Phase III Trial of the Safety and Efficacy of Eflornithine Combined With Sulindac Compared to Eflornithine, Sulindac as Single Agents in Patients With Familial Adenomatous Polyposis

The purpose of this randomized, double-blind, Phase III trial is to determine if the combination of eflornithine plus sulindac is superior to sulindac or eflornithine as single agents in delaying time to the first occurrence of any FAP-related event. This includes: 1) FAP related disease progression indicating the need for excisional intervention involving the colon, rectum, pouch, duodenum and/or 2) clinically important events which includes progression to more advanced duodenal polyposis, cancer or death.

开始日期2013-10-01

申办/合作机构

Cancer Prevention Pharmaceuticals, Inc.

NCT01349881 / Active, not recruiting临床3期IIT

A Double Blind Placebo-Controlled Trial of Eflornithine and Sulindac to Prevent Recurrence of High Risk Adenomas and Second Primary Colorectal Cancers in Patients With Stage 0-III Colon or Rectal Cancer, Phase III - Preventing Adenomas of the Colon With Eflornithine and Sulindac (PACES)

The investigators hypothesize that the combination of eflornithine and sulindac will be effective in reducing a three-year event rate of adenomas and second primary colorectal cancers in patients previously treated for Stages 0 through III colon or rectal cancer.

开始日期2013-08-23

申办/合作机构

SWOG

[+2]

NCT01245816 / Withdrawn临床3期

A Randomized Phase III Trial of Low Dose Sulindac Combined With Eflornithine in Patients With Familial Adenomatous Polyposis (FAP)

The purpose of this phase III study is to evaluate the safety and efficacy of the combination of eflornithine and sulindac compared to single agent sulindac or eflornithine in reducing the number of polyps in patients with familial adenomatous polyposis (FAP).

开始日期2011-03-01

申办/合作机构

Cancer Prevention Pharmaceuticals, Inc.

100 项与依氟鸟氨酸/舒林酸相关的临床结果

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100 项与依氟鸟氨酸/舒林酸相关的转化医学

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100 项与依氟鸟氨酸/舒林酸相关的专利（医药）

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项与依氟鸟氨酸/舒林酸相关的文献（医药）

2016-06-01·Leukemia1区 · 医学

Axl activates fibroblast growth factor receptor pathway to potentiate survival signals in B-cell chronic lymphocytic leukemia cells

1区 · 医学

Letter

作者: Warner, S L ; Bearss, D ; Kay, N E ; Ghosh, A K ; Boysen, J ; Sinha, S ; Nelson, M

The fibroblast growth factor (FGF) family and their four receptors, FGFR1/2/3/4, mediate multiple physiol. processes, including cell migration, proliferation, survival and differentiation.FGFRs are expressed on nearly every cell type of hematopoietic origin, and the deregulation of FGFR gene expression and/or gene mutation has been found in hematol. malignancies.¹ Given this, we and others have detected that CLL B cells spontaneously produce the basicFGF (bFGF) and CLL plasma contain elevated levels of bFGF.² However, the precise role of FGF/FGFR signaling pathway in CLL B-cell survival and apoptotic resistance remains undefined.To explore whether bFGF has a role in CLL B-cell survival, we first examined the expression profile of FGFR1/R2/R3/R4 in CLL B cells by western blot anal. using specific antibodies.We find that CLL B cells overexpress FGFR3 significantly (Figure 1a).Although a low-level expression of FGFR1/R2/R4 was noted in CLL B cells, these levels were no significantly different than those detected in normal B cells (Supplementary Figure 1A).It appears that CLL B cells predominantly express two splice variants of FGFR3 with mol. weights of ∼100/125 kDa in western blots.Thus, the banding pattern of FGFR3 as shown in Figure 1a was further confirmed using a different antibody to FGFR3 (Supplementary Figure 1B).Although several splice variants are known to exist for each member of the FGFR family,³ the mechanism of their regulation(s) is largely undefined.To validate our findings that CLL B cells primarily express FGFR3, individual FGFRs were immunoprecipitated from equal amount of lysates from CLL B cells or normal B cells followed by western blot analyses to detect FGFR1/R2/R3/R4.As expected, we detected significantly elevated levels of FGFR3 in CLL B cells as compared with normal B cells (Figure 1d).Although we were able to detect FGFR1 (Figure 1b), FGFR2 (Figure 1c) and FGFR4 (Figure 1e) in CLL B cells, the level of expression was comparable with those in normal B cells.Furthermore, significantly higher levels of FGFR3 were also detected on CLL B cells vs normal B cells in flow cytometric anal. (Figures 1f and g).Finally, FGFR3 transcript was detected in CLL B cells by semiquant. reverse transcriptase-PCR (Supplementary Figure 2) using specific primers (see Supplementary Methods) and confirmed by sequencing the PCR products.Of interest, we also found that exons-8 and -9 of FGFR3 are largely absent in CLL B cells as reverse primers designed for exon-8 or -9 could not amplify the transcript using the forward primer from exon-6, whereas the reverse primer for exon-11 and forward primer at exon-6 amplified FGFR3 transcript (Supplementary Figure 2).Deletions of FGFR3 exons-8-10 have been reported in multiple human malignancies including breast, squamous and osteosarcoma.⁴ However, an in-depth study is needed to define more clearly the nature of FGFR3 regulation in CLL B cells.In total, our results suggest that CLL B cells overexpress primarily FGFR3.Phosphorylation at tyrosine residues 653 and 654 (Y653/654) in the kinase domain is important for catalytic activity of the activated FGFRs and its downstream signaling.⁵ To that end we detected that FGFRs in CLL B cells remain constitutively phosphorylated at Y653/654 tyrosine residues (Figure 1h); indicating that the FGFR signaling pathway is catalytically active.Of interest, we have also detected that CLL B cells co-express both P-FGFR and P-Axl (Figure 1i), suggesting that there may exist a possible functional link between these two RTKs.However, as CLL B cells overexpress FGFR3, we hypothesized that FGFR3 remains as the constitutively active FGFR.Indeed FGFR3 displays elevated levels of phosphorylation at Y653/654 residues (Figure 1j).Further anal. demonstrates that FGFR3 in CLL B cells remains as a highly phosphorylated RTK (Figure 1k).Together, these findings suggest that (i) FGFR signaling is a constitutively active pathway in CLL B cells and that (ii), the heavily phosphorylated FGFR3 likely drives the FGFR signal in CLL B cells.To define the mechanism of constitutive phosphorylation on FGFRs, CLL B cells were treated with recombinant-bFGF or a bFGF-neutralizing antibody and analyzed the cells for alteration of P-FGFR levels.We found that neutralizing antibody treatment or recombinant-bFGF addition to CLL B-cell culture could not alter the phosphorylation levels on FGFRs from the basal level (Supplementary Figure 3); suggesting that FGFR phosphorylation in CLL B cells is likely independent of any autocrine/paracrine loop.Of interest, a recent report suggests that Axl, which remains as a highly active RTK in CLL B cells,^6, ⁷ can also cross-talk with the epidermal growth factor receptor and exists in a complex with the latter RTK in cetuximab (targets epidermal growth factor receptor)-resistant non-small cell lung cancer cells.⁸ These information and our findings that CLL B cells co-express P-FGFR (Figure 1h) and P-Axl (Figure 1i) prompted us to investigate whether Axl is also involved in a cross-talk with the FGFR signaling in CLL B cells.To address this, we first inhibited Axl phosphorylation in CLL B cells using a high-affinity Axl inhibitor TP-0903⁹ and determined P-Axl/P-FGFR levels.Results demonstrate that TP-0903-mediated inhibition of P-Axl in CLL B cells (Figure 1l) resulted in reduced levels of P-FGFR (Figure 1m).On the other hand, treatment of CLL B cells with the FGFR-inhibitor TKI-258¹⁰ could not alter Axl phosphorylation (Figure 1n, bottom panel), whereas the reduction of P-FGFR levels was evident (upper panel), suggesting that Axl is likely an upstream regulator of the FGFR signaling.Next, to rule out the possibility that TP-0903-mediated inhibition of P-FGFR was not an off-target effect, Axl in CLL B cells was targeted using an Axl-specific siRNA.Indeed, a partial depletion of Axl in CLL B cells resulted into reduction of P-FGFR levels (Figure 1o, Supplementary Figure 4).As primary CLL B cells are difficult to transfect, we chose a breast cancer cell line MDA-MB-231 reported to express both Axl and FGFR1/3^11, ¹² as a model to further confirm Axl/FGFR functional relationship.As expected, siRNA-mediated depletion of Axl in MDA-MB-231 cells significantly reduced P-FGFR level (Figure 1p), corroborating well with the findings in primary CLL B cells described above (Figures 1l, m and o).Furthermore, induced activation of Axl in MDA-MB-231 cells by Gas6-ligation resulted into increased phosphorylation on FGFR (Figure 1q).Interestingly, Gas6-ligation did not alter significantly the P-Axl levels in CLL B cells (Supplementary Figure 5A), whereas BCR stimulation augmented Axl phosphorylation in CLL B cells expressing low basal level of P-Axl (Supplementary Figure 5B).However, the mechanism of Axl activation by BCR signal remains unknown.Next, we wished to interrogate whether Axl forms a complex with FGFR3, which we have found predominantly expressed and heavily phosphorylated FGFR in CLL B cells (Figures 1a, d, j and k).Using IP/western blot techniques we detected that Axl and FGFR3 indeed form a complex in CLL B cells (Figures 2A and B).To confirm the specificity, Axl was deplted in MDA-MB-231 cells using an Axl-specific siRNA to detect Axl/FGFR3 associationWe did find co-precipitation of FGFR3 in the immune complex of Axl obtained from the control cells; however, the level of co-precipitated FGFR3 was reduced significantly in the immune complex upon depletion of Axl in MDA-MB-231 cells (Figure 2C); whereas it appears that complex formation between Axl and FGFR3 may not depend on phosphorylation status of Axl (Supplementary Figure 6).We also found that Axl and FGFR3 co-localize in CLL B cells (Figure 2D) where a punctate plasma membrane distribution of FGFR3 (red) and Axl (green) was observedFurther anal. of images using Image-pro premier software suggests that Axl and FGFR3 were highly co-localized in CLL B cells with an average overlap coefficient of 0.83 (Figure 2E).Together, these findings suggest that Axl forms a complex with FGFR3, co-localize in the cells and regulates FGFR signaling pathway in human malignant cells.Depending on cellular context, several pathways are activated by FGFRs including the p38 MAPK, Jun N-terminal kinase, AKT, phospholipase Cγ and Stat pathways.However, the Ras-MAPK and Stat are the major pathways mediating the oncogenic effects of FGFR3.¹³ Given this, a TKI-258-mediated inhibition of the constitutively active FGFR signal induced significant levels of apoptosis in CLL B cells from previously untreated CLL patients (n=12; Supplementary Table 1) in a time- and dose-dependent manner (Figure 2F).Relevant to this, anal. of the TKI-258 treated CLL B-cell lysates used in Figure 1n demonstrates that inhibition of P-FGFR in CLL B cells reduces phosphorylation of c-Src, Stat3 and Erk1/2, but not of AKT (Figure 2G), and expression of Mcl-1 but not XIAP or Bcl-2 (Figure 2G).In addition, a partial depletion of FGFR3 also reduces phosphorylation on Erk1/2, Stat3, c-Src and expression of Mcl-1 in CLL B cells (Figure 2H), thus ruled out any off-target effect of TKI-258.However, CLL bone marrow stromal cells showed a significant level of protection of the leukemic B cells from TKI-258-induced apoptosis (Figure 2I).Recently, the overexpression of FGFR3 has been reported in Waldenstrom macroglobulinemia and that inhibition of FGFR3 induces apoptosis in Waldenstrom macroglobulinemia cells and overcomes stromal protection.¹⁴ Of interest, we also found that while in vitro combined treatment of CLL B cells with TKI-258 and ibrutinib produced synergistic effects in five of seven cases (Figure 2J), combination of TKI-258 with TP-0903 was mostly antagonistic (Figure 2K) in augmenting apoptosis levels.Collectively, these findings suggest that FGFR signaling is constitutive and may have an important role in regulating CLL B-cell survival.In summary, we report that CLL B cells express high levels of FGFR3, which remains as a constitutively active RTK.Through a series of experiments, we, for the first time, report that Axl regulates FGFR signaling via complex formation with FGFR3.Cross-talk between RTKs is widespread; for example, ErbB3 robustly couples to the PI3-kinase pathway and it is used by epidermal growth factor receptor and ErbB2 as well as other RTKs to activate this pathway.¹⁵ Most recently, Axl was found to activate epidermal growth factor receptor in cetuximab-resistant clones via complex formation, previously reported in triple-neg. breast cancer cells.⁸ We found that FGFR signaling is a downstream target of Axl and a novel addition to the growing list of RTKs in the Axl signaling network.Thus, targeting Axl signaling axis either alone or in combination with other signal inhibitors warrants further attention as a maneuver to more effectively induce apoptosis in CLL B cells, particularly in the relapsed/refractory setting.

1966-09-01·Toxicology and applied pharmacology3区 · 医学

Excretion of certain polyethylene glycol ether adducts of nonylphenol by the rat

3区 · 医学

Article

作者: L.J. Sullivan ; Jane M. Eldridge ; J.B. Knaak

A nonylphenol polyethylene glycol ether (Tergitol TP-9) containing an average of 9 moles of ethylene oxide per mole of nonylphenol was sep. labeled with ethylene-1,2-¹⁴C oxide and nonylphenol-¹⁴C (uniformly labeled aromatic ring) and characterized on thin-layer chromatoplates.In 7 days, the rat excreted 39% of an oral dose (67 mg./kg.) of ethylene oxide-labeled TP-9 in urine, 52% in feces, and 1.2% as ¹⁴CO₂, while over the same time interval the rat excreted 20% of the nonylphenol-labeled TP-9 in urine, 78% in feces, and none as ¹⁴CO₂.Nonylphenol-¹⁴C per se was excreted in a similar manner.The 7-, 10-, 12-, and 15-mole adducts of nonylphenol were isolated by column chromatography from ethylene oxide-labeled TP-9 and administered individually to rats.The 12- and 15-mole adducts were excreted to a greater extent in the feces than were the 7- and 10-mole adducts, while the reverse situation occurred in urine.Free TP-9 per se was found in urine to an extent of 1.0% of the dose.The 14- and 15-mole adducts were present in the highest concentrationIon exchange chromatographic studies of the urinary metabolites of ethylene-¹⁴C oxide TP-9 and nonylphenol-¹⁴C TP-9 indicate that the principal metabolites of TP-9 are the mono- and dicarboxylic acids of polyethylene glycol and the glucuronic acid conjugates of nonylphenol.

项与依氟鸟氨酸/舒林酸相关的新闻（医药）

2024-06-10

·GlobeNewswire-Health Care

Panbela Announces Oral Presentation at Digestive Disease Week (DDW):

Evaluation of the Safety and Efficacy of Eflornithine (Difluoromethylornithine, DFMO) in Patients with Gastric Premalignant Conditions in the High Incidence Areas of Latin AmericanMINNEAPOLIS, June 10, 2024 (GLOBE NEWSWIRE) -- Panbela Therapeutics, Inc. (OTCQB: PBLA), a clinical stage biopharmaceutical company developing disruptive therapeutics for the treatment of patients with cancer, today announces an oral presentation at the Digestive Disease Week (DDW) conference, which was held May 18-21, 2024. The work reflects the Company’s on-going collaboration with Vanderbilt University Medical Center. “Gastric adenocarcinoma is the fifth leading global cause of cancer mortality and leading infection-associated cancer. In the U.S., gastric adenocarcinoma represents a major cancer disparity, with incidence rates 2-3 times or more greater in all non-white populations. Patients with gastric premalignant conditions, intestinal metaplasia and atrophic gastritis, represent a high unmet need for chemopreventative approaches,” said Dr. Douglas R. Morgan, UAB Division of Gastroenterology and Hepatology, The University of Alabama at Birmingham, AL and Dr. Keith T. Wilson, Division of Gastroenterology and Hepatology, Vanderbilt University Medical Center, Nashville, TN. A National Cancer Institute funded, Phase IIa placebo-controlled Randomized Clinical Trial of eflornithine in patients with gastric premalignant conditions was conducted between September 2016 and December 2022 in rural Honduras and Puerto Rico and was an oral presentation at DDW by Dr. Wilson on May 21, 2024. H. pylori (Hp) positive and negative subjects ages 30-60 were treated with eflornithine or placebo for 18 months, with endoscopy at baseline, and 6, 18, and 24 months. At baseline, 80% of subjects were Hp positive, and 46% and 54% had global histology of atrophy and intestinal metaplasia, respectively. A total of 78, 69, and 55 patients reached the 6-month primary outcome, the end-of-treatment 18 month (EoT), and the end-of-study (EoS) 24 month time points, respectively. Eflornithine treatment was safe and well-tolerated. Overall grade 1-2 adverse events (AEs) were greater in the placebo group (108 vs 81) and grade 3 AEs were also higher in the placebo (3 vs 1). The results of the study demonstrated that eflornithine reduced DNA damage long-term in patients after completing treatment, as measured by pH2AX immunostaining, a DNA damage marker was significantly lower at the 24 month vs. 18 month time point in the eflornithine group and unchanged in the placebo group. “Panbela’s focus on the polyamine pathway has implications for both the prevention and treatment of cancer. It is established that pro-tumorigenic and cancer cells are highly dependent on polyamines for survival and the ability of eflornithine to reduce gastric epithelial cell DNA damage may have implications for prevention in those patients at high risk for developing infection-associated gastric cancer,” said Jennifer K. Simpson, PhD, MSN, CRNP, President & Chief Executive Officer of Panbela. Details of the presentation are as follows: Oral Presentation Title: Evaluation of the Safety and Efficacy of Eflornithine (Difluoromethylornithine, DFMO) in Patients with Gastric Premalignant Conditions in the High Incidence Areas of Latin America Session Type: Research Forum Session Title: Chemoprevention for GI Cancers: Drugs and/or Bugs Session Date and Time: May 21, 2024 from 2:00 PM to 3:30 PM EDT (UTC –4) Additional meeting information can be found on the DDW website: https://eppro02.ativ.me/src/EventPilot/php/express/web/planner.php?id=DDWLITE24 The abstract will also be available on the Company's website at https://panbela.com/events-presentations/ once the information has been released by DDW. About Panbela’s PipelineThe pipeline consists of assets currently in clinical trials with an initial focus on familial adenomatous polyposis (FAP), first-line metastatic pancreatic cancer, neoadjuvant pancreatic cancer, colorectal cancer prevention and ovarian cancer. The combined development programs have a steady cadence of anticipated catalysts with programs ranging from pre-clinical to registration studies. Ivospemin (SBP-101)Ivospemin is a proprietary polyamine analogue designed to induce polyamine metabolic inhibition (PMI) by exploiting an observed high affinity of the compound for pancreatic ductal adenocarcinoma and other tumors. It has shown signals of tumor growth inhibition in clinical studies of metastatic pancreatic cancer patients, demonstrating a median overall survival (OS) of 14.6 months and an objective response rate (ORR) of 48%, both exceeding what is typical for the standard of care of gemcitabine + nab-paclitaxel suggesting potential complementary activity with the existing FDA-approved standard chemotherapy regimen. In data evaluated from clinical studies to date, ivospemin has not shown exacerbation of bone marrow suppression and peripheral neuropathy, which can be chemotherapy-related adverse events. Serious visual adverse events have been evaluated and patients with a history of retinopathy or at risk of retinal detachment will be excluded from future SBP-101 studies. The safety data and PMI profile observed in the previous Panbela-sponsored clinical trials provide support for continued evaluation of ivospemin in the ASPIRE trial. Flynpovi ™Flynpovi is a combination of CPP-1X (eflornithine) and sulindac with a dual mechanism inhibiting polyamine synthesis and increasing polyamine export and catabolism. In a Phase III clinical trial in patients with sporadic large bowel polyps, the combination prevented > 90% subsequent pre-cancerous sporadic adenomas versus placebo. Focusing on FAP patients with lower gastrointestinal tract anatomy in the recent Phase III trial comparing Flynpovi to single agent eflornithine and single agent sulindac, FAP patients with lower GI anatomy (patients with an intact colon, retained rectum or surgical pouch), showed statistically significant benefit compared to both single agents (p≤0.02) in delaying surgical events in the lower GI for up to four years. The safety profile for Flynpovi did not significantly differ from the single agents and supports the continued evaluation of Flynpovi for FAP. CPP-1XCPP-1X (eflornithine) is being developed as a single agent tablet or high dose powder sachet for several indications including prevention of gastric cancer, treatment of neuroblastoma and recent onset Type 1 diabetes. Preclinical studies as well as Phase I or Phase II investigator-initiated trials suggest that CPP-1X treatment may be well-tolerated and has potential activity. About PanbelaPanbela Therapeutics, Inc. is a clinical-stage biopharmaceutical company developing disruptive therapeutics for patients with urgent unmet medical needs. Panbela’s lead assets are Ivospemin (SBP-101) and Flynpovi. Further information can be found at www.panbela.com. Panbela’s common stock is eligible for quotation on the OTCQB under the symbol “PBLA”. Cautionary Statement Regarding Forward-Looking StatementsThis press release contains “forward-looking statements,” including within the meaning of the Private Securities Litigation Reform Act of 1995. Forward-looking statements can be identified by words such as: “anticipate,” “believe,” “can,” “design,” “expect,” “focus,” “intend,” “looking forward,” “may,” “plan,” “positioned,” “potential,” and “will.” All statements other than statements of historical fact are statements that should be deemed forward-looking statements. Forward-looking statements are neither historical facts nor assurances of future performance. Instead, they are based only on our current beliefs, expectations, and assumptions regarding the future of our business, future plans and strategies, projections, anticipated events and trends, the economy and other future conditions. Because forward-looking statements relate to the future, they are subject to inherent uncertainties, risks and changes in circumstances that are difficult to predict and many of which are outside of our control. Our actual results and financial condition may differ materially and adversely from the forward-looking statements. Therefore, you should not rely on any of these forward-looking statements. Important factors that could cause our actual results and financial condition to differ materially from those indicated in the forward-looking statements include, among others, the following: (i) our ability to obtain additional funding to execute our business and clinical development plans; (ii) progress and success of our clinical development program; (iii) the impact of the current COVID-19 pandemic on our ability to conduct our clinical trials; (iv) our ability to demonstrate the safety and effectiveness of our product candidates: ivospemin (SBP-101) and eflornithine (CPP-1X); (v) our reliance on a third party for the execution of the registration trial for our product candidate Flynpovi ; (vi) our ability to obtain regulatory approvals for our product candidates, SBP-101 and CPP-1X in the United States, the European Union or other international markets; (vii) the market acceptance and level of future sales of our product candidates, SBP-101 and CPP-1X; (viii) the cost and delays in product development that may result from changes in regulatory oversight applicable to our product candidates, SBP-101 and CPP-1X; (ix) the rate of progress in establishing reimbursement arrangements with third-party payors; (x) the effect of competing technological and market developments; (xi) the costs involved in filing and prosecuting patent applications and enforcing or defending patent claims; (xii) our ability to obtain a listing of our common stock on a national securities exchange; and (xii) such other factors as discussed in Part I, Item 1A under the caption “Risk Factors” in our most recent Annual Report on Form 10-K, any additional risks presented in our Quarterly Reports on Form 10-Q and our Current Reports on Form 8-K. Any forward-looking statement made by us in this press release is based on information currently available to us and speaks only as of the date on which it is made. We undertake no obligation to publicly update any forward-looking statement or reasons why actual results would differ from those anticipated in any such forward-looking statement, whether written or oral, whether as a result of new information, future developments or otherwise.

临床结果临床2期临床3期

2024-05-15

·BioSpace

Panbela Provides Business Update and Reports Q1 2024 Financial Results

MINNEAPOLIS, May 15, 2024 (GLOBE NEWSWIRE) -- Panbela Therapeutics Inc. (OTCQB: PBLA), a clinical stage company developing disruptive therapeutics for the treatment of patients with urgent unmet medical needs, today provides a business update and reports financial results for the quarter ended March 31, 2024. As previously announced, management is hosting earnings call today at 4:30 p.m. ET. Q1 2024 and recent Highlights: Clinical Announced revised timing for the interim data analysis for its ongoing ASPIRE trial, evaluating ivospemin (SBP-101) in combination with standard-of-care for metastatic pancreatic ductal adenocarcinoma (mPDAC). The analysis is now expected in Q1 2025 due to a lower-than-anticipated event rate, which suggests high potential for improved survival outcomes for patients in the trial. Poster presentation of Ivospemin (SBP-101) at AACR highlighting the efficacy of SBP-101 in combination with doxorubicin to treat platinum-resistant ovarian cancer ASPIRE trial has exceeded 50% enrollment; complete enrollment of approximately 600 patients anticipated by Q1 2025 Publication of Clinical Data: Phase 1 study of high-dose DFMO, celecoxib, cyclophosphamide and topotecan for patients with relapsed neuroblastoma: a New Approaches to Neuroblastoma Therapy trial. Br J Cancer 130, 788–797 (2024) Financial / Business Gained eligibility for quotation of common stock on the OTCQB Closed $9.0 million public offering of common stock and warrants Issuance of a New Patent in the US and Canada for Claims of a Fixed Dose Combination of Eflornithine and Sulindac "We were thrilled to announce that our ongoing ASPIRE trial, evaluating ivospemin (SBP-101) in combination with standard-of-care for metastatic pancreatic ductal adenocarcinoma, or mPDAC, is now expected to reach its interim data analysis in the first quarter of 2025, due to a lower-than-anticipated event rate, suggesting improved survival outcomes for patients in the trial. This gives us hope for meaningful advancements in mPDAC treatment beyond the incremental benefits seen with recently approved therapies," said Jennifer K. Simpson, PhD, MSN, CRNP, President & CEO of Panbela. "In addition to the progress in our ASPIRE trial, which has now exceeded 50% enrollment with complete enrollment of approximately 600 patients anticipated by Q1 2025, we were pleased to present a poster highlighting the efficacy of SBP-101 in combination with doxorubicin for treating platinum-resistant ovarian cancer at AACR. We also welcomed the publication of clinical data from our Phase I study of high-dose DFMO, celecoxib, cyclophosphamide, and topotecan for patients with relapsed neuroblastoma in the British Journal of Cancer. On the financial and business front, we announced the transfer of our common stock to the OTCQB market and successfully closed a $9.0 million public offering. As we look ahead, Panbela remains steadfast in its commitment to improving patient outcomes and driving value for our stockholders, with several key catalysts on the horizon, including the highly anticipated overall survival interim analysis in our Phase III ASPIRE Trial." First Quarter ended March 31, 2024 Financial Results General and administrative expenses were approximately $1.2 million in the quarter, compared to $1.4 million in the same period last year. The decrease is due primarily to reduced legal and other professional services. Research and development expenses were approximately $5.5 million, compared to $3.5 million in the same period last year. This increase is primarily due to significant growth in the number of active sites and enrollment in project ASPIRE. Net loss in the quarter was approximately $7.1 million, or $2.28 per diluted share, compared to a net loss of $5.1 million, or $392.76 per diluted share, in the same period last year. This increased loss is due to the incremental research and development expenses. Total cash was $262,000 as of March 31, 2024. Total current assets were $1.8 million and current liabilities were $10.5 million as of the same date. In April the Company’s partner in Pediatric Neuroblastoma, US WorldMeds®, provided a nondilutive payment of approximately $0.8 million in exchange for a reduction in the potential future milestone payments. Notes payable, plus accrued interest, on the balance sheet, the result of the acquisition of CPP, totaled approximately $4.2 million. The current portion of the notes payable plus accrued interest totaled approximately $1.3 million and was paid to the noteholder in the first quarter of 2024. During the first quarter, the Company completed a registered public offering. Net proceeds from the raise, which closed on January 31, 2024, were approximately $8.1 million. Conference Call Information May 15, 2024 at 4:30PM EST Toll Free: 877-545-0523 International: 973-528-0016 Participant Access Code: 234396 Webcast Link: Conference Call Replay Information Toll Free: 877-481-4010 International: 919-882-2331 Replay Passcode: 50531 Webcast Replay: About our Pipeline The pipeline consists of assets currently in clinical trials with an initial focus on familial adenomatous polyposis (FAP), first-line metastatic pancreatic cancer, neoadjuvant pancreatic cancer, colorectal cancer prevention, ovarian cancer and diabetes. The combined development programs have a steady cadence of catalysts with programs ranging from pre-clinical to registration studies. SBP-101 Ivospemin Ivospemin is a proprietary polyamine analogue designed to induce polyamine metabolic inhibition (PMI) by exploiting an observed high affinity of the compound for pancreatic ductal adenocarcinoma and other tumors. It has shown signals of tumor growth inhibition in clinical studies of metastatic pancreatic cancer patients, demonstrating a median overall survival (OS) of 14.6 months and an objective response rate (ORR) of 48%, both exceeding what is typical for the standard of care of gemcitabine + nab-paclitaxel suggesting potential complementary activity with the existing FDA-approved standard chemotherapy regimen. In data evaluated from clinical studies to date, ivospemin has not shown exacerbation of bone marrow suppression and peripheral neuropathy, which can be chemotherapy-related adverse events. Serious visual adverse events have been evaluated and patients with a history of retinopathy or at risk of retinal detachment will be excluded from future SBP-101 studies. The safety data and PMI pro in the previous Panbela-sponsored clinical trials provide support for continued evaluation of ivospemin in the ASPIRE trial. For more information, please visit . Flynpovi™ Flynpovi is a combination of CPP-1X (eflornithine) and sulindac with a dual mechanism inhibiting polyamine synthesis and increasing polyamine export and catabolism. In a Phase 3 clinical trial in patients with sporadic large bowel polyps, the combination prevented > 90% subsequent pre-cancerous sporadic adenomas versus placebo. Focusing on FAP patients with lower gastrointestinal tract anatomy in the recent Phase III trial comparing Flynpovi to single agent eflornithine and single agent sulindac, FAP patients with lower GI anatomy (patients with an intact colon, retained rectum or surgical pouch), Flynpovi showed statistically significant benefit compared to both single agents (p≤0.02) in delaying surgical events in the lower GI for up to four years. The safety pro Flynpovi did not significantly differ from the single agents and supports the continued evaluation of Flynpovi for FAP. CPP-1X Eflornithine CPP-1X (eflornithine) is being developed as a single agent tablet or high dose power sachet for several indications including prevention of gastric cancer and recent onset Type 1 diabetes. Preclinical studies as well as Phase 1 or Phase 2 investigator-initiated trials suggest that CPP-1X treatment may be well-tolerated and has potential activity. About Panbela Panbela Therapeutics, Inc. is a clinical-stage biopharmaceutical company developing disruptive therapeutics for patients with urgent unmet medical needs. Panbela’s lead assets are Ivospemin (SBP-101) and Flynpovi. Further information can be found at . Panbela’s common stock is eligible for quotation on the OTCQB under the symbol “PBLA”. Cautionary Statement Regarding Forward-Looking Statements This press release contains “forward-looking statements, “which can be identified by words such as: “anticipate,” “design,” “hope,” “may,” “plan,” and “will.” Examples of forward-looking statements include statements we make regarding timing of trials and results of collaborations with third parties and future studies. All statements other than statements of historical fact are statements that should be deemed forward-looking statements. Forward-looking statements are neither historical facts nor assurances of future performance. Instead, they are based only on our current beliefs, expectations, and assumptions regarding the future of our business, future plans and strategies, projections, anticipated events and trends, the economy and other future conditions. Because forward-looking statements relate to the future, they are subject to inherent uncertainties, risks and changes in circumstances that are difficult to predict and many of which are outside of our control. Our actual results and financial condition may differ materially and adversely from the forward-looking statements. Therefore, you should not rely on any of these forward-looking statements. Important factors that could cause our actual results and financial condition to differ materially from those indicated in the forward-looking statements include, among others, the following: (i) our ability to obtain additional capital, on acceptable terms or at all, required to implement our business plan; (ii) our lack of diversification and the corresponding risk of an investment in our Company; (iii) our ability to maintain our listing on a national securities exchange; (iv) progress and success of our randomized Phase II/III clinical trial; (v) our ability to demonstrate the safety and effectiveness of our product candidates: ivospemin ( SBP-101 ), Flynpovi, and eflornithine (CPP-1X) (v) our ability to obtain regulatory approvals for our product candidates, SBP-101, Flynpovi and CPP-1X in the United States, the European Union or other international markets; (vii) the market acceptance and level of future sales of our product candidates, SBP-101, Flynpovi and CPP-1X ; (viii) the cost and delays in product development that may result from changes in regulatory oversight applicable to our product candidates, SBP-101, Flynpovi and CPP-1X ; (ix) the rate of progress in establishing reimbursement arrangements with third-party payors; (x) the effect of competing technological and market developments; (xi) the costs involved in filing and prosecuting patent applications and enforcing or defending patent claims; and (xii) such other factors as discussed in Part I, Item 1A under the caption “Risk Factors” in our most recent Annual Report on Form 10-K , any additional risks presented in our Quarterly Reports on Form 10-Q and our Current Reports on Form 8-K. Any forward-looking statement made by us in this press release is based on information currently available to us and speaks only as of the date on which it is made. We undertake no obligation to publicly update any forward-looking statement or reasons why actual results would differ from those anticipated in any such forward-looking statement, whether written or oral, whether as a result of new information, future developments or otherwise. Contact Information: Investors: James Carbonara Hayden IR (646) 755-7412 james@haydenir.com Media: Tammy Groene Panbela Therapeutics, Inc. (952) 479-1196 Panbela Therapeutics, Inc. Consolidated Statements of Operations and Comprehensive Loss (unaudited) (In thousands, except share and per share amounts) Three months ended March 31, 2024 2023 Percent Change Operating expenses: General and administrative $ 1,204 $ 1,352 -10.9 % Research and development 5,522 3,508 57.4 % Operating loss (6,726 ) (4,860 ) 38.4 % Other income (expense): Interest income 0 16 - Interest expense (63 ) (102 ) -38.2 % Other income (expense) (469 ) (167 ) 180.8 % Total other income (expense) (532 ) (253 ) 110.3 % Loss before income tax benefit (7,258 ) (5,113 ) 42.0 % Income tax benefit 138 - - Net loss (7,120 ) (5,113 ) 39.3 % Foreign currency translation adjustment 459 163 181.6 % Comprehensive Loss $ (6,661 ) $ (4,950 ) 34.6 % Basic and diluted net loss per share $ (2.28 ) $ (392.76 ) -99.4 % Weighted average shares outstanding - basic and diluted 3,125,835 13,018 23911.6 % Panbela Therapeutics, Inc. Consolidated Balance Sheets (unaudited) (In thousands, except share amounts) March 31, 2024 December 31, 2023 ASSETS (Unaudited) Current assets: Cash and cash equivalents $ 262 $ 2,578 Prepaid expenses and other current assets 1,210 299 Income tax receivable 313 183 Total current assets 1,785 3,060 Other non-current assets 8,742 8,742 Total assets $ 10,527 $ 11,802 LIABILITIES AND STOCKHOLDERS' DEFICIT Current liabilities: Accounts payable $ 8,506 $ 9,939 Accrued expenses 979 1,141 Accrued interest payable 34 238 Debt, current portion 1,000 1,000 Total current liabilities 10,519 12,318 Debt, net of current portion 3,194 4,194 Total non-current liabilities 3,194 4,194 Total liabilities 13,713 16,512 Stockholders' deficit: Preferred stock, $0.001 par value; 10,000,000 authorized; no shares issued or outstanding as of March 31, 2024 and December 31, 2023 - - Common stock, $0.001 par value; 100,000,000 authorized; 4,854,931 and 480,095 issued as of March 31, 2024 and December 31, 2023 respectively; 4,854,861 and 480,025 shares outstanding as of March 31, 2024 and December 31, 2023, respectively 5 - Treasury Stock at cost; 70 shares at both of March 31, 2024 and December 31, 2023 (1 ) (1 ) Additional paid-in capital 128,223 120,043 Accumulated deficit (132,617 ) (125,497 ) Accumulated comprehensive income 1,204 745 Total stockholders' deficit (3,186 ) (4,710 ) Total liabilities and stockholders' deficit $ 10,527 $ 11,802 Panbela Therapeutics, Inc. Consolidated Statements of Cash Flows (unaudited) (In thousands) Three Months Ended March 31, 2024 2023 Cash flows from operating activities: Net loss $ (7,120 ) $ (5,113 ) Adjustments to reconcile net loss to net cash used in operating activities: Stock-based compensation 103 180 Non-cash interest expense 34 42 Changes in operating assets and liabilities: Income tax receivable (140 ) - Prepaid expenses and other current assets (912 ) (2,108 ) Other non-current assets - (5,441 ) Accounts payable (957 ) 4,644 Accrued liabilities (400 ) (1,955 ) Net cash used in operating activities (9,392 ) (9,751 ) Cash flows from financing activities: Proceeds from public offering of common stock and warrants net of underwriters discount and offering costs of $926 and $1,302 respectively 8,082 15,358 Cash paid for fractional shares - (4 ) Principal payments on notes (1,000 ) (1,650 ) Net cash provided by financing activities 7,082 13,704 Effect of exchange rate changes on cash (6 ) (3 ) Net change in cash (2,316 ) 3,950 Cash and cash equivalents at beginning of period 2,578 1,285 Cash and cash equivalents at end of period $ 262 $ 5,235 Supplemental disclosure of cash flow information: Cash paid during period for interest $ 266 $ 386 Supplemental disclosure of non-cash transactions: Cashless exercise of warrants $ - $ (8 )

临床结果临床1期临床3期财报临床2期

2024-05-06

·GlobeNewswire-Health Care

Panbela Announces Issuance of New Patent in the US and Canada; Patent is for Claims of a Fixed Dose Combination of Eflornithine and Sulindac

Developed in collaboration with Sanofi.MINNEAPOLIS, May 06, 2024 (GLOBE NEWSWIRE) -- Panbela Therapeutics, Inc. (OTCQB: PBLA), a clinical-stage biopharmaceutical company developing disruptive therapeutics for the treatment of patients with cancer, today announced an Issue Notification for the US continuation patent US 11,925,613 B2 and Canadian patent CA 3003149 titled “EFLORNITHINE AND SULINDAC, A FIXED DOSE COMBINATION FORMULATION”. These patents claim a novel composition of a fixed dose combination of eflornithine and sulindac, which is called Flynpovi. The product was developed in collaboration with Sanofi, an innovative global healthcare company. Flynpovi is Panbela’s lead investigational product for the treatment of patients with Familial Adenomatous Polyposis (FAP). The patents are valid until 2036, have issued in the US, Australia, Mexico, Taiwan, and Chile. The application is under review in additional countries. Jennifer K. Simpson, PhD, MSN, CRNP, President & Chief Executive Officer of Panbela Therapeutics, commented, “We’re excited to have this patent in Canada as well as the continuation in the US. Expansion of our patent portfolio further supports our global clinical programs. First issued in the United States in 2021 and now in several other territories, this patent covers the novel co-formulation of Flynpovi, our lead FAP product in development." Dr. Simpson added, “We are pleased with the continued growth of our patent portfolio with this latest patent issuance. The co-formulated product described in this patent has the potential to be the first pharmacotherapy approved for patients with FAP. By co-formulating eflornithine and sulindac in the same tablet, it provided FAP patients with an easier option for administration and compliance.” About Panbela’s PipelineThe pipeline consists of assets currently in clinical trials with an initial focus on familial adenomatous polyposis (FAP), first-line metastatic pancreatic cancer, neoadjuvant pancreatic cancer, colorectal cancer prevention and ovarian cancer. The combined development programs have a steady cadence of anticipated catalysts with programs ranging from pre-clinical to registration studies. Ivospemin (SBP-101)Ivospemin is a proprietary polyamine analogue designed to induce polyamine metabolic inhibition (PMI) by exploiting an observed high affinity of the compound for pancreatic ductal adenocarcinoma and other tumors. It has shown signals of tumor growth inhibition in clinical studies of metastatic pancreatic cancer patients, demonstrating a median overall survival (OS) of 14.6 months and an objective response rate (ORR) of 48%, both exceeding what is typical for the standard of care of gemcitabine + nab-paclitaxel suggesting potential complementary activity with the existing FDA-approved standard chemotherapy regimen. In data evaluated from clinical studies to date, ivospemin has not shown exacerbation of bone marrow suppression and peripheral neuropathy, which can be chemotherapy-related adverse events. Serious visual adverse events have been evaluated and patients with a history of retinopathy or at risk of retinal detachment will be excluded from future SBP-101 studies. The safety data and PMI profile observed in the previous Panbela-sponsored clinical trials provide support for continued evaluation of ivospemin in the ASPIRE trial. Flynpovi ™Flynpovi is a combination of CPP-1X (eflornithine) and sulindac with a dual mechanism inhibiting polyamine synthesis and increasing polyamine export and catabolism. In a Phase III clinical trial in patients with sporadic large bowel polyps, the combination prevented > 90% subsequent pre-cancerous sporadic adenomas versus placebo. Focusing on FAP patients with lower gastrointestinal tract anatomy in the recent Phase III trial comparing Flynpovi to single agent eflornithine and single agent sulindac, FAP patients with lower GI anatomy (patients with an intact colon, retained rectum or surgical pouch), showed statistically significant benefit compared to both single agents (p≤0.02) in delaying surgical events in the lower GI for up to four years. The safety profile for Flynpovi did not significantly differ from the single agents and supports the continued evaluation of Flynpovi for FAP. CPP-1XCPP-1X (eflornithine) is being developed as a single agent tablet or high dose powder sachet for several indications including prevention of gastric cancer, treatment of neuroblastoma and recent onset Type 1 diabetes. Preclinical studies as well as Phase I or Phase II investigator-initiated trials suggest that CPP-1X treatment may be well-tolerated and has potential activity. About PanbelaPanbela Therapeutics, Inc. is a clinical-stage biopharmaceutical company developing disruptive therapeutics for patients with urgent unmet medical needs. Panbela’s lead assets are Ivospemin (SBP-101) and Flynpovi. Further information can be found at www.panbela.com. Panbela’s common stock is eligible for quotation on the OTCQB under the symbol “PBLA”. Cautionary Statement Regarding Forward-Looking StatementsThis press release contains “forward-looking statements,” including within the meaning of the Private Securities Litigation Reform Act of 1995. Forward-looking statements can be identified by words such as: “anticipate,” “believe,” “can,” “design,” “expect,” “focus,” “intend,” “looking forward,” “may,” “plan,” “positioned,” “potential,” and “will.” All statements other than statements of historical fact are statements that should be deemed forward-looking statements. Forward-looking statements are neither historical facts nor assurances of future performance. Instead, they are based only on our current beliefs, expectations, and assumptions regarding the future of our business, future plans and strategies, projections, anticipated events and trends, the economy and other future conditions. Because forward-looking statements relate to the future, they are subject to inherent uncertainties, risks and changes in circumstances that are difficult to predict and many of which are outside of our control. Our actual results and financial condition may differ materially and adversely from the forward-looking statements. Therefore, you should not rely on any of these forward-looking statements. Important factors that could cause our actual results and financial condition to differ materially from those indicated in the forward-looking statements include, among others, the following: (i) our ability to obtain additional funding to execute our business and clinical development plans; (ii) progress and success of our clinical development program; (iii) the impact of the current COVID-19 pandemic on our ability to conduct our clinical trials; (iv) our ability to demonstrate the safety and effectiveness of our product candidates: ivospemin (SBP-101) and eflornithine (CPP-1X); (v) our reliance on a third party for the execution of the registration trial for our product candidate Flynpovi ; (vi) our ability to obtain regulatory approvals for our product candidates, SBP-101 and CPP-1X in the United States, the European Union or other international markets; (vii) the market acceptance and level of future sales of our product candidates, SBP-101 and CPP-1X; (viii) the cost and delays in product development that may result from changes in regulatory oversight applicable to our product candidates, SBP-101 and CPP-1X; (ix) the rate of progress in establishing reimbursement arrangements with third-party payors; (x) the effect of competing technological and market developments; (xi) the costs involved in filing and prosecuting patent applications and enforcing or defending patent claims; (xii) our ability to obtain a listing of our common stock on a national securities exchange; and (xii) such other factors as discussed in Part I, Item 1A under the caption “Risk Factors” in our most recent Annual Report on Form 10-K, any additional risks presented in our Quarterly Reports on Form 10-Q and our Current Reports on Form 8-K. Any forward-looking statement made by us in this press release is based on information currently available to us and speaks only as of the date on which it is made. We undertake no obligation to publicly update any forward-looking statement or reasons why actual results would differ from those anticipated in any such forward-looking statement, whether written or oral, whether as a result of new information, future developments or otherwise.

临床结果临床3期临床2期

100 项与依氟鸟氨酸/舒林酸相关的药物交易

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腺瘤性结肠息肉病	申请上市	欧盟	Cancer Prevention Pharmaceuticals, Inc.	2020-07-10

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研究	分期	人群特征	评价人数	分组	结果	评价	发布日期


NCT01483144 (CTgov)	临床3期	腺瘤性结肠息肉病	171	Sulindac+Eflornithine (Eflornithine Plus Sulindac)	憲鑰壓範觸衊憲齋鹹夢(積衊艱衊觸範繭範網範) = 艱衊築蓋範製構廠願願衊構顧顧壓簾網餘淵餘 (遞選繭壓窪廠襯廠繭鹹, 衊願觸壓鬱網鹹鹹醖繭 ~ 製觸齋醖襯製鬱鹹糧遞) 更多	-	2021-06-08
				placebo+Sulindac+Eflornithine (Eflornithine Plus Sulindac Placebo)	憲鑰壓範觸衊憲齋鹹夢(積衊艱衊觸範繭範網範) = 衊繭艱選鹽廠網製鑰製衊構顧顧壓簾網餘淵餘 (遞選繭壓窪廠襯廠繭鹹, 憲選鹹獵觸憲鑰餘膚壓 ~ 餘鏇壓願衊鹽製顧範製) 更多