It's a Fractious World After All

FDA's Pe­ter Marks over­rode re­view­ers’ call to re­ject Sarep­ta’s new Duchenne gene ther­a­py
by Lei Lei Wu

Pe­ter Marks, the se­nior FDA of­fi­cial who over­sees the reg­u­la­tion of gene ther­a­pies, over­rode agency re­view­ers’ de­ci­sion to re­ject Sarep­ta Ther­a­peu­tic­s' Duchenne mus­cu­lar dy­s­tro­phy gene ther­a­py af­ter he dis­agreed with parts of their in­ter­pre­ta­tion of the lim­it­ed ef­fi­ca­cy da­ta.

The FDA on Thurs­day grant­ed ac­cel­er­at­ed ap­proval to Sarep­ta’s gene ther­a­py, to be mar­ket­ed as Ele­v­idys, in boys aged 4 and 5 years old. The de­ci­sion fol­lowed months of reg­u­la­to­ry twists and a close vote by an ad­vi­so­ry com­mit­tee.

For an FDA of­fi­cial to over­rule the rec­om­men­da­tion of their team is ex­ceed­ing­ly un­usu­al, but it has now hap­pened twice for a Duchenne drug de­vel­oped by Sarep­ta.

"This is quite rare," said Resh­ma Ra­machan­dran, co-di­rec­tor of Yale's Col­lab­o­ra­tion for Reg­u­la­to­ry Rig­or, In­tegri­ty, and Trans­paren­cy. "Was­n't it Califf who said the re­al ex­perts who know the da­ta best are the med­ical re­view­ers? The ap­proval of Ele­v­idys seems to fly in the face of that."

In a de­ci­sion memo re­leased by the FDA on Thurs­day, Marks wrote, “Al­though I agree with the re­view team’s con­clu­sions re­gard­ing prod­uct qual­i­ty and safe­ty, I dis­agree with cer­tain in­ter­pre­ta­tions of the ef­fi­ca­cy da­ta and come to a dif­fer­ent con­clu­sion re­gard­ing in­di­vid­u­als ages 4 through 5 years.”

Three re­view teams — CBER Clin­i­cal Re­view, Clin­i­cal Phar­ma­col­o­gy Re­view, and Sta­tis­ti­cal Re­view — did not rec­om­mend ap­proval. Marks said he agreed “in large part” with the teams’ ef­fi­ca­cy analy­ses that da­ta from open-la­bel stud­ies and con­trol groups out­side Sarep­ta’s stud­ies were not help­ful. But he didn’t agree with their in­ter­pre­ta­tion of very lim­it­ed da­ta in eight pa­tients aged 4 and 5 from a ran­dom­ized tri­al that Sarep­ta con­duct­ed.

CHMP rec­om­mends re­ject­ing Amy­lyx ALS drug, pit­ting EMA against FDA and Health Cana­da
by Max Gelman

The Eu­ro­pean Med­i­cines Agency rec­om­mend­ed that Amy­lyx Phar­ma­ceu­ti­cals’ ALS drug be re­ject­ed with­in the EU.

The drug, known as Re­lyvrio in the US and Al­bri­oza in Cana­da and the EU, did not “con­vinc­ing­ly” show that it could slow the wors­en­ing of ALS in a clin­i­cal tri­al, the EMA’s Com­mit­tee for Med­i­c­i­nal Prod­ucts for Hu­man Use (CHMP) said Fri­day. As a re­sult, reg­u­la­tors could not say for cer­tain that the ben­e­fits out­weigh the risks.

The sur­vival da­ta were al­so un­re­li­able, “giv­en the way the da­ta were col­lect­ed and an­a­lyzed,” the com­mit­tee added.

Amy­lyx co-CEOs Joshua Co­hen and Justin Klee said in a joint state­ment Amy­lyx will pur­sue a “re-ex­am­i­na­tion process” to con­tin­ue to pur­sue con­di­tion­al ap­proval with­in the bloc. The process takes about four to six months, ac­cord­ing to the com­pa­ny, af­ter which CHMP will fi­nal­ize its opin­ion.

The de­ci­sion does not come as a sur­prise, as Amy­lyx said last month the EMA was trend­ing to­ward a neg­a­tive opin­ion. At the time, Co­hen told End­points News that “we very much dis­agree with this as­sess­ment,” and that the com­pa­ny still sees a pos­si­ble EU ap­proval on the ta­ble this year.

The CHMP opin­ion, how­ev­er, has cre­at­ed a sit­u­a­tion where the FDA and Health Cana­da have ap­proved the drug (“with con­di­tions” in Cana­da) while the EU looks primed to re­ject it. Amy­lyx sub­mit­ted its EU ap­pli­ca­tion us­ing the same Phase II tri­al da­ta and sur­vival analy­ses as in the US and Cana­di­an pack­ages.