BioInvent’s phase I/IIa study with first-in-class anti-TNFR2 antibody BI-1808 in advanced malignancies has produced positive results. The strong interim safety data paves the way for the phase IIa part of the study. BioStock contacted the company’s CMO Andres McAllister to learn more.
BioInvent is a biotech company that develops first-in-class drugs for cancer therapy. The focus is to identify new antibodies that can significantly improve the efficacy of current checkpoint inhibitors and/or achieve immune activation in patients who no longer respond to treatment.
BI-1808 – a first-in-class candidate
The company has a broad range of candidates discovered through its proprietary technology platform F.I.R.S.T., including BI-1808, which aims to treat solid tumour diseases, such as non-small cell lung cancer (NSCLC) and ovarian cancer as well as CTCL (cutaneous T-cell lymphoma), a type of blood cancer. The drug candidate BI-1808 is an antibody that targets TNFR2 (tumour necrosis factor receptor 2). This protein plays an important role in tumour spread and survival, and it has been recognised as a new and promising target for immunotherapy.
BI-1808 is considered a first-in-class drug candidate. It is currently being evaluated in a phase I/IIa study for safety, tolerability and possible signals of efficacy as a monotherapy as well as in combination with anti-PD-1 checkpoint inhibitor pembrolizumab. The subjects for the trial are patients with advanced malignancies, whose disease has progressed after standard therapy.
Positive phase I/IIa data
Last week, BioInvent announced positive interim data for the trial, showing no significant safety concerns in relation to the administration of BI-1808 as single agent. 24 subjects were dosed with a range of 25-1000 mg with 22 patients evaluated for efficacy. The BI-1808 infusions were well tolerated and no dose-limiting toxicity or serious adverse events related were observed, at any dose level.
Stable disease was observed in six patients subjects so far – one in the 25 mg cohort, three subjects at 75 mg, one at 225 mg, and one at 1000 mg. The efficacy of BI-1808 as a single agent and in combination with pembrolizumab will be further explored in the subsequent phase IIa part of the trial, which is intended to enroll patients with pre-defined malignancies and will consist of a larger sample size. The Phase IIa study of BI-1808 as a single agent is planned to start during H2 2023.
BioStock was able to speak to BioInvent’s CMO Andres McAllister for an expert perspective on the significance of these results.
Andres, for those who are not aware, why is TNFR2 a promising target?
– TNRF2 is the second receptor for TNF. As opposed to TNFR1, which is expressed widely in the body, and is an important target for the treatment of autoimmune diseases such as Rheumatoid Arthritis, TNFR2 has a limited expression, and in cancer it is highly expressed in the tumor microenvironment (TME). There, it is mostly expressed by regulatory T cells (Tregs), which are tumor promoting cells that help cancer escape from immune recognition. Our goal is to drastically modify the existing dynamics of the TME to alter the tumor promoting conditions that prevail, and modify them to enhance tumor recognition and immune attack of the tumor.
In terms of mechanism of action, how does BI-1808 act upon TNFR2, and what are the downstream effects?
– In that context, BI-1808 has the capacity to accomplish two highly desirable effects: first, it significantly decreases the number of Tregs present in the TME; and second it increases the number of cytotoxic T cells (CD8+ T cells), which are the cells capable of attacking and destroying the tumor. It turns out that this ratio (Tregs / CD8+ T cells ) is a key determinant of the capacity of the immune system to destroy the cancer cells. Our preclinical data demonstrates that BI-1808 has a very positive effect on this ratio, and not surprisingly, the best antitumoral effect we have observed as compared with other immune checkpoint inhibitors. Needless to say, the potentially synergistic activity with other immune checkpoint inhibitors appears blatant and, of course, has elicited a great deal of interest from clinical investigators and key opinion leaders.
Why are these phase I/IIa interim safety data important?
– In the process of drug development, safety and tolerability of the drug is a key component. This is related to the doses one can administer safely, and more importantly, to the exposure of the patient to the drug. For the most part, this safety aspects are difficult to predict. In the case of BI-1808, we are happy to report that our first-in-class drug candidate has been extremely well tolerated and we have observed no safety concerns whatsoever. This means that we can treat cancer patients at doses where we are sure the target is being reached and “engaged” at near 100% saturation, e.g., every TNFR2 present in the individual should be reached by the antibody. And this without side effects! Thus, it allows us to give patients the best chances to respond to the drug, and to explore the best regimens that should be employed to use the drug in the most optimal way.
How do these results shape your planning for future clinical evaluation with BI-1808?
– The combination with other drugs is the future, not only for BI-1808, but also for most drugs intended to treat cancer. When those combinations are put in place, a matter of concern is the safety profile of the combination treatment. In that context, having one of the components that poses little concern is a tremendous asset. Since we are now in the dose-escalation part of our study in combination with pembrolizumab (an anti-PD1 agent), and we can safely expect little or no increased toxicity from the combination. This combination can therefore be tested in different patient populations, and different lines of treament without reasons for concern. The possibilities are therefore enormous.