Novel HDIs on Trial
Because of mounting evidence that HDIs need to be more specific, companies developing this class of drugs are designing them for more selectivity. Acetylon (Boston, MA), has developed a portfolio of oral, selective HDAC inhibitors targeting oncology, hematology, immunology, and neurologic disease indications. The company presented Phase Ib clinical data regarding its lead candidate, ACY-1215, for the treatment of relapsed or refractory multiple myeloma at the European Hematology Association this past June in Stockholm.
ACY-1215, an orally administered drug, selectively inhibits HDAC6, an extranuclear member of the HDAC enzyme family. The drug is currently being evaluated in a Phase Ib clinical trial in combination with Celgene’s Revlimid® (lenalidomide) and a Phase I/II trial in combination with Takeda Millennium’s Velcade® (bortezumib) for the treatment of relapsed or refractory multiple myeloma.
Of those studies, Catherine A. Wheeler, M.D., vice president, clinical development of Acetylon said, “We are encouraged by the number of early clinical responses that have been observed in combination therapy. In the Phase Ib study in combination with Revlimid, eight out of ten evaluable patients to date achieved disease response, including one complete response (with marrow confirmation), two very good partial and four partial responses observed.”
The company also reported that the drug proved active in heavily pretreated patients in combination with Velcade in the ongoing Phase I/II study, including three partial responses and one minor response to date in thirteen evaluable patients. “Responses in both trials have been durable, with patients remaining on study for up to 11 months.” Dr. Wheeler said.
She further noted that no dose limiting toxicities or severe adverse events, which are common with previous generation nonselective HDAC inhibitors, have been observed in this trial, and “dose escalation is continuing.”
Acetylon president and CEO Walter Ogier told GEN, “Ten years ago, people only had a vague idea about the scope of the different HDAC enzymes and were designing nonselective HDAC inhibitors. It’s become more clear what each HDAC enzyme isoform does, and it’s now possible to design small molecule inhibitors that are selective. We have initially focused on inhibition of HDAC6.”
One downside of epigenetic drug targets, he noted, is their broad effect on fundamental cellular mechanisms, as they target the nuclear histone protein around which DNA is wrapped and have general effects on gene expression. They cause multiple side effects—anorexia, nausea, vomiting, suppression of white blood cells and thrombocytopenia, and profound fatigue, “not unlike those associated with conventional chemotherapy, and which reduce the tolerability of combination drug regimens for cancer, thereby reducing effectiveness.”
HDAC6, a unique member of the HDAC family, acts outside the nucleus, interfering with the degradation of misfolded proteins similarly to proteasome inhibitors like Velcade. “One of our therapeutic approaches,” he said, “is to combine our inhibitors with Velcade to deal a death blow to cancer cells, which inherently produce large amounts of protein, by choking them on their own waste protein refuse through synergistic proteasome inhibition plus HDAC6 inhibition. We are seeing similar synergy with drugs like Celgene’s Revlimid.”
Acetylon disclosed last July that it had entered into a strategic collaboration and option agreement with Celgene. The collaboration, the company said, supports the development of Acetylon’s portfolio of oral, selective HDAC inhibitors and includes an exclusive option for the future acquisition of Acetylon by Celgene.
The collaboration will focus on the continued clinical advancement of Acetylon’s lead candidate, ACY-1215, an oral first-in-class selective HDAC6 inhibitor being developed for hematological malignancies, a second highly selective HDAC6 inhibitor for neurological diseases, and an HDAC1/2 inhibitor for sickle cell disease and beta-thalassemia, the world’s two most prevalent, severe genetic diseases.
Syndax of Waltham, MA, says it employs epigenetic drugs to selectively target reversible epigenetic changes in cancer cells that lead to the development of drug tolerance to certain targeted therapies. The company’s lead compound, an HDI called entinostat, has shown promising activity in randomized, Phase II clinical trials in combination with the targeted therapies.
Syndax uses a combination approach with entinostat to epigenetically modulate the development of drug tolerance. Two such drugs include endocrine agents that block the production of estrogen, which drives tumor growth in estrogen receptor-positive postmenopausal women with metastatic breast cancer, and tyrosine kinase inhibitors of the epidermal growth factor receptor, which compete with the growth factor that stimulates tumor proliferation in non-small cell lung cancer. In both cases epigenetic changes in these tumor types—which can be reversed by entinostat, the company says—have been show to correlate with the development of resistance to these drugs in preclinical animal models.
Currently the company has multiple clinical trials underway, testing entinostat activity in combination with, for example, aromatase inhibitors in breast cancer studies underway. Syndax hopes its epigenetic drug candidate will make the tumor cells vulnerable to aromatase inhibitors again.
Syndax CEO Arlene Morris says that this would enable women with breast cancer that has spread to continue with more cycles of hormone therapy before shifting to chemotherapy, which has much stronger side effects.
“The goal is to keep women from going onto chemotherapy as long as possible,” she says.
In the meantime, the epigenome will continue to provide a wealth of novel drug targets.