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Enhertu approved in China for patients with HER2-low metastatic breast cancer

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Enhertu approved in China for patients with HER2-low metastatic breast cancer

July 12, 2023: “AstraZeneca and Daiichi Sankyo’s Enhertu (trastuzumab deruxtecan) has been approved in China as a monotherapy for the treatment of adult patients with unresectable or metastatic HER2-low (IHC 1+ or IHC 2+/ISH-) breast cancer who have received a prior systemic therapy in the metastatic setting or developed disease recurrence during or within six months of completing adjuvant chemotherapy.

Enhertu is a specifically engineered HER2-directed antibody drug conjugate (ADC) being jointly developed and commercialised by AstraZeneca and Daiichi Sankyo.

The approval by China’s National Medical Products Administration (NMPA) is based on the results of the DESTINY-Breast04 Phase III trial, first presented at the American Society of Clinical Oncology 2022 Annual Meeting and published in The New England Journal of Medicine.

It follows the approval granted by China’s NMPA for Enhertu in patients with previously treated unresectable or metastatic HER2-positive breast cancer in February 2023.

In China, breast cancer is the most common cancer in women, with more than 415,000 patients diagnosed in 2020.2 There were nearly 120,000 breast cancer deaths in China in 2020, representing around 18% of global breast cancer deaths.

Approximately half of all breast cancers are considered HER2-low.

Binghe Xu, MD, Director of the National Clinical Research Center for New Anticancer Drugs, Tenured Professor and Former Director, Department of Medical Oncology, Cancer Hospital Chinese Academy of Medical Sciences and Peking Union Medical College, said: “Historically, breast cancer tumours with low levels of HER2 expression have been classified as HER2-negative and have not been eligible for treatment with HER2-directed therapies.

With this approval in China, based on the results of the DESTINY-Breast04 trial, clinicians will now be able to identify and potentially treat a distinct patient population based on HER2-low status.”

Dave Fredrickson, Executive Vice President, Oncology Business Unit, AstraZeneca, said: “Patients with HR-positive or HR-negative, HER2-low metastatic breast cancer previously had few effective treatment options beyond chemotherapy.

The results from the DESTINY-Breast04 trial show Enhertu provides a significant improvement in outcomes compared to chemotherapy for patients whose tumours are determined to be HER2-low via routine testing.

This approval is an important advance in the way breast cancer is classified and treated in China and supports our vision to bring Enhertu to more patients worldwide.”

Kiminori Nagao, Head of the Asia, South & Central America (ASCA) Business Unit, Daiichi Sankyo, said: “This approval of Enhertu for patients with HER2-low metastatic breast cancer, which comes shortly after the approval of Enhertu in patients with HER2-positive disease, marks the first time patients with HER2-low tumours will have the opportunity to be treated with a HER2-directed therapy. 

Enhertu now has the potential to become a new standard of care treatment option in China for a broad range of patients with HER2-expressing metastatic breast cancer.”

In DESTINY-Breast04, Enhertu reduced the risk of disease progression or death by 50% versus physician’s choice of chemotherapy (median progression-free survival [PFS] 9.9 vs. 5.1 months; hazard ratio [HR] of 0.50; 95% confidence interval [CI] 0.40-0.63; p<0.0001) in all randomised patients with HER2-low metastatic breast cancer (either hormone receptor (HR)-positive or HR-negative disease).

A 36% reduction in the risk of death (HR of 0.64; 95% CI 0.49-0.84; p=0.001) also was seen with Enhertu compared to chemotherapy with a median overall survival (OS) of 23.4 months in patients treated with Enhertu versus 16.8 months in those treated with chemotherapy.

The safety profile observed in patients treated with Enhertu in the DESTINY-Breast04 trial was consistent with that seen in other trials of Enhertu in breast cancer with no new safety signals identified.”

https://www.astrazeneca.com/media-centre/press-releases/2023/enhertu-approved-in-china-as-the-first-her2-directed-therapy-for-patients-with-her2-low-metastatic-breast-cancer.html

FDA Approves First Drug to Treat Agitation Symptoms Associated with Dementia due to Alzheimer’s Disease

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FDA Approves First Drug to Treat Agitation Symptoms Associated with Dementia due to Alzheimer’s Disease

May 11, 2023: “The U.S. FDA is announcing the supplemental approval of Rexulti (brexpiprazole) oral tablets for the treatment of agitation associated with dementia due to Alzheimer’s disease.

This is the first FDA-approved treatment option for this indication.

“Agitation is one of the most common and challenging aspects of care among patients with dementia due to Alzheimer’s disease.

‘Agitation’ can include symptoms ranging from pacing or restlessness to verbal and physical aggression,” said Tiffany Farchione, M.D., director of the Division of Psychiatry in the FDA’s Center for Drug Evaluation and Research.

“These symptoms are leading causes of assisted living or nursing home placement and have been associated with accelerated disease progression.”

Dementia is a serious and debilitating neurological condition characterized by progressive decline in one or more cognitive domains in the brain.

Dementia can seriously impair an individual’s ability to function independently. Many people living with dementia require permanent at-home or residential care. 

Alzheimer’s disease is the most common cause of dementia. Alzheimer’s disease is an irreversible, progressive brain disorder affecting more than 6.5 million Americans.

Patients with dementia often have behavioral and psychological disturbances. Agitation is among the most persistent, complex, stressful, and costly aspects of care among patients with behavioral and psychological symptoms of dementia.

The effectiveness of Rexulti for the treatment of agitation associated with dementia due to Alzheimer’s disease was determined through two 12-week, randomized, double-blind, placebo-controlled, fixed-dose studies.

In these studies, patients were required to have a probable diagnosis of Alzheimer’s dementia; have a score between 5 to 22 on the Mini-Mental State Examination, a test that detects whether a person is experiencing cognitive impairment; and exhibit the type, frequency, and severity of agitation behaviors that require medication.

Trial participants ranged between 51 to 90 years of age. 

In the first study patients received 1 or 2 milligrams (mg) of Rexulti; in the second study patients received 2 or 3 mg of Rexulti.

The primary efficacy endpoint in these two studies was the change from baseline in the Cohen-Mansfield Agitation Inventory total (CMAI) score at week 12. CMAI is a survey tool that uses input from caregivers to rate the frequency of certain agitative behaviors in dementia patients on a scale from 1 to 7.

In both studies, patients who received 2 mg or 3 mg of Rexulti showed statistically significant and clinically meaningful improvements in total CMAI scores compared to patients in the placebo group at week 12.

The recommended starting dosage for the treatment of agitation associated with dementia due to Alzheimer’s disease is 0.5 mg taken once daily on days 1 to 7. Patients should increase the dosage on days 8 through 14 to 1 mg once daily, and on day 15 to 2 mg once daily. The recommended target dose is 2 mg once daily.

The dosage can be increased to the maximum recommended daily dosage of 3 mg once daily after at least 14 days, based on clinical response and tolerability.

The most common side effects among patients with agitation associated with dementia due to Alzheimer’s disease include headache, dizziness, urinary tract infection, nasopharyngitis, and sleep disturbances (both somnolence and insomnia).

Rexulti will retain the Boxed Warning for medications in this class that elderly patients with dementia-related psychosis treated with antipsychotic drugs are at an increased risk of death.

The FDA granted this application Fast Track designation. 

Fast Track is a process designed to facilitate the development and expedite the review of drugs to treat serious conditions and fill an unmet medical need.

The purpose is to get important new drugs to the patient earlier.

The supplemental approval of Rexulti was granted to Otsuka Pharmaceutical Company Ltd., and Lundbeck Inc.”

https://www.fda.gov/news-events/press-announcements/fda-approves-first-drug-treat-agitation-symptoms-associated-dementia-due-alzheimers-disease

FDA Approves Novel Drug to Treat Moderate to Severe Hot Flashes Caused by Menopause

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FDA Approves Novel Drug to Treat Moderate to Severe Hot Flashes Caused by Menopause

May 12, 2023: “The U.S. FDA approved Veozah (fezolinetant), an oral medication for the treatment of moderate to severe vasomotor symptoms, or hot flashes, caused by menopause.

Veozah is the first neurokinin 3 (NK3) receptor antagonist approved by the FDA to treat moderate to severe hot flashes from menopause.

It works by binding to and blocking the activities of the NK3 receptor, which plays a role in the brain’s regulation of body temperature.

“Hot flashes as a result of menopause can be a serious physical burden on women and impact their quality of life,” said Janet Maynard, M.D., M.H.S., director of the Office of Rare Diseases, Pediatrics, Urologic and Reproductive Medicine, in the FDA’s Center for Drug Evaluation and Research.

“The introduction of a new molecule to treat moderate to severe menopausal hot flashes will provide an additional safe and effective treatment option for women.”

Menopause is a normal, natural change in a woman’s life when her period stops, usually occurring between ages 45 and 55. Menopause is often referred to as “the change of life” or “the change.” During menopause a woman’s body slowly produces less of the hormones estrogen and progesterone.

A woman has reached menopause when she has not had a menstrual period for 12 consecutive months. Hot flashes occur in around 80% of menopausal women and can include periods of sweating, flushing and chills lasting for several minutes.

Some women who experience hot flashes and have a history of vaginal bleeding, stroke, heart attack, blood clots or liver disease, cannot take hormone therapies. Veozah is not a hormone.

It targets the neural activity which causes hot flashes during menopause. 

Patients taking Veozah should take one 45 milligram pill orally, once a day, with or without food. The pill should be taken at the same time each day.

If a dose is missed, or not taken at the regular time, patients should take it as soon as possible and return to their regular schedule the following day.

The effectiveness of Veozah to treat moderate to severe hot flashes was demonstrated in each of the first 12-week, randomized, placebo-controlled, double-blind portions of two phase 3 clinical trials.

In both trials, after the first 12 weeks, the women on placebo were then re-randomized to Veozah for a 40-week extension study to evaluate safety. Each trial ran a total of 52 weeks. The average age of the trial participants was 54 years old.

The prescribing information for Veozah includes a warning for elevated hepatic transaminase, or liver injury. Before using Veozah, patients should have blood work done to test for liver damage.

While on Veozah, routine bloodwork should be performed every three months for the first nine months of using the medication.

Patients experiencing symptoms related to liver damage—such as nausea, vomiting, or yellowing of the skin and eyes—should contact a physician.

Veozah cannot be used with CYP1A2 inhibitors. Patients with known cirrhosis, severe renal damage or end-stage renal disease should not take Veozah. 

The most common side effects of Veozah include abdominal pain, diarrhea, insomnia, back pain, hot flush and elevated hepatic transaminases. 

The FDA granted the Veozah application Priority Review designation.

The approval of Veozah was granted to Astellas Pharma US, Inc.”

https://www.fda.gov/news-events/press-announcements/fda-approves-novel-drug-treat-moderate-severe-hot-flashes-caused-menopause

Farxiga extended in US to reduce risk of cardiovascular death and hospitalisation for heart failure to a broader range of patients

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Farxiga extended in US to reduce risk of cardiovascular death and hospitalisation for heart failure to a broader range of patients

May 09, 2023: “AstraZeneca’s Farxiga (dapagliflozin) has been approved in the US to reduce the risk of cardiovascular (CV) death, hospitalisation for heart failure (hHF) and urgent heart failure (HF) visits in adults with HF.

The approval by the Food and Drug Administration (FDA) was based on positive results from the DELIVER Phase III trial.1 Farxiga was previously approved in the US for adults with HF with reduced ejection fraction (HFrEF).

Ruud Dobber, Executive Vice-President, BioPharmaceuticals Business Unit, AstraZeneca, said: “Approximately half of heart failure patients die within five years of diagnosis, highlighting an urgent unmet need for well-tolerated treatment options that can bring life-saving benefits and reduce the risk of cardiovascular death.

The approval of Farxiga in the US not only reinforces AstraZeneca’s commitment to reducing the burden of this complex and life-threatening disease, but will help patients across the full spectrum of heart failure lead healthier lives.”

HF is a chronic, long-term condition that worsens over time and affects almost seven million people in the US.3 It is also the leading cause of hospitalisation for those over 65 years and represents a significant clinical and economic burden.

Approximately half of all HF patients have HF with mildly reduced ejection fraction (HFmrEF) or HF with preserved ejection fraction (HFpEF) and these patients are not only at greater risk of death and hospitalisations but experience an especially high burden of symptoms and physical limitations, and a poor quality of life.

The data from the DELIVER Phase III trial, published in The New England Journal of Medicine, showed Farxiga reached a statistically significant and clinically meaningful early reduction in the primary composite endpoint of CV death or worsening HF in patients with HF with HFmrEF or HFpE.F1 The results from a pre-specified, pooled analysis of the DAPA-HF and DELIVER Phase III trials, published in Nature Medicine, showed that the treatment effect of Farxiga on the composite endpoint of cardiovascular death, hospitalisation for heart failure or urgent heart failure was consistent across the left ventricular ejection fraction (LVEF)  range and established Farxiga as the first sodium-glucose cotransporter 2 (SGLT2) inhibitor to demonstrate a mortality benefit.

Farxiga is approved for the treatment of patients with type-2 diabetes (T2D), HFrEF and chronic kidney disease (CKD) in more than 100 countries around the world including the US, the European Union (EU), China and Japan.

It has most recently received regulatory approvals in the EU, Great Britain, Japan and Turkey to extend the HF indication to include patients across the full LVEF range.”

https://www.astrazeneca.com/media-centre/press-releases/2023/farxiga-extended-in-the-us-for-heart-failure.html

BMS Receives EC Approval for CAR T Cell Therapy Breyanzi for Relapsed or Refractory Large B-cell Lymphoma After One Prior Therapy

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BMS Receives EC Approval for CAR T Cell Therapy Breyanzi for Relapsed or Refractory Large B-cell Lymphoma After One Prior Therapy

May 05, 2023: “Bristol Myers Squibb announced that the European Commission (EC) has granted approval for Breyanzi (lisocabtagene maraleucel; liso-cel), a CD19-directed chimeric antigen receptor (CAR) T cell therapy, for the treatment of adult patients with diffuse large B-cell lymphoma (DLBCL), high grade B-cell lymphoma (HGBCL), primary mediastinal large B-cell lymphoma (PMBCL) and follicular lymphoma grade 3B (FL3B), who relapsed within 12 months from completion of, or are refractory to, first-line chemoimmunotherapy.

This approval covers all European Union (EU) member states.*

The approval is based on results from the pivotal Phase 3 TRANSFORM trial in which Breyanzi demonstrated statistically significant and clinically meaningful improvements in the study’s primary endpoint of event-free survival (EFS), and key secondary endpoints of complete responses (CR) and progression-free survival (PFS) compared to standard therapy (consisting of salvage immunochemotherapy followed by high-dose chemotherapy and hematopoietic stem cell transplant [HSCT]), along with a manageable and well-established safety profile.

“With Breyanzi, people in Europe living with relapsed or refractory DLBCL now have a differentiated CAR T cell therapy option earlier in the treatment paradigm that provides long-term clinical benefit,” said Anne Kerber, senior vice president, head of Cell Therapy Development, Bristol Myers Squibb.

“This marks the approval of our third indication in Europe for our CAR T cell therapy portfolio, underscoring our continued drive to deliver the promise of cell therapy with curative potential for more patients.”

In DLBCL, the most common form of non-Hodgkin lymphoma, up to 40% of patients have disease that is refractory to or relapses following initial therapy.

The standard therapy for these patients consists of intensive salvage immunochemotherapy followed by high-dose chemotherapy and HSCT for those whose disease responds to the salvage therapy and are eligible for transplant.

However, only an estimated 25% of patients are considered eligible for transplant and experience long-term clinical benefit, leaving a continued unmet need for second-line treatment options with curative potential.

“Based on results of the TRANSFORM trial, Breyanzi provides significantly improved outcomes compared to the standard of care that has been in place for decades, along with a well-established safety profile, demonstrating the benefit of using a CAR T cell therapy earlier for patients with relapsed or refractory DLBCL,” said Bertram Glass, M.D., TRANSFORM trial investigator and Chief Physician of the Department of Hematology and Stem Cell Transplantation, Helios Klinikum, Berlin, Germany.

“This approval represents a significant milestone for patients with continued progress toward transforming second-line treatment practice to provide a personalized treatment option that offers the potential for durable remission.”

*Centralized Marketing Authorization does not include approval in Great Britain (England, Scotland and Wales).

TRANSFORM Clinical Trial Results

In the TRANSFORM study, Breyanzi more than quadrupled median EFS compared to standard therapy (10.1 months vs. 2.3 months [HR: 0.349; 95% CI (0.229-0.530) p<0.0001]) at the time of prespecified interim analysis with a median follow-up of 6.2 months.

Results of the primary analysis, with a median follow-up of 17.5 months were consistent with the interim analysis, with median EFS not reached for Breyanzi (95% CI: 9.5-NR) vs. 2.4 months for standard therapy (95% CI: 2.2-4.9).

With Breyanzi, the majority (73.9%) of patients achieved a CR compared to less than half (43.5%) of those who were treated with standard therapy.

Median PFS was not reached (95% CI: 12.6-NR) with Breyanzi vs. 6.2 months (95% CI: 4.3-8.6) with standard therapy (HR: 0.400; 95% CI: 0.261-0.615; p<0.0001).

The safety profile of Breyanzi is well-established, and in the TRANSFORM study, occurrences of cytokine release syndrome (CRS) and neurologic events were generally low-grade, and mostly resolved quickly with standard protocols and without the use of prophylactic steroids. Any-grade CRS was reported in less than half of patients (48.9%), with Grade 3 CRS reported in 1% of patients.

The median time to onset of CRS was five days (range: 1 to 63) and median duration of CRS was four days (range: 1 to 16). Any-grade neurologic events were reported in 10.9% of patients treated with Breyanzi, with Grade 3 neurologic events reported in 4.3% of patients.

The median time to onset of neurologic events was 11 days (range: 7 to 17 days). The median duration of neurologic toxicities was 4.5 days (range: 1 to 30 days).

For full details on the Special Warnings and Precautions for Use and Adverse Reactions (including appropriate management), please refer to the EU Summary of Product Characteristics (SmPC).

About TRANSFORM

TRANSFORM (NCT03575351) is a pivotal, global, randomized, multicenter Phase 3 trial evaluating Breyanzi compared to current standard of care (platinum-based salvage chemotherapy followed by high-dose chemotherapy and autologous hematopietic stem cell transplant [HSCT] in patients responding to salvage chemotherapy) in patients with large B-cell lymphoma that was primary refractory or relapsed within 12 months after CD20-antibody and anthracycline containing first-line therapy.

Patients were randomized to receive Breyanzi or standard of care salvage therapy, including rituximab plus dexamethasone, high-dose cytarabine, and cisplatin (R-DHAP), rituximab plus ifosfamide, carboplatin and etoposide (R-ICE), or rituximab plus gemcitabine, dexamethasone and cisplatin (R-GDP) per the investigators’ choice before proceeding to high-dose chemotherapy (HDCT) and auto-HSCT.

The primary endpoint of the study was event-free survival, defined as time from randomization to death from any cause, progressive disease, failure to achieve complete response or partial response, or start of new antineoplastic therapy due to efficacy concerns, whichever occurs first.

Complete response rate was a key secondary endpoint. Other efficacy endpoints included progression-free survival, overall survival, overall response rate and duration of response.

About Breyanzi

Breyanzi is a CD19-directed CAR T cell therapy with a 4-1BB costimulatory domain, which enhances the expansion and persistence of the CAR T cells. 

Breyanzi is approved by the U.S. Food and Drug Administration (FDA) for the treatment of adult patients with large B-cell lymphoma (LBCL), including diffuse large B-cell lymphoma (DLBCL) not otherwise specified (including DLBCL arising from indolent lymphoma), high-grade B-cell lymphoma, primary mediastinal LBCL, and follicular lymphoma grade 3B who have refractory disease to first-line chemoimmunotherapy or relapse within 12 months of first-line chemoimmunotherapy, or refractory disease to first-line chemoimmunotherapy or relapse after first-line chemoimmunotherapy and are not eligible for hematopoietic stem cell transplant due to comorbidities or age, or relapsed or refractory disease after two or more lines of systemic therapy. 

Breyanzi is not indicated for the treatment of patients with primary central nervous system lymphoma.

Please see the Important Safety Information section below, including Boxed WARNINGS for Breyanzi regarding cytokine release syndrome and neurotoxicity.

Breyanzi is also approved in Japan for the second-line treatment of relapsed or refractory LBCL, and in Japan, Europe, Switzerland and Canada for relapsed or refractory LBCL after two or more lines of systemic therapy.

Bristol Myers Squibb’s clinical development program for Breyanzi includes clinical studies in earlier lines of treatment for patients with relapsed or refractory LBCL and other types of lymphomas and leukemia. For more information, visit clinicaltrials.gov.

Full European Summary of Product Characteristics for Breyanzi is available from the EMA website at www.ema.europa.eu .

U.S. Important Safety Information

BOXED WARNING: CYTOKINE RELEASE SYNDROME and NEUROLOGIC TOXICITIES

  • Cytokine Release Syndrome (CRS), including fatal or life-threatening reactions, occurred in patients receiving BREYANZI. Do not administer BREYANZI to patients with active infection or inflammatory disorders. Treat severe or life-threatening CRS with tocilizumab with or without corticosteroids.
  • Neurologic toxicities, including fatal or life-threatening reactions, occurred in patients receiving BREYANZI, including concurrently with CRS, after CRS resolution or in the absence of CRS. Monitor for neurologic events after treatment with BREYANZI. Provide supportive care and/or corticosteroids as needed.
  • BREYANZI is available only through a restricted program under a Risk Evaluation and Mitigation Strategy (REMS) called the BREYANZI REMS.

Cytokine Release Syndrome (CRS)

CRS, including fatal or life-threatening reactions, occurred following treatment with BREYANZI. CRS occurred in 46% (122/268) of patients receiving BREYANZI, including ≥ Grade 3 (Lee grading system) CRS in 4% (11/268) of patients. One patient had fatal CRS and 2 had ongoing CRS at time of death. The median time to onset was 5 days (range: 1 to 15 days).

CRS resolved in 119 of 122 patients (98%) with a median duration of 5 days (range: 1 to 17 days). Median duration of CRS was 5 days (range 1 to 30 days) in all patients, including those who died or had CRS ongoing at time of death.

Among patients with CRS, the most common manifestations of CRS include fever (93%), hypotension (49%), tachycardia (39%), chills (28%), and hypoxia (21%). 

Serious events that may be associated with CRS include cardiac arrhythmias (including atrial fibrillation and ventricular tachycardia), cardiac arrest, cardiac failure, diffuse alveolar damage, renal insufficiency, capillary leak syndrome, hypotension, hypoxia, and hemophagocytic lymphohistiocytosis/macrophage activation syndrome (HLH/MAS).

Ensure that 2 doses of tocilizumab are available prior to infusion of BREYANZI. Sixty-one of 268 (23%) patients received tocilizumab and/or a corticosteroid for CRS after infusion of BREYANZI.

Twenty-seven (10%) patients received tocilizumab only, 25 (9%) received tocilizumab and a corticosteroid, and 9 (3%) received corticosteroids only.

Neurologic Toxicities

Neurologic toxicities that were fatal or life-threatening, occurred following treatment with BREYANZI.

CAR T cell-associated neurologic toxicities occurred in 35% (95/268) of patients receiving BREYANZI, including ≥ Grade 3 in 12% (31/268) of patients.

Three patients had fatal neurologic toxicity and 7 had ongoing neurologic toxicity at time of death.

The median time to onset of the first event was 8 days (range: 1 to 46 days). The onset of all neurologic events occurred within the first 8 weeks following BREYANZI infusion.

Neurologic toxicities resolved in 81 of 95 patients (85%) with a median duration of 12 days (range: 1 to 87 days).

Three of four patients with ongoing neurologic toxicity at data cutoff had tremor and one subject had encephalopathy.

Median duration of neurologic toxicity was 15 days (range: 1 to 785 days) in all patients, including those with ongoing neurologic events at the time of death or at data cutoff.

Seventy-eight (78) of 95 (82%) patients with neurologic toxicity experienced CRS. Neurologic toxicity overlapped with CRS in 57 patients.

The onset of neurologic toxicity was after onset of CRS in 30 patients, before CRS onset in 13 patients, same day as CRS onset in 7 patients, and same day as CRS resolution in 7 patients. Neurologic toxicity resolved in three patients before the onset of CRS. Eighteen patients experienced neurologic toxicity after resolution of CRS.

The most common neurologic toxicities included encephalopathy (24%), tremor (14%), aphasia (9%), delirium (7%), headache (7%), dizziness (6%), and ataxia (6%).

Serious events including cerebral edema and seizures occurred with BREYANZI. Fatal and serious cases of leukoencephalopathy, some attributable to fludarabine, have occurred in patients treated with BREYANZI.

CRS and Neurologic Toxicities Monitoring

Monitor patients daily at a certified healthcare facility during the first week following infusion, for signs and symptoms of CRS and neurologic toxicities.

Monitor patients for signs and symptoms of CRS and neurologic toxicities for at least 4 weeks after infusion; evaluate and treat promptly. Counsel patients to seek immediate medical attention should signs or symptoms of CRS or neurologic toxicity occur at any time.

At the first sign of CRS, institute treatment with supportive care, tocilizumab or tocilizumab and corticosteroids as indicated.”

https://news.bms.com/news/corporate-financial/2023/Bristol-Myers-Squibb-Receives-European-Commission-Approval-for-CAR-T-Cell-Therapy-Breyanzi-lisocabtagene-maraleucel-for-Relapsed-or-Refractory-Large-B-cell-Lymphoma-After-One-Prior-Therapy/default.aspx

Koselugo approved in China for paediatric patients with neurofibromatosis type 1 and plexiform neurofibromas

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Koselugo approved in China for paediatric patients with neurofibromatosis type 1 and plexiform neurofibromas

May 8, 2023: “Koselugo (selumetinib) has been approved in China for the treatment of symptomatic, inoperable plexiform neurofibromas (PN) in paediatric patients with neurofibromatosis type 1 (NF1) aged three years and above.

The approval by the National Medical Products Administration (NMPA) in China was based on positive results from the SPRINT Stratum 1 trial sponsored by the National Institutes of Health’s National Cancer Institute (NCI) Cancer Therapy Evaluation Program (CTEP).

The trial showed Koselugo, an oral treatment option, reduced the size of inoperable tumours in children.

NF1 is a rare, progressive genetic condition affecting one in 3,000 individuals worldwide, most commonly diagnosed in children under the age of 10.

In 30-50% of patients, tumours develop on the nerve sheaths (plexiform neurofibromas) and cause clinical issues such as disfigurement, motor dysfunction, pain, airway dysfunction, visual impairment and bladder or bowel dysfunction.

Li Qingfeng, Vice President of Shanghai Ninth People’s Hospital, JiaoTong University School of Medicine, Chairman of Department of Plastic and Reconstructive Surgery, said: “Children living with NF1 PN may face physical challenges and significant disruption to their daily lives, and early intervention is essential as tumour growth is often progressive and rapid, especially in the first decade of life.

The approval of Koselugo in China has the potential to change the treatment trajectory of this debilitating genetic condition, providing a new option for addressing inoperable tumours by targeting the underlying cause of tumour growth through MEK inhibition.”

Marc Dunoyer, Chief Executive Officer, Alexion, said: “Koselugo offers hope for children whose quality of life and overall well-being is impacted by the growth of painful, debilitating tumours throughout the body.

We are proud to bring forward a new, innovative treatment option to the NF1 community in China, delivering on Alexion’s commitment to reach more people living with rare diseases in China, and transform the lives of patients and caregivers across the globe.”

Results from the SPRINT Stratum 1 Phase II trial were published in The New England Journal of Medicine and showed that Koselugo demonstrated an objective response rate (ORR) of 66% (33 of 50 patients, confirmed partial responses) in paediatric patients with PNs in NF1 when treated with Koselugo as twice-daily oral monotherapy.

ORR is defined as the percentage of patients with confirmed complete (disappearance of PNs) or partial response (at least 20% reduction in tumour volume).

The most common adverse reactions in the SPRINT trial were vomiting, blood creatine phosphokinase increase, diarrhoea and nausea.

In addition to China, Koselugo is also approved in the US, EU, Japan and several other countries for the treatment of paediatric patients with NF1 and symptomatic, inoperable PNs.

Notes

NF1
NF1 is a debilitating genetic condition that is caused by a spontaneous or inherited mutation in the NF1 gene.

NF1 is associated with a variety of symptoms, including soft lumps on and under the skin (cutaneous neurofibromas) and skin pigmentation (so-called ‘café au lait’ spots) and, in 30-50% of patients, tumours develop on the nerve sheaths (plexiform neurofibromas).

These plexiform neurofibromas (PNs) can cause clinical issues such as disfigurement, motor dysfunction, pain, airway dysfunction, visual impairment and bladder or bowel dysfunction.

PNs begin during early childhood, with varying degrees of severity, and can reduce life expectancy by up to 15 years.

SPRINT
The SPRINT Stratum 1 Phase II trial was designed to evaluate the objective response rate and impact on patient-reported and functional outcomes in paediatric patients with NF1-related inoperable PNs treated with Koselugo (selumetinib) monotherapy.

This trial sponsored by NCI CTEP was conducted under a Cooperative Research and Development Agreement between NCI and AstraZeneca with additional support from Neurofibromatosis Therapeutic Acceleration Program (NTAP).

Koselugo
Koselugo (selumetinib) is the first and only approved therapy by China’s NMPA for the treatment of symptomatic, inoperable PNs in paediatric patients with NF1 aged three years and above.

Koselugo blocks specific enzymes (MEK1 and MEK2), which are involved in stimulating cells to grow.

In NF1, these enzymes are overactive, causing tumour cells to grow in an unregulated way. By blocking these enzymes, Koselugo slows down the growth of tumour cells.

Koselugo is approved for use in the US, EU, Japan and China and has received Orphan Drug Designation in the US, EU, Russia, Switzerland, South Korea, Taiwan, Japan and Australia, and health authorities worldwide are reviewing regulatory submissions.

AstraZeneca and MSD Strategic Collaboration
In July 2017, AstraZeneca and Merck & Co., Inc., Rahway, NJ, US, known as MSD outside the US and Canada, announced a global strategic collaboration to co-develop and co-commercialise Lynparza and Koselugo (selumetinib), a mitogen-activated protein kinase (MEK) inhibitor, for multiple cancer types.

Working together, the companies will develop Lynparza and Koselugo in combination with other potential new medicines and as monotherapies.

Independently, the companies will develop Lynparza and Koselugo in combination with their respective PD-L1 and PD-1 medicines.

Alexion
Alexion, AstraZeneca Rare Disease, is the group within AstraZeneca focused on rare diseases, created following the 2021 acquisition of Alexion Pharmaceuticals, Inc.

As a leader in rare diseases for more than 30 years, Alexion is focused on serving patients and families affected by rare diseases and devastating conditions through the discovery, development and commercialisation of life-changing medicines.

Alexion focuses its research efforts on novel molecules and targets in the complement cascade and its development efforts on haematology, nephrology, neurology, metabolic disorders, cardiology and ophthalmology.

Headquartered in Boston, Massachusetts, Alexion has offices around the globe and serves patients in more than 50 countries.”

https://www.astrazeneca.com/media-centre/press-releases/2023/koselugo-approved-in-china-for-paediatric-patients-with-neurofibromatosis-type-1-and-plexiform-neurofibromas.html

FDA Takes Additional Steps to Advance Decentralized Clinical Trials

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FDA Takes Additional Steps to Advance Decentralized Clinical Trials

May 02, 2023: “The U.S. FDA is taking additional steps to support the use of decentralized clinical trials (DCTs) for drugs, biologics and devices, where some or all the trial-related activities occur at locations other than traditional clinical trial sites. 

The agency released a new draft guidance that provides recommendations for sponsors, investigators and other stakeholders regarding the implementation of DCTs to advance medical product development and research.

Examples of decentralized elements include obtaining laboratory tests at a local facility rather than a research medical center or conducting a clinical follow-up visit in the trial participant’s home using telemedicine.

Decentralizing clinical trials will allow some or all trial-related activities to take place at trial participants’ homes or other convenient locations, instead of having them visit research sites.

By reducing barriers to participation, we expect that DCTs will increase the breadth and diversity of participants in clinical trials and improve accessibility for those with rare diseases or mobility challenges.

We anticipate that this approach will facilitate the development of drugs including in areas of medical need, resulting in more treatment options and improved patient outcomes.

This draft guidance builds on agency recommendations issued in 2020, which provided clarity for investigators to facilitate trial decentralization in response to the COVID-19 public health emergency and associated disruptions such as quarantines, site closures and travel limitations.

“The FDA has long considered the benefits of decentralized clinical trials. Advancements in digital health technologies and the COVID-19 pandemic—when in-person visits were limited or unavailable for many trial participants—have accelerated the broader adoption of these activities,” said FDA Commissioner Robert M. Califf, M.D.

“As we seek to improve our evidence generation system, decentralized clinical trials may enhance convenience for trial participants, reduce the burden on caregivers, expand access to more diverse populations, improve trial efficiencies, and facilitate research on rare diseases and diseases affecting populations with limited mobility.”  

While the FDA’s regulatory requirements for investigations of medical products are the same for DCTs and traditional site-based clinical trials, the new draft guidance covers recommendations on topics such as:  

  • design considerations for a DCT;
  • conduct of remote clinical trial visits and clinical trial-related activities in a DCT;
  • use of digital health technologies to remotely acquire data in a DCT;
  • roles and responsibilities of the sponsor and investigators in a DCT;
  • obtaining informed consent (IC) and institutional review board oversight of the IC process in a DCT;
  • determination of the appropriateness of investigational products for use in a DCT;
  • packaging and shipping of investigational products in a DCT; and
  • safety monitoring of trial participants in a DCT.

The FDA expects that clinical trials with decentralized elements will play an important role in addressing public health needs. The FDA is committed to working with sponsors to discuss how decentralized elements may fit into a clinical trial.

https://www.fda.gov/news-events/press-announcements/fda-takes-additional-steps-advance-decentralized-clinical-trials

FDA Approves First Respiratory Syncytial Virus (RSV) Vaccine

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FDA Approves First Respiratory Syncytial Virus (RSV) Vaccine

May 03, 2023: “The U.S. FDA approved Arexvy, the first respiratory syncytial virus (RSV) vaccine approved for use in the United States.

Arexvy is approved for the prevention of lower respiratory tract disease caused by RSV in individuals 60 years of age and older.

“Older adults, in particular those with underlying health conditions, such as heart or lung disease or weakened immune systems, are at high risk for severe disease caused by RSV,” said Peter Marks, M.D., Ph.D., director of the FDA’s Center for Biologics Evaluation and Research.

“Today’s approval of the first RSV vaccine is an important public health achievement to prevent a disease which can be life-threatening and reflects the FDA’s continued commitment to facilitating the development of safe and effective vaccines for use in the United States.”

RSV is a highly contagious virus that causes infections of the lungs and breathing passages in individuals of all age groups. RSV circulation is seasonal, typically starting during the fall and peaking in the winter.

In older adults, RSV is a common cause of lower respiratory tract disease (LRTD), which affects the lungs and can cause life-threatening pneumonia and bronchiolitis (swelling of the small airway passages in the lungs).

According to the U.S. Centers for Disease Control and Prevention, each year in the U.S., RSV leads to approximately 60,000-120,000 hospitalizations and 6,000-10,000 deaths among adults 65 years of age and older. 

The safety and effectiveness of Arexvy is based on the FDA’s analysis of data from an ongoing, randomized, placebo-controlled clinical study conducted in the U.S. and internationally in individuals 60 years of age and older.

The main clinical study of Arexvy was designed to assess the safety and effectiveness of a single dose administered to individuals 60 years of age and older.

Participants will remain in the study through three RSV seasons to assess the duration of effectiveness and the safety and effectiveness of repeat vaccination. Data for a single dose of Arexvy from the first RSV season of the study were available for the FDA’s analysis.  

In this study, approximately 12,500 participants have received Arexvy and 12,500 participants have received a placebo.

Among the participants who have received Arexvy and the participants who have received a placebo, the vaccine significantly reduced the risk of developing RSV-associated LRTD by 82.6% and reduced the risk of developing severe RSV-associated LRTD by 94.1%.

Among a subset of these clinical trial participants, the most commonly reported side effects by individuals who received Arexvy were injection site pain, fatigue, muscle pain, headache and joint stiffness/pain.

Among all clinical trial participants, atrial fibrillation within 30 days of vaccination was reported in 10 participants who received Arexvy and 4 participants who received placebo. 

In two other studies, approximately 2,500 participants 60 years of age and older received Arexvy.

In one of these studies, in which some participants received Arexvy concomitantly with an FDA-approved influenza vaccine, two participants developed acute disseminated encephalomyelitis (ADEM), a rare type of inflammation that affects the brain and spinal cord, seven and 22 days, respectively, after receiving Arexvy and the influenza vaccine. One of the participants who developed ADEM died.

In the other study, one participant developed Guillain-Barré syndrome (a rare disorder in which the body’s immune system damages nerve cells, causing muscle weakness and sometimes paralysis) nine days after receiving Arexvy.

The FDA is requiring the company to conduct a postmarketing study to assess the signals of serious risks for Guillain-Barré syndrome and ADEM.

In addition, although not an FDA requirement, the company has committed to assess atrial fibrillation in the postmarketing study.

This application was granted Priority Review designation. 

The FDA granted approval of Arexvy to GlaxoSmithKline Biologicals.”

https://www.fda.gov/news-events/press-announcements/fda-approves-first-respiratory-syncytial-virus-rsv-vaccine

Bayer and Cat Creek Energy Sign Landmark Renewable Energy Deal

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Bayer and Cat Creek Energy Sign Landmark Renewable Energy Deal

May03,2023: “Bayer, a global enterprise with core competencies in the life science fields of health care and nutrition, and Cat Creek Energy (CCE), a renewable energy Independent Power Producer announced a long-term Structured Renewable Energy Credit (REC) Purchase Agreement that will satisfy Bayer´s renewable electricity needs and lead to the construction by CCE of multiple variable renewable energy resources plus energy storage facilities in Idaho.

The renewable energy projects will generate 1.4 terawatt hours of clean electricity annually.

“The innovative agreement with CCE marks one of the biggest single renewable energy deals in the United States.

It will secure 40 percent of Bayer’s global and 60 percent of Bayer´s U.S.-purchased electricity demand out of renewable sources, while meeting Bayer’s ambitious quality criteria for renewable electricity,” said Werner Baumann, CEO of Bayer AG.

The project will realize 1.4 terawatt hours of power, an amount equal to the energy consumption of 150,000 households. In terms of CO2, the deal enables Bayer to reduce annual emissions by 370,000 tons.

That’s roughly equivalent to the emissions of 270,000 mid-sized cars, or the amount that 31.7 million trees are capable of binding annually.

In accordance with the United Nations Sustainable Development Goals and the Paris Agreement to limit global warming to 1.5 degrees Celsius by 2050, Bayer aims to continuously reduce greenhouse gas (GHG) emissions within the company and along its entire value chain.

The company aims to become climate neutral in its own operations in 2030. A key strategy to achieving Bayer’s reduction targets is to purchase 100 percent sustainable renewable electricity by 2030.

These reduction targets have been approved by the Science Based Targets, an initiative that drives ambitious climate action in the private sector by enabling organizations to set science-based emissions reduction targets.

Additionally, Bayer is committed to the highest standards for sustainable renewable electricity based on guidelines from the World Wide Fund for Nature (WWF), including the proximity of renewable energy production facilities to Bayer sites.

For Idaho, the renewable plus energy storage projects will continue the state’s conversion to clean reliable energy by 2045.

For rural communities, the result will be over $1.5 billion in new electrical infrastructure, the creation of hundreds of jobs, and contribution of millions of dollars in year-over-year tax revenues contributed for counties and schools where the projects are built.

Construction will commence in the third quarter of this year.

“As an innovation driven company, Bayer recognizes the need to introduce renewable energy solutions that are healthier for the planet and healthier for humans,” said Bayer EVP of Public Affairs, Science, Sustainability and HSE Matthias Berninger.

“This project with Cat Creek Energy is exciting because it catapults our energy goal target fulfilments while also supporting Idaho, a state many of our employees call home.”

“I appreciate Bayer’s alignment with the CCE vision and efforts to build out our multi-technology 1,760 MW platform,” said fourth generation Idaho rancher and president of Cat Creek Energy John Faulkner.

“We admire Bayer’s commitment to find projects near its Idaho facility, which has the highest electricity use within Bayer in the United States, signifying a major milestone in their global energy goals.” 

Energy storage is a vital technological component in the successful transition to clean energy.

As CCE continues its Large Volume Long Duration storage development through its Pumped Storage Hydro project, the installations under the Agreement allow for battery storage of 160 MW nameplate capacity to support and strengthen regional transmission grid integrity and reliability.’

https://www.bayer.com/media/en-us/bayer-and-cat-creek-energy-sign-landmark-renewable-energy-deal/

Sandoz to exclusively commercialize six products in the US, reinforcing global leadership position in off-patent medicines

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Sandoz to exclusively commercialize six products in the US, reinforcing global leadership position in off-patent medicines

May 4, 2023: “Sandoz, a global leader in generic pharmaceuticals and biosimilars, announced that it has signed a distribution and collaboration agreement with Adalvo for exclusive Sandoz rights to commercialize six products in the US across key therapeutic areas, including antifungal/antibiotic, oncology and pulmonary.

“Sandoz is putting patients first by securing the rights to bring more affordable, equally effective treatments for a range of disorders that collectively affect millions of people in the US every year,” said Keren Haruvi, President, Sandoz Inc. “This agreement also helps advance our ambition to be the world’s largest and most valued generics company.”

These products, which are slated for near- to mid-term launches beginning in 2024, have a total addressable market size of approximately USD 3 bn, further advancing the Sandoz product pipeline in the key US generics market.

The agreement also demonstrates the unwavering Sandoz commitment to pioneering patient access to critical medicines in areas of greatest unmet need.

In addition to building out the Sandoz US offering in these key areas, the antibiotic products would also underpin the Sandoz strategy of combatting the global spread of antimicrobial resistance (AMR) by driving responsible access to a broad range of appropriate treatments.”

https://www.novartis.com/news/media-releases/sandoz-exclusively-commercialize-six-products-us-reinforcing-global-leadership-position-patent-medicines

XTANDI® plus Leuprolide Reduced the Risk of Metastasis by 58% in Non-Metastatic Hormone-Sensitive Prostate Cancer versus Placebo plus Leuprolide

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XTANDI® plus Leuprolide Reduced the Risk of Metastasis by 58% in Non-Metastatic Hormone-Sensitive Prostate Cancer versus Placebo plus Leuprolide

April 29, 2023: “Astellas Pharma Inc. and Pfizer Inc. announced that XTANDI® (enzalutamide) plus leuprolide significantly reduced the risk of metastasis or death by 58% versus placebo plus leuprolide (Hazard Ratio [HR]: 0.42; 95% Confidence Interval [CI], 0.30–0.61; P<0.0001), as assessed by the primary endpoint of metastasis-free survival (MFS), in men with non-metastatic hormone-sensitive prostate cancer (nmHSPC; also known as non-metastatic castration-sensitive prostate cancer or nmCSPC) with high-risk biochemical recurrence (BCR).

These data from the Phase 3 EMBARK trial, which evaluated patients across three study arms (XTANDI plus leuprolide [n=355], placebo plus leuprolide [n=358], or XTANDI monotherapy [n=355]), were presented as a plenary session during the 2023 American Urological Association Annual Meeting (Saturday, April 29 at 9:45 a.m. CT). 

The overall safety profile was consistent with the known safety profile of each of the medicines.

The most common adverse events in those treated with XTANDI plus leuprolide were fatigue, hot flush, and arthralgia and in those treated with XTANDI monotherapy were fatigue, gynecomastia, and arthralgia.

“There are patients with localized prostate cancer who undergo prostatectomy or radiation therapy in an attempt to cure their disease, but, unfortunately, some patients will develop BCR,” said Neal Shore, M.D., F.A.C.S., U.S. Chief Medical Officer of Urology and Surgical Oncology, GenesisCare, Director, Carolina Urologic Research Center, and Primary Investigator for the EMBARK study.

“Importantly, some patients with BCR are at very high risk for developing metastatic disease, which can lead to a cascade of therapeutic interventions.

The clinical goal of BCR therapy is to delay cancer progression and avoid metastatic disease.

The MFS results from the EMBARK study demonstrate that this intervention with XTANDI plus leuprolide was statistically significant for patients with high-risk BCR.” 

“The EMBARK study is a Phase 3 trial exploring the potential of enzalutamide in patients with non-metastatic hormone-sensitive prostate cancer with high-risk BCR,” said Stephen J. Freedland, M.D., Director of the Center for Integrated Research in Cancer and Lifestyle and the Warschaw Robertson Law Families Chair in Prostate Cancer at Cedars-Sinai Cancer and Co-Principal Investigator of the Clinical Trial.

“If approved, we hope to bring a new option to men earlier in the course of their disease.”  

Consistent with the study’s primary endpoint, statistically significant and clinically meaningful improvements were also observed in the trial’s key secondary endpoints in both the XTANDI combination and monotherapy arms.

Specifically, the XTANDI monotherapy arm demonstrated that treatment with XTANDI reduced the risk of metastasis or death by 37% versus leuprolide plus placebo (HR: 0.63; 95% CI, 0.46–0.87; P=0.0049), meeting its MFS endpoint.

Treatment with XTANDI plus leuprolide and XTANDI monotherapy reduced the risk of PSA progression by 93% (HR: 0.07; 95% CI, 0.03–0.14; P<0.0001) and 67% (HR: 0.33; 95% CI, 0.23–0.49; P<0.0001), respectively, versus placebo plus leuprolide.

The progression risk in starting a new antineoplastic therapy was reduced by 64% in those treated with XTANDI plus leuprolide (HR: 0.36; 95% CI, 0.26–0.49; P<0.0001) and 46% in those treated with XTANDI monotherapy (HR: 0.54; 95% CI, 0.41–0.71; P<0.0001) versus placebo plus leuprolide.

A positive trend in the key secondary endpoint of overall survival (OS) was also observed in the XTANDI combination arm at the time of the analysis, but these data were not yet mature. Patients in the trial will be followed for a subsequent final OS analysis. 

Detailed results from the trial will be submitted for peer-reviewed publication. Additionally, the EMBARK data will be discussed with regulatory authorities, including the U.S. Food and Drug Administration (FDA), to support a potential regulatory submission for XTANDI in this indication in 2023.

About EMBARK
The Astellas- and Pfizer-led Phase 3, randomized, double-blind, placebo-controlled, multi-national trial enrolled 1,068 patients with non-metastatic hormone-sensitive prostate cancer (nmHSPC; also known as non-metastatic castration-sensitive prostate cancer or nmCSPC) with high-risk biochemical recurrence (BCR) at sites in the United States, Canada, Europe, South America and the Asia-Pacific region.

Patients who were considered to experience high-risk BCR had a prostate-specific antigen doubling time (PSA-DT) ≤ 9 months; serum testosterone ≥ 150 ng/dL (5.2 nmol/L); and screening PSA by the central laboratory ≥ 1 ng/mL if they had a radical prostatectomy (with or without radiotherapy) as primary treatment for prostate cancer, or at least 2 ng/mL above the nadir if they had radiotherapy only as primary treatment for prostate cancer.

Patients in the EMBARK trial were randomized to receive enzalutamide 160 mg daily plus leuprolide (n=355), enzalutamide 160 mg as a monotherapy (n=355), or placebo plus leuprolide (n=358). Leuprolide 22.5 mg was administered every 12 weeks. 

The primary endpoint of the trial was metastasis-free survival (MFS) for enzalutamide plus leuprolide versus placebo plus leuprolide. MFS is defined as the duration of time in months between randomization and the earliest objective evidence of radiographic progression by central imaging or death.

For more information on the EMBARK trial (NCT02319837) go to www.clinicaltrials.gov.

XTANDI, either in combination with leuprolide or as a monotherapy, has not been approved by any regulatory agency for the treatment of patients with nmHSPC with high-risk BCR. 

About Non-Metastatic Hormone-Sensitive Prostate Cancer with High-Risk Biochemical Recurrence
In non-metastatic hormone- (or castration-) sensitive prostate cancer (nmHSPC or nmCSPC), no evidence of the cancer spreading to distant parts of the body (metastases) is detectable with conventional radiological methods (CT/MRI), and the cancer still responds to medical or surgical treatment designed to lower testosterone levels.

Of men who have undergone definitive prostate cancer treatment, including radical prostatectomy, radiotherapy, or both, an estimated 20-40% will experience a biochemical recurrence (BCR) within 10 years.

About 9 out of 10 men with high-risk BCR will develop metastatic disease, and 1 in 3 will die as a result of the recurrence.

The EMBARK trial focused on men with high-risk BCR. Per the EMBARK protocol, patients with nmHSPC and high-risk BCR are those initially treated by radical prostatectomy or radiotherapy, or both, with a prostate-specific antigen doubling time (PSA-DT) ≤ 9 months. High-risk BCR patients with a PSA-DT of ≤ 9 months have a higher risk of metastases and death.5

About XTANDI® (enzalutamide)
XTANDI (enzalutamide) is an androgen receptor signaling inhibitor.

XTANDI has received regulatory approvals in one or more countries around the world for use in men with metastatic hormone-sensitive prostate cancer (mHSPC), metastatic castration-resistant prostate cancer (mCRPC), and non-metastatic castration-resistant prostate cancer (nmCRPC).

XTANDI is currently approved for one or more of these indications in more than 100 countries, including in the United States, European Union and Japan. One million patients have been treated with XTANDI globally.6

U.S. Important Safety Information
XTANDI (enzalutamide) is indicated in the U.S. for the treatment of patients with castration-resistant prostate cancer (CRPC) and metastatic castration-sensitive prostate cancer (mCSPC).

Warnings and Precautions

Seizure occurred in 0.5% of patients receiving XTANDI in seven randomized clinical trials. In a study of patients with predisposing factors for seizure, 2.2% of XTANDI-treated patients experienced a seizure.

It is unknown whether anti-epileptic medications will prevent seizures with XTANDI.

Patients in the study had one or more of the following predisposing factors: use of medications that may lower the seizure threshold, history of traumatic brain or head injury, history of cerebrovascular accident or transient ischemic attack, and Alzheimer’s disease, meningioma, or leptomeningeal disease from prostate cancer, unexplained loss of consciousness within the last 12 months, history of seizure, presence of a space-occupying lesion of the brain, history of arteriovenous malformation, or history of brain infection.

Advise patients of the risk of developing a seizure while taking XTANDI and of engaging in any activity where sudden loss of consciousness could cause serious harm to themselves or others.

Permanently discontinue XTANDI in patients who develop a seizure during treatment. 

Posterior Reversible Encephalopathy Syndrome (PRES): There have been reports of PRES in patients receiving XTANDI.

PRES is a neurological disorder that can present with rapidly evolving symptoms including seizure, headache, lethargy, confusion, blindness, and other visual and neurological disturbances, with or without associated hypertension.

A diagnosis of PRES requires confirmation by brain imaging, preferably MRI. Discontinue XTANDI in patients who develop PRES. 

Hypersensitivity: Reactions, including edema of the face (0.5%), tongue (0.1%), or lip (0.1%) have been observed with XTANDI in seven randomized clinical trials.

Pharyngeal edema has been reported in post-marketing cases. Advise patients who experience any symptoms of hypersensitivity to temporarily discontinue XTANDI and promptly seek medical care. Permanently discontinue XTANDI for serious hypersensitivity reactions. 

Ischemic Heart Disease: In the combined data of four randomized, placebo-controlled clinical studies, ischemic heart disease occurred more commonly in patients on the XTANDI arm compared to patients on the placebo arm (2.9% vs 1.3%).

Grade 3-4 ischemic events occurred in 1.4% of patients on XTANDI versus 0.7% on placebo.

events led to death in 0.4% of patients on XTANDI compared to 0.1% on placebo. Monitor for signs and symptoms of ischemic heart disease. Optimize management of cardiovascular risk factors, such as hypertension, diabetes, or dyslipidemia. Discontinue XTANDI for Grade 3-4 ischemic heart disease. 

Falls and Fractures occurred in patients receiving XTANDI. Evaluate patients for fracture and fall risk. Monitor and manage patients at risk for fractures according to established treatment guidelines and consider use of bone-targeted agents.

In the combined data of four randomized, placebo-controlled clinical studies, falls occurred in 11% of patients treated with XTANDI compared to 4% of patients treated with placebo.

Fractures occurred in 10% of patients treated with XTANDI and in 4% of patients treated with placebo. 

Embryo-Fetal Toxicity: The safety and efficacy of XTANDI have not been established in females. XTANDI can cause fetal harm and loss of pregnancy when administered to a pregnant female.

Advise males with female partners of reproductive potential to use effective contraception during treatment with XTANDI and for 3 months after the last dose of XTANDI. 

Adverse Reactions (ARs): In the data from the four randomized placebo-controlled trials, the most common ARs (≥ 10%) that occurred more frequently (≥ 2% over placebo) in XTANDI-treated patients were asthenia/fatigue, back pain, hot flush, constipation, arthralgia, decreased appetite, diarrhea, and hypertension.

In the bicalutamide-controlled study, the most common ARs (≥ 10%) reported in XTANDI-treated patients were asthenia/fatigue, back pain, musculoskeletal pain, hot flush, hypertension, nausea, constipation, diarrhea, upper respiratory tract infection, and weight loss.

In AFFIRM, the placebo-controlled study of metastatic CRPC (mCRPC) patients who previously received docetaxel, Grade 3 and higher ARs were reported among 47% of XTANDI-treated patients. Discontinuations due to adverse events (AEs) were reported for 16% of XTANDI-treated patients.

In PREVAIL, the placebo-controlled study of chemotherapy-naive mCRPC patients, Grade 3-4 ARs were reported in 44% of XTANDI patients and 37% of placebo patients. Discontinuations due to AEs were reported for 6% of XTANDI treated patients.

In TERRAIN, the bicalutamide-controlled study of chemotherapy-naive mCRPC patients, Grade 3-4 ARs were reported in 39% of XTANDI patients and 38% of bicalutamide patients.

Discontinuations with an AE as the primary reason were reported for 8% of XTANDI patients and 6% of bicalutamide patients. 

In PROSPER, the placebo-controlled study of non-metastatic CRPC (nmCRPC) patients, Grade 3 or higher ARs were reported in 31% of XTANDI patients and 23% of placebo patients.

Discontinuations with an AE as the primary reason were reported for 9% of XTANDI patients and 6% of placebo patients. 

In ARCHES, the placebo-controlled study of metastatic CSPC (mCSPC) patients, Grade 3 or higher AEs were reported in 24% of XTANDI-treated patients. Permanent discontinuation due to AEs as the primary reason was reported in 5% of XTANDI patients and 4% of placebo patients.

Lab Abnormalities: Lab abnormalities that occurred in ≥ 5% of patients, and more frequently (> 2%) in the XTANDI arm compared to placebo in the pooled, randomized, placebo-controlled studies are neutrophil count decreased, white blood cell decreased, hyperglycemia, hypermagnesemia, hyponatremia, and hypercalcemia. 

Hypertension: In the combined data from four randomized placebo-controlled clinical trials, hypertension was reported in 12% of XTANDI patients and 5% of placebo patients. Hypertension led to study discontinuation in < 1% of patients in each arm.  

Drug Interactions 

Effect of Other Drugs on XTANDI Avoid strong CYP2C8 inhibitors, as they can increase the plasma exposure to XTANDI.

If co-administration is necessary, reduce the dose of XTANDI. Avoid strong CYP3A4 inducers as they can decrease the plasma exposure to XTANDI. If coadministration is necessary, increase the dose of XTANDI.

Effect of XTANDI on Other Drugs Avoid CYP3A4, CYP2C9, and CYP2C19 substrates with a narrow therapeutic index, as XTANDI may decrease the plasma exposures of these drugs.

If XTANDI is co-administered with warfarin (CYP2C9 substrate), conduct additional INR monitoring.”

https://www.pfizer.com/news/press-release/press-release-detail/xtandir-enzalutamide-plus-leuprolide-reduced-risk

Update on FDA Advisory Committee vote on Lynparza plus abiraterone for metastatic castration-resistant prostate cancer

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Update on FDA Advisory Committee vote on Lynparza plus abiraterone for metastatic castration-resistant prostate cancer

April 28, 2023: “The Food and Drug Administration’s Oncologic Drugs Advisory Committee (ODAC) has recognised a favourable benefit risk profile for AstraZeneca and MSD’s Lynparza (olaparib) plus abiraterone and prednisone or prednisolone for the treatment of adult patients with BRCA-mutated (BRCAm) metastatic castration-resistant prostate cancer (mCRPC) based on the PROpel Phase III trial.

The Committee voted 11 to 1, with 1 abstaining, that the indication should be limited to patients whose tumours have a BRCA mutation.

In August 2022, the FDA accepted the supplemental New Drug Application (sNDA) for Lynparza based on positive results from the pivotal PROpel trial, also published in NEJM Evidence.

The ODAC provides the FDA with independent, expert advice and recommendations on marketed and investigational medicines for use in the treatment of cancer.

The FDA is not bound by the Committee’s guidance but takes its advice into consideration. AstraZeneca and MSD will continue to work with the FDA as it completes its review of the application.

Neal Shore, Chief Medical Officer of Urology and Surgical Oncology for Genesis Care, US and PROpel trial investigator, said: “Today’s recommendation by the ODAC is disappointing news for clinicians and prostate cancer patients alike.

Preventing or delaying radiographic progression is an important clinical endpoint in assessing oncologic treatment and is very relevant to patients, their caregivers and their families. It is essential that physicians and patients have an opportunity to choose treatment with the goal of optimising cancer care outcomes.”

Susan Galbraith, Executive Vice President, Oncology R&D, AstraZeneca said: “Novel treatment options are urgently needed for patients with metastatic castration-resistant prostate cancer.

While we are pleased with the recognition of the benefit of Lynparza plus abiraterone for patients with BRCA-mutated metastatic castration-resistant prostate cancer, we are disappointed with the outcome of today’s ODAC meeting.

We strongly believe in the results of the PROpel trial, which demonstrated the clinically meaningful benefit for this combination in a broad population of patients regardless of biomarker status.”

Eliav Barr, Senior Vice President, Head of Global Clinical Development and Chief Medical Officer, MSD Research Laboratories, said “With the incidence and mortality of prostate cancer set to double in the coming decades, it is critical that we bring new treatment options with the potential to reduce the risk of disease progression or death to patients at the earliest possible moment in their care.

While we are pleased that the ODAC recommended Lynparza for patients with metastatic castration-resistant prostate cancer who have BRCA mutations, we believe in the potential of Lynparza plus abiraterone for a broad range of patients with metastatic castration-resistant prostate cancer, based on the results of PROpel. We look forward to the outcome of the FDA’s review of the application.”

Results from the PROpel trial showed a statistically significant and clinically meaningful 34% reduction in the risk of radiographic disease progression or death with Lynparza plus abiraterone with prednisone or prednisolone, versus abiraterone alone in patients with mCRPC (hazard ratio [HR] 0.66; 95% confidence interval [CI] 0.54-0.81; p<0.001). Median radiographic progression-free survival (rPFS) was 24.8 months and 16.6 months, respectively.

Further results from the final prespecified overall survival (OS) analysis presented at ASCO Genitourinary Cancers Symposium 2023 showed Lynparza plus abiraterone and prednisone or prednisolone demonstrated median OS of 42.1 months versus 34.7 months for abiraterone plus placebo.

This result represents a 7.4-month absolute difference in median OS versus a standard of care (47.9% maturity, HR of 0.81, 95% CI 0.67-1.00; p=0.0544).

While this numerical increase in median OS did not achieve statistical significance, it builds on the meaningful survival gains achieved for patients in this setting treated with abiraterone alone, a current standard of care.

In exploratory analyses of the BRCAm subgroup, Lynparza plus abiraterone demonstrated improvements in both rPFS (HR of 0.23, 95% CI, 0.12-0.43) and OS (HR of 0.29, 95% CI, 0.14-0.56).

In the non-BRCAm subgroup, Lynparza plus abiraterone also showed improvements in rPFS (HR of 0.76, 95% CI, 0.61-0.94), and a modest trend for OS (HR of 0.91, 95% CI, 0.73-1.13).

The safety and tolerability of Lynparza plus abiraterone in PROpel was in line with that observed in prior clinical trials and the known profiles of the individual medicines.

Lynparza in combination with abiraterone and prednisone or prednisolone is approved in the EU and several other countries for the treatment of adult patients with mCRPC based on the PROpel trial.”

https://www.astrazeneca.com/media-centre/press-releases/2023/odac-vote-on-lynparza-combo-in-prostate-cancer.html

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