An extremely interesting drug in the pipeline which has been featured at ENETS, NANETS, ESMO and ASCO.
Chi-Med will submit a New Drug Application (NDA) to the US FDA for them to consider approval. It is anticipated the NDA will arrive in FDA by the end of this year.
The story follows
PRESS RELEASE: LONDON, June 01, 2020 (GLOBE NEWSWIRE) — Hutchison China MediTech Limited (“Chi-Med”) (Nasdaq/AIM: HCM) today announces that it has held its pre-New Drug Application (“NDA”) meeting with the U.S. Food and Drug Administration (“FDA”) for surufatinib for the treatment of patients with advanced neuroendocrine tumors (“NET”). Chi-Med has reached an agreement with the FDA that the completed SANET-ep (non-pancreatic NET) and SANET-p (pancreatic NET) studies, along with existing data from surufatinib in U.S. non-pancreatic and pancreatic NET patients, could form the basis to support a U.S. NDA submission.
The FDA granted Fast Track Designation status to surufatinib for the non-pancreatic and pancreatic NET development programs in April 2020. Chi-Med has initiated preparatory work for the U.S. NDA and intends to utilize a rolling submission under Fast Track Designation Status. The rolling NDA allows completed portions of an NDA to be submitted and reviewed by the FDA on an ongoing basis. Filing acceptance of the NDA is subject to FDA review of the complete application. The planned start of the NDA submission is late 2020.
Surufatinib is a novel, oral angio-immuno kinase inhibitor that selectively inhibits the tyrosine kinase activity associated with vascular endothelial growth factor receptor (VEGFR) and fibroblast growth factor receptor (FGFR), which both inhibit angiogenesis, and colony stimulating factor-1 receptor (CSF-1R), which regulates tumor-associated macrophages, promoting the body’s immune response against tumor cells. Its unique dual mechanism of action may be very suitable for possible combinations with other immunotherapies, where there may be synergistic anti-tumor effects.
Chi-Med currently retains all rights to surufatinib worldwide.
NET in the U.S., Europe and Japan: In the U.S., surufatinib was granted Fast Track Designations for development in pancreatic and non-pancreatic (extra-pancreatic) NET in April 2020, and Orphan Drug Designation for pancreatic NET in November 2019. A U.S. FDA NDA submission is being prepared. Regulatory interactions in Europe and Japan are also underway to confirm the clinical development strategy and potential path to registration. All such interactions are based on the robust data from the two positive Phase III studies of surufatinib in NET in China, and the ongoing multi-cohort Phase Ib study in the U.S. that began in November 2015 (clinicaltrials.gov identifier: NCT02549937).
Non-pancreatic neuroendocrine tumors in China: In November 2019, a NDA for surufatinib for the treatment of patients with advanced non-pancreatic NET was accepted for review by the China National Medical Products Administration (NMPA) and granted Priority Review status in December 2019. The NDA is supported by data from the successful SANET-ep study, a Phase III study of surufatinib in patients with advanced non-pancreatic neuroendocrine tumors in China for whom there is no effective therapy. A 198-patient interim analysis was conducted in June 2019, leading the Independent Data Monitoring Committee (“IDMC”) to determine that the study met the pre-defined primary endpoint of progression-free survival (“PFS”) and should be stopped early. The positive results of this trial were highlighted in an oral presentation at the 2019 European Society for Medical Oncology Congress (clinicaltrials.gov identifier: NCT02588170).
Pancreatic neuroendocrine tumors in China: In 2016, we initiated the SANET-p study, which is a pivotal Phase III study in patients with low- or intermediate-grade, advanced pancreatic NET in China. A second NDA for surufatinib for the treatment of patients with advanced pancreatic NET is being prepared for submission, following an interim analysis review conducted in January 2020 by the IDMC that recommended the registrational study be terminated early as the pre-defined primary endpoint of PFS had already been met (clinicaltrials.gov identifier: NCT02589821). Study results will be submitted for presentation at an upcoming scientific conference.
Biliary tract cancer in China: In March 2019, we initiated a Phase IIb/III study comparing surufatinib with capecitabine in patients with advanced biliary tract cancer whose disease progressed on first-line chemotherapy. The primary endpoint is overall survival (OS) (clinicaltrials.gov identifier NCT03873532).
Immunotherapy combinations: We have entered into collaboration agreements to evaluate the safety, tolerability and efficacy of surufatinib in combination with anti-PD-1 monoclonal antibodies, including with tislelizumab (BGB-A317), Tuoyi® (toripalimab) and Tyvyt® (sintilimab), which are approved in China.
I first heard about this drug at ENETS Barcelona 2017 and then again in 2018. It’s now starting to be discussed in USA including at the 2019 ASCO and more recently in the 2019 ESMO conference. It was known then as Sulfatinib but for reasons unclear to me it was changed later to Surufatinib. It’s a novel, oral angio-immuno kinase inhibitor that selectively inhibits the tyrosine kinase activity (TKI) associated with vascular endothelial growth factor receptor (VEGFR) and fibroblast growth factor receptor (FGFR), which both inhibit angiogenesis, and colony stimulating factor-1 receptor (CSF-1R), which regulates tumor-associated macrophages, promoting the body’s immune response against tumor cells. Its unique dual mechanism of action may be very suitable for possible combinations with other immunotherapies. Surufatinib, manufactured by Hutchinson China MediTech Ltd (Chi-Med), is in proof-of-concept clinical trials in the USA and several proof-of-concept and late-stage clinical trials in China.
If you’ve heard of VEGFR and TKI before, you may be thinking of a known NET drug called Sutent (Sutininib) which works in a similar fashion – although Surufatinib looks more thorough and complex in its method of operation. Interestingly, no anti-angiogenic treatment is yet approved for extrapancreatic neuroendocrine tumors (NETs). Extrapancreatic simply means outside the pancreas, i.e. anywhere except the pancreas. Worth noting for context, Sutent (Sutininib) is only approved for pNETs. This type of drug, along with something called mammalian Target Of Rapamycin (mTOR) inhibitor used in Everolimus (Afinitor) are collectively known as ‘Targeted Therapy’ – they are not a type of chemotherapy.
The Phase Ib/II Clinical Trial
In the single-arm phase Ib/II study of surufatinib in advanced NETs, clinicaltrials.gov identifier: NCT02267967, the following outcome was reported:
Experimental Design: Patients with histologically well-differentiated, low or intermittent grade, inoperable or metastatic NETs were enrolled into a pancreatic or extrapancreatic NETs cohort. Patients were treated with surufatinib 300 mg orally, once daily. The primary endpoints were safety and objective response rate (ORR) according to Response Evaluation Criteria in Solid Tumors (version 1.1). Results: Of the 81 patients enrolled, 42 had pancreatic NETs, and 39 had extrapancreatic NETs. Most patients had radiological progression within one year prior to enrollment (32 patients in each cohort). In the pancreatic and extrapancreatic NETs cohorts, ORRs were 19% (95% CI 9-34) and 15% (95% CI 6-31), disease control rates were 91% (95% CI 77-97) and 92% (95% CI 79-98), and median progression-free survival was 21.2 months (95% CI 15.9-24.8) and 13.4 months (95% CI 7.6-19.3), respectively. The most common grade ≥3 treatment-related adverse events were hypertension (33%), proteinuria (12%) hyperuricemia (10%), hypertriglyceridemia and diarrhea (6% for each), and increased alanine aminotransferase (5%). Conclusions: Surufatinib showed encouraging anti-tumor activity and manageable toxicities in patients with advanced NETs. Two ongoing phase III studies, validating the efficacy of surufatinib in patients with NETs, will contribute to the clinical evidence.
The Phase III Clinical Trial (non Pancreatic NETs)
SANET-ep is a Phase III study in China of surufatinib in patients with low- or intermediate-grade. SANET-ep is an acronym for “Surufatinib Advanced NET (ExtraPancreatic) aimed at patients for whom there is no effective therapy. ExtraPancreatic’ simply means outside the pancreas, i.e. anywhere except the pancreas.
In this study, patients are randomized at a 2:1 ratio to receive either 300 mg of surufatinib orally daily or placebo, on a 28-day treatment cycle. The primary endpoint of the study is to evaluate the progression free survival (PFS), with secondary endpoints including objective response rate (ORR), disease control rate (DCR), time to response (TTR), duration of response (DoR), overall survival (OS), safety, and tolerability. Additional details may be found at clinicaltrials.gov, using identifier NCT02588170.
London: Friday, June 14, 2019: Hutchison China MediTech Limited today announces that the independent Data Monitoring Committee (IDMC) of the Phase III pivotal study of SANET has completed a planned interim analysis. The IDMC determined that the study has already met the pre-defined primary endpoint of PFS and as a result the study will be stopped. (note: results detail awaited).
Chi-Med will now arrange for a pre-New Drug Application (NDA) meeting with the China National Medical Products Administration (NMPA) to discuss the preparation of the NDA for surufatinib for this indication. We intend to submit the results of the SANET-ep study for presentation at an upcoming scientific conference.
Any Trials for Pancreatic NETs?
In 2016, the manufacturer initiated the SANET-p study, which is a pivotal Phase III study in patients with low- or intermediate-grade, advanced pNETs. They expect an interim analysis in late 2019 and enrollment to complete in 2020 – clinicaltrials.gov identifier: NCT02589821.
Any Trials for other types of Neuroendocrine Neoplasm?
There’s one trial showing called “Study of Sulfatinib in Treating Advanced Medullary Thyroid Carcinoma and Iodine-refractory Differentiated Thyroid Carcinoma” – see NCT02614495
Any Trials for other cancers?
There’s another clinical trial of surufatinib in Biliary tract cancer in China: In March 2019, the manufacturer initiated a Phase IIb/III study comparing surufatinib with capecitabine in patients with advanced biliary tract cancer whose disease progressed on first-line chemotherapy. The primary endpoint is overall survival (OS) – see – NCT03873532
Any combo surufatinib with immunotherapy?
In November 2018, the manufacturer entered into collaboration agreements to evaluate the safety, tolerability and efficacy of surufatinib in combination with checkpoint inhibitors. This included a global collaboration to evaluate the combination of surufatinib with Tuoyi®, a PD-1 monoclonal antibody approved in China in late 2018 by Shanghai Junshi Biosciences Co. Ltd. Check out this clinical trial entitled “Trial of Sulfatinib (sic) Combined With JS001 in the Treatment of Advanced Solid Tumors” – NCT03879057. As at 14th Jan 2020, they’re also recruiting for the phase 2 trial – click here.
Interest point – incidence of Neuroendocrine Tumours in China
Some of my research indicated that the manufacturer estimates there were approximately 67,600 newly diagnosed neuroendocrine patients in 2018 and, considering the U.S. incidence to prevalence ratio, potentially as many as 490,000 patients living with the disease. Authors note: Many specialists agree that the US figures are under-reported so the Chinese estimates are probably also under-reported and possibly have excluded Neuroendocrine Carcinomas from their figures. In fact, given the population of China compared to USA, the prevalence figure is more likely to be nearer one million and the annual incidence rate is likely to be closer to 90,000 (extrapolated and based on 2012 published figures of 23,000 annual incidence rates and a 171,321 prevalence figure). Read more about the incidence and prevalence of Neuroendocrine Neoplasms in my running article – Not as rare as you think.
Please note the above clinical trials documents do not list USA as a trial location but I have at least one person from USA in my closed Facebook group on one of the trials.
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