CLINSQUARE: CLINICAL RESEARCH COURSES
Saturday, December 21, 2024
CLINSQUARE: Clinical Rsearch Courses by LIFEPRONOW
Home Blog Page 3

EMA validates marketing authorisation application for Jemperli plus chemotherapy for dMMR/MSI-H primary advanced or recurrent endometrial cancer

admin
-
0
EMA validates marketing authorisation application for Jemperli plus chemotherapy for dMMR/MSI-H primary advanced or recurrent endometrial cancer

April 25, 2023: “GSK announced that the EMA validated the Company’s Type II Variation for a potential new indication for Jemperli (dostarlimab) in combination with chemotherapy for the treatment of adult patients with a type of gynaecological cancer known as mismatch repair deficient (dMMR)/microsatellite instability-high (MSI-H) primary advanced or recurrent endometrial cancer.

As a result, the EMA’s Committee for Medicinal Products for Human Use will begin the formal review process to make a recommendation to the European Commission regarding marketing authorisation for the potential new indication.

The regulatory submission is based on the interim results of the RUBY/ENGOT-EN6/GOG3031/NSGO phase III trial.

The trial met its primary endpoint of investigator-assessed progression-free survival (PFS), showing a statistically significant and clinically meaningful benefit versus placebo plus chemotherapy in patients treated with dostarlimab plus carboplatin-paclitaxel in the dMMR/MSI-H population.

In addition, the safety and tolerability profile of dostarlimab in combination with carboplatin-paclitaxel was generally consistent with the known safety profiles of the individual agents.

The results were presented on 27 March 2023 at a European Society for Medical Oncology Virtual Plenary and the Society of Gynecologic Oncology Annual Meeting and simultaneously published in The New England Journal of Medicine.

Hesham Abdullah, Senior Vice President, Global Head of Oncology Development, GSK said: “New treatment options are urgently needed for patients with primary advanced or recurrent endometrial cancer. With this initial filing, we are accelerating the submission of a potential new indication for dostarlimab in the patient population that demonstrated the strongest treatment effect in the RUBY phase III trial.

These patients currently face significant unmet medical needs, and this combination could change the treatment paradigm for this condition. The RUBY phase III trial continues to follow patients for the dual-primary endpoint of overall survival in the intent-to-treat population.”

GSK expects US regulatory filing review based on the RUBY phase III trial results to occur in the first half of 2023.

About endometrial cancer
Endometrial cancer is found in the inner lining of the uterus, known as the endometrium.

Endometrial cancer is the most common gynaecologic cancer in developed countries, with approximately 417,000 new cases reported each year worldwide, and incidence rates are expected to rise by almost 40% by 2040.

Approximately 15-20% of patients with endometrial cancer will be diagnosed with advanced disease at the time of diagnosis.

About RUBY
RUBY is a two-part global, randomised, double-blind, multicentre phase III trial of patients with primary advanced or recurrent endometrial cancer.

Part 1 is evaluating dostarlimab plus carboplatin-paclitaxel followed by dostarlimab versus carboplatin-paclitaxel plus placebo followed by placebo.

Part 2 is evaluating dostarlimab plus carboplatin-paclitaxel followed by dostarlimab plus niraparib versus placebo plus carboplatin-paclitaxel followed by placebo.

The primary endpoints in Part 1 are investigator-assessed PFS based on the Response Evaluation Criteria in Solid Tumours v1.1 and overall survival (OS).

The statistical analysis plan included pre-specified analyses of PFS in the dMMR/MSI-H and intent-to-treat populations and OS in the overall population. Pre-specified exploratory analyses of PFS in the mismatch repair proficient/microsatellite stable population and OS in the dMMR/MSI-H populations were also performed.

RUBY Part 1 included a broad population, including histologies often excluded from clinical trials and had approximately 10% of patients with carcinosarcoma and 20% with serous carcinoma.

In Part 2, the primary endpoint is investigator-assessed PFS. Secondary endpoints in Part 1 and Part 2 include PFS per blinded independent central review, overall response rate, duration of response, disease control rate, patient-reported outcomes, and safety and tolerability.

About Jemperli (dostarlimab)
Jemperli is a programmed death receptor-1 (PD-1)-blocking antibody that binds to the PD-1 receptor and blocks its interaction with the PD-1 ligands PD-L1 and PD-L2.

Jemperli is not approved anywhere in the world for use in combination with standard-of-care chemotherapy (carboplatin-paclitaxel) followed by dostarlimab for primary advanced or recurrent endometrial cancer.

In the US, Jemperli is approved for adult patients with mismatch repair deficient (dMMR) recurrent or advanced endometrial cancer, as determined by a US FDA-approved test, that has progressed on or following a prior platinum-containing regimen in any setting and are not candidates for curative surgery or radiation. 

Jemperli is also indicated in the US for patients with dMMR recurrent or advanced solid tumours, as determined by a US FDA-approved test, that have progressed on or following prior treatment and have no satisfactory alternative treatment options.

The latter indication is approved in the US under accelerated approval based on tumour response rate and durability of response.

Continued approval for this indication in solid tumours may be contingent upon verification and description of clinical benefit in a confirmatory trial(s).

Jemperli was discovered by AnaptysBio, Inc. and licensed to TESARO, Inc., under a collaboration and exclusive license agreement signed in March 2014.

The collaboration has resulted in three monospecific antibody therapies that have progressed into the clinic. These are: Jemperli (GSK4057190), a PD-1 antagonist; cobolimab, (GSK4069889), a TIM-3 antagonist; and GSK4074386, a LAG-3 antagonist.

GSK is responsible for the ongoing research, development, commercialisation, and manufacturing of each of these medicines under the agreement.

Important Information for Jemperli in the EU

Indication 
Jemperli is indicated as monotherapy for treating adult patients with mismatch repair deficient (dMMR)/microsatellite instability-high (MSI-H) recurrent or advanced endometrial cancer that has progressed on or following prior treatment with a platinum-containing regimen.

Refer to the Jemperli EMA Reference Information for a full list of adverse events and the complete important safety information in the EU.

GSK in oncology
GSK is committed to maximising patient survival through transformational medicines. GSK’s pipeline is focused on immuno-oncology, tumour cell targeting therapies and synthetic lethality.

Our goal is to achieve a sustainable flow of new treatments based on a diversified portfolio of investigational medicines utilising modalities such as small molecules, antibodies, and antibody-drug conjugates, either alone or in combination.”

https://www.gsk.com/en-gb/media/press-releases/european-medicines-agency-validates-marketing-authorisation-application-for-jemperli-dostarlimab/

FDA Authorizes Changes to Simplify Use of Bivalent mRNA COVID-19 Vaccines

admin
-
0
FDA Authorizes Changes to Simplify Use of Bivalent mRNA COVID-19 Vaccines

April 18, 2023: “The U.S. FDA amended the emergency use authorizations (EUAs) of the Moderna and Pfizer-BioNTech COVID-19 bivalent mRNA vaccines to simplify the vaccination schedule for most individuals.

This action includes authorizing the current bivalent vaccines (original and omicron BA.4/BA.5 strains) to be used for all doses administered to individuals 6 months of age and older, including for an additional dose or doses for certain populations.

The monovalent Moderna and Pfizer-BioNTech COVID-19 vaccines are no longer authorized for use in the United States.

What You Need to Know:

  • Most individuals, depending on age, previously vaccinated with a monovalent Coronavirus treatment: List of Vaccines and drugs in the pipeline for COVID-19 vaccine who have not yet received a dose of a bivalent vaccine may receive a single dose of a bivalent vaccine. 
  • Most individuals who have already received a single dose of the bivalent vaccine are not currently eligible for another dose.

    The FDA intends to make decisions about future vaccination after receiving recommendations on the fall strain composition at an FDA advisory committee in June.
  • Individuals 65 years of age and older who have received a single dose of a bivalent vaccine may receive one additional dose at least four months following their initial bivalent dose. 
  • Most individuals with certain kinds of immunocompromise who have received a bivalent COVID-19 vaccine may receive a single additional dose of a bivalent COVID-19 vaccine at least 2 months following a dose of a bivalent COVID-19 vaccine, and additional doses may be administered at the discretion of, and at intervals determined by, their healthcare provider.
  • However, for immunocompromised individuals 6 months through 4 years of age, eligibility for additional doses will depend on the vaccine previously received.
     
  • Most unvaccinated individuals may receive a single dose of a bivalent vaccine, rather than multiple doses of the original monovalent mRNA vaccines. 
  • Children 6 months through 5 years of age who are unvaccinated may receive a two-dose series of the Moderna bivalent vaccine (6 months through 5 years of age) OR a three-dose series of the Pfizer-BioNTech bivalent vaccine (6 months through 4 years of age).

    Children who are 5 years of age may receive two doses of the Moderna bivalent vaccine or a single dose of the Pfizer-BioNTech bivalent vaccine.
     
  • Children 6 months through 5 years of age who have received one, two or three doses of a monovalent COVID-19 vaccine may receive a bivalent vaccine, but the number of doses that they receive will depend on the vaccine and their vaccination history.

“At this stage of the pandemic, data support simplifying the use of the authorized mRNA bivalent COVID-19 vaccines and the agency believes that this approach will help encourage future vaccination,” said Peter Marks, M.D., Ph.D., director of the FDA’s Center for Biologics Evaluation and Research.

“Evidence is now available that most of the U.S. population 5 years of age and older has antibodies to SARS-CoV-2, the virus that causes COVID-19, either from vaccination or infection that can serve as a foundation for the protection provided by the bivalent vaccines.

COVID-19 continues to be a very real risk for many people, and we encourage individuals to consider staying current with vaccination, including with a bivalent COVID-19 vaccine.

The available data continue to demonstrate that vaccines prevent the most serious outcomes of COVID-19, which are severe illness, hospitalization, and death.”

Available data show that almost all of the U.S. population 5 years of age and older now have antibodies as a result of either vaccination or infection against SARS-CoV-2.

The use of bivalent COVID-19 vaccines for all doses administered to individuals 6 months of age and older is supported by the data described below, as well as post-marketing data, including real-world data, with the monovalent and bivalent mRNA COVID-19 vaccines, which have been administered to millions of people, including young children.

A second bivalent dose for individuals 65 years of age and older is supported by data showing the waning of immunity in this population over time and its restoration by an additional dose.  Additionally, based on evidence from studies conducted previously, immunocompromised individuals may require additional doses.

Moderna COVID-19 Vaccine, Bivalent

The safety and effectiveness of Moderna COVID-19 Vaccine, Bivalent is based on FDA’s previous analyses of clinical trials data of monovalent Moderna COVID-19 Vaccine in individuals 6 months of age and older and an investigational bivalent Moderna COVID-19 vaccine (original and omicron BA.1) in individuals 18 years of age and older. 

In addition, effectiveness of a single dose is supported by the FDA’s analysis of immune response data from clinical studies in which 145 individuals 6 years of age and older who had evidence of prior SARS-CoV-2 infection and 1,376 individuals 6 years of age and older without evidence of prior SARS-CoV-2 infection had received two doses of monovalent Moderna COVID-19 Vaccine.

The immune response after one dose of vaccine among participants with evidence of prior infection was comparable to the immune response after two doses among participants without evidence of prior infection.

The data accrued with the investigational bivalent Moderna COVID-19 vaccine (original and omicron BA.1) and with the monovalent Moderna COVID-19 Vaccine are relevant to the Moderna COVID-19 Vaccine, Bivalent because these vaccines are manufactured using the same process.

Pfizer-BioNTech COVID-19 Vaccine, Bivalent

The safety and effectiveness of Pfizer-BioNTech COVID-19 Vaccine, Bivalent is based on the FDA’s previous analyses of clinical trials data of monovalent Pfizer-BioNTech COVID-19 Vaccine for use in individuals 6 months of age and older, an investigational bivalent Pfizer-BioNTech COVID-19 vaccine (original and omicron BA.1) in individuals greater than 55 years of age, as well as safety data with Pfizer-BioNTech COVID-19 Vaccine, Bivalent (original and omicron BA.4/BA.5) in individuals 6 months of age and older and immune response data in individuals 6 months through 4 years of age.  

In addition, effectiveness of a single dose is supported by observational data from England on the effectiveness of one dose of monovalent Pfizer-BioNTech COVID-19 Vaccine.

Among individuals 12 to 17 years of age who had received only one dose of Pfizer-BioNTech COVID-19 Vaccine, those who had evidence of previous infection with alpha, delta or omicron variants had increased protection against symptomatic omicron infection compared with those with no evidence of previous infection. 

The data accrued with the investigational Pfizer-BioNTech bivalent COVID-19 vaccine (original and omicron BA.1) and with the monovalent Pfizer-BioNTech COVID-19 Vaccine are relevant to the Pfizer-BioNTech COVID-19 Vaccine, Bivalent because these vaccines are manufactured using the same process.

With today’s authorizations, the fact sheets have been updated and consolidated for the Moderna COVID-19 Vaccine, Bivalent and the Pfizer-BioNTech COVID-19 Vaccine, Bivalent.

Each vaccine now has one fact sheet for healthcare providers and one fact sheet for recipients and caregivers, rather than different fact sheets for the various authorized age groups. 

Vaccines and Related Biological Products Advisory Committee

Today’s authorizations follow discussions that occurred during a meeting with the FDA’s Vaccines and Related Biological Products Advisory Committee (VRBPAC) on Jan. 26.

At that time, by a unanimous vote, the committee recommended harmonizing the strain composition of COVID-19 vaccines used in the U.S. There was also support for simplifying the vaccine dosing schedule. 

In June, the FDA will hold a meeting of its VRBPAC to discuss the strain composition of the COVID-19 vaccines for fall of 2023. Much like the FDA does yearly with the influenza vaccines, the agency will seek input from the committee on which SARS-CoV-2 variants and lineages are most likely to circulate in the upcoming year.

Once the specific strains are selected for the COVID-19 vaccines, the FDA expects manufacturers to make updated formulations of the vaccines for availability this fall.

The amendments to the EUAs were issued to ModernaTX Inc. and Pfizer Inc.”

https://www.fda.gov/news-events/press-announcements/coronavirus-covid-19-update-fda-authorizes-changes-simplify-use-bivalent-mrna-covid-19-vaccines

Bayer’s New data from pivotal studies with aflibercept 8 mg

admin
-
0
Bayer’s New data from pivotal studies with aflibercept 8 mg

April 17, 2023: “Bayer and its collaborator Regeneron will present new clinical data analyses for the investigational formulation aflibercept 8 mg at the Annual Meeting of The Association for Research in Vision and Ophthalmology (arvo.org) 2023, in New Orleans, Louisiana, 23-27 April 2023.

The data will highlight Bayer’s commitment to advancing the unmet need of extended treatment intervals in exudative retinal disease.

New subgroup and further analyses of the pivotal studies PULSAR, PHOTON and CANDELA will provide further insights into durability results of extended treatment intervals, patient characteristics as well as efficacy and safety of aflibercept 8 mg versus aflibercept 2 mg (EyleaTM) in patients with neovascular (wet) age-related macular degeneration (nAMD) and diabetic macular degeneration (DME).

The following new abstracts for aflibercept 8 mg will be presented at ARVO 2023:

The pooled safety analysis compares the safety of aflibercept 8 mg with aflibercept 2 mg across the clinical trial program which includes data from the phase II trial CANDELA in nAMD and the pivotal phase II/III trial PHOTON in DME and the phase III trial PULSAR in nAMD.

· Pooled Safety Analysis of Aflibercept 8 mg in the CANDELA, PHOTON, and PULSAR Trials

o Poster presentation # 3724 – C0501

o April 25, 2023; 15.30-17.15 EST

The analysis of the phase III trial PULSAR reports safety and tolerability outcomes of aflibercept 8 mg every 12 or 16 weeks versus aflibercept 2 mg every 8 weeks through to week 48.

· Tolerability and safety of intravitreal aflibercept 8 mg in the phase III PULSAR trial of patients with neovascular (wet) age-related macular degeneration

o Poster presentation # 278 – C0115

o April 23, 2023; 8.00-9.45 EST

The post-hoc analysis of the phase III trial PULSAR describes baseline characteristics of patients maintained on their original randomized dosing regimens of aflibercept 8 mg every 12 or 16 weeks or aflibercept 2 mg every 8 weeks versus those who had shortened intervals according to prespecified dose regimen modification criteria denoting disease activity.

· Baseline disease characteristics in patients maintaining q12 and q16 dosing with aflibercept 8 mg versus patients with shortened treatment intervals: A Phase 3 PULSAR post hoc analysis

o Poster presentation # 2238-C0192

o April 24, 2023; 15.15-17.00 EST

In a subgroup analysis from the phase III trial PULSAR the treatment effect on the primary endpoint in patients with treatment-naïve nAMD was determined for clinically relevant subgroups by baseline BCVA, central retinal thickness (CRT) or lesion type.

· Subgroup analyses from the Phase 3 PULSAR trial of aflibercept 8 mg in patients with treatment-naïve neovascular age-related macular degeneration

o Poster presentation # 2239 – C0191

o April 24, 2023; 15.15-17.00 EST

The analysis of the PHOTON trial evaluates baseline clinical characteristics of patients with diabetic macular edema (DME) who received intravitreal aflibercept 8 mg and maintained their randomized dosing intervals versus those whose intervals were shortened after meeting prespecified criteria through Week 48.

· Baseline Disease Characteristics of Patients Who Maintained 12- and 16-Week Aflibercept 8 mg Dosing Versus Patients with Shortened Treatment Intervals Through Week 48 in the Phase 2/3 PHOTON Trial

o Podium presentation

o April 25, 2023; 12.15-12.30 EST

The analysis of the PHOTON trial evaluates the treatment effects of aflibercept 8 mg versus 2 mg at Week 48 in patients with diabetic macular edema (DME) by baseline demographics.

· Intravitreal Aflibercept 8 mg for Diabetic Macular Edema: Week 48 Efficacy Outcomes by Baseline Demographics in the Phase 2/3 PHOTON Trial

o Poster presentation # 2707 – B0529

o April 25, 2023; 8.45-10.30 EST

Aflibercept 8 mg is being jointly developed by Bayer and Regeneron. Regeneron maintains exclusive rights to Eylea and aflibercept 8 mg in the United States. Bayer has licensed the exclusive marketing rights outside the United States, where the companies share equally the profits from sales of Eylea.

Aflibercept 8 mg is investigational, and its safety and efficacy have not yet been evaluated by any regulatory authority.

About aflibercept 8 mg
Aflibercept 8 mg has been developed with the aim to increase intervals between injections without compromising vision gains.

Aflibercept 8 mg was investigated in neovascular (wet) age-related macular degeneration (PULSAR) and diabetic macular edema (PHOTON) to evaluate efficacy and safety compared to Eylea (aflibercept 2 mg).

About PULSAR, PHOTON and CANDELA
PULSAR and PHOTON are double-masked, active-controlled pivotal trials. Both trials were conducted in multiple centers globally with similar designs and endpoints.

The Phase III PULSAR trial in nAMD and Phase II/III PHOTON trial in DME evaluated the efficacy and safety of aflibercept 8 mg with 12- and 16-week dosing regimens versus Eylea (aflibercept 2 mg) dosed every 8 weeks, following initial monthly doses, with the primary endpoint of non-inferiority in terms of best corrected visual acuity (BCVA) at week 48.

Patients in both clinical trials were randomized at baseline and assigned to the three different arms.

Across both studies, 1,164 patients were treated with aflibercept 8 mg. All patients in the aflibercept 8 mg arms were continuously evaluated under stringent, clinically relevant, patient focused dose regimen modification (DRM) criteria starting from week 16 throughout the study.

In the first year, patients in the aflibercept 8 mg groups could have their dosing intervals shortened down to an every 8-week interval if DRM criteria for disease progression were observed.

Intervals could not be extended until the second year of the study, with those results still to be assessed.

Patients in all Eylea groups maintained a fixed 8-week dosing regimen throughout their participation in the trials.

CANDELA was a Phase II trial investigating aflibercept 8 mg with regards to safety and efficacy and to determine if aflibercept 8 mg provides longer durability compared to Eylea (aflibercept 2 mg) in patients with nAMD.

About nAMD and DME
Neovascular (wet) age-related macular degeneration (nAMD) is an eye disease that progresses rapidly and if left untreated can lead to vision loss in as little as three months.

nAMD is one of the leading causes of irreversible blindness and vision impairment around the world.

nAMD may affect people as they age. It occurs when abnormal blood vessels grow and leak fluid under the macula, the part of the eye responsible for sharp central vision and seeing fine detail.

This fluid can damage and scar the macula, which can cause vision loss. 196 million people worldwide are living with AMD – it is anticipated that this figure will increase to 288 million by 2040.

Diabetic macular edema (DME) is a common complication in eyes of people living with diabetes. DME occurs when high levels of blood sugar lead to damaged blood vessels in the eye that leak fluid into the macula.

This can lead to vision loss and, in some cases, blindness. Globally, 146 million people are currently living with diabetic retinopathy (DR), which can develop into a more serious condition which is diabetic macular edema (DME).”

https://www.bayer.com/media/en-us/new-data-from-pivotal-studies-with-aflibercept-8-mg/#

BMS Submits Application for Abecma® for Relapsed or Refractory Multiple Myeloma

admin
-
0

April 17, 2023: “Bristol-Myers Squibb announced that the company has submitted the supplemental New Drug Application for the manufacturing and marketing approval of an additional indication for Abecma® (idecabtagene vicleucel), a B-cell maturation antigen (BCMA)-directed chimeric antigen receptor (CAR) T cell immunotherapy, for patients with relapsed or refractory multiple myeloma (RR/MM) who have received at least two prior regimens, including an immunomodulatory agent, a proteasome inhibitor, and an anti-CD38 antibody.

The application is based on the interim analysis from KarMMa-3 (BB2121-MM-003), a global phase 3 study that evaluated the efficacy and safety of Abecma® in subjects with relapsed or refractory multiple myeloma who had received two to four prior regimens, including an immunomodulatory agent, a proteasome inhibitor, and daratumumab.

Multiple myeloma is a disease in which plasma cells—differentiated B cells—transform into cancerous myeloma cells, which grow primarily in the bone marrow. Plasma cells produce antibodies that protect the body from invasive foreign substances, such as bacteria and viruses.

When transforming into cancerous myeloma cells, however, plasma cells continue to produce monoclonal immunoglobulin (M protein) that is not capable of attacking the foreign substances.

The increase in myeloma cells and M protein causes a variety of clinical manifestations, including hematopoietic disorders (mainly anemia), kidney damage, and osteolytic lesions.

Despite advances in treatment, multiple myeloma repeatedly recurs after initial response to treatment, with increased malignancy with an increasing number of therapies, ultimately progressing to a refractory state. 

In patients with RR/MM treated with the three major drug classes, including proteasome inhibitors, immunomodulatory agents, and anti-CD38 antibodies, the prognosis is poor regardless of the number of prior therapies, and treatment options are limited.

In recent years, there has also been an increase in the use of anti-CD38 antibodies in combination with immunomodulatory agents or proteasome inhibitors for the initial treatment or at the first relapse.

Thus, there is a need for drugs with novel mechanisms of action, highly effective in patients with multiple myeloma who have relapsed or are refractory to these treatments, irrespective of the number of lines of therapy received.

Commenting on the application acceptance, Makoto Sugita, Bristol Myers Squibb’s head of R&D in Japan, said, “We participate in almost global studies conducted by BMS, undertaking simultaneous development and submission, in order to bring new treatment options as quickly as possible to patients in Japan suffering from serious diseases.

We are pleased that we achieved nearly simultaneous filing with the United States and the European Union for approval of Abecma® for use in earlier lines of treatment.

We hope to be able to offer the option of CAR T cell therapy to patients with relapsed or refractory multiple myeloma in Japan in their earlier treatment stages at the same time as the U.S. and Europe.”

About KarMMa-3 (Study BB2121-MM-003)
KarMMa-3 (BB2121-MM-003) is a pivotal, Phase 3, open-label, global, randomized, controlled trial evaluating Abecma compared to standard regimens in patients with relapsed and refractory multiple myeloma who have received two to four prior lines of treatment, including an immunomodulatory agent, a proteasome inhibitor, and daratumumab and were refractory to the last treatment regimen.

Patients were randomized to receive Abecma or standard regimens that consisted of combinations that included daratumumab, pomalidomide, and dexamethasone (DPd), daratumumab, bortezomib, and dexamethasone (DVd), ixazomib, lenalidomide, and dexamethasone (IRd), carfilzomib and dexamethasone (Kd) or elotuzumab, pomalidomide and dexamethasone (EPd) chosen by investigators based on their most recent treatment regimen.

The primary endpoint evaluated in this study is progression-free survival, defined as time from randomization to the first documentation of progressive disease or death due to any cause, whichever occurs first.

Key secondary endpoints include overall response rate and overall survival.

About Abecma
Abecma is a B-cell maturation antigen (BCMA)-directed chimeric antigen receptor (CAR) T cell immunotherapy. 

Abecma recognizes and binds to BCMA on the surface of multiple myeloma cells, which leads to the proliferation of CAR T cells and cytokine release, resulting in the dissolution and death of BCMA-expressing cells.

In Japan, Abecma was approved for manufacturing and marketing on January 20, 2022, and indicated for patients with relapsed or refractory multiple myeloma who have received at least three prior therapies, including an immunomodulatory agent, a proteasome inhibitor and an anti-CD38 antibody.

Overseas, in the United States, Abecma was approved in March 2021 for the treatment of adult patients with relapsed or refractory multiple myeloma after four or more prior lines of therapy, including an immunomodulatory agent, a proteasome inhibitor, and an anti-CD38 monoclonal antibody.

In the EU, Abecma was approved for the treatment of adult patients with relapsed and refractory multiple myeloma who have received at least three prior therapies, including an immunomodulatory agent, a proteasome inhibitor and an anti-CD38 antibody and have demonstrated disease progression on the last therapy.

In addition, Abecma has been approved for production and marketing in Canada, Switzerland, Great Britain, and Israel.

Based on the interim results of the KarMMa-3 study, applications for the earlier use of Abecma have been filed in the United States, in the EU and in Japan.

Abecma U.S. FDA-Approved Indication

ABECMA (idecabtagene vicleucel) is a B-cell maturation antigen (BCMA)-directed genetically modified autologous T cell immunotherapy indicated for the treatment of adult patients with relapsed or refractory multiple myeloma after four or more prior lines of therapy, including an immunomodulatory agent, a proteasome inhibitor, and an anti-CD38 monoclonal antibody. 

U.S. Important Safety Information

BOXED WARNING: CYTOKINE RELEASE SYNDROME, NEUROLOGIC TOXICITIES, HLH/MAS, AND PROLONGED CYTOPENIA

  • Cytokine Release Syndrome (CRS), including fatal or life-threatening reactions, occurred in patients following treatment with ABECMA. Do not administer ABECMA to patients with active infection or inflammatory disorders.
    Treat severe or life-threatening CRS with tocilizumab or tocilizumab and corticosteroids.
  • Neurologic Toxicities, which may be severe or life-threatening, occurred following treatment with ABECMA, including concurrently with CRS, after CRS resolution, or in the absence of CRS. Monitor for neurologic events after treatment with ABECMA.
    Provide supportive care and/or corticosteroids as needed.
  • Hemophagocytic Lymphohistiocytosis/Macrophage Activation Syndrome (HLH/MAS) including fatal and life-threatening reactions, occurred in patients following treatment with ABECMA. HLH/MAS can occur with CRS or neurologic toxicities.
  • Prolonged Cytopenia with bleeding and infection, including fatal outcomes following stem cell transplantation for hematopoietic recovery, occurred following treatment with ABECMA.
  • ABECMA is available only through a restricted program under a Risk Evaluation and Mitigation Strategy (REMS) called the ABECMA REMS

WARNINGS AND PRECAUTIONS:
Cytokine Release Syndrome (CRS): CRS, including fatal or life-threatening reactions, occurred following treatment with ABECMA in 85% (108/127) of patients. Grade 3 or higher CRS occurred in 9% (12/127) of patients, with Grade 5 CRS reported in one (0.8%) patient.

The median time to onset of CRS, any grade, was 1 day (range: 1 – 23 days) and the median duration of CRS was 7 days (range: 1 – 63 days). The most common manifestations included pyrexia, hypotension, tachycardia, chills, hypoxia, fatigue, and headache.

Grade 3 or higher events that may be associated with CRS include hypotension, hypoxia, hyperbilirubinemia, hypofibrinogenemia, acute respiratory distress syndrome (ARDS), atrial fibrillation, hepatocellular injury, metabolic acidosis, pulmonary edema, multiple organ dysfunction syndrome, and HLH/MAS.

Identify CRS based on clinical presentation. Evaluate for and treat other causes of fever, hypoxia, and hypotension.

CRS has been reported to be associated with findings of HLH/MAS, and the physiology of the syndromes may overlap.

In patients with progressive symptoms of CRS or refractory CRS despite treatment, evaluate for evidence of HLH/MAS. Fifty four percent (68/127) of patients received tocilizumab (single dose: 35%; more than 1 dose: 18%).

Overall, 15% (19/127) of patients received at least 1 dose of corticosteroids for treatment of CRS.

All patients that received corticosteroids for CRS received tocilizumab. Ensure that a minimum of 2 doses of tocilizumab are available prior to infusion of ABECMA.

Monitor patients at least daily for 7 days following ABECMA infusion at the REMS-certified healthcare facility for signs or symptoms of CRS and monitor patients for signs or symptoms of CRS for at least 4 weeks after ABECMA infusion.

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

Counsel patients to seek immediate medical attention should signs or symptoms of CRS occur at any time.

Neurologic Toxicities: Neurologic toxicities, which may be severe or life-threatening, occurred following treatment with ABECMA in 28% (36/127) of patients receiving ABECMA, including Grade 3 in 4% (5/127) of patients. One patient had ongoing Grade 2 neurotoxicity at the time of death.

Two patients had ongoing Grade 1 tremor at the time of data cutoff. The median time to onset of neurotoxicity was 2 days (range: 1 – 42 days). CAR T cell-associated neurotoxicity resolved in 92% (33/36) of patients with a median time to resolution of 5 days (range: 1 – 61 days).

The median duration of neurotoxicity was 6 days (range: 1 – 578) in all patients including 3 patients with ongoing neurotoxicity.

Thirty-four patients with neurotoxicity had CRS with onset in 3 patients before, 29 patients during, and 2 patients after CRS. The most frequently reported manifestations of CAR T cell-associated neurotoxicity include encephalopathy, tremor, aphasia, and delirium.

Grade 4 neurotoxicity and cerebral edema in 1 patient, Grade 3 myelitis, and Grade 3 parkinsonism have been reported with ABECMA in another study in multiple myeloma.

Monitor patients at least daily for 7 days following ABECMA infusion at the REMS-certified healthcare facility for signs or symptoms of neurologic toxicities and monitor patients for signs or symptoms of neurologic toxicities for at least 4 weeks after ABECMA infusion and treat promptly.

Rule out other causes of neurologic symptoms. Neurologic toxicity should be managed with supportive care and/or corticosteroids as needed.

Counsel patients to seek immediate medical attention should signs or symptoms occur at any time.

Hemophagocytic Lymphohistiocytosis (HLH)/Macrophage Activation Syndrome (MAS): HLH/MAS occurred in 4% (5/127) of patients receiving ABECMA. One patient developed fatal multi-organ HLH/MAS with CRS and another patient developed fatal bronchopulmonary aspergillosis with contributory HLH/MAS. Three cases of Grade 2 HLH/MAS resolved.

All events of HLH/MAS had onset within 10 days of receiving ABECMA with a median onset of 7 days (range: 4 – 9 days) and occurred in the setting of ongoing or worsening CRS. Two patients with HLH/MAS had overlapping neurotoxicity.

The manifestations of HLH/MAS include hypotension, hypoxia, multiple organ dysfunction, renal dysfunction, and cytopenia.

HLH/MAS is a potentially life-threatening condition with a high mortality rate if not recognized early and treated. Treatment of HLH/MAS should be administered per institutional guidelines.

ABECMA REMS: Due to the risk of CRS and neurologic toxicities, ABECMA is available only through a restricted program under a Risk Evaluation and Mitigation Strategy (REMS) called the ABECMA REMS.
Further information is available at www.AbecmaREMS.com or 1-888-423-5436.

Hypersensitivity Reactions: Allergic reactions may occur with the infusion of ABECMA. Serious hypersensitivity reactions, including anaphylaxis, may be due to dimethyl sulfoxide (DMSO) in ABECMA.

Infections: ABECMA should not be administered to patients with active infections or inflammatory disorders. Severe, life-threatening, or fatal infections occurred in patients after ABECMA infusion. Infections (all grades) occurred in 70% of patients. Grade 3 or 4 infections occurred in 23% of patients.

Overall, 4 patients had Grade 5 infections (3%); 2 patients (1.6%) had Grade 5 events of pneumonia, 1 patient (0.8%) had Grade 5 bronchopulmonary aspergillosis, and 1 patient (0.8%) had cytomegalovirus (CMV) pneumonia associated with Pneumocystis jirovecii. Monitor patients for signs and symptoms of infection before and after ABECMA infusion and treat appropriately. Administer prophylactic, pre-emptive, and/or therapeutic antimicrobials according to standard institutional guidelines.

Febrile neutropenia was observed in 16% (20/127) of patients after ABECMA infusion and may be concurrent with CRS. In the event of febrile neutropenia, evaluate for infection and manage with broad-spectrum antibiotics, fluids, and other supportive care.

Viral Reactivation: CMV infection resulting in pneumonia and death has occurred following ABECMA administration. Monitor and treat for CMV reactivation in accordance with clinical guidelines. Hepatitis B virus (HBV) reactivation, in some cases resulting in fulminant hepatitis, hepatic failure, and death, can occur in patients treated with drugs directed against plasma cells. Perform screening for CMV, HBV, hepatitis C virus (HCV), and human immunodeficiency virus (HIV) in accordance with clinical guidelines before collection of cells for manufacturing.

Prolonged Cytopenias: In the clinical study, 41% of patients (52/127) experienced prolonged Grade 3 or 4 neutropenia and 49% (62/127) experienced prolonged Grade 3 or 4 thrombocytopenia that had not resolved by Month 1 following ABECMA infusion. In 83% (43/52) of patients who recovered from Grade 3 or 4 neutropenia after Month 1, the median time to recovery from ABECMA infusion was 1.9 months. In 65% (40/62) of patients who recovered from Grade 3 or 4 thrombocytopenia, the median time to recovery was 2.1 months.

Three patients underwent stem cell therapy for hematopoietic reconstitution due to prolonged cytopenia. Two of the three patients died from complications of prolonged cytopenia. Monitor blood counts prior to and after ABECMA infusion. Manage cytopenia with myeloid growth factor and blood product transfusion support.

Hypogammaglobulinemia: Hypogammaglobulinemia was reported as an adverse event in 21% (27/127) of patients; laboratory IgG levels fell below 500 mg/dl after infusion in 25% (32/127) of patients treated with ABECMA.

Monitor immunoglobulin levels after treatment with ABECMA and administer IVIG for IgG <400 mg/dl. Manage appropriately per local institutional guidelines, including infection precautions and antibiotic or antiviral prophylaxis.

The safety of immunization with live viral vaccines during or after ABECMA treatment has not been studied. Vaccination with live virus vaccines is not recommended for at least 6 weeks prior to the start of lymphodepleting chemotherapy, during ABECMA treatment, and until immune recovery following treatment with ABECMA.

Secondary Malignancies: Patients treated with ABECMA may develop secondary malignancies. Monitor life-long for secondary malignancies. If a secondary malignancy occurs, contact Bristol-Myers Squibb at 1-888-805-4555 to obtain instructions on patient samples to collect for testing of secondary malignancy of T cell origin.

Effects on Ability to Drive and Operate Machinery: Due to the potential for neurologic events, patients receiving ABECMA are at risk for altered or decreased consciousness or coordination in the 8 weeks following ABECMA infusion.

Advise patients to refrain from driving and engaging in hazardous occupations or activities, such as operating heavy or potentially dangerous machinery, during this initial period.

Adverse Reactions: The most common nonlaboratory adverse reactions include CRS, infections – pathogen unspecified, fatigue, musculoskeletal pain, hypogammaglobulinemia, diarrhea, upper respiratory tract infection, nausea, viral infections, encephalopathy, edema, pyrexia, cough, headache, and decreased appetite.”

https://investors.bms.com/iframes/press-releases/press-release-details/2023/Bristol-Myers-Squibb-Submits-Application-for-Abecma–a-CAR-T-Cell-Therapy-for-Patients-with-Relapsed-or-Refractory-Multiple-Myeloma-Who-Have-Received-at-Least-Two-Prior-Therapies-/default.aspx

FDA Approves Cell Therapy for Patients with Blood Cancers to Reduce Risk of Infection Following Stem Cell Transplantation

admin
-
0
FDA Approves Cell Therapy for Patients with Blood Cancers to Reduce Risk of Infection Following Stem Cell Transplantation

April 17, 2023: “The U.S. FDA approved Omisirge (omidubicel-onlv), a substantially modified allogeneic (donor) cord blood-based cell therapy to quicken the recovery of neutrophils (a subset of white blood cells) in the body and reduce the risk of infection.

The product is intended for use in adults and pediatric patients 12 years and older with blood cancers planned for umbilical cord blood transplantation following a myeloablative conditioning regimen (treatment such as radiation or chemotherapy). 

“Today’s approval is an important advance in cell therapy treatment in patients with blood cancers,” said Peter Marks, M.D., Ph.D., director of the FDA’s Center for Biologics Evaluation and Research.

“Hastening the return of the body’s white blood cells can reduce the possibility of serious or overwhelming infection associated with stem cell transplantation.

This approval reflects the FDA’s continued commitment to supporting development of innovative therapies for life-threatening cancers.”

Blood cancers are a form of cancer caused by uncontrolled growth of cells in the blood, disrupting the ability of blood cells to perform their normal functions.

This abnormal cell growth often begins in the bone marrow, which is made up of stem cells that form into different types of blood cells with specific functions in the body. Blood cancers represent about 10% of all cases of cancer each year in the U.S. Blood cancers can be fatal, with varying survival rates based on multiple factors including the specific type of blood cancer diagnosed.

This type of cancer can also cause serious and damaging effects to the body and lead to symptoms such as fatigue, bone and joint pain, night sweats, infections, weakness, weight loss and fever. 

Stem cell transplantation is a common treatment for blood cancers. It involves putting healthy stem cells into the body to help restore the normal production and function of blood cells.

One source of healthy stem cells is umbilical cord blood. Generally, before receiving this kind of transplant, the patient will undergo a course of treatments to remove their own stem cells and prepare the body for the new stem cells.

This process may include undergoing therapies such as radiation or chemotherapy, both of which may weaken an individual’s immune system. As a result, a frequent and serious risk of this treatment is the occurrence of severe and sometimes deadly infections.

Omisirge, administered as a single intravenous dose, is composed of human allogeneic stem cells from umbilical cord blood that are processed and cultured with nicotinamide (a form of vitamin B3). Each dose is patient-specific, containing healthy stem cells from an allogeneic pre-screened donor, meaning it comes from a different individual rather than using the patient’s own cells. 

The safety and effectiveness of Omisirge was supported by a randomized, multicenter study comparing transplantation of Omisirge to transplantation of umbilical cord blood, in subjects between the ages of 12 and 65 years. The study enrolled a total of 125 subjects.

All subjects in the study had confirmed blood cancers. The efficacy of Omisirge was based on the amount of time needed for recovery of the subject’s neutrophils (a type of white blood cell that helps protect the body from infections) and the incidence of infections following transplantation.

Eighty-seven percent of subjects who were randomized to receive Omisirge achieved neutrophil recovery with a median of 12 days following treatment with the product, compared to 83% of subjects who were randomized to receive umbilical cord blood transplantation and who achieved neutrophil recovery with a median of 22 days.

Bacterial or fungal infections by 100 days following transplantation were seen in 39% of subjects receiving Omisirge versus 60% of subjects in the control group who received umbilical cord blood.

Treatment with Omisirge has the potential to cause severe side effects, which must be considered in assessing the risks and benefits of using this product.

Similar to all approved umbilical cord products, the label carries a Boxed Warning for infusion reactions, graft versus host disease (GvHD – a condition that occurs when donor bone marrow or stem cells attack the graft recipient), engraftment syndrome (characterized by a noninfectious fever and rash), and graft failure (occurs when new cells do not produce white blood cells, red blood cells and platelets). 

The most common adverse reactions associated with Omisirge included infections, GvHD, and infusion reactions.

Patients who receive Omisirge should be monitored for signs and symptoms of infusion reactions, GvHD, engraftment syndrome, graft failure, transmission of serious infections or rare genetic diseases from the donor cells, as well as life-long for secondary malignancies (cancers that can spread from the original site or emerge following treatment). 

This application received Priority Review, Breakthrough Therapy and Orphan designations. 

The FDA granted regular approval of Omisirge to Gamida Cell Ltd.”

https://www.fda.gov/news-events/press-announcements/fda-approves-cell-therapy-patients-blood-cancers-reduce-risk-infection-following-stem-cell

Update to contractual arrangements between AstraZeneca, Swedish Orphan Biovitrum AB and Sanofi

admin
-
0
Update to contractual arrangements between AstraZeneca, Swedish Orphan Biovitrum AB and Sanofi

April 11, 2023: “AstraZeneca, Swedish Orphan Biovitrum AB (publ) (Sobi) and Sanofi have updated and simplified their contractual arrangements relating to the development and commercialisation of nirsevimab in the US.

Given the upcoming launch of nirsevimab in the US and other markets, simplification of the prior arrangements clarifies the roles and responsibilities of relevant parties.  

Under the updated arrangements, Sobi has entered into a direct relationship with Sanofi, replacing the previous participation agreement with AstraZeneca entered into in November 2018.

Under the previous agreement, from the day of the transaction with Sobi, AstraZeneca had to provision the risk adjusted value of the discounted cash flow of future payments to be made to Sobi as a liability.

As a result of this simplification agreement, Sanofi will pay royalties to Sobi as US nirsevimab sales arise, and the liability related to future obligations is eliminated.

AstraZeneca will record a gain of $0.7 billion, to be recognised in Core Other operating income in 2023. This does not impact AstraZeneca’s financial guidance for 2023.

Notes

About nirsevimab
Nirsevimab is a single dose long-acting antibody, developed and commercialised in partnership by AstraZeneca and Sanofi using AstraZeneca’s YTE technology.

It is designed to protect infants entering or during their first respiratory syncytial virus (RSV) season and for children up to 24 months of age who remain vulnerable to severe RSV disease through their second RSV season.

Nirsevimabhas been developed to offer newborns and infants direct RSV protection via an antibody to help prevent lower respiratory tract disease (LRTD) caused by RSV.Monoclonal antibodies do not require the activation of the immune system to help offer timely, rapid and direct protection against disease.

In November 2022, Beyfortus was approved by the European Commission and by the UK Medicines and Healthcare products Regulatory Agency (MHRA).

Sanofi Alliance
In March 2017, AstraZeneca and Sanofi announced an agreement to develop and commercialise nirsevimab.

Under the terms of the agreement, AstraZeneca leads development and manufacturing activities, and Sanofi leads commercialisation activities and records revenue.

Under the terms of the global agreement, Sanofi made an upfront payment of €120m, has paid a development milestone of €30m and will pay further milestones subject to achievement of certain development and sales-related milestones.

The two companies share costs and profits. Revenue from the agreement is reported as Alliance Revenue and Collaboration Revenue in the Company’s financial statements.”

https://www.astrazeneca.com/media-centre/press-releases/2023/update-to-arrangements-with-sobi-and-sanofi.html

FDA Accepts Pfizer’s sNDA for BRAFTOVI + MEKTOVI

admin
-
0
FDA Accepts Pfizer’s sNDA for BRAFTOVI + MEKTOVI

April 04, 2023: “Pfizer announced that the U.S. Food and Drug Administration has accepted for review the Supplemental New Drug Applications for BRAFTOVI® (encorafenib) + MEKTOVI® (binimetinib) for patients with metastatic non-small cell lung cancer (NSCLC) with a BRAF V600E mutation, as detected by an FDA-approved test.

The Prescription Drug User Fee Act (PDUFA) goal date for a decision by the FDA is in Fourth-Quarter 2023 for the sNDAs.

In the U.S., BRAFTOVI + MEKTOVI is currently approved for the treatment of patients with unresectable or metastatic melanoma with a BRAF V600E or V600K mutation, as detected by an FDA-approved test.

BRAFTOVI is also approved, in combination with cetuximab, for the treatment of adult patients with metastatic colorectal cancer (CRC) with a BRAF V600E mutation, as detected by an FDA-approved test, after prior therapy.

“For more than a decade, Pfizer Oncology has been at the forefront of bringing biomarker-driven treatment options to patients with cancer.

Since their initial regulatory approvals, BRAFTOVI and MEKTOVI have helped improve outcomes in their respective indications of BRAF-mutated metastatic melanoma and BRAF-mutated metastatic colorectal cancer,” said Chris Boshoff, M.D., Ph.D., Chief Development Officer, Oncology and Rare Disease, Pfizer Global Product Development.

“Through our comprehensive development program, the BRAFTOVI and MEKTOVI combination has shown the potential to help more patients, such as those living with BRAF V600E-mutant non-small cell lung cancer. These sNDAs build on Pfizer’s long heritage of meeting the diverse needs of people with NSCLC, and we look forward to working with the FDA on their review of these applications.”

These sNDAs are supported by results from the PHAROS trial (NCT03915951), an open-label, multicenter, non-randomized, Phase 2 study (n=98) to determine the safety, tolerability, and efficacy of BRAFTOVI given in combination with MEKTOVI in patients with BRAF V600E-mutant metastatic NSCLC. PHAROS met its primary endpoint of objective response rate.

Detailed results from the PHAROS study will be presented at an upcoming scientific congress.

About Non-Small Cell Lung Cancer (NSCLC)

Lung cancer is the second most common type of cancer and the number one cause of cancer-related death around the world.

In 2023, the American Cancer Society estimates there will be about 238,340 new cases of lung cancer diagnosed in the U.S. NSCLC accounts for approximately 80-85% of all lung cancers.

Some lung cancers are linked to acquired genetic abnormalities.

For instance, a BRAF V600E mutation occurs in approximately 2% of NSCLC cases and stimulates tumor cell growth and proliferation by altering the MAP kinase (MAPK) signaling pathway.

Targeting components of this pathway could potentially inhibit unchecked tumor growth and proliferation caused by BRAF mutations.

Precision medicine is increasingly being developed for NSCLC patients with genetic changes, such as BRAF mutations, that can be detected using biomarker tests.

Advances in targeted therapy have been associated with significant improvements in population-level NSCLC mortality in recent years.

About PHAROS

PHAROS (NCT03915951) is an open-label, multicenter, non-randomized, Phase 2 study to determine the safety, tolerability, and efficacy of BRAFTOVI given in combination with MEKTOVI in 98 patients with BRAF V600E-mutant metastatic NSCLC.

The primary endpoint is objective response rate, based on independent radiologic review (per RECIST v1.1); secondary objectives will evaluate additional efficacy endpoints and safety. Duration of response is a key secondary endpoint.

The trial is conducted across 53 sites in: Italy (5 sites), the Netherlands (2 sites), South Korea (3 sites), Spain (4 sites), and the U.S. (39 sites).

About BRAFTOVI + MEKTOVI

BRAFTOVI is an oral small molecule BRAF kinase inhibitor and MEKTOVI is an oral small molecule MEK inhibitor which target key proteins in the MAPK signaling pathway (RAS-RAF-MEK-ERK).

Inappropriate activation of this pathway has been shown to occur in many cancers, including melanoma, CRC, and NSCLC.

In 2018, the FDA approved BRAFTOVI + MEKTOVI in combination for patients with unresectable or metastatic melanoma with a BRAF V600E or V600K mutation, as detected by an FDA-approved test.

The approval was based on COLUMBUS, a randomized, active-controlled, open-label, Phase 3 trial.

In 2020, BRAFTOVI was FDA-approved, in combination with cetuximab, for the treatment of adults with metastatic CRC with a BRAF V600E mutation, as detected by an FDA-approved test. The approval was based on results from the BEACON CRC trial.

Pfizer has exclusive rights to BRAFTOVI and MEKTOVI in the U.S., Canada, and all countries in the Latin America, Africa, and Middle East regions.

Ono Pharmaceutical Co. Ltd. has exclusive rights to commercialize both products in Japan and South Korea, Medison has exclusive rights in Israel, and Pierre Fabre has exclusive rights in all other countries, including Europe and Asia-Pacific (excluding Japan and South Korea).

INDICATIONS AND USAGE

BRAFTOVI® (encorafenib) and MEKTOVI® (binimetinib) are kinase inhibitors indicated for use in combination for the treatment of patients with unresectable or metastatic melanoma with a BRAF V600E or V600K mutation as detected by an FDA-approved test.

BRAFTOVI is indicated, in combination with cetuximab, for the treatment of adult patients with metastatic colorectal cancer (CRC) with a BRAF V600E mutation, as detected by an FDA-approved test, after prior therapy.

Limitations of Use: BRAFTOVI is not indicated for treatment of patients with wild-type BRAF melanoma or wild-type BRAF CRC.

IMPORTANT SAFETY INFORMATION

This information applies to the safety of BRAFTOVI when used in combination with either MEKTOVI or cetuximab.

WARNINGS AND PRECAUTIONS

New Primary Malignancies, cutaneous and non-cutaneous malignancies can occur with BRAFTOVI.

BRAFTOVI may promote malignancies associated with activation of RAS through mutation or other mechanisms.

Perform dermatopathologic evaluations prior to initiating treatment, every 2 months during treatment, and for up to 6 months following discontinuation of treatment. Manage suspicious skin lesions with excision and dermatopathologic evaluation.

Dose modification is not recommended for new primary cutaneous malignancies. Monitor patients receiving BRAFTOVI for signs and symptoms of non-cutaneous malignancies. Discontinue BRAFTOVI for RAS mutation-positive non-cutaneous malignancies.

  • BRAF-mt metastatic melanoma (COLUMBUS study): Cutaneous squamous cell carcinoma (cuSCC), including keratoacanthoma (KA), occurred in 2.6% and basal cell carcinoma occurred in 1.6% of patients receiving BRAFTOVI with MEKTOVI. Median time to first occurrence of cuSCC/KA was 5.8 months
  • BRAF-mt metastatic CRC (BEACON CRC study): cuSCC, including KA, occurred in 1.4% of patients with CRC, and new primary melanoma occurred in 1.4% of patients who received BRAFTOVI with cetuximab

Tumor Promotion in BRAF Wild-Type Tumors: In vitro experiments have demonstrated paradoxical activation of MAP-kinase signaling and increased cell proliferation in BRAF wild-type cells exposed to BRAF inhibitors. Confirm evidence of BRAF V600E or V600K mutation using an FDA-approved test prior to initiating BRAFTOVI.

Hemorrhage: Hemorrhage can occur when BRAFTOVI is administered in combination with MEKTOVI or cetuximab. Withhold, reduce dose, or permanently discontinue based on severity of adverse reaction.

  • BRAF-mt metastatic melanoma (COLUMBUS study): Hemorrhage occurred in 19% of patients receiving BRAFTOVI with MEKTOVI and Grade 3 or higher hemorrhage occurred in 3.2% of patients.
    The most frequent hemorrhagic events were gastrointestinal, including rectal hemorrhage (4.2%), hematochezia (3.1%), and hemorrhoidal hemorrhage (1%). Fatal intracranial hemorrhage in the setting of new or progressive brain metastases occurred in 1.6% of patients
  • BRAF-mt metastatic CRC (BEACON CRC study): Hemorrhage occurred in 19% of patients receiving BRAFTOVI with cetuximab; Grade 3 or higher hemorrhage occurred in 1.9% of patients, including fatal gastrointestinal hemorrhage in 0.5% of patients.

    The most frequent hemorrhagic events were epistaxis (6.9%), hematochezia (2.3%), and rectal hemorrhage (2.3%)

Uveitis: Uveitis, including iritis and iridocyclitis, has been reported in patients treated with BRAFTOVI with MEKTOVI. Assess for visual symptoms at each visit. Perform an ophthalmological evaluation at regular intervals and for new or worsening visual disturbances, and to follow new or persistent ophthalmologic findings.

Withhold, reduce dose, or permanently discontinue based on severity of adverse reaction. In the COLUMBUS study, uveitis, including iritis and iridocyclitis, was reported in 4% of patients treated with BRAFTOVI with MEKTOVI.

QT Prolongation: BRAFTOVI is associated with dose-dependent QTc interval prolongation in some patients. Monitor patients who already have or who are at significant risk of developing QTc prolongation, including patients with known long QT syndromes, clinically significant bradyarrhythmias, severe or uncontrolled heart failure and those taking other medicinal products associated with QT prolongation.

Correct hypokalemia and hypomagnesemia prior to and during BRAFTOVI administration. Withhold, reduce dose, or permanently discontinue for QTc >500 ms.

  • BRAF-mt metastatic melanoma (COLUMBUS study): An increase in QTcF to >500 ms was measured in 0.5% (1/192) of patients who received BRAFTOVI in combination with MEKTOVI

Embryo-Fetal Toxicity: Both BRAFTOVI and MEKTOVI can cause fetal harm when administered to a pregnant woman. BRAFTOVI can render hormonal contraceptives ineffective.

  • BRAF-mt metastatic melanoma (COLUMBUS study): Nonhormonal contraceptives should be used during treatment and for at least 30 days after the final dose for patients taking BRAFTOVI + MEKTOVI
  • BRAF-mt metastatic CRC (BEACON CRC study): Advise females of reproductive potential to use effective nonhormonal contraception during treatment with BRAFTOVI and for 2 weeks after the final dose

BRAFTOVI as a Single Agent is associated with increased risk of certain adverse reactions compared to when BRAFTOVI is used with MEKTOVI.

  • BRAF-mt metastatic melanoma (COLUMBUS study): Grades 3 or 4 dermatologic reactions occurred in 21% of patients receiving BRAFTOVI as a single agent compared to 2% in patients receiving the combination of BRAFTOVI with MEKTOVI
  • If MEKTOVI is temporarily interrupted or permanently discontinued, reduce the dose of BRAFTOVI as recommended

Risks Associated with Combination Treatment

  • In BRAF-mt metastatic melanoma (COLUMBUS study), BRAFTOVI is used in combination with MEKTOVI so refer to the prescribing information for MEKTOVI for additional risk information
  • In BRAF-mt metastatic CRC (BEACON CRC study), BRAFTOVI is used in combination with cetuximab so refer to the prescribing information for cetuximab for additional risk information

Additional WARNINGS and PRECAUTIONS for MEKTOVI When Used With BRAFTOVI in BRAF-mt Metastatic Melanoma (COLUMBUS study)

Cardiomyopathy, manifesting as left ventricular dysfunction associated with symptomatic or asymptomatic decreases in ejection fraction, has been reported in patients. Patients with cardiovascular risk factors should be monitored closely. Withhold, reduce dose, or permanently discontinue based on severity of adverse reaction.

  • Assess left ventricular ejection fraction (LVEF) by echocardiogram or multi-gated acquisition (MUGA) scan prior to initiating treatment, 1 month after initiating treatment, and then every 2 to 3 months during treatment
  • The safety has not been established in patients. In with a baseline ejection fraction that is either below 50% or below the institutional lower limit of normal (LLN)
  • BRAF-mt metastatic melanoma (COLUMBUS study): evidence of cardiomyopathy occurred in 7% and Grade 3 left ventricular dysfunction occurred in 1.6% of patients. receiving MEKTOVI with BRAFTOVI.
    The median time to first occurrence of left ventricular dysfunction (any grade) was 3.6 months. Cardiomyopathy resolved in 87% of patients.

Venous Thromboembolism (VTE): VTE occurred in 6% of patients with BRAF-mt metastatic melanoma (COLUMBUS study), including 3.1% of patients who developed pulmonary embolism. Withhold, reduce dose, or permanently discontinue based on severity of adverse reaction.

Other Ocular Toxicities:

  • Serous retinopathy occurred in 20% of patients receiving MEKTOVI with BRAFTOVI; 8% were retinal detachment and 6% were macular edema. Symptomatic serous retinopathy occurred in 8% of patients with no cases of blindness. The median time to onset of the first event of serous retinopathy (all grades) was 1.2 months.
  • Retinal vein occlusion (RVO) is a known class-related adverse reaction of MEK inhibitors and may occur in patients receiving MEKTOVI with BRAFTOVI. In BRAF-mt metastatic melanoma (COLUMBUS study), 1 patient experienced RVO (0.1%) in the MEKTOVI with BRAFTOVI group (n=690).
    • The safety of MEKTOVI has not been established in patients with a history of RVO or current risk factors for RVO including uncontrolled glaucoma or a history of hyperviscosity or hypercoagulability syndromes
    • Perform ophthalmological evaluation for patient-reported acute vision loss or other visual disturbance within 24 hours. Permanently discontinue MEKTOVI in patients with documented RVO

Interstitial Lung Disease (ILD): ILD, including pneumonitis occurred in 0.3% (2 of 690 patients) with BRAF-mt metastatic melanoma receiving MEKTOVI with BRAFTOVI. Assess new or progressive unexplained pulmonary symptoms or findings for possible ILD. Withhold, reduce dose, or permanently discontinue based on severity of adverse reaction.

Hepatotoxicity: Hepatotoxicity can occur when MEKTOVI is taken with BRAFTOVI.Monitor liver laboratory tests before initiation of MEKTOVI, monthly during treatment, and as clinically indicated. Withhold, reduce dose, or permanently discontinue based on severity of adverse reaction.

  • BRAF-mt metastatic melanoma (COLUMBUS study): The incidence of Grade 3 or 4 increases in liver function laboratory tests in patients receiving MEKTOVI with BRAFTOVI was 6% for alanine aminotransferase (ALT), 2.6% for aspartate aminotransferase (AST), and 0.5% for alkaline phosphatase. No patient experienced Grade 3 or 4 serum bilirubin elevation

Rhabdomyolysis: Rhabdomyolysis can occur when MEKTOVI is taken with BRAFTOVI. Monitor creatine phosphokinase and creatinine levels prior to initiating MEKTOVI, periodically during treatment, and as clinically indicated. Withhold, reduce dose, or permanently discontinue based on severity of adverse reaction.

  • BRAF-mt metastatic melanoma (COLUMBUS study): Elevation of laboratory values of serum CPK occurred in 58% of patients receiving MEKTOVI with BRAFTOVI. Rhabdomyolysis was reported in 0.1% (1 of 690 patients) with BRAF mutation-positive melanoma receiving MEKTOVI with BRAFTOVI

ADVERSE REACTIONS

BRAF-mt Metastatic Melanoma (COLUMBUS study)

  • Most common adverse reactions (≥ 20%, all grades) for patients receiving BRAFTOVI and MEKTOVI compared to vemurafenib were fatigue (43% vs 46%), nausea (41% vs 34%), diarrhea (36% vs 34%), vomiting (30% vs 16%), abdominal pain (28% vs 16%), arthralgia (26% vs 46%), myopathy (23% vs 22%), hyperkeratosis (23% vs 49%), rash (22% vs 53%), headache (22% vs 20%), constipation (22% vs 6%), visual impairment (20% vs 4%), serous retinopathy/RPED (20% vs 2%)
  • Other clinically important adverse reactions occurring in <10% of patients who received BRAFTOVI with MEKTOVI were facial paresis, pancreatitis, panniculitis, drug hypersensitivity, and colitis
  • Most common laboratory abnormalities (≥ 20%, all grades) for BRAFTOVI with MEKTOVI compared to vemurafenib included increased creatinine (93% vs 92%), increased CPK (58% vs 3.8%), increased gamma glutamyl transferase (GGT) (45% vs 34%), anemia (36% vs 34%), increased ALT (29% vs 27%), hyperglycemia (28% vs 20%), increased AST (27% vs 24%), and increased alkaline phosphatase (21% vs 35%)

BRAF-mt Metastatic CRC (BEACON CRC study)

  • Most common adverse reactions (≥25%, all grades) in patients receiving BRAFTOVI with cetuximab compared to irinotecan with cetuximab or FOLFIRI with cetuximab (control) were fatigue (51% vs 50%), nausea (34% vs 41%), diarrhea (33% vs 48%), dermatitis acneiform (32% vs 43%), abdominal pain (30% vs 32%), decreased appetite (27% vs 27%), arthralgia (27% vs 3%), and rash (26% vs 26%)
  • Other clinically important adverse reactions occurring in <10% of patients who received BRAFTOVI with cetuximab was pancreatitis
  • Most common laboratory abnormalities (≥20%, all grades) in patients receiving BRAFTOVI with cetuximab compared to irinotecan with cetuximab or FOLFIRI with cetuximab (control) were anemia (34% vs 48%) and lymphopenia (24% vs 35%)

DRUG INTERACTIONS With BRAFTOVI When Used in Combination With Either MEKTOVI or Cetuximab

  • Avoid coadministration of BRAFTOVI with strong or moderate CYP3A4 inhibitors (including grapefruit juice) or CYP3A4 inducers and use caution with sensitive CYP3A4 substrates. Avoid coadministration of BRAFTOVI with hormonal contraceptives.
  • Modify BRAFTOVI dose if coadministration with a strong or moderate CYP3A4 inhibitor cannot be avoided.
  • Avoid coadministration of BRAFTOVI with drugs known to prolong QT/QTc interval.
  • Dose reductions of drugs that are substrates of OATP1B1, OATP1B3, or BCRP may be required when used concomitantly with BRAFTOVI.

Lactation: Advise women not to breastfeed during treatment with BRAFTOVI and for 2 weeks after final dose.

Infertility: Advise males of reproductive potential that BRAFTOVI may impair fertility.

For BRAF-mt metastatic melanoma, see full Prescribing Information and Medication Guide for BRAFTOVI and full Prescribing Information and Patient Information for MEKTOVI. See full Prescribing Information for BRAFTOVI and for MEKTOVI for dose modifications for adverse reactions.

For BRAF-mt metastatic CRC, see full Prescribing Information and Medication Guide for BRAFTOVI. See full Prescribing Information for BRAFTOVI for dose modifications for adverse reactions.

Refer to cetuximab prescribing information for recommended dosing and safety information.“

https://www.pfizer.com/news/press-release/press-release-detail/fda-accepts-pfizers-supplemental-new-drug-applications

Job interview questions for Health Economics and Outcomes Research(HEOR)

admin
-
0
Job interview questions for Health Economics and Outcomes Research(HEOR)

1. What is HEOR, and why is it important in the healthcare industry?

HEOR stands for Health Economics and Outcomes Research. It is important in the healthcare industry because it provides insights into the value of healthcare interventions and helps to inform decision-making regarding resource allocation.

2. What are the different types of economic evaluations used in HEOR, and how are they conducted?

The different types of economic evaluations used in HEOR include cost-effectiveness analysis, cost-utility analysis, and cost-benefit analysis. They are conducted by comparing the costs and outcomes of different healthcare interventions.

3. What is a systematic review, and why is it important in HEOR?

A systematic review is a type of research that summarizes the findings of multiple studies on a particular topic. It is important in HEOR because it helps to provide a comprehensive and unbiased assessment of the available evidence.

4. What is a real-world evidence (RWE), and how is it used in HEOR?

RWE refers to data collected outside of clinical trials, such as electronic health records or claims data. It is used in HEOR to provide insights into the effectiveness and safety of healthcare interventions in real-world settings.

5. What are the challenges in conducting economic evaluations, and how are they addressed?

Some challenges in conducting economic evaluations include data availability and quality, uncertainty in the estimates, and differing perspectives of stakeholders. These challenges can be addressed by using sensitivity analyses, involving multiple perspectives in the analysis, and improving data collection and analysis method.

6. What are the different types of healthcare costs, and how are they measured in economic evaluations?

The different types of healthcare costs include direct medical costs, direct non-medical costs, and indirect costs. They are measured in economic evaluations by using a variety of methods, such as surveys and administrative data.

7. What is the role of HEOR in drug development and pricing?

HEOR plays a critical role in drug development and pricing by providing evidence of the value of healthcare interventions and helping to inform decisions regarding pricing and reimbursement.

8. What are the ethical considerations in HEOR, and how are they addressed?

Ethical considerations in HEOR include ensuring that the research is conducted with the highest standards of ethical conduct, respecting the privacy and autonomy of study participants, and ensuring that the results of the research are disseminated in a transparent and unbiased manner.

These considerations are addressed through institutional review board (IRB) review, informed consent procedures, and peer review of research results.

9. What is a value proposition, and how is it developed in HEOR?

A value proposition is a statement that summarizes the value of a healthcare intervention for a particular stakeholder. It is developed in HEOR by conducting economic evaluations and synthesizing the available evidence to create a compelling argument for the value of the intervention.

10. What is a health technology assessment (HTA), and how is it used in HEOR?

HTA is a process that evaluates the safety, effectiveness, and value of healthcare interventions. It is used in HEOR to provide evidence to decision-makers regarding the adoption, pricing, and reimbursement of healthcare interventions.

Sandoz receives approval by EC for Hyrimoz® high-concentration formulation

admin
-
0
Sandoz receives approval by EC for Hyrimoz® high-concentration formulation

April 3, 2023: “Sandoz, a global leader in off-patent (generic and biosimilar) medicines announced that the European Commission (EC) granted marketing authorization in the European Union (EU) for a citrate-free high concentration formulation (HCF; 100 mg/mL) of its biosimilar Hyrimoz® (adalimumab).

The approval includes all indications covered by the reference medicine*: rheumatic diseases, Crohn’s disease, ulcerative colitis, plaque psoriasis, uveitis and hidradenitis suppurativa.

“Living with a chronic disease can take a significant toll on a patient’s quality of life. Biosimilars help patients to gain broader access to effective and high-quality treatments that improve their disease therapies,” said Rebecca Guntern, Head of Region Europe, Sandoz.

“With eight marketed biosimilars Sandoz is offering the broadest biosimilar portfolio and is the leading biosimilars company in Europe with more than two decades of experience.

Today’s approval brings Sandoz one step closer to providing European patients with chronic conditions an additional treatment option that offers increased convenience and a reduction in injection volume.” 

The adalimumab citrate-free HCF (100 mg/mL) formulation offers a 50 percent reduction in injection volume compared to the 50 mg/ml concentration and potentially decreases the number of injections required for patients who need 80 mg/mL or higher dosing.

The HCF formulation is presented in the same auto-injector as currently available to patients, aiming for an enhanced yet familiar patient experience.

As part of the comprehensive submission package to the European Marketing Authorization, Sandoz conducted a Phase I pharmacokinetics (PK) bridging study comparing its approved adalimumab 50 mg/mL2 with the 100 mg/mL (HCF).

The study met all its primary objectives, demonstrating comparable pharmacokinetics and showing similar safety and immunogenicity between the two concentrations.

Recently, US Food and Drug Administration (FDA) also approved the citrate-free HCF of Hyrimoz® (adalimumab-adaz) injection. 

Sandoz is committed to helping millions of patients sustainably and affordably access critical and potentially life-changing biologic medicines across a range of areas including immunology, oncology, supportive care and endocrinology.

It has a leading global portfolio with eight marketed biosimilars and a further 15+ in various stages of development.

Since launching the first biosimilar in Europe in 2006, Sandoz has proven biosimilars create early and expanded patient access to life-altering medicines while increasing healthcare savings and creating competition that fuels innovation and development of new and enhanced treatments in areas of unmet need.

About adalimumab
Adalimumab is a human immunoglobulin G1 (IgG(1)) monoclonal antibody targeting tumor necrosis factor alpha (TNF-a).

The adalimumab reference medicine (Humira®*) was first approved with an adalimumab concentration of 50 mg/mL. In 2015, the EMA and US FDA approved Humira® HCF, which contains adalimumab at a concentration of 100 mg/mL.”

https://www.novartis.com/news/media-releases/sandoz-receives-approval-european-commission-hyrimoz-adalimumab-high-concentration-formulation

AZ’s Lynparza and Imfinzi combination shows positive results in advanced ovarian cancer

admin
-
0
AZ’s Lynparza and Imfinzi combination shows positive results in advanced ovarian cancer

April 05, 2023: “Positive high-level results from a planned interim analysis of the DUO-O Phase III trial showed treatment with a combination of Lynparza (olaparib), Imfinzi (durvalumab), chemotherapy and bevacizumab demonstrated a statistically significant and clinically meaningful improvement in progression-free survival (PFS) versus chemotherapy plus bevacizumab (control arm) in newly diagnosed patients with advanced high-grade epithelial ovarian cancer without tumour BRCA mutations.

Patients were treated with Imfinzi in combination with chemotherapy and bevacizumab followed by Imfinzi, Lynparza and bevacizumabas maintenance therapy.

In an additional arm, Imfinzi, chemotherapy plus bevacizumab showed a numerical improvement in PFS versus the control arm but did not reach statistical significance at this interim analysis.

At the time of this planned interim analysis, the overall survival (OS) and other secondary endpoints are immature and will be formally assessed at a subsequent analysis.

Ovarian cancer is one of the most common gynaecologic cancers.

Over two thirds of patients are diagnosed with advanced disease which can progress quickly, often within two years, diminishing their quality of life despite treatment. Unfortunately, 50-70% of patients with advanced disease die within five years.

Philipp Harter, Director, Department of Gynaecology and Gynaecologic Oncology, Evangelische Kliniken Essen-Mitte, Germany and principal investigator for the trial, said: “DUO-O showcases the power of academia and industry collaboration in advancing new treatment combinations for patients with ovarian cancer.

I’m grateful for the academic cooperative study groups and patients around the world that made this trial possible and look forward to sharing the results with the clinical community.”

Susan Galbraith, Executive Vice President, Oncology R&D, AstraZeneca, said: “While there has been significant progress for patients with advanced ovarian cancer, an unmet need still remains.

These data from the DUO-O trial provide encouraging evidence for this Lynparza and Imfinzi combination in patients without tumour BRCA mutations and reinforce our continued commitment to finding new treatment approaches for these patients.

It will be important to understand the key secondary endpoints as well as data for relevant subgroups.”

The safety and tolerability of these combinations are broadly consistent with that observed in prior clinical trials and the known profiles of the individual medicines.

The data will be presented at forthcoming medical meetings and shared with health authorities.

Notes

Ovarian cancer
Ovarian cancer is the eighth most common cancer in women worldwide with more than 314,000 new patients diagnosed with ovarian cancer in 2020 and over 207,000 deaths.

This number is expected to rise by almost 42% by 2040 to over 445,000 newly diagnosed patients and 314,000 deaths.

DUO-O
DUO-O is a Phase III randomised, double-blind, placebo-controlled, multi-centre trial to evaluate the efficacy and safety of Imfinzi in combination with platinum-based chemotherapy and bevacizumab followed by maintenance treatment with Imfinzi and bevacizumab with or without Lynparza in newly diagnosed patients with advanced ovarian cancer without tumour BRCA mutations.

Patients were randomized 1:1:1 to: Arm 1 (control), induction therapy with platinum-based chemotherapy in combination with bevacizumab and placebo followed by maintenance treatment with bevacizumab plus placebo; Arm 2, induction therapy with platinum-based chemotherapy in combination with bevacizumab and Imfinzi followed by maintenance Imfinzi and bevacizumab plus placebo; or Arm 3, induction therapy with platinum-based chemotherapy in combination with bevacizumab and Imfinzi followed by maintenance Imfinzi and bevacizumabplus Lynparza.

In all arms, platinum-based chemotherapy was administered every 3 weeks (q3w) for up to 6 cycles, bevacizumab was administered q3w for up to 15 months, Imfinzi or placebo was administered q3w for up to 24 months, and Lynparza or placebo was administered twice daily for up to 24 months.

The primary endpoint of the trial is PFS as assessed by investigator for Arm 3 compared to Arm 1 (control) in the overall trial population which included patients without tumour BRCA mutations and in the subset of these patients with HRD positive disease.

Key secondary endpoints include PFS as assessed by investigator in Arm 2 compared to control, as well as comparisons for OS. DUO-O enrolled over 1200 patients across all treatment arms at 179 study locations. For more information about the trial, visit ClinicalTrials.gov.

Imfinzi
Imfinzi (durvalumab) is a human monoclonal antibody that binds to the PD-L1 protein and blocks the interaction of PD-L1 with the PD-1 and CD80 proteins, countering the tumour’s immune-evading tactics and releasing the inhibition of immune responses.

Imfinzi is the only approved immunotherapy and the global standard of care in the curative-intent setting of unresectable, Stage III non-small cell lung cancer (NSCLC) in patients whose disease has not progressed after chemoradiation therapy based on the PACIFIC Phase III trial.

Imfinzi is also approved in the US, EU, Japan, China and many other countries around the world for the treatment of extensive-stage small cell lung cancer (SCLC) based on the CASPIAN Phase III trial.

Additionally, Imfinzi is approved in combination with a short course of Imjudo (tremelimumab) and chemotherapy for the treatment of metastatic NSCLC in the US, EU and Japan based on the POSEIDON Phase III trial.

In addition to its indications in lung cancer, Imfinzi is also approved in combination withchemotherapy in locally advanced or metastatic biliary tract cancer in the US, EU, Japan and several other countries; in combination with Imjudo in unresectable hepatocellular carcinoma in the US, EU and Japan; and in previously treated patients with advanced bladder cancer in a small number of countries.

Since the first approval in May 2017, more than 150,000 patients have been treated with Imfinzi.

As part of a broad development programme, Imfinzi is being tested as a single treatment and in combinations with other anti-cancer treatments for patients with SCLC, NSCLC, bladder cancer, several gastrointestinal cancers, ovarian cancer, endometrial cancer and other solid tumours. 

Lynparza
Lynparza (olaparib) is a first-in-class PARP inhibitor and the first targeted treatment to block DNA damage response (DDR) in cells/tumours harbouring a deficiency in homologous recombination repair (HRR), such as those with mutations in BRCA1 and/or BRCA2, or those where deficiency is induced by other agents (such as new hormonal agents [NHAs]).

Inhibition of PARP with Lynparza leads to the trapping of PARP bound to DNA single-strand breaks, stalling of replication forks, their collapse and the generation of DNA double-strand breaks and cancer cell death.

Lynparza is currently approved in a number of countries across multiple tumour types including maintenance treatment of platinum-sensitive relapsed ovarian cancer and as both monotherapy and in combination with bevacizumab for the 1st-line maintenance treatment of BRCA-mutated (BRCAm) and homologous recombination deficiency (HRD)-positive advanced ovarian cancer, respectively; for germline BRCA-mutated (gBRCAm), HER2-negative metastatic breast cancer (in the EU and Japan this includes locally advanced breast cancer); for gBRCAm, HER2-negative high-risk early breast cancer (in Japan this includes all BRCAm HER2-negative high-risk early breast cancer); for gBRCAm metastatic pancreatic cancer; in combination with abiraterone for the treatment of metastatic castration-resistant prostate cancer (mCRPC) in whom chemotherapy is not clinically indicated (in the EU) and as monotherapy in HRR gene-mutated mCRPC in patients who have progressed on prior NHA treatment (BRCAm only in the EU and Japan).

In China, Lynparza is approved for the treatment of BRCA-mutated mCRPC, as a 1st-line maintenance therapy in BRCA-mutated advanced ovarian cancer as well as 1st-line maintenance treatment with bevacizumab for HRD-positive advanced ovarian cancer.

Lynparza, which is being jointly developed and commercialised by AstraZeneca and MSD, has been used to treat over 75,000 patients worldwide.

The companies develop Lynparza in combination with their respective PD-L1 and PD-1 medicines independently. Lynparza is the foundation of AstraZeneca’s industry-leading portfolio of potential new medicines targeting DDR mechanisms in cancer cells.”

https://www.astrazeneca.com/media-centre/press-releases/2023/lynparza-imfinzi-met-endpoint-in-ovarian-cancer.html

FDA Moves Forward with Mail-back Envelopes for Opioid Analgesics Dispensed in Outpatient Settings

admin
-
0
FDA Moves Forward with Mail-back Envelopes for Opioid Analgesics Dispensed in Outpatient Settings

April 03, 2023: “The U.S. FDA announced it is requiring manufacturers of opioid analgesics dispensed in outpatient settings to make prepaid mail-back envelopes available to outpatient pharmacies and other dispensers as an additional opioid analgesic disposal option for patients.

“Expanding impactful opioid disposal options, such as mail-back envelopes and in-home disposal, for patients to safely and securely dispose of their unused opioid medications is part of the agency’s comprehensive approach to addressing the overdose crisis,” said FDA Commissioner Robert M. Califf, M.D.

“We believe these efforts will not only increase convenient disposal options for many Americans, but also reduce unfortunate opportunities for nonmedical use, accidental exposure, overdose and potential new cases of opioid use disorder.

We’re pleased to take this first critical step to increase mail-back envelope options in partnership with the U.S. Postal Service.” 

The FDA issued notice today to all manufacturers of opioid analgesics used in outpatient settings that they are required to submit the proposed modification to the Opioid Analgesic Risk Evaluation and Mitigation Strategy (OA REMS) within 180 days of the date of the notification letter.

The agency anticipates approval of the modified REMS in 2024. When implemented, outpatient pharmacies and other dispensers will have the option to order prepaid mail-back envelopes from opioid analgesic manufacturers, which they may then provide to patients prescribed opioid analgesics.

The REMS modification also requires manufacturers to develop educational materials for patients on safe disposal of opioid analgesics, which outpatient pharmacies and other dispensers may also provide to patients. 

This action follows a Federal Register notice issued in April 2022 that sought public comment on a potential modification of the OA REMS to require that mail-back envelopes be dispensed and education on safe disposal be provided with opioid analgesics dispensed in an outpatient setting. 

Patients commonly report having unused opioid analgesics following surgical procedures and many Americans gain access to opioids through friends or relatives who have unused opioids.

Data show educating patients about disposal options may increase the disposal rate of unused opioids and that providing a disposal option along with education could further increase that rate. 

Currently, there are multiple mail-back envelope programs operating in the U.S. and mail-back envelopes are commercially available from multiple entities.

There are long-standing regulations and policies, under the Drug Enforcement Administration and United States Postal Service, in place to ensure that mail-back envelopes are nondescript, fit for purpose, and can safely and securely transport unused medicines from the patient’s home to the location where they will be destroyed.

“The U.S. Postal Service is proud to partner with the FDA to expand the use of mail-back envelopes as a safe and secure disposal option for prescription opioid analgesics,” said Postal Service Chief Customer and Marketing Officer and Executive Vice President Steven Monteith.

“Serving nearly 165 million addresses each day, with more than 31,000 retail locations across the country, the Postal Service makes it convenient for Americans to dispose of unused prescription drugs to help prevent accidental exposure and overdose.” 

The FDA continues to consider additional ways to increase safe disposal of unused opioid analgesics. Specifically, the agency is exploring whether manufacturers of opioid analgesic should also be required to make in-home disposal products available to patients who are prescribed opioid analgesics.

In an effort to further evaluate this potential option, the agency will participate in the workshop, Defining and Evaluating In-Home Drug Disposal Systems for Opioid Analgesics External Link Disclaimer, to examine current in-home disposal options hosted by the National Academies of Sciences, Engineering and Medicine’s (NASEM’s) Forum on Drug Discovery, Development, and Translation in June 2023.

The FDA has also issued a Federal Register Notice to seek information and comments from the public to aid the agency’s assessment of in-home disposal methods.

These collective efforts are part of the agency’s implementation of the FDA Overdose Prevention Framework that aims to prevent drug overdoses and reduce deaths through impactful and creative actions.

The FDA remains focused on responding to all facets of substance use, misuse, substance use disorders, overdose and death in the U.S. through the four priorities of the framework, including; supporting primary prevention by eliminating unnecessary initial prescription drug exposure and inappropriate prolonged prescribing; encouraging harm reduction through innovation and education; advancing development of evidence-based treatments for substance use disorders; and protecting the public from unapproved, diverted or counterfeit drugs presenting overdose risks.”

https://www.fda.gov/news-events/press-announcements/fda-moves-forward-mail-back-envelopes-opioid-analgesics-dispensed-outpatient-settings

Ultomiris recommended for approval in EU for neuromyelitis optica spectrum disorder

admin
-
0
Ultomiris recommended for approval in EU for neuromyelitis optica spectrum disorder

April 03, 2023: “Ultomiris (ravulizumab) has been recommended for marketing authorisation in the European Union (EU) for the treatment of adult patients with neuromyelitis optica spectrum disorder (NMOSD) who are anti-aquaporin-4 (AQP4) antibody positive (Ab+).

If authorised, Ultomiris would be the first and only approved long-acting C5 complement inhibitor for the treatment of AQP4 Ab+ NMOSD in the EU.

The Committee for Medicinal Products for Human Use (CHMP) of the European Medicines Agency based its positive opinion on results from the CHAMPION-NMOSD Phase III trial.

In the CHAMPION-NMOSD trial, Ultomiris was compared to an external placebo arm from the pivotal Soliris PREVENT clinical trial.

Ultomiris met the primary endpoint of time to first on-trial relapse as confirmed by an independent adjudication committee. Notably, data showed zero relapses were observed among Ultomiris patients with a median treatment duration of 73 weeks (relapse risk reduction: 98.6%, hazard ratio (95% CI): 0.014 (0.000, 0.103), p<0.0001), and continuing through a median duration of 90 weeks.

NMOSD is a rare and debilitating autoimmune disease that affects the central nervous system (CNS), including the spine and optic nerves.

Most people living with NMOSD experience unpredictable relapses, characterised by a new onset of neurologic symptoms or worsening of existing neurologic symptoms, which tend to be severe and recurrent and may result in permanent disability.

The diagnosed prevalence of adults with NMOSD in the EU is estimated at approximately 6,000.

Orhan Aktas, MD, Professor at the Department of Neurology, Medical Faculty at Heinrich-Heine-University, Düsseldorf, Germany, said: “Even one NMOSD relapse can lead to devastating long-term effects like vision loss, chronic pain and paralysis, which underscores the need for treatment innovations that help prevent relapses and optimise disease management.

The sustained relapse risk reduction observed in the CHAMPION-NMOSD Phase III trial supports the critical role this long-acting C5 complement inhibitor may have for the NMOSD community.”

Marc Dunoyer, Chief Executive Officer, Alexion, said: “Today’s positive opinion advances our commitment to transform outcomes for patients with rare neurological diseases and reflects the exceptional efficacy of C5 inhibition in reducing the risk of life-altering relapses in NMOSD. 

For patients with AQP4 Ab+ NMOSD, Ultomiris, the first and only long-acting C5 complement inhibitor, may have the potential to eliminate relapses, while also offering a convenient treatment schedule of infusions every eight weeks.

We look forward to the European Commission decision as we work to make Ultomiris available to people living with NMOSD in the EU and around the world.”

Overall, the safety and tolerability of Ultomiris were consistent with previous clinical studies and real-world use. No new safety signals were observed.

The most common adverse events (AEs) were COVID-19, headache, back pain, arthralgia and urinary tract infection. All cases of COVID-19 were non-serious and considered to be unrelated to Ultomiris.

Regulatory submissions for Ultomiris for the treatment of NMOSD are also currently under review with multiple health authorities, including in the United States (US) and Japan.

Notes

NMOSD
NMOSD is a rare disease in which the immune system is inappropriately activated to target healthy tissues and cells in the CNS.

Approximately three-quarters of people with NMOSD are anti-AQP4 Ab+, meaning they produce antibodies that bind to a specific protein, aquaporin-4 (AQP4).

This binding can inappropriately activate the complement system, which is part of the immune system and is essential to the body’s defence against infection, to destroy cells in the optic nerve, spinal cord and brain.

NMOSD most commonly affects women and begins in the mid-30s. Men and children may also develop NMOSD, but it is even more rare.

People with NMOSD may experience vision problems, intense pain, loss of bladder/bowel function, abnormal skin sensations (e.g., tingling, prickling or sensitivity to heat/cold) and impact on coordination and/or movement.

Most people living with NMOSD experience unpredictable relapses, also known as attacks. Each relapse can result in cumulative disability including vision loss, paralysis and sometimes premature death.

NMOSD is a distinct disease from other CNS diseases, including multiple sclerosis. The journey to diagnosis can be long, with the disease sometimes misdiagnosed.

CHAMPION-NMOSD
CHAMPION-NMOSD is a global Phase III, open-label, multicentre trial evaluating the safety and efficacy of Ultomiris in adults with NMOSD.

The trial enrolled 58 patients across North America, Europe, Asia-Pacific and Japan. Participants were required to have a confirmed NMOSD diagnosis with a positive anti-AQP4 antibody test, at least one attack or relapse in the twelve months prior to the screening visit, an Expanded Disability Status Scale Score of 7 or less and body weight of at least 40 kilograms at trial entry. Participants could stay on stable supportive immunosuppressive therapy for the duration of the trial.

Due to the potential long-term functional impact of NMOSD relapses and available effective treatment options, a direct placebo comparator arm was precluded for ethical reasons.

The active treatment was compared to an external placebo arm from the pivotal Soliris PREVENT clinical trial.

Over a median treatment duration of 73 weeks, all enrolled patients received a single weight-based loading dose of Ultomiris on Day 1, followed by regular weight-based maintenance dosing beginning on Day 15, every eight weeks.

The primary endpoint was time to first on-trial relapse, as confirmed by an independent adjudication committee.

The end of the primary treatment period could have occurred either when all patients completed or discontinued prior to the Week 26 visit and two or more adjudicated relapses were observed, or when all patients completed or discontinued prior to the Week 50 visit if fewer than two adjudicated relapses were observed.

In the trial, there were zero adjudicated relapses, so the end of the primary treatment period occurred when the last enrolled participant completed the 50-week visit.

Patients who completed the primary treatment period were eligible to continue into a long-term extension period, which is ongoing.

Ultomiris
Ultomiris (ravulizumab), the first and only long-acting C5 complement inhibitor, provides immediate, complete and sustained complement inhibition.

The medication works by inhibiting the C5 protein in the terminal complement cascade, a part of the body’s immune system. When activated in an uncontrolled manner, the complement cascade over-responds, leading the body to attack its own healthy cells. 

Ultomiris is administered intravenously every eight weeks in adult patients, following a loading dose.

Ultomiris is approved in the US, EU and Japan for the treatment of certain adults with generalised myasthenia gravis.

Ultomiris is also approved in the US, EU and Japan for the treatment of certain adults with paroxysmal nocturnal haemoglobinuria (PNH) and for certain children with PNH in the US and EU.

Additionally, Ultomiris is approved in the US, EU and Japan for certain adults and children with atypical haemolytic uraemic syndrome to inhibit complement-mediated thrombotic microangiopathy.

As part of a broad development programme, Ultomiris is being assessed for the treatment of additional haematology and neurology indications.

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/ultomiris-recommended-for-nmosd-eu-approval.html

1234...156Page 3 of 156

EDITOR PICKS

POPULAR POSTS

POPULAR CATEGORY

ABOUT US

LifeProNow provides guidance and high quality contents to help job seekers to get their dream Job. All the contents are written by experienced folks and peer reviewed by experts.

Contact us: [email protected]

FOLLOW US

© LifeProNow | All Rights Reserved