A snap­shot of neg­a­tive da­ta from an on­go­ing 52-week mid-stage NASH study eval­u­at­ing CymaBay Ther­a­peu­tics’ lead drug has trig­gered alarm, af­ter the ex­per­i­men­tal liv­er drug, se­ladel­par, per­formed worse than a place­bo at a three-month read­out.

Sur­prised and aghast, in­vestors of the San Fran­cis­co-based biotech wast­ed lit­tle time in reg­is­ter­ing their dis­ap­point­ment. The com­pa­ny’s shares $CBAY plum­met­ed about 44.5% to $6.16 in ear­ly Tues­day trad­ing.

In the 181-pa­tient tri­al, pa­tients were ei­ther giv­en place­bo, se­ladel­par 10 mg, 20 mg, or 50 mg once dai­ly. The main goal at the end of 12 weeks was to in­duce a sta­tis­ti­cal­ly sig­nif­i­cant im­prove­ment in liv­er fat con­tent. Pa­tients giv­en the place­bo saw a re­duc­tion of 20.8% in liv­er fat, while those giv­en the three es­ca­lat­ing dos­es of se­ladel­par ex­pe­ri­enced small­er im­prove­ments: 10 mg (9.8%), 20 mg (14.2%) and 50 mg (13%).

Cymabay has pre­vi­ous­ly said it ex­pect­ed to see a 20-30% rel­a­tive — place­bo-ad­just­ed — change in liv­er fat at 12 weeks.

Pol Boudes Linkedin

“While the re­duc­tions in liv­er fat were min­i­mal, we re­main en­cour­aged by the sig­nif­i­cant im­prove­ments in bio­chem­i­cal mark­ers of liv­er in­jury…” Pol Boudes, CymaBay’s chief med­ical of­fi­cer, said in a state­ment.

The ex­per­i­men­tal drug’s 52-week biop­sy read­out is ex­pect­ed in mid-2020. Se­ladel­par be­longs to a fam­i­ly of drugs that ac­ti­vate pro­teins called per­ox­i­some pro­lif­er­a­tor-ac­ti­vat­ed re­cep­tors (PPARs), which reg­u­late gene ex­pres­sion. Ex­ist­ing ev­i­dence sug­gests that in the liv­er, PPAR ag­o­nists play a role in bile acid syn­the­sis, in­flam­ma­tion, fi­bro­sis and lipid me­tab­o­lism.

“While there is still a 52-week fol­low-up, we be­lieve that these 12-week re­sults sig­nif­i­cant­ly lessen the com­pet­i­tive threat of se­ladel­par in NASH. Hence, by less­en­ing the com­pet­i­tive threat, we be­lieve these re­sults should ben­e­fit In­ter­cept, as OCA re­mains the on­ly med­ica­tion to show a ben­e­fit on fi­bro­sis in a Phase 3 tri­al. While OCA has some is­sues of its own, we think it is no­table that one of those is NOT a failed ran­dom­ized, place­bo con­trolled study,” Baird’s Bri­an Sko­r­ney wrote in a note.

Akin to CymaBay, French drug de­vel­op­ers Gen­fit (set to re­port piv­otal da­ta in 2019) and In­ven­ti­va are work­ing on their own PPAR ag­o­nists for NASH.

On Tues­day morn­ing, shares of Gen­fit $GN­FT — that re­cent­ly made its Nas­daq de­but — were al­so down about 15% at $20.37. The move­ment like­ly re­flects in­vestors tak­ing the CymaBay da­ta as ev­i­dence against the ef­fi­ca­cy of Gen­fit’s elafi­bra­nor, Sko­r­ney not­ed. “We think this move is some­what un­jus­ti­fied…the two med­ica­tions were thought to have dif­fer­en­ti­at­ed mech­a­nisms of ac­tion, it seems that this may not be the case, as se­ladel­par’s da­ta sug­gest that the med­ica­tion does not re­duce liv­er fat, which is sim­i­lar to what we have seen from ear­li­er tri­als of elafi­bra­nor.”

How­ev­er, as a con­se­quence of the new CymaBay da­ta, the two PPAR ag­o­nists now look more sim­i­lar than dif­fer­ent, he said. “CymaBay may be at a sig­nif­i­cant dis­ad­van­tage mov­ing for­ward as we be­lieve that even if PPAR ag­o­nism is suc­cess­ful in Gen­fit’s Phase 3 tri­al, with­out any clear signs of dif­fer­en­ti­a­tion, CymaBay may have an up­hill bat­tle as they work to catch up to Gen­fit in NASH. If elafi­bra­nor fails in NASH, it would prob­a­bly be pre­dic­tive of the out­come of se­ladel­par in NASH. Ei­ther way, we think this makes the PPAR class, as a whole, look like a less sig­nif­i­cant com­pet­i­tive threat to OCA.”

Oth­er ma­jor NASH con­tenders — Gilead $GILD (fail in Phase III) and In­ter­cept $ICPT (mixed win in Phase III) — have dis­closed the top line num­bers of their late-stage tri­als. In­ter­cept is poised to sub­mit its mar­ket­ing ap­pli­ca­tion lat­er this year.

Im­age: Shut­ter­stock

Since losing a controversial court case over orphan drug exclusivity last year, the FDA’s Office of Orphan Products Development has remained entirely silent on orphan exclusivity for any product approved since last November, leaving many sponsors in limbo on what to expect.

That silence means that for more than 70 orphan-designated indications for more than 60 products, OOPD has issued no public determination on the seven-year orphan exclusivity in the Orange Book, and no new listings of orphan exclusivity appear in OOPD’s searchable database, as highlighted recently by George O’Brien, a partner in Mayer Brown’s Washington, DC office.

The first generation of personalized CAR-T therapies made big waves in the treatment of lymphoma for their stunning efficacy. Nkarta is hoping its off-the-shelf natural killer cell approach will stand out on safety — while keeping some of those impressive numbers on responses.

In a new update from its Phase I dose escalation study, the South San Francisco-based biotech reported that seven out of 10 patients treated with the highest doses of its NK cell therapy, NKX019, achieved a complete response, translating to a complete response rate of 70%.

A biotech centered on treating fibrosis — born out of Mass General and Brigham and Women’s Hospital — has received a financial boost.

According to an SEC filing, the company has raised $31,761,186 in its latest funding round, which includes 17 investors. The filing lists six names attached to the company, including Meredith Fisher, a partner at Mass General Brigham Ventures and Mediar’s acting CEO.

We now know why Verve’s lead candidate was placed on hold last month by US regulators.

In an SEC filing, Verve laid out the FDA’s conditions for lifting the hold on its lead therapy, VERVE-101. That includes submitting preclinical data about potency differences in human versus non-human cells, risks of gene editing germline cells, and off-target analyses in non-hepatocyte cell types.

The FDA also wants clinical data from the ongoing Heart-1 trial, and to modify the trial protocol in the US to add additional contraceptive measures and increase the length of a staggering interval between the dosing of participants.