On April 11, 2021 StoneWise, a medical technology company that accelerates novel drug discovery with artificial intelligence, reported that it has completed its series B and B+ financing to raise a total of US$100 million (Press release, Stonewise, APR 11, 2021, View Source [SID1234654561]).

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The series B financing was led by Legend Capital, while the series B+ funding was co-led by Greater Bay Area Community Development Fund and Lightspeed China. New investors include CDH VGC Fund and Eastern Bell Capital. Existing shareholders HillHouse Ventures, SIG, Long Hill Capital, and Linear Capital made additional investments.

The proceeds will be used to recruit and retain world-leading talents and upgrade the AI-enabled drug discovery platform so as to advance innovation and improve R&D efficiency.

"We will use the proceeds from these two rounds of financing to strengthenour talent team, accelerate technology iteration, and support project execution," says Zhou Jielong, founder of StoneWise. "We expect more eminent professionals to join us in the early stage of pharmaceutical development. Together, we will identify promising drug candidates faster, advance the use of AI in drug innovation, and improve life quality," he continues.

StoneWise completed four rounds of financing in 2020. Its investors include high impact players in both the pharmaceutical and the AI sectors. The latest financing will empower StoneWise to leverage its molecular design platform and knowledge graph to gear up AI-driven discovery of novel drugs.

It takes up to 15 years and around US$2.6 billion on average to develop a new drug. As one of the global pioneers to apply AI to small molecule drug R&D, StoneWise makes drug development more time-efficient and cost-effective with its drug discovery platform.

The platform provides pharmaceutical companies an integrated solution, featuring a vast range of tools such as a wide range of AI models, interactive medical knowledge graph, deep learning-driven scaffold hopping/derivatization, and generative molecular creation and design.

Richard Li, President of Legend Capital says, "Drug innovation is at the core of pharmaceutical development, and it is also a major entry point for AI application. StoneWise is an industry leader in terms of new technology development, strategic planning and project execution. We are confident that via integrating AI with computational chemistry, pharmacology, molecule dynamics, quantum mechanics, and other cutting-edge technologies, StoneWise will strive to lead AI-driven drug innovation."

"Drug discovery industry faces challenges such as long R&D cycles, low success rates, and sky-rocketing costs, which can be more effectively addressed by AI technologies. Up to now, multiple drugs developed with the support of AI entered into clinical development stages," says Mingyu Wang, senior partner of CDH VGC. "StoneWise’s AI platform has been well received by many pharmaceutical companies. We are confident on its growth potential and expect a continuous output of high-quality drug candidates., and a significantly improved drug discovery R&D system."

On April 11, 2021 Blueprint Medicines Corporation (NASDAQ: BPMC) reported that multiple presentations across the company’s leading systemic mastocytosis (SM) program are being reported at the virtual American Association for Cancer Research (AACR) (Free AACR Whitepaper) Annual Meeting 2021 (Press release, Blueprint Medicines, APR 11, 2021, View Source [SID1234577847]). The presentations focus on registrational PATHFINDER trial data of AYVAKIT (avapritinib) in advanced SM, PIONEER Part 1 data highlighting the impact of AYVAKIT on skin manifestations of SM, and Phase 1 trial data for BLU-263, a next-generation KIT D816V inhibitor. Blueprint Medicines is developing AYVAKIT for advanced and non-advanced SM, and BLU-263 to further address the range of patient needs in non-advanced SM and other mast cell disorders.

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"Data reported at AACR (Free AACR Whitepaper) reflect our commitment to transform treatment for patients living with systemic mastocytosis," said Becker Hewes, M.D., Chief Medical Officer at Blueprint Medicines. "In the PATHFINDER trial, AYVAKIT had high response rates consistent with EXPLORER trial data, reinforcing the profound clinical benefits that can be achieved by precisely targeting the underlying driver of disease. For BLU-263, data in healthy volunteers showed a well-tolerated safety profile and support our plans to initiate the Phase 2/3 HARBOR study, which expands our development efforts into a broader population of patients with non-advanced SM. We are currently on the precipice of our first potential approval in advanced SM, and we are committed to working closely with the SM community so we may meet the needs of patients as quickly as possible."

AYVAKIT – Highlights from the Registrational Phase 2 PATHFINDER Trial

In a pre-specified interim analysis from the PATHFINDER trial, 32 patients who primarily received a starting dose of 200 mg once daily were evaluable for response, as of a data cutoff date of June 23, 2020. Combined with Phase 1 EXPLORER trial results, these data support Blueprint Medicines’ marketing applications in advanced SM under review in the U.S. and Europe. Overall, 75 percent (95% CI: 57%, 89%) of patients had a confirmed response, which was defined as complete remission with full or partial recovery of peripheral blood counts (CR/CRh), partial remission or clinical improvement. The median time to response was two months, and all responses were ongoing at a median follow-up of 10.4 months. The CRh rate was 19 percent, with a median time to CRh of 5.6 months. These results show that responses deepened over time at a rate consistent with the EXPLORER trial.

AYVAKIT led to robust and durable benefits across a number of additional clinical activity measures. In new patient-reported outcomes data, AYVAKIT showed a statistically significant reduction in total symptom score after 40 weeks (p<0.001), as measured by the Advanced Systemic Mastocytosis Symptom Assessment Form. Treatment with AYVAKIT resulted in robust improvements in patient-reported quality of life, based on the European Organization for Research and Treatment of Cancer Quality of Life Questionnaire. Across multiple measures of mast cell burden, AYVAKIT showed profound reductions in serum tryptase, bone marrow mast cells, KIT D816V allele burden and spleen volume.

Consistent with previously disclosed data, AYVAKIT was generally well-tolerated in 62 patients enrolled in the PATHFINDER trial, and most adverse events (AEs) were reported as Grade 1 or 2. The most common AEs (≥15 percent) were peripheral edema, periorbital edema, thrombocytopenia, anemia, neutropenia, diarrhea, nausea, vomiting and fatigue. Three patients (5 percent) discontinued AYVAKIT due to treatment-related AEs, and most patients (84 percent) have remained on treatment as of the data cutoff date.

"These data reinforce the potential of avapritinib to improve the standard of care for patients with advanced systemic mastocytosis, a disease characterized by organ damage due to mast cell infiltration," said Daniel DeAngelo, M.D., Ph.D., Chief of the Division of Leukemia at Dana-Farber Cancer Institute. "I am highly encouraged by the rapid and durable responses shown across multiple measures of mast cell burden, patient-reported symptoms as well as quality of life. Furthermore, avapritinib was generally well-tolerated, with 5 percent of patients discontinuing due to treatment-related adverse events. Since avapritinib is able to selectively target the primary driver of the disease, it has the potential to fundamentally change the outlook for patients with advanced SM."

AYVAKIT – Statistically Significant Reductions of Aberrant CD30-Positive Mast Cells in Skin Lesions Shown in Phase 2 PIONEER Trial

In non-advanced SM, skin symptoms frequently persist and can severely impact quality of life. To assess the effects of AYVAKIT on mast cell burden in skin lesions, skin biopsies were obtained at baseline and week 12 in Part 1 of the PIONEER trial. Immunohistochemistry tests were performed to determine the proportion of aberrant mast cells in skin tissue, based on expression of CD25, CD30 and other transmembrane receptors observed in SM. Skin lesional tissue at baseline had more CD30-positive than CD25-positive mast cells. Following 12 weeks of treatment, AYVAKIT significantly reduced the proportion of aberrant CD30-positive mast cells in skin lesions compared to placebo (p=0.0082), as of a data cutoff date of December 4, 2020. These data expand on previously reported results showing the impact of AYVAKIT on skin manifestations of SM, and suggest that CD30 may be an important biomarker of aberrant mast cells in SM-related skin lesions.

BLU-263 – Safety and Pharmacokinetics Profile from Phase 1 Trial in Healthy Volunteers

A placebo-controlled, Phase 1 trial evaluated the safety, tolerability and pharmacokinetics of BLU-263 in healthy volunteers. This AACR (Free AACR Whitepaper) presentation reported on single ascending dose cohorts (15 to 200 mg doses) and multiple ascending dose cohorts (25 to 100 mg once-daily doses for ten consecutive days), as of a data cutoff date of November 9, 2020. BLU-263 was well-tolerated across all doses studied, and all AEs were reported as Grade 1. Pharmacokinetic data showed dose-dependent increases in systemic exposure of BLU-263, with the half-life of BLU-263 supporting once-daily dosing. Based on these results, the company plans to evaluate BLU-263 at doses ranging from 25 to 100 mg once daily in Part 1 of the Phase 2/3 HARBOR trial in patients with non-advanced SM, which the company plans to initiate in mid-2021.

Copies of Blueprint Medicines data presentations from the AACR (Free AACR Whitepaper) annual meeting are available in the "Science—Publications and Presentations" section of the company’s website at www.BlueprintMedicines.com.

Conference Call Information

Blueprint Medicines will host a live webcast on Monday, April 12, 2021 beginning at 8:00 a.m. ET to review data for multiple research- and clinical-stage programs presented at the AACR (Free AACR Whitepaper) annual meeting. To access the live call, please dial (855) 728-4793 (domestic) or (503) 343-6666 (international) and refer to conference ID 5548976. A webcast of the conference call will be available under "Events and Presentations" in the Investors & Media section of Blueprint Medicines’ website at View Source The archived webcast will be available on Blueprint Medicines’ website approximately two hours after the conference call and will be available for 30 days following the call.

About SM

SM is a rare disease driven by the KIT D816V mutation. Uncontrolled proliferation and activation of mast cells result in chronic, severe and often unpredictable symptoms for patients across the spectrum of SM. The vast majority of those affected have non-advanced (indolent or smoldering) SM, with debilitating symptoms that lead to a profound, negative impact on quality of life. A minority of patients have advanced SM, which encompasses a group of high-risk SM subtypes including aggressive SM, SM with an associated hematological neoplasm and mast cell leukemia. In addition to mast cell activation symptoms, advanced SM is associated with organ damage due to mast cell infiltration and poor survival.

Debilitating symptoms, including anaphylaxis, maculopapular rash, pruritis, diarrhea, brain fog, fatigue and bone pain, often persist across all forms of SM despite treatment with a number of symptomatic therapies. Patients often live in fear of severe, unexpected symptoms, have limited ability to work or perform daily activities, and isolate themselves to protect against unpredictable triggers. Currently, there are no approved therapies for the treatment of SM that selectively inhibit D816V mutant KIT.

About AYVAKIT (avapritinib)

AYVAKIT (avapritinib) is a kinase inhibitor approved by the U.S. Food and Drug Administration (FDA) for the treatment of adults with unresectable or metastatic gastrointestinal stromal tumors (GIST) harboring a PDGFRA exon 18 mutation, including PDGFRA D842V mutations. For more information, visit www.AYVAKIT.com. This medicine is approved in Europe under the brand name AYVAKYT for the treatment of adults with unresectable or metastatic GIST harboring the PDGFRA D842V mutation, and in China for the treatment of adults with unresectable or metastatic PDGFRA exon 18 mutant GIST.

AYVAKIT/AYVAKYT is not approved for the treatment of any other indication, including SM, in the U.S. by the FDA, in Europe by the European Commission or in China by the National Medical Products Administration, or for any indication in any other jurisdiction by any other health authority.

Blueprint Medicines is developing AYVAKIT globally for the treatment of advanced and non-advanced SM. The FDA granted breakthrough therapy designation to AYVAKIT for the treatment of advanced SM, including the subtypes of aggressive SM, SM with an associated hematological neoplasm and mast cell leukemia, and for the treatment of moderate to severe indolent SM.

To learn about ongoing or planned clinical trials, contact Blueprint Medicines at [email protected] or 1-888-BLU-PRNT (1-888-258-7768). Additional information is available at www.pioneertrial.com or www.clinicaltrials.gov.

Blueprint Medicines has an exclusive collaboration and license agreement with CStone Pharmaceuticals for the development and commercialization of AYVAKIT in Mainland China, Hong Kong, Macau and Taiwan. Blueprint Medicines retains development and commercial rights for AYVAKIT in the rest of the world.

About BLU-263

BLU-263, a next-generation KIT D816V inhibitor, has the potential to expand the reach of KIT D816V-targeted therapy to a broad population of patients with non-advanced SM and related mast cell disorders. BLU-263 was designed to target D816V mutant KIT with similar sub-nanomolar potency as AYVAKIT, enhanced selectivity and minimal central nervous system penetration. BLU-263 was developed based on learnings from the AYVAKIT clinical program. The initial focus of the BLU-263 development program is non-advanced SM.

On April 11, 2021 Antengene Corporation Limited ("Antengene", SEHK: 6996.HK), a leading innovative biopharmaceutical company dedicated to discovering, developing and commercializing global first-in-class and/or best-in-class therapeutics in hematology and oncology, reported that the first patient has been dosed in a phase II trial (BUNCH) in China of ATG-008 (onatasertib), a second-generation mTORC1/2 inhibitor, for the treatment of advanced solid tumors harboring NFE2L2, STK11, RICTOR or other specific genetic alterations (Press release, Antengene, APR 11, 2021, View Source [SID1234577870]). The purpose of the single-arm, open-label trial is to evaluate the safety and efficacy of ATG-008 in patients with such advanced solid tumors that may be predictably sensitive to inhibition of mTORC1/2.

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According to the latest report by the World Health Organization, there were an estimated 19.3 million newly diagnosed cancer cases and 10 million cancer-related mortalities in 2020 globally. Furthermore, the report also projected a 47% increase in cancer-related disease burden in the coming 20 years. China now ranks number one in both cancer incidence and mortality rates[i]. This reminds us of the daunting challenges in cancer treatment and the ever more urgent need for effective novel anti-cancer therapies in China.

There is a close association between the mTOR signaling pathway and genetic mutations in NFE2L2, STK11 and RICTOR. ATG-008, a potent selective inhibitor of mTOR kinase that is currently under clinical development, may induce the cell death of multiple tumor types through the dual-inhibition of mTORC1 and mTORC2. Therefore, mTOR inhibitor ATG-008 has the potential to offer a new treatment option for patients with advanced solid tumors with such genetic alterations. Moreover, preclinical and clinical data also demonstrated the potent antitumor activity of ATG-008 in multiple tumor types.

Dr. Jay Mei, Founder, Chairman and CEO of Antengene, commented: "There are urgent needs for more effective treatment options for patients with various advanced solid tumors. We believe ATG-008 has strong potential to address a serious unmet medical need in a hard-to-treat group of cancers. This trial also marks an important step in the development of our innovative pipeline for the treatment of patients with solid tumors in China. We look forward to producing important clinical data to guide the further development and continue to demonstrate Antengene’s leadership in drug development for mTORC1/2 inhibitors."

Antengene has initiated several clinical trials in China and other Asia Pacific countries and regions with ATG-008 in the treatment of advanced hepatocellular carcinoma (HCC), advanced non-small-cell lung cancer (NSCLC) and in combination with an anti-PD-1 antibody in advanced solid tumors including hepatocellular carcinoma (HCC).

About ATG-008 (onatasertib)

ATG-008 (onatasertib) is a second-generation mTORC1/2 inhibitor, for which development and commercialization rights in Asia Pacific were licensed from Celgene (now Bristol Myers Squibb). ATG-008 is currently being studied in multi-regional clinical trials for the treatment of advanced hepatocellular carcinoma (HCC), as well as non-small-cell lung cancer (NSCLC), advanced solid tumors harboring NFE2L2, STK11, RICTOR or other specific genetic alterations and other cancers as a single agent or in combination with an anti-PD-1 antibody.

On April 11, 2021 Taiho Oncology, Inc. reported efficacy and safety results from the Phase 2 FOENIX-CCA2 trial, a single-arm multicenter Phase 2 study evaluating futibatinib (TAS-120) in patients with intrahepatic cholangiocarcinoma (iCCA) harboring FGFR2 gene rearrangements including gene fusions who have failed at least one line of therapy (Press release, Taiho, APR 11, 2021, View Source [SID1234577871]). The data were presented online as an oral presentation at the American Association for Cancer Research (AACR) (Free AACR Whitepaper) Annual Meeting 2021 Week 1 Clinical Trials Plenary from 2:00 – 3:45 PM ET on April 11, 2021.

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In the FOENIX-CCA2 trial, 103 patients with locally advanced or metastatic unresectable iCCA harboring FGFR2 gene rearrangements including fusions who had received one or more prior lines of systemic therapy received futibatinib 20 mg once daily until disease progression or unacceptable toxicity. The study met its primary endpoint of a greater than 20% objective response rate (ORR) assessed by independent central review with an ORR of 41.7%. Secondary endpoints of duration of response (DOR) and disease control rate (DCR) were also reported; responses were durable, with a median DOR of 9.7 months and 72% of responses ≥6 months, and a DCR of 82.5%. Median progression-free survival (PFS) was 9.0 months and median overall survival (OS) was 21.7 months, with 72% of patients alive at 12 months.

Common treatment-related adverse events (TRAEs) were hyperphosphatemia (85%), alopecia (33%) and dry mouth (30%). The most frequent grade 3 TRAE was hyperphosphatemia (30%), which resolved in patients with adequate management. One grade 4 TRAE of increased ALT was reported and there were no treatment related deaths.

"The results of FOENIX-CCA2 are significant for patients living with refractory intrahepatic cholangiocarcinoma with FGFR2 gene fusions or other rearrangements as futibatinib showed a meaningful ORR of 41.7% and good durability of responses," said medical oncologist Lipika Goyal, MD, MPhil, Massachusetts General Hospital Cancer Center, and lead investigator on the study. "These results represent another example of the promise of precision medicine in cholangiocarcinoma and indicate that futibatinib could be an option for patients with refractory CCA if approved."

The U.S. Food and Drug Administration (FDA) granted Breakthrough Therapy Designation (BTD) for futibatinib for the treatment of patients with previously treated locally advanced or metastatic cholangiocarcinoma harboring FGFR2 gene rearrangements, including gene fusions in February 2021 based on efficacy and safety results from the FOENIX-CCA2 study. The FDA Office of Orphan Drug Development granted futibatinib orphan drug status for the treatment of cholangiocarcinoma in May 2018.

Additional Data on Futibatinib (TAS-120) in iCCA Presented

Taiho Oncology also presented preclinical and Phase 1 clinical data for futibatinib at AACR (Free AACR Whitepaper) as poster presentations. Presentations include:

Acquired resistance to ATP-competitive and irreversible FGFR inhibitors (FGFRi’s): A library-based approach: Hiroshi Sootome, MS, Manager, Translational Research Planning & Management group, Taiho Pharmaceutical Co., Ltd. (1117). Results were shared online as a poster presentation from 8:30 AM – 11:59 PM ET on April 10, 2021.
Effect of futibatinib on QT/QTc interval: a randomized, controlled, double-blind study: Ikuo Yamamiya, PhD, Associate Director, Bioanalytics & DMPK, Taiho Oncology, Inc. (CT128). Results were shared online as a poster presentation from 8:30 AM – 11:59 PM ET on April 10, 2021.
Evaluation of potential drug-drug interactions (DDIs) between futibatinib and CYP3A inhibitors/inducers, CYP3A substrates, or proton pump inhibitors (PPIs): Ikuo Yamamiya, PhD, Associate Director, Bioanalytics & DMPK, Taiho Oncology, Inc. (CT125). Results were shared online as a poster presentation from 8:30 AM – 11:59 PM ET on April 10, 2021.
Please visit Taiho Oncology’s virtual Medical Booth for more information.

"With the low survival rates typically seen in patients with intrahepatic cholangiocarcinoma, the possibility of a new treatment option with demonstrated efficacy and safety is an important development for the oncology community," said Martin J. Birkhofer, MD, Senior Vice President and Chief Medical Officer, Taiho Oncology, Inc. "Taiho Oncology looks forward to sharing these data with regulatory authorities, with the hope of supporting approval for this important investigational therapy."

About Futibatinib (TAS-120)
Futibatinib (TAS-120) is an investigational, oral, potent, selective, and irreversible small-molecule inhibitor of FGFR1, 2, 3 and 4 being studied as a potential treatment for patients with advanced solid tumors with FGFR1-4 genetic aberrations, including cholangiocarcinoma, who were previously treated with chemotherapy or other therapies. Futibatinib selectively and irreversibly binds to the ATP binding pocket of FGFR1-4 resulting in the inhibition of FGFR-mediated signal transduction pathways, reduced tumor cell proliferation and increased tumor cell death in tumors with FGFR1-4 genetic aberrations.

About Cholangiocarcinoma
Cholangiocarcinoma (CCA), also known as bile duct cancer, is not common. About 8,000 people in the U.S. are diagnosed with CCA each year.1 This includes both intrahepatic (inside the liver) and extrahepatic (outside the liver) cancers. CCA can occur at younger ages, but it is seen mainly in older people. The average age of people in the U.S. diagnosed with cancer of the intrahepatic bile ducts is 70, and for cancer of the extrahepatic bile ducts it is 72.1 The five-year survival rate of intrahepatic CCA (all SEER stages combined) is 9%.2

The main treatment for CCA is surgery. Radiation therapy and chemotherapy may be used if the cancer cannot be entirely removed with surgery and in cases where the edges of the tissues removed at the operation show cancer cells (also called a positive margin). Both stage III and stage IV cancers cannot be completely removed surgically. Currently, standard treatment options are limited to radiation, palliative therapy, liver transplantation, surgery, chemotherapy and interventional radiology.3

On April 10, 2021 Spectrum Pharmaceuticals (NasdaqGS: SPPI), a biopharmaceutical company focused on novel and targeted oncology therapies, reported a data update on the safety and tolerability of twice daily (BID) administered poziotinib in NSCLC patients with EGFR or HER2 exon 20 insertion mutations (Press release, Spectrum Pharmaceuticals, APR 10, 2021, View Source [SID1234577824]). These preliminary data, from Cohort 5 of the ZENITH20 clinical trial, continue to show improved tolerability with BID dosing, reduced dose interruption compared to once daily (QD) dosing, and a reduction in treatment emergent Grade 3 or higher adverse events. The preliminary data also demonstrate improved anti-tumor activity with 8mg BID dosing. The presentation is part of the AACR (Free AACR Whitepaper) Virtual Meeting 2021 taking place April 10-15, 2021.

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"The 8mg BID dosing arm is showing the best performance we have seen across the various dosing arms for a mixed population of EGFR and HER2 exon 20 insertion mutations in NSCLC patients. There is clearly an improved therapeutic effect and a lower adverse event rate which is highly encouraging," said Francois Lebel, M.D., Chief Medical Officer of Spectrum Pharmaceuticals. "We are currently expanding the 8mg BID dataset and look forward to evaluating this dose in additional NSCLC patients and other solid tumors."

A copy of the AACR (Free AACR Whitepaper) presentation titled "Poziotinib administered twice daily improves safety and tolerability in patients with EGFR or HER2 exon 20 mutations" is available on Spectrum’s website at View Source

ZENITH20 Trial Design and Preliminary Safety and Efficacy Data for Cohort 5

Cohort 5 of the ZENITH20 trial includes previously treated NSCLC patients with EGFR or HER2 exon 20 insertion mutations. This cohort is investigating the efficacy of poziotinib with various dosing levels including BID administration. For the 38 patients randomized to poziotinib 16mg QD or 8mg BID in Cohort 5, improved responses were reported in the BID arm with 31.6% of patients (6/19) reaching a partial response. For the 38 patients randomized to poziotinib 12mg QD or 6mg BID, these dosing levels were not as active as 8mg BID but showed improved tolerance with BID dosing relative to QD dosing.

Improved tolerability was also observed for the typical TKI related adverse events, with a clinically meaningful reduction in Grade 3 or higher adverse events for the 8mg BID dose relative to 16mg QD. In addition, there were fewer dose interruptions and dose reductions for the BID arms relative to the same QD dose. Cohort 5 is now enrolling exclusively in the 8mg BID arm and data collection is ongoing.

About Poziotinib

Poziotinib is a novel, oral epidermal growth factor receptor tyrosine kinase inhibitor (EGFR TKI) that inhibits the tyrosine kinase activity of EGFR as well as HER2 and HER4. Importantly this, in turn, leads to the inhibition of the proliferation of tumor cells that overexpress these receptors. Mutations or overexpression/amplification of EGFR family receptors have been associated with a number of different cancers, including non-small cell lung cancer (NSCLC), breast cancer, and gastric cancer. The company holds an exclusive license from Hanmi Pharmaceuticals to develop, manufacture, and commercialize poziotinib worldwide, excluding Korea and China. Poziotinib is currently being investigated by the company and Hanmi in several mid-stage trials in multiple solid tumor indications.