CML-Gleevec example Just a few years ago, chronic myeloid leukemia (CML) was a death sentence. Now with the drug Gleevec, many people with CML are free of the disease for years and may be cured. The Gleevec story demonstrates that drug development can go very fast when specific hurdles are passed. CML is caused by a single gene mutation, not one that is inherited like HD, but one that occurs later in life due to gene damage. For CML the hurdles were finding the defective gene, finding the "switch" the gene turned on to cause the disease, and making a safe drug that turned off the switch.
CML Timeline It took more than 20 years and several teams of research scientists to find the gene and the molecular switch that caused leukemia. During some of these same years, scientists at Novartis, a large pharmaceutical company, were developing drugs (for another disease) that could work at this switch. Then in 1993 they got together. After two years of drug development at Novartis, they found a drug that cured leukemia in a mouse model. Then delay. Novartis, who owned the drug, wasn't sure it wanted to proceed, because CML (like HD) is a rare disease, and the company wasn't convinced the drug would make money. Finally in late 1998, this drug, now called Gleevec entered clinical trials.
Huntington 's Timeline Starting to sound familiar? It has taken more than 20 research years to find the Huntington's gene and to sort through the multitude of disease switches it turns on. Then, in a very important breakthrough in 2006, Dr. Hayden and colleagues identified what may be the master switch that starts the disease process and cured the mouse by turning the switch off. This switch is a natural chemical in the body called caspase-6. And in the exciting follow up to that research, CHDI partnered with Amphora Discovery Corp, a drug company already working on drugs that can block this switch. And in a time frame that could be similar to Gleevec, they predict it will take about a year to identify the best drug candidates to test in mice, and another year or two years to complete these tests. Clinical trials in people could start soon after that.
Gleevec Clinical Trials Novartis announced amazingly good first clinical trial results in 1999: all 31 CML patients had remission of their disease. The follow-on trials were quickly begun, with enrollment of more than one thousand CML people (at 3 stages of the disease) by the end of 2000. In an equally amazing accomplishment, patient advocacy groups, their doctors, and Novartis created expanded access (compassionate care) programs for another 5000 patients, before FDA approval in 2001. And still amazing, Novartis had the drug ready to ship to pharmacies the day after FDA approval. That's right: it took just a little more than 2 years of clinical trials until every CML patient could use the drug.
Huntington's Analogy Not sounding as familiar now? Clinical trials are harder in HD than CML, because drug response is much harder to measure in HD. But a bigger problem is that we do not yet have a clinical trial system that is ready to move fast even when the perfect drug is found.
Why is the Gleevec analogy important?First it gives us perspective on how far we've come, and it should get us to thinking about what might be possible in the next few years. There is a real chance that we'll have a drug that cures the HD mouse in two or three years. The time is right to fix the HD clinical trial system so we can get drugs to people as quickly as Gleevec.
Links to related material
Graham RK, Deng Y, Slow EJ, Haigh B, Bissada N, Lu G, Pearson J, Shehadeh J, Bertram L, Murphy Z, Warby SC, Doty CN, Roy S, Wellington CL, Leavitt BR, Raymond LA, Nicholson DW, Hayden MR. Cleavage at the caspase-6 site is required for neuronal dysfunction and degeneration due to mutant huntingtin. Cell. 2006 Jun 16;125(6):1179-91. PubMed abstract