AMN107 and BMS-354825 Trials

Posted by rob on January 26, 2005 under Uncategorized | Be the First to Comment

Drugs for leukaemia on trial

LOH FOON FONG attended a haematology meeting in San Diego, the United States, recently and gives an update on treatment for chronic myeloid leukaemia.  

TWO drugs â?? codenamed AMN107 and BMS-354825 â?? will be moving into Phase II trials on patients who do not respond to higher doses of, or are intolerant to, imatinib mesylate (IM), the drug in current use to treat myeloid leukaemia, a type of blood cancer.  

Encouraging results of both drugs from Phase I trials were reported during the 46th Annual Meeting of the American Society of Hematology in San Diego, the United States, recently. 

Dr Francis Giles

Patients in the chronic phase of chronic myeloid leukaemia (CML) who did not react to IM were said to have responded well to the new drugs. â??We hope that the AMN107 drug has less resistance problem than the IM,â? said Dr Francis Giles, chief of developmental therapeutics from the MD Anderson Cancer Centre in Houston, Texas.  

â??We have a molecule that is more potent, binds more tightly and should be less vulnerable to mutations, and hopefully a better toxicity profile. So far what we have from the Phase 1 study is some marrow toxicity but interestingly the only marrow toxicity we have was transient to people who went on to respond to the treatment,â? he said. 

There were also some skin rashes that did not go away with any drug and some changes in the liver which went away even when patients continued the drug at the same dosage, he said. The researchers are working on defining the dosage toxic limit, he said. 

When IM was discovered five years ago, it was a major breakthrough in leukaemia treatment because it targeted specific proteins in cancer cells and stopped them from growing without killing the normal cells like traditional treatment did. 

The results from IM, or also commonly called Imatinib, were so significant that the drug was quickly introduced to the world. IM is now recognised as the main standard treatment for CML patients and offers more than 90% survival in newly-diagnosed patients. Interferon alpha was previously considered the standard treatment for this group of patients. 

CML is a cancer that starts in the bone marrow and invades the blood. The incidence of CML is 1.6 per 100,000 per year. The American Cancer Society estimates that 4,600 cases will be diagnosed in the United States this year. It usually occurs among middle-aged adults, mostly among 50-year-olds. 

Dr Jorges Cortes

About 95% of CML patients have a genetic abnormality called the Philadelphia (Ph+) chromosome. The chromosome produces an abnormal enzyme Bcr-Abl tyrosine kinase that blocks the normal signal that tells the body to stop producing white blood cells. As such, there is a proliferation of white blood cells. IM is a relatively selective inhibitor of the abnormal enzyme. 

Despite the breakthrough, the disease in a small number of chronic phase CML patients continues to deteriorate and patients in worse stages, accelerated and blast phases of CML, have a poorer prognosis and higher IM resistance rates. 

Close to 80% of patients who are treated with IM as the first line therapy on the standard 400gm dose achieve a complete cytogenic response (the disease is no longer detected in the genes), said Dr Jorge Cortes, the scientist from the MD Anderson Cancer Centre in a press briefing on Five years of Imatinib: Lessons Learned in CML Treatment Strategy organised by Novartis Corporation (Malaysia).  

After three years, over 90% of them are still sustaining the cytogenic response and the molecular response rate continues to improve, he said. 

â??It clearly changed the way we manage patients. We have gone from an era of trying to control the manifestation of the disease to trying to achieve cytogenic responses, which we had learned from the use of interferon. Now we are trying to achieve molecular responses,â? he said. 

In CML, improvement in molecular response means the reduction in quantities of Bcr-Abl while a complete molecular response means the Bcr-Abl levels are undetectable. 

Australian data has indicated that more patients are getting into complete molecular response after four years. If they achieve a good response, especially if it is cytogenic within 12 months and molecular by 12 months, their survival rate is good, said Dr Cortes. 

â??But what happens after 10 years, we donâ??t know. Four or five years is remarkable considering anything we had in the past,â? he said. 

Dr Oliver Ottmann.

â??There is a new method our (American) group and the Australian team are looking at â?? higher doses of IM and trying to improve on the early responses to get more durable responses. We are seeing more early responses,â? he said. 

Dr Oliver Ottmann, study coordinator and head of the Experimental Haematology at the Johann Wolfgang Goethe University, Frankfurt, Germany, said combination therapy would be the future direction of leukaemia treatment: IM can be combined with non-targeted conventional therapy or two intelligent agents can be combined together.  

Since IM was introduced, transplantation has taken a back seat. What is the role of transplantation today? 

Although it can cure patients, the number of transplants carried out on CML patients has decreased, said Dr Cortes. 

â??Patients are reluctant to go for a transplant because of the mortality risk. But for young patients, transplant will still be an option,â? he said. 

The problem with transplantation is that patients can have a relapse 10-15 years after the transplant, he said. â??Since medical treatment has become more defined, hopefully, we will develop transplantation into a more defined therapy,â? he said.  

Dr Ottmann said the transplant method when combined with IM has worked in some elderly patients, who usually cannot tolerate the method. 

The greatest challenge with mutations for IM and the two new drugs being researched is with one particular mutation known as T315I. 

â??In IM-treated patients, all of the common mutations except T315I appear to be highly sensitive to IM,â? said Dr Giles. â??At this stage, we are highly suspicious based on the pre-clinical data that the T3151 may be particularly resistant. We canâ??t say it clinically yet although I suspect it would be true,â? he said adding that less than 10% of patients have the mutations. 

â??However, we do not have to worry about mutations if there is no disease. These mutations need time to develop. If we can eliminate them, it will not be a long-term issue,â? he said. 

Dr Nicholas Choong, oncologist and haematologist at the University of Chicago, said the challenge with IM, ANM107 and BMS-354825 is that they might block the signal of the receptors on normal cells, and stop the receptors from conveying messages to the chromosomes for certain genes to be expressed. The implications are that normal blood cells with the receptors can be affected and platelets level can fall and patients become anaemic or have their white blood count wiped out and patients become susceptible to infections, he said. As such, doctors will have to find the right dosage for each patient so that the normal cells are not affected, he said. 

Dr Choong added that the AMN and BMS are promising drugs for a difficult disease but further studies need to be done for the toxicity. â??In the first phase BMS study, patients had irregular heart beats. They may or may not be related to the toxicity. Itâ??s too early to say. They are better defined in larger clinical trials,â? he said. 

IM is also being tested for treating other cancers. Now more than 150 clinical trials are evaluating IM in certain forms of prostate, lung and brain cancers, and blood diseases. 

 

http://thestar.com.my/lifestyle/story.asp?file=/2005/1/26/features/9648305&sec=features