Navitoclax

Navitoclax (previously ABT-263) is an experimental orally active anti-cancer drug, which is a Bcl-2 inhibitor similar in action to obatoclax.

Mechanism of action
Navitoclax inhibits not only Bcl-2, but also Bcl-XL and Bcl-w proteins. Because navitoclax inhibits Bcl-XL, it reduces platelet lifespan, causing thrombocytopenia, and this makes it dose-limiting.

Effects against senescent cells
In animal studies, navitoclax was found to be a senolytic agent, inducing apoptosis in senescent, but not non-senescent cells. Oral administration of ABT263 to either sublethally irradiated or normally aged mice reduced senescent cells, including senescent bone marrow hematopoietic stem cells and senescent muscle stem cells. This depletion mitigated total-body irradiation-induced premature aging of the hematopoietic system and rejuvenated the aged hematopoietic stem cells and muscle stem cells in normally aged mice.

On September 19, 2018, an article was published in Nature about using this drug to kill senescent glial cells in mice. The drug had a protective effect against memory loss in mice genetically engineered to simulate Alzheimer's Disease.

Clinical trials
ABT-263 was studied in 2009. In January 2017, Navitoclax was evaluated as a combination treatment against solid tumors together with trametinib in a clinical trial sponsored by the National Cancer Institute. In this phase Ib/II study, patients with RAS-mutant tumors were enrolled to received trametinib plus navitoclax in dose-escalation part followed by multiple dose expansion cohorts.

In ESMO Congress 2023, the final results of 91 patients (including 38 patients from dose escalation part) were reported. At RP2D, 8/49 (16.3%) evaluable patients had a partial response (PR) with disease control rate (DCR) 59.2%. Though 35.2% objective response rate (0RR) and a disease control rate (DCR) of 85.7% was achieved among the 32 patients with GYN cancers, but the median duration of response (DOR) of 8.2 months was only moderately fine and no complete response was achieved.

The product is currently under development by AbbVie. Navitoclax as mono-therapy as well as in combination with chemotherapies (paclitaxel, docetaxel, gemcitabine, and irinotecan), olaparib, erlotinib, venetoclax, and rituximab in advanced hematological malignancies (in both pediatric and adult patients) and solid tumors including ovarian cancer, breast cancer, lung cancer.

In addition, a global multi-center, randomized, open-label, phase 3 study evaluating efficacy and safety of navitoclax in combination with ruxolitinib versus best available therapy in adult patients with relapsed/refractory myelofibrosis was initiated at 31 Aug, 2020 and is on recruiting (NCT04468984).

Antisclerotic
Not directly related to cancer, rather as a therapy for scleroderma, Navitoclax appeared to reduce existing fibrosis through inducing apoptosis of myofibroblasts. Further research is required to elucidate the exact mechanisms and confirm studies.