Data from a Phase I/II clinical trial was presented Saturday during the 62nd ASH Annual Meeting and Exposition (ASH).
Bioniz Therapeutics’ lead compound, BNZ-1, is potentially the first anti-cytokine therapy to demonstrate efficacy against refractory cutaneous T cell lymphoma (CTCL), a rare and aggressive form of cancer. Data from a Phase I/II clinical trial was presented Saturday during the 62nd ASH Annual Meeting and Exposition (ASH).
BNZ-1 is a novel immuno-modulator drug candidate. What’s most unique is that this PEGylated peptide antagonist inhibits three cytokines – IL-2, IL-9 and IL-15, which are important in the pathogenesis of CTLC – rather than one cytokine.
“It always seemed inadequate to inhibit only one cytokine – since we know there are multiple cytokines that are disease drivers – or to use JAK inhibitors, which are broad, non-specific inhibitors of all cytokines regardless if they are disease drivers or not,” Nazli Azimi, Ph.D., PharmD, co-founder, president and CEO of Bioniz, told BioSpace. “Ours is one drug with three independent actions that collectively help patients stay on the treatment longer because of its clean safety profile.”
Specifically, “IL-2 and IL-15 inhibition blocks cytokine-driven propagation/survival of tumor cells, IL-2 and IL-9 inhibition lowers the activity of regulatory T cells that may impede the anti-lymphoma immune response, and IL-15 inhibition may provide an additional anti-inflammatory effect,” Christiane Querfeld, M.D., director of the cutaneous lymphoma program at the City of Hope, and principal investigator of the study, explained in her ASH presentation.
“By blocking IL-2 and IL-15, BNZ-1 prevents the proliferation of malignant cells without impacting the healthy lymphocytes and induces their death since tumor cells are highly dependent on these cytokines,” Azimi said.
The Phase I/II study followed a total of 30 patients and included the basic safety study, a three-month extension and a long-term extension.
“BNZ-1 showed activity in all doses. One patient (5%) achieved a complete response, 11 (58%) achieved a partial response (defined as a 50% reduction over baseline) and seven patients (37%) showed stable disease during the study period,” Querfeld reported.
The overall response rate was 63.2%, based on the Global Response Score in a heavily pretreated, relapsed, refractory CTCL patient population.
“We see a reduction of the regulatory T cells in patients and activation of the patients’ own immune system to attack the malignant cells,” Azimi said. “In this patient population, there’s evidence that the drug lowered the inflammation commonly associated with CTCL. Patients have a lot of itching, redness, and discomfort, which they relieve with topical steroids. It’s a debilitating lifestyle. Our drug relieves those symptoms, so they also feel better.”
There was no disease recurrence during the study, and the duration of response in some patients reached about 15 months. Importantly, BNZ-1 was well-tolerated, with no dose-limiting toxicities or serious treatment-related adverse effects.
“For those who do not achieve a complete response, our goal is to stop the disease progression. If you can manage the symptoms and the disease progression, the patient can have a relatively okay life,” Azimi said.
CTCL is a rare, progressive, incurable cancer that occurs when CD4 T cells become malignant. It manifests with disfiguring skin lesions. “Once disease advances to later stages, it can become lethal quickly,” Azimi said.
“There are some therapies, but their side effects are so severe that patients typically drop out after about three months,” she added.
Since the first-generation therapies were developed, researchers have discovered additional knowledge – such as the role of cytokines in CTCL progression – and thus enabling ever-better therapies.
“Ideally, we want to get rid of the cancers,” Azimi said.
She and her team expect to meet with the FDA around the end of December to discuss plans for a Phase III study that she hopes will launch in 2021.
“We hope enrollment will be broader, to enroll not only refractory patients but those in earlier stages of the disease,” Azimi said.
If that occurs, response rates probably will be higher because, presumably, the malignant cells in less refractory patients will be less resistant to therapy.
BNZ-1 is being developed as a monotherapy, but has the potential to be used in combination with other drugs, too, Azimi suggested. “We have to learn more, as we study the molecular signature of the drug, to decide which combinations work best.”
Going forward, Bioniz also is considering applications for other autoimmune diseases. For BNZ-1, alopecia areata, (immune-mediated hair loss) and vitiligo (immune-mediated skin depigmentation) are likely indications because they both are driven by the same cytokines.
“Hopefully, Phase II trials can start for alopecia areata and vitiligo in parallel with the beginning of the Phase III trials for CTCL,” she said. “Additionally, because we believe the data from the CTCL clinical trial validates the platform, we’re looking at additional compounds to modulate other inflammatory diseases, such as celiac disease and Type 1 diabetes, using BNZ-2 to inhibit IL-15 and IL-21.”
“This started as an intellectual exercise, so the fact that we’re seeing the drug actually working is something I can’t put a value on,” Azimi said. “This is a new class of drug with targeted efficacy and an impressive safety profile, which is helping in real life, providing tangible benefits for patients. We look forward to bringing them to the patients most in need.”
