Un­cov­er­ing the Po­ten­tial of Tar­get­ing the CD38 Path­way for Im­mune-Me­di­at­ed Dis­eases

Since 2023, Bio­gen has worked to trans­form its port­fo­lio, build­ing up­on its lega­cy in mul­ti­ple scle­ro­sis and neu­ro­science to ex­pand in im­munol­o­gy and rare dis­eases, where the com­pa­ny has well-es­tab­lished glob­al de­vel­op­ment com­mer­cial­iza­tion ca­pa­bil­i­ties. A key cat­a­lyst: the 2024 ac­qui­si­tion of HI-Bio, bring­ing new depth to Bio­gen’s R&D ef­forts in im­mune-me­di­at­ed con­di­tions, which now in­cludes rare kid­ney dis­eases. While HI-Bio brought nephrol­o­gy ex­per­tise, the path to treat­ment goes through the im­mune sys­tem, and that’s where Bio­gen sees long-term po­ten­tial. With in­ves­ti­ga­tion­al pro­grams now un­der­way in three rare kid­ney dis­eases and a dif­fer­en­ti­at­ed ap­proach to CD38-tar­get­ed ther­a­pies, Bio­gen is en­ter­ing its next chap­ter.

In this Q&A, Dr. Up­tal Pa­tel, who joined Bio­gen through the HI-Bio ac­qui­si­tion and now leads de­vel­op­ment at the com­pa­ny’s West Coast Hub, shares what’s next for its in­ves­ti­ga­tion­al an­ti-CD38 an­ti­body, and why im­mune tar­get­ing is open­ing up po­ten­tial new pos­si­bil­i­ties in nephrol­o­gy.

Q&A

1. What drove your per­son­al in­ter­est in kid­ney dis­ease? What did you hear from pa­tients?  

When I was in res­i­den­cy train­ing, I had the chance to meet sev­er­al pa­tients who had kid­ney dis­ease. I was im­pressed by their sto­ries of re­silience and how they adapt­ed to their chal­lenges with kid­ney fail­ure – hav­ing been ei­ther a re­cip­i­ent of a kid­ney trans­plant or un­der­go­ing he­modial­y­sis as a treat­ment for kid­ney fail­ure. I saw the pow­er of sec­ond chances. Kid­ney dis­ease is unique in that it has these life­sav­ing treat­ments for or­gan fail­ure.

But pa­tients of­ten asked me why I didn’t have bet­ter treat­ments for them to pre­vent kid­ney fail­ure rather than man­ag­ing it with dial­y­sis or trans­plan­ta­tion. As a spe­cial­ty, we of­ten bor­rowed ther­a­pies from car­di­ol­o­gy and rheuma­tol­ogy but we hadn’t re­al­ly de­vel­oped ther­a­pies that pre­vent­ed pro­gres­sion for peo­ple with kid­ney dis­ease. Be­cause of that, I start­ed do­ing trans­la­tion­al work to iden­ti­fy bet­ter bio­mark­ers that could be used in clin­i­cal tri­als, work­ing with spon­sors while I was in acad­e­mia, en­rolling pa­tients in stud­ies, and be­ing part of steer­ing com­mit­tees for tri­als.

What I found, how­ev­er, was that it was of­ten hard to in­flu­ence de­ci­sions that bio­phar­ma com­pa­nies were mak­ing from the out­side, so when I got the chance to build a pro­gram fo­cused on kid­ney dis­ease at Gilead in the in­flam­ma­tion ther­a­peu­tic area, I saw it as a tremen­dous op­por­tu­ni­ty. The im­mune path­ways, whether au­toim­mune or in­flam­ma­to­ry, were some of the most promis­ing mech­a­nisms that I saw could be tar­get­ed with the goal of im­prov­ing longer-term out­comes in peo­ple with kid­ney dis­ease, and there re­al­ly hadn’t been a fo­cused ef­fort in de­vel­op­ing those ther­a­pies. I’m now grate­ful to be able to con­tin­ue that work at Bio­gen.

2. In your work at Bio­gen, you are de­vel­op­ing po­ten­tial treat­ments that tar­get a pro­tein called CD38. What is the ad­van­tage to tar­get­ing CD38 that this ap­proach could have for im­mune-me­di­at­ed dis­eases?

There are mul­ti­ple dis­eases caused by au­toan­ti­bod­ies that at­tack the body’s tis­sues. While the or­gans af­fect­ed vary, the mech­a­nisms that un­der­lie these dis­eases are shared. Most au­toan­ti­bod­ies are gen­er­at­ed by two types of cells, plas­ma blasts and long-lived plas­ma cells. Both of these cell types, which are our bod­ies’ pro­fes­sion­al an­ti­body fac­to­ries, have high sur­face ex­pres­sion of CD38, which makes it a very in­ter­est­ing tar­get for treat­ing an­ti­body-dri­ven im­mune dis­eases.

The mech­a­nism by which an­ti-CD38 ther­a­py works is by di­rect­ly de­plet­ing these cells that pro­duce au­toan­ti­bod­ies. We be­lieve this has the po­ten­tial to treat im­mune-me­di­at­ed dis­eases in a more durable and tar­get­ed way. At the same time, crit­i­cal­ly, we avoid de­plet­ing ear­ly lin­eage B-cells, and this has the po­ten­tial to pro­vide a dif­fer­en­ti­at­ed safe­ty pro­file al­low­ing pa­tients to mount an im­mune re­sponse and re­tain im­mu­ni­ty from vac­cines, for ex­am­ple.

3. What makes Bio­gen’s ap­proach to tar­get­ing CD38 nov­el?

Our as­set tar­get­ing CD38 has been shown in ear­ly, small clin­i­cal stud­ies to se­lec­tive­ly de­plete CD38+ cells, in­clud­ing plas­ma cells and nat­ur­al killer, or NK, cells. It is hy­poth­e­sized to have a safe­ty pro­file that may be more ap­pro­pri­ate for long-term use in im­mune-me­di­at­ed dis­eases for three im­por­tant rea­sons.

First, ini­tial clin­i­cal stud­ies have shown that the drug un­der de­vel­op­ment binds to CD38 and de­pletes CD38 ex­press­ing cells in a man­ner that doesn’t in­volve com­ple­ment-de­pen­dent cy­to­tox­i­c­i­ty, a process that can lead to more in­flam­ma­tion and se­vere in­fu­sion re­ac­tions. Sec­ond­ly, it al­so has long-term pre­clin­i­cal safe­ty da­ta, which show that it was gen­er­al­ly well-tol­er­at­ed in chron­ic and re­pro­duc­tive tox­i­c­i­ty stud­ies in an­i­mals. Fi­nal­ly, it is thought to bind in a way that does not in­hib­it CD38’s ec­toen­zyme ac­tiv­i­ty which may al­so re­duce on-tar­get ad­verse events.

Based on these char­ac­ter­is­tics, the in­ves­ti­ga­tion­al drug can­di­date has shown sci­en­tif­ic vi­a­bil­i­ty in an­ti­body me­di­at­ed re­jec­tion (AMR), IgA nephropa­thy (IgAN) and pri­ma­ry mem­bra­nous nephropa­thy (PMN), and we’re in­ves­ti­gat­ing its po­ten­tial in three Phase 3 piv­otal stud­ies, all of which have al­ready been ini­ti­at­ed.

Juan Car­los, a Bio­gen em­ploy­ee, is a re­cip­i­ent of a kid­ney trans­plant.

4. And how does this work ap­ply to your ex­pe­ri­ence treat­ing nephrol­o­gy pa­tients? When you re­al­ized there was ap­pli­ca­tion of CD38 to nephrol­o­gy, how did you de­cide which dis­eases to tar­get?

We’ve fo­cused on de­vel­op­ing treat­ments for three rare kid­ney dis­eases with sig­nif­i­cant un­met need, in­clud­ing an­ti­body me­di­at­ed re­jec­tion (AMR) in kid­ney trans­plant, a lead­ing cause of kid­ney trans­plant loss; IgA nephropa­thy (IgAN), a lead­ing cause of kid­ney fail­ure; and pri­ma­ry mem­bra­nous nephropa­thy (PMN), a se­vere an­ti­body-me­di­at­ed dis­ease of the kid­ney that is a lead­ing cause of nephrot­ic syn­drome and car­ries a sig­nif­i­cant risk of kid­ney fail­ure.

We have the op­por­tu­ni­ty to po­ten­tial­ly pro­vide ei­ther the first or a new, dif­fer­en­ti­at­ed treat­ment for each of these dis­eases in the fu­ture, which aligns with our strat­e­gy to pur­sue po­ten­tial break­throughs for pa­tients.

5. How im­por­tant was Bio­gen’s ex­per­tise in get­ting treat­ments for rare dis­eases to pa­tients when HI-Bio when de­cid­ing on the pre­ferred part­ner for an ac­qui­si­tion?

Bio­gen’s deep ex­per­tise com­mer­cial­iz­ing rare dis­ease treat­ments was a key dif­fer­en­tia­tor for us. Bring­ing in­no­va­tion to pa­tients means that a mar­ket of­ten must be de­vel­oped since there has been no treat­ment un­til that point. This is some­thing Bio­gen has done, with great suc­cess, in spinal mus­cu­lar at­ro­phy (SMA) and Friedrich atax­ia (FA).

We saw that Bio­gen had ca­pa­bil­i­ties to not on­ly bring a drug through de­vel­op­ment to ap­proval but, most im­por­tant­ly, how to ef­fec­tive­ly get it to pa­tients once it is ap­proved. The com­pa­ny has the ge­o­graph­ic scope and pa­tient sup­port ex­per­tise in place based on ex­pe­ri­ence with treat­ments for SMA (which is now avail­able in more than 70 coun­tries) and for Friedrich atax­ia (which is avail­able in more than 40 coun­tries and grow­ing). We’ll now be able to ap­ply that same ex­per­tise and key learn­ings to rare kid­ney dis­eases, if suc­cess­ful.

Nic­hole is a re­cip­i­ent of two kid­ney trans­plants.

6. Fi­nal­ly, Bio­gen has stat­ed its in­ten­tion to ex­pand in­to im­munol­o­gy, which is a broad and crowd­ed space. How are you choos­ing where to fo­cus?

Broad­ly, when we de­cide to en­ter any new area, we look for op­por­tu­ni­ties where there are sci­en­tif­ic break­throughs that of­fer the chance to bring for­ward ad­vances in ar­eas of sig­nif­i­cant un­met need. We al­so want to en­sure we have a clear un­der­stand­ing of the dis­ease bi­ol­o­gy, as well as the path­way to tar­get. In this in­stance, tar­get­ing CD38 is a well-known ap­proach to se­lec­tive B-cell de­ple­tion that a grow­ing num­ber of clin­i­cians are fa­mil­iar with (and has ori­gins in on­col­o­gy) but we’ve ap­plied here to im­mune-me­di­at­ed kid­ney dis­eases.

When it comes to im­munol­o­gy, it’s al­so im­por­tant to re­mem­ber that Bio­gen has a deep lega­cy in mul­ti­ple scle­ro­sis, an au­toim­mune dis­ease which af­fects the cen­tral ner­vous sys­tem. To­geth­er with the ex­per­tise from the team at HI-Bio, we have ex­pe­ri­ence across many im­mune path­ways, so it’s a nat­ur­al place for Bio­gen to con­tin­ue ex­pand­ing its pipeline.