Business Overview and History

Panbela Therapeutics, Inc. is a clinical-stage biopharmaceutical company developing disruptive therapeutics for the treatment of patients with urgent unmet medical needs. The company's pipeline is focused on utilizing a polyamine platform to target dysregulated biology present in various diseases, with a particular emphasis on cancer.

Panbela Therapeutics, Inc. was founded in 2011 with the primary purpose of developing disruptive therapeutics for the treatment of patients with urgent unmet medical needs. The company's pipeline consists of assets focused on utilizing pharmacotherapies to reduce or normalize increased disease-associated polyamines. Panbela's lead candidates are ivospemin (SBP-101), for which the company has exclusively licensed the worldwide rights, and Flynpovi, a combination of eflornithine and sulindac.

In 2015, the FDA accepted Panbela's Investigational New Drug (IND) application for ivospemin. The company then completed an initial clinical trial of ivospemin in patients with previously treated locally advanced or metastatic pancreatic cancer. This Phase I trial evaluated the safety and tolerability of ivospemin. In 2018, Panbela began enrolling patients in a Phase Ia/Ib study to evaluate the safety, efficacy and pharmacokinetics of ivospemin administered in combination with standard-of-care chemotherapy agents.

In 2009, the FDA accepted Panbela's IND application for the combination product Flynpovi. The company conducted a Phase III study evaluating the efficacy and safety of the Flynpovi combination compared to eflornithine or sulindac alone in adults with familial adenomatous polyposis (FAP). While the study failed to meet the primary endpoint, Panbela plans to seek FDA and EMA guidance on a registration path with a focus on the lower gastrointestinal patient population.

Panbela has faced several challenges over the years. In 2024, the company was notified that the Nasdaq Hearings Panel had determined to delist its common stock, and trading was suspended. Panbela's common stock then became eligible for quotation on the OTCQB market. Additionally, in 2024 the company's contract research organization for the ASPIRE trial began the process of terminating their relationship due to Panbela's inability to pay invoiced amounts, though the trial continues with new arrangements. Despite these setbacks, Panbela has remained focused on advancing its pipeline of polyamine-targeted therapeutics to address critical unmet needs in cancer and other diseases.

Building on these results, Panbela initiated the pivotal Phase 3 ASPIRE trial in 2022, which is evaluating ivospemin in combination with gemcitabine and nab-paclitaxel for the first-line treatment of metastatic pancreatic ductal adenocarcinoma (mPDAC). The trial's enrollment has progressed rapidly, with over 395 patients enrolled as of the third quarter of 2024, and the company expects to complete enrollment by the first quarter of 2025 – earlier than initially anticipated.

Notably, the Data Safety Monitoring Board (DSMB) has conducted three pre-specified safety reviews of the ASPIRE trial, each time recommending the study continue without modification. This consistent safety profile, coupled with a lower-than-expected event rate, suggests the potential for meaningful survival benefits for patients, a critical unmet need in this devastating disease.

In addition to ivospemin, Panbela's pipeline includes Flynpovi, a combination of eflornithine (CPP-1X) and sulindac, which is being evaluated for the treatment of familial adenomatous polyposis (FAP) and the prevention of high-risk adenomas and second primary colorectal cancers. The company regained the North American rights to develop and commercialize Flynpovi in 2023, and is currently working to finalize the registration protocol for regulatory review.

Panbela's polyamine-focused approach also extends to eflornithine, which is being investigated in several Phase 2 trials, including for the treatment of castration-resistant metastatic prostate cancer, non-small cell lung cancer, and early-onset type 1 diabetes. The company has also recently divested its pediatric neuroblastoma program to US WorldMeds, securing up to $9.5 million in non-dilutive funding.

Financials and Liquidity

As of September 30, 2024, Panbela reported cash and cash equivalents of approximately $142,000, with total current assets of $5.2 million and current liabilities of $20.1 million, resulting in a working capital deficit of $14.97 million. The company's net loss for the nine months ended September 30, 2024, was $21.44 million, with negative cash flow from operations of $12.49 million.

To bolster its financial position, Panbela secured a $12 million strategic loan commitment from Nant Capital in October 2024. The financing includes two tranches of convertible promissory notes, with the first tranche of $2.85 million funded immediately and the second tranche of $9.15 million expected to be issued by November 15, 2024, subject to customary conditions.

The proceeds from this financing will be used for general corporate purposes, including the advancement of Panbela's clinical pipeline, as well as the repayment of certain existing indebtedness. While the company's liquidity position remains challenging, the Nant Capital investment represents a significant vote of confidence in Panbela's strategy and the potential of its polyamine-targeted approach.

For the most recent fiscal year (2023), Panbela reported an annual net loss of $25.26 million. The company does not currently generate revenue from product sales. In the most recent quarter (Q3 2024), the quarterly net loss was $7.17 million.

Panbela's liquidity position is characterized by a debt-to-equity ratio of -0.35 as of September 30, 2024. The company has a $1.5 million term loan from USWM, LLC and several smaller promissory notes outstanding. The current ratio and quick ratio both stand at 0.26, indicating potential short-term liquidity challenges.

Since its inception in 2011, Panbela has incurred cumulative losses of $146.9 million. The company will need to raise additional capital to continue its operations and execute its business plan, including completing the required future trials and pursuing regulatory approvals.

Product Portfolio and Clinical Development

Ivospemin (SBP-101)

Ivospemin is Panbela's lead product candidate, for which the company has exclusively licensed worldwide rights from the University of Florida Research Foundation. An initial Phase I clinical trial in patients with previously treated locally advanced or metastatic pancreatic cancer enrolled 29 patients across six cohorts and evaluated the safety of ivospemin. No drug-related bone marrow toxicity or peripheral neuropathy was observed at any dose level.

A subsequent Phase Ia/Ib study of ivospemin in combination with gemcitabine and nab-paclitaxel enrolled 50 subjects across four cohorts. Interim results presented in January 2022 showed promising efficacy signals, with a best response of complete response in 1 of 29 evaluable subjects, partial response in 13 of 29, stable disease in 10 of 29, and progressive disease in 5 of 29. Median progression-free survival was 6.5 months.

The ongoing ASPIRE trial, a global, randomized, double-blind, placebo-controlled Phase III study, is evaluating ivospemin in combination with gemcitabine and nab-paclitaxel in patients with previously untreated metastatic pancreatic cancer. As of September 30, 2024, there were 89 sites open across 10 countries, with the full complement of 600 planned sites expected to be open by the first quarter of 2025. The company anticipates completing enrollment by the second quarter of 2025, with an interim data analysis on overall survival expected in the first quarter of 2025.

Flynpovi

Flynpovi is a combination of eflornithine (CPP-1X) and sulindac, licensed from the Arizona Board of Regents of the University of Arizona. While a previous Phase III study in familial adenomatous polyposis (FAP) failed to meet its primary endpoint, post-hoc analysis showed promising results in preventing progression to lower gastrointestinal surgery. Panbela is seeking regulatory guidance on a potential registration path for Flynpovi, focusing on the lower gastrointestinal patient population.

The ongoing PACES trial, a double-blind, placebo-controlled Phase III study funded by the National Cancer Institute, is evaluating Flynpovi's efficacy in preventing the recurrence of high-risk adenomas and second primary colorectal cancers in patients with stage 0-III colon or rectal cancer. Data readout for this trial is anticipated in the second half of 2026.

Eflornithine (CPP-1X)

Eflornithine is being evaluated in several indications, including:

• A trial of eflornithine sachets in patients with non-small cell lung cancer harboring STK11 mutations, with data readout expected by mid-2025 and Phase 2 initiation targeted for later in 2025.
• A Phase II trial of eflornithine tablets in early-onset type I diabetes, opened in January 2023 in collaboration with Indiana University and the Juvenile Diabetes Research Foundation, with an interim analysis expected in 2025.
• A Phase II trial in combination with high-dose testosterone and enzalutamide in metastatic castration-resistant prostate cancer.

In July 2023, Panbela divested certain rights to its eflornithine pediatric neuroblastoma program to US World Meds, potentially receiving up to $7.6 million in additional non-dilutive funding upon achievement of certain milestones.

Risks and Challenges

Panbela faces several risks and challenges common to clinical-stage biopharmaceutical companies, including the inherent uncertainties of drug development, the need for additional financing to support its operations, and the potential for regulatory hurdles or delays.

The success of the company's lead asset, ivospemin, is heavily dependent on the outcome of the ongoing ASPIRE trial. While the trial's progress has been encouraging thus far, with a consistent safety profile and lower-than-expected event rates, there is no guarantee that the study will ultimately demonstrate a statistically significant survival benefit.

Additionally, Panbela's reliance on third-party contract research organizations (CROs) to conduct its clinical trials introduces operational risks, as evidenced by the recent termination of its relationship with the ASPIRE trial's CRO. The company's ability to successfully navigate such challenges and ensure the timely completion of its studies will be crucial to its future success.

Furthermore, the company's delisting from the Nasdaq Stock Market and subsequent move to the OTCQB exchange has the potential to impact its visibility and access to capital markets, which could hinder its ability to secure additional financing and fund its ongoing operations.

Outlook and Conclusion

Panbela Therapeutics is at a pivotal juncture, as it continues to advance its polyamine-targeted pipeline and execute on the critical ASPIRE trial for its lead candidate, ivospemin. The consistent safety profile and lower-than-expected event rates observed in the study suggest the potential for meaningful survival benefits in metastatic pancreatic cancer, a disease with an urgent need for more effective therapies.

The company's recent $12 million financing commitment from Nant Capital further validates its strategic approach and provides much-needed capital to support its ongoing development efforts. As Panbela navigates the challenges of the current landscape, including its delisting from Nasdaq, the company's ability to execute on its clinical programs and secure additional financing will be crucial in determining its long-term success.

Looking ahead, Panbela has outlined several key milestones:

• Full enrollment of approximately 600 patients for the ASPIRE trial is expected by Q2 2025.
• An interim analysis for the ASPIRE trial is anticipated in Q1 2025.
• Submission of the protocol for the FAP global registration trial to the FDA and EMA for feedback.
• Data readout for the Phase 1 dose escalation study of CPP-1X in STK11 mutant non-small cell lung cancer by mid-2025, with Phase 2 initiation targeted for later in 2025.
• Data readout for the Phase 3 PACeS trial of Flynpovi expected in the second half of 2026.
• An interim analysis for the Phase 2 type 1 diabetes trial in collaboration with Indiana University School of Medicine and JDRF in 2025.

Ultimately, Panbela's focus on exploiting the polyamine pathway as a therapeutic target represents a novel and potentially disruptive approach to cancer treatment. If the company can continue to demonstrate the safety and efficacy of its assets, particularly ivospemin, it may be well-positioned to reshape the treatment paradigm for some of the most challenging and devastating forms of cancer.