Clofarabine co-inventor Jack Secrist talks about drug discovery
September 30, 2016
Drug discovery researchers like Jack Secrist are motivated by a strong desire to see their work save lives and make a profound difference.
Secrist, the former head of Drug Discovery at Southern Research, is co-inventor of clofarabine, a drug approved by the Federal Drug Administration in 2004 for acute lymphoblastic leukemia (ALL) in pediatric patients like Frances Grace Hirs.
Frances Grace was battling a third bout of ALL in 2013 when she was treated with clofarabine, which helped put her on the road to recovery. (Read a story about her treatment.)
“This is what we all aspire to as drug discovery researchers, moving life-saving compounds from conception to clinic,” Secrist said in 2005, shortly after clofarabine received FDA approval.
In a new interview, Secrist talks about how he and his Southern Research colleagues discovered clofarabine and how the drug moved along to the path to become the first treatment for childhood cancer approved by the FDA in more than a decade.
In this Q&A, Secrist also shares his views on how Southern Research, which has discovered seven FDA-approved drugs used in cancer treatment, has been able to consistently develop new therapies that address unmet medical needs.
Southern Research was visited recently by Frances Grace Hirs, who was treated with clofarabine after a second leukemia relapse. Her parents credit the drug with stabilizing her condition, making a bone marrow transplant possible. As a co-inventor of the drug, do you hear stories like this often?
Secrist: In my experience, at least as it pertains to chemists who are inventors of cancer drugs that end up being FDA approved, it is rare that you would meet someone who had benefited from the drug unless it happens to be a family member, friend, or acquaintance. The inventors are far removed from both the oncologists who select the drugs and the patients who take them.
In this situation, I can relate two stories. I did meet a father and a daughter who had benefited from the drug in Birmingham, and they were focused on making sure that others who might benefit from the drug would be appropriately informed.
The other time that I saw patients who benefited from the drug was at the FDA hearing where the drug was approved. A father brought his son to the hearing and he took advantage of the public forum to relate the story of his son and how this drug has certainly saved his life. He was holding the boy, who was perhaps five or six, in his arms as he spoke. It was a moving scene.
How did the work that led to clofarabine get started?
Secrist: This question is somewhat more technical, but I will provide some information about how we moved toward the drug that became clofarabine. First, we were working in the nucleoside area, looking for drugs that would affect DNA function in cancer cells, which was at the time the best way to develop a new cancer drug. We chose to work on nucleosides since they are the building blocks of DNA, and we felt that finding something that would be recognized by the cancer cells, and perhaps have selectivity, was more likely in this area.
At the time, around 1983, we had funding from National Institutes of Health (NIH) in the form of what is called a program project grant to search for new drugs in this area, and to evaluate them in biological systems. There were two potential drugs that looked promising at the time that were nucleosides, and we had the detailed biological data to be aware of structural concerns with both drugs.
John Montgomery (an organic chemist and key member of the cancer research team) and I then formulated a plan to make a series of new compounds that would be similar enough that they might have activity, but would have structural changes that would overcome the concerns we saw with these two potential drugs. We made this series of compounds, and the end result was clofarabine.
By the way, both of the other compounds also became FDA approved: one of them is fludarabine and the other is cladribine. Interestingly, the three compounds, though very similar in structure, are used for different forms of leukemia.
Can you recount any significant developments or insights that occurred during your work on this project?
Secrist: The first insight that we developed, which really was just a confirmation of what we already felt, was that very small changes in the structure of a molecule can result in very large changes in biological and clinical activity. The utility of clofarabine, fludarabine and cladribine is a clear demonstration of that fact, and it can be seen in other areas, as well.
Another insight that was strengthened was that the more robust the biological (anticancer) data is on a compound, the more likely it is to become FDA approved. Compounds with some activity and selectivity, but not really strong data, most likely will not make it through to approval. Clofarabine had very strong data supporting its move into clinical trials.
It is also true, by the way, that there is not a connection between what human tumors a potential drug can cure in model systems and what tumors it may cure in humans. It would be wonderful if that was the case, but at least with the current models no such correlation exists. Again, we get back to the fact that robust activity and selectivity data across a wide range of tumor types is the best indicator.
When clofarabine received FDA approval in 2004, it was the first new pediatric leukemia to hit the market in more than a decade. How would you assess its significance?
Secrist: Thinking back to the clinical development of the drug, which started at M. D. Anderson Cancer Center in Texas, there was a critical chance happening. A family had a child who had gone through the available drugs for his leukemia, and he was not responding. They asked to be able to try clofarabine, which was not yet available for trials, and their request was granted. The child responded immediately, and the family was truly grateful.
That chance happening suggested the best path to approval, that is, through a focus on childhood leukemia, though there were of course adult trials as well. The drug clearly helped children, and the FDA was very interested in finding a new drug for childhood cancers, and they were very helpful and supportive.
When the ODAC (Oncology Drug Advisory Committee), a group of outside clinicians, voted for approval, the FDA was really pleased to have the first new drug to treat childhood cancers in more than a decade.
Southern Research has discovered seven drugs used in cancer treatment. What made the organization such a hotbed for the discovery of anticancer drugs?
Secrist: In considering why Southern Research was so successful in developing new cancer drugs, I believe that there are a number of reasons. First, we had extremely talented scientists who were dedicated to the development of new drugs that would be useful in the treatment of cancer. The Dream Team in that regard comprised Howard Skipper, John Montgomery, Frank Schabel, and Lee Bennett. They worked together for many years, and together with their staff, were a very effective team.
Second, that team developed an efficient and effective approach to the development of potential new drugs. New compounds were evaluated rapidly, and those with potential were subjected to more detailed evaluations as soon as possible, and compounds that had no activity or weak activity were set aside to make way for new compounds. This iterative approach to drug discovery is still in use today, though the biological systems have evolved over the years.
Finally, in the early years the Dream Team had not only their own ideas on the type of compounds to pursue in the search for new cancer drugs, but also the input of the cancer research team at the NIH. Thus, Southern Research scientists had access to the latest information available to NIH, including areas of activity, clinical results, and evaluation model advances.
In the early years Institute scientists would go up to NIH to present results, and would of course hear presentations about the results of others. In later years we used scientific meetings and personal contacts to gain that information. The result was an ability on our part to look in more fertile fields for new cancer drugs.
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