Ex­plor­ing new fron­tiers in rare dis­ease re­search to meet the needs of pa­tients

Col­lec­tive­ly, rare dis­eases af­fect mil­lions of peo­ple world­wide, a num­ber that is grow­ing each year as more rare dis­eases are iden­ti­fied. These con­di­tions place a sub­stan­tial bur­den on pa­tients, care­givers and so­ci­ety as a whole. It’s es­ti­mat­ed that rare dis­eases im­pact more peo­ple than can­cer and Alzheimer’s com­bined, yet most of these con­di­tions have lim­it­ed or no treat­ment op­tions. For­tu­nate­ly, bold sci­ence is con­tin­u­ing to dri­ve progress, link­ing a com­mon part of hu­man bi­ol­o­gy to some of the rarest dis­eases.

Specif­i­cal­ly, re­searchers are find­ing an­swers in a part of the im­mune sys­tem called the com­ple­ment sys­tem. De­spite be­ing an im­por­tant part of our body’s pro­tec­tion against in­fec­tion, aware­ness of this crit­i­cal sys­tem re­mains low. Prob­lems arise when this sys­tem is thrown out of bal­ance, or dys­reg­u­lat­ed, which can lead the body to at­tack its own healthy cells and tis­sues, dri­ving many dev­as­tat­ing dis­eases.

Alex­ion, As­traZeneca’s Rare Dis­ease group, was the first com­pa­ny to demon­strate the ther­a­peu­tic po­ten­tial of se­lec­tive­ly tar­get­ing the com­ple­ment sys­tem, a jour­ney that be­gan more than 30 years ago. This led to the de­vel­op­ment of mul­ti­ple first-of-their-kind med­i­cines for sev­er­al rare dis­eases with­out treat­ments, in­clud­ing rare and po­ten­tial­ly life-threat­en­ing blood and neu­ro­log­i­cal dis­or­ders. To­day, the com­pa­ny is the leader in dri­ving com­ple­ment sci­ence for­ward and re­mains at the fore­front of in­no­va­tions aimed at un­lock­ing the full po­ten­tial of the com­ple­ment sys­tem to bring trans­for­ma­tive ther­a­pies to rare dis­ease com­mu­ni­ties.

Gi­an­lu­ca Pirozzi, SVP, Head of De­vel­op­ment, Reg­u­la­to­ry and Safe­ty at Alex­ion, shares more about com­ple­ment sci­ence, what’s next, and what this re­search means for the rare dis­ease com­mu­ni­ty and to him per­son­al­ly.

What un­tapped po­ten­tial do you see in com­ple­ment re­search?

The com­ple­ment sys­tem is made up of three unique path­ways and more than 30 pro­teins, so we’ve on­ly just scratched the sur­face of its po­ten­tial to ad­dress many dev­as­tat­ing con­di­tions that af­fect so many peo­ple. We be­lieve there is still an in­cred­i­ble op­por­tu­ni­ty to de­liv­er mean­ing­ful treat­ments through the ad­vance­ment of com­ple­ment sci­ence, es­pe­cial­ly in ar­eas where there is sig­nif­i­cant need.

Peo­ple fa­mil­iar with the com­ple­ment sys­tem will have like­ly heard of the C5 pro­tein, which has been a treat­ment tar­get for more than 15 years. For sev­er­al rare dis­eases, in­clud­ing cer­tain hema­to­log­i­cal and neu­ro­log­i­cal con­di­tions, our ap­proved ther­a­pies fo­cus on in­hibit­ing ter­mi­nal com­ple­ment ac­ti­va­tion by block­ing this pro­tein.

We con­tin­ue to build on our work by ex­plor­ing the promise of C5 in­hi­bi­tion for oth­er rare neu­ro­log­i­cal dis­eases as well as cer­tain kid­ney dis­eases. We are al­so in­ves­ti­gat­ing new com­ple­ment tar­gets with a di­verse range of mol­e­cules that act at mul­ti­ple points in the com­ple­ment cas­cade. For ex­am­ple, we are ex­plor­ing the in­hi­bi­tion of prop­erdin, or Fac­tor P, and ad­vanc­ing re­search on the first po­ten­tial oral Fac­tor D in­hibitor as a treat­ment for sev­er­al dis­eases.

Why is Fac­tor D an im­por­tant tar­get?

Re­search sug­gests that in­hibit­ing the Fac­tor D pro­tein may pro­vide a unique op­por­tu­ni­ty to treat cer­tain dis­eases. Fac­tor D is an es­sen­tial en­zyme of the al­ter­na­tive path­way of the com­ple­ment sys­tem, which plays a crit­i­cal role to am­pli­fy the com­ple­ment re­sponse. In­hibit­ing this pro­tein has the po­ten­tial to block this path­way while leav­ing oth­er path­ways in­tact to fight in­fec­tions.

We are ex­cit­ed to ad­vance our Fac­tor D pro­gram by first ex­plor­ing as­sets that have po­ten­tial to tar­get cer­tain rare hema­to­log­i­cal dis­eases with an oral treat­ment op­tion. We have heard di­rect­ly from pa­tient com­mu­ni­ties about their in­ter­est in mul­ti­ple ad­min­is­tra­tion op­tions to fit a va­ri­ety of lifestyles, and we are en­cour­aged by the op­por­tu­ni­ty to ad­dress these pref­er­ences through our con­tin­ued in­no­va­tions in com­ple­ment sci­ence.

In ad­di­tion, we are study­ing po­ten­tial syn­er­gies with our C5 in­hibitors and how this may cre­ate new op­tions for a small sub­set of pa­tients with a par­tic­u­lar un­met med­ical need.

Does Fac­tor D in­hi­bi­tion show po­ten­tial in oth­er dis­eases?

In ad­di­tion to hema­tol­ogy, we see the op­por­tu­ni­ty for Fac­tor D in­hibitors to make an im­pact in sev­er­al oth­er ther­a­peu­tic ar­eas, in­clud­ing rare dis­eases in oph­thal­mol­o­gy, nephrol­o­gy and neu­rol­o­gy.

We are work­ing dili­gent­ly to ad­vance these clin­i­cal pro­grams in col­lab­o­ra­tion with pa­tient com­mu­ni­ties and ad­vo­ca­cy part­ners in the hopes of de­liv­er­ing new treat­ments where there is a large un­met need or where the treat­ment ex­pe­ri­ence could be en­hanced through an oral op­tion.

How has work­ing in rare dis­ease shaped your ap­proach to sci­en­tif­ic dis­cov­ery at Alex­ion?

As pi­o­neers in com­ple­ment sci­ence, Alex­ion’s re­searchers pur­sued this path at a time when few un­der­stood or read­i­ly ac­cept­ed these mol­e­c­u­lar tar­gets, so they are not strangers to un­chart­ed ter­ri­to­ry. So to­geth­er we em­brace the un­known be­cause that is where im­pact­ful sci­ence lives.

In rare dis­ease, where pa­tient pop­u­la­tions are small and many dis­eases are not well-known or un­der­stood, you need tenac­i­ty, grit and cu­rios­i­ty to nav­i­gate and over­come these ob­sta­cles. We not on­ly delve in­to the dis­tinct com­plex­i­ties of each dis­ease on a bi­o­log­i­cal lev­el but, equal­ly as im­por­tant, we strive to un­der­stand how these dis­eases im­pact the lives of those af­fect­ed, both pa­tients and their care­givers. This is some­thing I un­der­stand deeply both as a sci­en­tist and par­ent of a child with a rare dis­ease.

As we con­tin­ue to fol­low the sci­ence of com­ple­ment in­to new fron­tiers, the rare dis­ease com­mu­ni­ty is our best source of knowl­edge. By lis­ten­ing to and learn­ing from pa­tients and care­givers, we can make in­formed de­ci­sions about where to fo­cus and how to best de­sign our clin­i­cal pro­grams. Pa­tients’ needs are our dri­ving force every­day as we work to ad­vance care in rare dis­ease.

To learn more about Alex­ion’s com­mit­ment to in­no­va­tion for rare dis­ease com­mu­ni­ties and ex­per­tise in com­ple­ment sci­ence, vis­it https://alex­ion.com/our-re­search/re­search-and-de­vel­op­ment.