Orphan Designation of ATMPs for Rare Diseases: MPS II Case Study

August 22, 2022

Orphan Designation of ATMPs for Rare Diseases: MPS II Case Study Many advanced therapy medicinal products (ATMPs) in development in the EU are for rare diseases and conditions. Since the establishment of the Advanced Therapies Regulation in 2008 in the European Union, ATMPs are emerging as a growing and increasing class of innovative medicinal products which potentially present an alternative approach to traditional small molecule medicinal products or biologicals (learn more about ATMPs and their classification in this blog article). ATMPs can represent a more specific and causal/targeted treatment for many rare diseases for which the specific underlying cause is known, e.g., a gene defect; therefore, this trend is expected to continue. Indeed, gene therapy medicinal products seem to be of greatest interest possibly due to the potential they have for curing certain rare diseases, in particular those caused by single gene defects. Consequently, a rise in requests for services offered by the European Medicines Agency could be expected. Cooperation between sponsors and regulators on the development of orphan drug ATMPs could support successful outcomes.

Because a return on the investment into the development of the medicine for rare diseases may not be obtained, the development of medicines designated for small patient populations may have restricted commercial value. Securing an orphan designation carries with it determinate advantages endeavoured to incentivizing the development of new medicines for rare diseases, since orphan designation applications can be submitted early in the development of a drug and clinical data are not required. Learn more about orphan designations and their incentives in this blog article.

On another note, when target diseases have available treatment options, the notion of significant benefit is of pivotal importance to orphan designation for medicines in development: significant benefit means that a medicine provides a clinically relevant advantage or a critical contribution to patient care, weighed against established treatments. In addition, significant benefit may mean that an orphan medicine is designed for patients for whom available treatments do not work, it is likely to ameliorate patient outcomes in association with an established treatment, or it is as effective as other treatments but is substantially simpler or more convenient to utilise.

For a real-world context, let’s examine the case of orphan designations for the treatment of mucopolysaccharidosis type II.

Mucopolysaccharidosis type II (Hunter's syndrome)

Mucopolysaccharidosis type II (MPS II, also known as Hunter's syndrome) is a rare inherited disease caused by the lack of an enzyme called iduronate-2-sulfatase. This enzyme is needed to break down substances in the body called glycosaminoglycans (GAGs). Since patients with mucopolysaccharidosis type II cannot break these substances down, the GAGs gradually build up in most organs in the body and damage them. This causes a wide range of symptoms, particularly difficulty breathing, difficulty walking, mental disability, and behavioural problems. Without treatment, these symptoms become increasingly severe. MPS II primarily affects male patients. It is a seriously debilitating and life-threatening disease that leads to mental disability and death during youth. Depending on the severity and form of MPS II, the onset of disease occurs around 18 months to 4 years after seemingly normal development. The average life expectancy for patients with nonattenuated neuronopathic MPS II is usually not beyond the second decade of life, whereas patients with the milder attenuated form can survive into their fifth or sixth decade (Muenzer et al., 2021a).

Some patients are treated with haematopoietic stem cell transplantation (HSCT), a procedure where the patient’s bone marrow is replaced by stem cells from a donor; the stem cells develop into healthy blood cells that can produce the missing enzyme. However, the limitations of HSCT as a treatment are the scarcity of suitably matched donors and the risk of graft versus host disease or transplant rejection despite offering a single administration for lifelong supply of enzyme. For MPS II, HSCT has been restricted in preference of enzyme replacement therapy (ERT). At present, idursulfase, given by infusion into a vein, is authorised in the European Union (EU) for the treatment of MPS II. This is an ERT for the enzyme that patients are lacking. While ERT can significantly slow disease progression in MPS II, it is not curative. Standard of care consists of supportive care to treat the consequences of progressive somatic and CNS disease not benefited by ERT and is the only available option for patients with this disease.

There are a total of eight active orphan medicinal products for MPS II.

Date of decision EU Designation date Product Opinion
10 August 2015 EU/3/15/1540 Adeno-associated viral vector serotype 9 containing the human iduronate-2-sulfatase gene Granted based on nonclinical data only which indicated that treatment may improve the outcome of patients with this condition:


08 November 2017 EU/3/17/1943 Recombinant adeno-associated viral vector serotype 9 containing human iduronate-2-sulfatase gene Granted based on nonclinical data only which indicated that a single treatment may improve behavioural problems and problems with thinking, learning and memory:


17 January 2018 EU/3/17/1956 Adeno-associated viral vector serotype 2/6 encoding zinc-finger nucleases and the human iduronate 2-sulfatase gene Granted based on nonclinical data only which indicated that treatment may slow the worsening of the patient's mental functions:


26 February 2019 EU/3/19/2140 Humanised IGg1 monoclonal antibody targeting human transferrin receptor conjugated to human iduronate-2-sulfatase Granted based on nonclinical data only which indicated that treatment may reduce GAGs build-up in different tissues and organs, including the brain:


06 January 2021 EU/3/20/2391 Idursulfase Granted based on nonclinical data (ongoing clinical trials and FDA designation) which indicated that treatment may stabilise cognitive function in children under the age of 6 years:


20 August 2021 EU/3/21/2493 Autologous CD34+ haematopoietic stem and progenitor cells genetically modified with the lentiviral vector encoding for the human iduronate 2-sulfatase gene Granted based on nonclinical data only which indicated that treatment may improve neurological and skeletal abnormalities:


15 October 2021 EU/3/21/2512 Idursulfase beta Granted based on nonclinical data (ongoing clinical trials) which indicated that treatment may improve neurological symptoms:


16 March 2022 EU/3/22/2592 Adeno-associated virus serotype HSC 15 expressing human iduronate 2-sulfatase Granted based on nonclinical data only which indicated that treatment may reduce GAGs build-up in different tissues and organs, including the brain:



Elaprase (idursulfase, cited above) is no longer an orphan medicine. It was originally designated an orphan medicine on 11 December 2001 and was withdrawn from the Community register of orphan medicinal products in January 2017 at the end of the 10-year period of market exclusivity.

Interestingly, two other idursulfase medicinal products have obtained orphan designations despite the established idursulfase treatment. Indeed, EU/3/20/2391 and EU/3/21/2512 were granted each an orphan designation for intrathecal and intracerebroventricular administration, respectively, in MPS II patients, as opposed to the current intravenous injection.

Clinical experience of ATMPs such as gene and genome editing therapies targeting MPS II have demonstrated their potential to be more promising prospects when compared to ERT, especially in terms of CNS pathology and long-term benefit. For instance, the non-integrating viral vector AAV was adopted for an in vivo gene therapy via an intracisternal route of administration following promising results using an AAV serotype 9 capsid (AAV9) in MPS II mice showing the amelioration of CNS pathology.  In an ongoing Phase I//II, multicentre, open-label dose escalating study, twelve paediatric subjects received intracisternal injections of AAV9 encoding for iduronate-2-sulfatase gene and are monitored for neurocognition and behaviour, and it is estimated to be completed by 2024 [ClinicalTrials.gov Identifier: NCT03566043].  Moreover, the innovative technology of genome editing has been utilised in vivo using zinc finger nuclease (ZFN) to replace the defective IDS gene through a specific double strand break. An in vivo approach using an AAV2/6 viral vector with albumin locus targeting ZFN for expression in the liver was conducted in three dose cohorts in patients. Urinary levels of GAGs showed a reduction from baseline levels [ClinicalTrials.gov Identifier: NCT03041324].

Orphan Designation of ATMPs for Rare Diseases: MPS II Case Study - Conclusions

ATMPs, being innovative and complex biological products, demand in many cases thorough and challenging clinical and preclinical developments. EMA provides incentives, scientific advice, and protocol assistance for the developers of designated orphan medicines, therefore, early interaction with the regulators is crucial while developing promising ATMPs treatments targeting rare diseases. ATMPs hold great potential as a therapeutic alternative in rare diseases for which the specific underlying cause is known, compared to other medicinal products, as they can represent a more specific and targeted treatment.

We have shown that obtaining an orphan designation is feasible even when a current medicine with marketing authorisation is available for the disease of interest. Developers should be aware that identical medicinal products with different administration routes can be granted different orphan designations, as well as medicinal products providing, after a single treatment, longer term and/or improved benefit in comparison to current approved treatments

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aMuenzer, J., Botha, J., Harmatz, P. et al. Evaluation of the long-term treatment effects of intravenous idursulfase in patients with mucopolysaccharidosis II (MPS II) using statistical modeling: data from the Hunter Outcome Survey (HOS). Orphanet J Rare Dis 16, 456 (2021). https://doi.org/10.1186/s13023-021-02052-4


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