David Kirn, 4D Molecular Therapeutics CEO

4D Mol­e­c­u­lar paus­es en­roll­ment in Fab­ry tri­als af­ter kid­ney prob­lems in three pa­tients

4D Mol­e­c­u­lar Ther­a­peu­tics said it has stopped en­rolling pa­tients in its two clin­i­cal tri­als of a gene ther­a­py be­ing in­ves­ti­gat­ed for Fab­ry dis­ease.

The biotech will wait un­til the sec­ond half to eval­u­ate 12-month clin­i­cal da­ta on the six pa­tients en­rolled on 4D-310. The two tri­als, one in the US and the oth­er in Tai­wan and Aus­tralia, were each es­ti­mat­ed to en­roll 18 adults with the dis­ease, in which the body lacks the en­zymes need­ed to break down fats. For those with the in­her­it­ed lipid stor­age dis­or­der, fats build up in blood ves­sels and tis­sue, which leads to dif­fi­cul­ties in the kid­neys, heart and ner­vous sys­tem.

The Cal­i­for­nia gene ther­a­py de­vel­op­er said it found three cas­es of atyp­i­cal he­molyt­ic ure­mic syn­drome (aHUS) in the two tri­als. One was con­sid­ered a grade 4 dose-lim­it­ing tox­i­c­i­ty and the 69-year-old pa­tient, with an un­der­ly­ing kid­ney dys­func­tion, re­quired tem­po­rary he­modial­y­sis. The oth­er two pa­tients did not re­ceive dial­y­sis, 4DMT said, not­ing the aHUS process, in which ab­nor­mal blood clots form in blood ves­sels in the kid­neys, was re­solved in all three pa­tients with­in two to four weeks.

4DMT said three pa­tients were evalu­able for 12-month car­diac da­ta, all in the US study, at the Dec. 5 cut-off. Im­prove­ments in mul­ti­ple car­diac end­points were seen in all three pa­tients, the biotech said.

De­spite the en­roll­ment pause on the Phase I/II stud­ies, 4DMT said it has aligned with the FDA on end­points for a po­ten­tial piv­otal tri­al, in­clud­ing two pri­ma­ry end­points test­ing changes in car­diopul­monary ex­er­cise at months 12 and 24 and a qual­i­ty of life ques­tion­naire.

Go­ing for­ward, the drug de­vel­op­er said it does not plan to in­cor­po­rate the cor­ti­cos­teroid reg­i­men that it has been us­ing.

“In par­al­lel with pa­tient fol­lowup, 4DMT will eval­u­ate its pre­ferred ap­proach of uti­liz­ing the rit­ux­imab-sirolimus im­mune in­hi­bi­tion reg­i­men with 4D-310; the rit­ux­imab and sirolimus com­bi­na­tion is an es­tab­lished clin­i­cal reg­i­men to pre­vent AAV-as­so­ci­at­ed aHUS,” the com­pa­ny said, not­ing that would like­ly re­quire new clin­i­cal pro­to­col and amend­ed or new INDs.

More safe­ty da­ta will come out at the WORLDSym­po­sium on Feb. 25, 4DMT said.

4DMT’s en­roll­ment pause rep­re­sents the lat­est set­back in the field for Fab­ry gene ther­a­py R&D. Around this time last year, Avro­bio axed its can­di­date, AVR-RD-01, af­ter re­view­ing Phase II da­ta. The biotech had pre­vi­ous­ly eyed an ac­cel­er­at­ed ap­proval but changed those plans af­ter Sanofi got FDA ap­proval for its en­zyme re­place­ment ther­a­py Fab­razyme.

Oth­ers in the Fab­ry gene ther­a­py space in­clude Free­line Ther­a­peu­tics, Sang­amo, Am­i­cus Ther­a­peu­tics and CAN­bridge Phar­ma­ceu­ti­cals, which has a world­wide li­cense on a cap­sid from As­traZeneca-ac­quired Log­icBio. Am­i­cus al­ready mar­kets an oral ther­a­py for Fab­ry, sold un­der the brand name Galafold.

Sang­amo had a few da­ta drops last Au­gust and Oc­to­ber, show­ing its gene ther­a­py ap­peared to be work­ing. Lon­don-based Free­line ex­pects to re­port ini­tial safe­ty and ef­fi­ca­cy da­ta from a sec­ond co­hort of its Fab­ry gene ther­a­py in the first half of this year.

In the broad­er Fab­ry dis­ease space, Chiesi and Pro­tal­ix Bio­sciences re­ceived an FDA no-go in April 2021, but they sent their ex­per­i­men­tal drug back to the agency and now have a May 9 PDU­FA date.

Ed­i­tor’s note: This sto­ry has been up­dat­ed to note As­traZeneca-ac­quired Log­icBio’s cap­sid has been li­censed to CAN­bridge Phar­ma­ceu­ti­cals.

Illustration: Assistant Editor Kathy Wong for Endpoints News

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Don Kyle spent more than 20 years working for Purdue Pharma, right through the US opioid epidemic that led to the company’s rise and eventual infamy. But contrary to Purdue’s focus on OxyContin, Kyle was researching non-opioid painkillers — that is, until the company shelved his research.

As the company’s legal troubles mounted, Kyle found an unlikely way to reboot the project. In 2019, he took his work to an Oklahoma State University center that’s slated to receive more than two-thirds of the state’s $272 million settlement with Purdue over claims that the drugmaker’s behavior ignited the epidemic of opioid use and abuse.

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Richard Francis, newly-appointed Teva CEO (Novartis via Facebook)

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Bill Haney, Dragonfly CEO (Dave Pedley/Getty Images for SXSW)

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FDA Commissioner Robert Califf on Capitol Hill, Feb. 8, 2023 (Drew Angerer/Getty Images)

FDA com­mis­sion­er floats ideas on how to bet­ter han­dle the pan­dem­ic

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Sanofi is renewing its #VaccinesForDreams campaign with more stories, such as Juan's in Argentina (Sanofi)

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