Assessment of Dupilumab Efficacy and Safety in Asthma Treatment

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A NEW DRUG FOR ASTMA TREATMENT
Contents
A NEW DRUG FOR ASTHMA TREATMENT....................................................................................................1
INITIAL PHASE OF DRUG DEVELOPMENT.................................................................................................1
GENERAL INFORMATION REGARDING THE DRUG (DUPILUMAB)........................................................1
FDA REVIEW FOR DUILUMAB..............................................................................................................1
STAGES OF DRUG REVIEW...................................................................................................................2
DETERMINING THE SAFETY AND EFFECTIVENESS OF THE DRUG.........................................................5
CLINICAL TRIAL EXPERIENCE................................................................................................................5
EFFECTIVENESS....................................................................................................................................6
LISTING ND MEETING OBLIGATION TO FDA.........................................................................................6
FDA REVIEW PROCESS.........................................................................................................................7
DRUG LABEL / PACKAGE INSERT..........................................................................................................8
LEARNING OUTCOMES FROM THIS LESSON........................................................................................9
REFERENCES..........................................................................................................................................10
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INITIAL PHASE OF DRUG DEVELOPMENT
GENERAL INFORMATION REGARDING THE DRUG (DUPILUMAB)
Asthma is one of the leading conditions that make a person suffer physically as well as
emotionally. 5.4 million People in UK are diagnosed and being treated for asthma in UK
currently. Almost 3 people die every day due to asthma in UK. In 2016 the data crossed
ever mark by 1410 death in the year due to asthma (Israel and Reddel, 2017). Among
many other drugs available in the market, I consider use of a monoclonal antibody
named Dupilumab for treatment of asthma. This monoclonal antibody drug belongs to
human IgG4 subclass (Shirley, 2017). It has approximately molecular weight of 147kDa.
It is used in adult asthmatic patient with severe to moderate extent of disease. This is
the choice of drug for patients whose condition is uncontrolled by other modalities and
topical drugs of choice. It basically works by inhibiting interleukin-4 (IL-4) and
interleukin-3 (IL-3). It binds to the IL-4Rα subunit that is shared by the receptor complex
of these interleukin 3 and 4 (Kim and Doherty, 2016). These are two main proteins in
human body that signals the type 2 inflammatory reaction that produce asthma. The
mechanism behind inhibiting the signaling is associated with result of decreasing the
inflammatory biomarkers that are fractional exhaled nitric oxide, eotaxin 3 and
immunoglobulin E (IgE).
FDA REVIEW FOR DUILUMAB
FDA stands for Food and Drug Administration that is an association that approves the
use of any drug before it can be prescribed and sold out to the counters ( Frank et al,
2014). The journey of the drug from the laboratory to the patients has multiple steps of
pre-clinical and clinical trials but the most important step is the FDA affiliation of
approval, without this the drug cannot be consumed or prescribed in health and social
care system in USA. FDA approval system is extensive and full of reviewing of minute
details and based solely on the results of evidence provided. FDA works with CDER
(Center for Drug Evaluation and Research) that provides proper evidences for the
approval process of any drug. Main criteria of FDA are the drug should be safe and
effective for the desired use. FDA inspects every step for drug development from clinical
trials, analyze the target condition and available treatments, asessments of benefits and
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risks from clinical data, and strategies for managing risks like drug labelling and risk
mitigation strategies (Ciociola et al, 2014).
STAGES OF DRUG REVIEW
1. Standard treatment available for the condition in the market
 The standards treatment available for asthma in the market since years is
albuterol and levalbuterol.
 These are short term beta agonist that is usually taken with use of portable hand-
held nebulizer machines.
 Long acting bronchodilators also can be used that includes salmeterol, formoterol
and preformist (Israel and Reddel, 2017).
 Leukotriene modifiers block the inflammatory always and avoid inflammation the
airway that causes asthma.
 Mast cell stabilizer, theophylline and immune modulators are also used to treat
asthma.
 Some drugs are taken individually and some are taken as multidrug therapy by
mixing it together.
There are various drug combinations and variety of medications provider over the table
to treat asthma but majority of it has some major complications and side effects. The
control drugs usually cause hoarseness, sore throat, oral thrush and infections.
Tachycardia is also found as common side effects of relievers. Oral steroids may disturb
the sleep patterns, cause hyperactivity and increased diet. Since the drug Dupilumab is
interleukin inhibitor that directly acts on the inflammation pathway it does not work on
other systems and have major side effects. It is collected from Chinese hamster ovary
cell line. The side effect of bio derived drug is less than synthetic ones so this drug has
less harmful effects and is more reliable. Taking in consideration all these facts about
our drug, I would like to suggest my sponsor to convince FDA to review this drug and
after all the procedures of clinical trials and authentication processes if the results are
satisfactory and good for intended use the drug shall be casted in the market to benefit
the population (Wenzel et al, 2013).
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2. Investigational new drug application
Before administering any drug to conduct the clinical trial in humans, an approval from
FDA is necessary to. For this the company must submit a form to FDA notifying the
experimental pharmaceutical agent that will be used in their trial this application is
known as Investigational New Drug Application. It includes pre-clinical testing studies,
manufacturing information of the chemical, Clinical Trial protocols, information of
investigators who will conduct the study and other commitments. Since decades this
application is meant to be the first pioneer in the drug industry in the US. The sponsor
has role to first present the results of preclinical studies that are the (animal studies) for
the given drug and must explain it to the FDA that what process is going to take place in
the clinical trial of the drug with human as subjects. The review of this application and
approval is done by the members in FDA and the IRB board which consist of panel of
scientists and doctors who are eligible to review the forms and approve that the drug is
safe for use in human or not (Frank et al 2013). Any clinical trial cannot be initiated
without getting an approval from all the members of this panel. Institutional review board
has major duty to review the forms of new drug application and approve only after
knowing about the signed consent of the participants, objectives of the trial, risks,
dosage, schedule and duration. They also make sure all participants should have
required thorough information of the risks of the trial and have provided their consent.
Phase 1
In this phase of the trial the investigators spend months to look for the signs of the drug
use in the sample of healthy people in whom they have administered the drug. The
sample size in this phase is usually 20 to 80 participants. The focus of this phase is to
determine the value of highest dose of drug in human before it shows any side effects.
With evaluating the safe dosage at this phase investigators also evaluate best method
to administer the drug (Ginn et al, 2013).
Phase 2
Now in this phase several hundred participants are given the medication to treat the
disease. The sample is usually 100-300 patients suffering the said diseases e.g.
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asthma. The dose of the medication is kept like what is determined as safe dose in
previous phase. Here investigators keep an eye on the participants and monitor them
for months and years to determine the efficacy of the drug and potential side effect it
can cause. Tis phase still do not have such sample size to generalize the results but it
helps in conduction of phase 3. It is seen that only 33% of all medications in clinical trial
can move to Phase 3 (Ginn et al, 2013).
Phase 3
Medications that reach this phase and pass it can last for several years in the market
maintaining gold standards of treatment. Here about 1000-3000 participants are
selected who has the health condition for which drug is used. Aim of this phase is to
determine the confirm the drug’s efficacy, evaluate its effectiveness, monitor side effects
as compared to older regime. Usually randomized sampling is done some of
participants receive older drugs while some receive new drug and hence the effects are
monitored and compared. FDA usually requires has 3 reports of any trial to approve
drug for safe use in market (Ginn et al, 2013).
Phase 4
Phase 4 usually is conducted after FDA approves the marketing of the new drug. In this
phase the drug is evaluated for its long-term effects in general population. These are
usually safety studies once drug is marketed and during sales. NDA means New Drug
Application and this is written by the sponsor to the FDA. This application is approved
after phase 3 and before the drug is out in the market (and phase 4 studies) the NDA
meeting can be organized between sponsor and the DA where FDA can be given
reference of results of trial ad asked to consider drug for marketing. Based on the
results and their review FDA has 60 days to either approve the drug or issue response
letter (Ginn et al, 2013).
This approach for the reviewing and getting approval for the drug is easier and effective
method. It reduces the effort that otherwise would be very tedious and time consuming
in nature. The routine meetings between the sponsor and the FDA make the things
clear and more understandable. Here the company with the help of sponsor can
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convince DA by showing the mechanism of drug and explaining the better efficacy of
their drug to already preset regime.
DETERMINING THE SAFETY AND EFFECTIVENESS OF THE DRUG
1. Safety
Safety of the drug is determined before its use in humans and health care. The safety is
determined during all phases of clinical trials esp. pivotal studies. The important safety
information about Dupilumab is gathered by three pivotal studies in adults with
moderate to severe asthma. The trials were looking after 2888 adults with asthma who
received subcutaneous injections of 600mg (Shirley, 2017). Safety can also be
determined after the drug is out in the market through safety surveillance and adverse
drug reporting of the study
The side effects for Dupilumab are as follows
 Injection site reaction
 Conjunctivitis and keratitis
 Swollen or puffy eyelids
 Oral herpes
 Eye itching, herpes simplex virus infection, dry eye etc.
These details are collected from clinical and preclinical trials of the drug.
CLINICAL TRIAL EXPERIENCE
Among all the phases of trials conducted with Dupilumab, safety and efficacy of
Dupilumab is majorly determined by phase 3 clinical trial by conducting three placebo
controlled double blind, multicenter trials and one dose ranging trial (Trial 4).
In one of the phase 3 studies, total 1902 participants with moderate to severe asthma
were selected and were introduced in the study by randomized sampling method for
group study on comparison basis. Our groups were selected to receive different doses
of treatment.). Patients were randomized to receive dupilumab in different doses and
compared with corticosteroids and placebo.
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The results indicated that primary outcomes measured annualized rate for severe
exacerbation of asthma at 52 week and absolute change from baseline in pre-
bronchodilator FEV1 at week 12. Secondary outcomes revealed absolute change from
baseline in FEV1 in patient with eosinophil count ≥0.3 Giga/L. The efficacy of drug was
identified as drug induced exacerbation was declined and lung functioning in overall
population receiving Dupilumab increased. In patients with 150 eosinophilia count the
exacerbation data improved and in patient with higher eosinophil count efficacy
improved (Israel and Reddel, 2017). Dupilumab also reduced use of oral corticosteroid
and improved baseline FEV1 irrespective of eosinophil count. Where patients with
moderate-severe asthma suffer from proper treatment option for their asthma,
Dupilumab works on different biology and provides new treatment option to the patient
Though some of the side effects were identified as conjunctivitis, injection site reaction,
eye pruritus, keratitis, dry eye and herpes simplex.
EFFECTIVENESS
The effectiveness of any drug can be known once the drug is out in the market after its
phase 3 and used in general population. With Dupilumab, an extension of its phase 3
study, TRAVERSE is done to describe the long term safety.750 participants were given
dupilumab and no placebo or comparator is used. An open label cohort study is
undergoing and the primary outcome is treatment emergent adverse events . In
previous studies of Brodalumab, showed comparatively very safe profile and is effective
in providing relief to the patients with uncontrolled asthma as compared to what other
drugs as inhalers and oral corticosteroids can provide (McCracken, Tripple and
Calhoun, 2016).
LISTING ND MEETING OBLIGATION TO FDA
 IND (Investigational New Drug) APPLICATION SUBMISSIONMEETING
This is initial step and first exposure to FDA for the drug is done in this meeting. Here
initially the application form for new drug is submitted to the FDA and IRB. The
application form along with evidence of drug safety and results of preclinical trials and
other studies are submitted. FDA and IRB members review the application and give
green signal for the drugs to undergo clinical trial or can keep it on hold if they find it
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unsafe (Ciociola et al, 2014). They can also make it as partial hold process where trial
will be allowed but with notable restrictions. 30-day time is usually waited after
submission of the application and FDA under 30 days gives following answer to the
sponsor.
 Phase 1 report (IND safety report)
The phase one trial usually includes couple of day observation, any suspected side
effects, and observed adverse effects of the drug on human should be reported to FDA
in no more than 7 days from the trial initiation and observation. Other studies on animals
and other trials if suspects any adverse reaction or any kind of life threatening reaction
from drug it should be reported to FDA in less than 15 days of observation (Downing et
al, 2014).
 End of phase 2A meeting
This meeting is held to report all the findings from phase 1 trials. It is essential to report
all the findings of the trial, and safety issues with the drug. If there are no harmful effects
identified and correct dose and administration method is recognized by the phase we
can continue with another phase. The sponsor submits details to FDA to provide
appropriate information regarding the drug.
 End of phase 2 meeting
This meeting aims to report the pharmacokinetic and pharmacodynamics findings of the
drug and to find the efficacy of the drug for phase 3 trial. It is essential to determine the
efficacy and primary efficacy markers of drug before continuing with phase 3. This
report is to be submitted less than 60 days of the phase 2 completion (Downing et al,
2014).
 Phase 3 reporting
Here the phase 3 findings are reported in same manner as done in previous meetings.
As annual report for phase 2 is submitted same is done for phase 3 but as phase 3 on
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goes for several years still the NDAA findings will back the findings and help in
formulation of the report about efficacy of the drug (Downing et al, 2014).
FDA REVIEW PROCESS
The very first stage of FDA review that is submission of NDA application can be of two
types as submitted that is standard review and priority review.
Standard review process is defined as the review process which has duration of 12
months and last for around 10 months since the submission of application, whereas,
priority review refers to the process is completed in 8 months and DA approves priority
review if the applicant provides evidence for effectiveness and efficacy of drug than
existing treatment of the disease.
FDA also visit sites where clinical trials are taken place to ensure the safe and authentic
procedure for drug development. Every year around 700 clinical sites are visited by
FDA. There are three kinds of meeting a sponsor has with FDA. Type A meeting is held
for discussing on hold applications. Type B meetings are the end of phase 2, phase 3
reporting, pre- NAD meetings etc. whereas Type C meeting are the ones where the
marketing and review of the drug is discussed with the sponsor. FDA takes 75 days
after the application for review to conduct Type C meeting.
DRUG LABEL / PACKAGE INSERT
The package insert is the written or printed document that is inserted with the drug
package that contains the information regarding the use of drug. It also aims to provide
information regarding the composition of drug and dosage to be prescribed by the
professionals. The insert or label usually shows the basic information about drug as
clinical pharmacology, dosage, administration method, indication and use.
 Indication for use
Dupilumab is an interleukin 4 alpha antagonist indicated for use in patients with severe
to moderate asthma whose disease is not adequately controlled with the other
treatment regime.
 Dosage and administration
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Administration by subcutaneous injection
Recommended dose is 600mg (300mg injection) 2 subcutaneous dose repeated by one
dose every week
Solution is in a single prefilled syringe single use with a needle shield. 300 mg fill
 Contraindication
Know hypersensitivity for Dupilumab
 Warnings and precaution
Hypersensitivity reaction: monitoring for the reaction in case
Conjunctivitis and keratitis: consult your doctor in case of worsening eye symptoms
Comorbid asthma; patient with comorbid asthma should never stop the use of this drug
without consultation
 Adverse reaction
Most common adverse reaction is injection site reaction (≥1%)
Keratitis, conjunctivitis, herpes simplex, blepharitis, eye pruritus, dry eye
To report SUSPECTED ADVERSE REACTIONS, contact at 1-844-387-4936 or FDA at
1-800-FDA-1088 or www.fda.gov/medwatch.
 Drug interaction
Avoid use of live vaccines with use of Dupilumab
LEARNING OUTCOMES FROM THIS LESSON
1) After studying this lesson and creating this plan for drug review I learnt various things
regarding the FDA drug review system. I learnt about the NDA that is initial and
essential step for process of drug development and about the clinical trials. I updated
my knowledge regarding the different phases of clinical trials and how they work. I also
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learnt about the uncontrolled persistent asthma disease that is one of the leading
causes of low quality life in the country. The prevalence of disease is increasing and the
current treatment modalities cannot provide relief from the persistent exacerbation of
severe to moderate asthma patients. Dupilumab will help in assuring better lung
function and FEV1 for reduced exacerbation.
2) I also learnt about the different phases of meeting with FDA and how to overcome the
challenges through these meetings. The importance of the FDA approval for
development of any drug and whole procedure of FDA approval, I learnt that while
submitting the application to FDA it is essential for the company to submit all the details
and to provide details on how their drug is effective than other already present
treatments. While the process of drug development is going on the sponsors are in
routine contact of FDA and take feedback and advice for the same from the members of
FDA ad IRB. FDA notices the continuous efforts of company and the sponsor of the
communication and seeking advice during the process and provides advice for better
scope of drug in the market and support the approval process.
REFERENCES
1) Ciociola, A.A., Cohen, L.B., Kulkarni, P., Kefalas, C., Buchman, A., Burke, C.,
Cain, T., Connor, J., Ehrenpreis, E.D., Fang, J. and Fass, R., 2014. How drugs
are developed and approved by the FDA: current process and future
directions. The American journal of gastroenterology, 109(5), p.620.
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2) Downing, N.S., Aminawung, J.A., Shah, N.D., Krumholz, H.M. and Ross, J.S.,
2014. Clinical trial evidence supporting FDA approval of novel therapeutic
agents, 2005-2012. Jama, 311(4), pp.368-377.
3) Frank, C., Himmelstein, D.U., Woolhandler, S., Bor, D.H., Wolfe, S.M., Heymann,
O., Zallman, L. and Lasser, K.E., 2014. Era of faster FDA drug approval has also
seen increased black-box warnings and market withdrawals. Health
Affairs, 33(8), pp.1453-1459.
4) Ginn, S.L., Alexander, I.E., Edelstein, M.L., Abedi, M.R. and Wixon, J., 2013.
Gene therapy clinical trials worldwide to 2012–an update. The journal of gene
medicine, 15(2), pp.65-77.
5) Israel, E. and Reddel, H.K., 2017. Severe and difficult-to-treat asthma in
adults. New England Journal of Medicine, 377(10), pp.965-976.
6) Kim, A.S. and Doherty, T.A., 2016. New and emerging therapies for
asthma. Annals of allergy, asthma & immunology: official publication of the
American College of Allergy, Asthma, & Immunology, 116(1), p.14.
7) Levine, W.C., Davison, J.K., Dempsey, M., Donovan, K., Driscoll III, W.D.,
Fishman, G.A. and Sims, N.M., Codonics Inc, 2014. Drug labeling. U.S. Patent
8,639,525.
8) McCracken, J., Tripple, J. and Calhoun, W.J., 2016. Biologic therapy in the
management of asthma. Current opinion in allergy and clinical
immunology, 16(4), p.375.
9) Pocock, S.J., 2013. The size of a clinical trial. Clinical trials: a practical approach,
pp.123-141.
10)Shirley, M., 2017. Dupilumab: first global approval. Drugs, 77(10), pp.1115-1121.
11)Wenzel, S., Castro, M., Corren, J., Maspero, J., Wang, L., Zhang, B., Pirozzi, G.,
Sutherland, E.R., Evans, R.R., Joish, V.N. and Eckert, L., 2016. Dupilumab
efficacy and safety in adults with uncontrolled persistent asthma despite use of
medium-to-high-dose inhaled corticosteroids plus a long-acting β2 agonist: a
randomised double-blind placebo-controlled pivotal phase 2b dose-ranging
trial. The Lancet, 388(10039), pp.31-44.
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