The Rare Kid­ney Dis­ease Play­book: How New Re­search and In­no­va­tion is Trans­form­ing the RKD Treat­ment Land­scape

As kid­ney pro­fes­sion­als from around the world con­verge at ASN’s Kid­ney Week 2023, Tra­vere Ther­a­peu­tics’ Er­ic Dube, Chief Ex­ec­u­tive Of­fi­cer, Ju­la In­rig, Chief Med­ical Of­fi­cer, and Pe­ter Heer­ma, Chief Com­mer­cial Of­fi­cer share their per­spec­tives on how in­no­va­tion in rare kid­ney dis­ease (RKD) is trans­form­ing the treat­ment land­scape. 

How has the R&D land­scape in rare kid­ney dis­ease (RKD) changed?

Ju­la In­rig,
Chief Med­ical Of­fi­cer

In­rig: “For decades, very few clin­i­cal tri­als were con­duct­ed in chron­ic kid­ney dis­ease, and al­most none in RKDs like IgA nephropa­thy (IgAN). A key fac­tor lim­it­ing ear­ly re­search was us­ing kid­ney fail­ure or death as end­points, which made clin­i­cal tri­als for new ther­a­pies pro­hib­i­tive­ly long and cost­ly to con­duct, and tri­al re­cruit­ment in­cred­i­bly chal­leng­ing. In 2012, the Kid­ney Health Ini­tia­tive (KHI), a pub­lic-pri­vate part­ner­ship com­prised of the Amer­i­can So­ci­ety of Nephrol­o­gy (ASN), the US Food and Drug Ad­min­is­tra­tion (FDA), and nu­mer­ous bio­phar­ma com­pa­nies, aca­d­e­m­ic re­searchers, and pa­tient ad­vo­ca­cy or­ga­ni­za­tions, came to­geth­er de­ter­mined to ad­vance the nephrol­o­gy field and ac­cel­er­ate RKD re­search. We iden­ti­fied pro­tein­uria (high lev­els of pro­tein in the urine that in­di­cate dam­age to the fil­ters in the kid­ney), which means the kid­neys are no longer fil­ter­ing prop­er­ly, as a po­ten­tial new sur­ro­gate end­point. Pro­tein­uria re­duc­tion and re­mis­sion of pro­tein­uria were al­ready key mea­sures of kid­ney func­tion and reg­u­lar­ly used in clin­i­cal prac­tice all over the world.  Test­ing for pro­tein­uria is sim­ple and non-in­va­sive, mak­ing it an ide­al way to mea­sure risk of kid­ney dis­ease pro­gres­sion. To­day, there are over 30 on­go­ing tri­als in IgAN. As a nephrol­o­gist, it’s ex­cit­ing to see the ad­vance­ments in re­search and that these pa­tients now have new treat­ment op­tions for their con­di­tion – which wasn’t the case for so many years. It’s al­so ex­cit­ing to see the po­ten­tial these med­i­cines have of be­ing com­bined and work­ing to­geth­er to help de­lay the pro­gres­sion to kid­ney fail­ure. As a physi­cian, every year that you can keep a pa­tient from dial­y­sis or a kid­ney trans­plant, is a year with a high­er qual­i­ty of life… it’s a year that can be spent earn­ing a de­gree, grow­ing a ca­reer, or start­ing a fam­i­ly free from that bur­den. That’s grat­i­fy­ing, and a tes­ta­ment to the pow­er of pub­lic-pri­vate part­ner­ships and the in­no­va­tion that com­pa­nies like Tra­vere are bring­ing to the field.”

Be­fore we dig deep­er in­to sur­ro­gate end­points in RKD and IgAN. For those who may not be fa­mil­iar with Tra­vere or IgAN, can you tell us a lit­tle more about the com­pa­ny and the con­di­tion?

Er­ic Dube,
Chief Ex­ec­u­tive Of­fi­cer

Dube: “Tra­vere Ther­a­peu­tics is bio­phar­ma­ceu­ti­cal com­pa­ny based out of San Diego. We’re proud to be in rare for life. We are ad­vanc­ing a pipeline of po­ten­tial first-in-class med­i­cines tar­get­ing rare dis­eases with sig­nif­i­cant un­met needs. Many of the peo­ple who work at Tra­vere are rare dis­ease pa­tients, sur­vivors, and care­givers them­selves and we’re for­tu­nate to have many pas­sion­ate col­leagues, like Ju­la, who have been a dri­ving force in de­liv­er­ing in­no­va­tion in RKD for years. Keep­ing pa­tients’ in­ter­ests top of mind is at the heart of our mis­sion and dri­ves our com­mit­ment to meet­ing the unique needs of the rare pa­tient com­mu­ni­ties we serve. It’s why Tra­vere has ac­tive­ly tried to raise the bar in our re­search of RKD by de­sign­ing tri­als us­ing an ac­tive con­trol that is a stan­dard of care in­stead of place­bo — some of the most ro­bust and rig­or­ous piv­otal tri­als in the cat­e­go­ry.”

Pe­ter Heer­ma,
Chief Com­mer­cial Of­fi­cer

Heer­ma: “Al­so called Berg­er’s dis­ease, IgAN dam­ages the small blood ves­sels that fil­ter waste in your kid­neys. While clas­si­fied as rare – af­fect­ing ap­prox­i­mate­ly 150,000 in the Unit­ed States – IgAN is one of the most com­mon and more rapid­ly pro­gress­ing kid­ney dis­eases lead­ing to kid­ney fail­ure. The dis­ease typ­i­cal­ly de­vel­ops in peo­ple who are in their 20s or 30s – who are in the prime of their lives, and then sud­den­ly feel fa­tigue, pain, ex­pe­ri­ence swelling in their hands or feet, and don’t know what’s hap­pen­ing to them. Many pa­tients face a long jour­ney to di­ag­no­sis, and more than two-thirds of pa­tients are at an ad­vanced stage of the dis­ease once di­ag­nosed. A high pro­por­tion of in­di­vid­u­als di­ag­nosed with IgAN do not suf­fi­cient­ly re­spond to the his­tor­i­cal stan­dard of care treat­ment, which of­ten in­cludes hy­per­ten­sion drugs such as an­giotensin re­cep­tor block­ers (ARBs), an­giotensin-con­vert­ing en­zyme (ACE) in­hibitors, and steroids. As a re­sult, many will strug­gle to man­age their dis­ease and progress more quick­ly to kid­ney fail­ure.”

How has us­ing pro­tein­uria as a sur­ro­gate end­point in clin­i­cal tri­als spurred in­no­va­tion in IgA nephropa­thy?

In­rig: “KHI iden­ti­fied pro­tein­uria as a re­li­able pre­dic­tor of a treat­ment’s ef­fect on long-term kid­ney out­comes, and re­search con­tin­ues to show ev­i­dence of the con­nec­tion be­tween pro­tein­uria and kid­ney fail­ure. A re­cent ground­break­ing analy­sis of the UK Na­tion­al Reg­istry of Rare Kid­ney Dis­eases (RaDaR) showed that pa­tients that have been tra­di­tion­al­ly re­gard­ed as ‘low risk’ (with pro­tein­uria <1 g/day) can still progress to kid­ney fail­ure with­in 10-15 years. The RaDaR find­ings can be prac­tice-chang­ing be­cause his­tor­i­cal­ly pa­tients and physi­cians did not re­al­ize just how ag­gres­sive IgAN is, and how much dam­age it can do in a rel­a­tive­ly short pe­ri­od of time. While that find­ing was sober­ing, the study al­so re­vealed some good news – the de­cline in kid­ney func­tion can be slowed, with da­ta show­ing that a 50% re­duc­tion in pro­tein­uria can de­lay time to kid­ney fail­ure or death by 8.5 years. For a pa­tient fac­ing kid­ney fail­ure and po­ten­tial­ly dial­y­sis, every day counts.”

Heer­ma: “We reg­u­lar­ly speak with pa­tients who share not on­ly the phys­i­cal, but the over­whelm­ing psy­cho­log­i­cal, so­cial, and fi­nan­cial chal­lenges that can be part of liv­ing with RKD. These are in­di­vid­u­als who con­sid­ered them­selves healthy and then very quick­ly find them­selves putting their lives on hold to pre­pare for dial­y­sis or trans­plant. Dial­y­sis is bur­den­some for these pa­tients, of­ten re­quir­ing at least 9 hours or more per week con­nect­ed to a ma­chine that helps to par­tial­ly re­place your kid­ney func­tion by clean­ing and fil­ter­ing your blood. RaDaR demon­strat­ed the con­nec­tion be­tween in­creased pro­tein­uria lev­els and de­clin­ing kid­ney func­tion is in­dis­putable and has cre­at­ed a new ur­gency to treat IgAN pa­tients ear­li­er and more ag­gres­sive­ly to pre­vent rapid dis­ease pro­gres­sion.”

What in­spires you to be in rare dis­ease?

Dube: “I of­ten say I’m ‘im­pa­tient for pa­tients.’ My de­ci­sion to work in the life sci­ences in­dus­try was re­in­forced when I was di­ag­nosed with two rare can­cers. That gave me a new per­spec­tive on the im­por­tance of time. I am cer­tain our in­dus­try can pro­vide that time and change peo­ple’s lives. Af­ter my own ex­pe­ri­ence, I was al­so mo­ti­vat­ed to do my part in en­sur­ing no fam­i­ly has to hear ‘there’s no ef­fec­tive ther­a­py for your rare con­di­tion.’ Work­ing in rare dis­ease, there’s a true sense of com­mu­ni­ty and a shared feel­ing that we are stronger to­geth­er – and in this to­geth­er. A step for­ward is progress for the en­tire com­mu­ni­ty.”

In­rig: “De­vel­op­ing ef­fec­tive ther­a­pies is about im­prov­ing qual­i­ty of life as much as it is adding years to a life. I chose to go in­to nephrol­o­gy be­cause it was an un­der-re­searched area – the need, com­bined with the com­plex prob­lems the field presents and the abil­i­ty to de­vel­op re­la­tion­ships with pa­tients while work­ing with them over long pe­ri­ods of time, made the choice ob­vi­ous for me. One of my for­mer pa­tients start­ed dial­y­sis when she was 17 years old and lived trans­fu­sion-to-trans­fu­sion un­til she passed away. She served as a mem­ber of a Pa­tient and Fam­i­ly Coun­cil that ad­vised the KHI and helped ush­er in a new era of tri­al de­sign. Not a week goes by that I don’t think about her – and what she might have ac­com­plished, giv­en the op­por­tu­ni­ty.”