Dr. John N. Allan, MD, is Assistant Professor of Medicine in the Division of Hematology and Medical Oncology at Weill Cornell Medicine and a CLL specialist. He is interviewed by Dr. Brian Koffman, MDCM, CLL Society Co-Founder and Chief Medical Officer.. The interview was recorded at the 61st Annual Meeting of the American Society of Hematology (ASH), in 2019, in Orlando, FL.
In this interview, Dr. Allan discusses updates contained in an abstract he presented at ASH 2019 entitled: Preliminary Safety, Pharmacokinetic, and Pharmacodynamic Results From a Phase Ib/II Dose-Escalation and Cohort Expansion Study of the Noncovalent, Reversible Bruton’s Tyrosine Kinase Inhibitor, Vecabrutinib, in B-Lymphoid Malignancy Patients With Prior BTKi Therapy.
While we have witnessed radical change in how we treat and control Chronic Lymphocytic Leukemia (CLL) with BTKi drugs such as ibrutinib (Imbruvica®) and acalabrutinib (Calquence®), the fact remains that patients who remain on long-term treatment can develop resistance to the drug and a subsequent relapse of their CLL. We are beginning to learn more about this development of resistance and research such as this study is designed to find ways to respond to or avoid the development of resistance. This finding has changed the way we address CLL dramatically and was one of the first pathways identified to help control CLL.
The currently available BTK Inhibitors are classified as irreversible blockers of the protein BTK. BTK is a pathway that controls the function of the B cell antigen receptor (BCR) which is virtually the “business end” of mature b-cells. The BCR is the receptor that binds to pathogens such as bacteria and viruses that invade the body. When the BCR binds to an antigen a cascade of signals ensue that promote prolonged survival of the cell. We now know that CLL cells “over-express” BTK which causes this prolonged survival.
Ibrutinib and Acalabrutinib bind covalently to BTK which essentially makes them “irreversible” agents. This means that when a molecule of the BTKi binds to BTK, the enzyme is dead and a CLL cell must reproduce BTK. In CLL, there is an “addiction” of the CLL cell to BTK but BTK is not found much in non-CLL cells so the signaling inhibition is rather specific to CLL and other b-cell malignancies.
Patients with higher risk genomics have more of a tendency to mutate around BTK blockade and develop resistance to the irreversible BTKi. This mutation results in changes to the BTK molecule that no longer allow the drug to bind to BTK and stop the proliferation pathway. At this point the drug is no longer effective. To understand how this mutation blocks the binding, consider that the binding site where the drug and enzyme meet is a lock and key. Only your key, with its unique shape will open your door. If the lock is changed, your key no longer works. Essentially the enzyme develops a way to “change the lock”. The most common mutation that causes BTKi resistance is C481S. Click here to watch another interview on Ibrutinib resistance.
Reversible BTKi drugs, such as Vecabrutinib, being studied here have been developed “pre-clinically”, to take advantage of better pharmacokinetics [the formal study of processes of absorption, distribution, metabolism and excretion (ADME) of medicinal products] particularly longer “half-lives” which means that these drugs remain in the body longer than the irreversible agents. In addition, these drugs can move in and out of the “kinase pocket”, the site where binding occurs in CLL.
Pre-clinical studies (animal studies) have shown this drug to be effective in the restoring inhibition of BTK in animal subjects who had developed resistance with prior BTK therapy. In addition, this agent has shown effectiveness in patients with the “wild-form”, or naturally occurring CLL, as well. Currently, for this clinical trial, they are looking at patients who have mutations or develop resistance, to determine if this agent can overcome the resistance in humans and once again inhibit the BTK protein and kill the CLL cell.
The Phase I portion of this clinical trial enrolled approximately 30 patients, which is standard in this level trial. Phase I trials are always about safety first and start with low doses of the trial drug and then escalate to help researchers determine the recommended Phase II dose, which means finding the lowest dose with the least toxicities.
Very early results, among this very small sample, are encouraging in that the normal toxicities associated with current BTKi agents such as: rash, arthralgias, bruising and bleeding have been low. To date, no cardiac toxicities have been noted.
The Phase I trial was exciting and promising.
Phase II studies involving larger numbers of patients are coming.
The exciting aspect of this clinical trial is that if successful in larger numbers of patients in Phase II and Phase III studies, it gives CLL providers one more option to deal with the variability of patient’s disease and response to various therapies.
There are currently, three reversible BTK Inhibitors in various stages of study and each appears to have different properties.
The link to find out where this clinical trial is available and more information is: https://clinicaltrials.gov/ct2/show/NCT0303765. To learn more about clinical trials, in general, go to https://cllsociety.org/clinical-trials/
The original abstract for this Phase I/II study can be found at: https://www.sunesis.com/data-pdf/062/sunesis-sns-062-20181202-ASH.pdf
Thanks for reading and viewing this interview.
Stay strong, we are all in this together.
Thomas. E. Henry III, MBA, RPh, CPh