Frequently Asked Questions

  • Has the patent been approved? Yes. The patent is also public. We are starting the national approval phase. We decided to go for a broad coverage (Europe, North America, Asia...). There are additional patents in the pipeline.
     
  • How is the "Freedom to Operate"? Excellent: this has been confirmed in writing by an independent  patent office ("No relevant patent applications were found that would block the use of the above indicated nitro-imidazol compounds as carbonic anhydrase inhibitors, radiosensitizer or in cancer treatment”).
     
  • What makes this anti-cancer drug unique? The drug has a double mechanism of action that increases the attacks on tumors in a targeted fashion: it regulates the pH of tumor cells, which helps limit tumor development, and it sensitizes hypoxic tumor cells to radiation and other treatments (doxorubicin, Temozolomide...). In animal trials, it has proven to be non-toxic to normal tissue and can be administered orally.
     
  • Is CA IX present in all tumors? No. However, if CA IX expression were present in all tumors, it would likely be present in normal tissue and the risk of toxicity would rise. It is advantageous to have biomarkers that identify tumors for which the drug is more likely to be effective. This will also reduce the cost of clinical trials.
     
  • Was the drug found through a drug library? No it is a rationally designed drug. We first screened more then 100 compounds with an in vitro CA IX assay. Then we used the ”delta pH” assay (proving that the drugs were inhibiting he function of CA IX) followed by clonogenic assays in vitro. Finally out of the 10 best drugs we picked one after having done animal experiments.
     
  • Could the drug prevent metastasis? Yes, they are several publications showing that (e.g. Gieling J Med Chem 2012). It has been suggested that CA IX inhibitors acts on stem cells (Lock et al. Oncogene 2012).
     
  • What is the difference between this drug (DH348) and Nimorazole, the radiosensitizer of reference? Nimorazole does not block CA IX and is "CA IX independent" (therefore has no effect on metastasis)
    • Nimorazole has no antitumoral effect as single treatment in contrast with DH348 which acidifies the cell and increases the uptake or the activation of certain drugs.
    • Nimorazole has does not sensitize tumors to drugs such Temozolomide, Doxorubicine (in contrast with DH348 which acidifies the cell and increases the uptake or the activation of certain drugs).
    • While Nimorazole works at much higher doses(mM), DH348 is effective at a microMolar concentration. In short, DH348 is much more than a radio sensitizer: it is a "smart anticancer drug".
    • In vivo, Nimorazole needs effective concentrations starting from 300 up to 1000 mg/kg (with DH348, we observe an effect as from 10 mg/kg).
       
  • What is the difference between your compound and the antibody RENCaREX® (Girentuximab) which failed in a phase III trial in renal cell cancer? Girentuximab is not a CA IX inhibitor. It does not bind to the CA active site but on the backbone of the protein without interfering with its activity. After binding, the cells expressing CA IX are killed by immune system mediated processes. So, it is very different from our compounds, which inhibit the enzyme activity and therefore interfere with pH regulation.
     
  • What is the competitive advantage of your product? Until now all the CA IX inhibitors tested were hardly specific with a significant "off target effect" (e.g. Indisulfam, Acetazolomide...) or were not specifc for the hypoxic CA IX (Girentuximab). Conversely, DH348 is extremely specific for hypoxic CA9 resulting in no liver and stomach toxicity.  Additionally, there is no "off target effect" when the CA9 is not present as opposed to acetazolamide. Furthermore, no toxicity is found at 100 mg/kg, no weight loss is observed, and the therapeutic effect starts at 10 mg/kg while the effect of the average LD50 sulf(on)amide based drugs is above 600 mg/kg. Last, the drug has two effects, and CA9 impacts stem and metastatic cells.
     
  • What if the drug's toxicity in Phase 1 trials were higher than expected? Animal trials suggest no toxicity, so we are very optimistic. If we see signs of toxicity, we will continue to optimize the current drug. We will also begin tests on other promising drugs that are covered by the patent.
     
  • Do you have a partner for clinical trials? MAASTRO Clinic has been engaged to conduct clinical trials. MAASTRO is a well-respected cancer hospital with €28 million research budget and a solvability ratio of 25%.
     
  • What rights have been contracted? An exclusive worldwide license has been given to DualTpharma as well as a "first right of refusal" to other new patents related to CA IX inhibition. These contracts were audited and positively evaluated by an independent office.
     
  • What indication strategy will you pursue? Even if the therapeutic target is present in several solid tumors, we intend to focus on two priorities: a frequent cancer “Non Small Cell Lung Cancer” and an orphan indication (for which there are several regulatory incentives) “Small Cell Lung Cancer”.
     
  • How long will it take to complete Phase 1 and Phase 2a trials? Four years is a conservative but realistic period to complete Phases 1 and 2a.
     
  • Are the bioisosters of your leading compound covered by your patent? Yes the active bioisosters of the  pharmacophoric function responsible of the CA inhibitory activity are covered. We patented the sulfonamide, sulfamate and sulfamide series. Sulfamate and sulfamide  are bioisosters of sulfonamide. The other  sulfonamide bioisosters for example, amide function, are not covered by the patent because they  are not active against Carbonic Anhydrase IX. We have experimental evidence to prove this.