New Drug Development For Mediterranean Anemia Associated Iron Overload

New Drug Development For Mediterranean Anemia Associated Iron Overload

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Part 1: Mediterranean Anemia

Introduction

In the need to develop an orphan drug for any disease, several critical factors need evaluations. These factors include the epidemiology factors and previous limitations faced in the development of a drug to treat the same condition. In the United States, Mediterranean Anemia is one the most important orphan disease affecting only 1000 individuals. However, Mediterranean Anemia treatments with contemporary medicines such as iron chelators have been known to cause an iron overload. This has necessitated the need for development of a new drug that will counter iron overload challenge.

Mediterranean Anemia

Mediterranean Anemia can also be called the β-Thalassemia Major or Cooleyanemia. Thalassemia Major is a division of thalassemia . It is a genetic complication affecting the generation of hemoglobin through the defective β. This hemoglobin chain causes the emission of damaged hemoglobin that causes red blood cells to be damaged. A blood transfusion is necessary in overcoming the problem. The red blood cells number in the blood decreases. This condition is not healthy for the normal operation of the body system. This means that the normal functioning of the red blood cells is affected by the complication (NHI, 2014). The blood is not capable of picking up the right amounts if oxygen from the lungs for the supply to the other body parts. The damage to the red blood cells is so intense that the coordinating effect of the blood constituents is affected negatively. The patients develop a complication that makes it difficult for their breathing patterns to be maintained. The oxygen that is available for intake by the blood is ignored. The different purposes for oxygen is necessary in the body are left behind causing an abnormal functioning of the body system (Iron health alliance, 2014).

Thalassemia major diagnosis

The production of new drugs calls for an understanding and developing of the right diagnosis screening. The patients have small red blood cells and slow red blood cell counting. Thalassemia is diagnosed through blood testing and molecular testing. These procedures make it possible for the diagnosis to be carried out before birth (FDA, 2014). A careful screening of the blood comes up with a better understanding of the constituent components that have been negatively affected by the minimal red blood cells. The diagnosis needs to be carried out before the symptoms can be noticed because this advances the general procedures of determining the best corrective action.

In any medical complication, prevention is better than cure. The diagnosis perspective comes in with the right framework of procedures that are necessary in dealing with the complication at its early stages. The testing is carried out from time to time in an attempt to make an evaluation of the different signs that may be indicative of the condition’s development within the body system (Eugene, 2001). Thalassemia calls for an adequate understanding of the red blood cells counts in the blood system. Such a procedures creates a better evaluation of the right perspective in dealing with the other side effects. The diagnosis process facilitates the different strategies that are necessary in developing the scientific approach in dealing with the procedural aspects of the treatment procedures.

Thalassemia symptoms

Tiredness, weakness, inability to breathe, pale colorations, irritation, yellowing of the skin, bone protrusions on the face, low growth, swelling of the abdomen and Darkurine are the main signs. A quality understanding of all signs is useful in the development of new drugs and quality screening on the potential participants (NHI, 2014). The patients are not capable of carrying out their daily activities because the ability of the body to use oxygen in the normal function has been greatly affected. Those suffering from the complication are incapable of controlling their breathing patterns. The inability of the red blood cells to deal with the oxygen intake determines the rate at which an advancement of the productive ability of the body system is determined.

Β-Thalassemia treatment

Blood transfusion facilitates the replacement of the defective blood cells. This process needs to be carried out on a constant basis. Blood transfusion may result in iron overloading that is necessary in the establishment of new drugs for the treatment of iron overloading. The blood transfusion considers the at rate at which the patient’s body requires the red blood cells that are necessary in the oxygen uptake process (Iron health alliance, 2014). A professional approach in the transfusion process is necessary in ensuring that the right blood component are integrated into the patient’s system for an excellent performance of the blood to be realized.

Iron overload

The disease results in the production of more iron in the body and the constant blood transfusion. Extra iron in the body causes heart and endocrine system damages. Glands for the production of hormones for regulating body processes are damaged. A continuous intake of iron crates a condition that may not be favorable to the body system of the patients. A qualitative approach is necessary in ensuring that the different issues of consideration are taken into account before the final treatment procedure can be realized (FDA, 2014). It is important that the treatment procedure does not result in a additional complication in the body system. Doctors need to come up with a professional approach of dealing with the advanced procedures that necessary in dealing with the iron overload. Any given procedure in dealing with Mediterranean Anemia considers the bets clinical practices in administering the drugs.

Iron regulation

The intestinal absorption can be regulated. Mediterranean anemia patient’s iron level can be controlled through regulating the rate of blood transfusions. Blood transfusions need to consider the amount of iron that is required in the body systems of the patients. A thorough screening of the blood facilitates a consideration regarding the critical blood factors that necessary in maximizing the health of the patients. The intervals between the different transfusions are to be controlled through an evaluation of the iron requirement in the patient’s body. Different aspects of the transfusion procedures determine the ease with which the treatment procedures facilitate a better understanding of the patient’s conditions.

Iron chelators

Iron chelators have small molecules binding on iron ions. Different chelators can be manufactured. Transferring is a complicated protein from animals. Chelators have a iron ion bond that has chemical inertia. Chelators detoxify the metal irons that avoid poisoning. Iron chelators are useful in determining the rate at which the transfusion process is to come up with a conclusive approach in ensuring that Mediterranean Anemia is completely treated (Eugene, 2001). Through a prevention of the poisoning effect, the blood transfused functions in the normal way. The uptake of oxygen by the red blood cells is therefore maximized for a health life to be realized by the patient.

Iron overload drugs

A study an analysis of the current drugs is necessary in the development of new drugs.

Desferal® (DeferoxamineMesylate), Exjade®(Deferasirox), and Ferriprox® (Deferiprone) are common in treating iron overloads. A study of their regulatory helps in the development of regulation plans in understanding the complications that exist. Time and resources are saved in this entire process regarding the understanding of the current drugs.

1- Desferal®(DeferoxamineMesylate)

Approval Status: Approved May 25,2000

Route of Administration: Parenteral.

Main drawback: Injection, Renal and hepatic toxicity.

(Eugene, 2001)

2- Exjade®(Deferasirox)

Approval Status: Approved Nov 02,2005

Route of Administration: Oral

Main drawback: cause low blood count. WBC and platelets, renal toxicity

(Iron health alliance, 2014)

3- Ferriprox®(Deferiprone)

Approval Status: Approved Oct 14,2011

Route of Administration: Oral.

Main drawback: Blackbox warning(AGRANULOCYTOSIS/NEUTROPENIA)

4- HYPERLINK “http://reference.medscape.com/drug/kalbitor-ecallantide-999410″FerrokHYPERLINK hin

Approval Status: Under development

Route of Administration: Oral

Main drawback: Not yet officially established.

(FDA, 2014)

Prevalence

Studies indicate that that 30 out 1,000 people globally suffer from Mediterranean Anemia (Cooley’s anemia Foundation, 2014). The condition is more prevalent in Greece, Italy and the Middle East since 150 to 300 individuals out of 1,000 suffer from the condition (Cooley’s anemia foundation, 2014). Southeast Asia and Africa come in second and third respectively since 50 to 100 out of 1,000 individuals suffer from the condition in Asia; and 50 out of 1,000 individuals in Africa (Cooley’s anemia Foundation, 2014). Surprisingly, the United States has a significantly lower prevalence rate since only 3 to 5 out of 1.2 million people have the condition. In fact, out of the 313,121,421 people living in the United States only 783 to 1,305 have Mediterranean Anemia (Iron Health Alliance, 2014).

Figure 1.Global Mediterranean Anemia, by severity

Table 1.Global Mediterranean Anemia, by severity

number Region severity

1 Europe (Italy, Greece) 150-300/1000

2 southeast Asia 50-100/1000

3 African-Americans 50/1000

4 US 3-5/1,200,000

worldwide 30/1000

In the US, the disease is an orphan disease because only Mediterranean Anemia affects a small percentage of individuals (Table 1). On the hand, European countries such as Italy and Greece are characterized by high incidences (Table 1) (Thalassemia interntional Federation, 2014). Consequently, phase 2 and 3 can be done in Europe to take advantage of the high incidences in those countries notably, according to table 2, preschool-age children (pediatrics) are highly affected by the disease. This has made it imperative to develop the necessary measures

Table 2: Global Mediterranean Anemia, by number of individuals affected

PART 2: FICTIONAL NEW DRUG FOR IRON OVERLOAD TREATMENT

Fictional New Drug-Ferrara

The new drug to treat Mediterranean Anemia is known as Ferrara and it come in tablet and powder forms for adults and infants accordingly. The drug is administered orally once a day and it needs to be taken with food for safety and effectiveness. The drug is water-soluble and therefore it binds to iron molecules through creating chemical bonds. Ferrara is a mew molecular entity since it has not been yet marketed in the US since it has not yet been approved by the Food and Drug Administration (FDA). Furthermore, the drug is made from chemical synthesis process and like the rest of the iron chelating agents; the metal-ion attached to the chelator is chemically inert (NHI, 2014). However, unlike other agents the drug has a lower molecular weight.

CMC profile for Ferrara

The main goal of the new drug is to deal with the existing problems existing associated with contemporary iron chelators. The properties include Efficient absorption from the gastrointestinal tract (Braunwald, 2001), Oral administration of the new drug and Tablet and powder Formulation

Efficient absorption from the gastrointestinal tract (Braunwald, 2001)

For development purposes, we need to assume that this new drug will be a superior alternative to the rest of the contemporary drugs. One of the main problems associated with contemporary iron chelators is the efficiency by which they are absorbed by the body once they get into the gastrointestinal tract. For example, Desferrioxamine that is one of the most effective chelators is characterized by substandard absorption from the gastrointestinal tract. Studies indicate that many contemporary chelators like desferrioxamine decreases the levels of iron-vitamin B complex and liver extract oral, which in turn reduces drug absorption from the intestines and stomach (Medscape Pediatric Thessalemia, 2014). In fact, the drug must be administered parentally through continuous intravenous infusion or continuous subcutaneous infusion. The medical apparatus for administrating desferrioxamine makes the treatment overly expensive and its availability in many parts of the world is quite tricky (NHI, 2011)

Oral administration of the new drug

The disadvantages associated with pumps that are mostly used in continuous intravenous infusion or continuous subcutaneous infusion is the fact that patients have to walk around with a needle inserted in their bodies in order to continually receive desferrioxamine dosage. Notably, patients are very indifferent to this apparatus due to its invasive nature (Cooley’s anemia Foundation, 2014).On the other hand, the development of an oral dosage is beneficial because it enhances absorption in the gastrointestinal tract. Better absorption means that a patient will not have to constantly need additional dosage during the day once they take one pill.

Tablet and powder Formulation

Furthermore, the oral administration, which comes in tablet and powder, will save individuals who do not like having to deal with needles or constantly being fixed to the parenteral administrating device (Cooley’s anemia Foundation, 2014). The tablet and powder forms of the drug are very efficient in maintaining the stability of drugs. The powder form for pediatric use was chosen over the liquid solution since not only does the powder maintain the stability but it also gives the drug longer shelf life than the liquid solution (NHI, 2011). Unlike contemporary iron chelators, the drugs solid form maintains the stability in the chemical ion-bonds, which carry the effectiveness of the drug.

New Drug Development Phases

Pre-clinical development

One of the first pre-clinical stage concerns has to with blood volume. Traditionally, the test subjects for drugs have always been rodents such as rats and guinea pigs because they share 99% of the genes humans have (FDA, 2011). However, in order to properly evaluate the effect of Ferrara over the body’s iron concentration, the test needs to use primates. Primarily for pediatrics, the process involving selecting the animal to undergo the test needs to have an approximate weight range that compares to human infants in order to have a feasible estimate and prediction of the most effective dosage to be used by pediatrics (FDA, 2011). Several factors are important to note in the selection process such as the bioavailability, absorption rate, metabolism rate and protein binding of the primate’s body (NHI, 2014).

The first part of the clinical trial process would be to inject the animal with an iron overload in order to effectively match the degree which individuals with Mediterranean Anemia are affected (Clinical Key, 2014). One of the goals of this drug is to quicken the absorption rate for an iron chelator. Therefore, time sampling is essential during the process because it will provide an estimation of the dosage regimen for both the humans and primates. Furthermore, the ion bonds might bind too quickly for the possibility of measuring so it is essential the serum level of the drug to be obtained (Clinical Key, 2014).

Phase 1 Clinical Development

The first phase of this clinical study needs that we use a small number of people ranging from about 10-20. Contemporary drug administration test for Mediterranean Anemia usually requires a small number of healthy individuals to take part in the study. However, the high level of toxicity involved with this particular profile will cause normal levels of iron to substantially drop which can lead to many complications (Orpha.net, 2014). In fact, the test subjects will only be individuals who are suffering from high levels of iron overload. Furthermore, the tests for our drug will take place in the United States and as a result, we need a solution to the problem of getting the enough participants in one place. Due to the country’s low prevalence rate, we have to fly in participants from all from all the country into one location in order to control and minimize costs, the oversight duties, and regulations, which will have to be dealt with if we were to set up testing centers all over the country.

The first phase will be also characterized with the initial stages of administering the dosage and it is crucial to begin by giving small dosages followed by keen observation relating to some of the expected side effects contributed by iron chelators. Some of the expected side effects include anaphylactic shock, blurred vision, cramps in the legs and stomach, diarrhea, dizziness, fever, hypertension, itching, visual disturbances and vomiting (Cooley’s anemia Foundation, 2014). Some of the more severe side effects that should be carefully monitored in the long term include kidney failure, liver damage or the loss of hearing.

Phase 2 & 3 Clinical Development

Unlike the first phase of this test, the second stage needs close to 200 volunteers to participate in the study (FDA, 2011). Therefore, that eliminates the option of conducting the clinical development in the United States due to its low prevalence rate. The ideal setting to carry out the study is in Europe particularly in Italy and Greece because high prevalence rate (Table 1 and figure 1). Consequently, not only do the countries have high prevalence rates of Mediterranean Anemia but also they have similar development regulations as those in the United States. The regulations involve subjects having to comply with regulations that govern clinical research. These compliance regulations in many countries can be quite cumbersome since they can require a lot of time and physical involvement through appearances (FDA, 2011). However, the United States and European countries only require individuals to submit their applications through the Electronic Common Technical Document.

Studies in the second phase of the clinical development are primarily focused on the effectiveness of a new drug and monitoring the safety aspect of symptoms and the degree to which they are either going as expected or deviating from expectations (Iron Health Alliance, 2014). Furthermore, the effectiveness of the test is going to be measured in comparison to other iron chelating treatments. The use of Placebo medication has always been a part of medical studies however, for Anemia that will be unethical due to the severity of the illness. Phase 3 is simply an extension of the objective of phase 2 however; the test involves close to 500 subjects in order to increase the random testing aspect of the study (NIH, 2011). To increase safety levels in the study is important to include a surrogate endpoint to the study protocol. A surrogate endpoint is way to predict the outcome of the study based on the intended results in terms of treatment or the severity of the expected side effects which can sometimes involve death depending on the complexity of the treatment in question (Braunwald, 2001).

Regulatory Consideration

The test study of Ferrara is going to be done in two different nations and it is crucial that we follow regulations not only according to FDA requirements but also according to the host country during phases 2 and 3. In the US, we are going to need an Investigational New Drug (IND) application and in Europe, we are going to need a Clinical Trial Application (CTA) (FDA, 2014). Such a study is going to require a lot of diligence because the slightest assumption that does not follow either the FDA or host country’ protocols can very well result in a rejection of our study. While the host country might accept the study is if completely follows their protocols, the FDA can reject it because their guidelines and regulations have to be followed if the drug is to be marketed in the US. To make sure the test study go according to protocol it is important that Institutional Review Groups (IRBs) are present in both countries to monitor the process (Braunwald, 2001). Once the research process is over and we have the FDA’s permission to market the drug, it is also important to also get a Market Authorization Application (MAA) to be able to market the drug in Europe.

Part III: Regulatory Time Line

Fast track designation.

There are few victims of Mediterranean anemia in America and northern Europe. The medical researchers have done little to fight against Mediterranean anemia and this is attributed to the small number of people who are not disease tolerant. However, quite a good number of the anemia patients die due to lack of personalized attention. Therefore, Mediterranean anemia can be an epidemic especially to those with a family history of the condition, which is caused by lack of iron. We intend to innovate a drug to cure this and we definitely require support. We are expected to give details about the new drug that we are about to develop to the FDA (Food and, Drug Administration) so that we can get it support to launch the drug (Braunwald, 29)

The drug that we are about to develop will be a solution to Mediterranean anemics since it will provide their bodies with iron. After clinical tests, it was established that the drug does not have any harmful effects to the body. Previously, the victims of this disease were reporting serious side effects as a result of administering some anemia drugs. Some of these side effects include vomiting, skin rushes and loss of appetite. The drug that we are about to make seeks to eliminate side effects that patients have been experiencing.

We have also identified that most patients diagnosed with Mediterranean anemia are subjected to drugs for a long time. It will be a different issue with this new drug since it will only be administered for a short time and the patient will be completely cured. Patients will feel the effect of using the drug in few hours after taking it. This means that the drug reacts very fast and begins to take effect before the patient’s condition worsens.

This drug is also highly compatible with other drugs. There certain cases whereby Mediterranean anemic are required to take more than one type of drug in the same duration. Due to the incompatibility of the drugs, there are situations where patients have to quit administering different kinds of drugs to avoid the related negative effects. With this new type of drug, there is no problem taking a wide range of drugs, which is necessitated by patient’s condition.

Accelerated approval

The objective of the accelerated approval is verifying that the drug actually helps to cure anemia. We intend to involve the FDA in order to determine the appropriateness of this new drug in administering Mediterranean anemia. Successful approval of this drug by the FDA, which is a requirement, will help us secure continued assistance from it (FDA, 2011). The new drug approval process will involve using clinical endpoints or surrogate endpoints, which can help to save time. The FDA can use the evidence based on the increased presence of iron in the patients’ body in a few weeks of administering the new drug, which is the beginning of the healing process, to approve the drug (Eugene, 2001 p. 83)

We are also looking forward to carrying out studies to confirm the clinical benefits that this new drug has to people suffering from Mediterranean anemia. These confirmatory trials, if successfully done, can help to eliminate the above requirement by FDA and still get its financial assistance. As mentioned earlier, patient do not administer this drug for a long time before they start feeling well. This means the patients will not be hospitalized for a long time hence go back to their daily routines in full health within a short period of treatment.

Pediatric indication development

Mediterranean anemia affects pediatrics patient’s more than adult patients. Therefore, a development plan that does not accommodate pediatric patients is meaningless (Table 2). It has been realized that prolonged use of this new drug can lead to iron overload. Young people (below 18 years) have a very high sensitivity to iron overload. If one does not get treatment in time, iron overload can lead to serious complications, for example heart attack (Eugene, 2001 p.54)

With this regard, various ways of preventing iron overload should be exercised to improve the lives of Mediterranean anemia patients. These include paying attention to duration of administering the drug and altering blood transfusion program. We are making efforts to ensure the right dosage for every pediatric patient and submitting information regarding this issue to the relevant agency like the Pediatric Investigation Plan (PIP) and the FDA (FDA, 2011).

29552902847340Pediatric indication development

accredited approval indication

Confirmatory study in case of accredited approval

Pediatric indication development

accredited approval indication

Confirmatory study in case of accredited approval

5664203155315Phase 3

Phase 3

30613351217295Orphan designation application

Fast track designation application

Orphan designation application

Fast track designation application

3462020295910Conducted in the US

Conducted in the US

6959601445895Phase 2

Phase 2

695960263525Phase 1

Phase 1

Figure 2:fictional new drug regulatory time line

References

Braunwald, E. (2001) Harrison’s Principles of Internal Medicine. New York: McGraw-Hill

Clinical Key. (2014). Hermatology Thalassemia. Retrieved April 18, 2014 from

<https://www.clinicalkey.com/topics/hematology/thalassemia.htHYPERLINK hml Retrieved April 18 2014>

Cooley’s Anemia Foundation. (2014). Retrieved April 18, 2014 from

< http://www.thalassemia.org/ Retrieved April 18, 2014>

FDA. (2011). FDA approves Ferriprox to treat patients with excess iron in the body. Retrieved April 18, 2014 from <http://www.fda.gov/newsevents/newsroom/pressannouncements/ucm275814.htm>

FDA. (2014) September 12, 2013: Oncologic Drugs Advisory Committee Meeting Announcement. Retrieved April 17, 2014 from <http://www.fda.gov/AdvisoryCommittees/Calendar/ucm364526.htm>

Iron health alliance (2014) Disease management. Retrieved April 18, 2014<http://www.ironhealthalliance.com/index.jsp> 

Medscape pediatric Thalassemia (2014) Retrieved April 18, 2014 from

e http://emedicine.medscape.com/article/958850-clinical. Retrieved April 18, 2014

NHI (2014) National Heart, Lung, and Blood Institute. Retrieved April 18, 2014 https://www.nhlbi.nih.gov/

NHI (2011) Cellular Hematology Scientific Research, See https://grants.nih.gov/grants/guide/rfa-files/RFA-HL-98-022.html. Retrieved April 18, 2014

Thalassemia international Federation (2014). See HYPERLINK “http://www.thalassaemia.org.cy/”http://www.thalassaemia.org.cy/ Retrieved April 18, 2014

Orpha.net (2014) Meditation Anemia See Orpha.net, Retrieved April 18, 2014

Eugene, B. (2001) Harrison’s Principles of Internal Medicine. New York: McGraw-Hill

FDA (2014) September 12, 2013: Oncologic Drugs Advisory Committee Meeting Announcement,

See Retrieved April 17, 2014

Iron health alliance (2014) Disease management, Retrieved April 18, 2014 from

HYPERLINK “http://www.ironhealthalliance.com/index.jsp”http://www.ironhealthalliance.com/index.jsp

NHI (2014) National Heart, Lung, and Blood Institute, Retrieved April 18, 2014 from

HYPERLINK “https://www.nhlbi.nih.gov/”https://www.nhlbi.nih.gov/