Rare diseases and Horizon 2020

What do you think have diseases like Huntington´s disease, Fabry disease, Amyotrophic lateral sclerosis, Fragile X syndrome and cystic fibrosis in common? They belong to rare diseases, diseases that affect no more than 5 people out of 10 000 in EU which means that about 250 000 people maximally are affected by a single disease. However, in most cases there is 1 person in 100 000 affected by a disease. It is therefore not so hard to imagine that this number of patients is not so attractive for drug developers since they reasonably expect that they cannot get returned their investment into a drug development by selling such medicine on this small market.

Just to imagine how many people together are affected by rare diseases- a few numbers from the European Medicine Agency (EMA) webpage: There exist 5000 to 8000 distinct rare diseases, affecting between 27 mil and 36 mil people in EU. Most of the rare diseases are caused by a genetic origin and rest is accounted to degenerative and proliferative causes.

Taken in account that there are a few medicines available and there is a lack of any scientific information about most of the rare diseases, we can see an urgent unmet medical need here and millions of people left without any hope.

Despite predominantly governments are in duty to take care of public health and act in public interest and to provide help also to people with rare diseases, we see numerous initiatives supporting development of orphan drugs funded above all by non-governmental bodies.

On the European level, the European commission via the EMA supports similarly to the Food and Drug administration (FDA), orphan drugs development. In case of the EMA regulatory body, an orphan drug must meet certain criteria:

  • it must be intended for the treatment, prevention or diagnosis of a disease that is life-threatening or chronically debilitating;
  • the prevalence of the condition in the EU must not be more than 5 in 10,000 or it must be unlikely that marketing of the medicine would generate sufficient returns to justify the investment needed for its development;
  • no satisfactory method of diagnosis, prevention or treatment of the condition concerned can be authorised, or, if such a method exists, the medicine must be of significant benefit to those affected by the condition.

This is quite straightforward definition. Such medicine can then benefit from certain incentives such as protection from competition once on the market (for 10 years) or protocol assistance. There are further incentives for SMEs like reduced fees and administrative and procedural assistance from EMA.

As we will discuss next, in frame of the Horizon 2020, an EU funding program for scientific projects, there have been calls running and in preparation to support development of orphan drugs.

In the past, there have been already some calls within the Horizon 2020 which fully or partly touched rare diseases like PHC-14-2015, FPA-01-2014, SC1-PM-12-2016 or INFRAIA-1-2014-2015. For the open calls, we can mention the NMBP-10-2016 call (Nanoformulation of biologicals) ending in May 2016 and ERN-01-2016 (ERN-2016 – European Reference Networks – Framework Partnership Agreement) with deadline in June 2016 which are partly focused also on rare diseases.

Two forthcoming calls are the most relevant and specifically focused on rare diseases.

The SC1-PM-03-2017 call (Diagnostic characterisation of rare diseases) will be open in July, 29th, 2016 and closed in April, 11th, 2017. Aim of this call is to apply genomics and other –omics or high–throughput approaches for molecular characterization of rare diseases. This is thought to be a large-scale proposal with an expected EU contribution at around 15 mil EUR. The selected proposal shall contribute to the objectives of, and follow the guidelines and policies of the International Rare Diseases Research Consortium IRDiRC (

The second call SC1-PM-08-2017 (New therapies for rare diseases ) is fully dedicated to clinical development of orphan drugs, it is planned to be open in July 2016 and a deadline for the 1st stage is planned to be in October 2016 and for the 2nd stage in April 2017.

There are certain prerequisites to be fulfilled to apply for this call:

1) Orphan designation has been given by the European Commission (via EMA),

2) The proposed clinical trial design takes into account recommendations from protocol assistance given by EMA (The protocol assistance from EMA which is a kind of scientific advice attracts fees. For more details see the EMA web page), and

3) A clear patient recruitment strategy is presented.

Again here, the proposals should follow the guidelines and policies of IRDiRC.

According to the SC1-PM-08-2017 topic description, “the intervention must have been granted the EU orphan designation at the latest on the date of the full proposal call closure”. The whole procedure for orphan drug designation at EMA takes in full about 11,5 months from date of filing (it is also recommended to have free pre-submission meetings with the EMA Orphan Medicines Office and EMA Scientific Advice Office). So, if a drug developer does not have yet an orphan drug designation for a drug to be a part of the SC-1-PM-08-2017 call, it has to be applied at latest in next few days to keep Horizon 2020 timelines. Otherwise this call will be applicable only to drug developers having already the orphan drug designation or being already in process of getting it.

Though drug developers have not had in the past so much interest in orphan drug development, situation is changing due to more factors. An increasing support from EU, governments and non-governmental organizations is one reason. A second factor is that companies can use the orphan drug  as a “lift” for other drugs, e.g targeting the same molecule. Orphan drugs will take advantages of its designation to get incentives and to be on market quicker than a usual drug and to get longer protection and the second-use drug can profit from that. At last, involvement in development of a drug for people left without any hope and even knowing that the direct return of investment will be low or none, can improve public image of pharmaceutical industry and companies involved. None of these reasons is bad and if at the end they improve understanding of rare diseases and can help millions of people, this is something which counts and matters.

Picture used at this post ©

Another CETP inhibitor failure

Highly awaited results from the Phase III study with evacetrapib which was stopped in October 2015 on the recommendation of the independent Data Monitoring Committee after preliminary data suggested the study would not meet its primary endpoint of a reduction in major cardiovascular events were presented recently at the American College of Cardiology’s 65th Annual Scientific Session. The original article you can find here.

Results clearly showed that despite significant decrease of “bad” cholesterol- LDL (i.e LDL- low density lipoprotein) and increase of “good” cholesterol- HDL (high density lipoprotein), the rate of cardiovascular events was not reduced.

It means that cardiovascular deaths, heart attacks, strokes and others occurred at the same rate in people who has lowered “bad” cholesterol as compared to placebo treated people with no cholesterol lowering

High cholesterol is thought to be a risk factor for heart and vascular failures and changing a lipoprotein profile is thought to modify this risk. Diet recommendations as well as drug treatments by statins, PCSK9 inhibitors, selective cholesterol absorption inhibitors, bile acids-binding drugs and other lipid lowering therapies are ways how to lower LDL currently in clinic. In case of statins, large population studies showed an effect on cardiovascular diseases rate. A new group of cholesterol-lowering drugs targeting the PCSK9 molecule (among them two approved and marketed monoclonal antibodies) is awaiting outcome studies on modification of cardiovascular events soon, showing clearly significant cholesterol lowering in indications where statins were not effective or tolerated.

Evacetrapib belongs to a class of CETP inhibitors. CETP is a “cholesterylester transfer protein” which transfers cholesterol from HDL to VLDL (very low density lipoprotein) and LDL. Evacetrapib as a CETP inhibitor thus increases HDL and lowers LDL. The investigational name for this drug is LY2484595 and it has been in development at Eli Lilly and Company. The drug was tested in more than 12 000 people and most probably only such high participants number tested through sufficient time period could show a meaningful outcome.

This class of drugs has faced already a 3rd failure, all small molecules. The first failure, Torcetrapib, was in development at Pfizer and was stopped in 2006 after excessive deaths in the Phase III. Roche´s Dalcetrapib development discontinued in 2012 due to a lack of efficacy.

There are two candidates in active development at Merck and Amgen. Merck´s Anacetrapib is currently in 3 Phase II studies- NCT00685776 (a long-term study since 2008, running until 2017), NCT01252953 (REVEAL, running until 2017) and NCT01524289 for heterozygous familial hypercholesterolemia patients in combination with statins (results will be available in 2018). The drug previously also showed significant effect on cholesterol levels.

Another CETP inhibitor, originally developed by Dezima and Xention as TA-8995 and which is now in portfolio of Amgen as AMG 899 showed promising results on LDL decreasing and HDL increasing in the TULIP Phase II as announced in 2015 and it was claimed that it is the most potent CETP inhibitor in means of cholesterol lowering. There is no active clinical trial with AMG 899 or TA-8995 running according to

Of course, now, everybody is watching whether it will be possible to see an effect on cardiovascular diseases rate with these two active CETP drugs.

Let´s have a look on other cholesterol-lowering drugs, PCSK9 inhibitors. Two monoclonal antibodies were approved and marketed in 2015, other drugs are in development at Pfizer, Lilly, AFFiRiS, Alnylam and others. These drugs are of other class than CETP inhibitors, lowering LDL and increasing HDL by other mechanisms. Several “outcome” trials are running with Pfizer´s bococizumab and Amgen´s and Sanofi´s/Regeneron´s marketed mAbs to bring an evidence that these drugs in parallel to modifying a lipoprotein profile can also reduce cardiovascular diseases rate. Pfizer recently announced positive results on one Phase III study with bococizumab which met its primary endpoints and led to a significant LDL decrease. The study is expected to be a part of potential regulatory filing.

It automatically comes to one´s mind: Why significant decrease of bad cholesterol and increase of good cholesterol induced so far by CETP inhibitors was not accompanied by any effect on prevention of cardiovascular mortality and morbidity? Can this happen also with other cholesterol-lowering drugs of the same class and of other classes? What mechanisms prevented a positive impact of cholesterol lowering on cardiovascular diseases incidence? Coming years will bring answers.

Scientists now speculate that new ways of cholesterol lowering are needed. In light of CETP inhibitors failures there could be however a lower appetite of drug developers to bring another drug to development without a strong evidence of its potential to affect the cardiovascular disease rate in parallel to cholesterol lowering. It will be also interesting to watch how PCSK9 inhibitors will perform in outcome studies and whether they will translate significant cholesterol lowering  into prevention of cardiovascular deaths and diseases. There is a hope for that.