PBI-05204

The product PBI-05204 was developed early in PBI’s history and until recent years it was the primary object for research toward expanding the knowledge base for safety and therapeutic uses of Nerium oleander extracts.

That research has led toward further research on the use of PBI-05204 in treating tumor/cancer and viral infection in humans and animals, and in treating neurodegenerative diseases (such as Alzheimer’s disease and Parkinson’s disease) and stroke in humans.

PBI-05204 has undergone extensive preclinical testing and has completed an FDA approved Phase I clinical in heavily pretreated cancer patients at the University of Texas M. D. Anderson Cancer Center as well as an FDA approved Phase II clinical trial in patients with advanced pancreatic cancer. In each trial, the product was determined to be safe even when administered at high doses resulting in oleandrin plasma concentrations ranging from 2-8 ng/mL.

Malignant diseases

During the above-mentioned Phase II clinical trials, promising clinical observations were made, even though advanced pancreatic cancer is usually deemed untreatable. Results from these trials were encouraging and suggest the need for further clinical evaluation of this product against specific types of malignant disease.

PBI-05204 has been examined for relative activity in vitro against different patient derived tumor biopsy samples. These tumor biopsy samples are grown as tumor spheroids in culture and provide a facile way of determining which tumor types might be most responsive to treatment with this product. Analyses of patient derived tumor samples exposed to PBI-05204 are highly encouraging and suggest that many different types of tumors may be responsive to this drug.

PBI has developed a complementary technology whereby therapeutic responsiveness of tumor/cancer can be predicted with high accuracy. A tissue biopsy of the malignant tissue is subjected to an in vitro assay that determines the relative ratio of alpha-3 to alpha-1 isoforms of Na,K-ATPase.  The higher the relative expression of the alpha-3 isoform, the higher the likelihood of therapeutic responsiveness.

The combined use of the prognostic assay in conjunction with administration of PBI-05204 holds great promise in treating cancer.

Key findings: malignant diseases

The preclinical research and pharmacology studies conducted by Phoenix Biotechnology have to date shown the following with respect to efficacy against malignant diseases:

  • Extracts of Nerium oleander contain potent cardiac glycoside molecules such as oleandrin in addition to other compounds such as betulinic acid with known anticancer properties. READ MORE
  • Oleandrin suppresses activation of NF-κΒ, AP-1 and c-Jun NH2 terminal kinases all of which are important in driving malignant growth.
  • Oleandrin binds to subunits of an enzyme known as Na,K-ATPase. Human malignant cells express a specific ‘alpha’ subunit while normal cells do not and this is critical in explaining the selectivity of oleandrin with respect to tumor cell death. READ MORE
  • Oleandrin and other components of Nerium oleander readily cross the blood brain barrier and gain entry into brain tissue suggesting their usefulness against CNS malignancies. Ongoing research now has shown strong activity of PBI’s oleander extract against pediatric brain cancer known as glioblastoma multiforme. Samples of actual human brain tumors were grown in mouse brain tissue. Mice were then treated orally with PBI’s plant extract material. Given that there is currently no effective treatment for GBM the activity of PBI’s drug against this type of disease is highly encouraging.
  • Extracts of Nerium oleander produce cell death through a number of specific pathways including apoptosis and autophagy.

Clinical research: malignant diseases

  • PBI-05204 can be administered safely to patients with advanced cancers without exhibiting any evidence of cardiac toxicity.

  • In a Phase I trial of PBI-05204 conducted at the University of Texas M. D. Anderson Cancer Center (Houston, TX) it was observed that the drug produced a series of stable responses and partial remissions in heavily pretreated cancer patients which is encouraging at this step of development.

  • In recent Phase II trials of PBI-05204 against heavily pretreated pancreatic cancer patients, administration of PBI-05204 again was shown to be safe and, in addition, to produce some stable disease as well as partial responses.

  • Continued examination of the anticancer efficacy of PBI-05204 against tumor ‘spheroids’ obtained from tumor biopsies resected from cancer patients but which are grown in culture are also very promising. This constitutes an ex vivo “Phase II” series of studies pointing the direction for productive future clinical trials involving specific malignant diseases.

Neurodegenerative diseases and neuroprotection

We have reported in a series of publications work done in conjunction with Duke University that shows that oleandrin as well as PBI-05204 can provide significant neuroprotection to neural tissues damaged by oxygen and glucose deprivation as occurs in ischemic stroke. Critically, we have shown that the neuroprotective activity of PBI-05204 is maintained for a significant length of time after oxygen and glucose deprivation (OGD) which simulates stroke mediated neuronal injury.

The microphotograph above depicts healthy neurons depicted with a yellow fluorescent stain and the loss of healthy neurons following oxygen and glucose deprivation (i.e. stroke mediated ischemic injury), The prevention of OGD-mediated damage is depicted in the third photo panel whereby administration (oral) of PBI-05204 to mice resulted in protection of brain ischemic injury.

Research conducted at the Univ. Texas at San Antonio has shown that PBI-05204 reduces mRNA expression of pro-inflammatory cytokines and neuroinflammatory reactions within microglial cells. Administration of PBI-05204 to transgenic mice which develop βamyloid deposits within brain tissue has shown the ability of PBI’s drug to significantly reduce Aβ plaque formation which may indicate a potential use as a drug capable of treating or maybe even preventing Alzheimer’s disease.

Finally, we have shown directly that both oleandrin and the protective activity of PBI-05204 are blood brain barrier penetrant in a novel model for in vivo neuroprotection. Together, these findings suggest clinical potential for PBI-05204 in the treatment of ischemic stroke and prevention of associated neuronal death.

Viral diseases

We recently reported (PMID: 33262663) that many investigators have now published reports on the antiviral activity of oleandrin and extracts that contain this molecule. Our products PBI-05204, PBI-01220, PBI-01207, and PBI-06150 contain oleandrin and exhibit high antiviral activity even when dosed at extremely low levels, i.e. levels well below those required for anticancer activity.

Recent research has focused on elucidation of the underlying mechanisms responsible for such activity.  The findings have been dramatic. Oleandrin asserts both therapeutic and prophylactic antiviral activity by affecting intracellular and extracellular aspects of the immune response (unpublished data).

There are many types of viruses that affect human as well as animal health and wellbeing. A number of those viruses contain an ‘outer envelope structure’ or corona (aka crown) that surrounds and protects the viral genetic material. Proper formation of the envelope is required for progeny virus to retain their infectivity.

In 2013, PBI explored the ability of oleandrin to inhibit HIV (human immunodeficiency virus), an envelope virus. A major finding in that research (PMID: 23127567) was that progeny virus particles lost a significant ability to infect new human white blood cells. We determined that within the infected cell oleandrin interfered with formation of a proper viral ‘envelope’, thereby causing formation of defective progeny virions.

It has also been determined that oleandrin impacts the intracellular unfolded protein response that occurs in virally infected cells. GRP78 is a protein that plays a key role in the unfolded protein response that occurs during periods of cellular stress. At such times, the overexpression of GRP78 on the cell membrane mediates the vast amount of disordered proteins. Unfortunately, this makes GRP78 a tool for pathogens (bacterial, fungal and viral) to enter the cell and to initiate different cellular pathways leading to pathogenesis. For example, GRP78 is overexpressed on the membranes of virally infected cells and increases the aggressiveness of the disease. This has already been established for numerous viral infections including SARS-CoV-2. In 2017, Zhao reported the effect that some small molecules have upon the cell surface translocation of GRP78. The premise of that research was that reduction of the translocation might reduce the aggressiveness of diseases relying upon the presence of cell surface GRP78. Zhao found that oleandrin inhibits cell surface translocation of GRP78, thereby pointing to that as another aspect of oleandrin’s antiviral activity.

Based upon its effect on viral envelope formation and on inhibition of GRP78 translocation, PBI developed a hypothesis that oleandrin might be effective as both a prophylactic and therapeutic agent against this broad variety of viruses.  Indeed, that is proving to be true.  These novel mechanisms of antiviral activity opened a wide door to testing the ability of oleandrin and our products to possibly serve as effective antiviral agents against a potentially wide array of enveloped viruses.

Research has been conducted on a wide assortment of viruses including Ebolavirus, Marburgvirus, cytomegalovirus, Herpes viruses (several), HTLV-1, and most recently SARS-CoV-2, the virus that causes COVID-19. That research, conducted by U.S. Army, Univ. Texas MD Anderson Cancer Center, Johns Hopkins Medical Center, Southern Methodist University and University of Texas Medical Branch’s World Reference Center for Emerging Viruses and Arboviruses, has shown that oleandrin and extracts such as PBI-05204 significantly and potently inhibit the ability of these viruses to infect new cells, thus providing the immune system greater opportunity to fight the infection.

In addition to investigating viruses of relevance to human health, PBI has recently extended its investigations of the antiviral efficacy of PBI-05204 against viruses of importance to commercial animal production as well. For example, Bovine viral diarrhea virus (BVDV), bovine respiratory syncytial virus (BRSV), bovine coronavirus (BCV), porcine influenza virus (PIV), porcine reproductive and respiratory syndrome virus (PRRSV), porcine coronavirus (PCV), and equine encephalitis virus (EEV) threaten the productivity of these animals worldwide. Development of therapeutics that can control the spread of these viruses is an unmet need. Oleandrin and PBI-05204 have been found to exhibit high therapeutic and prophylactic activity against those viruses even at extremely low concentrations. The company is currently working toward commercialization of related veterinary products for livestock and companion animals.

References


Abstract

2011 ASCO Poster of Phase I trial of PBI-05204

Human tumor cell sensitivity to oleandrin is dependent on relative expression of Na+, K+ -ATPase subunits. Lin Y, Ho DH, Newman RA. J Exp Ther Oncol. 2010;8(4):271-86. PMID: 21222360

Oleandrin-mediated inhibition of human tumor cell proliferation: importance of Na,K-ATPase alpha subunits as drug targets. Yang P, Menter DG, Cartwright C, Chan D, Dixon S, Suraokar M, Mendoza G, Llansa N, Newman RA. Mol Cancer Ther. 2009 Aug;8(8):2319-28. PMID: 19671733

Determinants of human and mouse melanoma cell sensitivities to oleandrin. Lin Y, Dubinsky WP, Ho DH, Felix E, Newman RA. J Exp Ther Oncol. 2008;7(3):195-205. PMID: 19066128

Autophagic cell death of human pancreatic tumor cells mediated by oleandrin, a lipid-soluble cardiac glycoside. Newman RA, Kondo Y, Yokoyama T, Dixon S, Cartwright C, Chan D, Johansen M, Yang P. Integr Cancer Ther. 2007 Dec;6(4):354-64. PMID: 18048883

Oleandrin-mediated oxidative stress in human melanoma cells. Newman RA, Yang P, Hittelman WN, Lu T, Ho DH, Ni D, Chan D, Vijjeswarapu M, Cartwright C, Dixon S, Felix E, Addington C. J Exp Ther Oncol. 2006;5(3):167-81. PMID: 16528968

Murine pharmacokinetics and metabolism of oleandrin, a cytotoxic component of Nerium oleander. Ni D, Madden TL, Johansen M, Felix E, Ho DH, Newman RA. J Exp Ther Oncol. 2002 Sep-Oct;2(5):278-85. PMID: 12416031

Inhibition of export of fibroblast growth factor-2 (FGF-2) from the prostate cancer cell lines PC3 and DU145 by Anvirzel and its cardiac glycoside component, oleandrin. Smith JA, Madden T, Vijjeswarapu M, Newman RA. Biochem Pharmacol. 2001 Aug 15;62(4):469-72. PMID: 11448457

Composition and preliminary pharmacology studies with Anvirzel: An extract of Nerium oleander. Newman RA, Cisneros A, Felix E, et al. J. Herbal Pharmacotherapy 2001 1(3): 1-16.

Anvirzel, an extract of Nerium oleander, induces cell death in human but not murine cancer cells. Pathak S, Multani AS, Narayan S, Kumar V, Newman RA. Anticancer Drugs. 2000 Jul;11(6):455-63. PMID: 11001386

LC/MS/MS analyses of an oleander extract for cancer treatment. Wang X, Plomley JB, Newman RA, Cisneros A. Anal Chem. 2000 Aug 1;72(15):3547-52. PMID: 10952541

Oleandrin suppresses activation of nuclear transcription factor-kappaB, activator protein-1, and c-Jun NH2-terminal kinase. Manna SK, Sah NK, Newman RA, Cisneros A, Aggarwal BB. Cancer Res. 2000 Jul 15;60(14):3838-47. PMID: 10919658

Cardiac glycosides stimulate Ca2+ increases and apoptosis in androgen-independent, metastatic human prostate adenocarcinoma cells. McConkey DJ, Lin Y, Nutt LK, Ozel HZ, Newman RA. Cancer Res. 2000 Jul 15;60(14):3807-12. PMID: 10919654

A hydroalcoholic extract from the leaves of Nerium oleander inhibits glycolysis and induces selective killing of lung cancer cells. Calderón-Montaño JM, Burgos-Morón E, Orta ML, Mateos S, López-Lázaro M. Planta Med. 2013 Aug;79(12):1017-23. PMID: 23824549