ODC

Pictured: FDA sign outside its headquarters/iStock, JHVEPhoto The FDA on Wednesday approved US WorldMeds’ oral drug eflornithine for the maintenance therapy of high-risk neuroblastoma. Eflornithine, which will now carry the brand name Iwilfin, is indicated to reduce the risk of relapse in adult and pediatric patients. Wednesday’s approval, announced by the company and FDA on Thursday, makes Iwilfin the first authorized oral maintenance therapy for this indication, according to the announcements. The drug is indicated to decrease the risk of relapse in adults or children with high-risk neuroblastoma (HRNB) who had shown at least a partial response to multiagent, multimodality treatment—including anti-GD2 immunotherapy. Iwilfin is also the first approved therapy meant to reduce the risk of relapse in children with HRNB, according to the FDA’s announcement. US WorldMeds CEO Breck Jones in a statement called Iwilfin a “new and much-needed treatment option” for HRNB, particularly for pediatric patients. “The goal for treating these young patients is to prevent relapse, and advancing therapeutic options is critical to this mission,” Jones said. “Iwilfin offers new hope and improved outcomes for these vulnerable children.” Iwilfin is an orally available inhibitor of ornithine decarboxylase, which is a key enzyme involved in neoplastic transformation. According to the drug’s label, using Iwilfin led to a drop in expression levels of two oncogenic drivers—MYCN and LIN28B—which in turn could promote cell aging and prevent cancer development. The FDA’s approval is backed by data from a single-arm, externally controlled study of children with HRBN, who had initially been treated with standard regimens, including immunotherapy. Results showed an 84% event-free survival at four years compared with 73% in an external control arm. Overall survival after Iwilfin treatment was 96% at four years versus 84% in external controls. These data indicate that Iwilfin cut the risk of relapse by 52% and the risk of death by 68%, according to US WorldMeds. In October 2023, the FDA’s Oncologic Drugs Advisory Committee was split on whether to recommend elfornithine for approval but eventually voted 14-6 in favor of US WorldMeds—despite the lack of a randomized clinical trial to support the drug’s efficacy. At the time, adcomm panelists said that elfornithine was of a lower toxicity than the drugs that they usually discuss, while also noting that its efficacy in the externally controlled study might be overstated given the lack of randomization. Adcomm members also cautioned that the drug’s approval without a randomized trial might lead to a slippery slope in what the FDA requires of manufacturers for future applications. Iwilfin’s label does not come with a boxed warning but carries precautions against myelosuppression, hepatotoxicity, hearing loss and embryo-fetal toxicity. Tristan Manalac is an independent science writer based in Metro Manila, Philippines. He can be reached at tristan@tristanmanalac.com or tristan.manalac@biospace.com.

A Phase 1 clinical study showed that DFMO treatment may provide metabolic benefits to preserve β cell function and health in T1D. MINNEAPOLIS, Nov. 02, 2023 (GLOBE NEWSWIRE) --Panbela Therapeutics Inc. (Nasdaq: PBLA), a clinical stage biopharmaceutical company developing disruptive therapeutics for the treatment of patients with urgent unmet medical needs announces the publication of preclinical and clinical data from studies of CPP-1X (also known as α-Difluoromethylornithine (DFMO) or Eflornithine) in recent onset type 1 diabetes (T1D). According to Sims et al, although therapy of T1D has improved, the morbidity, mortality and cost continue to impact the quality of life for those affected highlighting the need for safe and effective therapies that address the underlying pathology. Data published in the journal Cell Reports Medicine investigated the mechanism of polyamines and polyamine inhibition by CPP-1X on β cell stress that plays a role in the onset of type 1 diabetes in in vitro and ex vivo models. Results showed that DFMO treatment may preserve β cell function, reflected by C-peptide levels in patients with T1D through the modulation of urinary polyamines, in particular putrescine. The work reflects the Company’s ongoing collaboration with Indiana University School of Medicine. A link to the publication can be found here: (23)00438-X. The research is part of a multi-site clinical trial led by Indiana University (IU) School of Medicine, supported by funding from JDRF, the leading global T1D research and advocacy organization. The preclinical data were generated by Raghavendra Mirmira's laboratory at the University of Chicago. Panbela Therapeutics is providing the drug at no cost to researchers and was not involved in the design and analysis of these studies. From the Phase 1 dose range finding study of CPP-1X in patients with recent onset T1D, CPP-1X was well tolerated and a dose dependent inhibition of ODC was observed. An exploratory secondary analysis showed that at the two highest dose levels, treatment with CPP-1X stabilized C-peptide areas under the curve compared to placebo. When assessing immune cell populations, there were no differences between the placebo and CPP-1X patients. Results from these studies suggest that CPP-1X is a safe, oral treatment option that may improve β cell function and/or survival in recent onset T1D. “By investigating β cell-specific deletion of ornithine decarboxylase (ODC) in preclinical models, our collaborators were able to demonstrate the protection against toxin-induced diabetes which suggests a role for polyamine dysregulation in T1D.” said Jennifer K. Simpson, PhD, MSN, CRNP, President & Chief Executive Officer of Panbela. “This observation was extended to the clinical setting where results from the multi-site randomized, placebo-controlled Phase I trial in patients with recent onset T1D showed that inhibition of ODC by CPP-1X may improve β cell function.” "Overall, we are excited by these results which suggest that CPP-1X may have a role in the clinical management of recent onset type 1 diabetes.” said Dr. Simpson. “These studies were the basis for the ongoing IU and JDRF Phase II trial in recent onset T1D to support the goal of developing effective novel therapies for patients with unmet medical needs.” First author Emily K. Sims, MD, an associate professor of pediatrics at IU School of Medicine and a pediatric endocrinologist at Riley Children's Health said, "With our promising early findings, we hold hope that DFMO, possibly as part of a combination therapy, could offer potential benefits not only to individuals with recent-onset type 1 diabetes but could ultimately also be tested for potential benefit to delay disease onset in those who are at risk of developing the condition." Indiana University School of Medicine is annually ranked among the top medical schools in the nation by U.S. News & World Report. The school offers high-quality medical education, access to leading medical research and rich campus life in nine Indiana cities, including rural and urban locations consistently recognized for livability. About Panbela’s 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 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 pro 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 pro Flynpovi did not significantly differ from the single agents and supports the continued evaluation of Flynpovi for FAP. CPP-1X CPP-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 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 listed on The Nasdaq Stock Market LLC under the symbol “PBLA”. Cautionary Statement Regarding Forward-Looking Statements This 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,” “can,” “continue,” “design,” “expect,” “focus,” “intend,” “may,” “plan,” “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 maintain the listing of our common stock on a national securities exchange; 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 Carbonara Hayden IR (646) 755-7412 james@haydenir.com Media: Tammy Groene Panbela Therapeutics, Inc. (952) 479-1196 IR@panbela.com

An FDA advisory panel voted 14 to 6 on Wednesday that US WorldMeds provided sufficient evidence to conclude that eflornithine improves event-free survival (EFS) in patients with high-risk neuroblastoma. The company is seeking US approval of the drug, also referred to as DFMO, to lower the risk of relapse in paediatric patients with high-risk neuroblastoma who have completed multiagent, multimodality therapy.Eflornithine is an oral irreversible inhibitor of ornithine decarboxylase, the first and rate-limiting enzyme in the biosynthesis of polyamines and a transcriptional target of MYCN. In neuroblastoma, the drug was initially developed by an investigator sponsor through multiple interactions with the FDA. In a 2015 meeting, the US regulator had recommended that a randomised controlled trial (RCT) be conducted, but "despite efforts by the sponsor to assess the feasibility of a randomised trial in this setting, the sponsor elected to develop the drug in single-arm cohorts," FDA staff wrote in briefing documents released this week ahead of the AdCom.Agency scientists noted that RCTs are the gold standard for evaluating time-to-event endpoints, but said results provided by US World Meds from a large, single-arm trial suggested "substantive improvement over a benchmark historic control." The company submitted results of a single externally controlled trial (ECT) and supportive data to bolster its application. The ECT was designed to compare data from an open-label, single-arm trial of eflornithine monotherapy for up to two years in paediatric patients in remission after immunotherapy, to an external control arm constructed from patients from another open-label, randomised trial of immunotherapy plus standard upfront therapy versus upfront therapy alone.According to the FDA briefing document, the primary analysis resulted in a hazard ratio (HR) for EFS of 0.48 and 0.32 for overall survival, favouring the eflornithine arm. Agency staff wrote that "the use of an external…controlled trial to support a marketing application may be acceptable in the setting of a rare disease with a well-defined natural history and poor prognosis if the expected treatment effect is estimated to be large, particularly in a setting where conduct of an RCT may be infeasible."Concerns over externally controlled trialsHowever, some AdCom members questioned that stance, including panelist Dan Spratt, who voted against eflornithine, asking why a randomised trial was not done given "this could be a very feasible small trial." Committee chair Christopher Lieu, who was a yes vote, highlighted "significant concerns about setting a precedent for using externally controlled trials."Meanwhile, panel member Caleb Alexander admitted "this is one of the tougher advisory committees I've participated in, in terms of managing uncertainty," although he said he does believe "the product works to some degree." However, Alexander was "hedging" his response to some degree, saying "I'm not clear that the evidence we've reviewed meets statutory thresholds, and I also think FDA has to be careful what they wish for and the ways that any favourable decision here may have significant consequences on future drug development and be precedence-setting."Committee member Shahab Asgharzadeh, who voted yes as well, noted that there are diseases where it is possible to run a randomised trial quickly, "but I felt in this setting, that the evidence shows that DFMO is effective. The preclinical studies are also compelling with the use of the TH-MYCN models."In July, US WorldMeds acquired certain assets in Panbela Therapeutics' eflornithine paediatric neuroblastoma programme for a total of up to $9.5 million.