China

1. Ripretinib

Overview

Ripretinib has been approved by the U.S. Food and Drug Administration (FDA) on May 15, 2020, and Health Canada (HC-SC) on June 19, 2020. The drug is developed and marketed by Deciphera Pharmaceuticals under the trade name It is QinlockTM. Ripretinib is a tyrosine kinase inhibitor that can target wild-type, primary and secondary mutant KIT kinases, platelet-derived factor receptor A kinase (PDGFRA), etc. The drug is approved for the treatment of adult patients with advanced gastrointestinal stromal tumor (GIST) who have been treated with 3 kinase inhibitors. QinlockTM is an oral tablet with a strength of 150 mg. The recommended medication is 150 mg once a day.

R&D milestones

The compound was approved as a U.S. orphan drug for the treatment of gastrointestinal stromal tumors in 2014 and was certified by the FDA as a breakthrough therapy for the treatment of patients with advanced GIST in 2019.

In June 2019, Zai Lab and Deciphera announced an exclusive licensing agreement to promote the development and commercialization of Ripretinib in Greater China (Mainland China, Hong Kong, Macau and Taiwan).

2. Avapritinib

Overview

Avapritinib was approved by the U.S. Food and Drug Administration (FDA) on January 9, 2020, and was approved by the European Medicines Agency (EMA) on September 24, 2020. It was developed and marketed by Blueprint Medicines under the trade name Ayvakit ®. Avapritinib is a tyrosine kinase inhibitor that targets the PDGFRA and PDGFRA D842 mutants and the KIT exon 11, 11/17, and 17 mutants. This product is approved for the treatment of adult patients with unresectable or metastatic gastrointestinal stromal tumors with PDGFRA exon 18 mutations, including PDGFRA D842V mutations. Ayvakit® is an oral film-coated tablet, each containing 100 mg, 200 mg, and 300 mg of Avapritinib. The recommended dose is 300 mg, once a day, orally on an empty stomach at least 1 hour before meals or 2 hours after meals.

Financing and trading

On June 4, 2018, CStone Pharmaceuticals and Blueprint Medicines reached an exclusive cooperation and licensing agreement. CStone Pharmaceuticals obtained the authorization for clinical development and commercialization of Avapritinib in mainland China, Hong Kong, Macau and Taiwan.

R&D milestones

In February 2019, Avapritinib was approved by the NMPA to launch its Phase III clinical trial (imported Class 1 new drug) in China as a third-line or above treatment of KIT gene mutation-driven gastrointestinal stromal tumor (GIST).

This product was granted Orphan Drug, Fast Track and Breakthrough Therapy qualifications by the U.S. FDA in January 2016, October 2016 and June 2017.

3. Pralsetinib

Overview

Pralsetinib was approved by the U.S. Food and Drug Administration (FDA) on September 4, 2020. It was developed and marketed by Blueprint Medicines under the trade name Gavreto®. The compound is also in clinical phase I/II for the treatment of solid tumors and thyroid cancer. Gavreto® is a kinase inhibitor used to treat adult patients with metastatic rearrangement during transfection (RET) fusion-positive non-small cell lung cancer (NSCLC). Gavreto® is a capsule containing 100 mg. The recommended dose of Gavreto® for adults is 400 mg orally once a day on an empty stomach (without food for at least 2 hours before taking Gavreto and at least 1 hour afterwards).

R&D milestones

In July 2020, Roche agreed to pay 775 million U.S. dollars to obtain the pre-marketing rights of Prasetinib.

On June 4, 2018, CStone Pharmaceuticals and Blueprint Medicines reached an exclusive cooperation and licensing agreement. CStone Pharmaceuticals obtained the authorization for clinical development and commercialization of BLU-667 in mainland China, Hong Kong, Macau and Taiwan.

In March 2017, clinical Phase I/II trials for the treatment of thyroid cancer, non-small cell lung cancer and other advanced solid tumors started to evaluate its safety, tolerability, pharmacokinetics, pharmacodynamics and preliminary anti-tumor Activity (NCT03037385).

4. Utidelone

Overview

Utidelone, developed by Huahao Zhongtian, is a derivative of epothilones that has been genetically engineered.

R&D milestones

Uti Delong started its project in 2003, and has undergone drug evaluation and systematic preclinical research.

In 2006, I submitted the IND application of Uti Delong, obtained clinical approval in 2007, and then completed two clinical phase I. Since the phase Ib study has observed significant efficacy, it was also declared for clinical phase II/III in 2009. After obtaining the clinical phase II/III approval, two clinical phase II and clinical phase III trials of advanced breast cancer were successively carried out.

A listing application was submitted in 2018, and it was selected as a priority review of new drug varieties.

5. Telitacicept

Overview

Taltazep is a fusion protein developed by Rongchang Biopharmaceutical. It is formed by fusion of the BLyS/APRIL binding domain of a transmembrane activator and calmodulin ligand interaction molecule (TACI) and human immunoglobulin Fc fragment. . The drug is currently used for the treatment of rheumatoid arthritis (RA) and neuromyelitis optica spectrum disease (NMOSD) in the clinical phase III study phase, and the treatment of systemic lupus erythematosus, IgA nephritis, myasthenia gravis and Sjogren’s syndrome phase II clinical phase the study. The drug's marketing application for the treatment of systemic lupus erythematosus has been accepted by the NMPA. This drug is the first marketed drug targeting APRIL.

R&D milestones

On March 9, 2021, the drug was approved by China's NMPA for the treatment of systemic lupus erythematosus (SLE).

In November 2019, NMPA accepted the BLA application for this product, and the indication is systemic lupus erythematosus.

In January 2018, another IND in China was accepted by the CDE, and was included in the 27th batch of priority review procedures as a new drug clinically in March 2018.

In October 2017, the Phase III clinical study (CTR20171252) of Tai'ai for the treatment of neuromyelitis optica spectrum diseases has been carried out in China.

As of June 2017, it has been approved to conduct clinical trials for neuromyelitis optica spectrum disorder (NMOSD) in China.

In November 2016, the Phase III clinical trial (CTR20160867) for moderate and severe rheumatoid arthritis (CTR20160867) was started in China.

In May 2016, the Phase II clinical trial (NCT02882087, CTR20160250) of Tai'ai in the treatment of moderate and severe RA with poor efficacy of TNFα antagonists was launched in China.

In March 2016, the Phase II clinical trial (CTR20150877) of recombinant human B lymphocyte stimulating factor receptor-antibody fusion protein for the treatment of systemic lupus erythematosus for injection began in China.

In July 2010, the IND was submitted in China, and in April 2011, it was approved for clinical use.

Clinical outcome

Since it was approved by the CFDA in April 2011 to conduct clinical studies on refractory rheumatoid arthritis and systemic lupus erythematosus, it has shown good safety through phase I and II clinical studies. In July 2019, Rongchang Biological released the results of R-C18 (Taltazep) clinical trial: the key clinical trial of systemic lupus erythematosus reached the primary endpoint. This key clinical trial was launched in 2015. It is a multi-center, randomized, double-blind, placebo-controlled study, enrolling a total of 249 SLE patients, and evaluating the efficacy and safety of Tetalicept in the treatment of SLE subjects . The results showed that the clinical response rate (systemic lupus erythematosus response index SRI4) between the tytacept treatment group and the placebo control group was significantly different, and the difference was statistically significant, reaching the primary endpoint of the clinical trial. The 48-week response rate of the high-dose group reached 79.2%, and the response rate of the placebo control group was 32.0%. Tetazep is also excellent in terms of safety, and it is well tolerated by patients.

Financing and trading

In December 2017, Yantai Rongchang Pharmaceutical Co., Ltd. announced the completion of a RMB 1 billion strategic financing. This financing was jointly led by Shenzhen Venture Capital, SDIC Ventures, Pacific Alliance Investment Group (PAG), Longpan Investment, and SDIC Chuanghe. , And Huatai Health Fund, Shandong Jifu Venture Capital, Sino-China Venture Capital, Luxin Venture Capital, and Zhongtai Huiyin Co-funded. On November 30, 2009, Gaotou Mingli Growth Venture Capital Co., Ltd. (management institution: Mingxin China Growth Fund) invested RMB 30 million in Rongchang Pharmaceutical Co., Ltd. and obtained 17% of the equity.

6. Alflutinib Mesylate (Iflutinib Mesylate)

Overview

Iflutinib mesylate is an irreversible and selective EGFR inhibitor developed by Shanghai Ailisi Pharmaceutical Technology Co., Ltd. It has significant inhibitory activity against EGFR T790M+ resistance mutations and EGFR sensitive mutations. The existing results indicate its anti-tumor efficacy Significant and safer, it has been supported by China's "Major New Drug Creation" National Science and Technology Major Project, and has submitted an NDA application for the treatment of advanced non-small cell lung cancer (NSCLC).

R&D milestones

In December 2019, the listing application of Iflutinib mesylate tablets was included in the priority review.

In January 2019, a Phase III clinical study (CTR20182519) comparing Iflutinib and Gefitinib in the first-line treatment of locally advanced or metastatic non-small cell lung cancer began to recruit patients in China.

In February 2018, the information of a multi-center, randomized, open phase IIb clinical trial (CTR20180154) to evaluate the effectiveness and safety of Iflutinib mesylate in patients with T790M mutation-positive locally advanced or metastatic NSCLC was disclosed, showing that it is in progress .

In June 2017, a multi-center, single-arm phase I/II clinical trial to evaluate the effectiveness and safety of Iflutinib mesylate in advanced NSCLC patients who progressed after 1/2-generation EGFR-TKI treatment (CTR20170447, ALSC002AST2818, NCT03127449, 20170405) were launched in China, and the expected completion date is December 2019.

In January 2017, an open, single-arm, multi-center, phase I clinical trial to evaluate the safety, tolerability, and pharmacokinetics of Iflutinib mesylate in patients with advanced NSCLC cancer (n=30) ( NCT02973763, 20161121, CTR20160743, ALSC001AST2818) began to recruit patients in China, and the 2017 IASLC meeting announced data from 17 patients.

On January 25, 2016, Shanghai Ailisi Pharmaceutical Technology Co., Ltd. submitted a clinical trial application (Chemical Drug Category 1.1) to the CFDA, and obtained clinical approval in September 2016.

Clinical outcome

In October 2017, data from 17 patients in the Phase I clinical trial (CTR20160743) of patients with advanced NSCLC were announced at the IASLC meeting. From December 27, 2016 to August 21, 2017, a total of 17 patients were recruited in the study and randomly assigned to four cohorts of the drug. The doses of AST2818 were 20, 40, 80, and 160 mg QD, respectively. The study showed that ORR and DCR were 58.3% and 91.7%, respectively. No adverse events above grade 3 were reported. MTD has not been reached. The Cmax of AST-2818 at doses of 20, 40, and 80 mg were 7.4, 20, and 45.3 ng/ml, respectively. AUC (0-24 h) are respectively 99.6, 275.7, 593.3h.ng/ml, overall AST-2818 is well tolerated.

7. Darolutamide

Overview

Darolutamide was approved by the U.S. Food and Drug Administration (FDA) on July 30, 2019, and was approved by the European Medicines Agency (EMA) on March 27, 2020, under the trade name Nubeqa®. The drug was first developed by Orion. In June 2014, Bayer obtained the global development and commercialization authorization for the drug to treat prostate cancer. Nubeqa® is a non-steroidal Androgen Receptor (AR) inhibitor for the treatment of patients with non-metastatic castration-resistant prostate cancer (nmCRPC). Nubeqa® is an oral tablet, each containing 300 mg darolutamide. The recommended dose is 600 mg (2 tablets). Oral, 2 times a day, swallow the whole tablet, and take it with meals.

Clinical pharmacology and clinical results

Darolutamide inhibits the function of the androgen receptor by blocking nuclear translocation, and does not have agonist activity when the androgen receptor is overexpressed. This approval is based on data from the pivotal phase III clinical study ARAMIS (NCT02200614). The results showed that in nmCRPC patients, compared with placebo + androgen deprivation therapy (ADT), darolutamide + ADT regimen significantly prolonged the metastasis-free survival (median MFS: 40.4 months vs 18.4 months, p<0.0001) , The risk of disease metastasis or death was significantly reduced by 59%. In this study, compared with placebo+ADT, the darolutamide+ADT regimen showed good safety.

Accelerated procedure qualification for new drugs

In October 2018, the FDA granted Darolutamide fast track qualification for the treatment of non-metastatic castration-resistant prostate cancer (nmCRPC).

R&D and transaction agreements

Darolutamide was first developed by Orion. In June 2014, Bayer obtained the global development and commercialization authorization for the drug to treat prostate cancer. According to the terms of the agreement, Bayer will commercialize the product on a global scale. Orion is responsible for manufacturing and reserves the right to jointly promote the product in Europe. Orion will receive an advance payment of 50 million euros, including 23 million euros as a profit during the review period and 27 million euros for development expenses. Orion will be eligible for technology transfer and commercialization milestone payments and sales royalties. 2

In January 011, Orion and Endo Pharmaceuticals signed a cooperation agreement for the discovery, development and commercialization of cancer treatment drugs. According to the terms of the agreement, the two companies will share up to 8 discovery stage drug candidates and share all development costs. Endo has exercised the license rights for the lead compound (darolutamide) originally discovered by Orion and paid Orion US$10 million for the exercise of the option. In October 2013, Orion announced that Endo Pharmaceuticals and Orion had terminated their cooperation in oncology research, development and commercialization, and all rights of darolutamide were returned to Orion.

8. Gilteritinib Fumarate

Overview

Gilteritinib fumarate was developed by Astellas. It was approved for marketing by the Japan Pharmaceuticals and Medical Devices Agency (PMDA) on September 21, 2018, and was approved by the U.S. Food and Drug Administration (FDA) on November 28, 2018. , And was approved by the European Medicines Agency (EMA) on October 24, 2019, under the trade name Xospata®. Gilteritinib has obtained fast track qualification and orphan drug qualification granted by the FDA. Gilteritinib fumarate is a FLT3/AXL inhibitor, Xospata® is approved for the treatment of FLT3 mutation-positive relapsed or refractory acute myeloid leukemia. Xospata® is an oral tablet, each containing 40 mg gilteritinib. The recommended dose is 120 mg once a day. The dosage should be increased or decreased according to the patient's condition, but should not exceed 200 mg per day.

Clinical outcome

The approval of Xospata® is based on an open-label, multi-center, randomized phase III clinical study (ADIMRAL, NCT02421939). The enrolled patients are adults with FLT3 mutant acute myeloid leukemia (AML) who are refractory to first-line therapy or have relapsed after treatment Patients, compared Xospata® with salvage chemotherapy. The primary endpoint of the study is overall survival (OS). The study enrolled 371 patients with relapsed or refractory AML who had FLT3 mutations positive in bone marrow or whole blood. In the study, patients were randomly assigned to receive Xospata® (120 mg) or salvage chemotherapy at a ratio of 2:1. The results showed that compared with the standard salvage chemotherapy group, the OS of the Xospata® treatment group showed significant statistical significance. The median OS in the Xospata® treatment group was 9.3 months, and the median OS in the salvage chemotherapy group was 5.6 months (HR=0.637, 95%CI: 0.490-0.830, p=0.007); the one-year survival rate in the Xospata® treatment group 37%, and 17% in the salvage chemotherapy group.

9. Azilsartan Medoxomil Potassium (Azilsartan Medoxomil Potassium)

Overview

Azilsartan medoxomil potassium salt/chlorthalidone was developed by Takeda Pharmaceuticals and was approved by the U.S. Food and Drug Administration (FDA) on December 20, 2011, under the trade name Edarbyclor®. Edarbyclor® is a compound preparation composed of angiotensin II-1 receptor (AT1 receptor) antagonist (azilsartan medoxomil potassium) and sodium chloride cotransporter inhibitor (chlorthalidone), used for Treat high blood pressure. Edarbyclor® is an oral tablet, available in two sizes, each containing 40mg azilsartan medoxomil potassium salt and 12.5mg or 25 mg chlorthalidone. The recommended initial dose is to take a 40/12.5mg tablet per day. The blood pressure will drop significantly within 1 to 2 weeks after taking it. After 2-4 weeks, the dosage can be increased to 40/25mg according to the need for lowering blood pressure. 10. Burosumab

Overview

Burosumab is a fully human IgG1 monoclonal antibody that targets fibroblast growth factor 23 (FGF23) and is approved for the treatment of X-linked hypophosphatemia (XLH). This is the first drug approved to treat X-linked hypophosphatemia (XLH) in children and adults 1 year and older. XLH is a rare hereditary rickets, which can cause low levels of phosphorus in the blood, leading to impaired bone growth and development in children and adolescents, and causing bone mineralization problems throughout their lives. The drug is also in the phase II clinical trial for the treatment of tumor osteomalacia (TIO). Crysvita® is an intravenous injection, each bottle (1 mL) contains 10 mg, 20 mg or 30 mg of Burosumab. The recommended initial dose is 0.4 mg/kg, then 0.8 mg/kg each time, once every two weeks.

R&D milestones

Burosumab was approved by the European Medicines Agency (EMA) on February 19, 2018, and was approved by the U.S. Food and Drug Administration (FDA) on April 17, 2018, under the trade name Crysvita®.

In 2015, the US FDA included Burosumab's application for the treatment of XLH on the fast-track approval list.

In 2014, Burosumab was certified by the European EMA as an orphan drug for the treatment of XLH.

In 2013, Ultragenyx was authorized to develop the drug.

This product was originally developed by Kyowa Hakko Kirin Co., Ltd. (Kyowa Hakko Kirin)

Clinical outcome

X-linked hypophosphatemia: This approval is based on a randomized, open-labeled Phase II clinical study. The primary efficacy endpoint of the trial is the Rickets Severity Score (RSS), and the secondary efficacy endpoint is the radiographic overall impression change (RGI-C). At the 40th week, the total RSS scores of the Burosumab biweekly medication (Q2W) and the biweekly medication (Q4W) decreased by an average of 1.06 and 0.73 points, respectively. At the 64th week, the total RSS scores of the Burosumab Q2W and Q4W groups were reduced respectively. The average drop was 1.00 points and 0.84 points. The RGI-C scores of the Q2W and Q4W groups increased by an average of 1.66 points and 1.47 points respectively at the 40th week, and 1.56 points and 1.58 points were respectively increased at the 64th week.

European Union

1. Risdiplam

Time to market

2021-03-30 Europe

2020-08-07 Beauty

Overview

Risdiplam was approved by the U.S. Food and Drug Administration (FDA) on August 7, 2020. It was developed and marketed by GENENTECH INC under the trade name EVRYSDI®. Risdiplam is a modulator of Survival Motor Neuron 2 (SMN2), a potential treatment for spinal muscular atrophy. The drug was originally developed by PTC Therapeutics and then licensed to Roche. On November 25, 2019, Genentech, a subsidiary of Roche, announced that the FDA has accepted the marketing application for its oral preparations and granted priority review qualifications. The PDUFA date is May 24, 2020. EVRYSDI® is an oral liquid, 60 mg risdiplam is a powder, and can be made into a 0.75 mg/mL solution. 0.2 mg/kg from 2 months to under 2 years; 0.25 mg/kg for 2 years and older with a body weight of not more than 20 kg; 2 years old and above, 5 mg for a body weight of 20 kg or above. In July 2017, Roche (China) Investment Co., Ltd. submitted a clinical application (Chemical Drug Import Category 1) to the China National Food and Drug Administration (CFDA), and obtained the clinical trial approval in December 2017 as a priority review product.

2. Pemigatinib

Time to market

2021-03-30 Europe

2021-03-26

2020-04-17 Beauty

Overview

Pemigatinib was approved by the U.S. Food and Drug Administration (FDA) on April 17, 2020, and was approved by Japan on March 26, 2021. It was developed and marketed by Incyte under the trade name PemazyreTM. Pemigatinib is an inhibitor of fibroblast growth factor receptors FGFR1, FGFR2 and FGFR3, which can inhibit the phosphorylation and signal transduction of FGFR 1-3, and reduce the cell viability of cancer cells expanded and fused by FGFR. This product is approved for use in previously treated adult patients with unresectable locally advanced or metastatic cholangiocarcinoma carrying FGFR2 fusion or other rearrangements. The gene fusion or rearrangement is detected by a test method approved by the FDA. PemazyreTM is an oral tablet, each containing 4.5 mg, 9 mg or 13.5 mg of pemigatinib. The recommended dose is 13.5 mg once a day for 14 consecutive days in every 21-day treatment cycle, and then the drug is stopped for 7 days. Pemigatinib is currently in a Phase II clinical study for the treatment of lymphocytic leukemia, myeloid leukemia, solid tumors and cancers of the genitourinary system, and a Phase I/II clinical study for the treatment of cancer. In March 2018, the US FDA recognized pemigatinib as an orphan drug for the treatment of cholangiocarcinoma.

R&D milestones

In November 2018, an open-label, randomized, active-controlled phase III clinical study (NCT03656536, INCB54828-302, FIGHT-302) was started to compare the drug with gemcitabine combined with cisplatin chemotherapy for FGFR2 gene rearrangement positive and unresectable / Efficacy and safety of patients with metastatic cholangiocarcinoma.

In October 2016, an open-label, single-arm, multi-center clinical phase II study (NCT02924376, INCB54828-202, FIGHT-202) was used to target locally advanced unresectable or metastatic FGFR2 rearrangement-positive intrahepatic cholangiocarcinoma that has failed previous treatments. In patients.

In August 2016, an open-label, multi-center clinical phase II study (NCT02872714, INCB54828-201, FIGH-201) for patients with locally advanced unresectable or metastatic bladder cancer and FGFR3 mutation/fusion positive began.

Clinical outcome

Pemigatinib treats unresectable cholangiocarcinoma and metastatic cholangiocarcinoma. The results of a Phase II clinical interim study published at the European Society of Oncology in 2018 showed the overall response rate (ORR) of pemigatinib in patients with metastatic cholangiocarcinoma or unresectable cholangiocarcinoma It was 40%, and the median progression-free survival (PFS) was 9.2 months. In September 2019, Incyte announced an update of the results from its Phase 2 FIGHT-202 trial, which evaluated the efficacy of Pemigatinib in patients with locally advanced or metastatic cholangiocarcinoma who had failed previous treatments. In patients with FGFR2 fusion or rearrangement, the overall response rate (ORR) of Pemigatinib monotherapy was 36% (primary endpoint), and the median progression-free survival (PFS) was 6.9 months (secondary endpoint).

Financing and trading

Innovent and Incyte reached a strategic cooperation and exclusive licensing agreement to promote the single-drug or combination therapy of pemigatinib (FGFR1/2/3 inhibitor), itacitinib (JAK1 inhibitor) and parsaclisib (PI3Kδ inhibitor) in Mainland China and Hong Kong , Macau and Taiwan area clinical development and commercialization. According to the cooperation agreement, Incyte will receive a US$40 million down payment from Cinda Bio, and the second US$20 million cash payment after the first new drug application is expected to be submitted in China in 2019.

3. Selinexor

Time to market

2021-03-30 Europe

2019-07-03 Beauty

Overview

Selinexor was developed by Karyopharm Therapeutics and was approved by the U.S. Food and Drug Administration (FDA) on July 3, 2019, under the trade name Xpovio®. On May 24, 2018, Karyopharm Therapeutics signed an agreement with Dece Pharma, Dece Pharma will have the right to develop and commercialize all oncology indications of Selinexor in Mainland China and Macau. Selinexor is an export protein-1 (XPO1) antagonist for the treatment of highly refractory multiple myeloma (MM) that is resistant to 5 existing therapies. Such patients have received one treatment in the past, namely 2 Proteasome inhibitors (PIs)—Velcade® (bortezomib) and Kyprolis® (carfilzomib), two immunomodulators (IMiDs)— Revlimid® (lenalidomide) and Pomalyst® (pomalidomide) ) And the CD38 monoclonal antibody Darzalex® (daratumumab). They are refractory to at least one PI, at least one IMiD, Darzalex®, and the latest therapies. Xpovio® is an oral tablet, each containing 20 mg Selinexor. The recommended starting dose is 80 mg. It is taken in combination with dexamethasone on the first and third days of the week.

R&D milestones

The NDA application submitted by Selinexor for the treatment of diffuse large B-cell lymphoma has been reviewed by the FDA as a priority. In addition, the Phase III clinical trial for the treatment of liposarcoma and the Phase II/III clinical trial for the treatment of endometrial cancer have been treated for acute myeloid Clinical Phase II of Leukemia.

The compound is used for the treatment of chronic lymphocytic leukemia, small lymphocytic lymphoma (including Richter's Transformation) and multiple myeloma, and is also in clinical phase II.

Another study of the compound is also in clinical phase II for the treatment of metastatic breast cancer, small cell lung cancer (SCLC), metastatic prostate cancer (CRPC), squamous cell carcinoma, and glioblastoma multiforme, Myelodysplastic syndrome (MDS) and neuroendocrine tumors.

In 2015, the compound was approved as an orphan drug in the United States for the treatment of multiple myeloma.

In 2014, the drug was approved as an orphan drug in the United States and the European Union for two indications of diffuse large B-cell lymphoma and acute myeloid leukemia.

In 2014, the drug obtained EU Orphan Drug Designation for these indications.

Clinical outcome

The approval of Xpovio® is based on a multi-center, single-arm, visiting-label phase II clinical trial of STORM (KCP-330-012; NCT02336815). 122 patients were enrolled and received Xpovio® (80 mg) combined with dexamethasone (20 mg) 2 times a week treatment. Among them, 83 patients were past

The fourth-line treatment still relapsed. The primary efficacy endpoint ORR (overall response rate) reached 25.3%, the median first response time was 4 weeks, and the median duration was 3.8 months.

4. Tucatinib

Time to market

2021-02-11 Euro

2020-04-17 Beauty

Overview

Tucatinib was approved by the U.S. Food and Drug Administration (FDA) on April 17, 2020. It was developed and marketed by Seattle Genetics under the trade name Tukysa®. Tucatinib is a tyrosine kinase inhibitor that targets HER2. In in vitro experiments, tucatinib can inhibit the phosphorylation of HER2 and HER3, thereby inhibiting downstream MAPK and Akt signaling pathways and cell proliferation, and expressing anti-tumor activity in tumor cells expressing HER2. This product is approved to be used in combination with trastuzumab and capecitabine for the treatment of adult patients with advanced unresectable or metastatic HER2-positive breast cancer, including those who have previously received 1 or Patients with brain metastases with multiple anti-HER2 therapies. Tukysa® is an oral film-coated tablet, each containing 50 mg or 150 mg of tucatinib. The recommended treatment regimen is combined with trastuzumab and capecitabine, 300 mg orally twice a day.

R&D milestones

The compound was originally developed by Array BioPharma and then licensed to Oncothyreon.

In 2018, Seattle Genetics acquired Cascadian Therapeutics (formerly Oncothyreon).

5. Moxetumomab pasudotox

Time to market

2021-02-08 Euro

2018-09-13 Beauty

Overview

Moxetumomab pasudotox was developed by AstraZeneca and was approved by the U.S. Food and Drug Administration (FDA) on September 13, 2018, under the trade name Lumoxiti®. The product has received FDA priority review and was certified by the European EMA in 2013 as an orphan drug for the treatment of B lymphocytic leukemia/lymphoma. Lumoxiti® is a recombinant cytotoxin that targets CD22 and is approved for the treatment of hairy cell leukemia. Lumoxiti® is an intravenous injection, each vial contains 1 mg freeze-dried powder. The recommended dose is intravenous infusion of 0.04 mg/kg, each instillation of more than 30 minutes, 28 days as a cycle, infusion on the first, third, and fifth days.

Clinical outcome

The approval of Lumoxiti® is based on a single-arm, open phase III clinical trial that performed systemic therapy on 80 patients who had received HCL therapy at least twice. The primary endpoint of the trial is a durable complete response. 30% of patients in the trial achieved a durable CR, and the overall response rate (the number of patients who responded partially or completely to the treatment) was 75%. The hematological remission rate was 80%.

6. Fedratinib

Time to market

2021-02-08 Euro

2019-08-16 Beauty

Overview

Fedratinib was approved by the U.S. Food and Drug Administration (FDA) on August 16, 2019, and is marketed by Impact Biomedicines in the U.S. under the trade name Inrebic®. Fedratinib was originally developed by TargeGen, and in 2010 TargeGen was acquired by Sanofi. However, due to the rare Wernicke's encephalopathy (WE) complication in clinical trials, the FDA stopped the clinical study of fedratinib at the end of 2013. Sanofi immediately announced the suspension of all clinical trials of fedratinib and abandoned the development of fedratinib. However, Dr. John Hood, the inventor of the drug, founded Impact Biomedicines to acquire fedratinib, and analyzed that the cause of the side effects may be related to the patient's vitamin B1 deficiency. In view of the urgent clinical needs of myelofibrosis, the FDA revoked the drug's clinical suspension order in August 2017. In January 2018, Celgene acquired Impact Biomedicines. Inrebic® is a JAK2 and FLT3 inhibitor, approved for the treatment of medium to high-risk primary myelofibrosis and secondary myelofibrosis (post-essential thrombocythemia myelofibrosis or post-polycythemia vera myelofibrosis)化). Inrebic® is an oral capsule, each containing 100 mg of fedratinib. The recommended dose is for patients with a baseline platelet count greater than or equal to 50x109/L, 400 mg orally per day, with or without meals. For patients taking strong CYP3A inhibitors or with severe renal insufficiency, the dose should be reduced as appropriate.

Clinical outcome

The approval of Inrebic® in the United States is mainly based on the positive results of a multi-center, randomized, double-blind, placebo-controlled phase 3 clinical trial (JAKARTA trial, NCT01437787). The main measure of curative effect is the proportion of patients whose spleen volume has shrunk >35% after 6 cycles. The results showed that 37% of patients treated with Inrebic® had a reduction of >35% in spleen volume, compared to 1% in the placebo group; 40% of patients improved myelofibrosis composite score by more than 50%, compared with 9% in the placebo group. The above two results show that the results of receiving Inrebic® treatment are significantly better than the placebo group.

7. Fostemsavir Tromethamine

Time to market

2021-02-04 Euro

2020-07-02 Beauty

Overview

Fostemsavir has been approved for marketing by the U.S. Food and Drug Administration (FDA) on July 2, 2020. The drug is developed and marketed by ViiV Healthcare under the trade name Rukobia®. Fostemsavir is a targeted HIV virus envelope glycoprotein. Inhibitor, approved for the treatment of multi-drug resistant type I HIV infection. Rukobia® is a sustained-release tablet for oral use, each containing 600 mg. It is not recommended to take it twice a day, one tablet at a time. The drug was originally discovered by Bristol-Myers Squibb. In February 2016, BMS divested its HIV drug development pipeline including BMS-986173 to ViiV Healthcare (owned by GSK, Pfizer and Shiono as shareholders).

R&D milestones

In July 2020, the FDA approved Rukobia (Fostemsavir) sustained-release tablets for the treatment of adult HIV-1 infection.

In January 2020, ViiV Healthcare submitted a marketing authorization application (MAA) for Fostemsavir for the treatment of HIV-1 infection to the European Medicines Agency (EMA).

In 2015, the FDA granted breakthrough therapy qualification for this indication.

8. Fam-trastuzumab deruxtecan

Time to market

2021-01-18 Euro

2020-03-25

2019-12-20 Beauty

Overview

Fam-trastuzumab deruxtecan has been approved for marketing by the U.S. Food and Drug Administration (FDA) on December 20, 2019, and approved for marketing by the Japan Pharmaceuticals and Medical Devices Agency (PMDA) on March 25, 2020. It was approved by Daiichi Sankyo. Developed and marketed, the product name is Enhertu®.

Fam-trastuzumab deruxtecan is an antibody conjugate drug targeting HER2, which consists of 3 parts: 1) recombinant humanized IgG1 kappa type anti-HER2 monoclonal antibody trastuzumab; 2) cathepsin B cleavable tetrapeptide GGFG molecule Type Linker; 3) The payload is a camptothecin derivative with topoisomerase I inhibition. The payload is coupled to the cysteinyl of the monoclonal antibody via a linker, and the drug monoclonal antibody ratio DAR is 8 on average. This product is approved for the treatment of adult patients with unresectable or metastatic HER2-positive breast cancer who have previously received at least two anti-HER2 therapies.

Enhertu® is a freeze-dried powder for intravenous infusion. Each bottle contains 100 mg of fam-trastuzumab deruxtecan. The recommended dose is 5.4 mg/kg, infusion every 3 weeks.

Pharmacological action and clinical trial analysis

The humanized HER2 antibody is coupled to the topoisomerase I inhibitor payload through the GGFG tetrapeptide linker activated by cathepsin B, and a small self-cleavage structure is introduced. The tetrapeptide linker is designed to deliver enhanced cytotoxic payload (or chemotherapy) to the destruction of cancer cells when released from within the cell and reduce systemic exposure. DS-8201a releases Dxd, a derivative of Exatecan, and studies have found that it is not discharged by the "drug pump" on the cell membrane, which can overcome the drug resistance problem. This series of new discoveries has allowed DS-8201a to advance all the way, and even directly challenge HER2-positive metastatic breast cancer that has not been treated by HER2 target therapy drugs (trastuzumab, pertuzumab, and T-DM1). In the treatment of other Her2-positive tumors (such as gastric cancer and lung cancer), DS-8201a also shows very good results. The ADC is currently undergoing phase III clinical trials and is expected to be marketed quickly.

Breast cancer | Phase I clinical study (NCT02564900) included HER2+ breast cancer after T-DM1 treatment, and breast cancer with low HER2 expression (IHC 1+ or 2+, ISH-) after trastuzumab treatment, 99 cases of HER2+ breast The objective response rate of DS-8201 in cancer patients was 54.5%, the disease control rate was 93.9%, the dose was 5.4 or 6.4 mg/kg, the median age of patients was 59 years old, and the median received 4 regimens of front-line treatment . At the time of the data cut-off, most subjects were still on treatment. In September 2018, Daiichi Sankyo announced the official launch of two clinical Phase III multicenter studies to evaluate the clinical efficacy of DS-8201 in the treatment of HER2-positive metastatic breast cancer. Current treatment guidelines for patients with HER2-positive metastatic breast cancer recommend the combination of Trastuzumab, Pertuzumab, and taxane as the first-line treatment. For patients whose cancer has progressed after the initial treatment, T-DM1 therapy is used for second-line treatment, and for patients who have progressed after second-line treatment, there is currently no standard treatment.

NSCLC | In September 2018, Daiichi Sankyo announced today that the ADC drug [Fam-]Trastuzumab deruxtecan in the treatment of HER2-positive non-small cell lung cancer was reported orally at the IASLC 19th World Lung Cancer Conference hosted by the International Association for the Study of Lung Cancer in Toronto, Canada. The latest clinical data. This latest subgroup analysis of 11 patients with HER2 mutant non-small cell lung cancer showed that the total effective rate of DS-8201 treatment was 72.7%, the disease control rate was 100%, and the patient's median response duration had reached 11.5. Months, the median progression-free survival rate has reached 14.1 months.

Gastric Cancer | At the 2018 American Society of Clinical Oncology (ASCO) Gastrointestinal Cancer Symposium, Daiichi Sankyo Pharmaceutical announced the preliminary results of the clinical phase I subgroup analysis of the HER2-expressing gastric cancer subgroup of patients who had previously received trastuzumab and chemotherapy Shows that DS-8201 achieved a proven total remission rate of 45.5% (20/44) and a disease control rate of 81.8% (36/44), with a median duration of remission of 7.0 months (95%CI: NR) In survival analysis, the median progression-free survival under Kaplan-Meier was 5.8 months (95%CI: 3.0, 8.3). At the time of data collection, a total of 17 of the 44 patients were continuing to receive treatment. Based on these Phase I data, the company is recruiting patients for the pivotal Phase II study DESTINY-Gastric01 (NCT03329690).

Accelerated procedure qualification for new drugs

In December 2016, the FDA granted the Fast Track designation of trastuzumab deruxtecan for the treatment of HER2-positive unresectable or metastatic breast cancer;

In August 2017, the FDA awarded it the title of Breakthrough Therapy (BTD) for the treatment of patients with HER2-positive, locally advanced or metastatic breast cancer;

In March 2018, Japan's Ministry of Health, Labour and Welfare (MHLW) granted it the SAKIGAKE qualification (pioneer qualification) for the treatment of HER2-positive advanced gastric cancer or gastroesophageal cancer based on the results of the ongoing clinical phase I study.

R&D Agreement

DS-8201 was originally developed by Daiichi Sankyo

In August 2017, Bristol-Myers Squibb and Daiichi Sankyo announced a collaborative clinical trial to evaluate the combination of nivolumab and DS-8201 in the treatment of HER2-expressing metastatic breast cancer and urothelial (bladder) cancer.

In December 2017, Daiichi Sankyo and Puma Biotechnology launched a research collaboration with Memorial Sloan Kettering Cancer Center (MSK) to study DS-8201 and Lena Tinib is used in combination to treat HER2 mutations or HER2 positive solid tumors.

In October 2018, Daiichi Sankyo signed a clinical trial cooperation agreement with Merck KGaA and Pfizer to study [fam-] trastuzumab deruxtecan combined with avelumab in the treatment of patients with solid tumors that express or mutate Her2.

In April 2019, AstraZeneca and Daiichi Sankyo announced that they have signed a global development and commercialization cooperation agreement for the antibody conjugate drug trastuzumab deruxtecan (DS-8201). The two parties are jointly responsible for DS-8201 worldwide (except Japan). ) Development and commercialization, Daiichi Sankyo (Daiichi Sankyo) remains in the city of Japan