This document summarizes clinical trial results of a new long-acting recombinant human G-CSF called lipegfilgrastim. Phase I studies in healthy volunteers found that lipegfilgrastim had a longer half-life and higher area under the curve compared to pegfilgrastim at equivalent doses, resulting in higher absolute neutrophil counts and CD34+ cell counts over time. Adverse events were mostly mild to moderate and consistent between the two drugs. Phase II studies are ongoing to evaluate the efficacy and safety of different doses of lipegfilgrastim compared to pegfilgrastim in breast cancer patients undergoing chemotherapy.
Role of plasma N-terminal proB-type natriuretic peptide (NT-proBNP) level in ...Apollo Hospitals
Cardioembolic stroke generally results in more severe disability, since it typically has a larger ischemic area than the other types of ischemic stroke. The correct identification of a stroke etiology as cardioembolic is important as it has been shown that these patients benefit from anticoagulation. However, it is difficult to differentiate cardioembolic strokes from non-cardioembolic strokes (atherothrombotic stroke and lacunar stroke). NT-proBNP is a well recognized biochemical marker of congestive heart failure. Recent studies suggest that NT-proBNP may be used as a marker of cardioembolic stroke.
Overview of marketing then specific marketing strategies for medical devices applicable to start-ups in the medical device, medical, and healthcare fields.
The basics of launching a pharmaceutical drug-
Based on studies done on the practices of 13 top pharmaceutical companies in the world.
For more, write to info@markivmedical.com
A concise overview of biased agonism, mechanism, beta arrestin pathway, types, examples, GPCR, pros and cons of biased agonism, beta blockers and angiostensin receptor in biased agonism.
Role of plasma N-terminal proB-type natriuretic peptide (NT-proBNP) level in ...Apollo Hospitals
Cardioembolic stroke generally results in more severe disability, since it typically has a larger ischemic area than the other types of ischemic stroke. The correct identification of a stroke etiology as cardioembolic is important as it has been shown that these patients benefit from anticoagulation. However, it is difficult to differentiate cardioembolic strokes from non-cardioembolic strokes (atherothrombotic stroke and lacunar stroke). NT-proBNP is a well recognized biochemical marker of congestive heart failure. Recent studies suggest that NT-proBNP may be used as a marker of cardioembolic stroke.
Overview of marketing then specific marketing strategies for medical devices applicable to start-ups in the medical device, medical, and healthcare fields.
The basics of launching a pharmaceutical drug-
Based on studies done on the practices of 13 top pharmaceutical companies in the world.
For more, write to info@markivmedical.com
A concise overview of biased agonism, mechanism, beta arrestin pathway, types, examples, GPCR, pros and cons of biased agonism, beta blockers and angiostensin receptor in biased agonism.
What is a 'Distribution Channel'
A distribution channel is a chain of businesses or intermediaries through which a good or service passes until it reaches the end consumer. It can include wholesalers, retailers, distributors and even the internet itself. Channels are broken into direct and indirect forms, with a "direct" channel allowing the consumer to buy the good from the manufacturer, and an "indirect" channel allowing the consumer to buy the good from a wholesaler or retailer.
BREAKING DOWN 'Distribution Channel'
A distribution channel is the path by which all goods and services must travel to arrive at the intended consumer. Conversely, it is also used to describe the pathway that payments make from the end consumer to the original vendor. Distribution channels can be short or long, and depend on the amount of intermediaries required to deliver a product or service.
However, goods and services are sometimes passed to consumers through multiple channels, a combination of short and long. While increasing the number of ways in which a consumer can find a good can increase sales, it can also create a complex system that sometimes makes distribution management difficult. In addition, the longer the distribution channel, the less profit a manufacturer might get from a sale due to the fact each intermediary charges for its service.
CAR T-cell Therapy_A New Era in Cancer ImmunotherapyTuhin Samanta
Illusory Antigen Receptor (CAR) T-cell treatment includes hereditary alteration of patient's autologous T-cells to express a CAR explicit for a tumor antigen, following by ex vivo cell extension and re-imbuement back to the patient. Vehicles are combination proteins of a chose single-chain section variable from a particular monoclonal immune response and at least one T-cell receptor intracellular flagging spaces. This T-cell hereditary change may happen either by means of viral-based quality exchange strategies or nonviral techniques, for example, DNA-based transposons, CRISPR/Cas9 innovation or direct exchange of in vitro deciphered mRNA by electroporation.
MAP of Motivation for Pharma Field ForceAnup Soans
Inside this Issue
1. Sales vs. Marketing: the Customer Doesn’t Care! by Salil Kallianpur
In the war between sales and marketing, the customer is hurt the most.
2. The Rural Healthcare Landscape in India by Soumalya Chatterjee
Serving the rural patient is an opportunity for and the responsibility of healthcare companies in India.
3. Differentiating through On-the-job Coaching by K. Hariram
Coaching is a day-to-day activity and not a one-off event.
4. Mastery, Autonomy and Purpose in Field Force Excellence by Anup Soans
MAP enables field sales people to see the big picture and use their abilities to implement strategies systematically even in the absence of oversight.
5. Free Medicines or Better Health? by Salil Kallianpur
The underlying assumption of Rahul Gandhi’s manifesto is that merely providing medicines free would help improve the health and the productivity of the nation. In isolation that is simply not true.
6. Improving the Efficiency of MRs by Dr. Aniruddha Malpani
Pharmaceutical companies need to invest in better ways of ensuring that their MRs get quality face to face time with the doctor.
7. Knowledge for the Field Force Series by Dr. Amit Dang
Oral Anti-Diabetic Agents – II
8. Book Review: Bad Pharma: How Medicine Is Broken and How We Can Fix It by Ben Goldacre reviewed by Prof. Vivek Hattangadi
Cell signaling is part of any communication process that governs basic activities of cells and coordinates all cell actions. The ability of cells to perceive and correctly respond to their microenvironment is the basis of development, tissue repair, and immunity, as well as normal tissue homeostasis
What is a 'Distribution Channel'
A distribution channel is a chain of businesses or intermediaries through which a good or service passes until it reaches the end consumer. It can include wholesalers, retailers, distributors and even the internet itself. Channels are broken into direct and indirect forms, with a "direct" channel allowing the consumer to buy the good from the manufacturer, and an "indirect" channel allowing the consumer to buy the good from a wholesaler or retailer.
BREAKING DOWN 'Distribution Channel'
A distribution channel is the path by which all goods and services must travel to arrive at the intended consumer. Conversely, it is also used to describe the pathway that payments make from the end consumer to the original vendor. Distribution channels can be short or long, and depend on the amount of intermediaries required to deliver a product or service.
However, goods and services are sometimes passed to consumers through multiple channels, a combination of short and long. While increasing the number of ways in which a consumer can find a good can increase sales, it can also create a complex system that sometimes makes distribution management difficult. In addition, the longer the distribution channel, the less profit a manufacturer might get from a sale due to the fact each intermediary charges for its service.
CAR T-cell Therapy_A New Era in Cancer ImmunotherapyTuhin Samanta
Illusory Antigen Receptor (CAR) T-cell treatment includes hereditary alteration of patient's autologous T-cells to express a CAR explicit for a tumor antigen, following by ex vivo cell extension and re-imbuement back to the patient. Vehicles are combination proteins of a chose single-chain section variable from a particular monoclonal immune response and at least one T-cell receptor intracellular flagging spaces. This T-cell hereditary change may happen either by means of viral-based quality exchange strategies or nonviral techniques, for example, DNA-based transposons, CRISPR/Cas9 innovation or direct exchange of in vitro deciphered mRNA by electroporation.
MAP of Motivation for Pharma Field ForceAnup Soans
Inside this Issue
1. Sales vs. Marketing: the Customer Doesn’t Care! by Salil Kallianpur
In the war between sales and marketing, the customer is hurt the most.
2. The Rural Healthcare Landscape in India by Soumalya Chatterjee
Serving the rural patient is an opportunity for and the responsibility of healthcare companies in India.
3. Differentiating through On-the-job Coaching by K. Hariram
Coaching is a day-to-day activity and not a one-off event.
4. Mastery, Autonomy and Purpose in Field Force Excellence by Anup Soans
MAP enables field sales people to see the big picture and use their abilities to implement strategies systematically even in the absence of oversight.
5. Free Medicines or Better Health? by Salil Kallianpur
The underlying assumption of Rahul Gandhi’s manifesto is that merely providing medicines free would help improve the health and the productivity of the nation. In isolation that is simply not true.
6. Improving the Efficiency of MRs by Dr. Aniruddha Malpani
Pharmaceutical companies need to invest in better ways of ensuring that their MRs get quality face to face time with the doctor.
7. Knowledge for the Field Force Series by Dr. Amit Dang
Oral Anti-Diabetic Agents – II
8. Book Review: Bad Pharma: How Medicine Is Broken and How We Can Fix It by Ben Goldacre reviewed by Prof. Vivek Hattangadi
Cell signaling is part of any communication process that governs basic activities of cells and coordinates all cell actions. The ability of cells to perceive and correctly respond to their microenvironment is the basis of development, tissue repair, and immunity, as well as normal tissue homeostasis
Ponencia sobre Mieloma Múltiple, presentada en el I Congreso Panamericano de Medicina Interna. Acapulco, Gro.
El mieloma múltiple es una neoplasia hematológica que consiste en la proliferación clonal de células plasmáticas, generalmente productoras de inmunoglobulinas.Representa aproximadamente 1% de todos los cánceres y 10% de los del tipo hematológico. En la actualidad la mediana de supervivencia no excede los cuatro años con quimioterapia convencional. No obstante, las mejoras en los métodos del trasplante hematopoyético y el uso creciente de agentes novedosos parecen prometedores.
Robert P. Edwards, MD, Chair of OB/GYN/RS, Co-Director of Women's Cancer Program at University of Pittsburgh, offers information about the current state of immunotherapy for recurrent ovarian cancer patients.
Sipuleucel_T Immunotherapy for Metastatic Prostate Cancer after Failing Hormo...mjavan2001
This PowerPoint presentation demonstrates findings on a clinical trial of sipuleucel-T in HRPC patients to evaluate overall survival in this group. The FDA approval of Provenge was based on the results of IMPACT study.
Fase III que utiliza Nab-Paclitaxel + Carboplatino y Pembrolizumab en NSCLC escamoso. El hazard ratio favorece a Nab paclitaxel en el análisis de subgrupos.
Metronomic Chemotherapy Vs Best Supportive Care in Progressive Pediatric Tumors.Pranav Sopory
Journaal Club discussing the Randomised Clinical Trial (RCT) of metronomic chemotherapy in extra cranial, non-hematopoietic solid malignancies in paediatric population (aged 5-18 years). Courtesy Dr Atul Batra, Asst. Prof. Medical Oncology, IRCH, AIIMS.
These lecture slides, by Dr Sidra Arshad, offer a quick overview of physiological basis of a normal electrocardiogram.
Learning objectives:
1. Define an electrocardiogram (ECG) and electrocardiography
2. Describe how dipoles generated by the heart produce the waveforms of the ECG
3. Describe the components of a normal electrocardiogram of a typical bipolar leads (limb II)
4. Differentiate between intervals and segments
5. Enlist some common indications for obtaining an ECG
Study Resources:
1. Chapter 11, Guyton and Hall Textbook of Medical Physiology, 14th edition
2. Chapter 9, Human Physiology - From Cells to Systems, Lauralee Sherwood, 9th edition
3. Chapter 29, Ganong’s Review of Medical Physiology, 26th edition
4. Electrocardiogram, StatPearls - https://www.ncbi.nlm.nih.gov/books/NBK549803/
5. ECG in Medical Practice by ABM Abdullah, 4th edition
6. ECG Basics, http://www.nataliescasebook.com/tag/e-c-g-basics
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Ethanol (CH3CH2OH), or beverage alcohol, is a two-carbon alcohol
that is rapidly distributed in the body and brain. Ethanol alters many
neurochemical systems and has rewarding and addictive properties. It
is the oldest recreational drug and likely contributes to more morbidity,
mortality, and public health costs than all illicit drugs combined. The
5th edition of the Diagnostic and Statistical Manual of Mental Disorders
(DSM-5) integrates alcohol abuse and alcohol dependence into a single
disorder called alcohol use disorder (AUD), with mild, moderate,
and severe subclassifications (American Psychiatric Association, 2013).
In the DSM-5, all types of substance abuse and dependence have been
combined into a single substance use disorder (SUD) on a continuum
from mild to severe. A diagnosis of AUD requires that at least two of
the 11 DSM-5 behaviors be present within a 12-month period (mild
AUD: 2–3 criteria; moderate AUD: 4–5 criteria; severe AUD: 6–11 criteria).
The four main behavioral effects of AUD are impaired control over
drinking, negative social consequences, risky use, and altered physiological
effects (tolerance, withdrawal). This chapter presents an overview
of the prevalence and harmful consequences of AUD in the U.S.,
the systemic nature of the disease, neurocircuitry and stages of AUD,
comorbidities, fetal alcohol spectrum disorders, genetic risk factors, and
pharmacotherapies for AUD.
Flu Vaccine Alert in Bangalore Karnatakaaddon Scans
As flu season approaches, health officials in Bangalore, Karnataka, are urging residents to get their flu vaccinations. The seasonal flu, while common, can lead to severe health complications, particularly for vulnerable populations such as young children, the elderly, and those with underlying health conditions.
Dr. Vidisha Kumari, a leading epidemiologist in Bangalore, emphasizes the importance of getting vaccinated. "The flu vaccine is our best defense against the influenza virus. It not only protects individuals but also helps prevent the spread of the virus in our communities," he says.
This year, the flu season is expected to coincide with a potential increase in other respiratory illnesses. The Karnataka Health Department has launched an awareness campaign highlighting the significance of flu vaccinations. They have set up multiple vaccination centers across Bangalore, making it convenient for residents to receive their shots.
To encourage widespread vaccination, the government is also collaborating with local schools, workplaces, and community centers to facilitate vaccination drives. Special attention is being given to ensuring that the vaccine is accessible to all, including marginalized communities who may have limited access to healthcare.
Residents are reminded that the flu vaccine is safe and effective. Common side effects are mild and may include soreness at the injection site, mild fever, or muscle aches. These side effects are generally short-lived and far less severe than the flu itself.
Healthcare providers are also stressing the importance of continuing COVID-19 precautions. Wearing masks, practicing good hand hygiene, and maintaining social distancing are still crucial, especially in crowded places.
Protect yourself and your loved ones by getting vaccinated. Together, we can help keep Bangalore healthy and safe this flu season. For more information on vaccination centers and schedules, residents can visit the Karnataka Health Department’s official website or follow their social media pages.
Stay informed, stay safe, and get your flu shot today!
Lung Cancer: Artificial Intelligence, Synergetics, Complex System Analysis, S...Oleg Kshivets
RESULTS: Overall life span (LS) was 2252.1±1742.5 days and cumulative 5-year survival (5YS) reached 73.2%, 10 years – 64.8%, 20 years – 42.5%. 513 LCP lived more than 5 years (LS=3124.6±1525.6 days), 148 LCP – more than 10 years (LS=5054.4±1504.1 days).199 LCP died because of LC (LS=562.7±374.5 days). 5YS of LCP after bi/lobectomies was significantly superior in comparison with LCP after pneumonectomies (78.1% vs.63.7%, P=0.00001 by log-rank test). AT significantly improved 5YS (66.3% vs. 34.8%) (P=0.00000 by log-rank test) only for LCP with N1-2. Cox modeling displayed that 5YS of LCP significantly depended on: phase transition (PT) early-invasive LC in terms of synergetics, PT N0—N12, cell ratio factors (ratio between cancer cells- CC and blood cells subpopulations), G1-3, histology, glucose, AT, blood cell circuit, prothrombin index, heparin tolerance, recalcification time (P=0.000-0.038). Neural networks, genetic algorithm selection and bootstrap simulation revealed relationships between 5YS and PT early-invasive LC (rank=1), PT N0—N12 (rank=2), thrombocytes/CC (3), erythrocytes/CC (4), eosinophils/CC (5), healthy cells/CC (6), lymphocytes/CC (7), segmented neutrophils/CC (8), stick neutrophils/CC (9), monocytes/CC (10); leucocytes/CC (11). Correct prediction of 5YS was 100% by neural networks computing (area under ROC curve=1.0; error=0.0).
CONCLUSIONS: 5YS of LCP after radical procedures significantly depended on: 1) PT early-invasive cancer; 2) PT N0--N12; 3) cell ratio factors; 4) blood cell circuit; 5) biochemical factors; 6) hemostasis system; 7) AT; 8) LC characteristics; 9) LC cell dynamics; 10) surgery type: lobectomy/pneumonectomy; 11) anthropometric data. Optimal diagnosis and treatment strategies for LC are: 1) screening and early detection of LC; 2) availability of experienced thoracic surgeons because of complexity of radical procedures; 3) aggressive en block surgery and adequate lymph node dissection for completeness; 4) precise prediction; 5) adjuvant chemoimmunoradiotherapy for LCP with unfavorable prognosis.
Explore natural remedies for syphilis treatment in Singapore. Discover alternative therapies, herbal remedies, and lifestyle changes that may complement conventional treatments. Learn about holistic approaches to managing syphilis symptoms and supporting overall health.
Report Back from SGO 2024: What’s the Latest in Cervical Cancer?bkling
Are you curious about what’s new in cervical cancer research or unsure what the findings mean? Join Dr. Emily Ko, a gynecologic oncologist at Penn Medicine, to learn about the latest updates from the Society of Gynecologic Oncology (SGO) 2024 Annual Meeting on Women’s Cancer. Dr. Ko will discuss what the research presented at the conference means for you and answer your questions about the new developments.
New Drug Discovery and Development .....NEHA GUPTA
The "New Drug Discovery and Development" process involves the identification, design, testing, and manufacturing of novel pharmaceutical compounds with the aim of introducing new and improved treatments for various medical conditions. This comprehensive endeavor encompasses various stages, including target identification, preclinical studies, clinical trials, regulatory approval, and post-market surveillance. It involves multidisciplinary collaboration among scientists, researchers, clinicians, regulatory experts, and pharmaceutical companies to bring innovative therapies to market and address unmet medical needs.
ARTIFICIAL INTELLIGENCE IN HEALTHCARE.pdfAnujkumaranit
Artificial intelligence (AI) refers to the simulation of human intelligence processes by machines, especially computer systems. It encompasses tasks such as learning, reasoning, problem-solving, perception, and language understanding. AI technologies are revolutionizing various fields, from healthcare to finance, by enabling machines to perform tasks that typically require human intelligence.
Title: Sense of Taste
Presenter: Dr. Faiza, Assistant Professor of Physiology
Qualifications:
MBBS (Best Graduate, AIMC Lahore)
FCPS Physiology
ICMT, CHPE, DHPE (STMU)
MPH (GC University, Faisalabad)
MBA (Virtual University of Pakistan)
Learning Objectives:
Describe the structure and function of taste buds.
Describe the relationship between the taste threshold and taste index of common substances.
Explain the chemical basis and signal transduction of taste perception for each type of primary taste sensation.
Recognize different abnormalities of taste perception and their causes.
Key Topics:
Significance of Taste Sensation:
Differentiation between pleasant and harmful food
Influence on behavior
Selection of food based on metabolic needs
Receptors of Taste:
Taste buds on the tongue
Influence of sense of smell, texture of food, and pain stimulation (e.g., by pepper)
Primary and Secondary Taste Sensations:
Primary taste sensations: Sweet, Sour, Salty, Bitter, Umami
Chemical basis and signal transduction mechanisms for each taste
Taste Threshold and Index:
Taste threshold values for Sweet (sucrose), Salty (NaCl), Sour (HCl), and Bitter (Quinine)
Taste index relationship: Inversely proportional to taste threshold
Taste Blindness:
Inability to taste certain substances, particularly thiourea compounds
Example: Phenylthiocarbamide
Structure and Function of Taste Buds:
Composition: Epithelial cells, Sustentacular/Supporting cells, Taste cells, Basal cells
Features: Taste pores, Taste hairs/microvilli, and Taste nerve fibers
Location of Taste Buds:
Found in papillae of the tongue (Fungiform, Circumvallate, Foliate)
Also present on the palate, tonsillar pillars, epiglottis, and proximal esophagus
Mechanism of Taste Stimulation:
Interaction of taste substances with receptors on microvilli
Signal transduction pathways for Umami, Sweet, Bitter, Sour, and Salty tastes
Taste Sensitivity and Adaptation:
Decrease in sensitivity with age
Rapid adaptation of taste sensation
Role of Saliva in Taste:
Dissolution of tastants to reach receptors
Washing away the stimulus
Taste Preferences and Aversions:
Mechanisms behind taste preference and aversion
Influence of receptors and neural pathways
Impact of Sensory Nerve Damage:
Degeneration of taste buds if the sensory nerve fiber is cut
Abnormalities of Taste Detection:
Conditions: Ageusia, Hypogeusia, Dysgeusia (parageusia)
Causes: Nerve damage, neurological disorders, infections, poor oral hygiene, adverse drug effects, deficiencies, aging, tobacco use, altered neurotransmitter levels
Neurotransmitters and Taste Threshold:
Effects of serotonin (5-HT) and norepinephrine (NE) on taste sensitivity
Supertasters:
25% of the population with heightened sensitivity to taste, especially bitterness
Increased number of fungiform papillae
- Video recording of this lecture in English language: https://youtu.be/lK81BzxMqdo
- Video recording of this lecture in Arabic language: https://youtu.be/Ve4P0COk9OI
- Link to download the book free: https://nephrotube.blogspot.com/p/nephrotube-nephrology-books.html
- Link to NephroTube website: www.NephroTube.com
- Link to NephroTube social media accounts: https://nephrotube.blogspot.com/p/join-nephrotube-on-social-media.html
Title: Sense of Smell
Presenter: Dr. Faiza, Assistant Professor of Physiology
Qualifications:
MBBS (Best Graduate, AIMC Lahore)
FCPS Physiology
ICMT, CHPE, DHPE (STMU)
MPH (GC University, Faisalabad)
MBA (Virtual University of Pakistan)
Learning Objectives:
Describe the primary categories of smells and the concept of odor blindness.
Explain the structure and location of the olfactory membrane and mucosa, including the types and roles of cells involved in olfaction.
Describe the pathway and mechanisms of olfactory signal transmission from the olfactory receptors to the brain.
Illustrate the biochemical cascade triggered by odorant binding to olfactory receptors, including the role of G-proteins and second messengers in generating an action potential.
Identify different types of olfactory disorders such as anosmia, hyposmia, hyperosmia, and dysosmia, including their potential causes.
Key Topics:
Olfactory Genes:
3% of the human genome accounts for olfactory genes.
400 genes for odorant receptors.
Olfactory Membrane:
Located in the superior part of the nasal cavity.
Medially: Folds downward along the superior septum.
Laterally: Folds over the superior turbinate and upper surface of the middle turbinate.
Total surface area: 5-10 square centimeters.
Olfactory Mucosa:
Olfactory Cells: Bipolar nerve cells derived from the CNS (100 million), with 4-25 olfactory cilia per cell.
Sustentacular Cells: Produce mucus and maintain ionic and molecular environment.
Basal Cells: Replace worn-out olfactory cells with an average lifespan of 1-2 months.
Bowman’s Gland: Secretes mucus.
Stimulation of Olfactory Cells:
Odorant dissolves in mucus and attaches to receptors on olfactory cilia.
Involves a cascade effect through G-proteins and second messengers, leading to depolarization and action potential generation in the olfactory nerve.
Quality of a Good Odorant:
Small (3-20 Carbon atoms), volatile, water-soluble, and lipid-soluble.
Facilitated by odorant-binding proteins in mucus.
Membrane Potential and Action Potential:
Resting membrane potential: -55mV.
Action potential frequency in the olfactory nerve increases with odorant strength.
Adaptation Towards the Sense of Smell:
Rapid adaptation within the first second, with further slow adaptation.
Psychological adaptation greater than receptor adaptation, involving feedback inhibition from the central nervous system.
Primary Sensations of Smell:
Camphoraceous, Musky, Floral, Pepperminty, Ethereal, Pungent, Putrid.
Odor Detection Threshold:
Examples: Hydrogen sulfide (0.0005 ppm), Methyl-mercaptan (0.002 ppm).
Some toxic substances are odorless at lethal concentrations.
Characteristics of Smell:
Odor blindness for single substances due to lack of appropriate receptor protein.
Behavioral and emotional influences of smell.
Transmission of Olfactory Signals:
From olfactory cells to glomeruli in the olfactory bulb, involving lateral inhibition.
Primitive, less old, and new olfactory systems with different path
Joseph Gligorov : Lipegfilgrastim : A new long-ac,ng recombinant human G-CSF
1. Lipegfilgras+m
A
new
long-‐ac,ng
recombinant
human
G-‐CSF
Joseph
Gligorov
MD,
PhD
ESO
Advanced
Breast
Cancer
Task
Force
APHP-‐HUEP-‐Tenon,
Paris
Ins+tut
Universitaire
de
Cancérologie
Université
Pierre
&
Marie
Curie,
Sorbonne
Universités
4. GlycoPEGyla+on
Explanation
§ Two enzymes - one-pot reaction
§ Two substrates
• Activated sugar
• Activated sugar linked to PEG
§ The PEGylation site is threonine 134 (THR134)
Filgrastim
(E. coli derived)
Lipegfilgrastim
(glycoPEGylated XM21)
ENZYME 1 ENZYME 2
XM21
S 1
THR134
XM21
THR134
XM21
S 1
S 2
THR134
S 1A1
A1
S 2A2
A2
S 1A1
S 2A2 PEG
5. Clinical
development
Phase I studies
XM22-01-CH PK/PD single dose, bodyweight adjusted dosing
N=53
25/50/100 µg/kg lipegfilgrastim vs
pegfilgrastim
XM22-05-CH PK/PD single dose, fixed dose
N=36
6 mg lipegfilgrastim vs pegfilgrastim
XM22-06
PK at three different injection sites (upper arm,
abdomen, thigh)
N=20
6 mg lipegfilgrastim vs pegfilgrastim
Phase II studie
XM22-02
Dose finding with three different doses of
Lonquex® compared to 6mg pegfilgrastim in
breast cancer patients
N=208
3/4.5/6 mg lipegfilgrastim vs 6mg
pegfilgrastim
phase III studies
XM22-03
Efficacy and safety of 6mg Lonquex® compared
to 6 mg pegfilgrastim in breast cancer patients
N=202
6 mg lipegfilgrastim vs 6mg
pegfilgrastim
XM22-04
Efficacy and safety of 6 mg Lonquex® compared
to placebo in non small cell lung cancer patients
N=373
6 mg lipegfilgrastim vs placebo
7. 1
ANC
:
absolute
neutrophil
count
XM22-‐01
XM22-‐05
Objec+ves
PK/PD
single
dose
25,
50,
100
μg/kg
of
lipegfilgras+m
or
100
μg/kg
pegfilgras+m
bodyweight
adjusted
dosing
(n
=
53)
PK/PD
single
6
mg
fixed
dose
lipegfilgras+m
or
pegfilgras+m
(n
=
36)
Methods
Phase
I
randomised,
single-‐blind
study
in
healthy
volunteers
Phase
I
randomised,
single-‐blind
study
in
healthy
volunteers
Primary
endpoint
ANC1
AOBEC
(area
over
baseline
effect
curve)
ANC
AOBEC
Secondary
endpoints
§ PD:
CD34+
AOBEC,
CD
34+
max
,
ANC
max,
§ PK:
AUC,
Cmax,
Tmax,
T
½
terminal
§ Safety
§ PD:
CD34+
AOBEC,
CD
34+
max
,
ANC
max,
§ PK:
AUC,
Cmax,
Tmax,
T
½
terminal
§ Safety
Phase
I
studies
8. 0 24 48 72 96 120 144 168 192 216 240
0
XM22-01-CH
body weight depending dosing
Bioavailability AUC of lipegfilgrastim
56-57% > AUC of pegfilgrastim
(Median ± SD)
XM22-05-CH
fixed dose
100000
200000
300000
400000
500000
600000
Time* [h]
Concentration[pg/ml]
0
0 24 48 72 96 120 144 168 192
100000
200000
300000
400000
500000
600000
Time* [h]
Concentration[pg/ml] 216 240
50 µg/kg lipegfilgrastim (n=15)
100 µg/kg pegfilgrastim
(n=15)
25 µg/kg lipegfilgrastim (n=8)
100 µg/kg lipegfilgrastim (n=15)
6 mg pegfilgrastim, n = 15
6 mg lipegfilgrastim, n = 18
Bioavailability AUC of lipegfilgrastim
63-64% > AUC of pegfilgrastim
(Median ± SD)
Seiberling M, et al. Research report. XM22-01-CH. Mannheim, Germany: BioGenerix, 2009.
Seiberling M, et al. Research report. XM22-05-CH. Mannheim, Germany: BioGenerix, 2009
9. 0
10
20
30
40
50
60
0
10
20
30
40
50
60
XM22-01-CH
body weight depending dosing
XM22-05-CH
fixed dose
96 168 192216 264288 360 384 408
Time*[h]
ANC[neut/nl]
3363122401441207248240 96 168 192 216 264 288 360 384 408
Time*[h]
ANC[neut/nl]
3363122401441207248240
50 µg/kg lipegfilgrastim (n=15)
100 µg/kg pegfilgrastim
(n=15)
25 µg/kg lipegfilgrastim (n=8)
100 µg/kg lipegfilgrastim (n=15)
6 mg pegfilgrastim, n = 15
6 mg lipegfilgrastim, n = 18
With equivalent doses, ANC AUC with lipegfilgrastim >
32% ANC AUC with pegfilgrastim
(Median ± SD)
ANC AUC with lipegfilgrastim > 30% ANC AUC with
pegfilgrastim
(Median ± SD)
Seiberling M, et al. Research report. XM22-01-CH. Mannheim, Germany: BioGenerix, 2009.
Seiberling M, et al. Research report. XM22-05-CH. Mannheim, Germany: BioGenerix, 2009
10. 0 48 96 168192216 240264 288 432 456 480504
20
0
60
80
100
120
140
Time (h)
CD34+[cellcount/ul)
40
24 72 120 144 312 336360 384 408
100 µg/kg lipegfilgrastim (n=15)
100 µg/kg pegfilgrastim (n=15)
25 µg/kg lipegfilgrastim (n=8)
50 µg/kg lipegfilgrastim (n=15)
0 48 96 168192 216240264 288 432 456 480504
20
0
60
80
100
120
140
Time (h)
40
24 72 120 144 312 336 360384 408
CD34+[cellcount/ul)
With equivalent doses: CD34+ 83% and CD34+ max
98% higher with lipegfilgrastim vs pegfilgrastim
(Median)
6 mg pegfilgrastim, (n=18)
6 mg lipegfilgrastim, (n=18)
Seiberling M, et al. Research report. XM22-01-CH. Mannheim, Germany: BioGenerix, 2009.
Seiberling M, et al. Research report. XM22-05-CH. Mannheim, Germany: BioGenerix, 2009
CD34+ 9% and CD34+ max 16% higher with
lipegfilgrastim vs pegfilgrastim (ns)
(Median)
XM22-01-CH
body weight depending dosing
XM22-05-CH
fixed dose
11. 11
XM22-‐01
n=53
XM-‐05
n=
36
Lipegfilgras+m
n=38
Pegfilgras+m
n=15
lipegfilgras+m
n=18
Pegfilgras+m
n=18
Any
AE
35
(92,5%)
14
(93,3%)
15
(83,3%)
17
(94,4%)
Gastrointes+nal
7
(18,4%)
1
(6,7%)
3
(16,7%)
3
(16,7%)
Arthralgia
30
(79%)
13
(86,7%)
1
(5,6%)
0
(0%)
Back
pain
4
(10,5%)
0
(0%)
-‐
-‐
Headaches
21
(55,2%)
7
(46,7%)
10
(55,6%)
9
(50%)
Bone
pain
1
(2,6%)
2
(13,3%)
12
(66,7%)
15
(83,3%)
• AEs
were
mostly
mild
to
moderate
in
severity
• No
serious
AEs
• No
clinicaly
significant
change
in
biologic
and
vital
signs,
ECG
and
sonographic
examina,on
of
the
spleen
• No
injec,on
site
was
observed
Seiberling M, et al. Research report. XM22-01-CH. Mannheim, Germany: BioGenerix, 2009.
Seiberling M, et al. Research report. XM22-05-CH. Mannheim, Germany: BioGenerix, 2009
Safety
in
studies
XM22-‐01,
XM22-‐05
*AE
=
adverse
events
12. Phase
II
study
Breast
cancer
lipegfilgras,m
3mg,
4.5
mg
,
6
mg
vs
pegfilgras,m
6mg
13. § Primary objective:
§ To identify the optimal fixed dose of lipegfilgrastim in breast
cancer patients treated with chemotherapy compared to 6mg
pegfilgrastim
§ Methods:
§ Multinational, multicentre, randomised, double-blind, controlled
study with 4 treatment arms (6 european countries; 37 centres)
§ Patients were stratified according to geographical localisation,
indication of chemotherapy (adjuvant/metastatic) and body
weight
Kaufmann M, et al. Research report XM22-02. Mannheim, Germany: BioGenerix, 2011.
Phase
II
study
14. § Main inclusion criteria:
§ Stage II,III,IV Breast Cancer Cancer treated with 4 cycles of AT
(doxorubicine 60 mg/m2- docetaxel 75 mg/m2) every 3 weeks
§ No previous chemo
§ ANC ≥ 1,5 x 109/L, thrombocytes ≥ 100 x 109/L
§ ECOG* ≤ 2
§ Normal heart, kidney and liver function
§ Main exclusion criteria:
§ Previous G-CSF exposure
§ Anti infectious treatment (antibiotics) ≤ 72 hours before chemo initiation
§ Radiotherapy ≤ 4 weeks before study inclusion
§ Previous bone marrow transplantation
*ECOG= Eastern Cooperative Oncology Group
Phase
II
study
15. Doxorubicin
60
mg/m2
+
Docetaxel
75
mg/m2
(
n=208)
lipegfilgrastim 3.0 mg (n=53)
lipegfilgrastim 4.5 mg (n=51)
lipegfilgrastim 6.0 mg (n=50)
pegfilgrastim 6.0 mg
(n=54)
Primary
breast
cancer
patients
(N=229)
Randomization
Next chemo
cycle if ANC
≥1.5 x 109/L
and platelet
count
≥100 x 109/LOne chemotherapy cycle
= 21 days
rGCS-‐F
therapy
Chemotherapy
Run-‐in
Cycle
1
Cycle
2
Cycle
3
Cycle
4
Follow-‐up
D1 D22 D43 D64
D85
End of study D180
Ab test
D360
Ab test
D2 D23 D44 D65
Ab=antibody test; D=day; chemo=chemotherapy.
Haematological and biochemical parameters measured on Day 15 of each cycle
Multinational, multicenter, randomized, double blind
Data on file
Buchner, A. et all JCO, 29:2011 (Suppl; abstr 9080)
Phase
II
study
16.
§ Primary
Endpoint:
Dura,on
of
Severe
Neutropenia
(DSN)
in
the
first
cycle
of
chemotherapy
in
the
respec,ve
arms
§ Secondary
Endpoint
§
Incidence
of
Febrile
Neutropenia
in
cycles
1,
2,
3,
and
4
and
across
all
cycles.
Febrile
§
DSN
in
cycles
2,
3,
and
4.
§ The
following
secondary
efficacy
endpoints
were
evaluated
in
cycles
1,
2,
3,
and
4:
§ Depth
of
ANC
nadir.
§
Time
to
ANC
recovery
(
ANC
≥2.0
x
109/L).
§ Incidence
of
grade
4
neutropenia
(ANC
<
0.5
x
109/L).
§ Safety
Data on file
Buchner, A. et all JCO, 29:2011 (Suppl; abstr 9080)
Severe Neutropenia =grade 4 neutropenia (ANC < 0.5 x 109/L).
Very Severe Neutropenia (ANC < 0.1 x 109/L)
Febrile Neutropenia was defined as axillary body temperature of > 38.5°C for more than 1 h and ANC <0.5 x 109/L, both measured on the same day L)
Phase
II
study
17. No significant difference between groups
4 groupes aux caractéristiques démographiques et médicales
comparables (en ITT et en PP)
Pegfilgrastim
N=54
lipegfilgrastim 3
mg, N=53
lipegfilgrastim
4,5 mg, N=51
lipegfilgrastim
6 mg, N=50
Total
N=208
Age (years)
Median ± SD
≤ 64 years, %
49,5 ±11,1
92,6%
53,1 ±9,2
86,8%
52,8 ± 10,1
88,2%
51,4 ± 9,8
90%
51,7 ±10,1
89,4%
Weight
≤ 60 kg
60 à 75 kg
> 75 kg
25,9%
33,3%
40,7%
22,6%
45,3%
32,1%
25,5%
39,2%
35,3%
26,0%
38,0%
36,0%
25,0%
38,9%
36,1%
CT indication
Adjuvant
Métastatic
79,6%
20,4%
81,1%
18,9%
86,3%
13,7%
82,0%
18,0%
82,2%
17,8%
Disease stage
High-risk stage II
Stage III
Stage IV
40,7%
42,6%
16,7%
39,6%
43,4%
17,0%
37,3%
51,0%
11,8%
36,0%
48,0%
16,0%
38,5%
46,2%
15,4%
ECOG status
0
1
2
61,1%
38,9%
0%
64,1%
34,0%
1,9%
51,0%
43,1%
5,9%
56,0%
42,0%
2,0%
58,2%
39,4%
2,4%
Patients caracteristics
18. Duration of Severe Neutropenia in cycle 1 (ITT population)
pegfilgrastim
6mg
Lonquex®
3mg
Lonquex®
4.5mg
Lonquex®
6mg
N valid,
Mean ± standard
deviation (median)
Minimum
to maximum
54
0.9±1.0 (1.0)
0.0 to 3.0
53
1.1±1.1 (1.0)
0.0 to 4.0
51
0.8±1.0 (1.0)
0.0 to 4.0
50
0.8±1.1 (0.0)
0.0 to 3.0
No statistically significant difference between treatment arms
Same results in PP population and within sub-groups analysis..
Phase
II
study
19. § Conclusion :
§ Non-inferiority of lipegfilgrastim 6 mg vs pegfilgrastim 6 mg was
demonstrated on DSN in cycle 1
§ Significantly more patients without severe neutropenia in the lipegfilgrastim
group vs pegfilgrastim group, in cycles 2, 3 and 4
§ Time to ANC recovery (ANC ≥ 2 x 10 9/L) significantly shorter with
lipegfilgrastim than pegfilgrastim 6 mg, in each cycle
§ Safety profile similar to pegfilgrastim 6 mg
Phase
II
study
20. Phase
III
study
XM22-‐03
Lipegfilgras,m
6mg
vs
pegfilgras,m
6
mg
Breast
cancer
Bondarenko I, et al. BMC Cancer. 2013: 2013;13(1): 386.
21. § Primary Objective :
§ Demonstration of non-inferiority of Lonquex® versus
pegfilgrastim in patients treated for breast cancer
(doxorubicine-docétaxel)
Non inferiority hypothesis demonstrated if :
Δ DSN (lipegfilgrastim –pegfilgrastim) < 1 day
§ Design:
§ Multinational, multicenter, randomized, double-blind, phase III
study
Phase
III
study,
XM22-‐03
22. Doxorubicin
60
mg/m2
+
Docetaxel
75
mg/m2
(Pooled
n=202)
Lipegfilgrastim 6 mg (n=101)
pegfilgrastim 6.0 mg
(n=101)
Ab=antibody test; D=day; CTX=chemotherapy;
ANC=absolute neutrophil count.
Primary
breast
cancer
patients
(n=218)
Randomization
Next CTX
cycle if ANC
≥1.5 x 109/L
and platelet
count
≥100 x 109/L
One chemotherapy cycle = 21 days
Multinational, multicenter, randomized, double-blind, phase III study
rGCS-‐F
therapy
Chemotherapy
Run-‐in
Cycle
1
Cycle
2
Cycle
3
Cycle
4
Follow-‐up
D1 D22 D43 D64
D85
End of
study
D180
Ab test
D360
Ab test
D2 D23 D44 D65
Bondarenko, I. et all JCO, 30, 2012 (Suppl; abstr 19587)
Bondarenko et al,Jcancer Research and Clin Oncology , 2012, Submitted
Phase
III
study,
XM22-‐03
23. § Primary Endpoint: Duration of Severe Neutropenia (DSN) in the first cycle of
chemotherapy.
§ Secondary Endpoints:
§ Efficacy parameters
§ Incidence of Febrile Neutropenia in cycles 1-4
§ Duration of Severe Neutropenia in cycle 2-4
§ Depth of ANC nadir in each cycle
§ Time to ANC recovery (ANC ≥ 2.0 109/L)
§ Incidence of severe neutropenia
§ Safety parameters
Bondarenko, I. et all JCO, 30, 2012 (Suppl; abstr 19587)
• Severe Neutropenia/Grade 4 (NCI) :ANC < 0.5X109/L
• Febrile neutropenia (FN): Severe Neutropenia + Axyllary temperature > 38.5° C for at least one hour +/-(documented
neutropenic sepsis
and /or documented of serious or life threatening infection)
Phase
III
study,
XM22-‐03
24. Patients caracteristics : similar in both groups
Pegfilgras+m
6
mg
N=101
Lipegfilgras+m
6
mg
N=101
Age
Median
±
SD
(years)
≤
64,
n
(%)
65
à
74,
n
(%)
51.1
±
9.4
94
(93.1)
7
(6.9)
49.9
±
10.1
94
(93.1)
7
(6.9)
Body
weight
Median
±
SD
(kg)
≤
60,
n
(%)
>60
à
≤75,
n
(%)
>75,
n
(%)
73.2
±
14.6
16
(15.8)
49
(48.5)
36
(35.6)
73.9
±
17.1
22
(21.8)
40
(39.6)
39
(38.6)
Indica+on
for
CT,
n
(%)
Adjuvant
Métasta,c
74
(73.3)
27
(26.7)
75
(74.3)
26
(25.7)
ECOG
status
0
1
2
47
(46.5)
54
(53.5)
0
(-‐)
45
(44.6)
56
(55.4)
0
(-‐)
Stage
High-‐risk
stage
II
III
IV
36
(35,6)
45
(44,6)
20
(19,8)
39
(38,6)
48
(47,5)
14
(13,9)
Bondarenko I, et al. BMC Cancer. 2013: 2013;13(1): 386.
Phase
III
study,
XM22-‐03
25. Tumor and treatment caracteristics similar in both arms
Variable
Pegfilgras+m
6
mg
N=101
(%)
Lipegfilgras+m
6
mg
N=101
(%)
Months
since
diagnosis
Mean
±
SD
Median
Varia,ons
6,1
±
26,6
1
0
à
185
5,3
±16,7
2
0
à
130
Surgery
59
(59,4)
50
(49,5)
Time
since
surgery
(months)
Mean
±
SD
9,1
±
34,1
6,7
±
15,5
Type
of
surgery
Conserva,ve
Mastectomy
Axillary
dissec,on
7
(6,9)
55
(54,5)
46
(45,5)
4
(4)
46
(45,5)
44
(43,6)
Bondarenko I, et al. BMC Cancer. 2013: 2013;13(1): 386.
Phase
III
study,
XM22-‐03
26. Primary endpoint : DSN in cycle 1
Non-inferiority of Lipegfilgrastim 6 mg vs Pegfilgrastim 6 mg demonstrated
(Δ DSN < 1 jour)
Results confirmed in sub-groups analysis by country, indication for CT and body weight
Lipegfilgrastim
6mg
Pegfilgrastim
6 mg
Δ Lipegfilgrastim-
pegfilgrastim (IC95)
p
PP population
DSN median ± SD
LS Mean (95% CI)
0,7 ± 0,9 jours
0
0,8 ±0,9 jours
1
- 0,218 jours
(-0,498 à 0,062)
0,1260
Bondarenko I, et al. BMC Cancer. 2013: 2013;13(1): 386.
Phase
III
study,
XM22-‐03
27. Secondary endpoints (PP population)
Pegfilgras+m
6mg
Lipegfilgras+m
6mg
p
DSN
Cycle
2
Cycle
3
Cycle
4
0,3
±
0,6
0,2
±
0,4
0,2
±
0,5
0,1
±
0,5
0,1
±
0,3
0,2
±
0,6
0,1287
0,6227
0,922
Incidence
of
FN
Cycle
1
Cycles
1
to
4
3,2%
3,2%
0,0%
0,0%
NS
Incidence
of
SN
Cycle
1
Cycle
2
Cycles
1
à
4
51,1%
21,5%
58,5%
43,6%
8,5%
50,0%
0,341
0,013*
0,269
Bondarenko I, et al. BMC Cancer. 2013: 2013;13(1): 386.
Phase
III
study,
XM22-‐03
28. Neutropenia in cycles 1-4 (PP population)
Nadir comparable in cycle 1 in both treatment groups
ANC values to nadir significantly higher in cycles 2 and 3 in the lipegfilgrastim group
Pegfilgrastim 6 mg
(N=94) [NCx109/L]
Lipegfilgrastim 6 mg
(N=94) [NCx109/L]
p
Nadir (109/L)
Cycle 1
Cycle 2
Cycle 3
Cycle 4
1,0 ± 1,3
2,0 ± 1,6
2,0 1,5
2,3 1,8
1,2 ± 1,3
2,6 ± 2,1
2,5 ± 1,6
2,7 ± 1,7
0,254
0,019
0,035
0,112
ANC recovery*
Cycle 1
Cycle 2
Cycle 3
Cycle 4
1,6 ± 1,2
0,8 ± 1,0
0,8 ± 1,0
0,7 ± 0,9
1,3 ± 1,0
0,5 ± 0,7
0,4 ± 0,7
0,4 ± 0,7
0,062
0,076
0,021
0,076
*Time to ANC recovery ≥1,5x109 /L after nadir (days)
Bondarenko I, et al. BMC Cancer. 2013: 2013;13(1): 386.
Phase
III
study,
XM22-‐03
29. Time to ANC recovery (≥ 2x 109/L after ANC < 2x 109/L ) in cycles 1-4 (PP
population)
Cycle
pegfilgras+m
6mg
N=94
Lipegfilgras+m
6mg
N=94
p
1
7.4±3.6
5.9±3.4
0.003*
2
5.3±4.6
3.6±4.1
0.008*
3
5.1±4.3
3.9±4.8
0.033*
4
4.3±4.7
3.3±4.1
0.223
Course of ANC in cycle 1
Bondarenko I, et al. BMC Cancer. 2013: 2013;13(1): 386.
Phase
III
study,
XM22-‐03
30. 30
Quality
of
life
• Global
decreasing
of
the
score
during
the
treatment
phase
• No
sta,s,cal
difference
among
the
2
arms
according
to
QLQ-‐C30
nor
QLQ-‐BR23
scales
Mean variations of EORTC QLQ-BR23 scoring scales between inclusion and end of the study
Phase
III
study,
XM22-‐03
31. Safety
Safety profile similar in both treatment groups
a : 1 neutropenia and 1 paroxysmal tachycardia
b : epistaxis
c : FN stage 3 and enterocolitis
Phase
III
study,
XM22-‐03
pegfilgras+m
6mg
N=101
lipegfilgras+m
6mg
N01=1
Category
of
TEAE
N
(%)
N
(%)
Any
TEAE
99
(98.0)
100
(99.0)
Drug
related
TEAE=TEADR
26
(25.7)
28
(27.7)
Serious
TEAE
7
(6.9)
3
(3.0)
Serious
TEADR
1
(1.0)
1
(1.0)
Severe
TEAE
35
(34.7)
26
(25.7)
Severe
TEADR
2
(2.0)
a
1
(1.0)
b
Discon,nued
due
to
TEAE
2
(2.0)
3
(3.0)
Discon,nued
due
to
TEADR
1
(1.0)
0
(0)
Death
0
(0)
1
(1.0)
c
32. Comparable safety profile
Phase
III
study,
XM22-‐03
Most
frequent
side
effects
occurring
in
≥
3
%
pa+ents
(ITT
popula+on)
Side
effects
Pegfilgras+m
6
mg
(N=101)
Lonquex®
6
mg
(N=101)
N
(%)
N
(%)
Bone
pain
10
(9.9)
13
(12.9)
Myalgia
5(5.0)
7
(6.9)
Erythema
3(3.0)
6
(5.9)
Arthralgia
0
(-‐)
3
(3.0)
Nausea
3
(3.0)
2
(2.0)
33. Conclusions :
§ Non inferiority of lipegfilgrastim 6 mg vs pegfilgrastim 6 mg demonstrated on
DSN in cycle 1
§ Secondary endpoints : significant differences in favor of lipegfilgrastim on following
endpoints :
§ Lower incidence of severe neutropenia in cycle 2
§ Lower depth of neutropenia in cycles 2 and 3
§ Time to ANC recovery ≥ 2 x109/L shorter in cycles 1, 2 and 3
§ Comparable safety profiles
Phase
III
study,
XM22-‐03
34. Conclusion
Lipegfilgras+m:
• Molecular
structure
:
«
glycoPEGyla,on
technology
»
• Long-‐ac,ng
human
recombinant
G-‐CSF
(r-‐metHuG-‐
CSF)
• Efficacy
and
safety
profile
comparable
to
pegfilgras,m