As I mentioned at the end of the previous post, the article being reviewed today is about a drug treatment that is applicable to patients with fibrinogen amyloidosis. This drug is the infamous CPHPC that has been discussed in the amyloidosis community for many years. It must be a popular search term because two of the three most often viewed posts on this blog have "CPHPC" in the title, and five of the top ten search terms that direct people here include "CPHPC."
Title: Sustained pharmacological depletion of serum amyloid P component in patients with systemic amyloidosis (1)
Authors: Julian D. Gillmore, Glenys A. Tennent, Winston L. Hutchinson, Janet Ruth Gallimore, Helen J. Lachmann, Hugh J. B. Goodman, Mark Offer, David J. Millar, Aviva Petrie, Philip N. Hawkins, Mark B. Pepys (National Amyloidosis Centre, London, UK; University College London Medial School, London, UK)
Journal: British Journal of Haematology (2010)
Serum amyloid P component (SAP) is a universal constituent of amyloid deposits and contributes to their formation and/or persistence. We therefore developed CPHPC ((R)-1-[6-[(R)-2-carboxy-pyrrolidin-1-yl]-6-oxo-hexanoyl]pyrrolidine-2 carboxylic acid), a novel bis(D-proline) drug, to specifically target SAP and report here a first, exploratory, open label proof of principle study in systemic amyloidosis. CPHPC produced sustained, >95% depletion of circulating SAP in all patients and c. 90% reduction in the SAP content of the two amyloidotic organs that became available. There were no significant adverse effects of either SAP depletion or CPHPC itself. No accumulation of amyloid was demonstrable by SAP scintigraphy in any patient on the drug. In hereditary fibrinogen amyloidosis, which is inexorably progressive, proteinuria was reduced in four of five patients receiving CPHPC and renal survival was prolonged compared to a historical control group. These promising clinical observations merit further study.
Here is a link to the PDF of this article if you would like to follow along: http://onlinelibrary.wiley.com/doi/10.1111/j.1365-2141.2009.08036.x/pdf
I have mentioned CPHPC and this particular article in a few previous posts, but I will write this post as if it is the first mention of either one so you do not have to read any of the older posts. But if you want to see what was written before, just search for "CPHPC" using the search box on the right side of the blog.
First I want to set the stage for the subject in this article. When a disease is caused by the buildup of some substance in the body, it can be addressed in a few different ways. One way is to prevent the buildup from occurring, which can be done by halting the production of the substance itself or some other substance that allows it to build up. Another way is to introduce another substance, usually a medication, that causes the unwanted buildup to dissolve so the body can get rid of it.
In the case of fibrinogen amyloidosis, a liver transplant halts the production of the substance that is building up (variant fibrinogen). In the case of AL amyloidosis, a stem cell transplant is an attempt to halt the overproduction of certain blood components so they are once again in the correct ratio. (In AL amyloidosis, think of the bone marrow as a factory that produces all the parts for building automobiles. Normally the various parts are produced in the correct ratio such that they all get used to build complete cars, with very few parts left over. When a person has AL amyloidosis, the factory produces way too many of one part, such as steering wheels. These extra steering wheels never get used to build cars, so they accumulate in the blood, eventually building up to form amyloid deposits throughout the body.)
So halting the production of the substance that builds up will be different for the different types of amyloidosis. Today's article is about an attempt to develop a drug that could be applicable to all types of amyloidosis, by either dissolving existing amyloid deposits, preventing further buildup, or both. The article begins with a one-paragraph overview of amyloidosis, and then it tells us what "serum amyloid P component" is. Serum amyloid P component (SAP) is a protein that normally circulates in the blood, but its function is unknown. That's right, in spite of all the advanced medical knowledge available today, the function of SAP, which is a component of your blood, is unknown. What is known, however, is that it is found in all types of amyloid deposits and it seems to help stabilize them.
Long before he was knighted by the Queen of England for services to biomedicine, Dr. Mark Pepys and some of his colleagues at the National Amyloidosis Centre in London developed a drug that was intended to prevent SAP from binding to amyloid deposits, with the hopes that the amyloid deposits could then be cleared by the body in a normal fashion. This drug, with the chemical name (R)-1-[6-[(R)-2-carboxy-pyrrolidin-1-yl]-6-oxo-hexanoyl]pyrrolidine-2 carboxylic acid, is referred to as CPHPC.
When CPHPC was first used in human patients, however, there were some unexpected results. They were hoping the CPHPC would prevent SAP from binding to amyloid deposits, as well as loosen the SAP that was already bound to those deposits. What they discovered was the SAP circulating in the blood would bind to the CPHPC, and that compound was easily cleared by the liver, reducing the level of SAP circulating in the blood to almost zero. If the level of SAP drops to essentially zero, that means there is very little SAP available to bind to amyloid deposits. Since there were no known side effects of not having SAP, nobody knows what it does anyway, and mice without SAP seem to do just fine, they decided to do the small study presented in this article.
From 2001 to 2006 they studied 31 amyloidosis patients who agreed to be given CPHPC for a year. They began with patients with advanced AL amyloidosis who were ineligible for additional chemotherapy treatment and had a poor prognosis. Once they were comfortable there were no adverse effects in administering CPHPC to humans, they treated patients with other types of amyloidosis, including six patients with fibrinogen amyloidosis. The results for each type of amyloidosis are thoroughly discussed within the article, and there is also a table of results with one row for each of the 31 patients. Given the title of this blog, I will focus on the results of the fibrinogen amyloidosis patients.
Of these six AFib patients, one was on dialysis when started on CPHPC and the other five were not. Of the five who were not on dialysis, their proteinuria ranged from 2.5 to 10.9 grams per day at the beginning of treatment. These five patients were compared to a group of six AFib patients who were not given CPHPC and had similar baseline measurements. The results were generally positive. In four patients given CPHPC, proteinuria decreased over that time period, whereas it increased in all of the Afib patients who were not given CPHPC. On the other hand, the rate of decline of GFR (glomerular filtration rate) among the CPHPC patients was only slightly lower than the GFR decline among the non-CPHPC patients. But the rate of decline of GFR varies over such a wide range anyway that the difference was not considered statistically significant.
Another measurement used for comparison, which I do not recall seeing before, is the ratio of urine protein to creatinine. If I understand it correctly, this measurement is important because as renal failure progresses and GFR declines, there is less protein loss in the urine because less filtration is occurring. The ratio of protein to creatinine in the urine tends to correct for that loss of GFR. An increase in that ratio indicates that a higher percentage of protein is being lost in the urine. The starting point for that ratio among the Afib patients who received CPHPC was 543, and among those not receiving CPHPC it was 539. (The units are mg/mmol.) Among the patients not receiving CPHPC, the median increase in the urine protein to creatinine ratio was 292, with a range of 169 to 428. Among the patients who did receive CPHPC, the median change was a decrease of 92, which ranged from a decrease of 245 to an increase of 108. So that measurement definitely indicated positive results for the CPHPC users.
A slightly subjective measurement done on all patients in the study was SAP scintigraphy, which is like a CT scan that shows amyloid deposits throughout the body. When these scans are compared over a period of time in an amyloidosis patient not undergoing any treatment, the amount of amyloid in the body (referred to as the whole body amyloid load) can clearly be seen to increase. Yet again we have positive results from the patients who received CPHPC. Quoting from the article: "None of the CPHPC-treated AFib patients showed the progressive amyloid deposition which is usual in this condition."
Although we have a few measurements showing positive results among the AFib patients who received CPHPC, what did it really do for the patients in the end? Well, at least three AFib patients felt they were benefitting enough to keep taking CPHPC for an additional year when it was offered. Although the results of this study were not good enough to call it a cure, the CPHPC definitely slowed down the progression of this disease in these patients. That slowing down is evident when comparing the onset of dialysis of the group that received CPHPC to the group that did not. Patients who did not receive CPHPC were on dialysis a median of 17 months after their initial measurements were taken, with a range of 9 to 24 months. Of the five patients who did receive CPHPC before they became dependent on dialysis, one had a kidney and liver transplant 41 weeks into the study, one was still not on dialysis nearly seven years after beginning the study (wow), and the other three started dialysis after 31, 39 and 71 months. Quoting from the article again, "renal survival was significantly longer in the CPHPC group."
This initial study of CPHPC in humans showed some good results, but it is a long way from being a miracle cure for all types of amyloidosis. The results in the fibrinogen amyloidosis patients were the most notable and featured prominently in the article. Although the use of CPHPC did not appear to stop or reverse the progression of the disease, it clearly slowed the progression. That is good news as it preserves kidney function, which delays the onset of the need for dialysis. Slowing the progression also gives a patient more time to consider transplant options and possibly qualify for a liver only transplant instead of a combined liver and kidney transplant. Hopefully the ongoing clinical trials with CPHPC at the NAC will bring us a little closer to a non-surgical cure for fibrinogen amyloidosis.
The next article up for review is another very important article regarding treatment for fibrinogen amyloidosis. As an added bonus, it initiates some discussion between two groups of doctors who disagree on some conclusions and recommendations in the article, and we get to see some of that debate unfold in the following month's issue of the same journal.
=====Monthly Blog Status Update=====
As of January 31, 2014:
Total posts: 124 (6 in January)
Total pageviews: 11,000 (~600 in January)
Email subscribers: 7
Total number of countries that have viewed the blog: 79
No new countries viewed the blog in January. :-(
(1) Gillmore JD, Tennent GA, Hutchinson WL, et al. Sustained pharmacological depletion of serum amyloid P component in patients with systemic amyloidosis. Br J Haematol. 2010;148(5):760-767.
[Edit 3-1-14: Corrected year in monthly blog stats.]