Blog entry by Arif Khwaja

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by Arif Khwaja - Friday, 7 June 2013, 6:11 PM
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This weeks NEJM sees the publication of 2 open label, phase 2 studies describing the experience of Eculizumab in atypical HUS (aHUS). Eculizumab is a humanised monoclonal antibody that inhibits activation of complement by binding to C5 complement protein thereby preventing the generation of proinflammatory C5a and C5b-9. Eculizumab is licensed for the treatment of paroxysmal nocturnal haemoglobinuria. aHUS is characterised by chronic activation of the complement system as a result of either genetic or acquired defects. (See here for excellent review on complement and aHUS).

All patients with evidence of Shiga-toxin producing E-Coli or low ADAMTS13 activity were excluded from the 2 trials. In study 1, 17 patients were treated if they had i) evidence of progressive thrombotic microangiopathy (TMA) as determined by declining platelet count ii) haemolysis iii) evidence of abnormal kidney function ( median eGFR was 19mls/min/1.73m2 and iv) > 4 plasma exchange/infusion sessions in the week prior to screening. 15/17 patients completed treatment to 26 weeks and another 13 continued through an extension phase. The primary endpoint was change in platelet count though GFR, requirement for plasma exchange and quality of life were also recorded. There was a significant increase in platelet count with 87-88% having normal platelet counts and LDH by 26 weeks ( ie. no significant evidence of TMA and haemolysis), a significant increase in eGFR from baseline to 26 weeks by 32mls/min/1.73m2 and a significant improvement in quality of life at 26 weeks ( not surprising as disease had effectively been controlled for most subjects). 15/17 patients required no further plasma exchange

Trial 2 involved more 'chronic' aHUS patients who were being treated with plasma exchange at least once every 2 weeks (but less than 3x week) for at least 8 weeks. 80% met the primary endpoint (no decrease in the platelet count of >25%, no plasma exchange or infusion, and no initiation of dialysis) and no patients required dialysis or plasma exchange.


In both studies serious adverse events were very common some of which were thought to be drug related including severe hypertension, peritonitis and influenza. All patients received meningococcal vaccination and prophylaxis.


So what does this tell us? Clearly doing an RCT in a rare, acute  and often explosive disease such as aHUS is very difficult and therefore the investigators are to be congratulated on conducting a trial in such a difficult area. The trial confirms that complement dysregulation is a central therapeutic target in aHUS. Whilst Eculizumab has significant toxicity (and the consequences of longterm use are not known), requires repeated infusions on a weekly to 2 weekly basis, aHUS itself has disastrous consequences with upto 40% dying or developing ESRD within the first year of presentation. Furthermore the drug clearly works preventing the need for long term plasma exchange and improving TMA, kidney function but also quality of life. An in vivo assay of complement activity revealed Eculizumab inhibited complement within one hour of infusion. Patients who missed doses of Eculizumab were more likely to develop severe complications of TMA.

So Eculizumab clearly represents a major step forward in the treatment of aHUS. Both the FDA and the European Medical Agency have granted a license for Eculizumab in aHUS. There is obviously huge interest in its use in other complement-mediated disease processes such as MPGN, catastrophic anti-phospholipid antibody syndrome and even antibody-mediated rejection in transplantation. However the real elephant in the room is what is cost - wikipaedia says that Eculizumab costs $600,000 USD per year. In the UK  haemodialysis is roughly £30,000 ($45,000) per annum which means that it doesnt compare favourably to dialysis in terms of cost-effectiveness. It is important that research into rare diseases continues and new therapies are developed and clearly those companies that take on such risky projects need to get their 'reward' otherwise others will stop doing research in the area. However this kind of price is prohibitively expensive for most healthcare economies unless a different pricing structure and/or model of funding is developed such as 'performance-related' funding in the UK for the use of bortezomib in myeloma.


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