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AstraZeneca’s US Breakthrough Therapy Designation for Enhertu

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AstraZeneca’s US Breakthrough Therapy Designation for Enhertu
May 11, 2020: “AstraZeneca and Daiichi Sankyo Company, Limited (Daiichi Sankyo)’s Enhertu (trastuzumab deruxtecan) has been granted Breakthrough Therapy Designation (BTD) in the US for the treatment of patients with HER2-positive unresectable or metastatic gastric or gastroesophageal junction adenocarcinoma who have received two or more prior regimens including trastuzumab.

Gastric cancer is the third leading cause of cancer mortality with a five-year survival rate of 5% for metastatic disease.

 Approximately one in five gastric cancers are considered HER2 positive.

The Food and Drug Administration’s (FDA) BTD is designed to accelerate the development and regulatory review of potential new medicines that are intended to treat a serious condition and address a significant unmet medical need.

The new medicine needs to have shown encouraging early clinical results that demonstrate substantial improvement on a clinically significant endpoint over available medicines.

José Baselga, Executive Vice President, R&D Oncology, said: “Current therapy options are limited for patients with HER2-positive metastatic gastric cancer and for those who relapse, there are no approved HER2-targeted medicines.

We look forward to working with the FDA to further explore the potential of Enhertu to become an important new treatment and the first antibody-drug conjugate for this devastating disease.”

Gilles Gallant, Senior Vice President, Global Head, Oncology Development, Oncology R&D, Daiichi Sankyo, said: “DESTINY-Gastric01 represents the first randomised trial of Enhertu to demonstrate clinically meaningful and statistically significant results, including objective response and survival increases compared to physician’s choice of chemotherapy.

We are thrilled that the FDA has granted Enhertu a second Breakthrough Therapy Designation.”

The FDA granted BTD based on data from the registrational Phase II DESTINY-Gastric01 trial and data from the Phase I trial published in The Lancet Oncology.

In DESTINY-Gastric01, patients treated with Enhertu, a HER2-directed antibody drug conjugate (ADC), demonstrated a statistically significant and clinically meaningful improvement in objective response rate (ORR), the primary endpoint, and overall survival (OS), a key secondary endpoint, versus patients treated with investigator’s choice of chemotherapy (irinotecan or paclitaxel monotherapy).

The overall safety and tolerability profile of Enhertu (6.4 mg/kg) in DESTINY-Gastric01 were consistent with that seen in the Phase I trial.

The most common adverse events were hematologic and gastrointestinal including neutrophil count decrease, anaemia, nausea and decreased appetite.

There were cases of drug-related interstitial lung disease (ILD) and pneumonitis, the majority of which were Grade 1 and 2, with two Grade 3 and one Grade 4. No ILD-related deaths (Grade 5) occurred in patients with gastric cancer in the Phase I trial or in Phase II DESTINY-Gastric01 trial.

The full results of DESTINY-Gastric-01 will be presented during the 2020 American Society of Clinical Oncology ASCO20 Virtual Scientific Program.

Enhertu received SAKIGAKE designation in March 2018 by Japan’s Ministry of Health, Labour and Welfare (MHLW) for potential use in the same HER2-positive gastric cancer patient population and was recently submitted to the MHLW for approval.

This is the second BTD granted for Enhertu in the US. Enhertu received BTD in 2017 for HER2-positive metastatic breast cancer and received approval in December 2019.

Gastric (stomach) cancer is the fifth most common cancer worldwide and the third leading cause of cancer mortality; there were approximately one million new cases reported in 2018 and 783,000 deaths.

 In the US, it is estimated that 27,600 new cases of gastric cancer will be diagnosed in 2020 and more than 11,000 people will die from the disease.

Approximately one in five gastric cancers are HER2 positive.

HER2 is a tyrosine kinase receptor growth-promoting protein expressed on the surface of many types of tumours including gastric, breast and lung cancers.

Gastric cancer is usually diagnosed in the advanced stage, but even when diagnosed in earlier stages of the disease the survival rate remains modest.

 Recommended 1st-line treatment for HER2-positive advanced or metastatic gastric cancer is combination chemotherapy plus trastuzumab, an anti-HER2 medicine, which has been shown to improve survival outcomes when added to chemotherapy.

For gastric cancer that progresses on 1st-line treatment, there are no other approved HER2-targeting medicines.

DESTINY-Gastric01 is a registrational Phase II, open-label, multi-centre trial testing the safety and efficacy of Enhertu in a primary cohort of 188 patients from Japan and South Korea with HER2-expressing, advanced gastric cancer or gastroesophageal junction adenocarcinoma (defined as IHC3+ or IHC2+/ISH+) who have progressed on two or more prior treatment regimens including fluoropyrimidine and platinum chemotherapy and trastuzumab.

Patients were randomised 2:1 to receive Enhertu or investigator’s choice of chemotherapy (paclitaxel or irinotecan monotherapy).

Patients were treated with Enhertu 6.4 mg/kg once every three weeks or chemotherapy. The primary endpoint of the trial is ORR, as assessed by an independent review committee.

Secondary endpoints include OS, progression-free survival, duration of response, disease control rate and time to treatment failure as well as pharmacokinetic and safety endpoints.

Enhertu (trastuzumab deruxtecan; fam-trastuzumab deruxtecan-nxki in the US) is a HER2-directed ADC and is the lead ADC in the oncology portfolio of Daiichi Sankyo and the most advanced programme in AstraZeneca’s ADC scientific platform.

ADCs are targeted cancer medicines that deliver cytotoxic chemotherapy (“payload”) to cancer cells via a linker attached to a monoclonal antibody that binds to a specific target expressed on cancer cells.

Enhertu is approved in the US and Japan for the treatment of adult patients with unresectable or metastatic HER2-positive breast cancer who have received two or more prior anti-HER2-based regimens based on the DESTINY-Breast01 trial.

A comprehensive development programme is underway globally with six registrational trials evaluating the efficacy and safety of Enhertu monotherapy across multiple HER2-driven cancers including breast, gastric and lung cancers.

Trials in combination with other anticancer treatments, such as immunotherapy, are also underway.

Collaboration between AstraZeneca and Daiichi Sankyo

In March 2019, AstraZeneca and Daiichi Sankyo entered into a global collaboration to jointly develop and commercialise Enhertu worldwide, except in Japan where Daiichi Sankyo maintains exclusive rights. Daiichi Sankyo is solely responsible for manufacturing and supply.“

https://www.astrazeneca.com/content/astraz/media-centre/press-releases/2020/enhertu-granted-breakthrough-therapy-designation-in-the-us-for-her2-positive-metastatic-gastric-cancer.html

Clinical Trial: Introduction & Types

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Clinical Trial: Introduction & Types

Table of Contents

“According to the FDA, Clinical investigation means any experiment in which a drug is administered or dispensed to, or used involving, one or more human subjects.

For the purposes of this part, an experiment is any use of a drug except for the use of a marketed drug in the course of medical practice.
Clinical trial is the branch of health care science that determines the safety and efficiency (effectiveness) of medications, devices, diagnostic products and treatment regimens intended for human use.
Each clinical trial is designed in order to learn about potential treatment and its effect on humans. 
They are clinical trials in which people volunteer to study experimental treatments, methods or experiments as a way of avoiding, identifying, treating or controlling different illnesses or disorders.
In the United States, Clinical trials are approved and monitored by an Institutional Review Board (IRB) to ensure that the risks are reduced and are outweighed by potential benefits.
The global demand for Contract Research Organization (CRO) is estimated at USD 34500 million in 2018 and is projected to hit USD 55300 million by the end of 2024, rising at a CAGR of 8.2% between 2019 and 2024.

There are 2 main types of clinical studies:

(a) On the basis of researchers behave:
  • Interventional study  (experimental studies)
  • Observational study
Types of clinical studies

Interventional clinical study:

Interventional clinical study is performed with the purpose of studying or representing clinical or pharmacological properties of drugs/devices, their side effects and to establish their efficacy or safety.

They also include studies in which surgical, physical or psychotherapeutic procedures are inspected.

Interventional studies are often prospective and are specially tailored to evaluate direct impacts of treatment or defensive measures on disease.

Each study design has precise outcome measures that rely on the type and quality of the data utilized.

Moreover, each study design has potential limitations that are more severe and need to be addressed in the design phase of the study.

Non-randomized trial

Non-randomized trials are interventional study designs that compare a group where an intervention was performed with the group where there was no intervention.

These are suitable study designs that are most frequently performed prospectively and can suggest possible relationships between the intervention and the outcome.

On the other hand, these study designs are often subject to many types of bias and error and are not measured as a strong study design.

The randomised controlled trial

The randomized controlled trial is considered the gold standard in clinical science because it is the only proven means of preventing bias and confusing preconceptions.

 Such experiments take a homogeneous sample of subjects from the study and split them into two different groups at random.

If the randomization is efficient then in all ways these two classes will be the same, all measurable confounders as well as unmeasured variables.

The experiment is then carried out in one group and not the other, and measurements of the efficacy of the experiment between the two groups are examined.
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4083571/

Observational Clinical study

Observational Clinical study involves giving the participant a particular treatment in accordance with clinical practice.

Observational studies are typically categorized into various categories such as case report or case series, ecologic, cross-sectional (prevalence study), case-control and cohort studies.

Other variants of these observational studies are also possible such as nested case-control study, case-cohort study etc.

1. Case reports and case series:

A definition of a particular or series of instances, respectively, where the medical modalities, therapeutic protocols, prognosis, etc. relevant to such characteristics are typically addressed without taking into account any protocol.

They are experimental inquiries or investigations of a patient or a group of patients in a natural, real-world clinical setting. 

https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5630458/

2. Cross-sectional studies

Cross-sectional studies where the data concerning both exposure and outcome are collected concurrently from a selected group of the individuals in an exact population at a given point of time.

In contrast to case–control studies (participants selected based on the outcome status) or cohort studies (participants selected based on the exposure status), the participants in a cross-sectional study are just selected based on the inclusion and exclusion criteria set for the study.
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4885177/

3. Ecological studies:

Group comparisons are made in these type of studies as opposed to the individual-level comparisons. Therapeutic factor and outcomes are measured at the population level.

Ecological studies may be either descriptive, such as exploring differences within populations, or considering associations.

Ecological experiments are also an interesting resource in health services science, where healthcare institutions rather than individual patients are often the object of the investigation.

For example, a present study looking at the features of general practices associated with lower coronary heart disease mortality was more alarmed with the practice at an organisational level than with individuals.
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3905433/

4. Cohort studies

Cohort studies are the group of subjects that represent the population of interest having certain common characteristics and studied over a sufficient period of time, for example, a cohort of survivors of Bhopal gas tragedy, the cohort of children born in a particular year.

They are selected based on the exposure status of the individual.

They are then followed over time in order to evaluate for the occurrence of the outcome of interest. Some examples of cohort studies are
(1) Framingham Cohort study,
(2) Swiss HIV Cohort Study, and
(3) The Danish Cohort study of psoriasis and depression.

These studies may be prospective, retrospective, or a combination of both of these types.
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4763690/

5. Case-control studies

Case-control studies start when the outcome/disease has already occurred. Here two groups namely cases (those having the outcome of interest, i.e., a particular disease, a complication) and controls (those not having the outcome of interest) are selected and information about their exposure(s)/ risk factor(s) under consideration are collected from existing records, patient examinations, personal interviews, etc., for comparison.

In theory, the case-control study can be described simply.

First, categorize the cases (a group known to have the outcome) and the controls (a group known to be free of the outcome).

Then, look back in time to study which subjects in each group had the exposure(s), comparing the frequency of the exposure in the case group to the control group.
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC1706071/

6. Nested case-control study: Variation of a case-control design

Cases of a disease that occurs in a given population are reported in the nested case-control study and, for each, a defined number of matched controls is selected from among those in the group that have not attained the disease by the time the disease occurs in the event.

The type of nested case-control study depends on how the controls are selected.

i) At the end of the cohort study, controls are selected at random bases  from the disease-free subjects.

Such design is known as exclusive design or total sampling of events, and is usually calculated for such design in case-control studies and odds ratio.

 ii) All controls are randomly selected from the cohort at the start of the follow-up.

Here, a control at the start of study may become case during the subsequent follow-up, hence, it is called inclusive design and as the controls are representative of full cohorts, it is also known as a case-cohort study.

 iii) The cohort is followed at standard intervals and as a new case is diagnosed, a control is selected from the population at-risk at that point of time. 

The main feature of these studies are both case and control are selected from the matching source of population and reduce the chance of selection bias.

Additionally, these studies are cost efficient compared with full cohort studies, albeit decrease in sample size may reduce the statistical power.

Example of a nested case-control study:

To evaluate whether treatment with sodium valproate (exposure) was associated with reduced risk of the stroke (outcome), a nested case-control study was implemented with cases diagnosed with incident nonhemorrhagic stroke and controls matched for sex, year of birth, and study start date.
http://www.astrocyte.in/article.asp?issn=2349-0977;year=2014;volume=1;issue=2;spage=154;epage=159;aulast=Kumar

7. Measures of association:

Relative risk (RR), risk difference (RD) and odds ratio (OR) are the measures of the association repeatedly reported in observational studies. RR is the ratio of the probability of the occurrence/incidence of an event in the exposed group to that in the nonexposed group.

RD is a difference in risk between the experimental group and control group. As temporality is ascertained in cohort studies, occurrence rates and hence risks can be computed by these type of study designs. In case-control studies, the measure of association is the odds ratio.

 Simply, OR is the ratio of odds of exposure among the diseased group to the odds of exposure among the non-diseased group. “

The ORs and RRs, even though conceptually different, are often mistakenly interpreted in the same way.”
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4083571/http://www.astrocyte.in/article.asp?issn=2349-0977;year=2014;volume=1;issue=2;spage=154;epage=159;aulast=Kumar


Phases of Clinical Trials

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Phases of Clinical Trials
Phases of Clinical Trials are the steps which are followed to test the drug in the different number of healthy volunteers/patients.
Clinical trials are experiments or observations done in clinical research. There are five Phases of Clinical Trial including Phase 0.
According to WHO a clinical trial is any research study that prospectively assigns human participants or groups of humans to one or more health-related interventions to evaluate the effects on health outcomes.
Phases of the clinical trial are as follows:
Phase
of Clinical Trial
Aim of the Phase

Study included
Phase 0   Pharmacodynamics and pharmacokinetics in humans  
Phase 0 trials are optional first-in-human trials. Single sub-therapeutic doses of the study drug or treatment are given to a small number of subjects
(typically 10 to 15) together preliminary data on the agent’s pharmacodynamics and pharmacokinetics.
 
Phase I   Screening for safety, MTD (Maximum tolerated dose)   First-in-Human trials.

Testing within a small group of people (typically 20–80) to evaluate safety, determine safe dosage ranges.  
Phase IA Single ascending dose
Small groups of subjects are given a single dose of the drug while they are observed and tested for a period of time to confirm safety.

A small number of participants, usually three, are entered sequentially at a particular dose.

This particular design assumes that the maximally tolerated dose occurs when approximately one-third of the participants experience unacceptable toxicity.  
Phase IB Multiple ascending dose
Investigating pharmacokinetics and pharmacodynamics of multiple doses of the drug, looking at safety and tolerability.

A group of patients receives multiple low doses of the drug, while samples (of blood and other fluids) are collected at various time points and analyzed to acquire information on how the drug is processed within the body.
Phase II Establishing the preliminary efficacy of a drug usually against a placebo.
Testing with a large group of people (typically 100-300) to determine efficacy and to further evaluate its safety.
Phase IIA Exploratory (non-pivotal) study that has clinical efficacy, Pharmacodynamics or biological activity Proof of concept, efficacy, Dose range exploration , Pilot studies  
Phase IIB Definite Dose finding studies.
Pilot studies designed to demonstrate clinical efficacy or biological activity (‘proof of concept’ studies)

Exceptionally, Phase II studies can be used as pivotal trials, if the drug is intended to treat life-threatening or severely debilitating illnesses.
Phase III Final confirmation of safety and effectiveness
Testing with large groups of people (typically 1,000–3,000) to confirm its efficacy, evaluate its effectiveness, monitor side effects, compare it to commonly used treatments, and collect information that will allow it to be used safely
Phase IIIA Pivotal studies clinical trials generate additional data on both safety and efficacy in relatively large numbers of patients in both controlled and uncontrolled trials
Trials conducted after +efficacy of the medicine is demonstrated, but prior to regulatory submission of a New Drug Application (NDA) or another dossier.

These clinical trials are conducted in patient populations for which the medicine is eventually intended
Phase IIIB
A study started prior to approval. These trials may supplement earlier trials, complete earlier trials, or maybe directed toward new types of trials (e.g., quality of life, marketing) or Phase IV evaluations.
Studies intended to support publication claims or to prepare launch, which starts before approval but is not intended for Regulatory submissions
Phase IV Different formulations, dosages, duration of treatment, medicine interactions, and other medicine comparisons may be evaluated.
Safety studies during sales Post-marketing studies related risks, benefits, and optimal use.

As such, they are ongoing during the drug’s lifetime of active medical use.

Phase I/II, II/III, IIA/IIIB, IA/IIB:

There are different combination of Phases used in the Clinical Trials Nowadays.
This combination of Phases into one protocol helps in achieving robust statistical power. Also, They are more efficient because the number of patients and time are reduced quite significantly.

Phase I/II clinical trial Example

Phase I/II Study of the Safety, Efficacy and Dose Evaluation of ProSavin for the Treatment of Bilateral Idiopathic Parkinson’s Disease

https://clinicaltrials.gov/ct2/show/NCT00627588

Phase II/III clinical trial Example

Phase IIb-III Study of BL-1020 Small Molecule for Schizophrenia (CLARITY)

https://clinicaltrials.gov/ct2/show/NCT0136334

Coronavirus (COVID-19) Update: FDA Authorizes First Antigen Test to Help in the Rapid Detection of the Virus that Causes COVID-19 in Patients

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Coronavirus (COVID-19) Update: FDA Authorizes First Antigen Test to Help in the Rapid Detection of the Virus that Causes COVID-19 in Patients

Table of Contents

May 09, 2020: “The U.S. Food and Drug Administration has issued the first emergency use authorization (EUA) for a COVID-19 antigen test, a new category of tests for use in the ongoing pandemic.
These diagnostic tests quickly detect fragments of proteins found on or within the virus by testing samples collected from the nasal cavity using swabs. The EUA was issued late Friday to Quidel Corporation for the Sofia 2 SARS Antigen FIA.
This test is authorized for use in high and moderate complexity laboratories certified by Clinical Laboratory Improvement Amendments (CLIA), as well as for point-of-care testing by facilities operating under a CLIA Certificate of Waiver.
Diagnostic testing is one of the pillars of our nation’s response to COVID-19 and the FDA continues to take actions to help make these critical products available, including by issuing EUAs.
During this pandemic, there have been two types of tests for which the FDA has issued EUAs. One type are polymerase chain reaction (PCR) tests, a molecular diagnostic testing technique that detects the genetic material from the virus and can help diagnose an active COVID-19 infection.
The other type are serological tests that look for antibodies to the virus, which can help identify individuals who have developed an adaptive immune response to the virus, as part of either an active infection or a prior infection (serological, or antibody, tests should not be used to diagnose active infection).
This latest FDA authorization is for an antigen test, which is a new type of diagnostic test designed for rapid detection of the virus that causes COVID-19.
Each category of diagnostic test has its own unique role in the fight against this virus. PCR tests can be incredibly accurate, but running the tests and analyzing the results can take time. One of the main advantages of an antigen test is the speed of the test, which can provide results in minutes.
However, antigen tests may not detect all active infections, as they do not work the same way as a PCR test. Antigen tests are very specific for the virus, but are not as sensitive as molecular PCR tests.
This means that positive results from antigen tests are highly accurate, but there is a higher chance of false negatives, so negative results do not rule out infection.
With this in mind, negative results from an antigen test may need to be confirmed with a PCR test prior to making treatment decisions or to prevent the possible spread of the virus due to a false negative.
Antigen tests are also important in the overall response against COVID-19 as they can generally be produced at a lower cost than PCR tests and once multiple manufacturers enter the market, can potentially scale to test millions of Americans per day due to their simpler design, helping our country better identify infection rates closer to real time.
This is just the first antigen test to be authorized and we expect more to follow. We also anticipate providing an EUA template for antigen tests, similar to ones we’ve released for other test types, to help manufacturers streamline submissions and help expedite our review and issuance of additional EUAs.
Antigen tests will play a critical role in the fight against COVID-19 and we will continue to offer support and expertise to help with the development of accurate tests, and to review and monitor marketed tests to ensure accuracy, while balancing the urgent need for these critical diagnostics.
The FDA, an agency within the U.S. Department of Health and Human Services, protects the public health by assuring the safety, effectiveness, and security of human and veterinary drugs, vaccines and other biological products for human use, and medical devices.
The agency also is responsible for the safety and security of our nation’s food supply, cosmetics, dietary supplements, products that give off electronic radiation, and for regulating tobacco products.”
https://www.fda.gov/news-events/press-announcements/coronavirus-covid-19-update-fda-authorizes-first-antigen-test-help-rapid-detection-virus-causes

Clinical Research Associate: Role, Responsibilities, Skills, and Salary

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Clinical Research Associate: Role, Responsibilities, Skills, and Salary

Table of Contents

Introduction:

Clinical Research Associate may be employed directly by the sponsor companies of clinical trials or by Clinical Research Organizations (CROs)
CROs conduct clinical trials on behalf of the sponsor companies.
Clinical Research Associates (CRAs) are also known as Clinical Trial Monitors, trial Monitors or Field Monitor (FM).
The primary duty of clinical research associates is to ensure that the
rights, safety and well-being of participant in clinical trials are secured.
Below one sentence can define the role of CRA:
Clinical Research Associate acts as a liaison between the Sponsor and the site.
“Sites” are the hospitals where clinical trials are performed.

What do you do as a clinical research associate?:

  1. Travel to (a lot!) and monitor clinical trial sites to ensure that ICH GCP guidelines, study protocol and other industry-specific regulations such as GCP (good clinical trial practics) are being followed correctly.
  2. Identify the protocol deviations and record them in Database or eDC (electronic data capture). eDCs are the tool to capture clinical trial-related data.
  3. Visit reports are prepared by clinical research associates.
  4. Answer the queries raised by site staff such as CRC (clinical research coordinator).
  5. They ensure data collected is accurate and verifiable. it is also called source data verification.
  6. Depends on designation, they can manage clinical trial site payments and handle any ongoing negotiations.
  7. Important documents archival are done by CRA.
  8. They update the site contact list.
  9. They respond to data management, Safety and other department queries as well.
Some quite specific responsibilities as per GCP section 5.18:
“Verifying that the investigator is competent and has sufficient resources And continue to be adequate throughout the trial duration to ensure that services, including laboratories, equipment and staff, are adequate to perform the trial safely and adequately and remain adequate throughout the trial.”
“verifying, for the investigational product(s):
  • That storage times and conditions are appropriate, and that supplies during the trial are adequate.
  • That the investigational product(s) are only supplied to subjects entitled to obtain it and at the dose(s) defined in the protocol.
  • Clinical research associate ensures that all the necessary instruction on properly using, handling, storing, and returning the investigational product are given to subjects enrolled in the trial.
  • Clinical Research Associate (CRA) ensures that there are sufficient monitoring and recording of the collection, use and return of the investigational product(s) at the testing sites
  • Clinical research associate ensures that disposal of the discarded testing product(s) at the trial sites satisfies the relevant regulatory criteria and is compliant with the sponsor.
Other responsibilities:

CRA verifies that investigator follows the approved protocol and all approved amendment(s) if any.

Verifying that site has taken as written informed consent or not before enrolling any subject.

CRA ensures that all the source documents and other trial records are accurate, complete, kept up-to-date and maintained.

CRA checks the entries in eCRFs (Electronic Case report forms) and double-checks with Source data. Case report forms are the documents which are used to capture clinical trial protocol. clinical research co-ordination enters the data in CRF.

CRA checks the below information in CRFs:
  • CRAs check if the site has entered all the required data in CRFs or not
  • The correctness of any dose and/or therapy modifications -documentation
  • Adverse Events, concomitant medication and Medical history are properly documented or not
  • Missing visits, Discontinuation of subjects, death are properly captured or not.

Monitoring Report

  • CRA has to submit a written report to the sponsor after each site visit
  • Monitoring reports include the following component:
  • Date, site, name of monitor, and name of investigator
    Any finding, if any action is taken

How do I become a clinical research associate?:

  • You should have a degree in Pharmaceutical science, or any life science subjects
  • Degree, exclusively in clinical research is not needed but it may help you to build a better understanding.
  • Basic understanding of clinical research such as Phases of trials and types, the drug approval process of various countries especially of the major market such US, EU, Japan, India and China.
  • Aspirants for CRA jobs should be well versed with clinical trial terminologies, GCP (Good clinical practice) and ICH guidelines.
  • Basic knowledge of Microsoft excels, Word and PPT
  • Good communication skills 
  • Last but most important thing you must be ready to travel a lot!. It is said that CRA should take home near Airport because travelling is quite more in this Job.

How much do clinical research associates get paid?:

These are the common factors which decide your salary in any organizations:

  • Experience,
  • Qualifications,
  • Countries and
  • Type of Organisations.

Average Salaries were calculated from four different sources: payscale.com, prospects.ac.uk and Glassdoor (as of May 2020)

Average Clinical Research Associate (CRA) Salary in India:

 3.5-4.5 L/annum (0-1 years of experience): Travelling allowns will be provided extra.

Average Clinical Research Associate (CRA) Salary in UK:
  •  £23,000 to £30,000 (0-1 years of experience)
Average Clinical Research Associate (CRA) Salary in US:

>$86,000 per year (0-1 Year of experience)

Career Path:

More than 100,000 clinical trials throughout the United States are being conducted each year and Clinical trial associated are the key players to monitor these trials. There are much growth expected in healthcare industries due to ongoing COVID19 crisis.

Commonly CRA I or Junior CRA is the designation, you will receive once you join any Pharmaceutical organization or CROs.
With your skills and experience, you can move into the role of senior CRA or CRA II or Senior Feild Monitor (SFM).
Once you get the experience of 8-9 years, you can be promoted to manager roles where many site CRAs will be reporting to you.
You can become a freelance CRAs as many organization recruits freelance CRAs as well.

It is necessary to have a good understanding about other job roles as well in Pharma and CRO industries so that if you can develop other skills as well to match the market demand and your expectations.

Coronavirus (COVID-19) Update: FDA Authorizes First Diagnostic Test Using At-Home Collection of Saliva Specimens

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Coronavirus (COVID-19) Update: FDA Authorizes First Diagnostic Test Using At-Home Collection of Saliva Specimens

May 08, 2020: “The U.S. Food and Drug Administration authorized the first diagnostic test with the option of using home-collected saliva samples for COVID-19 testing.

Specifically, the FDA issued an emergency use authorization (EUA) to Rutgers Clinical Genomics Laboratory for their COVID-19 laboratory developed test (LDT), which had been previously added to the high complexity molecular-based LDT “umbrella” EUA, to permit testing of samples self-collected by patients at home using the Spectrum Solutions LLC SDNA-1000 Saliva Collection Device.

This announcement builds on last month’s EUA for the first diagnostic test with a home-collection option, which uses a sample collected from the patient’s nose with a nasal swab and saline.

“Authorizing additional diagnostic tests with the option of at-home sample collection will continue to increase patient access to testing for COVID-19.

This provides an additional option for the easy, safe and convenient collection of samples required for testing without traveling to a doctor’s office, hospital or testing site,” said FDA Commissioner Stephen M. Hahn, M.D.

“We will continue to work around the clock to support the development of accurate and reliable tests, as we have done throughout this pandemic.

The FDA has authorized more than 80 COVID-19 tests and adding more options for at-home sample collection is an important advancement in diagnostic testing during this public health emergency.”

Today’s EUA for Rutgers Clinical Genomics Laboratory’s molecular test permits testing of a saliva sample collected from the patient using a designated self-collection kit.

Once patients collect their saliva sample, they return it to the Rutgers Clinical Genomics Laboratory in a sealed package for testing.

The Rutgers Clinical Genomics Laboratory test is currently the only authorized COVID-19 diagnostic test that uses saliva samples to test for SARS-CoV-2, the strain of coronavirus that causes COVID-19.

The test remains prescription only.

Today’s authorization is limited to testing performed at the Rutgers Clinical Genomics Laboratory using their molecular LDT COVID-19 authorized test for saliva specimens collected using the Spectrum Solutions LLC SDNA-1000 Saliva Collection Device.

It is important to note that this is not a general authorization for at-home collection of patient samples using other collection methods, saliva collection devices, or tests, or for tests fully conducted at home.

The FDA, an agency within the U.S. Department of Health and Human Services, protects the public health by assuring the safety, effectiveness, and security of human and veterinary drugs, vaccines and other biological products for human use, and medical devices.

The agency also is responsible for the safety and security of our nation’s food supply, cosmetics, dietary supplements, products that give off electronic radiation, and for regulating tobacco products.”

https://www.fda.gov/news-events/press-announcements/coronavirus-covid-19-update-fda-authorizes-first-diagnostic-test-using-home-collection-saliva

Coronavirus (COVID-19) Update: Daily Roundup May 8, 2020

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Coronavirus (COVID-19) Update: Daily Roundup May 8, 2020
May 08, 2020: The U.S. Food and Drug Administration today announced the following actions taken in its ongoing response effort to the COVID-19 pandemic:

The U.S. Food and Drug Administration authorized the first diagnostic test with the option of using home-collected saliva samples for COVID-19 testing.

Specifically, the FDA issued an emergency use authorization (EUA) to Rutgers Clinical Genomics Laboratory for their COVID-19 laboratory developed test (LDT), which had been previously authorized under the high complexity molecular-based LDT “umbrella” EUA, to permit testing of samples self-collected by patients at home using the Spectrum Solutions LLC SDNA-1000 Saliva Collection Device.

This announcement builds on last month’s EUA for the first diagnostic test with a home-collection option, which uses a sample collected from the patient’s nose with a nasal swab and saline.

Today, FDA issued two documents designed to assist retail food establishments that might have been closed or partially closed during the COVID-19 pandemic in preparing to reopen. The checklist and infographic documents are designed to help businesses that prepare food to serve or sell to the public directly, such as restaurants, bakeries, bars and carry-outs, protect employee and public health as they reopen for business. 

Today, the FDA issued an updated At-A-Glance that provides a quick look at facts, figures and highlights of agency’s response efforts.

The FDA and Federal Trade Commission (FTC) issued warning letters to four companies for selling fraudulent COVID-19 products, as part of the agency’s effort to protect consumers. There are currently no FDA-approved products to prevent or treat COVID-19. Consumers concerned about COVID-19 should consult with their health care provider.

Yesterday, the FDA issued an EUA for the Duke Decontamination System for use in decontaminating compatible N95 or N95-equivalent respirators for reuse by health care personnel when there are insufficient supplies of these respirators resulting from the COVID-19 pandemic. This is the sixth respirator decontamination system FDA has authorized for emergency use during this pandemic and the second based on public health emergency preparedness research funded by FDA.

Yesterday, FDA approved an Abbreviated New Drug Application for lidocaine hydrochloride injection USP, 1%, which is indicated for production of local or regional anesthesia and a drug listed in the FDA Drug Shortage Database. FDA recognizes the increased demand for certain products during the novel coronavirus pandemic and we remain deeply committed to facilitating access to medical products to help address critical needs of the American public.

Diagnostics update to date:

The FDA, an agency within the U.S. Department of Health and Human Services, protects the public health by assuring the safety, effectiveness, and security of human and veterinary drugs, vaccines and other biological products for human use, and medical devices. The agency also is responsible for the safety and security of our nation’s food supply, cosmetics, dietary supplements, products that give off electronic radiation, and for regulating tobacco products.

https://www.fda.gov/news-events/press-announcements/coronavirus-covid-19-update-daily-roundup-may-8-2020

FDA Approves First Therapy for Patients with Lung and Thyroid Cancers

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FDA Approves First Therapy for Patients with Lung and Thyroid Cancers

Table of Contents

May 08, 2020: “The U.S. Food and Drug Administration approved Retevmo (selpercatinib) capsules to treat three types of tumors – non-small cell lung cancer, medullary thyroid cancer and other types of thyroid cancers – in patients whose tumors have an alteration (mutation or fusion) in a specific gene (RET or “rearranged during transfection”).
Retevmo is the first therapy approved specifically for cancer patients with the RET gene alterations.
“Innovations in gene-specific therapies continue to advance the practice of medicine at a rapid pace and offer options to patients who previously had few,” said Richard Pazdur, M.D., director of the FDA’s Oncology Center of Excellence and acting director of the Office of Oncologic Diseases in the FDA’s Center for Drug Evaluation and Research.
“The FDA is committed to reviewing treatments like Retevmo that are targeted to specific subsets of patients with cancer.”

Specifically, the cancers that Retevmo is approved to treat include:

  • Non-small cell lung cancer (NSCLC) that has spread in adults,
  • Advanced medullary thyroid cancer (MTC) or MTC that has spread, in patients 12 and older who require systemic therapy (a treatment option that spreads across the entire body, is not targeted), and
  • Advanced RET fusion-positive thyroid cancer in those age 12 and older that requires systemic therapy that has stopped responding to radioactive iodine therapy or is not appropriate for radioactive iodine therapy.
Retevmo is a kinase inhibitor, meaning it blocks a type of enzyme (kinase) and helps prevent the cancer cells from growing.
Before beginning treatment, the identification of a RET gene alteration must be determined using laboratory testing.
The FDA approved Retevmo on the results of a clinical trial involving patients with each of the three types of tumors. During the clinical trial, patients received 160 mg Retevmo orally twice daily until disease progression or unacceptable toxicity.
The major efficacy outcome measures were overall response rate (ORR), which reflects the percentage of patients that had a certain amount of tumor shrinkage, and duration of response (DOR).
Efficacy for NSCLC was evaluated in 105 adult patients with RET fusion-positive NSCLC who were previously treated with platinum chemotherapy.
The ORR for the 105 patients was 64%.
For 81% of patients who had a response to the treatment, their response lasted at least six months.
Efficacy was also evaluated in 39 patients with RET fusion-positive NSCLC who had never undergone treatment.
The ORR for these patients was 84%. For 58% of patients who had a response to the treatment, their response lasted at least six months.
Efficacy for MTC in adults and pediatric patients was evaluated in those 12 years of age and older with RET-mutant MTC.
The study enrolled 143 patients with advanced or metastatic RET-mutant MTC who had been previously treated with cabozantinib, vandetanib or both (types of chemotherapy), and patients with advanced or metastatic RET-mutant MTC who had not received prior treatment with cabozantinib or vandetanib.
The ORR for the 55 previously treated patients was 69%. For 76% of patients who had a response to the treatment, their response lasted at least six months.
Efficacy was also evaluated in 88 patients who had not been previously treated with an approved therapy for MTC.
The ORR for these patients was 73%. For 61% of patients who had a response to the treatment, their response lasted at least six months.
Efficacy for RET fusion-positive thyroid cancer was evaluated in adults and pediatric patients 12 years of age and older.
The study enrolled 19 patients with RET fusion-positive thyroid cancer who were radioactive iodine-refractory (RAI, if an appropriate treatment option) and had received another prior systemic treatment, and eight patients with RET fusion-positive thyroid cancer who were RAI-refractory and had not received any additional therapy.
The ORR for the 19 previously treated patients was 79%. For 87% of patients who had a response to the treatment, their response lasted at least six months. Efficacy was also evaluated in eight patients who had not received therapy other than RAI.
The ORR for these patients was 100%. For 75% of patients who had a response to the treatment, their response lasted at least six months.
The most common side effects with Retevmo were increased aspartate aminotransferase (AST) and alanine aminotransferase (ALT) enzymes in the liver, increased blood sugar, decreased white blood cell count, decreased albumin in the blood, decreased calcium in the blood, dry mouth, diarrhea, increased creatinine (which can measure kidney function), increased alkaline phosphatase (an enzyme found in the liver and bones), hypertension, fatigue, swelling in the body or limbs, low blood platelet count, increased cholesterol, rash, constipation and decreased sodium in the blood.
Retevmo can cause serious side effects including hepatotoxicity (liver damage or injury), elevated blood pressure, QT prolongation (the heart muscle takes longer than normal to recharge between beats), bleeding and allergic reactions.
If a patient experiences hepatotoxicity, Retevmo should be withheld, dose reduced or permanently discontinued. Patients undergoing surgery should tell their doctor as drugs similar to Retevmo have caused problems with wound healing.
Retevmo may cause harm to a developing fetus or a newborn baby. Health care professionals should advise pregnant women of this risk and should advise both females of reproductive potential and males patients with female partners of reproductive potential to use effective contraception during treatment with Retevmo and for one week after the last dose.
Additionally, women should not breastfeed while on Retevmo.
Retevmo was approved under the Accelerated Approval pathway, which provides for the approval of drugs that treat serious or life-threatening diseases and generally provide a meaningful advantage over existing treatments.
The FDA also granted this application Priority Review and Breakthrough Therapy designation, which expedites the development and review of drugs that are intended to treat a serious condition, when preliminary clinical evidence indicates that the drug may demonstrate substantial improvement over available therapies.
Additionally, Retevmo received Orphan Drug designation, which provides incentives to assist and encourage the development of drugs for rare diseases.

The FDA granted approval of Retevmo to Loxo Oncology, Inc., a subsidiary of Eli Lilly and Company.

The FDA, an agency within the U.S. Department of Health and Human Services, protects the public health by assuring the safety, effectiveness, and security of human and veterinary drugs, vaccines and other biological products for human use, and medical devices.
The agency also is responsible for the safety and security of our nation’s food supply, cosmetics, dietary supplements, products that give off electronic radiation, and for regulating tobacco products.”

https://www.fda.gov/news-events/press-announcements/fda-approves-first-therapy-patients-lung-and-thyroid-cancers-certain-genetic-mutation-or-fusion

U.S. FDA Clears Pluristem’s IND Application for Phase II COVID-19 Study

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U.S. FDA Clears Pluristem’s IND Application for Phase II COVID-19 Study
May 8, 2020: “Pluristem Therapeutics Inc. announced that the U.S. Food and Drug Administration (FDA) has cleared the Company’s IND application for a Phase II study of its PLX cells in the treatment of severe COVID-19 cases complicated by Acute Respiratory Distress Syndrome (ARDS).

The study, titled “A Randomized, Double-Blind, Placebo-Controlled, Multicenter, Parallel-Group Phase II Study to Evaluate the Efficacy and Safety of Intramuscular Injections of PLX-PAD for the Treatment of severe COVID-19” will treat 140 adult patients that are intubated and mechanically ventilated and are suffering from respiratory failure and ARDS due to COVID-19.

The primary efficacy endpoint of the study is the number of ventilator free days during the 28 days from day 1 through day 28 of the study. The objective of the study is to evaluate the efficacy and safety of one or two intramuscular (IM) injections, in three different dosages, of PLX-PAD for the treatment of ARDS resulting from COVID-19.

The primary endpoint determination will be performed at the end of the 28 day main study period. Safety and survival follow-up will be conducted at week 8, 26 and 52.

Pluristem has been treating patients suffering from severe complications caused by COVID-19, such as ARDS and inflammatory complications, in the U.S. and Israel through compassionate use programs.

Preliminary data from these compassionate use programs in Israel was reported on April 7, 2020. A Clinical Trial Authorization (CTA) has also been filed in Europe for a Phase II COVID-19 trial, with the first European clinical sites planned in Germany and Italy.

“We are very pleased to gain clearance to commence our Phase II COVID-19 study in the U.S. We are shifting gears now with a main focus on a rapid initiation of the clinical trial, leveraging our technological and logistical competitive advantages developed through our clinical trial experience in the U.S. and Europe.

We believe we can complete enrollment quickly and we expect to provide guidelines on the expected study duration a few weeks following the commencement of the study,” stated Pluristem CEO and President, Yaky Yanay.

“In the last few weeks, we have received dozens of applications from physicians and families seeking to participate in the Expanded Access per patient program.

We look forward to working with hospitals and physicians on a larger scale to deliver our PLX cells, through an off-the-shelf, easy to use PLX cell product candidate, which may potentially accelerate recovery time from life-threatening conditions, and to improve survival, in the most severe COVID-19 cases.”

PLX Cells for COVID-19 PLX cells are available off-the-shelf and once commercialized, can be manufactured in large scale quantities. Pluristem believes its PLX cells will offer a key advantage in addressing the COVID-19 global pandemic.

PLX cells are allogeneic mesenchymal-like cells that have immunomodulatory properties that induce the immune system’s natural regulatory T cells and M2 macrophages, and thus may prevent or reverse the dangerous overactivation of the immune system.

Accordingly, PLX cells may potentially reduce the incidence and/or severity of COVID-19 pneumonia and pneumonitis leading hopefully to a better prognosis for the patients.

Previous pre-clinical findings of PLX cells revealed a therapeutic benefit in animal studies of pulmonary hypertension, lung fibrosis, acute kidney injury and gastrointestinal injury, which are potential complications of the severe COVID-19 infection.

Clinical data using PLX cells demonstrated the strong immunomodulatory potency of PLX cells in patients post major surgery.

Taken together, PLX cells’ potential capabilities with the safety profile observed from clinical trials involving hundreds of patients worldwide potentially position them as a therapy for mitigating the tissue-damaging effects of COVID-19. “

https://www.pluristem.com/wp-content/uploads/2020/05/FDA-Clearance-COVID-19-FINAL.pdf

PharmaCyte Biotech Receives Medical Devices Registration and Submits Pre-EUA Application to the FDA for COVID-19 Diagnostic

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PharmaCyte Biotech Receives Medical Devices Registration and Submits Pre-EUA Application to the FDA for COVID-19 Diagnostic
May 6, 2020: “PharmaCyte Biotech announced that it has received Medical Devices Establishment Registration with the FDA’s Center for Devices and Radiological Health (CDRH).

The CDRH requires this registration for companies that plan to import medical devices from overseas suppliers.

The company also established itself as the sole U.S. agent for Hai Kang Life Corporation Limited (Hai Kang) for the importation of SARS-CoV-2 in vitro diagnostic test kits.

The company plans to market its PCR-based diagnostic tests kits to Clinical Laboratory Improvement Amendments (CLIA) certified labs throughout the United States.

The company also announced that it is in dialogue with the U.S. Food and Drug Administration (FDA) through a Pre-Emergency Use Authorization (EUA) submission to the FDA.

An EUA is a legal means for the FDA to expeditiously approve new drugs and new medical devices during a declared national emergency.

For COVID-19 diagnostic test kits, the FDA recommends that manufacturers and suppliers file a Pre-EUA with the FDA in order to interactively work towards an eventual EUA submission and approval by the FDA.

The FDA encourages companies to file an early draft so that the FDA examiner can offer feedback to avoid delays during the review of the final EUA application.

Kenneth L. Waggoner, the Chief Executive Officer of PharmaCyte Biotech, stated, “We have satisfied all of the regulatory requirements to get our COVID-19 diagnostic test kits into the country and are actively working with our partner, Hai Kang, through the FDA’s preferred process of a Pre-EUA submission, dialoguing with our assigned examiner towards a final EUA submission to and approval by the FDA.”

PharmaCyte Biotech, Inc. (PharmaCyte) is a biotechnology company developing cellular therapies for cancer and diabetes based upon a proprietary cellulose-based live cell encapsulation technology known as “Cell-in-a-Box®.”

This technology will be used as a platform upon which therapies for several types of cancer and diabetes are being developed.

In addition, PharmaCyte is developing and preparing to obtain approval from the U.S. FDA to commercialize a Covid-19 diagnostic kit to meet a critical unmet medical need for such kits during the current pandemic.

PharmaCyte’s therapy for cancer involves encapsulating genetically engineered human cells that convert an inactive chemotherapy drug into its active or “cancer-killing” form.

For pancreatic cancer, these encapsulated cells are implanted in the blood supply to the patient’s tumor as close as possible to the site of the tumor.

Once implanted, a chemotherapy drug that is normally activated in the liver (ifosfamide) is given intravenously at one-third the normal dose.

The ifosfamide is carried by the circulatory system to where the encapsulated cells have been implanted.

When the ifosfamide flows through pores in the capsules, the live cells inside act as a “bio-artificial liver” and activate the chemotherapy drug at the site of cancer.

This “targeted chemotherapy” has proven effective and safe to use in past clinical trials and results in little to no treatment-related side effects.

PharmaCyte’s therapy for Type 1 diabetes and insulin-dependent Type 2 diabetes involves encapsulating a human cell line that has been genetically engineered to produce and release insulin in response to the levels of blood sugar in the human body.

PharmaCyte is developing the use of genetically modified liver cells and stem cells, as well as beta islet cells, to treat diabetes.

The encapsulation will be done using the Cell-in-a-Box® technology. Once the encapsulated cells are implanted in a diabetic patient, they will function as a “bio-artificial pancreas” for purposes of insulin production.

PharmaCyte’s diagnostic test kits, which were developed by and licensed from Hai Kang Life Corporation Limited (Hai Kang), for detecting the SARS-CoV-2 virus is the Enhanced Real-Time PCR (ERT-PCR) method.

The technology is the same as the previous test for the SARS outbreak in 2003 that was published in the New England Journal of Medicine, but the primers and probes used in the current test is specific for the novel coronavirus.

This means test results are positive only if the SARS-CoV-2 target sequences are present in the test sample.”

https://pharmacyte.com/pharmacyte-biotech-receives-medical-devices-registration-and-submits-pre-eua-application-to-the-fda-for-covid-19-diagnostic/

RedHill Biopharma Receives FDA Approval for COVID-19 Clinical Study

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RedHill Biopharma Receives FDA Approval for COVID-19 Clinical Study
May 08, 2020: “RedHill Biopharma Ltd. announced that the U.S.FDA has approved its IND application for a Phase 2a clinical study evaluating its investigational drug, opaganib (Yeliva®, ABC294640), in patients with confirmed moderate-to-severe SARS-CoV-2 infection (the cause of COVID-19). 

Kevin Winthrop, MD, M.P.H., Professor of Infectious Diseases and Public Health at the OHSU-PSU School of Public Health and Principal Investigator of the study, said: “We are pleased to offer opaganib to hospitalized patients as part of a clinical study and are hopeful to meet the strong unmet need for treatments to decrease the severity and duration of respiratory symptoms due to COVID-19.”

Mark L. Levitt, MD, Ph.D., Medical Director at RedHill, added: “We are grateful to the FDA for the timely review of our IND and look forward to initiating the study.

There is a strong scientific rationale for the potential efficacy of opaganib in the treatment of COVID-19, including pre-clinical data demonstrating that opaganib may inhibit viral replication and reduce levels of IL-6 and TNF-alpha, important mediators of inflammation that are elevated in moderate-to-severe COVID-19 patients.

This is coupled with encouraging preliminary data from the compassionate use program in Israel, which demonstrated objective measurable clinical improvement in all six patients analyzed, including a decrease in required supplemental oxygenation, higher lymphocyte counts, and decreased CRP levels.”

A total of 139 subjects have been dosed with opaganib to date in ongoing and completed Phase 1 and Phase 2 clinical studies in oncology indications, in pharmacokinetic studies in healthy volunteers in the U.S., under the existing FDA-approved expanded access requests from physicians for individual oncology patients and under expanded access for COVID-19 patients in Israel, establishing safety and tolerability in humans both in the U.S. and ex-U.S. 

The randomized, double-blind, placebo-controlled Phase 2a study aims to enroll up to 40 patients with moderate-to-severe SARS-CoV-2 infection and pneumonia requiring hospitalization and supplemental oxygenation.

The Company expects to promptly initiate patient enrollment. Patients will be randomized at a 1:1 ratio to receive either opaganib or placebo on-top of standard-of-care.

The primary objective of the study is to evaluate the reduction in total oxygen requirement over the course of treatment for up to 14 days.

Secondary endpoints include time to 50% reduction in oxygen requirements, the proportion of patients without fever at Day 14, and proportion with negative nasal swabs at Day 14. This clinical trial is not powered for statistical significance. 

Preliminary findings from six moderate-to-severe COVID-19 patients treated with opaganib in Israel under compassionate use have shown that all the patients demonstrated both subjective and objective significant measurable clinical improvement within days following treatment initiation with opaganib, including decreased required supplemental oxygenation, higher lymphocyte counts and decreased C-reactive protein (CRP) levels.

All six patients analyzed were weaned from oxygen and discharged from the hospital. Opaganib has been well tolerated and showed clinical improvement both with and without hydroxychloroquine.

At the time of treatment initiation, all of the patients were hospitalized, suffered from moderate-to-severe acute respiratory symptoms related to SARS-CoV-2 infection, were hypoxic, and required supplemental oxygen while being treated with standard-of-care, mostly hydroxychloroquine.

Pre-clinical data have demonstrated both anti-inflammatory and anti-viral activities of opaganib, with the potential to reduce lung inflammatory disorders, such as pneumonia, and mitigate pulmonary fibrotic damage.

Several prior pre-clinical studies support the potential role of sphingosine kinase-2 (SK2) in the replication-transcription complex of positive-strand single-stranded RNA viruses, similar to coronavirus, and its inhibition may potentially inhibit viral replication.

Pre-clinical in vivo studies have demonstrated that opaganib decreased fatality rates from influenza-virus infection and ameliorated Pseudomonas aeruginosa-induced lung injury by reducing the levels of IL-6 and TNF-alpha in bronchoalveolar lavage fluids. 

Opaganib, a new chemical entity, is a proprietary, first-in-class, orally-administered, sphingosine kinase-2 (SK2) selective inhibitor with anticancer, anti-inflammatory and anti-viral activities, targeting multiple oncology, inflammatory and gastrointestinal indications.

By inhibiting SK2, opaganib blocks the synthesis of sphingosine 1-phosphate (S1P), a lipid-signaling molecule that promotes cancer growth and pathological inflammation.

By inhibiting SK2, opaganib potentially blocks viral replication complex and pathological inflammation.

Opaganib was originally developed by U.S.-based Apogee Biotechnology Corp. and completed multiple successful pre-clinical studies in oncology, inflammation, GI and radioprotection models, as well as a Phase 1 clinical study in cancer patients with advanced solid tumors.

Opaganib received Orphan Drug designation from the U.S. FDA for the treatment of cholangiocarcinoma and is being evaluated in a Phase 1/2a in advanced cholangiocarcinoma and in a Phase 2 study in prostate cancer.

Opaganib is also being evaluated for the treatment of coronavirus (COVID-19). The development of opaganib has been supported by grants and contracts from U.S. federal and state government agencies awarded to Apogee Biotechnology Corp., including from the NCI, BARDA, the U.S. Department of Defense and the FDA Office of Orphan Products Development.“

https://www.redhillbio.com/RedHill/Templates/showpage.asp?DBID=1&LNGID=1&TMID=178&FID=2432&PID=0&IID=15264

Amgen Announces Positive Top-Line Results From Otezla® (apremilast) Phase 3 ADVANCE Study

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Amgen Announces Positive Top-Line Results From Otezla® (apremilast) Phase 3 ADVANCE Study
May 06, 2020: “Amgen announced positive top-line results from the ADVANCE trial, a Phase 3, multicenter, randomized, placebo-controlled, double-blind study to assess the efficacy of Otezla® (apremilast) in adults with mild-to-moderate plaque psoriasis.

The study showed that oral Otezla 30 mg twice daily achieved a statistically significant improvement, compared with placebo, in the primary endpoint of the static Physician’s Global Assessment (sPGA) response (defined as an sPGA score of clear (0) or almost clear (1) with at least a 2-point reduction from baseline) at week 16.

In addition, the week 16 secondary endpoints of achieving at least 75% improvement from baseline in the percent of affected body surface area (BSA); change in BSA total score from baseline; and change in Psoriasis Area and Severity Index (PASI) total score from baseline were each also statistically significant for the treatment effect of Otezla compared with placebo.

“Many patients with mild-to-moderate plaque psoriasis who use topical therapies still have challenges managing their psoriasis,” said David M. Reese, M.D., executive vice president of Research and Development at Amgen.

“We look forward to discussions with the FDA about the potential to bring Otezla, which has already been prescribed to hundreds of thousands of patients with moderate-to-severe psoriasis, to more patients who may need additional therapeutic options.”

The adverse events observed in this trial were consistent with the known safety profile of Otezla. The most commonly reported adverse events that occurred in at least 5% of patients in either treatment group were diarrhea, headache, nausea, nasopharyngitis and upper respiratory tract infection.

Detailed results will be submitted for presentation at an upcoming medical meeting.

In the U.S., Otezla is approved for the treatment of adult patients with moderate-to-severe plaque psoriasis who are candidates for phototherapy or systemic therapy, adult patients with active psoriatic arthritis and for adult patients with oral ulcers associated with Behçet’s Disease.

Since its initial FDA approval in 2014, Otezla has been prescribed to more than 250,000 patients with moderate-to-severe plaque psoriasis or active psoriatic arthritis in the U.S.[1] 

ADVANCE (PSOR-022) is a Phase 3, multicenter, randomized, placebo-controlled, double-blind study evaluating the efficacy and safety of Otezla in patients with mild-to-moderate plaque psoriasis (defined as BSA involvement of 2% to 15%, PASI score of 2 to 15, sPGA score of 2 to 3).

The study randomized 595 patients 1:1 to receive Otezla 30 mg twice daily or placebo for the first 16 weeks. All patients then received Otezla during an open-label extension phase through week 32.

The primary endpoint was the percentage of patients with sPGA response [defined as a sPGA score of clear (0) or almost clear (1) with at least a 2-point reduction from baseline] at week 16.

Psoriasis is a serious, chronic inflammatory disease that causes raised, red, scaly patches to appear on the skin, typically affecting the outside of the elbows, knees or scalp, though it can appear on any location.

 Approximately 125 million people worldwide have psoriasis, including around 14 million people in Europe and more than 7.5 million people in the United States.

 About 80% of those patients have plaque psoriasis.

Otezla® (apremilast) 30 mg tablets is an oral small-molecule inhibitor of phosphodiesterase 4 (PDE4) specific for cyclic adenosine monophosphate (cAMP). PDE4 inhibition results in increased intracellular cAMP levels, which is thought to indirectly modulate the production of inflammatory mediators.

The specific mechanism(s) by which Otezla exerts its therapeutic action in patients is not well defined.

Otezla® (apremilast) U.S. INDICATIONS

Otezla® (apremilast) is indicated for the treatment of adult patients with moderate to severe plaque psoriasis who are candidates for phototherapy or systemic therapy.

Otezla is indicated for the treatment of adult patients with active psoriatic arthritis.

Otezla is indicated for the treatment of adult patients with oral ulcers associated with Behçet’s Disease.

Otezla® (apremilast) U.S. IMPORTANT SAFETY INFORMATION

Contraindications

  • Otezla® (apremilast) is contraindicated in patients with a known hypersensitivity to apremilast or to any of the excipients in the formulation

Warnings and Precautions

  • Diarrhea, Nausea, and Vomiting: Cases of severe diarrhea, nausea, and vomiting were associated with the use of Otezla. Most events occurred within the first few weeks of treatment.

    In some cases patients were hospitalized. Patients 65 years of age or older and patients taking medications that can lead to volume depletion or hypotension may be at a higher risk of complications from severe diarrhea, nausea, or vomiting.

    Monitor patients who are more susceptible to complications of diarrhea or vomiting; advise patients to contact their healthcare provider. Consider Otezla dose reduction or suspension if patients develop severe diarrhea, nausea, or vomiting

  • Depression: Carefully weigh the risks and benefits of treatment with Otezla for patients with a history of depression and/or suicidal thoughts/behavior, or in patients who develop such symptoms while on Otezla.

    Patients, caregivers, and families should be advised of the need to be alert for the emergence or worsening of depression, suicidal thoughts or other mood changes, and they should contact their healthcare provider if such changes occur
    • Psoriasis: Treatment with Otezla is associated with an increase in depression. During clinical trials, 1.3% (12/920) of patients reported depression compared to 0.4% (2/506) on placebo.

      Depression was reported as serious in 0.1% (1/1308) of patients exposed to Otezla, compared to none in placebo-treated patients (0/506).

      Suicidal behavior was observed in 0.1% (1/1308) of patients on Otezla, compared to 0.2% (1/506) on placebo. One patient treated with Otezla attempted suicide; one patient on placebo committed suicide

    • Psoriatic Arthritis: Treatment with Otezla is associated with an increase in depression.

      During clinical trials, 1.0% (10/998) reported depression or depressed mood compared to 0.8% (4/495) treated with placebo.

      Suicidal ideation and behavior was observed in 0.2% (3/1441) of patients on Otezla, compared to none in placebo-treated patients.

      Depression was reported as serious in 0.2% (3/1441) of patients exposed to Otezla, compared to none in placebo-treated patients (0/495).

      Two patients who received placebo committed suicide compared to none on Otezla
    • Behcet’s Disease: Treatment with Otezla is associated with an increase in depression. During the clinical trial, 1% (1/104) reported depression or depressed mood compared to 1% (1/103) treated with placebo.

      No instances of suicidal ideation or behavior were reported in patients treated with Otezla or treated with placebo

      Weight Decrease: Monitor body weight regularly; evaluate unexplained or clinically significant weight loss, and consider discontinuation of Otezla
    • Psoriasis: Body weight loss of 5-10% occurred in 12% (96/784) of patients treated with Otezla and in 5% (19/382) of patients treated with placebo.

      Body weight loss of ≥10% occurred in 2% (16/784) of patients treated with Otezla compared to 1% (3/382) of patients treated with placebo
    • Psoriatic Arthritis: Body weight loss of 5-10% was reported in 10% (49/497) of patients taking Otezla and in 3.3% (16/495) of patients taking placebo
    • Behçet’s Disease: Body weight loss of >5% was reported in 4.9% (5/103) of patients taking Otezla and in 3.9% (4/102) of patients taking placebo
  • Drug Interactions: Apremilast exposure was decreased when Otezla was co-administered with rifampin, a strong CYP450 enzyme inducer; loss of Otezla efficacy may occur.

    Concomitant use of Otezla with CYP450 enzyme inducers (e.g., rifampin, phenobarbital, carbamazepine, phenytoin) is not recommended

Use in Specific Populations

  • Pregnancy: Otezla has not been studied in pregnant women. Advise pregnant women of the potential risk of fetal loss. Consider pregnancy planning and prevention for females of reproductive potential.

    There is a pregnancy exposure registry that monitors pregnancy outcomes in women exposed to Otezla during pregnancy. Information about the registry can be obtained by calling 1-877-311-8972 or visiting https://mothertobaby.org/ongoing-study/otezla/
  • Lactation: There are no data on the presence of apremilast or its metabolites in human milk, the effects of apremilast on the breastfed infant, or the effects of the drug on milk production.

    The developmental and health benefits of breastfeeding should be considered along with the mother’s clinical need for Otezla and any potential adverse effects on the breastfed child from Otezla or from the underlying maternal condition

  • Renal Impairment: Otezla dosage should be reduced in patients with severe renal impairment (creatinine clearance less than 30 mL/min) for details, see Dosage and Administration, Section 2, in the Full Prescribing Information.”

Amgen Completes Acquisition Of Otezla® (apremilast) for the treatment of moderate-to-severe plaque psoriasis, psoriatic arthritis

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