FDA Accepts NDA Resubmission for Dasynoc in CML

The FDA has accepted for filing the new drug application (NDA) resubmission for Dasynoc (XS004-dasatinib), a protein kinase inhibitor product candidate for patients with chronic myeloid leukemia (CML).¹

The first NDA submission for the agent was submitted in 2021 under the 505(b)(2) NDA procedure, the registration path for improved drugs.² In January 2022, the FDA announced to Xspray Pharma, the drug developer, that they would begin a full review of the application. However, in July 2023, the FDA issued a complete response letter (CRL) to Xspray Pharma when additional information about the drug’s proper dosing and third-party manufacturing facility was requested. This CRL pertained to all 6 dosing levels of Dasynoc under review by the FDA (15 mg, 36 mg, 50 mg, 57 mg, 70 mg, and 100 mg), but did not identify deficiencies in the stability of the agent or the clinical data that were submitted to the regulatory agency in support of the NDA. The CRL also requested that Xspray Pharma provide additional information to support its NDA.

The target action date for the current NDA is July 31, 2024, under the Prescription Drug User Fee Act (PDUFA).¹ With this established PDUFA date, Xspray Pharma plans to commercially launch Dasynoc on September 1, 2024. These dates align with Xspray Pharma’s comprehensive preparation for Dasynoc to become a new treatment option for patients with CML.

“We appreciate the FDA’s diligent review of our resubmission and look forward to collaborating closely with the agency in the lead-up to the PDUFA date,” Per Andersson, chief executive officer of Xspray Pharma, said in a news release. “Our team is fully committed to addressing the FDA’s requirements and ensuring that healthcare providers and patients have clear, comprehensive information on Dasynoc’s dosing and administration.”

Dasynoc is a bioequivalent, optimized, amorphous solid dispersion version of dasatinib (Sprycel), a TKI with improved properties for patients with CML, including potential administration at a 30% lower dose with improved variability.^4,5

Data from a retrospective registry study that were presented at the 2022 ASH Annual Meeting demonstrated that patients with CML who received concomitant treatment with TKIs and PPIs (n = 302) experienced an inferior 5-year overall survival rate of 79% vs 94% in patients who received a TKI alone (n = 374; HR, 3.5; 95% CI, 2.1-5.3; P < .0001).⁵ These findings indicate that TKI absorption levels are negatively affected by PPIs. However, comedication with the PPI omeprazole did not affect Dasynoc uptake in 16 healthy volunteers who participated in a crossover portion of the study.

Furthermore, dasatinib is highly pH dependent, resulting in plasma concentration reductions at higher gastric pH levels. Dasatinib comedication with PPIs decreases dasatinib plasma exposure by over 40% and is cautioned against by the FDA. However, this retrospective study showed that since Dasynoc is designed to increase solubility of the active drug at slightly acidic or neutral gastric pH levels, its reduced gastric pH dependency contributes to its efficacy during concomitant omeprazole treatment. 

In 2022, Dasynoc was granted orphan drug designation by the FDA for the treatment of patients with CML.⁶

References

1. FDA Accepts Xspray Pharma’s NDA resubmission for Dasynoc – PDUFA date set to 31 July 2024. News Release. Xspray Pharma AB. February 12, 2024. Accessed February 14, 2024. https://www.biospace.com/article/releases/fda-accepts-xspray-pharma-s-nda-resubmission-for-dasynoc-pdufa-date-set-to-31-july-2024/?keywords=cancer
2. About us – a timeline. Xspray Pharma. Accessed February 13, 2024. https://xspraypharma.com/about-us/2313-2/
3. Xspray Pharma receives request for additional information concerning Dasynoc from FDA. News Release. Xspray Pharma AB. July 11, 2023. Accessed February 13, 2024. https://xspraypharma.com/modular_finance_pressmeddelande/xspray-pharma-receives-request-for-additional-information-concerning-dasynoc-from-fda/
4. Xspray Pharma partners with EVERSANA for the U.S. launch and commercialization of its lead product, Dasynoc (XS004) for the treatment of chronic myeloid leukemia (CML) and acute lymphatic leukemia (ALL). News release. Xspray Pharma AB. February 23, 2023. Accessed February 13, 2024. https://www.prnewswire.com/news-releases/xspray-pharma-partners-with-eversana-for-the-us-launch-and-commercialization-of-its-lead-product-dasynoc-xs004-for-the-treatment-of-chronic-myeloid-leukemia-cml-and-acute-lymphatic-leukemia-all-301754015.html
5. Larfors G, Lennernäs H, Liljebris C, et al. Comedication of proton pump inhibitors and dasatinib is common in CML but XS004, a novel amorphous solid dispersion formulation of dasatinib, provides improved uptake and low pH-dependency, minimizing unwanted drug-drug interactions. Blood. 2022;149(suppl 1):6769-6770. doi:10.1182/blood-2022-156487
6. Dasynoc granted orphan drug designation in the US for the treatment of chronic myeloid leukemia. News release. Xspray Pharma. June 17, 2022. Accessed February 13, 2024. https://xspraypharma.com/modular_finance_pressmeddelande/dasynoc-granted-orphan-drug-designation-in-the-us-for-the-treatment-of-chronic-myeloid-leukemia/