Hematoma, Subdural

− ICLUSIG Becomes the First and Only Targeted Treatment Approved in the U.S. for Frontline Ph+ Acute Lymphoblastic Leukemia (ALL) in Combination with Chemotherapy − First FDA Approval in Ph+ ALL Based on Novel Primary Endpoint of Minimal Residual Disease (MRD)-negative Complete Remission (CR) − Accelerated Approval Based on Data from the Phase 3 PhALLCON Trial, in which ICLUSIG Demonstrated Superiority in MRD-negative Complete Remission Rates and Comparable Safety to Imatinib OSAKA, Japan & CAMBRIDGE, Mass.--(BUSINESS WIRE)-- Takeda (TSE:4502/NYSE:TAK) today announced that the U.S. Food and Drug Administration (FDA) has approved the supplemental New Drug Application (sNDA) for ICLUSIG® (ponatinib) for the treatment of adult patients with newly diagnosed Philadelphia chromosome-positive acute lymphoblastic leukemia (Ph+ ALL) in combination with chemotherapy. This indication is approved under accelerated approval based on minimal residual disease (MRD)-negative complete remission (CR) at the end of induction. Continued approval for this indication may be contingent upon verification and description of clinical benefit in confirmatory trials. This accelerated approval application was granted Priority Review and evaluated under the Real-Time Oncology Review (RTOR) program, an FDA initiative designed to expedite the delivery of cancer medicines by allowing components of an application to be reviewed before submission of the complete application. “This label expansion for ICLUSIG is an incredibly exciting milestone, allowing U.S. adult patients with newly diagnosed Ph+ ALL to have an approved, targeted treatment option in the frontline,” said Awny Farajallah, MD, chief medical officer, oncology at Takeda. “We are thrilled that the FDA has recognized the potential of ICLUSIG to fill a large gap in care for these patients and look forward to seeing the impact this can have on people with this rare and aggressive form of cancer.” The approval was supported by data from the PhALLCON study – the first, global, Phase 3, registrational, head-to-head clinical trial in adults with newly diagnosed Ph+ ALL. The study, in which patients received either ICLUSIG or imatinib, plus reduced-intensity chemotherapy, met its primary endpoint of MRD-negative CR at the end of induction. MRD-negative CR is a composite endpoint defined in alignment with the FDA that reflects deep molecular and clinical responses and is an important prognostic indicator for long-term outcomes for patients with Ph+ ALL. ICLUSIG demonstrated superiority compared to imatinib, with patients who received ICLUSIG achieving a greater than two-fold improvement in the rate of MRD-negative CR at the end of induction (cycle 3). In the trial, the safety pro ICLUSIG was comparable to imatinib, and no new safety signals were identified. “Ph+ ALL is an extremely aggressive cancer and patients with this disease suffer from poor outcomes. There has long been a need for a potent TKI that can suppress mutation development and elicit deep responses in the frontline,” said Elias Jabbour, MD, The University of Texas MD Anderson Cancer Center and lead investigator of the PhALLCON trial. “Ponatinib may help address these factors and impact long-term outcomes.” ICLUSIG is a kinase inhibitor indicated in the U.S. for adult patients with newly diagnosed Ph+ ALL in combination with chemotherapy. This indication is approved under accelerated approval based on MRD-negative CR at the end of induction. Continued approval for this indication may be contingent upon verification of clinical benefit in a confirmatory trial(s). In addition, it is approved as monotherapy in Ph+ ALL for whom no other kinase inhibitors are indicated or T315I-positive Ph+ ALL, chronic-phase (CP) CML with resistance or intolerance to at least two prior kinase inhibitors, accelerated phase (AP) or blast phase (BP) CML for whom no other kinase inhibitors are indicated or T315I-positive CML (chronic phase, accelerated phase, or blast phase). ICLUSIG is not indicated and is not recommended for the treatment of patients with newly diagnosed CP-CML. About the PhALLCON Trial The PhALLCON study is a Phase 3, randomized, international, open-label multicenter trial evaluating the efficacy and safety of ICLUSIG versus imatinib, in combination with reduced-intensity chemotherapy as a frontline therapy for adult patients with newly diagnosed Ph+ ALL. A total of 245 patients were randomized 2:1 and treated with ICLUSIG or imatinib plus reduced-intensity chemotherapy. The median age of patients was 54 and 52 in the ICLUSIG and imatinib arms, respectively. 164 patients were treated with ICLUSIG receiving a starting dose of 30mg/day and 81 patients were treated with imatinib at a starting dose of 600mg/day. All patients received either ICLUSIG or imatinib with reduced-intensity chemotherapy through induction, consolidation and maintenance phase. After combination therapy, patients continued to receive single-agent ICLUSIG or imatinib until relapse from CR, progressive disease (PD), hematopoietic stem cell transplantation (HSCT), start of alternative therapy or unacceptable toxicity. The primary endpoint of the study was MRD-negative CR rate at the end of induction (3 cycles of treatment). Event-free survival, the key secondary endpoint of the trial, is not yet mature. About Philadelphia chromosome-positive acute lymphoblastic leukemia (Ph+ ALL) Ph+ ALL is a rare form of ALL that affects approximately 25% of adult ALL patients in the U.S. and is characterized by the presence of an abnormal gene, known as the Philadelphia chromosome. In patients who are Philadelphia chromosome-positive (Ph+), an abnormal chromosome is formed when pieces of chromosomes 9 and 22 switch with each other. This forms a longer chromosome 9 and a shorter chromosome 22, which leads to the development of BCR::ABL1 and is associated with Ph+ ALL. About ICLUSIG® (ponatinib) tablets ICLUSIG is a kinase inhibitor targeting BCR::ABL1, an abnormal tyrosine kinase that is expressed in CML and Ph+ ALL. ICLUSIG is a targeted cancer medicine developed using a computational and structure-based drug-design platform, specifically designed to inhibit the activity of BCR::ABL1 and its mutations. ICLUSIG inhibits native BCR::ABL1, as well as all BCR::ABL1 treatment-resistant mutations, including the most resistant T315I mutation. This mutation has been associated with resistance to all other approved TKIs. ICLUSIG received full approval from the FDA in November 2016. ICLUSIG is a kinase inhibitor indicated in the U.S. for adult patients with newly diagnosed Ph+ ALL in combination with chemotherapy. This indication is approved under accelerated approval based on MRD-negative CR at the end of induction. Continued approval for this indication may be contingent upon verification of clinical benefit in a confirmatory trial(s). In addition, it is approved as monotherapy in Ph+ ALL for whom no other kinase inhibitors are indicated or T315I-positive Ph+ ALL, chronic-phase (CP) CML with resistance or intolerance to at least two prior kinase inhibitors, accelerated phase (AP) or blast phase (BP) CML for whom no other kinase inhibitors are indicated, or T315I-positive CML (chronic phase, accelerated phase, or blast phase). ICLUSIG is not indicated and is not recommended for the treatment of patients with newly diagnosed CP-CML. IMPORTANT SAFETY INFORMATION WARNING: ARTERIAL OCCLUSIVE EVENTS, VENOUS THROMBOEMBOLIC EVENTS, HEART FAILURE, and HEPATOTOXICITY See full prescribing information for complete boxed warning. Arterial occlusive events (AOEs), including fatalities, have occurred in ICLUSIG-treated patients. AOEs included fatal myocardial infarction, stroke, stenosis of large arterial vessels of the brain, severe peripheral vascular disease, and the need for urgent revascularization procedures. Patients with and without cardiovascular risk factors, including patients age 50 years or younger, experienced these events. Monitor for evidence of AOEs. Interrupt or discontinue ICLUSIG based on severity. Consider benefit-risk to guide a decision to restart ICLUSIG. Venous thromboembolic events (VTEs) have occurred in ICLUSIG-treated patients. Monitor for evidence of VTEs. Interrupt or discontinue ICLUSIG based on severity. Heart failure, including fatalities, occurred in ICLUSIG-treated patients. Monitor for heart failure and manage patients as clinically indicated. Interrupt or discontinue ICLUSIG for new or worsening heart failure. Hepatotoxicity, liver failure and death have occurred in ICLUSIG-treated patients. Monitor liver function tests. Interrupt or discontinue ICLUSIG based on severity. WARNINGS AND PRECAUTIONS Arterial Occlusive Events (AOEs): AOEs, including fatalities, have occurred in patients who received ICLUSIG in PhALLCON, OPTIC and PACE. These included cardiovascular, cerebrovascular, and peripheral vascular events. In PhALLCON, 6% of 163 patients experienced AOEs; 3.7% experienced Grade 3 or 4. The incidence of AOEs in OPTIC (45 mg-> 15 mg) was 14% of 94 patients; 6% experienced Grade 3 or 4. In PACE, the incidence of AOEs was 26% of 449 patients; 14% experienced Grade 3 or 4. Fatal AOEs occurred in 0.6% of patients in PhALLCON, 2.1% of patients in OPTIC, and in 2% of patients in PACE. Some patients in PACE experienced recurrent or multisite vascular occlusion. Patients with and without cardiovascular risk factors, including patients age 50 years or younger, experienced these events. The most common risk factors observed with these events in PACE were history of hypertension, hypercholesterolemia, and non-ischemic cardiac disease. In PhALLCON, OPTIC and PACE, AOEs were more frequent with increasing age. In PhALLCON, patients with uncontrolled hypertension, hypertriglyceridemia, or diabetes were excluded. Patients with clinically significant, uncontrolled, or active cardiovascular disease, including any history of myocardial infarction, peripheral vascular infarction, revascularization procedure, venous thromboembolism, clinically significant atrial/ventricular tachyarrhythmias, unstable angina, or congestive heart failure within the 6 months prior to the first dose of ICLUSIG, were also excluded. In OPTIC, patients with uncontrolled hypertension or diabetes and patients with clinically significant, uncontrolled, or active cardiovascular disease were excluded. In PACE, patients with uncontrolled hypertriglyceridemia and patients with clinically significant or active cardiovascular disease within the 3 months prior to the first dose of ICLUSIG were excluded. Consider whether the benefits of ICLUSIG are expected to exceed the risks. Monitor for evidence of AOEs. Interrupt, then resume at the same or decreased dose or discontinue ICLUSIG based on recurrence/severity. Consider benefit-risk to guide a decision to restart ICLUSIG. Venous Thromboembolic Events (VTEs): Serious or severe VTEs have occurred in patients who received ICLUSIG. In PhALLCON, VTEs occurred in 12% of 163 patients, including serious or severe (Grade 3 or 4) in 3.1% of patients. One of 94 patients in OPTIC experienced a VTE (Grade 1 retinal vein occlusion). In PACE, VTEs occurred in 6% of 449 patients including serious or severe (Grade 3 or 4) VTEs in 5.8% of patients. In PhALLCON and PACE VTEs included deep venous thrombosis, embolism, pulmonary embolism, superficial vein thrombosis, thrombosis, jugular vein thrombosis, superficial thrombophlebitis, retinal vein occlusion, and retinal vein thrombosis with vision loss. The incidence of VTEs in PACE was higher in patients with Ph+ ALL (9% of 32 patients) and BP-CML (10% of 62 patients). Monitor for evidence of VTEs. Interrupt, then resume at the same or decreased dose or discontinue ICLUSIG based on recurrence/severity. Heart Failure: Fatal, serious or severe heart failure events have occurred in patients who received ICLUSIG. In PhALLCON, heart failure occurred in 6% of 163 patients; 1.2% experienced serious or severe (Grade 3 or 4) heart failure. Heart failure occurred in 13% of 94 patients in OPTIC; 1.1% experienced serious or severe (Grade 3 or 4). In PACE, heart failure occurred in 9% of 449 patients; 7% experienced serious or severe (Grade 3 or higher). In PhALLCON the most frequently reported heart failure event (>1 patient) was increased brain natriuretic peptide (BNP) (2.5%). In OPTIC, the most frequently reported heart failure events (>1 patient each) were left ventricular hypertrophy (3.2%) and BNP increased (3.2%). In PACE, the most frequently reported heart failure events (≥2%) were congestive cardiac failure (3.1%), decreased ejection fraction (2.9%), and cardiac failure (2%). Monitor patients for signs or symptoms consistent with heart failure and manage heart failure as clinically indicated. Interrupt, then resume at reduced dose or discontinue ICLUSIG for new or worsening heart failure. Hepatotoxicity: ICLUSIG can cause hepatotoxicity, including liver failure and death. Fulminant hepatic failure leading to death occurred in 3 patients, with hepatic failure occurring within 1 week of starting ICLUSIG in one of these patients. These fatal cases occurred in patients with BP-CML or Ph+ ALL treated with monotherapy. Hepatotoxicity occurred in 66% of 163 patients in PhALLCON, in 28% of 94 patients in OPTIC and in 32% of 449 patients in PACE. Grade 3 or 4 hepatotoxicity occurred in PhALLCON (30% of 163 patients), in OPTIC (6% of 94 patients), and in PACE (13% of 449 patients). The most frequent hepatotoxic events were elevations of ALT, AST, GGT, bilirubin, and alkaline phosphatase. Monitor liver function tests at baseline, then at least monthly or as clinically indicated. Interrupt, then resume at a reduced dose or discontinue ICLUSIG based on recurrence/severity. Hypertension: Serious or severe hypertension, including hypertensive crisis, has occurred in patients who received ICLUSIG. Patients may require urgent clinical intervention for hypertension associated with confusion, headache, chest pain, or shortness of breath. Monitor blood pressure at baseline and as clinically indicated and manage hypertension as clinically indicated. Interrupt, dose reduce, or stop ICLUSIG if hypertension is not medically controlled. For significant worsening, labile or treatment-resistant hypertension, interrupt ICLUSIG and consider evaluating for renal artery stenosis. Pancreatitis: Serious or severe pancreatitis has occurred in patients who received ICLUSIG. Elevations of lipase and amylase also occurred. In the majority of cases that led to dose modification or treatment discontinuation, pancreatitis resolved within 2-3 weeks. Monitor serum lipase every 2 weeks for the first 2 months and then monthly thereafter or as clinically indicated. Consider additional serum lipase monitoring in patients with a history of pancreatitis or alcohol abuse. Interrupt, then resume at the same or reduced dose or discontinue ICLUSIG based on severity. Evaluate for pancreatitis when lipase elevation is accompanied by abdominal symptoms. Increased Toxicity in Newly Diagnosed Chronic Phase CML: In a prospective randomized clinical trial in the first-line treatment of newly diagnosed patients with CP-CML, single agent ICLUSIG 45 mg once daily increased the risk of serious adverse reactions 2-fold compared to single agent imatinib 400 mg once daily. The median exposure to treatment was less than 6 months. The trial was halted for safety. Arterial and venous thrombosis and occlusions occurred at least twice as frequently in the ICLUSIG arm compared to the imatinib arm. Compared to imatinib-treated patients, ICLUSIG-treated patients exhibited a greater incidence of myelosuppression, pancreatitis, hepatotoxicity, cardiac failure, hypertension, and skin and subcutaneous tissue disorders. ICLUSIG is not indicated and is not recommended for the treatment of patients with newly diagnosed CP-CML. Neuropathy: Peripheral and cranial neuropathy occurred in patients in PhALLCON, OPTIC and PACE. Some of these events in PhALLCON and PACE were Grade 3 or 4. Monitor patients for symptoms of neuropathy, such as hypoesthesia, hyperesthesia, paresthesia, discomfort, a burning sensation, neuropathic pain or weakness. Interrupt, then resume at the same or reduced dose or discontinue ICLUSIG based on recurrence/severity. Ocular Toxicity: Serious or severe ocular toxicity leading to blindness or blurred vision have occurred in ICLUSIG-treated patients. The most frequent ocular toxicities occurring in PhALLCON, OPTIC and PACE were dry eye, blurred vision, and eye pain. Retinal toxicities included age-related macular degeneration, macular edema, retinal vein occlusion, retinal hemorrhage, and vitreous floaters. Conduct comprehensive eye exams at baseline and periodically during treatment. Hemorrhage: Fatal and serious hemorrhage events have occurred in patients who received ICLUSIG. Fatal hemorrhages occurred in PACE and serious hemorrhages occurred in PhALLCON, OPTIC and PACE. In PACE, the incidence of serious bleeding events was higher in patients with AP-CML, BP-CML, and Ph+ ALL. Intracranial hemorrhage, gastrointestinal hemorrhage and subdural hematoma were the most frequently reported serious hemorrhages. Events often occurred in patients with Grade 4 thrombocytopenia. Monitor for hemorrhage and manage patients as clinically indicated. Interrupt, then resume at the same or reduced dose or discontinue ICLUSIG based on recurrence/severity. Fluid Retention: Fatal and serious fluid retention events have occurred in patients who received ICLUSIG. In PACE, one instance of brain edema was fatal and serious events included pleural effusion, pericardial effusion, and angioedema. In PhALLCON serious fluid retention included pericardial effusion. The most frequent occurrences of fluid retention in patients who received ICLUSIG were peripheral edema and pleural effusion. Monitor for fluid retention and manage patients as clinically indicated. Interrupt, then resume at the same or reduced dose or discontinue ICLUSIG based on recurrence/severity. Cardiac Arrhythmias: Cardiac arrhythmias, including ventricular, atrial arrhythmias, tachycardia, syncope, atrial fibrillation and supraventricular tachycardia occurred in patients in PhALLCON, OPTIC, and PACE. For some patients, events were serious or severe (Grade 3 or 4) and led to hospitalization. Monitor for signs and symptoms suggestive of slow heart rate (fainting, dizziness) or rapid heart rate (chest pain, palpitations or dizziness) and manage patients as clinically indicated. Interrupt, then resume at the same or reduced dose or discontinue ICLUSIG based on recurrence/severity. Myelosuppression: Grade 3 or 4 events of neutropenia, thrombocytopenia, and anemia occurred in patients in PhALLCON, OPTIC and PACE. In PACE, the incidence of myelosuppression was greater in patients with AP-CML, BP-CML, and Ph+ ALL treated with monotherapy than in patients with CP-CML. Obtain complete blood counts every 2 weeks for the first 3 months and then monthly or as clinically indicated. If ANC less than 1 x 109/L or platelets less than 50 x 109/L, interrupt ICLUSIG until ANC at least 1.5 x 109/L and platelets at least 75 x 109/L, then resume at same or reduced dose. Tumor Lysis Syndrome (TLS): Serious TLS was reported in ICLUSIG-treated patients in PhALLCON, OPTIC and PACE. Ensure adequate hydration and treat high uric acid levels prior to initiating ICLUSIG. Reversible Posterior Leukoencephalopathy Syndrome (RPLS): RPLS (also known as Posterior Reversible Encephalopathy Syndrome) has been reported in patients who received ICLUSIG. Patients may present with neurological signs and symptoms, visual disturbances, and hypertension. Diagnosis is made with supportive findings on magnetic resonance imaging (MRI) of the brain. Interrupt ICLUSIG until resolution. The safety of resumption of ICLUSIG in patients upon resolution of RPLS is unknown. Impaired Wound Healing and Gastrointestinal Perforation: Impaired wound healing occurred in patients receiving ICLUSIG. Withhold ICLUSIG for at least 1 week prior to elective surgery. Do not administer for at least 2 weeks following major surgery and until adequate wound healing. The safety of resumption of ICLUSIG after resolution of wound healing complications has not been established. Gastrointestinal perforation or fistula occurred in patients receiving ICLUSIG. Permanently discontinue in patients with gastrointestinal perforation. Embryo-Fetal Toxicity: Based on its mechanism of action and findings from animal studies, ICLUSIG can cause fetal harm when administered to a pregnant woman. Advise pregnant women of the potential risk to the fetus. Advise females of reproductive potential to use effective contraception during treatment with ICLUSIG and for 3 weeks after the last dose. ADVERSE REACTIONS The most common adverse reactions (occurring in >20% of patients) are: ICLUSIG as a single agent: rash and related conditions, arthralgia, abdominal pain, headache, constipation, dry skin, hypertension, fatigue, fluid retention and edema, pyrexia, nausea, pancreatitis/lipase elevation, hemorrhage, anemia, hepatic dysfunction and AOEs. The most common Grade 3 or 4 laboratory abnormalities (>20%) are platelet count decreased, neutrophil cell count decreased, and white blood cell decreased. ICLUSIG in combination with chemotherapy: hepatic dysfunction, arthralgia, rash and related conditions, headache, pyrexia, abdominal pain, constipation, fatigue, nausea, oral mucositis, hypertension, pancreatitis/lipase elevation, neuropathy peripheral, hemorrhage, febrile neutropenia, fluid retention and edema, vomiting, paresthesia and cardiac arrhythmias. The most common Grade 3 or 4 laboratory abnormalities (>20%) are decreased white blood cell count, decreased neutrophil cell count, decreased platelet count, decreased lymphocyte cell count, decreased hemoglobin, increased lipase and increased alanine aminotransferase. To report SUSPECTED ADVERSE REACTIONS, contact Takeda Pharmaceuticals at 1-844-817-6468 or FDA at 1-800-FDA-1088 or . DRUG INTERACTIONS Strong CYP3A Inhibitors: Avoid coadministration or reduce ICLUSIG dose if coadministration cannot be avoided. Strong CYP3A Inducers: Avoid coadministration. USE IN SPECIFIC POPULATIONS Lactation: Advise women not to breastfeed during treatment with ICLUSIG and for 1 week following last dose. Females and Males of Reproductive Potential: Verify pregnancy status of females of reproductive potential prior to initiating ICLUSIG. Ponatinib may impair fertility in females, and it is not known if these effects are reversible. Pre-existing Hepatic Impairment: For patients with CP-CML, AP-CML, BP-CML, and Ph+ ALL receiving monotherapy, reduce the starting dose of ICLUSIG to 30mg orally once daily for patients with pre-existing hepatic impairment as these patients are more likely to experience adverse reactions compared to patients with normal hepatic function. For patients with newly diagnosed Ph+ ALL, no dosage adjustment is recommended. 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Society of NeuroInterventional Surgery says shift in treatment protocol represents major advance for the field FAIRFAX, Va., Feb. 12, 2024 /PRNewswire/ -- The Society of Neurolnterventional Surgery (SNIS) is acknowledging middle meningeal artery embolization (MMAE) as a beneficial adjunctive treatment for chronic subdural hematoma in light of new research. The minimally invasive MMAE procedure significantly reduced the failure rates of traditional surgical and non-surgical management strategies without an increased rate of serious neurological complications. Chronic subdural hematoma refers to the gradual accumulation of blood over the surface of the brain. This disorder primarily affects elderly patients, is associated with significant morbidity and mortality, and represents a tremendous health care resource burden. As the U.S. population continues to age, studies show that chronic subdural hematomas may be the most prevalent neurosurgical diagnosis that requires treatment within the next decade. The existing standard of care for treating chronic subdural hematomas involves either drilling holes into the skull to drain the blood (i.e., surgical management) or watchful waiting with various medical interventions (i.e., non-surgical management) for patients who do not require early surgical intervention and/or are poor surgical candidates. However, an average of 10% to 30% of patients experience recurrence of chronic subdural hematoma after surgery, often necessitating reoperation. Studies show these surgical failure rates are higher among elderly patients. Failure rates in patients initially managed non-surgically are reported to be even higher. According to three new prospective randomized controlled trials (EMBOLISE, MAGIC-MT and STEM), adjunctive MMAE significantly reduces the failure rates of standard management strategies. The technically straightforward and minimally invasive MMAE procedure is performed using small catheters inserted through blood vessels in the arm or leg. These small catheters are then navigated into the middle meningeal artery and liquid agents are injected into these blood vessels, solidifying within them (like a glue), blocking them off and stopping the chronic bleeding into the subdural space. This treatment represents a major shift in the management of this disease. The effect sizes of adjunctive MMAE in patients in the non-surgical arms of MAGIC-MT and STEM indicate that many patients may be able to avoid open surgery completely as MMAE substantially reduced the failure rates of non-surgical management. For patients who required surgical drainage, EMBOLISE showed that adjunctive MMAE significantly reduced reoperation rates. The surgical management arm of the STEM trial showed a similar robust trend with MMAE cutting surgical failure rates by about half, however, STEM did not show differences in the non-surgical and surgical subgroups separately, and as such, the surgical arm findings were not significant as a stand-alone subgroup. Adjunctive MMAE with liquid agents started in 2018 with two members of SNIS who went on to lead the pivotal STEM trial (sponsored by BALT USA) — former SNIS President Adam Arthur, MD, MPH and David Fiorella, MD, PhD. "The presented data indicate that this novel adjunctive procedure represents an important advance as it reduces the failure rates of standard management strategies with a high margin of procedural safety. Chronic subdural hematoma is an exceedingly common problem, and these findings will be relevant to a large population of patients. We look forward to the final published results of all three studies," said Dr. Fiorella, professor of neurosurgery at Stony Brook University. "In many ways these data are really just the beginning. There will be a tremendous amount of additional insight coming very soon. The MEMBRANE trial from Cerenovus just recently completed enrollment and a combined analysis of all four of these randomized controlled trials of MMAE is planned. It is important to acknowledge that EMBOLISE and STEM were performed under investigational device exemptions within the context of U.S. FDA regulated prospective clinical trials. No liquid embolic agent currently has U.S. FDA clearance for MMAE and regulatory review is pending." "It is incredible to see the fruits of our labor after six years of research," said Dr. Arthur, chair of neurosurgery at the University of Tennessee Health Sciences Center and Semmes-Murphey Clinic. "Together as neurointerventionalists and neurosurgeons, we are making a difference by providing evidenced-based, effective and patient-centric minimally invasive alternatives to traditional treatment strategies. My SNIS colleagues are continually producing remarkable work to advance the field and I am eager to witness what is to come." To receive a copy of this research or to speak with the study authors, please contact Camille Jewell at [email protected] or 202-248-5460 About the Society of NeuroInterventional Surgery The Society of NeuroInterventional Surgery (SNIS) is a scientific and educational association dedicated to advancing the specialty of neurointerventional surgery through research, standard-setting, and education and advocacy to provide the highest quality of patient care in diagnosing and treating diseases of the brain, spine, head and neck. Visit and follow us on X (@SNISinfo) and Facebook (@SNISOnline). CONTACT: Camille Jewell [email protected] or 202-248-5460 SOURCE The Society of NeuroInterventional Surgery (SNIS)

☝ 点击上方 一键预约 ☝   最新最热的医药健康新闻政策打造“十亿美元分子”，几乎是每一家Biotech向BioPharma跃迁的必经之路，而血液瘤领域注定将成为国产创新药不断取得突破，并最终迈向“十亿美元分子”的应许之地。纵观国内创新药公司的现有管线布局，继百济神州的泽布替尼成功出海并且无限接近年销售额10亿美元之后，在血液瘤治疗这个热门领域，依然有很大概率诞生下一个有实力冲击“十亿美元分子”的国产创新药，而其中最有希望的种子选手，也已然崭露头角。2023年11月17日，亚盛医药正式宣布，其原创1类新药奥雷巴替尼（商品名：耐立克®），用于治疗一代和二代酪氨酸激酶抑制剂（TKIs）耐药和/或不耐受的慢性髓细胞白血病慢性期（CML-CP）的新适应症上市申请，获得药品审评中心（CDE）正式批准。该适应症的上市申请，于此前的2022年7月获NMPA受理，并被纳入优先审评程序。这是继2021年11月获批用于治疗携T315I突变的耐药CML患者后，奥雷巴替尼的又一个里程碑式进展，也意味着这款潜力巨大的药物，在向着“十亿美元分子”进军的征途中，又迈出了扎实的一大步。第三代TKI中的“Best-in-Class”之所以认为奥雷巴替尼是下一个“十亿美元分子”的最有力竞争者之一，主要基于两个原因。第一个原因：血液瘤治疗历来是重磅药物频出的一个领域，具体到TKI这个细分赛道，之前两代药物的销售峰值都远超“十亿美元”这个门槛。第一代TKI伊马替尼，也就是因为电影《我不是药神》而知名度极高的“格列卫”，其凭借革命性的CML治疗效果，其销售峰值近50亿美元。第二代TKI的代表药物达沙替尼、尼洛替尼，二者在2020年的峰值销售额合计超过40亿美元。因此，完全有理由认为，在三代TKI中，产生销售峰值超过10亿美元的重磅药物，是一件水到渠成的事情。第二个原因：作为第三代TKI，奥雷巴替尼不仅针对一代和二代TKI有明显的代际优势，甚至相比于其他的三代TKI，奥雷巴替尼也在临床研究中显示出巨大的“Best-in-Class”潜力。也就是说，在大概率将产生“十亿美元分子”的第三代TKI药物中，奥雷巴替尼是目前数据最好、临床治疗效果最佳，是“最能打”的那一个。在2023年的美国血液年会（ASH）上，亚盛医药公布的多项奥雷巴替尼的研究数据，都以高质量的循证医学证据，完美支持以上结论。在一项治疗一代和二代酪氨酸激酶抑制剂（TKI）耐药的CML-CP患者的随机对照注册性II期研究中，与最佳可用疗法（BAT）的对照组相比，奥雷巴替尼治疗组的无事件生存期（EFS）为21.22个月，而对照组仅仅达到2.86个月，差异非常显著。每一代TKI的出现，主要都是为了解决上一代TKI的耐药性问题，奥雷巴替尼作为三代TKI，针对一代和二代TKI的耐药性问题这个临床治疗最大的痛点，可谓交出了一份让人惊艳的答卷，显示了巨大的代际优势。三代TKI针对一代和二代TKI具备优势，似乎是应有之义，但是奥雷巴替尼的海外临床研究显示，针对其他三代TKI药物治疗失败的患者，该品种也展示了显著的临床治疗优势，这几乎可以直接奠定奥雷巴替尼在三代TKI中“Best in Class”的领头羊地位。在一项针对既往接受过深度治疗/难治性CML和Ph+ ALL患者的临床研究中，一共入组了57例CML-CP患者和19例晚期Ph+ ALL患者, 其中52.6%的患者曾接受过三代TKI药物ponatinib治疗，27.6%的患者曾接受过变构抑制剂asciminib治疗，但是都因为耐药、不耐受或者其他原因而治疗失败，此外还有32%的患者基线合并T315I突变。换句话说，这些适应症都属于临床上所谓的“疑难杂症”，是现有竞品药物都啃不下来的 “硬骨头”，相关患者面临着无药可用的窘境。但是临床研究结果表明，奥雷巴替尼具备啃下“硬骨头”的潜力：在ponatinib治疗失败的患者中，奥雷巴替尼治疗组的CCyR率和MMR率分别为53%和38%；在asciminib治疗失败的患者中，奥雷巴替尼治疗组的CCyR率和MMR率分别为43%和38%。这个结果，指向一个巨大的改变现有临床治疗格局的可能性：作为三代TKI的奥雷巴替尼，不仅可以作为一代和二代TKI药物耐药后的解决方案，甚至也可以作为其他三代TKI治疗失败的CML或Ph+ ALL患者提供挽救性治疗方案。同时，奥雷巴替尼的安全性，在三代TKI中也属于佼佼者；另一款三代TKI药物ponatinib引发的包括血栓在内的严重心血管不良事件发生率很高，甚至因为此类不良事件高发，曾经被FDA要求撤市，后因临床需求恢复上市，但被FDA标注“黑框警告”。不仅显著优于前两代药物，而且针对其他三代TKI也有明确的优势，如果在三代TKI药物中出现一个“十亿美元分子”，那么奥雷巴替尼毫无疑问具备最终撞线的巨大潜力。冲击Ph+ ALL的一线治疗除了在CML治疗上展示出优异的临床数据，现有的研究结果表明，奥雷巴替尼对Ph+ ALL的治疗同样有巨大的潜力。Ph+ ALL全称为费城染色体阳性（Ph+）急性淋巴细胞白血病（ALL），在成人ALL患者中约占20%-30%，具有复发率高、无病生存期短、预后差等特点，目前的一代和二代TKI针对Ph+ ALL的治疗效果并不能让人满意：不仅复发率高，而且3-5 年总生存率只有50%左右。 目前，临床上对于奥雷巴替尼治疗Ph+ ALL抱有极高的预期，业界认为其完全有希望冲击Ph+ ALL一线治疗的地位。在2023年的ASH会议上，奥雷巴替尼发布的多项Ph+ ALL治疗相关的临床研究数据，都展示了这款药物改写Ph+ ALL现有临床治疗格局的巨大潜力。除了针对其他TKI治疗失败的Ph+ ALL患者仍然有很好的疗效，在新诊断的Ph+ ALL患者治疗方面，奥雷巴替尼的临床数据依然惊艳。在一项联合Bcl-2抑制剂维奈克拉和低强度化疗治疗新诊断的Ph+ ALL患者的II期临床试验中，所有患者均在第一个周期结束时达到完全缓解（CR），没有出现TLS或治疗相关死亡。在第一个周期结束时，17例（54.8%）患者获完全分子学反应（CMR），8例（25.8%）患者获主要分子学反应(MMR)。在治疗第3个月s时，19例（61.3%）患者获CMR，10例（32.3%）患者获MMR。考虑到亚盛医药拥有全球潜在“BIC”的Bcl-2抑制剂APG-2575，这个临床研究结果表明，亚盛医药未来完全有实力推出针对Ph+ ALL治疗潜力更佳的联合治疗方案。鉴于奥雷巴替尼在Ph+ ALL这个适应症上的优异临床研究数据，NMPA已经在今年7月已经批准奥雷巴替尼开展联合化疗对比伊马替尼联合化疗治疗新诊断的Ph+ALL患者的全球注册性Ⅲ期临床研究。这意味着奥雷巴替尼有望成为国内首个获批用于一线治疗Ph+ ALL的TKI药物，一旦临床试验成功，不仅将彻底改写Ph+ ALL现有的临床治疗路径，也将成为奥雷巴替尼冲击“十亿美元分子”的重要里程碑。更重要的是，如果能显著提升Ph+ ALL仅为50%的3-5年生存率，将造福无数的患者，造福无数的家庭。商业化前景光明目前，奥雷巴替尼仅在中国市场上市销售，但是已经显示了巨大的商业化价值。奥雷巴替尼于今年1月获纳入新版国家医保药品目录，上半年已经放量显著，实现销售收入人民币1.08亿元，较去年同期增长37%。其中第二季度销售额同比增长153%，销售盒数同比增长560%。半年销售金额1.08亿元，这个绝对数字虽然不是很高，但是增速非常显著，同时也要考虑到，这是在仅获批治疗携T315I突变的耐药CML这样一个相对较小的适应症的前提下取得的成绩。此次用于治疗一代和二代TKIs耐药和/或不耐受的CML-CP新适应症获批之后，奥雷巴替尼的商业化将进入一个全新的阶段。在一代和二代TKI药物的多年努力下，CML已经逐渐成为一种慢性病，比如接受一代TKI伊马替尼治疗的CML患者，其10年生存率可达 82%，因此存量患者的数量庞大。有研究机构预计，到2030年我国 CML存量患者人数将达到8~10万人。目前奥雷巴替尼纳入医保后的年治疗费用为17.5万元，对应的理论市场规模大约为140亿~170亿元。即使考虑到后续医保进一步降价的可能性，耐药CML的治疗也是一个百亿人民币级别的庞大市场。此外，奥雷巴替尼正在进行的针对Ph+ ALL的关键注册性Ⅲ期临床试验，该适应症一旦获批，商业化空间也不可小觑。公开数据显示，2019年中国ALL患者约14.3万人，预计到2030年将达到15.7万人；假设其中有20%的Ph+ ALL患者，每年大约有3万左右的患者需要服药，这也是一个30亿~50亿级别的大市场。当然，和所有国产创新药的基本逻辑一样，国内市场只是奥雷巴替尼的基本盘，最具想象力的地方还是出海之后的国际市场，尤其是美国市场。以asciminib为例，其2023年上半年销售额大约为1.8亿美元，全年有望达到5亿美元左右，而这仅仅是其上市后的第二个完整销售年度，而且其主要获批用于治疗接受过两种或更多TKI治疗失败的CML患者。业界预测，asciminib的销售峰值超越10亿美金是大概率事件。目前，奥雷巴替尼用于治疗无论有否TKI耐药的CML以及Ph+ ALL患者的Ib期桥接试验正在美国、欧洲和加拿大进行，一旦最终获批上市，其覆盖的患者范围要比目前的asciminib大很多，且奥雷巴替尼针对asciminib治疗失败的患者仍然具备治疗潜力，因此完全有理由认为，奥雷巴替尼具备更大的商业化想象空间。或者说，一旦奥雷巴替尼在美国和欧洲市场获批，鉴于其在三代TKI中极大的“Best in Class”潜力，超越竞品并跻身 “十亿美元分子”的行列，或许只不过是一个水到渠成的目标。不止血液瘤虽然奥雷巴替尼已经在血液瘤的治疗领域展现了惊人的统治力，但是这并非奥雷巴替尼唯一的用武之地。2023年5月，国家药品监督管理局药品审评中心（CDE）公示，奥雷巴替尼被纳入“拟突破性治疗品种”公示名单，用于治疗既往经过一线治疗的琥珀酸脱氢酶（SDH）的缺陷型胃肠道间质瘤（GIST）患者。这是奥雷巴替尼第二次获CDE纳入突破性治疗品种，不同的是这次是针对的实体瘤治疗领域。GIST是一种起源于胃肠道间叶组织的肿瘤，SDH缺陷型的GIST亚型治疗领域，存在巨大的未被满足的临床需求：目前尚无针对复发和晚期SDH缺陷型GIST患者的标准治疗方案，5年无事件生存率（EFS）仅为24%。一项在中国进行的Ib/II期研究最新数据显示，奥雷巴替尼在SDH缺陷型GIST患者中的临床获益率（CBR）高达93.8%，该临床研究也因此连续两年入选美国临床肿瘤学会（ASCO）年会展示。这一研究结果表明，奥雷巴替尼在实体瘤治疗领域也有着巨大的应用前景，随着临床研究的不断推进，SDH缺陷型的GIST的治疗，极有可能成为奥雷巴替尼另一个极具差异化的“杀手锏”。同时，这也再次体现了亚盛医药的创新紧密围绕着“以患者为中心”的宗旨而展开：哪怕是相对较小的适应症，也要做出显著的差异化优势，追求实质性地改善现有的临床治疗局面，而不是盲目地去跟风和扎堆所谓的“热门”。亚盛医药的“十亿美元分子”，不止奥雷巴替尼说到奥雷巴替尼，就不能不提亚盛医药的另一款在研药物APG-2575，无论是作为单药还是联合用药使用，这款药物都是亚盛医药旗下另一款潜在的“十亿美元分子”。APG-2575是全球第二个，国内首个看到明确疗效的Bcl-2抑制剂，该品种在复发/难治（R/R）CLL和其他血液恶性肿瘤患者中，都体现了潜在的疗效，并且安全性更好、给药方案更便捷友好。随着临床研究的不断推进，一旦获批上市，APG-2575也完全具备冲击“十亿美元分子”的极大潜力。期待更多的国产创新药企业 ，和亚盛医药一样，坚持“以患者为中心”的根本宗旨，在有效满足临床需求的同时，取得更多“十亿美元”级别的商业化成功，共同缔造中国创新药产业的辉煌明天。(来源:医药投资部落 作者:Mc）药闻康策新媒体矩阵微信公众号点击下方  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