Abstract

Orphan drugs have been utilized to treat rare diseases since last three decades. The
incidences of such diseases have been increasing at a greater pace expanding at a more
prominent pace than the speed with which drugs are explored and created to treat such
diseases. One of the major reasons is that the pharmaceutical industry is not very keen to
carry out research on the development of orphan drugs as these drugs do not capture a
bigger market. This is the present situation inspite of the various incentives provided in
the Orphan drug act. However, in this review, we have tried to focus on the results of few
of the recently conducted clinical trials carried out towards the development of such
orphan drugs. The indications of a drug may also be considered as “orphan” since a
substance may be used in the treatment of a frequent disease but may not have been
developed for another, more rare indication.

Key phrases:

Introduction

As defined in the United States, any drug developed under the Orphan Drug Act of
January 1983 (ODA) is an orphan drug. The ODA is a federal law concerning rare
diseases (orphan diseases) that affect fewer than 200,000 people in the United States or
are of low prevalence (less than 5 per 10,000 in the community). As early as 1983, the
Public Health authorities realised that legislation on orphan drugs was needed signing of
the 'Orphan Drug Act'. This law defines the 'orphan drug' with regard to prevalence
(frequency) of the disease for which it is indicated in the American population. In the US,
the idea of 'orphan drug' does not simply cover pharmaceutical or biological products. It
also covers medical devices and dietary or diet products. The OOPD (Office of Orphan
Products Development) was created within the FDA (Food and Drug Administration). It
is responsible for advancing the accessibility of safe and efficacious products for the
treatment of rare diseases. The 'orphan' status permits the medication support to benefit
from incentives for the development of these products until the marketing approval.

The Food and Drug Administration has charged The Office of Orphan Products
Development (OOPD) to commit its goal to advancing the improvement of products that
demonstrate promise for the diagnosis and/or treatment of rare diseases or conditions. It
administers the major provisions of the orphan drug act (ODA), which provide incentives
for sponsors to develop products for rare diseases. The ODA has been very successful for
more than 200 drugs and biological products for rare diseases have been brought to
market since 1983. In contrast, the decade prior to 1983 saw fewer than ten such products
come to market. In addition, the OOPD administers the Orphan Products Grants Program
which provides funding for clinical research in rare diseases. The FDA funds the
development of orphan products through its grants program for clinical studies. The
Request for Applications (RFA) announcing availability of funds is published in the
Federal Register each year – usually in June. Eligibility for grant funding is extended to
medical devices and medical foods for which there is no reasonable expectation of
development without such assistance. Applications are reviewed by panels of outside
experts and are funded by priority score.

The so-called 'orphan drugs' are intended to treat diseases so rare that sponsors are
hesitant to create them under normal advertising conditions. The process from the
discovery of a new molecule to its marketing is long (10 years in average), expensive
(several tens of millions of euros) and very uncertain (among ten molecules tested, only
one may have a therapeutic effect). Developing a drug intended that is expected to treat a
rare disease does not allow the recovery of the capital invested for its research.

Orphan drugs may be defined as :

Drugs that are not developed by the pharmaceutical industry for economic reasons but
which respond to public health need.
Actually, the indications of a drug may also be considered as ' orphan ' since a substance
may be used in the treatment of a frequent disease but may not have been developed for
another, more rare indication.

A medicinal product designated as an orphan drug is one that has been developed
specifically to treat a rare medical condition referred to as “orphan disease.” It may be
defined as drugs that are not developed by the pharmaceutical industry for economic
reasons but which respond to public health need. The spiraling cost of drug development
coupled with strict regulations; along with the low return on investment are some
important factors that discourage pharmaceutical innovators from developing orphan
drug products. Such rare diseases in small patient populations have a few approved drug
treatment options available. Orphan drugs are an important public-health issue and a
challenge for the medical community. Modern society still has a lack of options for the
effective treatment of patients with rare diseases. As one of the consequences of this, the
demand for public health protection has increased the economic burden of patient
suffering from such diseases. Scientific advances have given researchers a new tool to
explore these orphan diseases, which are often more complex than common diseases. On
the brighter side, these rare diseases when taken together cannot be called rare at all.
There are approximately 7000 different types of rare diseases and disorders with more
being discovered today. It has been reported that there are about 250 new rare cases
reported every year, however the acceptable treatment is available only for 200-300
orphan diseases. It is known that the 80% of these rare diseases are of genetic origin and
the rest have environmental, bacterial, viral or unknown origin. Overall orphan diseases
are often chronic, progressive, disabling; even life threatening and most of these have
effective or curative treatment, having low prevalence and high complexity

The US Food and Drug Administration (FDA) and the European Medicines
Agency (EMA) have announced a more streamlined process to help regulators better
identity and share information throughout the development process of orphan drug and
biologic products, which are developed specifically to treat rare medical conditions. Both
agencies have agreed to accept the submission of a single annual report from sponsors of
orphan drug and biological products designated by both the US and the EU.

Currently, if an orphan product was granted designation on the exact same day in
both the US and EU, the sponsors must submit separate reports to their respective
regulatory agency. The use of one annual report will also benefit sponsors by eliminating
the duplication of efforts and by simplifying the process that meets the annual reporting
requirements of both the US and the EU for orphan designated products.

The single annual report, much like separate agency reports, will provide
information to both agencies on the development of orphan medical products, including a
review and status of ongoing clinical studies, a description of the investigation plan for
the coming year and anticipated or current problems in the process that may impact their
designation as an orphan product. The single annual report submission to both regulatory
agencies is voluntary and will apply only to sponsors who have obtained an orphan
designation status for their product from both the FDA and EMA.
Expected Side Effects

 Skin discoloration in cases of extravasation

 Thrombophlebitis in cases of peripheral vein infusion in less than 1% of cases
 The disappearance of superficial venous system
 Iron overload (250 g dose of haem contains 22.7 mg of iron content)

With regards to ethanol, side effects such as:

 flushing,
 tachycardia,
 weakness,
 other
 dysphoric symptoms

Allergic Reaction

 facial and thorax erythema

 urticaria
 facial angiodema
 dysphagia
 dyspnea coughing

Treatment

 Premedication and dysensithezation

Conclusion:

Orphan drugs qualify as drugs which are scientifically feasible but not viable from an
economic or financial perspective either because it is intended for rare diseases where the
number of patients who might benefit is too small, the drug is withdrawn due to some therapeutic
or economic complication, or the drug lacks further development for mass production. In the
case presentation, the patient is diagnosed with acute intermittent porphyria which was classified
as an orphan disease. Acute intermittent porphyria (AIP) is a rare metabolic disorder that is
characterized by partial deficiency of the enzyme hydroxymethylbilane synthase (also known as
porphobilinogen deaminase) and has a prevalence of approximately 1 in 20,000.The classic triad
of AIP described is of abdominal pain, mental changes, and autonomic dysfunctions. However,
90% of them manifest as autonomic changes (tachycardia and labile hypertension) associated
with abdominal pain, constipation, nausea, and vomiting, while 10% present with central nervous
system changes in the form of seizures, impaired consciousness, mental status changes, and
encephalopathy. The known drug that could treat this disease is an orphan drug named heme
arginate with a trade name Normosang which acts as an enzyme replacement. Haem is an
enzyme within our body and is created through a complex chemical reaction. In cases of
poryphyria, there exist a defect in haem production and this phenomenon causes accumulation of
poryphyrins which is an intermediate chemical.

The case presented was a 25-year-old female patient diagnosed with acute intermittent
porphyria, who had an anaphylactic reaction while receiving haem arginate. She developed an
allergic reaction to the drug while on her dose minutes after administration. The patient was
treated with a desensitization protocol for patients with hypersensitivity to haem arginate. Basing
on another case presentation of a 29-year-old woman also diagnosed with AIP. On the second
year of her treatment with haem arginate, during her 25th dose , the patient developed dyspnea
and severe urticaria and a decrease in blood pressure same symptoms developed by the 25-year
old patient stated above. These were considered symptoms of an acute anaphylactic reaction
which was supposedly caused by prolonged administration of heme arginate. Haem arginate is
the reaction product of hemin and L-arginine in a mixture of propylene glycol, ethanol, and
water. Heme arginate remains stable in ampules for years. Because heme arginate contains other
substances besides hemin, one of them might have caused the reaction. Due to this, hematin, a
lyophilized powder consisting of hemin, sodium carbonate, and sorbitol was tried in substitution.
However, the reason why hematin was not the first choice for treatment of poryphyria patients
was because hematin has been shown to cause disturbances in hemostasis, mainly because of its
degradation products is very unstable and should be administered within an hour after the
powder has been dissolved in sterile water. It is very unstable and should be administered within
an hour after the powder has been dissolved in sterile water. Thus, haem was considered to be
safer and more beneficial. But since the patient developed allergic reactions to the haem arginate,
hematin was administered to also pinpoint possible cause of reaction. Surprisingly, this greatly
eased the acute porphyric attack without bringing on shock, which indicated that hemin itself
was not the substance causing the shock. Heme arginate is very effective at easing the symptoms
of acute porphyric attacks, and has been thought to be very safe. It has therefore been
recommended as initial treatment. Many case studies have presented similar situations which
supports the claim that heme arginate is not always safe, because frequent administration may
lead to development of an immediate hypersensitivity reaction and anaphylactic shock. Orphan
drugs are hard to work with, not only because of its economic complications but because it is
dealing with rare diseases. Further researches and in-depth analysis of both drugs and the disease
should be conducted to ensure optimal patient care.
 Bulletin Points:

 Haem Arginate is a drug for enzyme replacement which supplements for heme deficiency
in the body thus blocking aggregation of intermediate heme metabolites that causes
manifestation of disorder.
 AIP is a multifactorial disorder which could arise due to genetic or environmental factors.
It is characterized by insufficient activity of an enzyme in the biosynthetic pathway.
 Hematin and haem arginate are used for treatment of poryphyria but latter proved to be
more beneficial. However, prolonged usage was proven to develop allergic reactions
having hematin in substitution There is deficient explanations regarding the
pathophysiological mechanisms underlying hypersensitivity to the drug involved thus
further studies should be conducted.

References:
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Chapman et al. (2018). Desensitization in patients with

hypersensitivity to haem arginate: A case report. Retrieved on
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Sharma et. al. (2010). Orphan drug: Development and Strategies. Retrieved on September 24, 2019
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