Orphan Drug Development: Shelter the World for Patients with Rare Diseases

Orphan drugs are drugs
for the treatment of rare diseases.
The FDA defines orphan drugs as "drugs used to treat, prevent, or diagnose rare diseases that affect fewer than 200,000 people in the United States" (which equates to approximately 6 cases per 10,000 people).

In Europe, a rare disease is defined as affecting fewer than 5 out of 10,000 people
.

Rare disease related data:

● Globally, there are approximately 6,000-7,000 known rare diseases, affecting approximately 300 million people
.

● Only about 5% of diseases have a cure
.

● Of the more than 6,000 known rare diseases, cancer accounts for 11.
1% and infectious diseases account for about 2.
6%.

● 72% of rare diseases are hereditary, the rest are caused
by infections, allergies, environmental or rare cancers.

● 70% of hereditary rare diseases are caused in childhood, and 30% of affected children die before the age of 5
.

The FDA has approved 891 orphan drugs
.

● In the 70s of the last century, there were fewer than 10
types of drugs on the market for rare diseases.

Orphan drug treatment cases for rare diseases

1 Cystic fibrosis

In the 1980s, people with cystic fibrosis rarely lived past the age of
10.
Drugs developed with the assistance of the Orphan Drug Act (ODA), such as dornase alfa (trade name Pulmozyme^®) and tobramycin (Figure 1), have revolutionized the treatment of the disease, dramatically improving patients' quality of life and life expectancy
.
Now such patients usually live into their thirties, and some live into their fifties
.

Figure 1.
Tobramycin Chemical structure

2 Familial hypercholesterolemia

Two researchers were awarded the 1985 Nobel Prize
in Physiology or Medicine for their work on familial hypercholesterolemia, which causes large and rapid increases in cholesterol levels.
Their work led to the development of statins, such as lovastatin lovastatin, Figure 2, which are now commonly used to treat people
with high cholesterol conditions.

Figure 2.
Chemical structure of lovastatin

3 Wilson's disease

Penicillamine (Figure 3) is used to treat the rare genetic disease Wilson's disease, which can lead to the accumulation of copper in the body with fatal results
.
Later, this drug was found to be effective in treating arthritis
.

Figure 3.
Penicillin Chemical Structure

4 PLA2G6-related neurodegenerative diseases

The FDA granted initial approval
for RT001 (ethyl dideuterated linoleate for the treatment of PLA2G6-associated neurodegeneration (type 1 intrabrain iron deposition neurodegeneration, Figure 4) orphan drug in 2017.

Figure 4.
RT001 Chemical structure

5 Transthyretin protein-associated hereditary amyloidosis

Patisiran (trade name Onpattro^®) involves a novel mechanism for RNA therapy that blocks the production of abnormal forms of transthyretin and has received preliminary FDA orphan drug approval and breakthrough therapy preliminary approval
.
Patisiran was officially approved by the FDA in
2018.

Orphan Drug History, Market Status and Outlook

The passage of the Orphan Drug Act (ODA) in the United States in 1983 inspired similar policies around the world
.
Orphan drugs now account for about one-third of all newly approved drugs and biologics (Figure 5).

Figure 5.
Comparison chart of the number of orphan drugs and non-orphan drugs approved by the FDA from 2004 to 2019

The United States was the first country to legislate for orphan drugs, and other countries have followed suit, such as Singapore (1991), Japan (1993), Australia (1998), and the European Union (EU) (2000).

The United States dominates the global orphan drug market, accounting for approximately 70% of global sales
.
The therapeutic areas of orphan drugs cover many fields including oncology, hematology, neurology, endocrinology, cardiovascular, respiratory, immunotherapy and many others
.
The primary indication for orphan drugs is oncology, as different types of rare cancers
continue to arise in an aging global population.

Spurred by the development of orphan drugs from regulators around the world, many pharmaceutical companies are increasingly enthusiastic about
investing in such products.
According to forecasts, the global orphan drug market will grow at a compound annual growth rate (CAGR) of about 12% from 2019 to 2024, which is about double the projected growth rate of the non-orphan drug market
.

Currently, the global market is worth about $150 billion for orphan drugs, and by 2024, the market size of orphan drugs is expected to reach $242 billion, accounting for about 20%
of global prescription drug sales.

The driving force behind the development of orphan drugs

Market exclusivity is often cited as the most important motivator for
orphan drug development.
Market exclusivity is an important measure
to protect brand-name drugs from generic drug competition.
Different situations have different periods
of market exclusivity.
Market exclusivity aims to promote a balance
between new drug innovation and generic competition.

FDA's regulations on the market exclusivity period:

1) NCE (New Chemical Entity): In most cases, branded drugs with new active ingredients have a five-year exclusivity period;

2) Orphan Drug: a 7-year market exclusivity period for a new brand of drugs that affect fewer than 200,000 patients in the U.
S.
(or more, but pharmaceutical companies still have no hope of paying development costs); This market exclusivity prevents the FDA from approving another product with the same active portion for the same disease or condition, unless the second product is shown to be clinically superior to the first
.

3) New Clinical Investigation: In some cases, such as the development of a new formulation or method of administration (e.
g.
tablets instead of liquids), or the discovery of a new indication for the original active ingredient (drug repurposing), drugs containing previously approved APIs can obtain a three-year exclusivity period
.
To do this, pharmaceutical companies must conduct new clinical studies
.

In addition to market exclusivity, protocol assistance and tax credits for clinical trials are also an incentive
for pharmaceutical companies to develop orphan drugs.
The driving factors behind the orphan drug strategy include:

● Low threshold for approval

● Longer market exclusivity

● Lower marketing costs

● Faster market share

● Premium pricing

● Tax credits

● R&D grants

● FDA fee waiver

● Shorter R&D cycle

● Greater regulatory access

Increasingly, orphan drug designation goes hand in hand with accelerated development pathways
.
In the U.
S.
, accelerated pathways include Fast Track, Priority Review, Accelerated Approval, Breakthrough Therapies, and Advanced Regenerative Medicine Therapeutics
.
EMAs have preferential conditions
for "conditional marketing permission" and "priority review".

Orphan drug market

1 Orphan drug market leader

Therapies for rare diseases come in a variety of forms, from traditional small molecule drugs to macromolecular biologics to cell and gene therapies
.
The three companies that generated the highest revenue from orphan drugs in 2018 were Celgene, Roche and Novartis, all with global sales of more than $10 billion
.
Celgene was the leader in the orphan drug market in 2019 and expects to maintain this position in 2024, with global sales of $13.
7 billion
.
Johnson & Johnson, Roche, Novartis, and Takeda occupy the remaining top five, with their projected total revenue of more than $60 billion in 2024, accounting for 26%
of the total orphan drug market.
The leading orphan drugs of each of the 10 companies expected to dominate the market in 2024 are shown
in Table 1.

Table 1.
Top 10 Orphan Drugs and Their Leading Products (2018-2024)

Small molecule drugs Revlimid^® (lenalidomide, treatment of multiple myeloma, smoking myeloma, and myelodysplastic syndrome (MDS)) and Tafinlar^® (dabrafenib, Drugs to treat cancers associated with mutated versions of the BRAF gene) are the main orphan drugs for Celgene and Novartis, respectively, while Roche's monoclonal antibody Hemlibra^® (emicizumab-kxwh) leads its orphan drug portfolio
.
3 Consistent with oncology as the primary indication for orphan drugs, 5 of the 10 highest-paying drugs treat malignancy
.
Companies such as Vertex Pharmaceuticals, Sanofi and Alexion are pioneers in the sale of non-oncology orphan drugs, which are used to treat respiratory, metabolic and blood disorders
, respectively.

Figure 6.
Lenalisomide and darafenib chemical structure

With these types of revenues, it's no surprise that big pharma is aggressively looking to acquire biotech companies with orphan drug assets
.
As recently as 2019, Bristol-Myers Squibb completed its acquisition of Celgene for $74 billion, and Roche acquired Spark Therapeutics
for $4.
8 billion.

2 Key business models of orphan drugs

● Classic hyperorphan disease: significant morbidity or mortality due to lack of suitable treatment options, genetic abnormalities resulting in missing or dysfunctional enzyme variants, and costly enzyme replacement therapy
.

● Perinatal developmental disorders: The development and delivery of healthy babies is an area
with great potential.

● Genetically defined subpopulations: Pursue genetically defined subpopulations
in rare diseases.

● Refractory subpopulation: represents a late, relapsed, or severe subpopulation
of patients with a specific disease.

● Orphan oncological diseases: late treatment of small cancer types or metastatic cancers in which the population is relatively small and the unmet need is significant
.

● "Curative" orphan diseases: orphan diseases
that are expected to be cured due to technological improvements related to cell and gene therapy.

● Supportive orphan care: Opportunities
also exist in target patient groups that require symptomatic support for orphan diseases.

3 Major challenges in orphan drug manufacturing

● Time pressure: Not all orphan drugs will receive a fast-track approval pathway, but the challenge for developers who do fast-track approval is to race against time to develop a reliable drug manufacturing process
in the shortest possible time.

● Production of low-volume, high-value products: Orphan drugs for the treatment of rare diseases and smaller patient populations require small batch production
.
Although the commercialization of orphan therapies involves a small volume, scaling up must still be addressed
.

● Development of analytical methods: Analytical methods need to be developed and verified
in a timely manner.

● Drug stability: The API and formulation process can affect the stability of the API, so it is important
to conduct stability testing to understand how the quality and stability of the final drug product are affected.

● Scarce patients: Rare diseases mean that the number of patients is very small and it takes longer to identify and recruit a sufficient number of patients for clinical trials
.
Many times, patients who qualify for final participation in a study are often distributed across the globe, making trial management complex and expensive
.
Conducting large randomized trials, or even two or more pivotal confirmatory studies, is very rare
for the orphan drug industry.
Given these challenges, regulators prefer to base on less comprehensive but supportive approval to expedite the passage of many orphan drugs through clinical trials and ultimately for patients
.

summary

Thanks to regulatory and government incentives, as well as the confidence that humanity has built up in the fight against life-threatening diseases, pharmaceutical companies are increasingly focusing on rare diseases
.
In the orphan drug industry, there are key connections between multiple processes, such as early product design decisions and developability, manufacturability, and "patient centricity," all driven
by a desire to reduce risk while accelerating timelines.

Despite growing calls to change orphan drug legislation, the growth of the orphan drug market shows no signs of
slowing down.
On March 4, 2022, the FDA announced that it would continue to prioritize rare diseases, and this statement is clearly supported
by the facts.
The share of drugs used for rare diseases is growing
.
In the first three months of 2022, six of the nine FDA-approved new drugs were for rare diseases (Table 2).

Three are cancer drugs, two are blood disease drugs, and one is a neurology drug
.
The prosperity of the orphan drug market will undoubtedly be a great benefit
for those suffering from rare diseases, especially those in children.

Table 2.
Orphan drug approved by the FDA in the first quarter of 2022