• Dr. Kurt Gehlsen

Dr. Kurt Gehlsen: Why Can We Cure Mice With Cancer And Not Our Patients?

Although, 5-year survival for all cancers and all stages is 72% and 10-year survival is 52%, for late-stage cancer patients the 5-year survival rates range from 8% to 25% depending on tumor type. Many of the drugs approved and in development demonstrate remarkable activity in mouse models but these results unfortunately do not fully translate to patients. There is a significant need to better destroy the tumors with products that are safe, curative and provide the expected quality of life.

I have been fortunate in my 35-year career in life sciences, with specific focus in oncology, to have seen tremendous improvements in our understanding of most forms of cancer. Moreover, treatments have significantly evolved from the staples of surgery, radiation and chemotherapy to immune-based therapy, cellular therapy, oncolytic viruses, targeted radiation, biologics, radiopharmaceuticals and antibody-drug conjugates. The expansion of our knowledge of very specific signaling pathways such as kinases, DNA repair mechanisms and the complex biology reported almost monthly can leave one’s head spinning. Moreover, the Pharma/Biotech industry spends a lot of time and money chasing the newest targets hoping they have found the one which can be curative. Unfortunately, most of these incredible discoveries fall short in our quest to cure patients.

While many new start-up companies in-license an inventor’s discovery and focus all efforts on that product and biology, DASH Therapeutics was founded on a different principle. We are focused on understanding why we don’t cure our patients and then how can we more effectively destroy the tumors and not be focused on the newest biology of one pathway or the new target of the month.

While virtually all current therapies outside immuno-oncology, specifically target the tumor cells, there is a long history of research looking at how tumors create a supportive environment by recruiting and modulating various stromal cells like macrophages, monocytes, dendritic cells, fibroblasts, pericytes and endothelial cells. Current drugs that target the tumor cells need to overcome many barriers created by the tumor microenvironment, these include immune-suppression mechanisms, a ‘not-so-leaky’ vasculature, diffusion barriers from a lack of lymphatics and the extracellular matrix that is formed by fibroblasts. Once a drug reaches the tumor, it still must attach to a receptor or be internalized into the cell in order to kill it. Most drugs fail to overcome many of these impediments and the drug concentrations required to really kill the tumor cannot be achieved.

DASH Therapeutics was founded to address many of the obstacle’s tumors create to avoid being killed. DASH Therapeutics identifies a particular obstacle and then develops or sources a solution it believes solves the problem, with the end goal to cure more patients. DASH Therapeutics is currently developing three products, with plans for several others as we grow.

DT-011 targets immune-suppression caused by tumor associated macrophages. The science around DT-011 has been well established with over 17 clinical studies, 350 publications and an approved small molecule- CepleneTM. Ceplene was studied in stage 4 melanoma, metastatic renal cell carcinoma and acute myeloid leukemia (AML). It is approved as the first remission maintenance therapy for AML with a remarkable improvement in long-term remission. Below are leukemia-free survival curves from two cohorts of a Phase 3 study (left panel represents the Intent-to-treat population (ITT) and the right panel represents the patients treated in their first remission, also ITT). The graphs show significant improvement in survival for patients using Ceplene (HDC) plus IL-2.

Brune, M., Castaigne, S., Catalano, J., Gehlsen, K., Hofmann, W-K., Ho, A., Hogge, D., Nilsson, B., Or, R., Rowe, J., Simonsson, B., Spearing, R., Stadtmauer, E., Szer, J., Wallhult, E., Hellstrand, K. Improved leukemia-free survival after post-consolidation treatment with histamine dihydrochloride and interleukin-2 in AML: A randomized phase III trial. Blood, 108:1, 88-96, July 2006.

The problem with Ceplene is that it is a twice-daily subcutaneous injection where each injection lasts for 10-30 minutes to allow the patient to tailor their side effects during injection. Patients inject themselves twice-daily for 3 weeks on and then 3 weeks off for up to 18 months. This clearly isn’t patient friendly. Both patients and physicians have not embraced the product despite the good clinical outcomes.

DASH will re-engineer this product so that it is patient friendly. The solution is to develop a biologic (antibody-based drug) that will be dosed once every 3 or 4 weeks. Because the original product also targeted four different receptors, DT-011 will target only the one required to shut down macrophage suppression, which should lead to a safer product.

DT-022 is a targeted radiopharmaceutical therapy that specifically targets and destroys both the tumor-associated vasculature and targets and kills the cancer-associated fibroblasts. Destroying the tumor-associated vasculature in essence starves the tumor and makes the vasculature ‘leaky’ so other drugs (in combination with DT-022), and immune cells, can have better access to the tumor. Most importantly, because the product will deliver a radioisotope warhead, the killing radius is such that all surrounding cancer-associated fibroblasts and the tumor cells will also be killed. With the improved success and growth of targeted radiopharmaceutical therapies, specifically delivering the radiation is a better and safer way to kill the tumor. An additional advantage to this approach is the ability to use PET imaging to visualize those tumors that have the DT-022 target. This creates an image of the true tumor burden in the entire patient. Radiopharmaceuticals and this ‘theranostic’ approach are fast becoming a growing area because one does not need to deliver as much drug, overcoming the tumor obstacles such as the diffusion barriers mentioned previously, while killing both the tumor cells and all the surrounding tumor-supportive cells. Imaging is the added bonus enabling a tailored and personalized approach. The power of a radiopharmaceutical was recognized by Novartis who acquired Endocyte for $2.1b for a Phase 2 prostate cancer asset, the data for which is shown in the figure below. Note, the significant tumor burden from PET imaging in the left paired panel and the demolition of the tumors after 3 months in the paired right panel.

SNMMI IMAGE OF THE YEAR 2018: PSMA PET before and after lutetium-177 PSMA617 theranostic in 8 patients with metastatic prostate cancer who exhausted standard therapeutic options. 68Ga-PSMA11 PET maximum intensity projection (MIP) images at baseline and 3 months after 177Lu-PSMA617 in 8 patients with PSA decline ≥ 98 percent in a prospective phase II study. Any disease with SUV over 3 is in red. Credit: Michael Hofman, John Violet, Shahneen Sandhu, Justin Ferdinandus, Amir Iravani, Grace Kong, Aravind Ravi Kumar, Tim Akhurst, Sue Ping Thang, Price Jackson, Mark Scalzo, Scott Williams and Rodney Hicks, Peter MacCallum Cancer Centre, Melbourne, Australia. J Nucl Med May 1, 2018 vol. 59 no. supplement 1 531

DT-033 is also a targeted radiopharmaceutical therapy using the theranostic approach that specifically targets and destroys both the tumor-associated vasculature and targets and kills the tumor cells. This product is much like DT-022 but to a different target and may be better for tumor types different from DT-022. CD276, also known as B7-H3 is a protein upregulated on tumor-associated blood vessels and not on normal blood vessels. CD276 is also expressed on tumor cells and potentially other tumor stromal cells. As seen below, CD276 (brown stain) is over-expressed in both vessels and tumor cells in cancers of the brain, breast, colon, kidney, lung and pancreatic. Yet it is not expressed in normal tissue. There is a “naked” monoclonal antibody against CD276 currently being tested in phase 1 clinical trials and no reported serious adverse side effects have been reported. This product does not deliver a tumor killing payload like what DASH will develop.

Core to the DASH development strategy is the ability to develop novel antibody-based product formats. By recognizing the obstacle’s tumors create to avoid being killed, we have designed formats that provide the best chance for success for each product. For example, for DT-011 we want a long retention time and therefore a full antibody format is best. For DT-022 and DT-033 we have designed much smaller formats through the use of engineered VH domains. Half-life extension technology and specialized linkers have been designed to allow for tuning of tumor targeting and blood clearance to better match the pharmacokinetics, half-life of the radioisotope used and the tumor types targeted. DASH cleverly uses all the available engineering tools available to the industry to tailor optimized drugs that should lead to better clinical outcomes.

Strategy and Economics

DASH will develop DT-011 to early partnering/out-licensing before Phase 2, either as a preclinical or Phase 1 asset. The licensing economics of such a product that performs as well or better than Ceplene can include significant license fees, milestone fees and royalties. Considering the extensive work done on the target to get Ceplene to market, it is expected that DT-011 is a lower risk program.

We expect DT-022 to be developed though a Phase 1/2a clinical study and then licensed to Pharma. A well designed Phase 1/2a study in cancer patients will produce both positive imaging data and response data. With this data, based on other transactions in the industry recently, it is expected we can out-license DT-022 for favorable economics due to demand for targeted radiopharmaceutical therapies. The strategy and economics for DT-033 is similar to DT-022 and by targeting a broad range of different cancers, we have products that have a high probability to be partnered and can be potentially curative for patients. Taken together, these opportunities further reduce the risk for shareholders.

For the initial three products, the targets have been selected to destroy the tumor supportive environment and therefore the tumors using well-validated targets. DASH has a sophisticated design and antibody engineering approach to tackle these targets in a better way. Moreover, a big advantage of all three programs is the broad nature of the cancer types that can be treated. Combined with the theranostic approach for patient selection using the same product for imaging as well, all these approaches aim for better clinical outcomes and with a vision to a cure for cancer.

DASH is looking to raise a seed round of $6 million USD to achieve the following:

a) DT-011 to an IND and then explore possible partnering/licensing transactions

b) DT-022 through a Phase 1/2a clinical trial and a possible partnering/licensing transaction

c) DT-033 to preclinical proof-of-concept studies

If both DT-011 and DT-033 need to proceed to a Phase 1 trial before partnering/licensing, then we anticipate raising a Series A round of $9-12 million USD in 2 years.

Although, DASH can exit via an IPO or acquisition, while we explore those options, DASH is offering the Seed Investors under the preferred share agreement, the rights to 40% of all licensing revenues received by DASH from partnering/licensing. This revenue-sharing should provide early returns on investment and a significant upside to the seed round investors.

If you would like to learn more, please contact Dr. Kurt R. Gehlsen at kurt.gehlsen@gmail.com or +1 (520) 904-8396.

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