Jun 04, 2021: Novartis announced the first published mature overall survival (OS) and updated overall response rate (ORR) data following treatment with Tabrecta® (capmatinib) in adult patients with metastatic non-small cell lung cancer (NSCLC) whose tumors have a mutation that leads to MET exon 14 skipping.
Data from the ongoing, pivotal, multi-cohort Phase II GEOMETRY mono-1 study will be presented today during the 2021 Annual American Society of Clinical Oncology (ASCO) Virtual Scientific Meeting (Poster Discussion Session, Lung Cancer—Non-Small Cell Metastatic; June 4, 2021, 9:00 AM-10:00 AM CT; abstract 9020).
“This new analysis further supports Tabrecta as a cornerstone targeted treatment for METex14 NSCLC patients and highlights the importance of biomarker testing,” said Juergen Wolf, MD, from the Center for Integrated Oncology, University Hospital Cologne, and lead investigator of the GEOMETRY study.
“The impressive overall survival outcome and confirmed outstanding response in the first-line setting will help oncologists decide upon a therapeutic option for patients.”
The analysis includes new data from the treatment-naïve (1L) expansion cohort 7 and previously-treated (2L+) cohort 6, and mature data from previously-reported cohorts, for a total of 160 patients.
“The introduction of Tabrecta a year ago dramatically changed the treatment landscape for patients with METex14 NSCLC. Now we have further evidence that Tabrecta, the market-leading treatment specifically for METex14 NSCLC patients, has the potential to help people live longer,” said Jeff Legos, Senior Vice President, Head of Oncology Drug Development, Novartis Oncology.
The results presented today provide additional data on the efficacy of Tabrecta in both treatment-naïve and previously-treated patients with METex14 metastatic NSCLC :
Overall response rate (ORR) based on the Blinded Independent Review Committee (BIRC) assessment per RECIST v1.1:
67.9% (95% CI: 47.6, 84.1) and 65.6% (95% CI: 46.8, 81.4) among treatment-naïve patients (Cohort 5b; n= 28 and Cohort 7; n= 32 patients, respectively)
40.6% (95% CI: 28.9, 53.1) and 51.6% (95% CI: 33.1, 69.8) among previously-treated patients (Cohort 4; n= 69 and Cohort 6; n= 31 patients, respectively)
Median duration of response (DOR) based on BIRC assessment:
12.6 months (95% Cl: 5.6‑NE) and NE (95% CI: 5.5-NE) among treatment-naïve patients (Cohort 5b; n= 28 and Cohort 7; n= 32 patients, respectively)
9.7 months (95% Cl: 5.6‑13.0) and 8.4 months (95% Cl: 4.2‑NE) among previously-treated patients (Cohort 4; n= 69 and Cohort 6; n= 31 patients, respectively)
Overall survival (OS):
20.8 months (95% CI: 12.42, NE [not estimated]) among treatment-naïve patients (Cohort 5b; n= 28)
Median OS for expansion Cohorts 6 & 7 are not reached
No new safety signals or unexpected safety findings were observed. Ninety-eight percent of subjects had at least one adverse event (AE) of any grade and 50.9% of subjects had at least one serious adverse event (SAE).
Thirteen percent were suspected to be treatment-related.
The most common adverse events (>20%, all grades) across all cohorts were peripheral edema, nausea, vomiting, increased blood creatinine, dyspnea, fatigue and decreased appetite. The majority of AEs were grade 3 or 4.
Currently, the five-year survival rate for lung cancer is less than 20%, decreasing further when the disease is diagnosed at later stages.
Nearly one in three patients with metastatic NSCLC may have an actionable mutation.
METex14 has been reported to occur in 3%-4% of metastatic NSCLC cases.
Many patients with mutations that lead to METex14 are not diagnosed with NSCLC until their disease has progressed to later stages and often have poor prognosis.
A separate analysis of patient-reported outcomes (PROs) evaluated cough, delayed time to lung symptom deterioration, and quality of life (QoL) in NSCLC patients with METex14 (abstract 9056).
Median time to definitive deterioration (TTDD) in global health status (GHS) was 16.6 months (95% CI: 9.7, NE) and 12.4 months (95% CI: 4.2, 19.4) in 1L and 2L+ patients, respectively
Median TTDD for cough and chest pain was NE in both 1L and 2L+ patients, and for dyspnea was 19.4 months (95% CI: 12.4, NE) and 22.1 months (95% CI: 9.9, NE), respectively
An exploratory post hoc analysis evaluated QLQ-LC13 symptoms (cough, chest pain, and dyspnea) over time for patients achieving a clinical response, as assessed by BIRC, found these symptoms improved at all cycles in patients achieving clinical complete response (CR) or partial response, while symptom worsening was seen in those with no clinical response
Additionally, a retrospective analysis of GEOMETRY mono-1 validates the clinical utility of liquid biopsy testing to identify METex14 positive patients for treatment with Tabrecta (Poster Session: Lung Cancer—Non-Small Cell Metastatic; abstract 9111).”
June 04, 2021: Updated results from the positive PACIFIC Phase III trial showed AstraZeneca’s Imfinzi (durvalumab) demonstrated a sustained, clinically meaningful overall survival (OS) and progression-free survival (PFS) benefit at five years in patients with unresectable, Stage III non-small cell lung cancer (NSCLC) who had not progressed following concurrent chemoradiation therapy (CRT).
Lung cancer is the leading cause of cancer death accounting for about one-fifth of all cancer deaths, and 80-85% of patients with lung cancer have NSCLC.
One in four patients with NSCLC are diagnosed at Stage III, where the majority of tumours are unresectable (cannot be removed with surgery).
The approval of Imfinzi in this setting based on the results of this trial was the first new treatment to be available to these patients in decades.
Results from the updated post-hoc analyses showed an estimated five-year OS rate of 42.9% for patients treated with Imfinzi versus 33.4% for those on placebo after CRT. Median OS was 47.5 months for Imfinzi versus 29.1 for placebo.
Following a maximum treatment course of one year, an estimated 33.1% of patients treated with Imfinzi had not progressed five years after enrolment versus 19% for placebo.
These results build on the primary PFS and OS analyses published in The New England Journal of Medicine in 2017 and 2018, which demonstrated a sustained, significant benefit with Imfinzi for these primary endpoints.8,9
David Spigel, MD, Chief Scientific Officer at the Sarah Cannon Research Institute, and investigator in the PACIFIC trial, said: “This trial has once again set a new precedent in the treatment of patients with unresectable, Stage III non-small cell lung cancer.
Historically, only 15-30% of these patients survived five years but these results show that with up to one year of treatment with Imfinzi, an estimated 43% of patients are still alive at five years.
Moreover, three quarters of these patients had also not progressed in that time. This is a momentous achievement at the five-year landmark in this curative-intent setting.”
Dave Fredrickson, Executive Vice President, Oncology Business Unit, said: “Five-year survival is a clinically significant and emotionally meaningful milestone for people with cancer and their families, and it’s incredible to see the majority of patients surviving that long have not progressed four years after completing treatment.
These results – the first of their kind in Stage III unresectable lung cancer – reinforce the long-term benefit of Imfinzi as the established standard of care in this curative-intent setting.
With trials like PACIFIC and our comprehensive development programme in early-stage disease across cancer settings, our strategy is to improve cancer outcomes by treating patients as early as possible, aiming to deliver life-changing treatments that increase the potential for cure.”
In the primary OS analysis of the PACIFIC Phase III trial, the most common adverse events (AEs) (greater than or equal to 20%) among patients treated with Imfinzi versus placebo were cough (35.2% versus 25.2%), fatigue (24.0% versus 20.5%), dyspnoea (22.3% versus 23.9%) and radiation pneumonitis (20.2% versus 15.8%). A grade 3 or 4 AE was experienced by 30.5% of patients treated with Imfinzi versus 26.1% for placebo, and 15.4% of patients discontinued treatment due to AEs with Imfinzi versus 9.8% for placebo.9
These results were presented on 4 June during the 2021 American Society of Clinical Oncology (ASCO) Annual Meeting.
Imfinzi is approved in the curative-intent setting of unresectable, Stage III NSCLC after CRT in the US, Japan, China, across the EU and in many other countries. Since the first approval in February 2018, more than 80,000 patients in this setting have been treated with Imfinzi.
AstraZeneca has several ongoing registrational trials focused on testing Imfinzi in earlier stages of lung cancer, including in potentially curative settings (PACIFIC-2, 4 and 5, MERMAID-1 and 2, AEGEAN, ADJUVANT BR.31, and ADRIATIC Phase III trials).
The Company is also testing novel combinations with Imfinzi in two Phase II platform trials in the Stage III unresectable setting (COAST) and neoadjuvant early-stage setting (NeoCOAST).
Stage III NSCLC In 2020, an estimated 2.2 million people were diagnosed with lung cancer worldwide. Lung cancer is broadly split into NSCLC and small cell lung cancer, with 80-85% classified as NSCLC.
Stage III NSCLC represents approximately one quarter of NSCLC incidence.
Stage III (locally advanced) NSCLC is divided into three subcategories (IIIA, IIIB and IIIC), defined by how much the cancer has spread locally.
In contrast to Stage IV, when cancer has spread (metastasised), the majority of Stage III patients are currently treated with curative intent.5,10
PACIFIC The PACIFIC trial was a Phase III, randomised, double-blinded, placebo-controlled, multi-centre trial of Imfinzi as treatment in ‘all-comer’ patients (regardless of PD-L1 status) with unresectable, Stage III NSCLC whose disease had not progressed following concurrent platinum-based CRT.
The trial was conducted at 235 centres across 26 countries involving 713 patients. The primary endpoints of the trial were PFS and OS, and secondary endpoints included landmark PFS and OS, objective response rate and duration of response.
Imfinzi Imfinzi (durvalumab) is a human monoclonal antibody that binds to PD-L1 and blocks the interaction of PD-L1 with PD-1 and CD80, countering the tumour’s immune-evading tactics and releasing the inhibition of immune responses.
In addition to approvals in the unresectable, Stage III NSCLC setting, Imfinzi is approved for the treatment of extensive-stage small cell lung cancer (ES-SCLC) based on the CASPIAN Phase III trial in the EU, US, Japan and many other countries around the world.
Imfinzi is also approved for previously treated patients with advanced bladder cancer in several countries.
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 NSCLC, SCLC, bladder cancer, hepatocellular carcinoma, biliary tract cancer (a form of liver cancer), oesophageal cancer, gastric and gastroesophageal cancer, cervical cancer, ovarian cancer, endometrial cancer and other solid tumours.
AstraZeneca in lung cancer AstraZeneca is working to bring patients with lung cancer closer to cure through the detection and treatment of early-stage disease, while also pushing the boundaries of science to improve outcomes in resistant and advanced settings.
By defining new therapeutic targets and investigating innovative approaches, the Company aims to match medicines to the patients who can benefit most.
The Company’s comprehensive portfolio includes leading lung cancer medicines and the next wave of innovations including Tagrisso (osimertinib) and Iressa (gefitinib); Imfinzi (durvalumab) and tremelimumab; Enhertu (trastuzumab deruxtecan) and datopotamab deruxtecan in collaboration with Daiichi Sankyo; and savolitinib in collaboration with HUTCHMED; as well as a pipeline of new medicines and combinations across diverse mechanisms of action.
AstraZeneca is a founding member of the Lung Ambition Alliance, a global coalition working to accelerate innovation and deliver meaningful improvements for people with lung cancer including and beyond treatment.
AstraZeneca in immunotherapy Immunotherapy is a therapeutic approach designed to stimulate the body’s immune system to attack tumours.
The Company’s IO portfolio is anchored in immunotherapies that have been designed to overcome anti-tumour immune suppression.
AstraZeneca is invested in using IO approaches that deliver long-term survival for new groups of patients across tumour types.
The Company is pursuing a comprehensive clinical-trial programme that includes Imfinzi as a single treatment and in combination with tremelimumab and other novel antibodies in multiple tumour types, stages of disease, and lines of treatment, and where relevant using the PD-L1 biomarker as a decision-making tool to define the best potential treatment path for a patient.
In addition, the ability to combine the IO portfolio with radiation, chemotherapy, small, targeted molecules from across AstraZeneca’s oncology pipeline, and from research partners, may provide new treatment options across a broad range of tumours.
AstraZeneca in oncology AstraZeneca is leading a revolution in oncology with the ambition to provide cures for cancer in every form, following the science to understand cancer and all its complexities to discover, develop and deliver life-changing medicines to patients.
The Company’s focus is on some of the most challenging cancers.
It is through persistent innovation that AstraZeneca has built one of the most diverse portfolios and pipelines in the industry, with the potential to catalyse changes in the practice of medicine and transform the patient experience.
June 03, 2021:The following quote is attributed to Donald D. Ashley, J.D., Director of the Office of Compliance for FDA’s Center for Drug Evaluation and Research
“Ensuring the quality of prescription drugs and safeguarding the integrity of pharmaceutical distribution are crucial roles the FDA plays in protecting the health of the American public. Illegitimate and unsafe products must be kept out of the U.S. drug supply chain.
Since 2013, when the FDA began phasing in new requirements added by the Drug Supply Chain Security Act (DSCSA), we have helped create a supply chain that is better at preventing and detecting the introduction of illegitimate products.
The new requirements can also enable stakeholders and the FDA to respond rapidly when such products are found.
To help our stakeholders understand these requirements, we are issuing guidance documents intended to assist trading partners in complying with the law and achieving a safer, more secure and more trusted drug supply chain.
We are also soliciting feedback for further improving the way our drug supply chain operates within the DSCSA framework.
We view these guidance recommendations as an important part of implementing the robust enhanced system envisioned under DSCSA.
We look forward to continuing open conversations on DSCSA-related issues and providing future guidance to stakeholders as part of our efforts to protect American patients and the drug supply chain we all rely on.”
Additional Information
Today, the U.S. Food and Drug Administration is finalizing two guidance documents and making available two draft guidance documents to help ensure that prescription drugs are identified and traced properly as they move through the supply chain.
These guidance documents lay out the FDA’s recommendations for how to comply with applicable DSCSA requirements, including those for enhanced drug distribution security at the package level that go into effect in November 2023.
As part of the DSCSA, manufacturers and repackagers are required to put a product identifier on drug packages.
This includes the product national drug code (NDC), serial number, lot number and expiration date on each package and homogenous case of product, in human- and machine-readable form.
The machine-readable form is generally a two-dimensional data matrix barcode.
Industry questions are clarified in the final guidance, Product Identifiers Under the Drug Supply Chain Security Act, Questions and Answers.
Additionally, the final guidance Drug Supply Chain Security Act Implementation: Identification of Suspect Product and Notification is intended to aid certain trading partners in identifying a suspect product and specific scenarios that could significantly increase the risk of a suspect product entering the pharmaceutical distribution supply chain.
The guidance also describes how trading partners should notify the FDA of illegitimate product and sets forth a process for terminating notifications of illegitimate product in consultation with the FDA.
In addition, this guidance describes when manufacturers should notify the FDA of a high risk that a product is illegitimate.
This guidance responds to comments from stakeholders to clarify certain points and finalizes the remaining draft portion of the otherwise final guidance for industry, Drug Supply Chain Security Act Implementation: Identification of Suspect Product and Notification issued in December 2016.
The revised draft guidance, Definitions of Suspect Product and Illegitimate Product for Verification Obligation under DSCSA, lays out the FDA’s current understanding of terms used to define “suspect” and “illegitimate” products.
These include “counterfeit,” “diverted,” “stolen,” “fraudulent transaction” and “unfit for distribution.” In response to comments received from stakeholders, this draft guidance revises the March 2018 draft guidance.
The new draft guidance, Enhanced Drug Distribution Security at the Package Level under DSCSA, is intended to assist supply chain stakeholders, particularly trading partners, with requirements for enhanced drug distribution security at the package level that go into effect on November 27, 2023.
This guidance provides recommendations on the system attributes necessary for enabling the secure tracing of product at the package level.
Congress enacted the Drug Supply Chain Security Act on November 27, 2013. DSCSA outlines steps to build an electronic, interoperable system to identify and trace certain prescription drugs as they are distributed in the United States.
Additionally, DSCSA directs the FDA to establish national licensure standards for wholesale distributors and third-party logistics providers and requires these entities to report licensure and other information to the FDA annually.”
June 03,2021: AstraZeneca and Merck announced the first presentation of data from the Phase 3 OlympiA trial, in which LYNPARZA demonstrated a statistically significant improvement in its primary endpoint of invasive disease-free survival (iDFS) versus placebo in the adjuvant treatment of patients with germline BRCA1/2 mutations and high-risk human epidermal growth factor receptor 2 (HER2)-negative early breast cancer following definitive local treatment and neoadjuvant or adjuvant chemotherapy.
Results will be presented during the Plenary Session at the 2021 American Society of Clinical Oncology (ASCO) Annual Meeting on June 6 (Abstract LBA#1). Results were also published today in the New England Journal of Medicine.
An estimated 2.3 million people were diagnosed with breast cancer worldwide in 2020, and germline BRCA mutations are found in approximately 5% of patients with breast cancer.
OlympiA is a Phase 3, multicenter, randomized, double-blind, placebo-controlled trial. In the overall trial population of 1,836 patients, results showed LYNPARZA (n=921) reduced the risk of invasive breast cancer recurrences, second cancers or death by 42% (HR=0.58 [99.5% CI, 0.41-0.82]; p<0.0001) versus placebo (n=915) based on a pre-specified event-driven interim analysis with a median follow-up of 2.5 years.
At three years following trial initiation, 85.9% of patients treated with LYNPARZA were alive and free of invasive breast cancer and second cancers versus 77.1% of patients treated with placebo (difference: 8.8% [95% CI, 4.5-13.0]).
Results also showed an improvement in the key secondary endpoint of distant disease-free survival (DDFS) in the overall trial population. LYNPARZA reduced the risk of distant disease recurrence or death by 43% (HR=0.57 [99.5% CI, 0.39-0.83]; p<0.0001).
At the time of data cut-off, overall survival (OS) data, while directionally encouraging, did not reach statistical significance and were not mature. The trial will continue to assess OS as a secondary endpoint.
The safety and tolerability profile of LYNPARZA in this trial was in line with that observed in prior clinical trials.
The most common adverse events (AEs) (≥20%) were nausea (57%), fatigue (40%), anemia (23%) and vomiting (23%). Grade ≥3 AEs were anemia (9%), neutropenia (5%), leukopenia (3%), fatigue (2%) and nausea (1%).
Approximately 10% of patients treated with LYNPARZA discontinued treatment due to AEs.
Andrew Tutt, chair of the OlympiA trial steering committee and professor of oncology, The Institute of Cancer Research, London, and Kings College London, said, “We are thrilled that our global academic and industry partnership in OlympiA has been able to help identify a possible new treatment option for patients with early-stage breast cancer and who have inherited mutations in their BRCA1 or BRCA2 genes.
Patients with early-stage breast cancer who have inherited BRCA mutations are typically diagnosed at a younger age compared to those without such a mutation.
Olaparib has the potential to be used as a follow-on to all the standard initial breast cancer treatments to reduce the rate of life-threatening recurrence and cancer spread for many patients identified through genetic testing to have mutations in these genes.”
Dave Fredrickson, executive vice president, oncology business unit, AstraZeneca, said, “By providing a treatment which significantly reduces the risk of breast cancer returning in these high-risk patients, we hope LYNPARZAwill set a new benchmark. We are working with regulatory authorities to bring LYNPARZAto these patients as quickly as possible.”
Dr. Roy Baynes, senior vice president and head of global clinical development, chief medical officer, Merck Research Laboratories, said, “Results of the OlympiA trial represent a potential step forward for patients with high-risk early breast cancer. These new data support the importance of testing at diagnosisfor BRCA1/2 mutations, which are actionable biomarkers that can help identify patients with early breast cancer who may be eligible for adjuvant treatment with LYNPARZA. Testing for BRCA mutations, in addition to hormone receptor status and the expression of the HER2 protein, will allow clinicians to better inform potential treatment plans for their patients.”
In February 2021, the Independent Data Monitoring Committee (IDMC) recommended for the OlympiA trial to move to early primary analysis and reporting. Based on the planned interim analysis, the IDMC concluded that the trial crossed the superiority boundary for its primary endpoint of iDFS.
Summary of OlympiA Results
LYNPARZA (n=921)
Placebo (n=915)
iDFS (primary endpoint)
HR (99.5% CI)
0.58 (0.41, 0.82)
p-value
p<0.0001
Events
106
178
iDFS ratesiii
One year
93.3%
88.4%
Two years
89.2%
81.5%
Three years
85.9%
77.1%
DDFS (secondary endpoint)
HR (99.5% CI)
0.57 (0.39, 0.83)
p-value
p<0.0001
Events
89
152
DDFS ratesiii
One year
94.3%
90.2%
Two years
90.0%
83.9%
Three years
87.5%
80.4%
OS at interim (secondary endpoint)ii
HR (99% CI)
0.68 (0.44, 1.05)
p-value
p=0.024
Events
59
86
OS ratesiii
One year
98.1%
96.9%
Two years
94.8%
92.3%
Three years
92.0%
88.3%
i
The data cut-off date for the interim analysis was March 27, 2020.
ii
Statistical significance was not reached based on the interim analysis plan for alpha conservation for future survival analyses.
iii
The study was not designed to assess a statistical difference between treatment groups at these timepoints.
OlympiA is a global, collaborative, Phase 3 trial coordinated by the Breast International Group (BIG) worldwide, in partnership with NRG Oncology, the U.S. National Cancer Institute (NCI), Frontier Science & Technology Research Foundation (FSTRF), AstraZeneca and Merck. The trial is sponsored by NRG Oncology in the U.S. and by AstraZeneca outside the U.S.
LYNPARZA is approved in the U.S., Japan and a number of other countries for germline BRCA-mutated, HER2-negative metastatic breast cancer previously treated with chemotherapy and, if hormone receptor-positive, endocrine therapy if appropriate. In the EU, this includes locally advanced breast cancer.
IMPORTANT SAFETY INFORMATION
CONTRAINDICATIONS
There are no contraindications for LYNPARZA.
WARNINGS AND PRECAUTIONS
Myelodysplastic Syndrome/Acute Myeloid Leukemia (MDS/AML): Occurred in approximately 1.5% of patients exposed to LYNPARZA monotherapy, and the majority of events had a fatal outcome. The median duration of therapy in patients who developed MDS/AML was 2 years (range: <6 months to >10 years). All of these patients had previous chemotherapy with platinum agents and/or other DNA-damaging agents, including radiotherapy.
Do not start LYNPARZA until patients have recovered from hematological toxicity caused by previous chemotherapy (≤Grade 1). Monitor complete blood count for cytopenia at baseline and monthly thereafter for clinically significant changes during treatment. For prolonged hematological toxicities, interrupt LYNPARZA and monitor blood count weekly until recovery.
If the levels have not recovered to Grade 1 or less after 4 weeks, refer the patient to a hematologist for further investigations, including bone marrow analysis and blood sample for cytogenetics. Discontinue LYNPARZA if MDS/AML is confirmed.
Pneumonitis: Occurred in 0.8% of patients exposed to LYNPARZA monotherapy, and some cases were fatal. If patients present with new or worsening respiratory symptoms such as dyspnea, cough, and fever, or a radiological abnormality occurs, interrupt LYNPARZA treatment and initiate prompt investigation. Discontinue LYNPARZA if pneumonitis is confirmed and treat patient appropriately.
Embryo-Fetal Toxicity: Based on its mechanism of action and findings in animals, LYNPARZA can cause fetal harm. A pregnancy test is recommended for females of reproductive potential prior to initiating treatment.
Females
Advise females of reproductive potential of the potential risk to a fetus and to use effective contraception during treatment and for 6 months following the last dose.
Males
Advise male patients with female partners of reproductive potential or who are pregnant to use effective contraception during treatment and for 3 months following the last dose of LYNPARZA and to not donate sperm during this time.
Venous Thromboembolic Events: Including pulmonary embolism, occurred in 7% of patients with metastatic castration-resistant prostate cancer who received LYNPARZA plus androgen deprivation therapy (ADT) compared to 3.1% of patients receiving enzalutamide or abiraterone plus ADT in the PROfound study. Patients receiving LYNPARZA and ADT had a 6% incidence of pulmonary embolism compared to 0.8% of patients treated with ADT plus either enzalutamide or abiraterone. Monitor patients for signs and symptoms of venous thrombosis and pulmonary embolism, and treat as medically appropriate, which may include long-term anticoagulation as clinically indicated.
ADVERSE REACTIONS—First-Line Maintenance BRCAm Advanced Ovarian Cancer
Most common adverse reactions (Grades 1-4) in ≥10% of patients in clinical trials of LYNPARZA in the first-line maintenance setting for SOLO-1 were: nausea (77%), fatigue (67%), abdominal pain (45%), vomiting (40%), anemia (38%), diarrhea (37%), constipation (28%), upper respiratory tract infection/influenza/ nasopharyngitis/bronchitis (28%), dysgeusia (26%), decreased appetite (20%), dizziness (20%), neutropenia (17%), dyspepsia (17%), dyspnea (15%), leukopenia (13%), UTI (13%), thrombocytopenia (11%), and stomatitis (11%).
Most common laboratory abnormalities (Grades 1-4) in ≥25% of patients in clinical trials of LYNPARZA in the first-line maintenance setting for SOLO-1 were: decrease in hemoglobin (87%), increase in mean corpuscular volume (87%), decrease in leukocytes (70%), decrease in lymphocytes (67%), decrease in absolute neutrophil count (51%), decrease in platelets (35%), and increase in serum creatinine (34%).
ADVERSE REACTIONS—First-Line Maintenance Advanced Ovarian Cancer in Combination with Bevacizumab
Most common adverse reactions (Grades 1-4) in ≥10% of patients treated with LYNPARZA/bevacizumab compared to a ≥5% frequency for placebo/bevacizumab in the first-line maintenance setting for PAOLA-1 were: nausea (53%), fatigue (including asthenia) (53%), anemia (41%), lymphopenia (24%), vomiting (22%) and leukopenia (18%). In addition, the most common adverse reactions (≥10%) for patients receiving LYNPARZA/bevacizumab irrespective of the frequency compared with the placebo/bevacizumab arm were: diarrhea (18%), neutropenia (18%), urinary tract infection (15%) and headache (14%).
In addition, venous thromboembolic events occurred more commonly in patients receiving LYNPARZA/bevacizumab (5%) than in those receiving placebo/bevacizumab (1.9%).
Most common laboratory abnormalities (Grades 1-4) in ≥25% of patients for LYNPARZA in combination with bevacizumab in the first-line maintenance setting for PAOLA-1 were: decrease in hemoglobin (79%), decrease in lymphocytes (63%), increase in serum creatinine (61%), decrease in leukocytes (59%), decrease in absolute neutrophil count (35%) and decrease in platelets (35%).
ADVERSE REACTIONS—Maintenance Recurrent Ovarian Cancer
Most common adverse reactions (Grades 1-4) in ≥20% of patients in clinical trials of LYNPARZA in the maintenance setting for SOLO-2 were: nausea (76%), fatigue (including asthenia) (66%), anemia (44%), vomiting (37%), nasopharyngitis/upper respiratory tract infection (URI)/influenza (36%), diarrhea (33%), arthralgia/myalgia (30%), dysgeusia (27%), headache (26%), decreased appetite (22%), and stomatitis (20%).
Most common laboratory abnormalities (Grades 1-4) in ≥25% of patients in clinical trials of LYNPARZA in the maintenance setting (SOLO-2/Study 19) were: increase in mean corpuscular volume (89%/82%), decrease in hemoglobin (83%/82%), decrease in leukocytes (69%/58%), decrease in lymphocytes (67%/52%), decrease in absolute neutrophil count (51%/47%), increase in serum creatinine (44%/45%), and decrease in platelets (42%/36%).
ADVERSE REACTIONS—Advanced gBRCAm Ovarian Cancer
Most common adverse reactions (Grades 1-4) in ≥20% of patients in clinical trials of LYNPARZA for advanced gBRCAm ovarian cancer after 3 or more lines of chemotherapy (pooled from 6 studies) were: fatigue/asthenia (66%), nausea (64%), vomiting (43%), anemia (34%), diarrhea (31%), nasopharyngitis/upper respiratory tract infection (URI) (26%), dyspepsia (25%), myalgia (22%), decreased appetite (22%), and arthralgia/musculoskeletal pain (21%).
Most common laboratory abnormalities (Grades 1-4) in ≥25% of patients in clinical trials of LYNPARZA for advanced gBRCAm ovarian cancer (pooled from 6 studies) were: decrease in hemoglobin (90%), mean corpuscular volume elevation (57%), decrease in lymphocytes (56%), increase in serum creatinine (30%), decrease in platelets (30%), and decrease in absolute neutrophil count (25%).
ADVERSE REACTIONS—gBRCAm, HER2-Negative Metastatic Breast Cancer
Most common adverse reactions (Grades 1-4) in ≥20% of patients in OlympiAD were: nausea (58%), anemia (40%), fatigue (including asthenia) (37%), vomiting (30%), neutropenia (27%), respiratory tract infection (27%), leukopenia (25%), diarrhea (21%), and headache (20%).
Most common laboratory abnormalities (Grades 1-4) in >25% of patients in OlympiAD were: decrease in hemoglobin (82%), decrease in lymphocytes (73%), decrease in leukocytes (71%), increase in mean corpuscular volume (71%), decrease in absolute neutrophil count (46%), and decrease in platelets (33%).
Most common adverse reactions (Grades 1-4) in ≥10% of patients in clinical trials of LYNPARZA in the first-line maintenance setting for POLO were: fatigue (60%), nausea (45%), abdominal pain (34%), diarrhea (29%), anemia (27%), decreased appetite (25%), constipation (23%), vomiting (20%), back pain (19%), arthralgia (15%), rash (15%), thrombocytopenia (14%), dyspnea (13%), neutropenia (12%), nasopharyngitis (12%), dysgeusia (11%), and stomatitis (10%).
Most common laboratory abnormalities (Grades 1-4) in ≥25% of patients in clinical trials of LYNPARZA in the first-line maintenance setting for POLO were: increase in serum creatinine (99%), decrease in hemoglobin (86%), increase in mean corpuscular volume (71%), decrease in lymphocytes (61%), decrease in platelets (56%), decrease in leukocytes (50%), and decrease in absolute neutrophil count (25%).
ADVERSE REACTIONS—HRR Gene-mutated Metastatic Castration Resistant Prostate Cancer
Most common adverse reactions (Grades 1-4) in ≥10% of patients in clinical trials of LYNPARZA for PROfound were: anemia (46%), fatigue (including asthenia) (41%), nausea (41%), decreased appetite (30%), diarrhea (21%), vomiting (18%), thrombocytopenia (12%), cough (11%), and dyspnea (10%).
Most common laboratory abnormalities (Grades 1-4) in ≥25% of patients in clinical trials of LYNPARZA for PROfound were: decrease in hemoglobin (98%), decrease in lymphocytes (62%), decrease in leukocytes (53%), and decrease in absolute neutrophil count (34%).
DRUG INTERACTIONS
Anticancer Agents: Clinical studies of LYNPARZA with other myelosuppressive anticancer agents, including DNA-damaging agents, indicate a potentiation and prolongation of myelosuppressive toxicity.
CYP3A Inhibitors: Avoid coadministration of strong or moderate CYP3A inhibitors when using LYNPARZA. If a strong or moderate CYP3A inhibitor must be coadministered, reduce the dose of LYNPARZA. Advise patients to avoid grapefruit, grapefruit juice, Seville oranges, and Seville orange juice during LYNPARZA treatment.
CYP3A Inducers: Avoid coadministration of strong or moderate CYP3A inducers when using LYNPARZA.
USE IN SPECIFIC POPULATIONS
Lactation: No data are available regarding the presence of olaparib in human milk, its effects on the breastfed infant or on milk production. Because of the potential for serious adverse reactions in the breastfed infant, advise a lactating woman not to breastfeed during treatment with LYNPARZA and for 1 month after receiving the final dose.
Pediatric Use: The safety and efficacy of LYNPARZA have not been established in pediatric patients.
Hepatic Impairment: No adjustment to the starting dose is required in patients with mild or moderate hepatic impairment (Child-Pugh classification A and B). There are no data in patients with severe hepatic impairment (Child-Pugh classification C).
Renal Impairment: No dosage modification is recommended in patients with mild renal impairment (CLcr 51-80 mL/min estimated by Cockcroft-Gault). In patients with moderate renal impairment (CLcr 31-50 mL/min), reduce the dose of LYNPARZA to 200 mg twice daily. There are no data in patients with severe renal impairment or end-stage renal disease (CLcr ≤30 mL/min).
INDICATIONS in the United States
LYNPARZA is a poly (ADP-ribose) polymerase (PARP) inhibitor indicated:
First-Line Maintenance BRCAm Advanced Ovarian Cancer
For the maintenance treatment of adult patients with deleterious or suspected deleterious germline or somatic BRCA-mutated (gBRCAm or sBRCAm) advanced epithelial ovarian, fallopian tube or primary peritoneal cancer who are in complete or partial response to first-line platinum-based chemotherapy. Select patients for therapy based on an FDA-approved companion diagnostic for LYNPARZA.
First-Line Maintenance HRD-Positive Advanced Ovarian Cancer in Combination with Bevacizumab
In combination with bevacizumab for the maintenance treatment of adult patients with advanced epithelial ovarian, fallopian tube or primary peritoneal cancer who are in complete or partial response to first-line platinum-based chemotherapy and whose cancer is associated with homologous recombination deficiency (HRD) positive status defined by either:
a deleterious or suspected deleterious BRCA mutation and/or
genomic instability
Select patients for therapy based on an FDA-approved companion diagnostic for LYNPARZA.
Maintenance Recurrent Ovarian Cancer
For the maintenance treatment of adult patients with recurrent epithelial ovarian, fallopian tube or primary peritoneal cancer, who are in complete or partial response to platinum-based chemotherapy.
Advanced gBRCAm Ovarian Cancer
For the treatment of adult patients with deleterious or suspected deleterious germline BRCA-mutated (gBRCAm) advanced ovarian cancer who have been treated with 3 or more prior lines of chemotherapy. Select patients for therapy based on an FDA-approved companion diagnostic for LYNPARZA.
gBRCAm HER2-Negative Metastatic Breast Cancer
For the treatment of adult patients with deleterious or suspected deleterious gBRCAm, human epidermal growth factor receptor 2 (HER2)-negative metastatic breast cancer, who have been treated with chemotherapy in the neoadjuvant, adjuvant or metastatic setting. Patients with hormone receptor (HR)-positive breast cancer should have been treated with a prior endocrine therapy or be considered inappropriate for endocrine therapy. Select patients for therapy based on an FDA-approved companion diagnostic for LYNPARZA.
First-Line Maintenance gBRCAm Metastatic Pancreatic Cancer
For the maintenance treatment of adult patients with deleterious or suspected deleterious gBRCAm metastatic pancreatic adenocarcinoma whose disease has not progressed on at least 16 weeks of a first-line platinum-based chemotherapy regimen. Select patients for therapy based on an FDA-approved companion diagnostic for LYNPARZA.
HRR Gene-mutated Metastatic Castration Resistant Prostate Cancer
For the treatment of adult patients with deleterious or suspected deleterious germline or somatic homologous recombination repair (HRR) gene-mutated metastatic castration-resistant prostate cancer (mCRPC) who have progressed following prior treatment with enzalutamide or abiraterone.”
June 03 2021: “As part of a long-standing commitment to reduce the environmental footprint of the company’s products and activities, Sanofi launched a €3 million Planet Mobilization fund to support employee ideas and projects that will further contribute to a healthier environment.
This year, three Sanofi teams will have their projects funded.
For several years, Sanofi has been implementing a global environmental roadmap, Planet Mobilization, which is embedded in Sanofi’s long-term strategy.
The program covers all Sanofi activities and sites and the entire lifecycle of products, from raw materials used in production all the way to their disposal.
“Because the fight against climate change is also a fight for the health and well-being, Sanofi commits to Planet Mobilization” says Philippe Luscan, Executive Vice President, Global Industrial Affairs.
“We strongly believe our employees are the most powerful agents of positive change for people, and for the planet.
It’s with this ambition and objectives in mind that we decided to create a fund of €3 million to finance ideas and projects coming from our employees in support of our environmental ambition.
Today, it is fair to say that teams all over the world took up the challenge, even beyond our expectations.That’s collective intelligence in motion.”
An EntrepreneurialProgram to Support Employee Ideas This year, more than 500 employees from 63 sites in 29 countries participated in the company’s environmental sustainability ideation program.
A full program of bootcamps, hack-a-thons, and design thinking workshops led by Sanofi’s Innovation Lab helped the teams turn their ideas into sustainable projects.
Three winning projects were selected this inaugural year. The projects will be implemented and financed by Sanofi’s Planet Mobilization fund:
Vietnam: “Rice is the New Green” is a project from Sanofi’s Hô Chi Minh team to implement the first green and circular large-scale rice husk biomass.
Rice husk is a byproduct of paddy processing in the rice mills and can provide a convenient and environmentally sustainable, convenient source of dry biomass energy.
This will allow Sanofi’s Hô Chi Minh site to become a fossil fuel free site, eliminating 2.3 thousand tons of carbon dioxide a year and reduce steam costs by 40%.
Europe: “IDRA” is a project from three country sites in Europe, including Anagni, Italy; Compiègne, France; and Geel, Belgium.
The project aims at recycling treated wastewater from the sites to be directly reused on site. The three pilot plants could save up to 220 million liters of water per year. This is the equivalent of filling nearly 70 Olympic pools.
Ireland: “Waterford Loves Planet Not Plastic” is an education project to help reduce plastic waste.
Through information via school programs, nature restoration programs such as coastal clean-ups, and an app measuring plastic waste and incentivizing reduced consumption, Sanofi Ireland ‘ambassadors’ will contribute to their communities more balanced use of plastic and the management of its waste.
Sanofi Aims for Carbon Neutrality Sanofi has committed to reduce its greenhouse gas emissions by 55% by 2030 in line with limiting global warming to 1.5°C and is aiming for carbon neutrality by 2050.
The new carbon reduction objectives are validated by the Science Based Target initiative, a partnership between Carbon Disclosure Project, the United Nations Global Compact, World Resources Institute, and WWF.
To that order and to minimize the potential direct and indirect impacts of its business on the environment throughout the whole lifecycle of its products, the company intends to:
protect ecosystems by introducing biodiversity protection plans at all its sites located near sensitive areas by 2025;
implement water stewardship and water efficiency plans on 100% of its manufacturing sites by 2030;
foster eco-design for all its new products and packaging by 2025 and for its top-selling products by 2030, and remove all pre-formed plastic packaging (blister packs) for its vaccines by 2027;
reduce, recycle, and recover more than 90% of its waste by 2025;
use 100% renewable electricity across its operations and target a carbon-neutral car fleet, both by 2030; and
prevent any impact of its medicines on the environment across 100% of its manufacturing sites by 2025.
Sanofi also supports and works with its suppliers all over the world to reduce their greenhouse gas emissions and environmental impact to create more sustainable sourcing of raw materials.
To date, the company has already notably:
reduced GHG emission from its activities by 27% since 2015;
designed a new entirely recyclable cardboard packaging for vaccines, which replaces aluminum and PVC blisters;
reused, recycled, or recovered 73% of its waste; and
reduced by 22% its water withdrawal from 2015 to 2020.”
June 3, 2021: Novartis reported the final analysis from the NETTER-1 phase III study comparing treatment using Lutathera® (INN: lutetium (177Lu) oxodotreotide / USAN: lutetium Lu 177 dotatate) plus 30 mg octreotide LAR to 60 mg of octreotide LAR in patients with midgut neuroendocrine tumors.
The previously reported primary analysis of the trial demonstrated a statistically significant improvement in progression free survival (PFS) (HR: 0.18*, p < 0.0001).
In the final analysis of overall survival, a secondary objective of the trial, treatment with Lutathera resulted in a clinically relevant prolongation in median overall survival of 11.7 months [48.0 months (95%CI: 37.4-55.2) compared to the control arm (36.3 months (95%CI: 25.9-51.7)].
While this analysis did not reach statistical significance (Hazard ratio for OS (HR): 0.84 with 95% CI: (0.60, 1.17) (p=0.30, two-sided)), the analyses of overall survival may have been impacted by multiple factors, including the crossover of patients from the control arm receiving subsequent radioligand therapy (36% of patients) as well as heterogenous subsequent anti-cancer treatments in both study arms.
No new safety signals emerged in the final analysis1. These results will be presented during the 2021 American Society of Clinical Oncology (ASCO) Annual Meeting on June 4.
Jonathan Strosberg, MD, Principal Investigator and Associate Professor, Section Head, Neuroendocrine Tumor Program at Moffitt Cancer Center, said, “Lutathera plus long-acting octreotide was associated with a nearly 12-month difference in median overall survival compared to high-dose long-acting octreotide in these difficult to treat patients with inoperable midgut NETs progressing under standard dose octreotide LAR treatment. While not statistically significant, I consider this difference to be clinically relevant for these patients. It is also important to emphasize that PFS was the primary endpoint of this study.
Moreover, 36% of patients in the control arm crossed over to receive subsequent radioligand treatment, which may have impacted the comparison of survival between both study arms.”
“We are proud of our 30-year legacy as an innovator for patients in the neuroendocrine tumor community,” said John Tsai, Head of Global Drug Development and Chief Medical Officer for Novartis.
“Since its approval by the European Commission in 2017 and the FDA in 2018, Lutathera has been administered to more than 9,000 gastroenteropancreatic neuroendocrine tumor (GEP-NET) patients in Europe and the United States.
We believe in the potential of targeted radioligand therapy and are investing in new discovery and expansion of this important platform, including exploration of new radioisotopes and combinations with complementary mechanisms of action, such as immunotherapy and inhibitors of DNA damage response.”
At this final analysis, no new safety signals emerged in the long-term safety follow-up with a median of 6.3 years.
In terms of secondary hematological malignancies, no new cases of MDS or acute leukemia were reported in the long term follow up.
Radioligand therapy combines a targeting compound that binds to receptors expressed by tumors and a radioactive isotope, causing DNA damage that inhibits tumor growth and replication and may lead to cell death.
In the case of Lutathera, it binds to somatostatin receptor type 2, which is over-expressed on certain types of cells, such as gastroenteropancreatic neuroendocrine tumor cells.
Novartis has established global expertise and specialized supply chain and manufacturing capabilities across its network of four radioligand therapy production sites, and is further increasing capacity to ensure delivery of future targeted radioligand therapies to patients in need.
Novartis is the only pharmaceutical company which is pursuing four different cancer treatment platforms.
These include targeted radioligand therapy, cell and gene therapy, targeted therapy and immunotherapy, with an opportunity to combine these platforms for the best outcomes for each cancer patient.
June 2, 2021: The Janssen Pharmaceutical Companies of Johnson & Johnson announced new efficacy and safety data for first-in-class TREMFYA® (guselkumab), including data from the first study evaluating a selective IL-23 inhibitor in adult patients with active PsA, all of whom had demonstrated inadequate response or intolerance to TNFi.
In the COSMOS Phase 3b study, significantly higher proportions of patients treated with TREMFYA showed joint symptom improvement and complete skin clearance versus placebo at week 24 in this true TNFi-IRa patient population, which is often more difficult to treat.1,2
These results are among the 34 scientific abstracts Janssen is presenting from the Company’s rheumatology portfolio at the EULAR E-Congress, many of which feature TREMFYA, the only selective IL-23 inhibitor therapy approved in the U.S. to treat both adults with moderate to severe plaque psoriasis (PsO) who are candidates for systemic therapy or phototherapy, as well as adults with active PsA.
PsA is a chronic, progressive, immune-mediated disease characterized by pain, stiffness, and swelling in and around both peripheral and axial joints as well as itch and discomfort from skin lesions.
People living with PsA can also suffer from sleep disorders, fatigue, stress, and depression.
Janssen data shared at EULAR show the severity of skin and joint symptoms of active PsA was significantly associated with a higher loss of work productivity and impact on daily activity outside of work.
“The diverse manifestations, varying natural history, and potential severity of PsA mean that delivering treatments that are safe and have long-term effectiveness is challenging. A number of patients do not reach treatment targets of remission or low inflammation with available therapies.
In particular, patients may either not respond well to TNFi, or respond but have a loss of response over time,” said study investigator Laure Gossec, M.D., Ph.D., Professor of Rheumatology in Pitie-Salpetriere Hospital and Pierre & Marie Curie University in Paris, France.b
“These COSMOS data reinforce TREMFYA as a therapeutic option with an alternative mechanism of action for adult patients with PsA when their disease management is complex because they have not responded to one or more therapies.”
COSMOS (Presentation #OP0230) results show:
Robust Joint Symptom Improvement: 44.4 percent of patients who received TREMFYA vs. 19.8 percent of patients who received placebo achieved at least 20 percent improvement in the American College of Rheumatology criteria (ACR20)c at week 24, the study’s primary endpoint.
ACR20 response rates increased at one year (57.7 percent of TREMFYA patients at week 48 utilizing non-responder imputation [NRI]; with this method of analysis, patients with missing data were considered non-responders).
TREMFYA was also superior to placebo in percentage of patients achieving ACR50 and improvement in physical function (Health Assessment Questionnaire Disability Index [HAQ-DI])d and general health outcomes (Short Form [SF]-36 and Physical Component Summary [PCS] scores).
Mean improvement in physical function increased at one year, with higher resolution rates of enthesitis and dactylitis seen as well (soft tissue inflammation measured by the Leeds Enthesitis Index [LEI]f and Dactylitis Severity Score [DSS], respectively).
Complete Skin Clearance: At week 24, the proportion of patients with ≥3 percent body surface area psoriatic involvement and an Investigator’s Global Assessment (IGA)g score ≥2 at baseline achieving complete skin clearance (100 percent improvement in Psoriasis Area Severity Index [PASI])h was significantly higher among those receiving TREMFYA than those receiving placebo (30.8 percent vs. 3.8 percent).
At one year (week 48), PASI 100 response rates increased to 53.4 percent of patients receiving TREMFYA (utilizing NRI).
TREMFYA efficacy and safety findings across additional abstracts (presentation numbers cited within) are also being presented:
Rapid and Durable Joint Symptom Improvement and Complete Skin Clearance:
In the DISCOVER-2 PsA trial, the robust response rates seen at week 24 for joint symptoms (ACR20/50/70), skin clearance (PASI 90/100), improved physical function (HAQ-DI), and enthesitis and dactylitis resolution persisted through two years, even when long-term response rates were conservatively estimated using NRI.
88 percent of patients who received TREMFYA (652/739) completed week 100 of the study, with low rates of radiographic progression of joint structural damage observed from week 52-100 (POS1027).
In DISCOVER-1 and -2, TREMFYA demonstrated meaningful improvements in individual components of the ACR criteria as early as week four.
At early study time points, both patients and physicians were able to discern improvements in signs and symptoms of arthritis that rapidly followed (within one assessment) reductions in systemic inflammation based on C-reactive protein levels (AB0525).
In a post-hoc analysis of pooled data from DISCOVER -1 and -2 patients with axial symptoms and imaging-confirmed sacroiliitis, TREMFYA resulted in numerically lower mean scores for all six Bath Ankylosing Spondylitis Disease Activity Index (BASDAI)j components compared with placebo as early as week eight and through week 24, with mean scores maintained at week 52 using NRI (AB0524).
Established Safety Profile:
Pooled data from the active PsA trials, DISCOVER-1 and -2, and the PsO trials, VOYAGE 1 and 2, showed the TREMFYA safety profile was generally consistent between patients with PsA and PsO through one year.
Decreased neutrophil counts and elevations in hepatic transaminases – generally mild, transient and without sequalae – were somewhat more common in PsA than PsO patients (AB0528).
Through one year of follow-up with TREMFYA treatment in pooled DISCOVER-1 and -2 and VOYAGE 1 and 2 data, gastrointestinal-related serious adverse event (SAE) rates were low.
There were no reported cases of uveitis, opportunistic infections, or new onset/exacerbation of inflammatory bowel disease in TREMFYA-treated patients.
No new safety concerns were identified through one year (POS1031).
Physical, Social and Work Activity:
In an assessment of DISCOVER 2, observed mean T-scores showed improvement from baseline to week 24 in TREMFYA-treated patients vs. placebo across all seven domains of The Patient-Reported Outcomes Measurement Information System-29 (PROMIS-29)k instrument: anxiety, depression, fatigue, pain interference, physical function, sleep disturbance, and social participation.
Maintenance of improvements in these health-reported outcomes was seen through week 52 (POS1029).
In patients with active PsA who were working at baseline, improvement in work productivity and non-work activity was greater with TREMFYA vs. placebo at week 24, and these improvements were sustained through week 52.
Improvements demonstrated may result in yearly indirect savings in costs associated with work productivity (POS1026).
“These results further our understanding of the efficacy of TREMFYA to treat the varied manifestations of PsA,” said Alyssa Johnsen, M.D., Ph.D., Vice President and Rheumatology Disease Area Leader, Janssen Research & Development, LLC.
“People with PsA live with joint, skin, and soft tissue symptoms, but also experience impacts on physical function and social and psychological well-being.
We are committed to continuing our research in PsA to advance therapeutic options that may help more patients reach their treatment goals.”
Later this year, Janssen will dose its first patient in the APEX (NCT04882098) study.
APEX is a newly initiated Phase 3b trial with long-term extension through three years to further assess the efficacy of TREMFYA on the inhibition of radiographic progression of joint structural damage in patients with active PsA.
June 02, 2021: “The U.S. FDA authorized marketing of a device to help diagnose autism spectrum disorder (ASD).
The Cognoa ASD Diagnosis Aid is a machine learning-based software intended to help health care providers diagnose ASD in children 18 months through 5 years of age who exhibit potential symptoms of the disorder.
“Autism spectrum disorder can delay a child’s physical, cognitive and social development, including motor skill development, learning, communication and interacting with others.
The earlier ASD can be diagnosed, the more quickly intervention strategies and appropriate therapies can begin,” said Jeff Shuren, M.D., J.D., director of the FDA’s Center for Devices and Radiological Health.
“Today’s marketing authorization provides a new tool for helping diagnose children with ASD.”
The Centers for Disease Control and Prevention defines ASD as a “developmental disability that can cause significant social, communication and behavioral challenges” and is estimated to affect about 1 in 54 children.
Because ASD symptoms can vary greatly, the disorder may be difficult to diagnose.
While ASD may be detected as early as 18 months old, many children are not diagnosed until later in childhood, which can delay treatment and early intervention. The average age of diagnosis for ASD is 4.3 years.
Some delays in diagnosis are due to the need for children to be referred to specialists with expertise in ASD.
The Cognoa ASD Diagnosis Aid is a software as a medical device that uses a machine learning algorithm to receive input from parents or caregivers, video analysts and health care providers to assist physicians evaluate a patient at risk of ASD.
The device consists of three main components: a mobile app for caregivers and parents to answer questions about behavior problems and to upload videos of their child; a video analysis portal that allows manufacturer-trained and certified specialists to view and analyze uploaded videos of patients; and a health care provider portal that is intended for a health care provider to enter answers to pre-loaded questions about behavior problems, track the information provided by parents or caregivers and review a report of the results.
After processing the information provided by parents, caregivers and healthcare providers, the ASD Diagnosis Aid reports a positive or negative diagnosis if there is sufficient information for its algorithm to make a diagnosis.
If there is insufficient information to render a “Positive for ASD” or “Negative for ASD” result to help determine a diagnosis, the ASD Diagnosis Aid will report that no result can be generated.
The FDA assessed the safety and effectiveness of the Cognoa ASD Diagnosis Aid in a study of 425 patients aged 18 months through 5 years in 14 different clinical care sites, with an average age of 2.8 years.
The study compared the assessments made by the device directly against the assessments made by a panel of clinical experts who used the current standard ASD diagnostic process.
The device provided a “Positive for ASD” or “Negative for ASD” result to aid in making a diagnosis in 32% of patients.
For those with a “Positive for ASD” or “Negative for ASD” result, the device results matched the panel’s conclusions for 81% of patients who tested positive for ASD by the device and 98% of patients who tested negative for ASD by the device.
In addition, the device made an accurate ASD determination in 98.4% of patients with the condition and in 78.9% of patients without the condition.
The risks associated with the use of the device include misdiagnosis and delayed diagnosis of ASD, based on a false positive result (observed in 15 out of 303 study subjects without ASD), a false negative result (observed in one out of 122 study subjects with ASD) or when no result was generated. Both misdiagnosis or missed diagnosis can result in delayed treatment of ASD and delivery of treatment not appropriate for ASD.
The FDA reviewed the Cognoa ASD Diagnosis Aid through the De Novo premarket review pathway, a regulatory pathway for low- to moderate-risk devices of a new type.
Along with this authorization, the FDA is establishing special controls for devices of this type, including requirements related to labeling and performance testing. When met, the special controls, along with general controls, provide reasonable assurance of safety and effectiveness for devices of this type.
This action creates a new regulatory classification, which means that subsequent devices of the same type with the same intended use may go through the FDA’s 510(k) premarket process, whereby devices can obtain marketing authorization by demonstrating substantial equivalence to a predicate device.
The Cognoa ASD Diagnosis Aid is indicated as an aid in the diagnosis of ASD for patients 18 months through 5 years of age who are at risk of developmental delay based on concerns of a parent, caregiver, or health care provider.
The device is not indicated for use as a stand-alone diagnostic device but as an adjunct to the diagnostic process.
The FDA granted the marketing authorization to Cognoa, Inc.”
June 02, 2021: “A new post-hoc analysis of pooled data from the TULIP Phase III clinical trials being presented at the annual European Congress of Rheumatology (EULAR 2021) showed anifrolumab was consistently associated with improvements in both skin rash and arthritis across three different disease measures each, compared to placebo, in patients with moderate to severe systemic lupus erythematosus (SLE).
The analysis examined disease manifestations in the two most commonly impacted organ domains in SLE.
Anifrolumab is a potential first-in-class type I interferon inhibitor.
For skin rash, the difference in response rates for anifrolumab versus placebo at week 52 were 13.5% SLE Disease Activity Index (SLEDAI), 15.5% British Isles Lupus Assessment Group index (BILAG) and 15.6% modified Cutaneous Lupus Erythematosus Disease Area and Severity Index (mCLASI).
For arthritis, differences in response rates were 8.2% SLEDAI, 11.8% BILAG and 12.6% joint response.
Joan Merrill, Oklahoma Medical Research Foundation, Arthritis & Clinical Immunology Research Program, US, said: “Arthritis and rash are the most common and persistent problems in lupus and often have a significant impact on a person’s life.
The strength of the data from this analysis is that anifrolumab was found to be consistently effective using three different ways of looking at rash and three different approaches to arthritis.
Capturing multiple aspects of improvement increases confidence that anifrolumab may be an important option for patients.”
Mene Pangalos, Executive Vice President, BioPharmaceuticals R&D, said: “The data being presented at EULAR add to the growing body of evidence for anifrolumab that demonstrate a compelling clinical profile with the potential to address significant unmet medical needs in this debilitating disease.
With no new systemic lupus erythematosus treatments in over a decade, we’re working to make this new medicine available as soon as possible.”
The most frequently reported adverse events for anifrolumab in the TULIP-1 and TULIP-2 trials were upper respiratory tract infection, bronchitis, infusion-related reactions and herpes zoster.
AstraZeneca’s application for anifrolumab in SLE is under review by regulatory authorities in the US, EU and Japan, with decisions anticipated in the second half of 2021. Anifrolumab is not currently approved in any country.
Systemic lupus erythematosus Systemic lupus erythematosus is an autoimmune disease in which the immune system attacks healthy tissue in the body.
It is a chronic and complex disease with a variety of clinical manifestations that can impact many organs and can cause a range of symptoms including pain, rashes, fatigue, swelling in joints and fevers.
More than 50% of patients with SLE develop permanent organ damage, caused by the disease or existing treatments, which exacerbates symptoms and increases the risk of mortality.
At least five million people worldwide have a form of lupus.
No new treatments have been approved for SLE in over 10 years.
TULIP-1, TULIP-2 in SLE The pivotal TULIP (Treatment of Uncontrolled Lupus via the Interferon Pathway) Phase III programme includes two trials, TULIP-1 and TULIP-2, that evaluated the efficacy and safety of anifrolumab versus placebo.
Both were randomised, double-blinded, placebo-controlled trials in patients with moderate to severe autoantibody-positive SLE who were receiving standard therapy.
Standard therapy consisted of oral corticosteroids (OCS), antimalarials and immunosuppressants (methotrexate, azathioprine or mycophenolate mofetil, known as MMF).
TULIP-2 demonstrated superiority across multiple efficacy endpoints versus placebo with both arms receiving standard therapy.
In the trial, 362 eligible patients were randomised (1:1) and received a fixed-dose intravenous infusion of 300mg anifrolumab or placebo every four weeks.
TULIP-2 assessed the effect of anifrolumab in reducing disease activity as measured by the BILAG-Based Composite Lupus Assessment (BICLA) scale.
In TULIP-1, 457 eligible patients were randomised (1:2:2) and received a fixed-dose intravenous infusion of 150mg anifrolumab, 300mg anifrolumab or placebo every four weeks, in addition to standard therapy.
The trial did not meet its primary endpoint based on the SLE Responder Index 4 (SRI4) composite measure.
In SLE, along with the pivotal TULIP Phase III programme, anifrolumab continues to be evaluated in a long-term extension Phase III trial.
A Phase II trial of anifrolumab in SLE using subcutaneous delivery has been completed.
In addition, AstraZeneca is exploring the potential of anifrolumab in a variety of diseases where type I interferon plays a key role, including lupus nephritis, cutaneous lupus erythematosus and myositis.
The analysis presented at EULAR included three different disease measures per organ domain.
Anifrolumab Anifrolumab is a fully human monoclonal antibody that binds to subunit 1 of the type I interferon receptor, blocking the activity of type I interferons.
Type I interferons such as IFN-alpha, IFN-beta and IFN-kappa are cytokines involved in regulating the inflammatory pathways implicated in lupus.
The majority of adults with lupus have increased type I interferon signalling, which is known to be associated with disease activity and severity.
AstraZeneca acquired global rights to anifrolumab through an exclusive license and collaboration agreement with Medarex, Inc. in 2004.
Medarex was acquired by Bristol-Myers Squibb in 2009.
AstraZeneca in Respiratory & Immunology Respiratory & Immunology, part of BioPharmaceuticals, is one of AstraZeneca’s three therapy areas and is a key growth driver for the Company.
AstraZeneca is an established leader in respiratory care with a 50-year heritage.
The Company aims to transform the treatment of asthma and COPD by focusing on earlier biology-led treatment, eliminating preventable asthma attacks, and removing COPD as a top-three leading cause of death.
The Company’s early respiratory research is focused on emerging science involving immune mechanisms, lung damage and abnormal cell-repair processes in disease and neuronal dysfunction.
With common pathways and underlying disease drivers across respiratory and immunology, AstraZeneca is following the science from chronic lung diseases to immunology-driven disease areas.
The Company’s growing presence in immunology is focused on five mid- to late-stage franchises with multi-disease potential, in areas including rheumatology (including systemic lupus erythematosus), dermatology, gastroenterology, and systemic eosinophilic-driven diseases.
AstraZeneca’s ambition in Respiratory & Immunology is to achieve disease modification and durable remission for millions of patients worldwide.”
June 01 2021: “A pivotal Phase 2/3 study of venglustat in autosomal dominant polycystic kidney disease (ADPKD) did not meet futility criteria, and the company has halted the clinical program in ADPKD.
The safety profile of venglustat remains consistent with previously reported results with more than 500 patients treated to date over a period of up to four years across all clinical programs.
Biomarker data from the study confirmed venglustat effectively inhibits the glycosphingolipid (GSL) pathway by demonstrating a reduction in GL-1, a lipid that accumulates in certain cells.
The STAGED-PKD study was stopped for futility following an independent analysis of the annualized rate of change in total kidney volume (TKV) in patients receiving venglustat compared to placebo.
Trends from the analysis showed venglustat did not provide a meaningful reduction in TKV growth rate, the primary endpoint of stage 1 of the Phase 2/3 study.
This interim analysis suggests the reduction of GSLs may not play a significant role in the prevention of kidney cyst growth, and as such, may not be a primary pathway associated with the progression of ADPKD.
The investigational research of venglustat in ADPKD was an attempt to explore a novel biological role for GSLs beyond the established role of these lipids in lysosomal storage diseases (LSDs).
“The venglustat development program started with our confidence in the promise of a potential breakthrough treatment to address the unmet needs of people living with lysosomal storage disorders,” said John Reed, M.D., Ph.D., Global Head of Research and Development at Sanofi.
“In parallel, weset out to evaluatevenglustatin autosomal dominant polycystic kidney disease, a leading cause of kidney transplant. This outcome is not what we hoped for, especially for these patients.
However, our research has furthered the scientific understanding of ADPKD by demonstrating that modulating the GSL pathway is insufficient to restore kidney function in adults affected by this disease.”
Sanofi has both completed and active studies evaluating venglustat in Gaucher disease type 3, Fabry disease and GM2 Gangliosidosis.
These diseases are LSDs caused by inherited genetic abnormalities. The abnormal accumulation of GSLs is central to certain LSDs and therapeutics promoting the clearing of these accumulated lipids have been validated in Fabry disease and Gaucher disease through clinical research.
In this context, venglustat operates as a Substrate Reduction Therapy (SRT), which is a concept that has also been previously validated for certain LSDs.
About venglustat
GSLs are cellular building blocks whose abnormal accumulation is implicated in several rare diseases, responsible for both cell dysfunction and disease progression.
Venglustat is a novel, oral investigational therapy that has the potential to slow the progression of certain diseases by inhibiting abnormal GSL accumulation.
Venglustat is currently under clinical investigation and its safety and efficacy have not been evaluated by any regulatory authority.”
May 28, 2021: Novartis reported the first interpretable year one results of the Phase III MERLIN study, a two-year study initiated in H2 2018, assessing the efficacy and safety of Beovu® (brolucizumab) 6 mg versus aflibercept 2 mg given every four weeks following the loading phase in patients with wet age-related macular degeneration (AMD) who have persistent retinal fluid despite anti-VEGF therapy.
Beovu met MERLIN’s primary endpoint of non-inferiority in change in best corrected visual acuity from baseline and superiority on select anatomical secondary endpoints at year one versus aflibercept when given every four weeks following the loading phase.
However, given every four weeks in MERLIN, IOI including RV, and RO were reported with a higher frequency in the Beovu 6 mg every four weeks arm when compared to aflibercept 2 mg every four weeks (IOI: 9.3% vs 4.5% of which RV: 0.8% vs 0.0%; RO: 2.0% vs 0.0%.).
The overall rate of vision loss (15 letters or more) due to all causes was 4.8% in the Beovu arm and 1.7% in the aflibercept arm1.
“Although longer dosing intervals may benefit many people living with wet AMD and other retinal diseases, some are in need of monthly dosing to address persistent fluid. We initiated MERLIN and other clinical programs to explore Beovu for these patients,” said John Tsai, MD, Global Head of Drug Development and Chief Medical Officer, Novartis.
“These data help inform our trials moving forward, so we can best determine how appropriate patients can benefit most from this important medicine.”
Novartis evaluated all ongoing brolucizumab clinical programs assessing studies with four week dosing intervals after the loading phase.
In the interest of patient safety, Novartis has decided to terminate the MERLIN study and the RAPTOR and RAVEN studies, which were assessing the efficacy and safety of brolucizumab with six initial monthly injections in retinal vein occlusion.
All other relevant ongoing trial protocols will be amended to discontinue four week dosing intervals after the loading phase.
Clinical trial investigators have been informed and will appropriately follow up with their patients. Physicians should not treat patients with Beovu 6 mg at intervals less than two months beyond the first three doses.
Novartis has proactively communicated these data to health authorities and will pursue an update to the Beovu prescribing information globally.
When used on a two- to three-month interval following the loading phase, Beovu continues to be an important and effective treatment option for appropriate patients with wet AMD.
Novartis remains committed to supporting the retina community with information regarding Beovu.
Beovu is contraindicated in patients with ocular or periocular infections, active intraocular inflammation or known hypersensitivity to brolucizumab.
Further analysis of the clinical data from MERLIN is ongoing, and detailed data will be presented at an upcoming medical meeting.
Novartis has a strong ongoing commitment to Ophthalmology and to bringing innovative treatments to patients with or at risk of developing eye conditions where there is a high unmet need.
About wet AMD Wet AMD is the leading cause of severe vision loss and legal blindness in people over the age of 65 in North America, Europe, Australia and Asia, impacting an estimated 20 million people worldwide.
Wet AMD occurs when abnormal blood vessels form underneath the macula, the area of the retina responsible for sharp, central vision.
These blood vessels are fragile and leak fluid, disrupting the normal retinal architecture and ultimately causing damage to the macula.
Early symptoms of wet AMD include distorted vision (or metamorphopsia) and difficulties seeing objects clearly.
Prompt diagnosis and intervention are essential. As the disease progresses, cell damage increases, further reducing vision quality.
This progression can lead to a complete loss of central vision, leaving the patient unable to read, drive or recognize familiar faces and potentially depriving them of their independence. Without treatment, vision can rapidly deteriorate.”
May 28, 2021: AstraZeneca’s Tagrisso (osimertinib) has been approved in the EU for the adjuvant treatment of adult patients with early-stage (IB, II and IIIA) epidermal growth factor receptor-mutated (EGFRm) non-small cell lung cancer (NSCLC) after complete tumour resection with curative intent.
Tagrisso is indicated for EGFRm patients whose tumours have exon 19 deletions or exon 21 (L858R) mutations.
The approval by the European Commission was based on positive results from the ADAURA Phase III trial in which Tagrisso demonstrated a statistically significant and clinically meaningful improvement in disease-free survival (DFS) in the primary analysis population of patients with Stage II and IIIA EGFRm NSCLC.
The trial also showed a statistically significant and clinically meaningful improvement in DFS for Tagrisso in the overall trial population, a key secondary endpoint.
While up to 30% of all patients with NSCLC may be diagnosed early enough to have surgery with curative intent, recurrence is still common in early-stage disease. Historically, nearly half of patients diagnosed in Stage IB, and over three quarters of patients diagnosed in Stage IIIA, have experienced disease recurrence within five years.
About a fifth of the world’s lung cancer patients are in the EU and among those with NSCLC, approximately 15% have tumours with an EGFR mutation.4-6
Margarita Majem, MD, PhD, Department of Medical Oncology, Hospital de la Santa Creu i Sant Pau, Spain, said: “In the early stages of lung cancer, where tumour resection is possible but recurrence is far too common, adjuvant Tagrisso has shown an unprecedented disease-free survival benefit for patients with EGFR mutations.
I expect this approval will change clinical practice in the EU, as it heightens the critical importance of EGFR mutation testing across all stages of lung cancer to ensure as many patients as possible can benefit from targeted medicines like Tagrisso.”
Dave Fredrickson, Executive Vice President, Oncology Business Unit, said: “We know the earlier a patient’s cancer is detected and treated, the greater chance they may have of being cured, which is why this approval is significant.
For the first time, patients in the EU with EGFR-mutated lung cancer have a targeted, biomarker-driven treatment option available in the early stages of their disease that can help them live cancer-free longer.”
In the ADAURA trial, adjuvant treatment with Tagrisso reduced the risk of disease recurrence or death by 83% in patients with Stage II and IIIA disease (hazard ratio [HR] 0.17; 99.06% confidence interval [CI] 0.11-0.26; p<0.001) and by 80% in the overall trial population of patients with Stage IB-IIIA disease (HR 0.20; 99.12% CI 0.14-0.30; p<0.001).
Consistent DFS results were seen regardless of prior adjuvant chemotherapy use and across all prespecified subgroups.
The safety and tolerability of Tagrisso in this trial was consistent with previous trials in the metastatic setting. The ADAURA results were published in The New England Journal of Medicine.
Tagrisso is now approved to treat early-stage lung cancer in more than fifty countries, including in the US and China, and additional global regulatory reviews are ongoing.
Tagrisso is also approved for the 1st-line treatment of patients with locally advanced or metastatic EGFRm NSCLC and for the treatment of locally advanced or metastatic EGFR T790M mutation-positive NSCLC in the EU, the US, Japan, China and many other countries.
Lung cancer Lung cancer is the leading cause of cancer death among men and women, accounting for about one-fifth of all cancer deaths. Lung cancer is broadly split into NSCLC and small cell lung cancer, with 80-85% classified as NSCLC.
The majority of NSCLC patients are diagnosed with advanced disease while approximately 25-30% present with resectable disease at diagnosis.
Early-stage lung cancer diagnoses are often only made when the cancer is found on imaging for an unrelated condition.
For patients with resectable tumours, the majority of patients eventually develop recurrence despite complete tumour resection and adjuvant chemotherapy.
Approximately 10-15% of NSCLC patients in the US and Europe, and 30-40% of patients in Asia have EGFRm NSCLC.
These patients are particularly sensitive to treatment with an EGFR-tyrosine kinase inhibitor (TKI) which blocks the cell-signalling pathways that drive the growth of tumour cells.
ADAURA ADAURA is a randomised, double-blind, global, placebo-controlled Phase III trial in the adjuvant treatment of 682 patients with Stage IB, II and IIIA EGFRm NSCLC following complete tumour resection and adjuvant chemotherapy as indicated.
Patients were treated with Tagrisso 80mg once-daily oral tablets or placebo for three years or until disease recurrence.
The trial enrolled patients in more than 200 centres across more than 20 countries, including the US, in Europe, South America, Asia and the Middle East.
The primary endpoint was DFS in Stage II and IIIA patients and a key secondary endpoint was DFS in Stage IB, II and IIIA patients.
The data readout was originally anticipated in 2022.
In April 2020, an Independent Data Monitoring Committee recommended for the trial to be unblinded two years early based on a determination of overwhelming efficacy.
Treating physicians and patients continue to participate and remain blinded to treatment. The trial will continue to assess overall survival.”
