Plinabulin

PLINABULIN

Plinabulin is a first-in-class selective immunomodulating microtubule-binding agent (SIMBA) with potential chemotherapy-induced neutropenia (CIN) prevention and anticancer benefits.

Plinabulin is investigational and not FDA approved.

SIMBA logo

Plinabulin is an investigational small molecule that is in the new selective immunomodulating microtuble-binding agent (SIMBA) class. It features a unique mechanism of action (MOA) compared to current standard-of-care chemotherapeutics and conventional microtubule-binding agents. This unique MOA has led to plinabulin’s clinical development for the prevention of chemotherapy-induced neutropenia (CIN), as well as for the treatment of late-stage non-small cell lung cancer (NSCLC) and other solid tumors.

PROPOSED MOA

MOA video animation

Plinabulin is investigational and not FDA approved.

In preventing CIN

Plinabulin is investigational and not FDA approved.

In treating NSCLC

Plinabulin is investigational and not FDA approved.

The highly differentiated MOA is published in numerous industry journals, including Chem and Cell Reports. Click a publication below to read the full article.

CHEM

Structure, Thermodynamics, and Kinetics of Plinabulin Binding to Two Tubulin Isotypes

CELL REPORTS

GEF-H1 Signaling upon Microtubule Destabilization is Required for Dendritic Cell Activation and Specific Anti-tumor Responses

CIN

Plinabulin is being evaluated for the prevention of CIN and is currently in two global multi-center clinical trials aiming for a broad indication of prevention of all CIN in all non-myeloid cancer types.

PROTECTIVE-1 (Study 105) is a phase 2/3 trial of plinabulin versus Neulasta after a standard regimen of docetaxel, an intermediate-risk chemotherapy, for advanced breast cancer, hormone-refractory prostate cancer and advanced NSCLC patients.

PROTECTIVE-2 (Study 106) is a phase 2/3 trial of plinabulin in combination with Neulasta, a long-lasting granulocyte-colony stimulating factor (G-CSF), (plinabulin/Neulasta combination) versus plinabulin monotherapy versus Neulasta monotherapy after a high risk myelosuppressive chemotherapeutic regimen composed of three agents, Taxotere (docetaxel), Adriamycin (doxorubicin) and Cytoxan (cyclophosphamide), or TAC, for patients with advanced breast cancer.

We believe that the clinical profile of plinabulin in combination of a G-CSF (plinabulin/G-CSF) such as its potential for improved clinical outcome in neutropenia, lower bone pain, prevention of immune suppression, and its anticancer effects, has the potential to set a new standard in the prevention of CIN in patients treated by high-risk chemotherapy. By improving clinical outcomes in neutropenia and reducing bone pain, the plinabulin/G-CSF combination has the potential to enable patients to maintain chemotherapy target dose, keep to their chemotherapy cycle times, and complete the full course of chemotherapy. When this occurs, patients have significantly better long-term outcomes.

Plinabulin is an investigational and first-in-class selective immunomodulating microtubule-binding agent (SIMBA) currently being studied in clinical trials (NCT03294577; NCT03102606) for concurrent administration with myelosuppressive chemotherapeutic regimens in patients with solid (non-myeloid) cancers for the prevention of CIN and may potentially show beneficial effects in lowering bone pain, preventing immune suppression, and reducing thrombocytopenia in patients treated by intermediate-risk chemotherapy where G-CSF is not recommended.

NSCLC

Plinabulin is being evaluated to be combined with docetaxel for the treatment of advanced NSCLC and is currently in a phase 3 global, multi-center clinical trial.

This trial is being conducted in the U.S., China, and Australia for plinabulin in combination with docetaxel in patients with advanced NSCLC with measurable lung lesions, or DUBLIN-3 (Study 103).

PROGRAMMED CELL DEATH PROTEIN 1 (PD-1) COMBINATION

PD-1 COMBINATION

Preclinical studies have identified some novel and intriguing activities of plinabulin associated with stimulation of the immune system consistent with plinabulin’s ability to enhance the activity of other immuno-oncology agents. We have observed in these preclinical studies that plinabulin works at multiple early steps in the process of immune activation against cancer. In particular, it works to activate dendritic cells and mobilize tumor antigen-specific T cells to the tumor. Studies in animals indicate that plinabulin has a range of immune-enhancing effects that may be synergistic to the effects of checkpoint inhibitors, which are antibodies that inhibit a key defense mechanism that tumors employ to avoid recognition by the immune system. In preclinical studies, plinabulin enhanced the antitumor efficacy of checkpoint inhibitors. We believe that plinabulin in combination with nivolumab, a checkpoint inhibitor approved for use in NSCLC and other indications, may demonstrate more antitumor activity than nivolumab alone without significantly increasing toxicity. Cumulative toxicity has been a concern when nivolumab is combined with other checkpoint inhibitors.

PLINABULIN + PD-1

In September 2016, the University of California San Diego enrolled the first patient in an investigator-initiated phase 1/2 trial of plinabulin in combination with nivolumab in patients with metastatic NSCLC. In addition, the Fred Hutchinson Center together with the University of Washington, launched an investigator-initiated phase 1/2 trial of plinabulin in combination with nivolumab in patients with advanced NSCLC who have failed up to two previous therapies. The Fred Hutchinson Center study had achieved the dose regimen end point, and therefore, the study site was closed.

TRIPLE COMBINATIONS

PLINABULIN + NIVOLUMAB + IPILIMUMAB

In October 2018, we announced the opening of an investigator-initiated phase 1 clinical trial with a triple combination therapy, consisting of plinabulin, nivolumab, and ipilimumab, for the treatment of small cell lung cancer. The trial, conducted through the Big Ten Cancer Research Consortium, is currently enrolling subjects at Rutgers Cancer Institute of New Jersey and other clinical centers in the U.S. This study investigates whether the addition of plinabulin results in a reduction of immune-related side effects of PD-1 and cytotoxic T-lymphocyte-associated protein 4 antibodies and if it provides efficacy synergy.

PLINABULIN + PD-1/PROGRAMMED DEATH LIGAND 1 (PD-L1) + RADIATION/CHEMO

In July 2018, we entered into a sponsored research agreement with MD Anderson to evaluate the benefits of adding plinabulin to radiation therapy plus immune checkpoint antibodies. The study has demonstrated that this triple combination approach (plinabulin + radiation + PD-1 antibody) has dramatic benefits in tumor reduction, increasing tumor dendritic cell maturation and increasing tumor T-cell infiltration. Given the high incidence of progression with PD-1/PD-L1 antibody therapies in the majority of cancers, we believe this novel triple combination approach will restore or enable the immune targeting of cancer in patients that have progressed on checkpoint-targeted therapy.

CLINICAL TRIALS

For details of these two trials, please visit below websites.