Starting Position

Numerous therapies for rare diseases are not (yet) approved.

Patients affected by a rare disease are participating in clinical trials, are being prescribed generics or off-label drugs.

They often show clinical improvement/stabilization on selected treatments and it is typical that a combination of therapies proves most effective.

For these therapies, the health insurance systems decide individually, usually at a national level based on comparable jurisdictions, whether they are taken funded or not. Very often they are not funded.

Patient face often a lack of adequate post-diagnosis holistic management.



How can we secure access to therapies that really help patients but have not reached the market authorization step?

Only 5% of rare disease therapies are authorized. For the other 95% percent, drugs in development, unlicensed pharmaceutical active ingredient and other therapies for rare disease patients are very often in an ambiguous situation without the possibility of rational evidence based evaluation.

Furthermore, when new therapies come up, they are usually very expensive and not automatically covered, depending on the country or the insurance system.

Patients affected by rare diseases often need more than one (expensive) drug in combination to stabilize or improve their symptoms.

Financial incentives for pharma industries exist (Orphan Drugs Act, USA, Orphan Designation, etc.) but even with such incentives new efforts remain often unattractive to the Pharma industry. Today orphan drugs remain orphan in spite of the efforts started 10 years ago to promote new drugs for rare and ultra-rare conditions.

Early diagnostic is fundamental. The earlier the treatment starts, the more effective it is.

Treatment interruptions are often devastating.

Treatment centres should often be strengthening in order to support the care of the patients, who once the diagnostic has been confirmed, needs continuous monitoring and natural history follow up.


Rapid, uncomplicated and safe reimbursement of therapies for all patients with a confirmed diagnostic of a rare disease.

Design processes so that patients receive the treatment options available to them in good time.

The health care professionals taking care of a rare disease patient know if a treatment helps or not. They should have their voices taken into consideration when determining drug efficacy.

Effective and continuous patients care, providing even non pharmacological therapies, should be organized under the control of disease specialized physician.


Specific NP-C Approach

NP-C is a heterogeneous neurodegenerative inborn error of metabolism. It is prematurely fatal. There is no cure. But treatments can very significantly slow disease progression (e.g. the now generic drug miglustat has been shown to extend life span by a decade, Patterson et al 2022).

Each NP-C patient suffers from different symptoms of different severities at different stages of the disease. Patients show different natural histories and cannot be treated by one universal therapy.

What is known? With an NP-C disorder the cellular pathogenesis is particularly complex including a deficiency in lysosomal calcium that leads to a defect in the transport of cholesterol and sphingolipids from the lysosome to the endoplasmic reticulum.

The process for restoring the transport of lipids in the cell is not known. Research into the development and trialling of disease modifying therapies is ongoing in this field.

To date progress has been obtained experimentally in mouse models without a complete understanding of the detailed pathogenic mechanisms.

Because of this complexity existing drug therapies will not be curative but may slow the disease progression.

Treatments should start before symptoms appear to maximize their benefit. So early diagnosis is key.

Gene therapy is an attractive solution for the future and could be curative if patients are pre-symptomatic when the gene therapy is delivered. But gene therapy is still many years away from a clinical application.

Gene therapy alone (one injection) will probably not solve all problems of a NP-C patient, particularly when the therapy starts late.

Non-invasive pre-symptomatic cheap biomarkers are needed. Several methods are possible. Important is to agree on one future standard approach.

Today is miglustat the only approved disease modifying drug for NP-C, but still does not have a full market authorisation in many countries in spite of a clear prolongation of life / quality of life.

Several additional treatments can be combined with miglustat and greatly improve the life the affected patients.

Within the defined rare diseases to be covered under the future health policies heterogeneous inborn error related metabolic diseases should be specifically included.

Natural history data is key for proving clinical patient specific efficacy and needs to be collected in coordinated fashion at the national and international levels through existing and new registries.

Based on recent examples of regulatory decisions, much more pragmatic innovative trials designs need to adopted in trials if treatments for NP-C are to be approved and made available to patients.

In particular, any patient specific successful trial should not be interrupted because of administrative matters. Drugs must remain available until marketing authorization. Timing remains an important issue.

Applying conventional trial design to rare and highly variable patient populations is today the main barrier to improving the lives of patients and also deters Pharma companies investing in rare diseases such as NP-C.


Christoph Poincilit, 12.08.2022