.

Delta F508 is by far the most common CF mutation. Approximately 50% of CF patients are homozygous Delta F508 (Both parents were Delta F508), and another 38% are heterozygous Delta F508 with another mutation. "Delta F508" literally means the deletion of a phenelalynine group at position 508 along the amino acid chain which forms the protein. It is a simple deletion of three base pairs, known as an "in-frame" deletion This means that it does not mess up the "reading" of the entire amino acid sequence, but rather that the amino acid is not folded into the proper three dimensional structure as the protein is formed by the cell.

There are four basic effects of mutations on proteins like CFTR: Class I leads to defective protein production. Class II leads to defective processing of the protein (ie. the way the protein is shaped or folded) Class III leads to defective regulation of the protein Class IV leads to defective conduction (ie. a decrease in ion flow)

The Delta F508 mutation of the CFTR protein is basically a Class II mutation, with some Class IV attributes.

It is important to note that because the Class II mutation causes an imperfection in the way the CFTR is folded, most of the CFTR produced (over 99%) is destroyed by the quality control function of the Endoplasmic Reticulum. (The ER is the section of the cell which produces proteins from the amino acid chains generated in the nucleus if I understand correctly.) This is critical to understand; the CPX drug is trying to achieve clinical effectiveness with less than 1% of the number of CFTR molecules which exist in healthy epithelial cells. However, some CFTR is produced and released to the cell interior, and it is this remaining CFTR which is targeted by CPX.

(As a sidenote, there are various classes of drugs being researched which attempt to either overcome the problem caused by incorrect folding of the protein structure, or by attempting to otherwise increase the function of the remaining CFTR. CPX is just one of them. Some others include cAMP inhibitors like Milrinone, drugs like Phenlybuterate which "chaperone" the CFTR into position, and drugs like Glycerol which affect folding.)

Dr Dave Karlin, who heads the CPX program for SciClone Pharmaceuticals:

CPX was discovered in National Institutes of Health (NIH) labs as part of a much broader study looking at compounds which affect molecular pumps.

CPX is a xanthene type molecule, in the same general class of molecules as caffeine.

CPX binds to the NBD1 region of the CFTR, directly adjacent to the location of the Delta F508 deletion.

It is not clear why this binding stimulates pumping of chloride. It may normalize the three dimensional structure of the protein, but this is conjecture.

SciClone bid against other drug companies to liscence the CPX molecule from the NIH; if they are successful in developing a marketable drug, the company would then pay royalties to the NIH to support future research.

The process to test and develop CPX is as follows:

Before clinical trials could precede, animal toxicity studies had to be performed. These studies include acute single doses, repeat doses, safety pharmocology studies and mutagenicity studies. These have been completed, and Phase I clinical trials in humans have been approved by the FDA.

It is important to note that a normal stage in testing of a new drug is clinical trials in healthy adult populations prior to testing in the target population. (Folks with CF.) FDA agreed to skip this step in the interest of getting the drug to market quicker... this could save a year.

The drug is actually manufactured by Abbot Labs under agreement with SciClone. Chemistry, manufacturing and control issues which must be fully resolved are batch comparisons, consistency of impurities in the drug manufactured, long term stability of the drug, etc.

Then: the clinical development of the drug.

1. A "New Drug Application" is filed with the FDA.
2. Each CF clinic doing the clinical trial must do an ethics review of the study by an IRB - Investigational Review Board. These IRB reviews are currently underway at 5 CF centers around the country.
3. Phase I studies; this will measure single dose safety and also measure efficacy.

   Five volunteers will each get one dose of the drug. (One out of the five will be a placebo as a control) Doses will start at 1mg. then go to 3, 10, 30, 100, 300 and 1000 mgs.

   Sweat tests will measure Cl concentration on both arms initially on dosing, then at 1, 2 and 4 hours following. Nasal epithelial cells will also be tested for electrical conductivity (a measure of Cl secretion). In addition, clinical, blood and urine tests will be performed, and heart monitoring will be done with an ECG during testing.

4. Continuing Phase I studies will look at multiple doses of CPX, given over 4 to 5 days.

   Essentially, this process will take 12 to 15 months from now; by then we should have indication whether CPX will be effective in correcting the basic CF defect.

   If all goes well, then:

5. Phase II studies will be performed. This will require additional animal toxicology studies for FDA approval to go ahead. These studies will look at multiple doses over 6 to 8 week periods. Phase II studies also look at possible interaction of CPX with foods or other drugs in detail. They also study the absorption, dilution and metabolism of the drug in detail.
6. Phase III studies. Typically this would consist of two 12 month studies with a larger group... The endpoint for monitoring drug efficacy would not be just sweat and nasal epithelium tests, but FEV.
7. File a New Drug Application with the FDA.

Altogether, if things go well, the process should take 3 to 4 years to bring CPX to market.

Some other notes...

The location of the CF centers will be posted on the CF Foundation web page as soon as Investigational Review Board (ethics panel) approval is given at each center. Stanford University is one location; IRB approval is expected in the first week of April there. Watch the CF Foundation web page for a location near you!

There are a number of restrictions on who can participate in these first Phase I trials. I will list the ones I took note of here, but if you are interested in participating, you should obviously contact the CF Center directly with your questions once the locations are announced.

Restrictions include:

1. 18 and older
2. If female, not pregnant
3. Homozygous Delta F508 only (Later trials will be broader and includeheterozygote mutations.)
4. FEV at least 70% of predicted
5. No recent exacerbation (1 month)
6. No multiresistant bugs
7. No URI or rhinitis
8. No gene therapy
9. No sinus irrigation (1 week)
10. No nasal surgery (1 month)
11. No investigational drugs (1 month)
12. No interfering drugs (generally 3 days, but varies)

That’s all folks!