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.

Start Date01 Oct 2013

Sponsor / Collaborator

Cancer Prevention Pharmaceuticals, Inc.

NCT01349881 / Active, not recruitingPhase 3IIT

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.

Start Date23 Aug 2013

Sponsor / Collaborator

National Cancer Institute

[+1]

NCT01245816 / WithdrawnPhase 3

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).

Start Date01 Mar 2011

Sponsor / Collaborator

Cancer Prevention Pharmaceuticals, Inc.

100 Clinical Results associated with Eflornithine Hydrochloride Hydrate/Sulindac

100 Translational Medicine associated with Eflornithine Hydrochloride Hydrate/Sulindac

100 Patents (Medical) associated with Eflornithine Hydrochloride Hydrate/Sulindac

Literatures (Medical) associated with Eflornithine Hydrochloride Hydrate/Sulindac

01 Jun 2016·LeukemiaQ1 · MEDICINE

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

Q1 · MEDICINE

Letter

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

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.

01 Sep 1966·Toxicology and applied pharmacologyQ3 · MEDICINE

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

Q3 · MEDICINE

Article

Author: 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.

News (Medical) associated with Eflornithine Hydrochloride Hydrate/Sulindac

31 Oct 2024

·www.globenewswire.com

Panbela to Host Third Quarter 2024 Earnings Conference Call on November 14, 2024

MINNEAPOLIS, Oct. 31, 2024 (GLOBE NEWSWIRE) -- Panbela Therapeutics, Inc. (OTCQB: PBLA), (“Panbela”), a clinical stage company developing disruptive therapeutics for the treatment of patients with urgent unmet medical needs, today announced that it will host a conference call on November 14, 2024, at 4:30 PM Eastern Time to discuss results for its third quarter ended September 30, 2024. Conference Call InformationToll Free: 877-545-0320International: 973-528-0002Participant Access Code: 370494Webcast Link: https://www.webcaster4.com/Webcast/Page/2556/51548 Conference Call Replay InformationToll Free: 877-481-4010International: 919-882-2331Replay Passcode: 51548Webcast Replay: https://www.webcaster4.com/Webcast/Page/2556/51548 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 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 and the corresponding risk of potential deterioration of our financial condition and results due to failure to diversify; (iii) our ability to obtain and maintain our listing on a national securities exchange; (iv) results, progress and success of our randomized Phase Ia/Ib and Phase II/III clinical trials; (v) our ability to demonstrate the safety and effectiveness of our product candidates: ivospemin ( SBP-101 ), Flynpovi, and eflornithine (CPP-1X); (vi) potential delays or risks to the success of our randomized Phase II/III clinical trial resulting from a termination in our relationship with our CRO; (vii) 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; (viii) the market acceptance and level of future sales of our product candidates, SBP-101, Flynpovi and CPP-1X ; (ix) 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 ; (x) the rate of progress in establishing reimbursement arrangements with third-party payors; (xi) the effect of competing technological and market developments; (xii) the costs involved in filing and prosecuting patent applications and enforcing or defending patent claims; and (xiii) 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 CarbonaraHayden IR(646) 755-7412james@haydenir.com Media:Tammy GroenePanbela Therapeutics, Inc.(952) 479-1196IR@panbela.com

Clinical ResultPhase 3Phase 2Financial Statement

24 Sep 2024

·www.globenewswire.com

First Patient Enrolled in Phase I Program in STK11 Mutant Non-Small Cell Lung Cancer at Moffitt Cancer Center

MINNEAPOLIS, Sept. 24, 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 announced the first patient enrolled in a Phase I dose escalation study to evaluate CPP-1X-S (eflornithine sachets) in STK11 mutant non-small cell lung cancer (NSCLC). The initial goal of the Phase I trial will be to determine the maximum tolerated dose of eflornithine in combination with the immune checkpoint inhibitor Keytruda, while evaluating efficacy and then moving into a Phase II efficacy trial. Data from the Phase I trial is expected by mid-2025, with a look to start the Phase II trial in 2024. The trial entitled “Targeting ODC as an Immunotherapeutic Target in STK11 (LKB1) Pathway- Deficient NSCLC” is a Phase I/II trial where Phase I is a dose escalation study establishing the safety, toxicity and recommended Phase II dose of CPP-1X-S in combination with Keytruda in patients with STK11 mutant NSCLC at approximately one academic medical center in the United States. Detailed information on the trial can be located at https://clinicaltrials.gov/study/NCT06219174?term=DFMO&rank=4. “Options for combining new agents with standard of care immunotherapy is critical to overcoming the reduced levels of anti-tumor T cells and immune evasion that is observed in STK11 mutant tumors,” said Jhanelle Gray, M.D., Principal Investigator of the clinical trial, Chair of Moffitt’s Department of Thoracic Oncology and Co-Leader of Moffitt’s Molecular Medicine Program. “By working with Panbela, we are using CPP-1X-S to modulate polyamine levels and potentially restimulate the immune system, which may be a valuable therapeutic strategy to target these hard-to-treat tumors.” “With the recent approval of CPP-1X (DFMO) for neuroblastoma, the first oncology approval for a polyamine targeted therapy, we’re really excited to have the first patient enrolled in the Phase I trial for CPP-1X-S led by Moffitt Cancer Center,” said Jennifer K. Simpson, PhD, MSN, CRNP, President & Chief Executive Officer of Panbela. “Preclinical studies have shown that polyamine modulation has the potential to restimulate the immune system. This trial allows us to explore the potential of CPP-1X-S clinically in the STK11 mutant NSCLC population which historically have a poor response to checkpoint inhibitor therapy. Once the safety of CPP-1X-S in combination with Keytruda is established in this Phase I trial, the planned Phase II trial will determine the potential efficacy of combining polyamine targeted therapies with checkpoint inhibitors hopefully demonstrating the first clinical proof of concept of this unique approach. In addition to the possibility of providing a better treatment option for this patient population, we are excited to evaluate the role of eflornithine and ivospemin as modulators of the immune system in combination with other immunotherapies such as CAR-T therapy for tumors where response rates have been low with immunotherapy.” 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 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 and the corresponding risk of potential deterioration of our financial condition and results due to failure to diversify; (iii) our ability to obtain and maintain our listing on a national securities exchange; (iv) results, progress and success of our randomized Phase Ia/Ib and Phase II/III clinical trials; (v) our ability to demonstrate the safety and effectiveness of our product candidates: ivospemin ( SBP-101 ), Flynpovi, and eflornithine (CPP-1X); (vi) potential delays or risks to the success of our randomized Phase II/III clinical trial resulting from a termination in our relationship with our CRO; (vii) 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; (viii) the market acceptance and level of future sales of our product candidates, SBP-101, Flynpovi and CPP-1X ; (ix) 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 ; (x) the rate of progress in establishing reimbursement arrangements with third-party payors; (xi) the effect of competing technological and market developments; (xii) the costs involved in filing and prosecuting patent applications and enforcing or defending patent claims; and (xiii) 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 CarbonaraHayden IR(646) 755-7412james@haydenir.com Media:Tammy GroenePanbela Therapeutics, Inc.(952) 479-1196IR@panbela.com

Clinical ResultImmunotherapyPhase 2Phase 3Phase 1

13 Aug 2024

·www.globenewswire.com

Panbela Provides Business Update and Reports Q2 2024 Financial Results

MINNEAPOLIS, Aug. 13, 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 June 30, 2024. As previously announced, management is hosting an earnings call today at 4:30 p.m. ET. Q2 2024 and Recent Highlights: Clinical Phase 3 ASPIRE clinical trial received favorable third independent safety review: DSMB recommended continuation without modification.Completed 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 American.Provided 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 the potential for improved survival outcomes for patients in the trial. Financial / Business Gained eligibility for quotation of common stock on the OTCQB.Issuance of a New Patent in the US and Canada for Claims of a Fixed Dose Combination of Eflornithine and Sulindac. Jennifer K. Simpson, PhD, MSN, CRNP, President & CEO of Panbela, commented: "In the second quarter, we continued to make significant progress in our clinical programs and corporate initiatives. Our Phase III ASPIRE clinical trial received a favorable third independent safety review, with the Data and Safety Monitoring Board (DSMB) recommending continuation without modification. We were also honored to have an oral presentation at Digestive Disease Week (DDW), where we evaluated the safety and efficacy of eflornithine (difluoromethylornithine, DFMO) in patients with gastric premalignant conditions in high incidence areas of Latin America. Furthermore, we recently announced revised timing for the interim data analysis of our ongoing ASPIRE trial, evaluating ivospemin (SBP-101) in combination with standard-of-care for metastatic pancreatic ductal adenocarcinoma (mPDAC). Due to a lower-than-anticipated event rate, which suggests the potential for improved survival outcomes for patients in the trial, the analysis is now expected in Q1 2025. This is a testament to the potential of our lead candidate, ivospemin, and its ability to make a meaningful difference in the lives of patients with mPDAC. As we move forward, Panbela remains committed to advancing our clinical programs, exploring new indications, and creating value for our stockholders. With several key milestones on the horizon, including the highly anticipated overall survival interim analysis in our Phase III ASPIRE Trial, we are excited about the future and the potential impact our therapies can have on patients in need." Second Quarter ended June 30, 2024 Financial Results General and administrative expenses were approximately $1.1 million in the quarter, compared to $1.6 million in the same period last year. The decrease is due primarily to reduced legal and compensation expense. Research and development expenses were approximately $7.0 million, compared to $4.2 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 $1.47 per diluted share, compared to a net loss of $5.8 million, or $159.15 per diluted share, in the same period last year. This increased loss is due to the incremental research and development expenses. Total cash was $59,000 as of June 30, 2024. Total current assets were $0.8 million and current liabilities were $16.8 million as of the same date. In April, Panbela’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. In July, Panbela secured a loan from this same partner for $1.5 million. Notes payable, plus accrued interest, on the balance sheet, the result of the acquisition of Cancer Prevention Pharmaceuticals, Inc., totaled approximately $4.3 million. The current portion of the notes payable plus accrued interest totaled approximately $1.1 million. Conference Call Information Toll Free: 888-506-0062International: 973-528-0011Participant Access Code: 405072Webcast Link: https://www.webcaster4.com/Webcast/Page/2556/50956 Conference Call Replay Information Toll Free: 877-481-4010International: 919-882-2331Replay Passcode: 50956Webcast Replay: https://www.webcaster4.com/Webcast/Page/2556/50956 The replay will be available within approximately two hours after the completion of the call for approximately one year. About our 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, 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 IvospeminIvospemin 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. For more information, please visit https://clinicaltrials.gov/study/NCT03412799. 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 profile for Flynpovi did not significantly differ from the single agents and supports the continued evaluation of Flynpovi for FAP. CPP-1X EflornithineCPP-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 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, “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 and the corresponding risk of potential deterioration of our financial condition and results due to failure to diversify; (iii) our ability to obtain and maintain our listing on a national securities exchange; (iv) results, progress and success of our randomized Phase Ia/Ib and Phase II/III clinical trials; (v) our ability to demonstrate the safety and effectiveness of our product candidates: ivospemin ( SBP-101 ), Flynpovi, and eflornithine (CPP-1X); (vi) potential delays or risks to the success of our randomized Phase II/III clinical trial resulting from a termination in our relationship with our CRO; (vii) 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; (viii) the market acceptance and level of future sales of our product candidates, SBP-101, Flynpovi and CPP-1X ; (ix) 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 ; (x) the rate of progress in establishing reimbursement arrangements with third-party payors; (xi) the effect of competing technological and market developments; (xii) the costs involved in filing and prosecuting patent applications and enforcing or defending patent claims; and (xiii) 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 CarbonaraHayden IR(646) 755-7412james@haydenir.com Media:Tammy GroenePanbela Therapeutics, Inc.(952) 479-1196IR@panbela.com Panbela Therapeutics, Inc.Consolidated Statements of Operations and Comprehensive Loss (unaudited)(In thousands, except share and per share amounts) Three months ended June 30, Six months ended June 30, 2024 2023 Percent Change 2024 2023 Percent ChangeOperating expenses: General and administrative $1,106 $1,643 -32.7% $2,310 $2,995 -22.9%Research and development 6,997 4,234 65.3% 12,519 7,750 61.5%Operating loss (8,103) (5,877) 37.9% (14,829) (10,745) 38.0% Other income (expense): Interest income - 49 -100.0% - 65 -100.0%Gain on sale of intellectual property 775 - - 775 - - Interest expense (59) (70) -15.7% (121) (173) -30.1%Other income (expense) 248 (82) -402.4% (223) (247) -9.7%Total other income (expense) 964 (103) -1035.9% 431 (355) -221.4% Loss before income tax benefit (7,139) (5,980) 19.4% (14,398) (11,100) 29.7% Income tax benefit - 147 -100.0% 138 149 -7.4% Net loss (7,139) (5,833) 22.4% (14,260) (10,951) 30.2%Foreign currency translation adjustment (242) 68 -455.9% 217 231 -6.1%Comprehensive Loss $(7,381) $(5,765) 28.0% $(14,043) $(10,720) 31.0% Basic and diluted net loss per share$(1.47) $(159.15) -99.1% $(3.58) $(441.77) -99.2%Weighted average shares outstanding - basic and diluted 4,854,861 36,650 13146.6% 3,984,355 24,790 15972.4% Panbela Therapeutics, Inc.Consolidated Balance Sheets (unaudited)(In thousands, except share amounts) June 30, 2024 December 31, 2023ASSETS (Unaudited) Current assets: Cash and cash equivalents $59 $2,578 Prepaid expenses and other current assets 393 299 Income tax receivable 320 183 Total current assets 772 3,060 Other non-current assets 8,642 8,742 Total assets $9,414 $11,802 LIABILITIES AND STOCKHOLDERS' DEFICIT Current liabilities: Accounts payable $14,293 $9,939 Accrued expenses 1,408 1,141 Accrued interest payable 87 238 Debt, current portion 1,000 1,000 Total current liabilities 16,788 12,318 Debt, net of current portion 3,194 4,194 Total non-current liabilities 3,194 4,194 Total liabilities 19,982 16,512 Stockholders' deficit: Preferred stock, $0.001 par value; 10,000,000 authorized; no shares issued or outstanding as of June 30, 2024 and December 31, 2023 - - Common stock, $0.001 par value; 100,000,000 authorized; 4,854,931 and 480,095 issued as of June 30, 2024 and December 31, 2023 respectively; 4,854,861 and 480,025 shares outstanding as of June 30, 2024 and December 31, 2023, respectively 5 - Treasury Stock at cost; 70 shares at both of June 30, 2024 and December 31, 2023 (1) (1)Additional paid-in capital 128,223 120,043 Accumulated deficit (139,757) (125,497)Accumulated comprehensive income 962 745 Total stockholders' deficit (10,568) (4,710)Total liabilities and stockholders' deficit $9,414 $11,802 Panbela Therapeutics, Inc.Consolidated Statements of Cash Flows (unaudited)(In thousands) Six Months Ended June 30, 2024 2023 Cash flows from operating activities: Net loss$(14,260) $(10,951)Adjustments to reconcile net loss to net cash used in operating activities: Stock-based compensation 103 509 Non-cash interest expense 87 107 Gain on sale of intellectual property (775) - Changes in operating assets and liabilities: Income tax receivable (140) (149)Prepaid expenses and other current assets (96) (2,967)Other non-current assets 100 (5,541)Accounts payable 4,578 5,811 Accrued liabilities 30 (2,311)Net cash used in operating activities (10,373) (15,492) Cash flows from investing activities: Proceeds from sale of intellectual property 775 - Net cash provided by investing activities 775 - Cash flows from financing activities: Proceeds from public offering of common stock and warrants, net of fees and offering costs of $0.9 million and $2.1 million respectively 8,082 23,071 Cash paid for fractional shares - (9)Principal payments on notes (1,000) (1,650)Net cash provided by financing activities 7,082 21,412 Effect of exchange rate changes on cash (3) - Net change in cash (2,519) 5,920 Cash and cash equivalents at beginning of period 2,578 1,285 Cash and cash equivalents at end of period$59 $7,205 Supplemental disclosure of cash flow information: Cash paid during period for interest$272 $386 Supplemental disclosure of non-cash transactions: Cashless exercise of warrants$- $(8)

Clinical ResultPhase 3Financial StatementPhase 2Phase 1

100 Deals associated with Eflornithine Hydrochloride Hydrate/Sulindac

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Indication	Highest Phase	Country/Location	Organization	Date
Adenomatous Polyposis Coli	NDA/BLA	EU	Cancer Prevention Pharmaceuticals, Inc.	10 Jul 2020

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Study	Phase	Population	Analyzed Enrollment	Group	Results	Evaluation	Publication Date


NCT01483144 (CTgov)	Phase 3	Adenomatous Polyposis Coli	171	Sulindac 150 MG+Eflornithine (Eflornithine Plus Sulindac)	bsoldkbiwl(nekflptnlz) = tnrdevxfcw trdxyvdnht (narocfetdp, bwvhjwrdvo - pklavuvtyz) View more	-	08 Jun 2021
				Sulindac placebo+Eflornithine (Eflornithine Plus Sulindac Placebo)	bsoldkbiwl(nekflptnlz) = esrhtektmn trdxyvdnht (narocfetdp, uxjqpcxbow - rfgjrlrxds) View more

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