On July 20, 2020 Zai Lab Limited (NASDAQ: ZLAB) and Deciphera Pharmaceuticals, Inc. (NASDAQ:DCPH) reported that the China National Medical Products Administration (NMPA) has accepted its New Drug Application (NDA) for ripretinib for the treatment of adult patients with advanced gastrointestinal stromal tumor (GIST) who have received prior treatment with 3 or more kinase inhibitors, including imatinib (Press release, Zai Laboratory, JUL 20, 2020, View Source [SID1234562114]). Ripretinib was recently granted full approval by the U.S. Food and Drug Administration (FDA) for the treatment of fourth-line GIST. Ripretinib is also approved by Health Canada for the treatment of adult patients with advanced GIST who have received prior treatment with imatinib, sunitinib, and regorafenib and by the Australian Therapeutic Goods Administration for the treatment of adult patients with advanced GIST who have received prior treatment with 3 or more kinase inhibitors, including imatinib.

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"There is a significant unmet medical need for patients with GIST in China, especially for those who are refractory to prior therapies. Based on the recent full U.S. FDA approval and compelling clinical data from the INVICTUS trial1, we believe ripretinib has the potential to alter the treatment landscape for GIST patients in China," said Dr. Samantha Du, Founder, Chairperson and Chief Executive Officer of Zai Lab. "We look forward to working closely with the NMPA to make a profound impact on the way GIST is treated in China."

"The earlier than expected acceptance of the ripretinib NDA in China underscores its potential and follows the recent FDA approval in the U.S.," said Steve Hoerter, President and Chief Executive Officer of Deciphera. "The magnitude of the unmet need for GIST patients in China is striking, with over 30,000 Chinese patients reportedly diagnosed each year. We look forward to our continued collaboration with Zai as we work to bring ripretinib to patients who are waiting for an additional treatment option."

INVICTUS is a Phase 3 randomized, double-blind, placebo-controlled, international, multicenter clinical study designed to evaluate the safety, tolerability, and efficacy of ripretinib compared to placebo in 129 patients with advanced GIST whose previous therapies have included imatinib, sunitinib, and regorafenib. Patients were randomized 2:1 to either 150 mg of ripretinib or placebo once daily. The primary efficacy endpoint was progression-free survival (PFS) as determined by independent radiologic review using modified Response Evaluation Criteria in Solid Tumors (RECIST). As previously reported, the median PFS in the study was 6.3 months compared to 1.0 month in the placebo arm, with significantly reduced the risk of disease progression or death of 85% (hazard ratio of 0.15, p<0.0001). Secondary endpoints as

determined by independent radiologic review using modified RECIST included Objective Response Rate (ORR) and Overall Survival (OS). Ripretinib demonstrated an ORR of 9.4% compared with 0% for placebo (p=0.0504). Ripretinib also demonstrated a median OS of 15.1 months compared to 6.6 months in the placebo arm and reduced the risk of death by 64% (hazard ratio of 0.36).

The most common adverse reactions (≥20%) were alopecia, fatigue, nausea, abdominal pain, constipation, myalgia, diarrhea, decreased appetite, palmar-plantar erythrodysesthesia syndrome, and vomiting. Adverse reactions resulting in permanent discontinuation occurred in 8% of patients, dosage interruptions due to an adverse reaction occurred in 24% of patients and dose reductions due to an adverse reaction occurred in 7% of patients who received ripretinib.

Note: (1) NDA submission is supported by strong results from the INVICTUS pivotal Phase 3 study showing clinically meaningful improvement in both progression-free survival and overall survival.

About Ripretinib

Ripretinib is a switch-control tyrosine kinase inhibitor that was engineered to broadly inhibit KIT and PDGFRα mutated kinases by using a unique dual mechanism of action that regulates the kinase switch pocket and activation loop. Ripretinib inhibits primary and secondary KIT mutations in exons 9, 11, 13, 14, 17, and 18, involved in GIST, as well as the primary exon 17 D816V mutation involved in systemic mastocytosis, or SM. Ripretinib also inhibits primary PDGFRα mutations in exons 12, 14, and 18, including the exon 18 D842V mutation, involved in a subset of GIST.

Ripretinib is approved by the U.S. FDA under the brand name QINLOCK for the treatment of adult patients with advanced GIST who have received prior treatment with 3 or more kinase inhibitors, including imatinib. Ripretinib is also approved by Health Canada under the brand name QINLOCK for the treatment of adult patients with advanced GIST who have received prior treatment with imatinib, sunitinib, and regorafenib and by the Australian Therapeutic Goods Administration under the brand name QINLOCK for the treatment of adult patients with advanced GIST who have received prior treatment with 3 or more kinase inhibitors, including imatinib.

Deciphera Pharmaceuticals is developing ripretinib for the treatment of KIT and/or PDGFRα-driven cancers, including GIST, SM, and other cancers.

Zai Lab has an exclusive license agreement with Deciphera for the development and commercialization of ripretinib in Greater China, including mainland China, Hong Kong, Macau and Taiwan.

On July 20, 2020 Forbius, a clinical-stage protein engineering company that develops biotherapeutics to treat cancer and fibrosis, reported that it will present at the H.C. Wainwright 22nd Annual Global Investment Conference September 14-16, 2020 (Press release, Forbius, JUL 20, 2020, View Source;utm_amedium=rss&utm_campaign=wainwright2020 [SID1234562113]).

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On July 20, 2020 Karyopharm Therapeutics Inc. (Nasdaq:KPTI), an innovation-driven pharmaceutical company, reported that the U.S. Food and Drug Administration (FDA) has accepted for filing its supplemental New Drug Application (sNDA) seeking approval for XPOVIO (selinexor), its first-in-class, oral Selective Inhibitor of Nuclear Export (SINE) compound, as a new treatment for patients with multiple myeloma after at least one prior line of therapy (Press release, Karyopharm, JUL 20, 2020, View Source [SID1234562112]). Karyopharm expects a decision from the FDA regarding this sNDA before the end of the first quarter of 2021.

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"This sNDA acceptance brings us one step closer to providing access to XPOVIO for a significantly larger patient population battling multiple myeloma," said Sharon Shacham, PhD, MBA, Founder, President and Chief Scientific Officer of Karyopharm. "If approved, we believe XPOVIO will become an important new, oral, once-weekly treatment option, used in combination with once-weekly Velcade, for patients with multiple myeloma after at least one prior line of therapy. We look forward to working closely with the FDA during their review process and we sincerely thank the many patients, caregivers and physicians whose immense contributions have helped us achieve this latest milestone."

XPOVIO has been previously approved by the FDA for the treatment of patients with penta-refractory multiple myeloma and relapsed or refractory diffuse large B-cell lymphoma. Provided marketing approval is granted by the FDA for this third oncology indication, Karyopharm plans to continue to commercialize XPOVIO in the U.S. using its existing commercial infrastructure. The Company also plans to submit a Marketing Authorization Application to the European Medicines Agency later this year for this same indication.

About XPOVIO (selinexor)

XPOVIO is a first-in-class, oral Selective Inhibitor of Nuclear Export (SINE) compound. XPOVIO functions by selectively binding to and inhibiting the nuclear export protein exportin 1 (XPO1, also called CRM1). XPOVIO blocks the nuclear export of tumor suppressor, growth regulatory and anti-inflammatory proteins, leading to accumulation of these proteins in the nucleus and enhancing their anti-cancer activity in the cell. The forced nuclear retention of these proteins can counteract a multitude of the oncogenic pathways that, unchecked, allow cancer cells with severe DNA damage to continue to grow and divide in an unrestrained fashion. Karyopharm received accelerated U.S. Food and Drug Administration (FDA) approval of XPOVIO in July 2019 in combination with dexamethasone for the treatment of adult patients with relapsed refractory multiple myeloma (RRMM) who have received at least four prior therapies and whose disease is refractory to at least two proteasome inhibitors, at least two immunomodulatory agents, and an anti-CD38 monoclonal antibody. Karyopharm has also submitted a Marketing Authorization Application (MAA) to the European Medicines Agency (EMA) with a request for conditional approval of selinexor in this same RRMM indication. Karyopharm’s supplemental New Drug Application (sNDA) requesting an expansion of its current indication to include the treatment for patients with multiple myeloma after at least one prior line of therapy has been accepted for filing by the FDA. In June 2020, Karyopharm received accelerated FDA approval of XPOVIO for its second indication in adult patients with relapsed or refractory diffuse large B-cell lymphoma (DLBCL), not otherwise specified, including DLBCL arising from follicular lymphoma, after at least 2 lines of systemic therapy. Selinexor is also being evaluated in several other mid-and later-phase clinical trials across multiple cancer indications, including as a potential backbone therapy in combination with approved myeloma therapies (STOMP), in liposarcoma (SEAL) and in endometrial cancer (SIENDO), among others. Additional Phase 1, Phase 2 and Phase 3 studies are ongoing or currently planned, including multiple studies in combination with approved therapies in a variety of tumor types to further inform Karyopharm’s clinical development priorities for selinexor. Additional clinical trial information for selinexor is available at www.clinicaltrials.gov.

For more information about Karyopharm’s products or clinical trials, please contact the Medical Information department at:

Tel: +1 (888) 209-9326
Email: [email protected]

IMPORTANT SAFETY INFORMATION

Thrombocytopenia: XPOVIO can cause life-threatening thrombocytopenia, potentially leading to hemorrhage. Thrombocytopenia was reported in patients with multiple myeloma (MM) and developed or worsened in patients with DLBCL.

Thrombocytopenia is the leading cause of dosage modifications. Monitor platelet counts at baseline and throughout treatment. Monitor more frequently during the first 3 months of treatment. Institute platelet transfusion and/or other treatments as clinically indicated. Monitor patients for signs and symptoms of bleeding and evaluate promptly. Interrupt, reduce dose, or permanently discontinue based on severity of adverse reaction.

Neutropenia: XPOVIO can cause life-threatening neutropenia, potentially increasing the risk of infection. Neutropenia and febrile neutropenia occurred in patients with MM and in patients with DLBCL.

Obtain white blood cell counts with differential at baseline and throughout treatment. Monitor more frequently during the first 3 months of treatment. Monitor patients for signs and symptoms of concomitant infection and evaluate promptly. Consider supportive measures, including antimicrobials and growth factors (e.g., G-CSF). Interrupt, reduce dose, or permanently discontinue based on severity of adverse reaction (AR).

Gastrointestinal Toxicity: XPOVIO can cause severe gastrointestinal toxicities in patients with MM and DLBCL.

Nausea/Vomiting: Provide prophylactic antiemetics. Administer 5-HT3 receptor antagonists and other anti-nausea agents prior to and during treatment with XPOVIO. Interrupt, reduce dose, or permanently discontinue based on severity of ARs. Administer intravenous fluids to prevent dehydration and replace electrolytes as clinically indicated.

Diarrhea: Interrupt, reduce dose, or permanently discontinue based on severity of ARs. Provide standard anti-diarrheal agents, administer intravenous fluids to prevent dehydration, and replace electrolytes as clinically indicated.

Anorexia/Weight Loss: Monitor weight, nutritional status, and volume status at baseline and throughout treatment. Monitor more frequently during the first 3 months of treatment. Interrupt, reduce dose, or permanently discontinue based on severity of ARs. Provide nutritional support, fluids, and electrolyte repletion as clinically indicated.

Hyponatremia: XPOVIO can cause severe or life-threatening hyponatremia. Hyponatremia developed in patients with MM and in patients with DLBCL.

Monitor sodium level at baseline and throughout treatment. Monitor more frequently during the first 2 months of treatment. Correct sodium levels for concurrent hyperglycemia (serum glucose >150 mg/dL) and high serum paraprotein levels. Assess hydration status and manage hyponatremia per clinical guidelines, including intravenous saline and/or salt tablets as appropriate and dietary review. Interrupt, reduce dose, or permanently discontinue based on severity of the AR.

Serious Infection: XPOVIO can cause serious and fatal infections. Most infections were not associated with Grade 3 or higher neutropenia. Atypical infections reported after taking XPOVIO include, but are not limited to, fungal pneumonia and herpesvirus infection.

Monitor for signs and symptoms of infection, and evaluate and treat promptly.

Neurological Toxicity: XPOVIO can cause life-threatening neurological toxicities.

Coadministration of XPOVIO with other products that cause dizziness or mental status changes may increase the risk of neurological toxicity.

Advise patients to refrain from driving and engaging in hazardous occupations or activities, such as operating heavy or potentially dangerous machinery, until the neurological toxicity fully resolves. Optimize hydration status, hemoglobin level, and concomitant medications to avoid exacerbating dizziness or mental status changes. Institute fall precautions as appropriate.

Embryo-Fetal Toxicity: XPOVIO can cause fetal harm when administered to a pregnant woman.

Advise pregnant women of the potential risk to a fetus. Advise females of reproductive potential and males with a female partner of reproductive potential to use effective contraception during treatment with XPOVIO and for 1 week after the last dose.

ADVERSE REACTIONS

The most common adverse reactions (ARs) in ≥20% of patients with MM are thrombocytopenia, fatigue, nausea, anemia, decreased appetite, decreased weight, diarrhea, vomiting, hyponatremia, neutropenia, leukopenia, constipation, dyspnea, and upper respiratory tract infection.

The most common ARs, excluding laboratory abnormalities, in ≥20% of patients with DLBCL are fatigue, nausea, diarrhea, appetite decrease, weight decrease, constipation, vomiting, and pyrexia. Grade 3-4 laboratory abnormalities in ≥15% of patients included thrombocytopenia, lymphopenia, neutropenia, anemia, and hyponatremia. Grade 4 laboratory abnormalities in ≥5% were thrombocytopenia, lymphopenia, and neutropenia.

In patients with MM, fatal ARs occurred in 9% of patients. Serious ARs occurred in 58% of patients. Treatment discontinuation rate due to ARs was 27%. The most frequent ARs requiring permanent discontinuation in ≥4% of patients included fatigue, nausea, and thrombocytopenia.

In patients with DLBCL, fatal ARs occurred in 3.7% of patients within 30 days, and 5% of patients within 60 days of last treatment; the most frequent fatal AR was infection (4.5% of patients). Serious ARs occurred in 46% of patients; the most frequent serious AR was infection. Discontinuation due to ARs occurred in 17% of patients.

USE IN SPECIFIC POPULATIONS

In MM, no overall difference in effectiveness of XPOVIO was observed in patients >65 years old when compared with younger patients. Patients ≥75 years old had a higher incidence of discontinuation due to an AR than younger patients, a higher incidence of serious ARs, and a higher incidence of fatal ARs.

Clinical studies in patients with relapsed or refractory DLBCL did not include sufficient numbers of patients aged 65 and over to determine whether they respond differently from younger patients.

The effect of end-stage renal disease (CLCR <15 mL/min) or hemodialysis on XPOVIO pharmacokinetics is unknown.

On July 20, 2020 Genocea Biosciences, Inc. (NASDAQ: GNCA), a biopharmaceutical company developing next-generation neoantigen immunotherapies, reported updates to its clinical programs, the neoantigen vaccine GEN-009 and the neoantigen cell therapy, GEN-011 (Press release, Genocea Biosciences, JUL 20, 2020, View Source [SID1234562111]).

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GEN-009
On July 30, 2020, the Company will share initial clinical data on the first 5 patients from Part B of the ongoing Phase 1/2a clinical trial exploring the combination of GEN-009 and immune checkpoint inhibitor-based regimens in advanced solid tumors. The lead investigator, Dr. Maura L. Gillison, MD, PhD, Professor of Medicine, Department of Thoracic/Head and Neck Medical Oncology at MD Anderson Cancer Center, will present.

GEN-011
In June 2020, the Company submitted the IND to support the initiation of a Phase 1/2 clinical trial and the 30-day FDA review period has just ended. The Company has received verbal notification from the U.S. Food and Drug Administration (FDA) that the agency has completed its review of the Company’s Investigational New Drug Application (IND) for GEN-011. In this verbal feedback, the FDA informed Genocea that it is placing the IND on clinical hold until it receives additional information pertaining to certain third-party reagents used in the GEN-011 manufacturing process. These reagents are not a component of the final cell therapy product. The Company expects to receive official written communication from the FDA regarding the hold and the FDA’s position in the near future and will work with the FDA to resolve their questions as quickly as possible.

On July 20, 2020 BerGenBio ASA (OSE: BGBIO), a clinical-stage biopharmaceutical company developing novel, selective AXL kinase inhibitors for severe unmet medical need, reported that the first patient has been dosed and continues on therapy in a trial assessing bemcentinib in recurrent glioblastoma (GBM) (Press release, BerGenBio, JUL 20, 2020, View Source [SID1234562076]). The trial is sponsored by Prof. Ichiro Nakano, MD, Professor in the Department of Neurosurgery and co-leader of the Neuro-Oncology Program at University of Alabama at Birmingham and funded by the National Cancer Institute (NCI).

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This is an open label, multi-centre, intra-tumoral tissue pharmacokinetic (PK) study of bemcentinib in patients with recurrent glioblastoma for whom a surgical resection is medically indicated. The study will enrol up to 20 recurrent GBM patients, at up to 15 sites in the USA. 10 patients will be treated prior to surgery and 10 patients will have no pre-surgical treatment. However, all patients will receive treatment with bemcentinib following surgery. The endpoints of the study include an evaluation of bemcentinib’s ability to cross the blood brain barrier, AXL expression, pharmacokinetics, safety and tolerability, as well as efficacy assessments including Progression Free Survival and Overall Survival. More information about the trial can be found at View Source

Increased expression of the receptor tyrosine kinase AXL is significantly correlated with poor prognosis in GBM patients and preclinical data has suggested that bemcentinib may be a promising therapeutic agent for GBM, particularly in post-irradiation mesenchymal-transformed GBM tumors[1]. A comprehensive translational research programme will run in parallel with the clinical trial, this will be conducted by Prof. Jeff Supko, Harvard Medical School and Director of the Clinical Pharmacology Laboratory, Massachusetts General Hospital (Boston, USA).

Prof. Burt Nabors MD, the Chairman of the trial and Director of Neuro-Oncology at University of Alabama at Birmingham (UAB) and Director of UAB’s Centre for Clinical Translational Science’s Clinical Research Unit, commented: "GBM is among the most lethal of adult cancers. The median survival of patients remains less than two years despite the current available therapies, including surgery, radiation, and chemotherapy; development of more effective therapies is urgently needed. We welcome the opportunity to offer patients access to the investigational AXL inhibitor bemcentinib in this pilot study and look forward to initiating additional trial sites across the Adult Brain Tumour Consortium in the USA later this year."

Richard Godfrey, Chief Executive Officer of BerGenBio, commented: "We congratulate Prof. Nakano and Prof. Nabors on the start of this exciting clinical study, which we believe will provide us with important data regarding the ability of bemcentinib to cross the blood-brain barrier and potentially treat GBM patients. This clinical trial is based on pioneering preclinical research carried out by our collaborators, conducted at high profile research hospitals in the USA and is funded by National Cancer Institute (NCI). We look forward to reporting the potential of bemcentinib to improve patient outcomes in this very aggressive cancer."