Proposal to treat CRGV in dogs with Eculizumab

By Christopher G. Street BSc(Hons) MBA PGDipMedChem

Idiopathic Cutaneous and Renal Glomerular Vasculopathy (CRGV) otherwise known as Alabama Rot in dogs has similar histopathological findings to Thrombotic Microangiopathy (TMA) in humans (Jepson, Jasani 2014). David Walker of Anderson Moores Veterinary Specialists (Walker 2014c) is researching whether affected dogs have an auto-immune disorder, present from birth (Walker, Lake 2014), similar to atypical Haemolytic Uraemic Syndrome (aHUS) in humans, which is triggered by an as yet unknown environmental factor. (Walker, Sherwood 2014)

CRGV is a dog disease that has been known about since 1988 (Walker 2014e, Walker 2014d, Walker 2014a, Walker 2014b). The first UK CRGV cases were observed in November 2012. Up to December 2014 there have been 65 recorded cases: 46 confirmed dog deaths, 12 unconfirmed deaths and 7 unconfirmed cases where dogs survived – 89% mortality rate (Street 2014c). In October 2014 35 unconfirmed dog deaths were cited (Walker, Sherwood 2014) totalling 88 cases - 92% mortality rate.

Of 46 confirmed CRGV cases, 21 cases (45%) are scattered throughout England, 25 cases (55%) are in 3 clusters (>3 confirmed cases): New Forest (16 cases), Greater Manchester (5 cases) and Guildford, Surrey (4 cases). (Street 2014c)

TMA (Noris, Remuzzi 2010, Richards, Kavanagh 2009) is three different diseases: typical Haemolytic Uraemic Syndrome (HUS) is caused by Shiga toxin-producing Escherichia coli (STEC-HUS) – tests for E.Coli and shiga toxin have been negative (Walker, Sherwood 2014) ; aHUS is associated with genetic or acquired disorders of regulatory components of the complement system; thrombotic thrombocytopaenic purpura (TTP) results from a deficiency of ADAMTS13, a plasma metalloprotease that cleaves von Willebrand factor (Noris, Mescia et al. 2012).

In humans, Plasma Exchange (Plasmapheresis) treats TTP, STEC-HUS & aHUS (Yenigun, Bardak et al. 2012, Ponticelli, Banfi 2006, Carter, Benador 2014). In April 2014 the first dog to be treated by Plasma Exchange for CRGV - survived (Glennie 2014). However Plasma therapy is very risky; up to 40% of humans die or progress to end-stage renal failure (NICE 2014b).

Targeting of complement with the anti-C5 monoclonal antibody Eculizumab can effectively treat not only aHUS (for which it is indicated), but also STEC-HUS and TTP (Noris, Mescia et al. 2012).

3 types of Eculizumab reviews are listed: Biochemistry (Zuber, Le Quintrec et al. 2011, Kerr, Richards 2012); Use in TMA treatment (Noris, Remuzzi 2013, Pickering, Cook 2011, Waters, Licht 2011, Keating 2013, Keir, Marks et al. 2012, Rathbone, Kaltenthaler et al. 2013) and; Case reports (Zuber, Fakhouri et al. 2012).

Approval for the treatment of aHUS by Eculizumab in the United States and Europe in humans was given in 2011 (Schmidtko, Peine et al. 2013).

Eculizumab is thirty times more expensive than other monoclonal antibodies (Laurance 2013, Stanton 2014). NICE recommends cost reduction in humans by dose reduction and stopping treatment early (NICE 2014d). Despite the high price (NICE 2014c), after a NICE evaluation in October 2014 (NICE 2014b), the final draft NICE guidance in November 2014 recommended NHS England fully fund Eculizumab to treat aHUS. The final NICE guidance to NHS England is due January 2015 (NICE 2014d). Until the final guidance is published, the current NHS England policy about Eculizumab for aHUS in humans applies (NHS 2013). 170 people in England with aHUS will be treated with Eculizumab at £340,200 per patient per year. NICE suggest that NHS England budget £57.8M for Eculizumab in year 1 rising to £85M in year 5 (NICE 2014d).

Interestingly, 20 - 30 new patients are diagnosed with aHUS each year (NICE 2014d) - a similar number to the new CRGV cases in dogs (65 - 88 cases November 2012 – December 2014).

Each 30ml Eculizumab vial contains 300mg (Soliris 2014) and costs £3150 per vial (NICE 2014d). Assuming dogs average 10-20kg, cost per dog is £88,200[1] per year. A £2.64M budget would allow 30 dogs to be treated in the first year.

Does CRGV have a specific environmental trigger or does it occur randomly? I suggest statistical analysis by (Spiegelhalter 2015) on the 25 confirmed cases in clusters (Street 2015).

When stakeholders are reasonably confident that CRGV is an aHUS TMA, I propose that a coalition group is formed similar to aHUS Action (aHUS 2014) and other professional groups (NICE 2014a). The group would campaign for a grant from Alexion Pharma UK, (Alexion 2014) to treat dogs with Eculizumab over a trial period. If the trials are successful, the group would campaign to get funding for Eculizumab treatment in all dogs with CRGV; in a similar manner that people with aHUS should get full funding through NHS England Specialised Commissioning Services (NHS 2012, NICE 2014d).

References

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[1] A 30ml vial contains 300mg Eculizumab. Assuming dose for dogs is same as for people, for a 10-20kg dog (Soliris 2014) (Table 1) dose is 600mg week 1, 300mg week 2, then 300mg every 2 weeks – total 28 vials x £3150 = £88,200 per dog per year. 30 dogs would cost £2.64M in the first year.