A Phase II, Single-Arm, Open-Label, Bayesian Adaptive Efficacy and Safety Study of PBI-05204 in Patients with Stage IV Metastatic Pancreatic Adenocarcinoma

Roth, Megan; Cardin, Dana Backlund; Borazanci, Erkut; Steinbach, Margaux; Picozzi, Vincent J.; Rosemury, Alexander; Wadlow, Raymond; Newman, Robert A.; Berlin, Jordan

doi:10.1634/theoncologist.2020-0440

Cited by 26 publications

(27 citation statements)

References 8 publications

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“…Previously we reported that oleandrin has a capability of crossing the blood brain barrier and selectively inhibits human malignant cell proliferation but not that of normal cells due to the ability of oleandrin to interact with a unique isoform of Na, K-ATPase that is preferentially expressed in malignant tissue (Ni et al, 2002;Lin et al, 2008;Yang et al, 2009). Given that PBI-05204, a defined extract of Nerium oleander containing oleandrin, has multiple mechanisms for inhibiting malignant cell growth and proliferation and has been through both phase I (Hong et al, 2014) and phase II (Roth et al, 2020) clinical trials in cancer patients, we sought to examine the potential role of this botanical drug in the treatment of GBM.…”

Section: Introductionmentioning

confidence: 99%

The Botanical Drug PBI-05204, a Supercritical CO2 Extract of Nerium Oleander, Inhibits Growth of Human Glioblastoma, Reduces Akt/mTOR Activities, and Modulates GSC Cell-Renewal Properties

et al. 2020

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Glioblastoma multiform (GBM) is the most common primary glial tumor resulting in very low patient survival despite current extensive therapeutic efforts. Emerging evidence suggests that more effective treatments are required to overcome tumor heterogeneity, drug resistance and a complex tumor-supporting microenvironment. PBI-05204 is a specifically formulated botanical drug consisting of a modified supercritical C0 2 extract of Nerium oleander that has undergone both phase I and phase II clinical trials in the United States for treatment of patients with a variety of advanced cancers. The present study was designed to investigate the antitumor efficacy of this botanical drug against glioblastoma using both in vitro and in vivo cancer models as well as exploring efficacy against glioblastoma stem cells. All three human GBM cell lines, U87MG, U251, and T98G, were inhibited by PBI-05204 in a concentration dependent manner that was characterized by induction of apoptosis as evidenced by increased ANNEXIN V staining and caspase activities. The expression of proteins associated with both Akt and mTOR pathway was suppressed by PBI-05240 in all treated human GBM cell lines. PBI-05204 significantly suppressed U87 spheroid formation and the expression of important stem cell markers such as SOX2, CD44, and CXCR4. Oral administration of PBI-05204 resulted in a dosedependent inhibition of U87MG, U251, and T98G xenograft growth. Additionally, PBI-05204-treated mice carrying U87-Luc cells as an orthotropic model exhibited significantly

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Section: Introductionmentioning

confidence: 99%

The Botanical Drug PBI-05204, a Supercritical CO2 Extract of Nerium Oleander, Inhibits Growth of Human Glioblastoma, Reduces Akt/mTOR Activities, and Modulates GSC Cell-Renewal Properties

et al. 2020

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“…86 PBI-05204, a carefully defined extract of N. oleander containing a controlled concentration of oleandrin was evaluated in both Phase I and Phase II clinical trials for treatment of advanced cancer patients. 14,15 Those studies showed that oleandrin, the active principle ingredient, and other compounds in the extract could be safely administered to humans without serious adverse effects. The Swiss physician Paracelsus has been quoted as saying that "The dose makes the poison".…”

Section: Discussionmentioning

confidence: 99%

“…Clinical trials of oleander extracts with carefully defined concentrations of oleandrin have shown promise that this cardenolide, at least when included in the PBI-05204 extract, can be safely administered to patients with therapeutic intent. 14,15 At the present time, the specific mechanism(s) by which oleandrin, or extracts containing this molecule, provide antiviral activity against specific viruses is not known; however, multiple mechanisms of the antiviral activity of oleandrin have been suggested and deserve further inquiry. For example, in addition to targeting HIV-1, 17 the findings by Hutchison et al, 19 that oleandrin and a N. oleander phytoextract can inhibit the infectivity and Env-dependent intercellular transmission of HTLV-1 across the VS allude to the therapeutic potential of oleandrin as a broad-spectrum antiviral to combat infections by enveloped viruses.…”

Section: Discussionmentioning

confidence: 99%

“…[10][11][12] Oleandrin, a unique lipid-soluble molecule derived exclusively from Nerium oleander (aka Nerium indicum, Common oleander, Adelfa, Kaner, Nerium odorum), 13 has been shown to be the active principle ingredient in the botanical extract drug PBI-05204 which has been through both Phase I and Phase II trials in patients with malignant disease. 14,15 These clinical studies demonstrated that oral administration of defined doses of oleandrin, as part of the extract, can be administered without serious adverse effects, suggesting its use for other diseases beyond cancer may be appropriate to consider.…”

Section: Introductionmentioning

confidence: 99%

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<p>Antiviral Effects of Oleandrin</p>

Newman¹,

Sastry²,

Arav‐Boger³

et al. 2020

JEP

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Over the past 15 years, investigators have reported on the utility and safety of cardiac glycosides for numerous health benefits including those as treatments for malignant disease, stroke-mediated ischemic injury and certain neurodegenerative diseases. In addition to those, there is a growing body of evidence for novel antiviral effects of selected cardiac glycoside molecules. One unique cardiac glycoside, oleandrin derived from Nerium oleander , has been reported to have antiviral activity specifically against ‘enveloped’ viruses including HIV and HTLV-1. Importantly, a recent publication has presented in vitro evidence for oleandrin’s ability to inhibit production of infectious virus particles when used for treatment prior to, as well as after infection by SARS-CoV-2/COVID-19. This review will highlight the known in vitro antiviral effects of oleandrin as well as present previously unpublished effects of this novel cardiac glycoside against Ebola virus, Cytomegalovirus , and Herpes simplex viruses.

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“…These include the use of oleandrin and extracts of the oleander ( N. oleander ) plant containing oleandrin, as effective therapeutics that range from cosmetic treatment of skincare problems [13] to the treatment of cancer [14] , [15] , [16] . Oleandrin, a unique lipid-soluble cardiac glycoside obtained solely from Nerium oleander , has been recognized as the active principal ingredient in PBI-05204 used in Phase I and Phase II clinical trials of patients with cancer [17] , [18] . These trials defined the pharmacokinetics of oleandrin and demonstrated that extracts containing this molecule, along with other components found in the extract, can be administered safely as an oral drug to patients without significant adverse events.…”

Section: Introductionmentioning

confidence: 99%

Antiviral activity of oleandrin and a defined extract of Nerium oleander against SARS-CoV-2

Plante¹,

Dwivedi²,

Plante³

et al. 2021

Biomedicine & Pharmacotherapy

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With continued expansion of the coronavirus disease (COVID-19) pandemic, caused by severe acute respiratory syndrome 2 (SARS-CoV-2), both antiviral drugs as well as effective vaccines are desperately needed to treat patients at high risk of life-threatening disease. Here, we present in vitro evidence for significant inhibition of SARS-CoV-2 by oleandrin and a defined extract of N. oleander (designated as PBI-06150). Using Vero cells, we found that prophylactic (pre-infection) oleandrin (as either the pure compound or as the active principal ingredient in PBI-06150) administration at concentrations as low as 0.05 µg/ml exhibited potent antiviral activity against SARS-CoV-2, with an 800- fold reduction in virus production, and a 0.1 µg/ml concentration resulted in a greater than 3,000-fold reduction in infectious virus production. The half maximal effective concentration (EC 50 ) values were 11.98 ng/ml when virus output was measured at 24 h post-infection, and 7.07 ng/ml measured at 48 h post-infection. Therapeutic (post-infection) treatment up to 24 h after SARS-CoV-2 infection of Vero cells also reduced viral titers, with 0.1 µg/ml and 0.05 µg/ml concentrations causing greater than 100-fold reduction as measured at 48 h, and the 0.05 µg/ml concentration resulting in a 78-fold reduction. Concentrations of oleandrin up to 10 µg/ml were well tolerated in Vero cells. We also present in vivo evidence of the safety and efficacy of defined N. oleander extract (PBI-06150), which was administered to golden Syrian hamsters in a preparation containing as high as 130 µg/ml of oleandrin. In comparison to administration of control vehicle, PBI-06150 provided a statistically significant reduction of the viral titer in the nasal turbinates (nasal conchae). The potent prophylactic and therapeutic antiviral activities demonstrated here, together with initial evidence of its safety and efficacy in a relevant hamster model of COVID-19, support the further development of oleandrin and/or defined extracts containing this molecule for the treatment of SARS-CoV-2 and associated COVID-19 disease and potentially also for reduction of virus spread by persons diagnosed early after infection.

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A Phase II, Single-Arm, Open-Label, Bayesian Adaptive Efficacy and Safety Study of PBI-05204 in Patients with Stage IV Metastatic Pancreatic Adenocarcinoma

Cited by 26 publications

References 8 publications

The Botanical Drug PBI-05204, a Supercritical CO2 Extract of Nerium Oleander, Inhibits Growth of Human Glioblastoma, Reduces Akt/mTOR Activities, and Modulates GSC Cell-Renewal Properties

The Botanical Drug PBI-05204, a Supercritical CO2 Extract of Nerium Oleander, Inhibits Growth of Human Glioblastoma, Reduces Akt/mTOR Activities, and Modulates GSC Cell-Renewal Properties

<p>Antiviral Effects of Oleandrin</p>

Antiviral activity of oleandrin and a defined extract of Nerium oleander against SARS-CoV-2

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