Active Biotech : Interview with Prof. Dr. Axel Glasmacher, Independent Board Member at Active Biotech

In collaboration with academic centers in the US and Europe, Active Biotech is about to start two clinical proof-of-concept studies with tasquinimod in Myelofibrosis, a rare blood cancer with high unmet medical need. We discussed with Prof. Glasmacher regarding his views on the biotech sector at present, his experience from working with academic groups and what he thinks about the potential of tasquinimod in myelofibrosis.

I cannot envisage the past or future development of drug treatment without the many contributions of small biopharma companies

- Please let us know about your professional development.

- I am a physician with a focus on hematological malignancies. From 1988 to 2006 I worked at the University Clinic in Bonn with a clinical and scientific focus on these patients, from 2000 as an attending physician with professorial teaching qualification (Privat-Dozent). In 2009 I was appointed adjunct professor of medicine at the faculty of the University of Bonn.

In 2006 I joined Celgene as Medical Director in Germany and led the medical side of the lenalidomide (Revlimid®), azacitidine (Vidaza®) and thalidomide launch, including the risk management systems.

From 2010 to 2014 I worked as Head of Medical Affairs in Europe, Middle East and Africa. In this period we worked intensively and successfully on the EMA Article 20 procedure for lenalidomide that was caused by a concern caused by second primary malignancies. From 2015-2017 my role was Therapeutic Area Head Myeloid Diseases in Global Clinical Research and Development working from Summit, NJ, USA. In this period we brought enasidenib (Idifa®) to FDA approval and established the clinical development plans for luspatercept (Reblozyl®) and durvalumab in hematological malignancies. In 2016 I was promoted to Senior Vice President and led the Global Clinical Research and Development team in hematology-oncology.

In 2018 I retired from Celgene and we returned to Europe. Since then I am working as a consultant for pharmaceutical companies and academic organisations as well as on the board of various biotech companies. I joined the board of the Cancer Drug Development Forum, CDDF, a non-profit organisation dedicated to advancing oncology drug development with all stakeholders, in 2018 (www.cddf.org).

I am also the treasurer of the CDDF.

I have been working with Active Biotech as a consultant since 2018 and joined its board of directors in 2020.

- How do you see the prospects of small biotech companies in the current climate?

- The financial crisis in the biotech sector began in 2022 with the abrupt withdrawal of capital from the sector after a huge inflow in 2020-2021. Since then the majority of small biotech companies have been under huge pressure to refinance and the number of companies that restructured or closed has increased significantly. IPOs were rare and of lower volume. However, in 2024 signs of an improvement have been observed on several parameters.

It is necessary to understand that these small biotech companies are the true source of innovative medicines. Last year, a study demonstrated that of the 138 drugs from the top 20 revenue companies approved by the FDA 70% originated from acquisitions or partnerships with biotech companies. Despite their enormous financial resources, the large pharmaceutical companies have not been able to scale up their research to match the success of small biotech companies.

Additionally, in an era of important financial constraints on healthcare systems small biotech companies have the opportunity to carry out development of new drugs at much lower cost which could potentially result in the introduction of innovative drugs at lower prices.

I cannot envisage the past or future development of drug treatment without the many contributions of small biopharma companies.

- How do you see the importance of tasquinimod for the treatment of hematological malignancies?

- Tasquinimod is an allosteric inhibitor of HDAC4 and interacts with the alarmins S100A8 and S100A9. Tasquinimod thus targets myeloid cells such as myeloid-derived suppressor cells (MDSC) and tumour-associated macrophages (TAM), which have proinflammatory and immunosuppressive effects. S100A8 and S100A9 are damage-associated molecules secreted by activated myeloid cells. S100A9 activates MDSCs, TLR4 and RAGE, which promote proinflammatory responses. Tasquinimod binds S100A8/S100A9 and blocks their effects. The laboratory of Prof Rebekka Schneider-Kramann was able to show that tasquinimod can effectively block fibrotic transformation of the bone marrow. This is the central pathogenic mechanism in myelofibrosis. At the same time there is good pre-clinical evidence that this mechanism could also result in disease-modifying activity in Myelodysplastic Neoplasias (MDS). Similarily, tasquinimod has demonstrated pre-clinical and clinical activity in Multiple Myeloma.

- What are the crucial pieces of data that you would like to see for proof-of-concept of tasquinimod in myelofibrosis?

- Active Biotech is collaborating with two very experienced groups to test tasquinimod in myelofibrosis: the Dutch multicentric group HOVON and the M.D. Anderson Cancer Center. These studies will be able to demonstrate proof-of-concept for tasquinimod in patients with myelofibrosis who have failed standard-of-care treatment (JAK inhibitors). The established endpoint in this disease is the reduction of spleen-size and health-related quality-of-life. Additionally, very important in regard to the findings of in-vitro studies, bone marrow fibrosis will be monitored. Together with an in-depth correlative science program it will be possible to demonstrate proof-of-concept for tasquinimod in myelofibrosis.

- What are your experiences working with Investigator Initiated Trials (IITs) in collaboration with academic groups?

- My experience goes back to the time in the clinic when I was the principal investigator in IITs that our group ran to explore new treatments in hematological malignancies. Later, during my work in Celgene Medical Affairs our team spearheaded a very large independent, investigator-lead research program with more than 200 trials for lenalidomide, pomalidomide and azacitidine in a broad range of indications. Measured by the number and quality of publications and citation indexes this program was very successful.

Celgene also ran pivotal phase III trials (e.g. in multiple myeloma, lymphoma and CNS malignandies) in close collaboration with multicenter study groups like IMF, GELARC/LYSARC and EORTC.

In general, my experience is highly positive. The close relationship with top researchers and clinical study groups that running such trials establish leads to a better alignment of trials with clinical practice and scientific insight. The disadvantage can be a somewhat slower clinical trial execution than in purely commercial structures.

- What are the biggest challenges and opportunities in the current regulatory environment?

- The FDA has brought forward a series of draft guidances documents that affect early clinical development, including Project Optimus for dose optimization and Project Frontrunner for accelerated approval. In my view these initiatives address important areas of clinical development and will lead to its improvement. The request for randomized dose optimization studies in phase II may increase the financial burden for small biotech companies in a critical phase of early development. However, tasquinimod has already a huge clinical data set in solid tumors and some data in hematological malignancies, so the need for dose optimization studies will need to be discussed once the necessary clinical and scientific data is available.

The mechanism of action of tasquinimod is likely to be more efficient in earlier disease stages. Therefore, the opportunity to achieve an early accelerated approval based on an intermediary endpoint out of a randomized study may be quite advantageous for the development of tasquinimod.