Clinical Insights from L-DOS47 Trials in NSCLC

Lung cancer is the most common form of cancer and the leading cause of cancer-related deaths worldwide. Smoking is responsible for approximately 85% of all cases, while other factors such as environmental and occupational exposures further elevate the risk. If detected early, lung cancer is often highly treatable; annual low-dose CT screenings can significantly improve survival outcomes, as revealed by the 20-year survival rate of 80% of patients with lung cancer screened under the International Early Lung Cancer Action Program. However, as early-stage lung cancer is typically asymptomatic, the disease often goes undiagnosed until it is at a more advanced stage and harder to treat. At this point in the disease progression, treatment options are severely limited and patients have a poor prognosis, contributing to high lung cancer mortality rates. 

Non-small cell lung cancer (NSCLC) accounts for the vast majority of all lung cancer diagnoses and up to 70% of these cases are only diagnosed once the cancer has reached advanced stage IV. Over the past decade, the approval of immune checkpoint inhibitors (ICIs), starting with pembrolizumab in 2016, has led to a transformation in first-line therapy for patients whose tumors express high levels of biomarkers such as PD-L1. Compared to platinum-based chemotherapy, pembrolizumab has been shown to improve median progression-free survival from 6 to 10.3 months and increased overall response rate from 27.8 % to 44.8 % as first-line therapy for NSCLC. However, eligibility for these treatments depends on the presence of specific biomarkers, leaving 70.5% of NSCLC patients not eligible for treatment with ICIs, while eligible patients continue to face significant challenges in achieving durable responses. This demonstrates a clear need for new and complementary approaches that will improve outcomes and expand patient access. 

How L-DOS47 Could Transform NSCLC Treatment

L-DOS47, our lead candidate at Helix BioPharma, is a clinical-stage antibody-enzyme conjugate (AEC) designed to enhance the effectiveness of today’s leading therapies for NSCLC. Administered intravenously, L-DOS47 consists of a urease enzyme linked to nanobodies that specifically target carcinoembryonic antigen-related cell adhesion molecule 6 (CEACAM6)—a protein minimally present in healthy tissues but over-expressed in NSCLC. The nanobodies act as precision guides, directing L-DOS47 to CEACAM6 on the surface of tumor cells in the lungs. Once anchored to the tumor, the urease enzyme reacts with naturally-occurring urea in the tumor microenvironment (TME), converting urea into ammonia and carbon dioxide. This reaction elevates pH, neutralizing the acidity of the TME—a hostile condition that fuels tumor survival, growth and spread, while helping the tumor evade immune cells and resist treatment. 

By neutralizing the acidity of the TME, L-DOS47 restores the conditions needed for immune cells to function—boosting their infiltration, activation, and cytokine production—so that immune checkpoint inhibitors can act on fitter, more responsive immune cells in a less hostile environment, and mount a more efficient attack on NSCLC. 

Early studies demonstrate that the L-DOS47 design works effectively to modulate the TME, leading to enhanced anti-tumor activity. L-DOS47 has completed two clinical studies in patients with lung cancer:

  1. A Phase I/II, open-label, non-randomized dose escalation study assessing the impact of L-DOS47 as a single agent (monotherapy) in patients with advanced-stage NSCLC (Stages IIIb or IV) and who were not eligible for chemotherapy or radiotherapy or who had refractory NSCLC (NCT02340208);
  2. A Phase I, open-label, dose-escalation study assessing the impact of L-DOS47 in combination with chemotherapy (Pemetrexed/Carboplatin) in patients with Stage IV recurrent or metastatic NSCLC (NCT02309892);

 

In this blog article, we discuss the outcomes of these studies, which ultimately set the stage for more durable responses in NSCLC.

Establishing the Safety and Efficacy of L-DOS47 

The first-in-human study of L-DOS47 was designed to identify safe dosage of L-DOS47, with intravenous administration as a monotherapy to patients with NSCLC. Each treatment cycle consisted of two weekly infusions (Days 1 and 8) followed by a 7-day rest period, and stable disease. The term ‘stable disease’ refers to tumor control during the period, with neither tumor shrinkage or progression. Weekly doses of L-DOS47 (0.12 – 13.55 μg/kg) were well tolerated, with only one dose-limiting toxicity (spinal pain) observed. Thirty-two patients achieved stable disease after two cycles, including 13 who showed measurable tumor shrinkage. One patient also remained progression-free through 10 cycles, highlighting L-DOS47’s favorable safety profile and suggesting that L-DOS47 may be most beneficial when used in combination therapies.

This study was followed by a Phase Ib study in NSCLC, in which we assessed L-DOS47 in combination with standard chemotherapy agents, pemetrexed and carboplatin. The trial did not find any dose-limiting toxicities, with patients tolerating the therapy well at doses of up to 9.0 μg/kg (the maximum dose in this study). In addition to demonstrating a favorable safety profile, the efficacy data for L-DOS47 was also encouraging. The trial reported an overall clinical benefit rate of 75%, which included partial RECIST responses (Response Evaluation Criteria in Solid Tumors – a standardized method for measuring changes in tumor size and appearance), as well as cases of stable disease. In light of the fact that prior studies with pemetrexed and carboplatin reported overall response rates (ORRs) ranging from just 24% to 31%, these results are especially encouraging. Across all patients, the median duration of response was 187 days, with progression-free survival extending beyond six months. One of the patients who had been heavily pretreated also achieved near-complete remission, highlighting the potential of L-DOS47 combination therapy to fundamentally alter the disease trajectory for some patients with late-stage NSCLC. 

These findings suggest that L-DOS47 can effectively disrupt the tumor’s defenses and enhance the activity of standard chemotherapy. The clinical outcomes observed not only validate the scientific rationale behind L-DOS47’s mechanism of action but also lay a strong foundation for future studies, especially those exploring combination strategies to further improve patient outcomes. In addition, a Phase II trial was launched in March 2019 to compare the safety, tolerability and efficacy of L-DOS47 in combination with vinorelbine and cisplatin. Unfortunately, the Ukraine-based study was discontinued due to the outbreak of war in 2022, and no further data was collected. 

Beyond NSCLC, preclinical work in CEACAM6-expressing pancreatic cancer models has shown that L-DOS47 raises the tumor extracellular pH by approximately 0.13 units for up to 96 hours, and when combined with anti-PD-1 therapy, it inhibits tumor growth for up to four weeks. Building on these insights, we are preparing a Phase Ib study of L-DOS47 in combination with pembrolizumab in NSCLC, slated to begin in 2025, to assess whether remodeling the tumor microenvironment can amplify checkpoint inhibitor efficacy.

Implications for the Future

As we move into the Phase Ib pembrolizumab study in 2025, we are cautiously optimistic about the future. If successful, L-DOS47 could not just transform outcomes in NSCLC but could also lay the groundwork for more robust therapies when dealing with other CEACAM6-positive tumors. Such advances may push the boundaries of precision oncology, making immunotherapy accessible to a larger group of patients, giving them renewed hope in the fight against NSCLC and other hard-to-treat cancers.

Reference:

1 https://www.wcrf.org/preventing-cancer/cancer-statistics/lung-cancer-statistics/; https://www.who.int/newsroom/fact-sheets/detail/lung-cancer
2 https://www.who.int/news-room/fact-sheets/detail/lung-cancer
3 https://pubs.rsna.org/doi/full/10.1148/radiol.231988
4 https://pmc.ncbi.nlm.nih.gov/articles/PMC8724440/
5 https://pmc.ncbi.nlm.nih.gov/articles/PMC10477621/
6 https://pmc.ncbi.nlm.nih.gov/articles/PMC10836497/
7 https://www.sciencedirect.com/science/article/abs/pii/S0223523424000503
8 https://www.biorxiv.org/content/10.1101/2023.08.28.555194v1.full
9 https://www.jto.org/article/S1556-0864(16)32740-X/fulltext
10 https://pmc.ncbi.nlm.nih.gov/articles/PMC9576893/
11 https://pubmed.ncbi.nlm.nih.gov/23434351/
12 https://www.mdpi.com/2227-9059/12/2/461

Jacek Antas

Chief Executive Officer

Jacek Antas is a shareholder of the Company, has spent more than 25 years in the financial services industry holding various positions in sales and consulting.

Mr. Antas obtained a master’s degree from the Warsaw School of Economics and has served as a board member of various
companies throughout his career.

This will close in 0 seconds

James B. Murphy

Chief Financial Officer

Mr. Murphy is a certified public accountant with over thirty years of experience in finance and operations management. He is currently a consultant with Danforth Advisors LLC (“Danforth”), a leading provider of outsourced strategic and operational specialists across functions in the life sciences industry. While at Danforth, Mr. Murphy has served over fifteen private and publicly held life sciences companies as CFO and CFO Advisor, helping them secure over USD 0.5 billion in financing and successfully execute pivotal asset transactions. Mr. Murphy functions as a consultant to Helix pursuant to a consulting agreement between the Company and Danforth.

This will close in 0 seconds

Thomas Mehrling

Medical Adviser

Thomas Mehrling (PhD in Pharmacology and MD) has over 20 years’ experience in multinational Pharma companies developing novel oncology compounds from preclinical research through to registration. Prior to entering the industry, he spent 13 years as an MD at the University Hospital in Frankfurt, working on preclinical and translational projects. He served as Director of European Oncology at Mundipharma International (2003–2013), building the company’s first European oncology business from the ground up out of Cambridge, UK, and completing the clinical development, registration and launch of two major products in Europe, DepoCyte® and Levact® (Ribomustin® and Treanda®). In 2013, he led the establishment of the Mundipharma Group’s start-up, Mundipharma EDO, developing anti-cancer therapeutics for solid tumours out of Basel, Switzerland.

This will close in 0 seconds

Christof Boehler

Chief Business Development Officer

Dr. Christof Boehler is a commercially oriented scientist with a proven track record in building and leading teams that successfully commercialize products and services in the life science industry. His core competencies are in technology transfer, business development and corporate governance with a focus on technology scouting, preclinical and clinical R&D, licensing, sales, capital raising and M&A.

Mr. Boehler is also a strategic advisor to Takeda.

This will close in 0 seconds

Kim Gaspar

Director Quality Assurance

Kim is the Director of Quality Assurance at Helix BioPharma Corp. An experienced quality assurance professional with expertise in Canadian, US, and EU regulations, she has been involved in all aspects of Phase I/II biopharmaceutical product development over the years, including regulatory submissions, QC laboratory compliance, tech transfer and third-party oversight of CMC activities, clinical QA, and bioanalytical data analysis. Kim joined Helix in 2000, transitioning into QA in 2003. She holds a B.Sc in Biochemistry and a Ph.D in Veterinary Physiological Sciences, both from the University of Saskatchewan.

This will close in 0 seconds

Brenda Lee

Director Clinical Operations

Brenda is the Clinical Operations Director at Helix Biopharma Corp. A clinical research operations professional with 25 years of experience managing clinical trials, ranging from early Phase I to late Phase IIIb/IV studies, she brings experience in clinical study protocol writing and development, trial start-up and vendor management, and a proven track record in planning and managing clinical trials to quality standards, timelines and budget. Brenda joined Helix Biopharma Corp. in 2018, working to advance the clinical program of L-DOS47. She holds B.Sc and M.Sc. degrees from the University of Toronto, specializing in Nutritional Sciences and Human Biology.

This will close in 0 seconds

Praveen Kumar

V.P. Drug Development

Praveen has experience working in the pharmaceutical industry for more than 25 years and has expertise in the development of drug products for small and macro-molecules using various dosage forms. He was involved in projects comprising the formulation development of generic drug products and their production and developed a novel transdermal drug product containing a protein-based drug (interferon alpha 2b) for the treatment of HPV infections.

Presently as a V.P. he manages the CMC-related activities (drug product formulation, technology transfer, quality, stability testing and interaction with regulatory agency) for the development of L-DOS47 drug product, an antibody drug conjugate, for the treatment of various cancers. He has a Ph.D. in Pharmaceutical sciences and he completed his post-doctoral fellowship in gene regulation. He was the author of multiple peer-reviewed published articles, a book chapter, and patents.

This will close in 0 seconds

Jerzy Leszczynski

Director

Jerzy Leszczynski is a shareholder of the Company, has spent more than 35 years developing businesses and has served in the capacity of board member of various real estate development companies. Mr. Leszczynski obtained his Master of Science in Chemistry from the Warsaw Institute of Technology.

This will close in 0 seconds

Janusz Grabski

Director, Chair of Audit Committee

Janusz (John) Grabski is a lawyer specialized in corporate and real estate law with over twenty years of experience.

This will close in 0 seconds

Malgorzata Laube

Director

Malgorzata Laube has over 19 years of experience in nuclear medicine. In her last role with Alberta Health Services, she was the Department Supervisor, Nuclear Medicine at Royal Alexandra Hospital. Ms. Laube obtained a MSc degree in Environmental Engineering from the Warsaw University of Technology and is based in Edmonton, Alberta, Canada.

This will close in 0 seconds

Jacek Antas

Chairman of the Board

Jacek Antas is a shareholder of the Company, has spent more than 25 years in the financial services industry holding various positions in sales and consulting.

Mr. Antas obtained a master’s degree from the Warsaw School of Economics and has served as a board member of various
companies throughout his career.

This will close in 0 seconds

Jonathan Davis

Advisor, ADC Discovery

Jonathan Davis received his Ph.D. from University of California, San Francisco, where he studied protein structure and function using NMR. After a post-doc at Harvard Medical School exploring RNA selection and structure in the labs of Jack Szostak and Gerhard Wagner, he went to work at EMD Serono, where his work involved improving antibody-based therapeutics, inventing a platform technology for generating heterodimeric Fcs as a basis for multifunctional molecules, and developing a novel scaffold based on an artificially-designed protein from David Baker’s lab. In 2008 he took a job at Bristol-Myers Squibb in Waltham/Cambridge MA, working on antibody discovery and platform development in a wide range of therapeutic areas, with a particular focus on multispecific therapeutics. He moved to Madison, WI in 2019 to take on the role of VP of Innovation and Strategy at Invenra, a biotech focused on bispecific antibodies, and where he is currently head of the Scientific Advisory Board. In early 2024 he left the corporate world to found Creative Antibodies, a consulting firm that helps guide companies to successful antibody discovery and development projects, from mAbs to multispecifics, ADCs, and other formats. Outside of science, Jonathan is a conservatory trained cellist, plays numerous other instruments, and founded the UCSF Orchestra (now Symphony Parnassus) in San Francisco, where he was Music Director for six years.

This will close in 0 seconds

Davide Guggi

Advisor, CMC

Davide graduated as a pharmacist and received his PhD in Pharmaceutical Technology and Biotechnology from the University of Vienna. He has over 20 years of experience in the pharmaceutical industry, principally in the field of oncology. At the beginning of his career, Davide led oncology business units and commercial departments at Mundipharma and Gilead across Austria and Eastern Europe. Since over 10 years he has been working as a CMC expert, covering operational and regulatory CMC functions on behalf of over 20 different small- and medium-sized biotech companies across the world. He has served as CMC Director and CSO/CTO for several years, developing both small molecules and biologics (mABs, Fab, ADCs and Radio-immuno-conjugates) from early discovery to NDA/BLA in the US, EU and Canada, with a focus on First-in-Human and Phase I/II studies in oncology indications.

This will close in 0 seconds