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FDA Accepts Pfizer’s sNDA for BRAFTOVI + MEKTOVI

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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)

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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

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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

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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

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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

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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

FDA Approves First Over-the-Counter Naloxone Nasal Spray

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FDA Approves First Over-the-Counter Naloxone Nasal Spray

March 29, 2023: “The U.S. FDA approved Narcan, 4 milligram (mg) naloxone hydrochloride nasal spray for over-the-counter (OTC), nonprescription, use – the first naloxone product approved for use without a prescription.

Naloxone is a medication that rapidly reverses the effects of opioid overdose and is the standard treatment for opioid overdose.

Today’s action paves the way for the life-saving medication to reverse an opioid overdose to be sold directly to consumers in places like drug stores, convenience stores, grocery stores and gas stations, as well as online. 

The timeline for availability and price of this OTC product is determined by the manufacturer.

The FDA will work with all stakeholders to help facilitate the continued availability of naloxone nasal spray products during the time needed to implement the Narcan switch from prescription to OTC status, which may take months. Other formulations and dosages of naloxone will remain available by prescription only. 

Drug overdose persists as a major public health issue in the United States, with more than 101,750 reported fatal overdoses occurring in the 12-month period ending in October 2022, primarily driven by synthetic opioids like illicit fentanyl. 

“The FDA remains committed to addressing the evolving complexities of the overdose crisis.

As part of this work, the agency has used its regulatory authority to facilitate greater access to naloxone by encouraging the development of and approving an over-the-counter naloxone product to address the dire public health need,” said FDA Commissioner Robert M. Califf, M.D.

“Today’s approval of OTC naloxone nasal spray will help improve access to naloxone, increase the number of locations where it’s available and help reduce opioid overdose deaths throughout the country.

We encourage the manufacturer to make accessibility to the product a priority by making it available as soon as possible and at an affordable price.”   

Narcan nasal spray was first approved by the FDA in 2015 as a prescription drug.

In accordance with a process to change the status of a drug from prescription to nonprescription, the manufacturer provided data demonstrating that the drug is safe and effective for use as directed in its proposed labeling.

The manufacturer also showed that consumers can understand how to use the drug safely and effectively without the supervision of a healthcare professional.

The application to approve Narcan nasal spray for OTC use was granted priority review status and was the subject of an advisory committee meeting in February 2023, where committee members voted unanimously to recommend it be approved for marketing without a prescription. 

The approval of OTC Narcan nasal spray will require a change in the labeling for the currently approved 4 mg generic naloxone nasal spray products that rely on Narcan as their reference listed drug product.

Manufacturers of these products will be required to submit a supplement to their applications to effectively switch their products to OTC status.

The approval may also affect the status of other brand-name naloxone nasal spray products of 4 mg or less, but determinations will be made on a case-by-case basis and the FDA may contact other firms as needed. 

The use of Narcan nasal spray in individuals who are opioid dependent may result in severe opioid withdrawal characterized by body aches, diarrhea, increased heart rate (tachycardia), fever, runny nose, sneezing, goose bumps, sweating, yawning, nausea or vomiting, nervousness, restlessness or irritability, shivering or trembling, abdominal cramps, weakness and increased blood pressure.

“Naloxone is a critical tool in addressing opioid overdoses and today’s approval underscores the extensive efforts the agency has undertaken to combat the overdose crisis,” said Patrizia Cavazzoni, M.D., director of the FDA’s Center for Drug Evaluation and Research.

“The FDA is working with our federal partners to help ensure continued access to all forms of naloxone during the transition of this product from prescription status to nonprescription/OTC status.

Further, we will work with any sponsor seeking to market a nonprescription naloxone product, including through an Rx to OTC switch, and encourage manufacturers to contact the agency as early as possible to initiate discussions.”

The FDA has taken a series of measures to help facilitate access to naloxone products.

In November 2022, the agency announced its preliminary assessment that certain naloxone products, such as the one ultimately approved today, have the potential to be safe and effective for over-the-counter use and encouraged sponsors to submit applications for approval of OTC naloxone products.

The agency previously announced in 2019 that it had designed, tested, and validated a model naloxone Drug Facts Label (DFL) with easy-to-understand pictograms on how to use the drug to encourage manufacturers to pursue approval of OTC naloxone products.

The model DFL was used to support the approved application along with the results of a simulated use Human Factors validation study designed to assess whether all the components of the product with which a user would interact could be used safely and effectively as intended.

Through the

 FDA Overdose Prevention Framework, the agency remains focused on responding to all facets of substance use, misuse, substance use disorders, overdose and death in the U.S. The framework’s priorities include: 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.
 
The FDA granted the OTC approval of Narcan to Emergent BioSolutions.”

https://www.fda.gov/news-events/press-announcements/fda-approves-first-over-counter-naloxone-nasal-spray

License agreement with KYM Biosciences for CMG901, a Claudin-18.2 antibody drug conjugate, completed

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License agreement with KYM Biosciences for CMG901, a Claudin-18.2 antibody drug conjugate, completed

March 30, 2023: “AstraZeneca has completed an exclusive global license agreement with KYM Biosciences Inc.i for CMG901, a potential first-in-class antibody drug conjugate (ADC) targeting Claudin 18.2, a promising therapeutic target in gastric cancers.

CMG901 is currently being evaluated in a Phase I trial for the treatment of Claudin 18.2-positive solid tumours, including gastric cancer. Preliminary results from the trial have shown an encouraging profile for CMG901, with early signs of anti-tumour activity across the dose levels tested.

Financial considerations
AstraZeneca has entered into an exclusive global license for the research, development, manufacture and commercialisation of CMG901 for an upfront payment of $63m, with potential development and sales-related milestone payments of up to $1.1bn and tiered royalties up to low double digits.

The transaction does not impact AstraZeneca’s financial guidance for 2023.

i. KYM Biosciences is a joint venture established by affiliates of Keymed Biosciences and Lepu Biopharma.

Notes

CMG901
CMG901 is a novel antibody drug conjugate targeting Claudin 18.2, and consists of an anti-Claudin 18.2 monoclonal antibody, a protease-degradable linker, and a cytotoxic small molecule monomethyl auristatin E (MMAE).

CMG901 is being developed for the treatment of solid tumours that express the cell surface protein Claudin 18.2, including gastric cancers.

CMG901 is owned by KYM Biosciences Inc. (KYM), a joint venture established by affiliates of Keymed Biosciences (70% of KYM ownership) and Lepu Biopharma (30% of KYM ownership).

AstraZeneca in gastrointestinal cancers
AstraZeneca has a broad development programme for the treatment of gastrointestinal (GI) cancers across several medicines and a variety of tumour types and stages of disease.

In 2020, GI cancers collectively represented approximately 5.1 million new cancer cases leading to approximately 3.6 million deaths.1

Within this programme, the Company is committed to improving outcomes in gastric, liver, biliary tract, oesophageal, pancreatic and colorectal cancers.

Imfinzi (durvalumab) is approved in the US in combination with chemotherapy (gemcitabine plus cisplatin) for advanced biliary tract cancer and in combination with Imjudo in unresectable hepatocellular carcinoma. 

Imfinzi is being assessed in combinations, including with Imjudo in liver, oesophageal and gastric cancers in an extensive development programme spanning early to late-stage disease across settings.

Enhertu (trastuzumab deruxtecan), a HER2-directed antibody drug conjugate, is approved in HER2-positive advanced gastric cancer and is being assessed in colorectal cancer. Enhertu is jointly developed and commercialised by AstraZeneca and Daiichi Sankyo.”

https://www.astrazeneca.com/media-centre/press-releases/2023/astrazeneca-completes-agreement-with-kym-for-cmg901.html

IOnctura Awarded UK’s MHRA Innovation Passport For Entry ILAP

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IOnctura Awarded UK’s MHRA Innovation Passport For Entry ILAP

MARCH 28, 2023: “iOnctura, a clinical stage biotechnology company developing breakthrough therapies for patients suffering with cancer announces that the innovative medicine designation, the Innovation Passport, has been awarded for roginolisib, for the treatment of metastatic uveal melanoma by the Medicines & Healthcare products Regulatory Agency (MHRA).

The Innovation Passport is the entry point to the Innovative Licensing and Access Pathway (ILAP) which aims to accelerate time to market and thereby patient access to novel treatments in the UK.

Reserved for innovative therapies for life-threatening or seriously debilitating conditions, ILAP provides applicants with a toolkit to support all stages of the design, development, and approval process.

Roginolisib is a first-in-class, non-ATP-competitive, allosteric modulator of PI3Kd which prevents tumor proliferation and breaks immune tolerance in patients with solid and hematological tumors.

Catherine Pickering, Chief Executive Officer of iOnctura, said: “The Innovation Passport is an exciting step in the clinical development programme for roginolisib, a drug with a game-changing clinical safety and activity profile.

Being awarded this passport will allow us to work closely with the MHRA and its partner agencies to chart out a roadmap for regulatory and key development milestones with the primary goal of achieving early patient access to roginolisib.”

PI3Kδ inhibition in solid tumors has recently emerged as a novel approach to treating cancer because of its potential in targeting multiple tumor survival pathways.

First-generation PI3Kδ inhibitors are used to treat hematological tumors, but safety concerns and limited target selectivity have curbed their clinical usefulness. These concerns are even more aggravated in patients with solid malignancies where rapid onset of toxicities have been observed.

In contrast, roginolisib has a favorable toxicity profile with less than 5% Grade 3/4 toxicities at the biologically effective dose in clinical studies. Importantly, these toxicities have to-date been transient in nature without the need for dose reductions.

Clinical activity, including partial and complete responses, are being seen in patients with both solid and hematologic malignancies.

Further details on clinical responses will be released at a future international clinical conference in 2023.

Fourteen of 43 patients (including 12 of 28 uveal melanoma patients) are still on treatment, with two patients having been on treatment for more than two years.

The one-year OS rate is currently 70%; median OS has not been reached.

A research paper recently published in Cancer Research Communications highlights that roginolisib has immune-modulatory properties that can be exploited in solid tumors and further reinforced the conclusion that roginolisib inhibits regulatory T cell proliferation while having limited anti-proliferative effects on conventional CD4+ T cells and no effect on CD8+ T cells; both immune cell types key to a robust immune response to tumors.”

https://www.ionctura.com/news/

EnteroBiotix Initiates Phase 2 study of microbiome drug EBX-102 in liver cirrhosis and hepatic encephalopathy

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EnteroBiotix Initiates Phase 2 study of microbiome drug EBX-102 in liver cirrhosis and hepatic encephalopathy

March 28, 2022: “EnteroBiotix Limited (“EBX”), a clinical stage biotechnology company focussed on developing best-in-class full-spectrum microbiome therapeutics announced the initiation of a multi-centre randomised double-blind placebo controlled Phase 2 clinical trial.

The trial has been designed to evaluate EBX-102, the company’s lead product candidate, for the treatment of liver cirrhosis and hepatic encephalopathy (“HE”).

EBX-102 is presented in the form of an orally administered capsule that contains diverse full-spectrum microbial ecosystems that are intended to restore microbial ecology and act in concert to target multiple key disease pathways.

The Phase II study, named ‘IMPuLCE’ (Intestinal Microbiota Product in Liver Cirrhosis and Encephalopathy) intends to enrol 56 patients with liver cirrhosis across sites in the United Kingdom. The trial evaluates EBX-102 in patients with cirrhosis and HE being treated with standard of care medications, including Rifaximin.”

https://www.enterobiotix.com/news/phase-2-study-of-microbiome-drug-ebx-102

BMS Sotyktu approves for the Treatment of Moderate-to-Severe Plaque Psoriasis

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BMS Sotyktu approves for the Treatment of Moderate-to-Severe Plaque Psoriasis

March 28, 2023: ” Bristol Myers Squibb announced that the European Commission has approved Sotyktu (deucravacitinib), a first-in-class, selective tyrosine kinase 2 (TYK2) inhibitor, for the treatment of adults with moderate-to-severe plaque psoriasis who are candidates for systemic therapy, representing a new way of treating this chronic immune-mediated disease.

The approval was based on results from the Phase 3 POETYK PSO-1 and POETYK PSO-2 clinical trials, which demonstrated superior efficacy of once-daily Sotyktu compared to placebo and twice-daily Otezla® (apremilast) at both 16 and 24 weeks, with responses maintained through 52 weeks.

Additional data from the POETYK PSO long-term extension trial (LTE) also supported approval.

The POETYK study program demonstrated a consistent safety profile in patients through three years of continuous treatment.

“Today’s approval is a landmark achievement as patients across Europe with moderate-to-severe plaque psoriasis will now have the opportunity to be treated with Sotyktu, the first once-daily oral option to provide significant symptom relief,” said Samit Hirawat, MD, chief medical officer, Bristol Myers Squibb.

“Discovered in our own labs, Sotyktu has a unique mechanism of action and a well-demonstrated safety, efficacy and tolerability profile, representing a potential new oral standard of care, and demonstrating our ability to develop breakthrough, first-in-class treatments with the potential to transform people’s lives.”

Psoriasis is a widely prevalent, chronic, systemic immune-mediated disease that impacts approximately 14 million people in Europe. Up to 90% of patients with psoriasis have psoriasis vulgaris, or plaque psoriasis, which is characterized by distinct round or oval plaques typically covered by silvery-white scales.

Nearly one-quarter of people with psoriasis have cases that are considered moderate to severe.

Current therapies include topicals, orals and biologics. Patients may prefer oral therapies, and many patients and physicians are looking for additional efficacious and tolerable options.

“The approval of Sotyktu is groundbreaking for the psoriasis community because we now have a tolerable, highly efficacious, once-daily oral treatment option that does not require lab monitoring,” said Diamant Thaçi, MD, PhD, director and full professor, Institute and Comprehensive Center for Inflammation Medicine, University Lübeck, Germany.

“The Phase 3 POETYK-PSO clinical trials showed that Sotyktu demonstrated significant, durable efficacy across multiple key endpoints, including skin clearance and symptom burden.

The results are particularly meaningful for dermatologists and patients who have been waiting for a more effective and convenient oral therapy to help manage this serious, chronic, immune-mediated disease.”

The most commonly reported adverse reaction was upper respiratory infections (18.9%), most frequently nasopharyngitis. The incidence of serious infection in the Sotyktu group was 0.6% compared to 0.5% in the placebo group.

The majority of infections were non-serious and mild to moderate in severity and did not lead to the discontinuation of Sotyktu. Infections occurred in 29.1% of patients in the Sotyktu group compared to 21.5% in the placebo group during the first 16 weeks.

The rate of infections and serious infections in the Sotyktu group did not increase through Week 52. The longer-term safety profile of Sotyktu was similar and consistent with previous experience.

“Psoriasis can greatly impact one’s life physically, emotionally and mentally, with symptoms, such as visible plaques and itching, and feelings of self-stigma and isolation,” said Frida Dunger Johnsson, Executive Director, IFPA (International Federation of Psoriasis Associations).

“There has been an acute need for treatment options offering higher levels of efficacy for people living with moderate-to-severe psoriasis, many of whom remain untreated, undertreated or dissatisfied with current medicines.

We are thrilled that we now have the first once-daily oral therapy to help people with plaque psoriasis and physicians as they work together toward the goal of relieving symptoms and improving their disease.”

Bristol Myers Squibb thanks the patients and investigators involved in the POETYK PSO clinical trial program.

About the POETYK PSO Clinical Trial Program

PrOgram to Evaluate the efficacy and safety of Sotyktu (deucravacitinib), a selective TYK2 inhibitor (POETYK) PSO-1 (NCT03624127) and POETYK PSO-2 (NCT03611751) were global Phase 3 studies designed to evaluate the safety and efficacy of Sotyktu compared to placebo and Otezla® (apremilast) in patients with moderate-to-severe plaque psoriasis.

Both POETYK PSO-1, which enrolled 666 patients, and POETYK PSO-2, which enrolled 1,020 patients, were multicenter, randomized, double-blind trials that evaluated Sotyktu (6 mg once daily) compared to placebo and Otezla (30 mg twice daily).

POETYK PSO-2 included a randomized withdrawal and retreatment period after Week 24.

The co-primary endpoints of both POETYK PSO-1 and POETYK PSO-2 were the percentage of patients who achieved Psoriasis Area and Severity Index (PASI) 75 response and those who achieved static Physician’s Global Assessment (sPGA) score of 0 or 1 (clear/almost clear) at Week 16 versus placebo.

Key secondary endpoints of the trials included the percentage of patients who achieved PASI 75 and sPGA 0/1 compared to Otezla at Week 16 and other measures evaluating Sotyktu versus placebo and Otezla.

Across both clinical trials and timepoints, significantly more Sotyktu-treated patients achieved a sPGA score of 0/1, PASI 75 response and PASI 90 response.

Responses persisted through Week 52, as 82% (187/228) of patients who achieved PASI 75 with Sotyktu at Week 24 maintained their response at Week 52 in POETYK PSO-1.

In POETYK PSO-2, 80% (119/148) of patients who continued Sotyktu maintained PASI 75 response compared to 31% (47/150) of patients who were withdrawn from Sotyktu.

Efficacy
endpoints		POETYK PSO-1POETYK PSO-2
Sotyktu
(n=332)
n (%)		Otezla
(n=168)
n (%)		Placebo
(n=166)
n (%)		Sotyktu
(n=511)
n (%)		Otezla
(n=254)
n (%)		Placebo
(n=255)
n (%)
sPGA 0/1
Week 16178 (53.6)54 (32.1)c12 (7.2)a,c253 (49.5)86 (33.9)c22 (8.6)a,c
Week 24195 (58.7)52 (31.0)c–251 (49.8)b75 (29.5)c–
PASI 75
Week 16194 (58.4)59 (35.1)c21 (12.7)a,c271 (53.0)101 (39.8)d24 (9.4)a,c
Week 24230 (69.3)64 (38.1)c–296 (58.7)b96 (37.8)c–
PASI 90
Week 16118 (35.5)33 (19.6)d7 (4.2)c138 (27.0)46 (18.1)e7 (2.7)c
Week 24140 (42.2)37 (22.0)c–164 (32.5)b50 (19.7)c–
Non-responder imputation (NRI) was used; patients who discontinued treatment or the study prior to the endpoint or had missing data were counted as non-responders.
a Co-primary endpoint comparing Sotyktu and placebo
b n=504 accounting for missed assessments due to COVID-19 pandemic
c p ≤0.0001 for comparison between Sotyktu and placebo or Sotyktu and Otezla
d p <0.001 for comparison between Sotyktu and Otezla
e p <0.01 for comparison between Sotyktu and Otezla

Following the 52-week POETYK PSO-1 and POETYK PSO-2 trials, patients could enroll in the ongoing POETYK PSO long-term extension (LTE) trial (NCT04036435) and receive open-label Sotyktu 6 mg once-daily.

In the LTE trial, 1,221 patients were enrolled and received at least one dose of Sotyktu.

Efficacy was analyzed utilizing treatment failure rules (TFR) method of imputation, along with sensitivity analyses using modified non-responder imputation and as-observed analysis, which have been used in similar analyses with other agents.

In addition to POETYK PSO-1, POETYK PSO-2 and POETYK PSO-LTE, Bristol Myers Squibb has evaluated Sotyktu in two other Phase 3 studies in psoriasis: POETYK PSO-3 (NCT04167462) and POETYK PSO-4 (NCT03924427).”

https://news.bms.com/news/corporate-financial/2023/Bristol-Myers-Squibb-Receives-European-Commission-Approval-of-Sotyktu-deucravacitinib-a-Once-Daily-Oral-Treatment-for-Adults-With-Moderate-to-Severe-Plaque-Psoriasis/default.aspx

FDA Outlines Immediate National Strategy to Further Increase the Resiliency of U.S. Infant Formula Market

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FDA Outlines Immediate National Strategy to Further Increase the Resiliency of U.S. Infant Formula Market

March 28, 2023: “The U.S. FDA released a national strategy outlining actions the agency will take immediately to help ensure one of the nation’s most vulnerable populations continue to have access to safe, nutritious infant formula and to increase resiliency of the U.S. infant formula market and supply.

“Safety and supply go hand-in-hand. We witnessed last year how a safety concern at one facility could be the catalyst for a nationwide shortage. That’s why we are looking to both strengthen and diversify the market, while also ensuring that manufacturers are producing infant formula under the safest conditions possible,” said FDA Commissioner Robert M. Califf, M.D.

“Now, with this strategy, we are looking at how to advance long-term stability in this market and mitigate future shortages, while ensuring formula is safe” 

The Food and Drug Omnibus Reform Act of 2022 (FDORA) directed the FDA, in consultation with other federal government partners, to develop this immediate strategy to increase the resiliency of the U.S. infant formula market.

Key elements of the immediate strategy released today include:

  • Ensuring industry is aware of requirements to develop and implement redundancy risk management plans.
    These plans are intended to help industry identify risks to the supply chains of infant formula and medical foods and to develop mitigation plans against potential disruptions that could impact production. 
  • Continuing to enhance inspections of infant formula manufacturers, including by expanding and improving infant formula training for investigators.
  • Expediting review of premarket submissions for new infant formula products to mitigate or prevent shortages.
  • Continuing to monitor the infant formula supply and developing a forecasting model to enable FDA to prepare for and mitigate future supply disruptions.
  • Engaging with U.S. government partners who play a role in mitigating other factors that may influence the infant formula supply, such as tariffs and market concentration, to sustain the safe, continuous production of infant formula.
  • Engaging with the U.S. Department of Agriculture to support efforts to build resiliency within its Special Supplemental Nutrition Program for Women, Infants, and Children (WIC).
  • Continuing to advance the agency’s Strategy to Help Prevent Cronobacter sakazakii Illnesses Associated with Consumption of Powdered Infant Formula.
  • Improving the agency’s consumer education materials relating to infant formula on FDA.gov.
  • Enhancing and leveraging the FDA’s partnerships with health care providers and professionals, particularly infant care professionals, to further expand the agency’s consumer education program. 

These actions are well underway. FDORA also called on the FDA to trace the events that led up to and followed the voluntary recall of infant formula in February 2022 by Abbott Nutrition, the temporary pause in production at the facility in Sturgis, Michigan, and the numerous factors that contributed to the fragility of this particular supply chain. 

“The events that led up to and ultimately resulted in the voluntary recall of certain infant formula products in February 2022 shocked the infant formula supply in the U.S., creating an unparalleled challenge for parents and caregivers,” said Susan Mayne, Ph.D., director of the FDA’s Center for Food Safety and Applied Nutrition.

“Since then, the agency has had ongoing and extensive engagement with the infant formula industry to identify and implement opportunities to strengthen preventive control practices.

The immediate strategy released today will play an important role in increasing the resiliency of the infant formula market as the agency continues its critical work to improve industry’s processes and programs for the protection of those who rely on infant formula while incentivizing additional infant formula manufacturers to enter the market.”

The strategy also describes initial actions the FDA took to address the infant formula shortage and details the agency’s plans for improving the safety and resiliency of the infant formula supply, while noting considerations beyond the purview of the FDA. 

The agency remains committed to improving the infant formula supply and ensuring that consumers have the utmost confidence that infant formula available in the U.S. is safe and nutritious. 

This initial strategy represents a first step toward issuing — with input from the National Academies of Science, Engineering and Medicine (NASEM)— a long-term national strategy, also called for in FDORA, to improve preparedness against infant formula shortages by outlining methods to improve information-sharing, recommending measures for protecting the integrity of the infant formula supply chain and preventing contamination.

That long-term strategy will follow the plan released today and outline methods to incentivize entry of new infant formula manufacturers to increase supply and mitigate future shortages and recommend necessary authorities to gain insight into the supply chain and risks for shortages.

The long-term strategy is due to Congress one year after enactment, or 90 days after the NASEM issues its report. The FDA anticipates issuing this strategy publicly in early 2024.”

https://www.fda.gov/news-events/press-announcements/fda-outlines-immediate-national-strategy-further-increase-resiliency-us-infant-formula-market

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