TUB-040

TUB-040 is a next-generation NaPi2b-targeting Exatecan ADC based on Tubulis’ proprietary P5 technology with superior biophysical properties that demonstrated effective and durable responses in a range of preclinical models The clinical trial will enroll up to 140 patients with platinum-resistant high-grade ovarian cancer or relapsed/refractory adenocarcinoma non-small cell lung cancer in the US, the UK and Europe MUNICH--(BUSINESS WIRE)-- Tubulis announced today that the first patient has been treated in its first Phase I/IIa trial (NAPISTAR 1-01, NCT06303505). The study is evaluating Tubulis’ next-generation antibody-drug conjugate (ADC) TUB-040 in patients with platinum-resistant high-grade ovarian cancer (PROC) or relapsed/refractory adenocarcinoma non-small cell lung cancer (NSCLC), who have exhausted other available treatment options. TUB-040 targets NaPi2b, a highly overexpressed antigen in ovarian cancer and lung adenocarcinoma. The candidate is the first to enter the clinic from the company’s growing pipeline and represents one of Tubulis’ two lead candidates developed using its proprietary suite of platform technologies, which enable the creation of uniquely matched ADCs with superior biophysical properties. The multicenter, first-in-human, dose escalation and optimization Phase I/IIa study aims to investigate the safety, tolerability, pharmacokinetics, and efficacy of TUB-040 as a monotherapy. The trial will be conducted in the US as well as the UK, Spain, Belgium, and Germany. Phase Ia comprises the dose escalation and will determine safety and the maximum tolerated dose or the identified dose for optimization, whereas Phase IIa will focus on dose optimization, safety, and preliminary efficacy of TUB-040. The first patient has been dosed in the US following IND approval by the FDA. “ADCs are beginning to show their potential as a core treatment modality replacing conventional chemotherapy for several solid tumor indications. Based on our preclinical data we are convinced that TUB-040 can represent a new option for the effective treatment of NSCLC and ovarian cancer patients,” said Günter Fingerle-Rowson, MD, PhD, Chief Medical Officer at Tubulis. “The novel P5 technology we use in TUB-040 improves upon current limitations due to off-target toxicity and restricted durability, the main challenges of current ADC treatments. By achieving reduced non-target toxicity together with a more specific, more powerful, and continued on-tumor delivery of the payload, we aim to improve long-term anti-tumor responses and, ultimately, clinical outcomes for patients.” “Initiating our first clinical trial represents an important milestone for the entire Tubulis team and underscores our vision to innovate on all fronts of the ADC design for patient benefit,” said Dominik Schumacher, PhD, Chief Executive Officer and Co-founder of Tubulis. “Our objective is to achieve clinical proof-of-concept for our lead candidate, TUB-040, and validate our differentiated platform approach to ADC development.” TUB-040 consists of a humanized, target-specific, Fc-silenced IgG1 antibody equipped with Tubulis’ proprietary Tubutecan linker-payload technology, which is based on P5 conjugation chemistry and the topoisomerase-1 inhibitor Exatecan. Tubulis recently presented a comprehensive preclinical data set at AACR, demonstrating the superior stability and minimal loss of linker-payload conjugation for their lead candidate. In a range of preclinical models, Tubulis was also able to show high and long-lasting anti-tumor responses, even at lower expression levels of NaPi2b, with an excellent safety and tolerability profile. About TUB-040 and the P5 Technology Tubulis’ lead antibody-drug conjugate (ADC) TUB-040 is directed against Napi2b, an antigen highly overexpressed in ovarian cancer and lung adenocarcinoma. It consists of an IgG1 antibody targeting Napi2b connected to the Topoisomerase I inhibitor Exatecan through a cleavable linker system based on the company’s proprietary P5 conjugation technology with a homogeneous DAR of 8. P5 conjugation is a novel chemistry for cysteine-selective conjugation that enables ADC generation with unprecedented linker stability and biophysical properties. It originated from the fundamental work of Prof. Christian Hackenberger at the Leibniz-Forschungsinstitut für Molekulare Pharmakologie im Forschungsverbund Berlin e.V. (FMP), which unlocked the use of phosphorus chemistry for superior bioconjugation. Preclinical pharmacokinetic analysis also demonstrated that TUB-040 efficiently delivers its payload to the tumor while reducing off-site toxicities. The candidate is currently being investigated in a multicenter Phase I/IIa study (NAPISTAR 1-01, NCT06303505) that aims to evaluate the safety, tolerability, pharmacokinetics, and efficacy of TUB-040 as a monotherapy. About Tubulis Tubulis’ suite of proprietary platform technologies generates uniquely matched antibody-drug conjugates with superior biophysical properties for treating solid tumors. By demonstrating durable on-tumor delivery of the payload and long-lasting anti-tumor activity, we have reached the clinic with our first program, TUB-040, in ovarian and non-small cell lung cancer. The second candidate from our growing pipeline, TUB-030, is set to follow in the near-term. We will solidify our leadership position by continuing to innovate on all aspects of ADC design to expand their therapeutic potential for our pipeline, our partners and for patients. Visit or follow us on LinkedIn. View source version on businesswire.com: Contacts For Tubulis Dominik Schumacher, CEO & Co-Founder Phone: +49 175 800 5594 Email: contact@tubulis.com Media Requests for Tubulis Trophic Communications Stephanie May, PhD Phone: +49 (0) 171 185 56 82 Email: tubulis@trophic.eu Source: Tubulis View this news release online at:

Pictured: An antibody-drug conjugate under construction by two scientists/ Nicole Bean for BioSpace† With antibody-drug conjugates well established in liquid tumors, companies are pivoting their focus to treating solid tumors, such as those of the breast, prostate and lung. If ADCs can be a viable treatment option for non-small cell lung cancer (NSCLC), which is particularly challenging given its resistance to chemotherapy and radiation, it could be a significant treatment advance with huge market potential. In August 2022, AstraZeneca and Daiichi Sankyo’s ADC Enhertu won FDA approval as the first antibody-drug conjugate (ADC) to treat patients with HER2-mutated metastatic NSCLC, and several more programs involving ADCs for lung cancer are moving forward. In December 2023, the FDA accepted the Biologics License Application (BLA) for Daiichi Sankyo and Merck’s patritumab deruxtecan (HER3-DXd) for the third-line treatment of NSCLC and set a PDUFA date of June 26, 2024. Then, in February, the regulator accepted the Biologics License Application for datopotamab deruxtecan (Dato-DXd), co-developed by Daiichi Sankyo and Daiichi Sankyo, for the second-line treatment of NSCLC, setting an action date of Dec. 20. “We’re very optimistic about this, and we think that [Dato-DXd] can be an important drug for non-squamous non-small cell lung cancer patients,” Mark Rutstein, SVP and head of global oncology clinical development at Daiichi Sankyo, told BioSpace. But a major challenge in developing ADCs for NSCLC is that unlike many cancers, lung cancer isn’t typically treated with antibody therapies, Christiana Bardon, co-managing partner at MPM BioImpact, told BioSpace. “The early data was not that positive.” Bardon said she believes ADCs will stall in lung cancer for the same reason: until compelling surface targets for lung cancer are developed that have good rates of internalization, there are no good markers to ensure sufficient payload delivery. TROP2 and Beyond But treatments like Dato-DXd could be making inroads. Results from the Phase III Tropion-Lung01 trial showed that Dato-DXd, which is directed at the TROP2 receptor, reduced the risk of disease progression or death by 25% in the overall trial population and by 37% in patients with non-squamous tumors when compared to chemotherapy. High-level overall survival results from the trial reported Monday numerically favored Dato-DXd, showing clinically meaningful improvement in a prespecified subgroup of patients. However, survival results did not reach statistical significance in the overall trial population. Bardon said TROP2 is one of the few targets where “good progress” has been made, “but the data hasn’t been that impressive” in NSCLC. Patients treated with Dato-DXd in the TROPION-Lung01 trial showed a progression-free survival (PFS) of only 4.4 median months vs. 3.7 with chemotherapy. “That’s not super exciting,” Bardon said, adding that Dato-DXd has not generated much excitement among lung cancer doctors. The PFS bare minimum hurdle for something to generate excitement in the field of lung cancer would be about six months, she said. Right now, chemotherapy provides about a 20% response rate, with a PFS of six months, Bardon noted, saying this is the low bar to meet with treatments for lung cancer. Another ADC targeting the TROP2 receptor is Gilead Sciences’ Trodelvy, which is FDA-approved to treat breast cancer. However, the company announced in January that the drug did not meet the primary endpoint of overall survival in a Phase III study in NSCLC. Gilead did observe a more than three-month difference in median overall survival in a subgroup of patients, so the company plans to continue researching effectiveness in these patients. “We will work to further identify the metastatic NSCLC patient populations that may benefit from Trodelvy,” Gilead Chief Medical Officer Merdad Parsey said in a statement. Rutstein is bullish on the potential of ADCs targeting TROP2 in NSCLC. “We haven’t seen the data yet, but [Gilead] described some evidence of benefit, despite a negative trial,” Rutstein said. “Overall, if you take the totality of the data with TROP2 antibody drug conjugates in NSCLC, we think there’s an important potential for patients,” he said. Beyond TROP2, there are several other ADCs in development for NSCLC targeting HER2, HER3, c-MET, EGFR, NaPi2b and more. Mythic Therapeutics is studying MYTX-011, an ADC targeting the c-MET receptor, in Phase I, and emerging ADC player Tubulis has TUB-040, which targets NaPi2b, a highly overexpressed antigen in lung and ovarian cancers, in preclinical studies. Data showed that TUB-040 led to complete eradication of tumors with a low-dose single treatment in multiple ovarian cancer mouse models. Additionally, repeat-dose toxicology studies in nonhuman primates demonstrated that TUB-040 was well tolerated with minor and reversible adverse effects. “The novel technology we use in TUB-040 aims to address one of the current main challenges of ADC treatments: to ensure long-term delivery of the payload to the tumor site in order to improve the durability of anti-tumor responses and ultimately clinical outcomes,” Tubulis CEO and Cofounder Dominik Schumacher told BioSpace in an email. This will ultimately improve clinical outcomes, he said, adding that the asset will soon advance to Phase I clinical trials. But some analysts are not convinced that ADCs are ready to make a substantive difference in lung cancer. ADCs Not Ready for Prime Time in NSCLC Thanks largely to the available targets of other cancers such as breast, ovarian and prostate cancers, ADCs are “much bigger” in these areas, Bardon said. ADCs need good antibody targets so they can bind to something on the tumor to deliver the payload, Bardon explained, adding that in breast cancer, that target is HER2. Indeed, Enhertu, which targets HER2, was approved for breast cancer the week before it got the green light for HER2-low metastatic NSCLC. “We have a good antibody that addresses that good target,” Bardon said. “Therefore, it’s easy to innovate on the payloads, and that’s why we’ve gotten more sophisticated with our ability to treat breast cancer with ADCs.” But no established treatments for lung cancer are antibody dependent, and that’s why there hasn’t been much progress developing mature ADCs in this area, she noted. That’s not to say they’re totally obsolete. Once ADCs are developed, Bardon sees the future of lung cancer treatment as a cocktail of therapies working together. “We’re just starting to get all the different ingredients of chemo, [immuno-oncology], targeted therapies, and in the future ADCs, and then we’ll combine and mix and match these for the first, second and third line.” Mollie Barnes is a freelance science writer. Reach her at mollie@100yearsco.com. Follow her on Threads and Instagram @shejustlikedtogo or LinkedIn. See more of her work at molliebarnes.contently.com.