Fab­ry dis­ease: FDA drafts drug de­vel­op­ment guid­ance

The FDA on Wednes­day is­sued draft guid­ance pro­vid­ing rec­om­men­da­tions to drug­mak­ers on clin­i­cal tri­al de­sign and el­i­gi­bil­i­ty cri­te­ria for prod­ucts to treat Fab­ry dis­ease.

Fab­ry dis­ease is a rare in­her­it­ed dis­or­der caused by a de­fi­cien­cy of the lyso­so­mal en­zyme al­pha-galac­tosi­dase A (α-Gal A). Ac­cord­ing to the FDA, pa­tients with Fab­ry dis­ease ex­pe­ri­ence chron­ic gas­troin­testi­nal and neu­ro­path­ic symp­toms and pro­gres­sive or­gan dam­age that even­tu­al­ly caus­es chron­ic re­nal dis­ease, re­nal fail­ure, car­dio­vas­cu­lar dis­ease and strokes.

There are on­ly two prod­ucts ap­proved by the FDA to treat Fab­ry dis­ease, Sanofi Gen­zyme’s en­zyme re­place­ment ther­a­py (ERT) Fab­razyme (agal­si­dase be­ta) and Am­i­cus Ther­a­peu­tics’ Galafold (mi­gala­s­tat), which was grant­ed ac­cel­er­at­ed ap­proval in Au­gust 2018. A sec­ond ERT drug, Shire’s Re­pla­gal (agal­si­dase al­fa) is ap­proved in Eu­rope, but was with­drawn from con­sid­er­a­tion in the US in 2012 af­ter the FDA in­di­cat­ed the com­pa­ny would need to con­duct ad­di­tion­al clin­i­cal tri­als to sup­port ap­proval.

The FDA says it hopes the draft guid­ance will “fos­ter greater ef­fi­cien­cy in drug de­vel­op­ment in this rare dis­ease with the goal of en­hanc­ing clin­i­cal tri­al da­ta qual­i­ty.”

In the 7-page draft guid­ance, the FDA sets out its ex­pec­ta­tions for clin­i­cal tri­al el­i­gi­bil­i­ty cri­te­ria and tri­al de­sign, in­clud­ing con­sid­er­a­tions for ef­fi­ca­cy end­points for treat­ments tar­get­ing spe­cif­ic man­i­fes­ta­tions of the dis­ease.

As for el­i­gi­bil­i­ty cri­te­ria, the FDA says that all pa­tients should have a “con­firmed di­ag­no­sis of [Fab­ry dis­ease] based on both bio­chem­i­cal test­ing and mol­e­c­u­lar test­ing” and that clin­i­cal tri­als should en­roll both male and fe­male pa­tients, pro­vid­ing spe­cif­ic en­rol­ment cri­te­ria for pa­tients of each sex. The FDA al­so says that spon­sors should con­sid­er en­rolling pe­di­atric pa­tients “as ear­ly as fea­si­ble.”

Due to how rare Fab­ry dis­ease is, the FDA says that a sin­gle ad­e­quate and well-con­trolled tri­al “show­ing a clin­i­cal­ly mean­ing­ful treat­ment ef­fect on core clin­i­cal as­pects” of the dis­ease, plus con­fir­ma­to­ry ev­i­dence, is suf­fi­cient for ap­proval.

The FDA al­so says that spon­sors should em­ploy a par­al­lel group de­sign with ei­ther a place­bo or ac­tive con­trol group and con­sid­er strat­i­fy­ing pa­tients by age and sex.

For treat­ments meant to slow or halt dis­ease progress rather than re­verse the dis­ease, the FDA says spon­sors should en­sure the tri­al is con­duct­ed over a long enough pe­ri­od to ob­serve dis­ease pro­gres­sion, not­ing that spe­cial con­sid­er­a­tion should be tak­en with re­gards to long-term fol­low up for gene ther­a­pies.

The draft guid­ance al­so pro­vides con­sid­er­a­tions for end­point se­lec­tion for prod­ucts tar­get­ing spe­cif­ic as­pects of Fab­ry dis­ease, in­clud­ing drugs to treat neu­ro­path­ic and gas­troin­testi­nal symp­toms, re­nal dis­ease and car­diac dis­ease.

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Regeneron CEO Leonard Schleifer speaks at a meeting with President Donald Trump, members of the Coronavirus Task Force, and pharmaceutical executives in the Cabinet Room of the White House (AP Photo/Andrew Harnik)

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Donald and Melania Trump watch the smoke of fireworks from the South Lawn of the White House on July 4, 2020 (via Getty)

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