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Periodic Report Summary 3 - PROFNAIT (Development of a prophylactic treatment for the prevention of fetal/neonatal alloimmune thrombocytopenia (FNAIT))

Project Context and Objectives:
Summary description of project context and objectives
PROFNAIT is a European Union-funded consortium ( consisting of eleven Northern European hospitals, blood banks and companies which aims to prevent 1,000 cases per year in EU and the US of potentially lethal or disabling internal bleeding in at-risk babies due to a condition known as fetal and neonatal alloimmune thrombocytopenia (FNAIT). Leading EU and US medical societies in the fields of obstetrics and gynecology have expressed their support of the PROFNAIT project and confirmed the unmet medical need in FNAIT.
FNAIT most often develops due to a difference between a mother and her baby with respect to their types of blood platelets. A fetal-maternal bleeding, an accidental mixing of blood, may cause a mother at-risk to develop antibodies which attack and destroy her 'alien' baby’s incompatible platelets; both in herself and in the baby. With only few platelets left, the baby cannot effectively stop any internal bleedings and in the brain such bleeding can be permanently disabling or even lethal. This is not only a tragedy for the afflicted families but also constitutes a substantial cost to society.
The fact that a mother may attack her very own fetus is well known. Anti-D (e.g. RhoGAM®, WinRho®) is a prophylaxis that prevents Rhesus negative mothers from attacking the red blood cells (not the platelets as in this project) in her fetus and cause hemolytic disease of the fetus and new-born (HDFN). Anti-D is such a safe and effective drug that routine Rhesus typing of all pregnant women and anti-D treatment of those who are Rh(D) negative are implemented with great success in most countries.
The FNAIT prophylaxis PROFNAIT aims to develop, tentatively named NAITgam, and anti-D are very similar. Both drugs are manufactured by the exact same process from blood plasma of immunized donors and they are both "hyperimmune" drugs where the active component is human immunoglobulin. Because of this similarity there is very good reasons to believe that NAITgam will be capable of safely and effectively eliminating the risk FNAIT.
The overall objective of the PROFNAIT project is:
− to manufacture NAITgam from plasma collected from women who have developed antibodies against their fetus and in compliance with guidelines of the European Medicines Agency (EMA),
− to demonstrate proof of concept for NAITgam in clinical studies,
− to target submission of a Marketing Authorization Application with EMA
− to prepare the market uptake of NAITgam through
1. increasing the awareness in the medical community and among health policy decision-makers of FNAIT and need for testing of pregnant women to identify at-risk pregnancies,
2. publishing clinical data on the safety and efficacy of FNAIT prophylaxis using NAITgam, and
3. establishing preliminary evidence of cost-effectiveness of combined HPA-1a typing, patient stratification and FNAIT prophylaxis.

Project Results:
Description of work performed and main results
Plasma collection–FNAIT is fortunately a rare condition but the scarcity of women who have developed antibodies against their babies also makes the collection of antibody-containing plasma a challenge. For regulatory reasons, the project can so far only accept plasma from women who live in the United States and initial efforts by Oslo, Karolinska and DRK to collect plasma in Europe have therefore been put on hold.
Substantial efforts have been made to recruit plasma donors at three different levels:
* Sign-up donors. Some of our potential donors, i.e. women who have given birth to an FNAIT child, learn about the project via the patient organization or the PROFNAIT Facebook page ( No matter how they get in touch with PROFNAIT, these women are encouraged to visit the PROFNAIT web site ( and sign up for donation.
* Referral donors. A second group of donors are recruited via physicians who reach out to their former FNAIT patients and invite them to donate. An infrastructure for recruitment of these donors has been established in collaboration with Dr. James B. Bussel at the highly esteemed Weill Cornell Medical College in New York who for 30 years have managed FNAIT cases all over the United States.
* Screening donors. 1 in 3,000 regular plasma donors also qualify as a PROFNAIT plasma donor and screening campaigns add valuable new donors to the programs. Donors identified this way have proven very stable and productive.
To date, 150 candidate donors have been contacted and those who live nearby a validated donation centre are encouraged to donate, either directly or after having passed a pre-screening by the PROFNAIT beneficiary UNN. At present, the PROFNAIT project has collected enough plasma for manufacturing of 2 out of 3 required batches and UNN and Aalborg have together with BloodCenter of Wisconsin been deeply involved in testing the quality and potency of the donated plasma portions.
The plasma donations must take place at EMA and FDA compliant and validated donation centres in the US. At present, 50 sites run by Biotest Pharmaceuticals, BPL Plasma and New York Blood Center are available for PROFNAIT plasma collection and manufacturing of the first batch of NAITgam by an established and EMA and FDA compliant process will soon be initiated. Manufacturing was approved to be subcontracted in an amendment #1 to the Grant Agreement.
Regulatory strategy and clinical development plan–NAITgam is a drug for a rare condition and EMA and FDA work proactively with companies developing such “orphan” drugs to facilitate their approval and commercialization to the benefit of a small population of often severely affected patients. In the beginning of RP2, Prophylix worked successfully with expert regulatory advisors in Germany and the US on developing and obtaining EMA and FDA approval of a lean, feasible and cost-effective plan for the clinical development of NAITgam. The new clinical development plan and budget were included in amendment #1 to the Grant Agreement.
Preparations for clinical development–The first phase I and II clinical studies of NAITgam will be conducted at Fraunhofer. DRK and Karolinska will provide bioanalyses, Larix will as contract research organization (CRO) train and monitor the site and be responsible for data management and reporting. As sponsor, Prophylix supervises the preparations. One of the larger preparatory activities have been DRK’s development, optimization and validation of a PROFNAIT project specific method that allows for specific and exact measurement of platelet clearance and dose estimation. Further, during RP3 Karolinska has optimized and validated a sensitive method that allows for pharmacokinetic analysis of NAITgam. This new method, called bead-MAIPA, is 10 times more sensitive than the previous state of the art method, MAIPA.
Also, in RP3 a world leading blood-typing company has, in collaboration with PPAS, started the development of a high throughput HPA 1a phenotyping assay using a monoclonal anti-HPA-1a antibody developed at UiT. The establishment and commercialization of an easy kit for HPA-1a phenotyping kit would allow for parallel HPA-1a typing and RhD typing of pregnant women.

Health-economic analysis—A preliminary model based on standard state-of-the art health economic methods was also developed during the RP3 period. The cost-effectiveness evaluation included the cost-effectiveness of combined HPA-1a typing, downstream testing and prophylactic treatment of risk pregnancies. To simulate the incremental benefit and economic savings, the NAITgam prophylactic strategy was compared against the currently practiced standard of care. Our calculations indicate that it is possible to establish a combine antenatal screening and treatment programme that is cost effective.

Potential Impact:
Dissemination activities
Expected final results and potential impacts
The project is anticipated to yield a number of distinct but related and interdependent results:
1. Increased understanding of FNAIT development and prevention as published in high-ranking, peer-reviewed journals;
2. Established HPA-1a plasma donor corps and infrastructure for plasma collection. HPA-1a plasma is so hard to get that it is to be considered as "liquid gold" and the network of HPA-1a donors that is established will represent a significant asset going forward;
3. Clinical data package and authorizations to market NAITgam with orphan drug privileges in EU;
4. Outside of - but in parallel to - the PROFNAIT project; obtain approved test for routine HPA-1a typing of pregnant women for identification of at-risk pregnancies and initiation of prophylaxis;
5. Penetration of the European and North American markets with the combination of the test for HPA-1a typing and the FNAIT prophylaxis NAITgam.
With a total of 9 million pregnancies in EU and the US, a very large number of HPA-1a tests are expected to be performed. Further, a maximum of 2% of these women (180,000) will require NAITgam treatment. Initially, at least, a significantly smaller number is anticipated.

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