Gilead Sciences and Tubulus have signed an exclusive option and license agreement to discover and develop an antibody-drug conjugate (ADC) against a solid tumor target.
Through this agreement, Gilead will access Tubulis’ proprietary Tubutecan and Alco5 platforms. The companies will collaborate to select the best technology to utilize, with Tubulis leading discovery and development efforts to design a Topoisomerase I inhibitor-based ADC candidate with superior biophysical properties and stability to address current treatment challenges such as durability and off-target toxicity.
“As we expand our oncology portfolio to address the greatest gaps in care, accessing novel technologies is critical to advancing our pipeline,” said Flavius Martin, MD, Executive Vice President, of Research, Gilead Sciences.
“With Gilead’s ongoing focus on innovating with next-generation therapies and combinations, we are excited to partner with Tubulis to explore a range of solutions that may help increase the therapeutic value of the ADC modality,” Martin added.
“Gilead has established a long track record of developing drugs that provide a significant step-up in therapeutic value, making them a great collaborator for leveraging our technology platforms, in line with our vision of fundamentally changing the ADC landscape,” said Dominik Schumacher, PhD, CEO and co-founder of Tubulis.
“Tubulis remains primarily focused on driving value through our own clinical development programs while selectively building partnerships with leaders in the industry,” Schumacher explained.
Terms of the Agreement
Under the terms of the agreement, Tubulis will receive an upfront payment of $20 million and, if Gilead exercises its option, a separate option exercise fee of $30 million. In addition, Tubulis will be eligible for development and commercialization milestone payments totaling up to $415 million, plus mid-single to low double-digit tiered royalties on sales of marketed products resulting from the collaboration. Tubulis will lead early-stage research and development activities for the ADC program. If Gilead exercises its option to exclusively license the program, Gilead will be responsible for further development and commercialization activities for all products resulting from the collaboration.
Gilead does not exclude acquired IPR&D expenses from its non-GAAP financial measures. This transaction with Tubulis is expected to reduce Gilead’s GAAP and non-GAAP 2024 EPS by approximately $0.01.
P5 conjugation platform
Tubulus has developed a suite of complementary platform technologies for the discovery and development of a new generation ADCs. Using the the company’s proprietary technology platform, drug developers are able to overcome some of the main limitations of current ADC technologies. The company’s P5 conjugation platformis a novel chemistry for cysteine-selective conjugation that enables ADC generation with unprecedented linker stability and superior biophysical properties.
The company’s proprietary Tubutecan – topo-I linker-payload platform optimized the on-target delivery of topoisomerase-I inhibitors combined with active reduction of unwanted target-independent toxicities. Using this technology, researchers at Tubulus were able to achieve stable and high payload attachment (DAR8) without compromising on the biophysical properties of the whole ADC molecule.
Approved Topo-I ADCs using maleimide-based conjugation, including trastuzumab deruxtecan (which uses a maleimide-based linker attached a potent topoisomerase I inhibitor (deruxtecan) to the HER2-targeting antibody trastuzumab) and sacituzumab govitecan (where the topoisomerase I inhibitor SN-38 is conjugated to a TROP2-targeting antibody using a similar maleimide-based linker), on average loses over 60% of their payload over time resulting in an average drug-to-antibody ratio (DAR) of only 3 after three days. In contrast, ADCs sing the Tubulus proprietary P5 conjugation technology remains stable over seven days in serum.
The unique profile of Tubulus’ Tubutecan based ADCs translates to long lasting in-vivo potency where a single dose treatment of 1 mg/kg results in significant benefit and complete remission in all animals over a period of 90 days.
TUB-040
In June 2024 the U.S. Food and Drug Administration (“FDA”) granted a Fast Track designation to Tubulis lead antibody-drug conjugate (ADC) TUB-040, a next-generation NaPi2b-targeting Exatecan ADC based on the company’s proprietary P5 technology, currently being evaluated in a multicenter Phase I/IIa study NAPISTAR 1-01 (NCT06303505).
The investigational agent demonstrated superior effective and durable responses in a range of preclinical models, including ovarian cancer and 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.
“Almost all patients with ovarian cancer who are not cured by initial therapy will develop resistance to platinum-based therapy over time. Once platinum-resistant, therapeutic options for these patients are poor with highly unsatisfactory outcomes. The FDA’s Fast Track designation of TUB-040 is an important step in the development of TUB-040 to provide these women with urgently needed new therapeutic options,” noted Günter Fingerle-Rowson, MD, PhD, Chief Medical Officer of Tubulis in June.
“The FDA decision brings us one step closer to our goal of delivering the true value of ADCs to patients in need, and we are grateful for the agency’s support on this path to develop TUB-040 fast and efficiently.”
TUB-030
Tubulis is also developing TUB-030, an investigational ADC directed against 5T4, a cancer-associated antigen expressed in a wide range of solid tumor indications. TUB-030 consists of an IgG1 antibody targeting 5T4 connected to the topoisomerase I inhibitor Exatecan through a cleavable linker system based on the company’s proprietary P5 conjugation technology with a homogeneous drug-to-antibody-ratio (DAR) of 8. In preclinical development, TUB-030 shows that it efficiently delivers its payload to the tumor while reducing off-site toxicities. TUB-030 demonstrated effective and durable responses, even at lower target expression levels, as well as an excellent safety profile in a range of preclinical solid tumor models. Based on these promising preclinical results, Tubulis is currently preparing the initiation of a first clinical trial with TUB-030.
Additional programs
In addition to the agreement signed with Gilead, Tubulus has a muotitargetd collaboration with Bristol Meyers Squibb (BMS) for the development of various, multi-target ADCs, and with Oncoteq for the development of TUB-010/TEQ102, wiich targers CD30 and is being developed for the treatment of in T-cell and Hodgkin’s Lymphoma.
Clinical trials
FiH Study to Investigate Safety, PK and Efficacy of the NaPi2b ADC TUB-040 in Patients with PROC or R/r Adenocarcinoma NSCLC (NAPISTAR1-01) – ClinicalTrials.gov ID NCT06303505
References
[1] Ochtrop P, Jahzerah J, Machui P, Mai I, Schumacher D, Helma J, Kasper MA, Hackenberger CPR. Compact hydrophilic electrophiles enable highly efficacious high DAR ADCs with excellent in vivo PK profile. Chem Sci. 2023 Jan 3;14(9):2259-2266. doi: 10.1039/d2sc05678j. PMID: 36873847; PMCID: PMC9977445.
[2] Kasper MA, Stengl A, Ochtrop P, Gerlach M, Stoschek T, Schumacher D, Helma J, Penkert M, Krause E, Leonhardt H, Hackenberger CPR. Ethynylphosphonamidates for the Rapid and Cysteine-Selective Generation of Efficacious Antibody-Drug Conjugates. Angew Chem Int Ed Engl. 2019 Aug 19;58(34):11631-11636. doi: 10.1002/anie.201904193. Epub 2019 Jul 18. PMID: 31250955; PMCID: PMC6851832.
[3] Kasper MA, Glanz M, Stengl A, Penkert M, Klenk S, Sauer T, Schumacher D, Helma J, Krause E, Cardoso MC, Leonhardt H, Hackenberger CPR. Cysteine-Selective Phosphonamidate Electrophiles for Modular Protein Bioconjugations. Angew Chem Int Ed Engl. 2019 Aug 19;58(34):11625-11630. doi: 10.1002/anie.201814715. Epub 2019 Apr 29. PMID: 30828930.
