Signpath Pharma is a development stage biotechnology company founded in 2006. Its lead compound is 99.2% pure synthesized curcumin (diferuloylmethane). Curcumin has an extensive and long history in humans as a mixture of naturally occurring curcuminoids in extracts of the root of the Curcuma longa plant.
Traditional use of curcumin has been restricted to topical skin and gastrointestinal conditions because of negligible absorption when given orally. To extend its clinical use Signpath is developing three different intravenous nanoparticle-sized formulations; liposomal, polymeric, and PLGA. Proof of efficacy of these formulations against human tumor xenografts in mice has been established. Following intravenous injection of each formulation, we observed transport across the blood brain barrier in mice, rats, and localization in the hippocampus, brainstem and the striatum.
Signpath Pharma Announces IND Approval of Liposomal Curcumin for Clinical Trials of Drug Resistant Non-Small Cell Lung Cancer
June 3, 2014– Signpath Pharma, Inc. (SGTH), a private, fully-reporting and non-trading development stage biotechnology company developing novel therapeutics based on its use of pure synthesized curcumin formulated (LipocurcTM) to target systemic cancer cells or tumor-initiating cells, today announced that it has received allowance to proceed with clinical trials in the United States.
Successive patients with refractory metastatic or recurrent non-small cell lung cancers will receive ascending doses of LipocurcTM intravenous infusions once weekly for 8 weeks (one cycle) in order to determine the optimal safe dosage schedule. The trial plans to enroll 20-24 patients with the same cancer, and secondarily observe objective tumor response rates, progression free survival, and overall survival. The analysis will include biomarkers, and the best overall improvement between pre-treatment and up to eight weekly treatments to determine optimal safe dosage. Additionally, the mean number of evaluable patients who exhibit overall tumor shrinkage (i.e., the disease control rate) will be determined. SignPath Pharma will also record partial responses, stable disease, and progressive disease by RECIST criteria. These data will allow the selection of dosage and clinical indications for phase 2 and phase 3 clinical trials.
A separate indication, progressive Parkinson’s disease is anticipated to be submitted in the United States 3Q 2014. The proposed clinical study will enroll 9-12 patients in order to determine the optimal safe dosage schedule, and will be followed by a phase 2 and phase 3 clinical trial. Dr. Lawrence Helson, Chief Executive Officer and President at SignPath Pharma, Inc., noted, “As our first pharmaceutical candidate, we believe this is a very important clinical step in the further development of liposomal curcumin to treat recurrent cancers and neurologic disorders.”
Publications and Posters
New Publication added October, 2014
Liposomes Ameliorate Crizotinib- and Nilotinib-induced Inhibition of the Cardiac IKr Channel and QTc Prolongation.
Shopp GM, Helson L, Bouchard A, Salvail D, Majeed M.
Crizotinib (Xalkori®) and nilotinib (Tasigna®) are tyrosine kinase inhibitors approved for the treatment of non-small cell lung cancer and chronic myeloid leukemia, respectively. Both have been shown to result in electrocardiogram rate-corrected Q-wave T-wave interval (QTc) prolongation in humans and animals. Liposomes have been shown to ameliorate drug-induced effects on the cardiac-delayed rectifier K(+) current (IKr, KV11.1), coded by the human ether-a-go-go-related gene (hERG). This study was undertaken to determine if liposomes would also decrease the effect of crizotinib and nilotinib on the IKr channel. Crizotinib and nilotinib were tested in an in vitro IKr assay using human embryonic kidney (HEK) 293 cells stably transfected with the hERG. Dose-responses were determined and the 50% inhibitory concentrations (IC50s) were calculated. When the HEK 293 cells were treated with crizotinib or nilotinib that were mixed with liposomes, there was a significant decrease in the IKr channel inhibitory effects of these two drugs. When isolated, rabbit hearts were exposed to crizotinib or nilotinib, there were significant increases in QTc prolongation. Mixing either of the drugs with liposomes ameliorated the effects of the drugs. Rabbits dosed intravenously (IV) with crizotinib or nilotinib showed QTc prolongation. When liposomes were injected prior to crizotinib or nilotinib, the liposomes decreased the effects on the QTc interval. The use of liposomal encapsulated QT-prolongation agents, or giving liposomes in combination with drugs, may decrease their cardiac liability.
Report: NCL, Characterization of Nanocurcumin
Sept 21 2013
PHASE 1b CANCER THERAPY IN AUSTRIA
Following completion of a Phase 1a clinical trial in normal subjects in Vienna,Signpath Pharma has initiated treatment of the first patient (with liver cancer) in a Phase 1b trial (SPP1002) today at the Paracelsus Medical University, Salzburg Austria. Successive patients with refractory metastatic or recurrent cancers will receive ascending doses of LipocurcTM as 24 hour intravenous infusions once weekly for 8 weeks(one cycle). The trial plans to enroll 20-24 patients with the same or other cancers in Salzburg and Graz in order to determine the optimal safe dosage schedule, and secondarily objective tumor response rates, progression free survival, and overall survival. The analysis will include biomarkers of each type of cancer, and the best overall improvement between pre-treatment and up to eight weekly treatments At the optimum safe dosage the mean number of evaluable patients who exhibit overall tumor shrinkage, i.e., the disease control rate will be determined. Additionally, Signpath Pharma will record partial responses, stable disease and progressive disease by RECIST criteria. These data will allow the selection of dosage and clinical indications to take into phase2 and phase 3 trials.
August 6th, 2013
LUNG CANCER, Signpath Pharma Plans in USA
Signpath Pharma has been approved a Phase 1b trial (SPP1003) in patients with non-small cell lung cancer (NSCLC) using 4 hour intravenous infusions weekly x 8 of the current supply of LipocurcTM A new batch of Lipocurc to cover both US and EU clinical 1b trials is undergoing analytical evaluation prior to release . The trial will enroll 20-24 patients with metastatic or recurrent NSCLC. The primary endpoint of the trial is to determine the optimal pharmacodynamics dosage and secondarily, objective tumor response rates, progression free survival, and overall survival. The analysis will identify percent best overall changes between pre-treatment and up to eight weekly treatments (one cycle). At the optimum pharmacodynamics dosage the mean number of evaluable patients who exhibit overall tumor shrinkage, i.e., the disease control rate will be determined. Additionally, Signpath Pharma will record partial responses, stable disease and progressive disease by RECIST criteria for the selection of dosage to take into phase 2 and phase 3 trials.
Lung cancer is responsible for 3 million deaths worldwide annually and is the number-one worldwide cause of cancer-related mortality. In the United States alone, the annual number of deaths due to lung cancer was 160,000 in 2012, with 225,000 new cases. After 5 years 15% of all patients diagnosed are alive, while in those with distant metastases less than 4% are alive.
The most common histologic type of lung cancer is non-small-cell lung cancer (NSCLC). It is comprised of squamous cell carcinoma, adenocarcinoma and large cell carcinoma, and accounts for 85% of all primary tumors.2 Twenty five percent of NSCLC patients are diagnosed in advanced stages where the standard of care is palliative chemotherapy combinations, or radiotherapy with or without chemotherapy. In the presence of numerous drugs and drug combinations approved for therapy, or under investigation the beneficial results remain limited, and are associated with serious adverse reactions. Eighty eight percent of the general population of patients with lung cancer are aged 65 or older, however, in the United States only 30% of elderly Medicare patients are treated with systemic chemotherapy out of concern for toxicity indicating there is an unmet need for a tolerable and safe systemic drug with significant anticancer activity.3 In addition to India, China, and Japan contain high risk for lung cancer populations because these countries have a growing older population, a high smoking prevalence, and few smoking bans.4,5.
Curcumin (diferuloylmethane) extracted from Curcuma longa Linn. root appears to be a reasonable candidate for NSCLC based upon a long history of use for oral or topical medicinal applications, and recent experimental observations in the pre-clinical setting. However, the extract has negligible oral bioavailability and aqueous insolubility at physiologic pH which confer major obstacle to its use for systemic disease such as lung cancer. To circumvent this, Signpath Pharma, Inc has collaborated with Sabinsa Inc, to synthesize 99.2% pure curcumin, and with Polymun Scientific GmbH, to manufacture a liposomal formulation capable of intravenous, or subcutaneous administration. In pre-clinical drug tissue distribution studies of liposomal curcumin in dogs following an eight-hour infusion, a preponderance of drug was distributed in lung tissues suggesting lung diseases would be appropriate indications.6 Subsequently, as proof of concept, growth inhibition of human lung tumor A543 xenografts by subcutaneous liposomal curcumin were demonstrated.7 To further support the application of liposomal curcumin to patients with advanced NSCLC, here is presented a literature review of Curcuma longa extract’s interactions with intracellular molecular targets having key roles in lung tumorigenesis, and progression of tumors among the cellular targets. These include KRAS mutations, EML4-ALK rearrangements and epidermal growth factor receptor (EGFR) over-expression in up to 80 % of tumors. All of which are noteworthy for their association with specific resistance to and or sensitivity to conventional chemotherapeutic agents. There are significant demographic differences in the incidence of EGFR mutations in NSCLC patients. A high (60%) incidence is reported in Asian populations compared to10-20% observed in Western patients. The mechanism of action of curcumin suggests it may be effective in patients with EGFR mutated tumors. By attenuating transcription factors Egr-1 and Sp which bind to the EGFR gene promoter, curcumin inhibits EGFR mRNA expression. Additionally, curcumin suppresses NSCLC proliferation-associated proteins: Akt, Cyclin D1, PCNA, and as a consequence of down-regulation of anti-apoptotic Bcl-2 protein via proteosomal degradation, curcumin induces programmed cell death. Curcumin also down regulates c-Met which in EML4-ALK rearranged lung tumors, is commonly activated, overexpressed, and mutated, inducing angiogenesis and invasive growth. Curcumin interactions with ErbB2, ERRC1, DNA methylation, PARP, PPAR gamma, notch signaling, Wif-1, OCT4, and BIRC5 lead to inhibition of cancer-stem-cell proliferation which may account for tumor recurrence following incomplete responses to conventional chemotherapy.8-12 Epigenetic processing of microRNAs by curcumin may be associated with anti-tumor effects and improved prognosis of NSCLC patients. By regulating the expression of miRNAs: hsa miR20a, miR21, miR22, miR34c, miR186, miR212 and LET7, curcumin may mitigate tumor cell survival.
These observations suggest either the use of curcumin alone in phase2 NSCLC clinical trials, or in combination with approved anti-cancer drugs in phase3 clinical trials where it may potentiate antitumor effects. In conclusion, there are numerous experimental data reporting multiple curcumin- responsive intracellular targets in human NSCLC. These are complemented by demographic data of a relatively lower incidence of NSCLC in India which could be due to the preventative influence of dietary derived curcumin and, or its active metabolites on initiation of NSCLC.13 While not addressing specific therapeutic potential, intracellular molecular target interactions and demographic data from Curcuma longa extract suggest a rationale for clinical trials of parenteral liposomal curcumin in patients with advanced NSCLC.
July 17th, 2013
CANCER, Signpath Pharma Plans in Europe
Signpath Pharma has been approved in Austria to conduct a Phase 1b trial (SPP1002) in patients with cancer using 24 hour intravenous infusions weekly x 8 of LipocurcTM The trial will enroll 20-24 patients with metastatic or recurrent cancer. The primary endpoint of the trial is to determine the optimal pharmacodynamics dosage and secondarily, objective tumor response rates, progression free survival, and overall survival. The analysis will identify, biomarkers of disease, percent best overall changes between pre-treatment and up to eight weekly treatments (one cycle). At the optimum pharmacodynamics dosage the mean number of evaluable patients who exhibit overall tumor shrinkage, i.e., the disease control rate will be determined. Additionally, SignPath will record partial responses, stable disease and progressive disease by RECIST criteria for the selection of dosage to take into phase2 and phase 3 trials.