Therapy Development

Orphan Drugs –
sind Mangelware

"Rare disease patients have no time to lose - especially since sufficient preliminary work has already been done at the country's most research-intensive hospitals to get promising therapies off the ground."
Prof. Dr. Annette Grüters-Kieslich
Specific drugs are only available for a good 2% of all rare diseases. There are currently 121 orphan drugs approved in the EU. For a further 63 drugs, the orphan drug status was returned after approval or expired after 10 years.

This includes many cancer drugs, because many tumors are considered rare diseases due to their prevalence of less than 5 in 10,000 people in the EU. For all other specialties, the quotient looks significantly worse. 

Due to the small number of cases in each case, the clinical studies required for the approval of a drug are so complex and expensive that the usual market mechanisms do not work. The sad truth: Rare diseases are not worthwhile for pharmaceutical companies.

Until 1999, there was virtually no market for orphan drugs in Germany. An important milestone for patients was the EU Regulation on Orphan Medicinal Products in 2000. It allowed for a simplified approval process for orphan drugs and granted the manufacturers exclusive rights for a limited period.
Grafische Darstellung, Kreisdiagramm
... the USA had already passed a law for simplified approval for orphan drugs in 1983?

Rising registration figures - financial hurdles

Because some orphan drugs are particularly expensive, discussions about pricing and access to these drugs have been increasing since the number of approvals began to rise in Germany as well.

Our healthcare system, which is financed on the basis of solidarity, is confronted with a wide range of challenges and must keep an eye on the costs for the insured community. However, in 2020, orphan drugs accounted for only about 4.4 percent of outpatient pharmaceutical expenditure in the statutory health insurance system.

The fact is: Causal treatments are available for only a small fraction of rare diseases. Targeted investments in the further development of promising therapeutic approaches can change this.

Today, researchers are increasingly succeeding in deciphering the pathological mechanisms of disease development. They are thus providing starting points for the development of targeted drugs and antibodies that can significantly reduce the symptoms of affected people.

Encouraging treatment successes with gene and cell therapy methods herald a real turning point in medicine. In particular, those affected by rare diseases with a monogenetic cause may hope for a cure if promising research approaches are now consistently pursued.

To advance the development of promising treatment approaches, Alliance4Rare initiated by our foundation, bundles the expertise of research-strong university children's hospitals along a cross-site research strategy for rare diseases.

Gene Replacement Therapies
Technological advances in genetic diagnostics and the identification of pathogenic mechanisms for the first time allow to develop therapies in which a therapeutic gene is introduced into the cells of the diseased organ, where it takes over the function of the defective gene.

Encouraging treatment successes show that gene replacement therapies are in principle capable of restoring the functionality of diseased organ systems. 

They give reason to hope that rare diseases, in particular which have a monogenic cause, can be cured in the future if existing approaches are consistently developed further. 
Adeno-associated viruses (AAV)
The use of adeno-associated viruses (AAV) as "gene ferries", which are used to introduce healthy DNA into the body cells of patients without side effects, is currently showing promise. Zolgesma is the first AAV-based drug to receive regular approval in Germany in 2020, and other promising drugs are in the advanced stages of clinical testing.
Sleeping Beauty approach
Meanwhile, a method similar to the AAV method is still the subject of basic research. In the so-called "Sleeping Beauty" approach, the intact gene sequences are transported virus-free into the target cells on a transposon - these are cellular mobile DNA segments that can change their position in the genome.
Auch das hierzulande als „Genschere“, bzw. international als „Gene Editing“ bekannt gewordene CRISPR/Cas-Verfahren der Geninsertion, das sich durch eine hohe Präzision und Effizienz auszeichnet, ist noch in einem vorklinischen Stadium. Da sich bei der systemischen Anwendung derzeit noch immer Risiken eines Off-target-Effekts im gesamten Genom ergeben, ist vor der klinischen Überprüfung weitere Grundlagenforschung erforderlich.

Opportunity or risk?

There is still insufficient long-term experience with the methods presented. However, they are used for diseases that already lead to death in childhood or are associated with particularly severe developmental limitations if left untreated. For patients with no alternative therapy, experience has shown that the uncertain long-term risk is more acceptable than the devastating short- to medium-term prognoses.

The way to optimize the long-term risk-benefit ratio is clear: 

1. Clinical studies on the efficacy, tolerability and practicability of the therapeutic approaches

2. Data-based acquisition and evaluation of the improvement of quality of life

3. Systematic long-term observations, to clarify possible late effects for children and adolescents. 

Consistent research funding makes a decisive contribution to minimizing the risks for those affected and to sustainably increasing their chances of survival and quality of life.

Eine Frau und ein Mann sitzen auf dem Boden, auf dem eine Kinderzeichnung mit Kreide gemalt ist.
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