Reata's bar­dox­olone of­fers promise in pa­tients with rare kid­ney dis­or­der

Af­ter sur­pris­ing Wall Street with pos­i­tive da­ta on its drug, omavelox­olone, in pa­tients suf­fer­ing from a no­to­ri­ous­ly hard-to-treat de­gen­er­a­tive neu­ro­mus­cu­lar dis­or­der last month, Rea­ta Phar­ma on Mon­day un­veiled piv­otal re­sults from a tri­al test­ing an­oth­er drug, bar­dox­olone, in pa­tients with a rare, ge­net­ic form of chron­ic kid­ney dis­ease for which there ex­ist no ap­proved ther­a­pies.

Bar­dox­olone, like Rea­ta’s oth­er lead drug — omavelox­olone — is a small mol­e­cule en­gi­neered to bind to a gene called Keap1 to en­hance the ac­tiv­i­ty of the pro­tein Nrf2 in or­der to defuse in­flam­ma­tion.

The Phase III por­tion of the CAR­DI­NAL study en­rolled 157 pa­tients with Al­port syn­drome — which is char­ac­ter­ized by pro­gres­sive loss in the kid­ney’s ca­pac­i­ty to fil­ter blood — were ei­ther giv­en bar­dox­olone or place­bo. The main goal of this tranche of the study was a change in eGFR (es­ti­mat­ed Glomeru­lar Fil­tra­tion Rate), a key mea­sure of the kid­ney’s abil­i­ty to pu­ri­fy blood, af­ter 48 weeks of treat­ment. The main sec­ondary end­point was the change in the re­tained eGFR af­ter 48 weeks of treat­ment and four weeks of drug with­draw­al.

Bri­an Sko­r­ney

Da­ta showed pa­tients treat­ed with bar­dox­olone had a sta­tis­ti­cal­ly sig­nif­i­cant im­prove­ment com­pared to place­bo in mean eGFR of 9.50 mL/min (p<0.0001) at 48 weeks — (in the bar­dox­olone arm pa­tients saw an in­crease of 4.72 mL/min  from base­line, while place­bo-treat­ed pa­tients saw of de­cline of -4.78 mL/min).

Mean­while, at week 52 fol­low­ing a month with­draw­al af­ter 48 weeks of treat­ment — bar­dox­olone in­duced a sta­tis­ti­cal­ly sig­nif­i­cant place­bo-cor­rect­ed ben­e­fit in mean re­tained eGFR of 5.14 mL/min (p=0.0012). In the bar­dox­olone arm, pa­tients ex­pe­ri­enced a mean re­tained eGFR de­cline of 0.96 mL/min, while pa­tients treat­ed with place­bo saw their rate slump by 6.11 mL/min.

“While the mag­ni­tude of re­tained ben­e­fit at 52 weeks in this Phase 3 study may not have been as great as the 8.3mL/min place­bo-cor­rect­ed ben­e­fit they had pro­ject­ed, and the ac­tive arm saw less of a re­tained ben­e­fit than in pre­vi­ous stud­ies, we still view this re­sult as sig­nif­i­cant,” Baird’s Bri­an Sko­r­ney wrote in a note, not­ing that the trou­ble seems to be if ear­ly eGFR im­prove­ments match those pre­vi­ous­ly seen on treat­ment of around 10mL/min, a de­cline from +10mL/min to +5mL/min could be­come a con­cern.

Joseph Schwartz SVB Leerink

SVB Leerink an­a­lyst Joseph Schwartz echoed the same con­cern. “Up­on clos­er scruti­ny, we think bears may in­ter­pret the ab­solute re­tained ben­e­fit da­ta as dis­ap­point­ing (i.e., bar­dox­olone (Bard) arm falling be­low base­line) will look for more de­tailed pro­tein­uria da­ta in or­der to dis­prove the po­ten­tial for hy­per­fil­tra­tion,” he said. Al­port syn­drome pa­tients typ­i­cal­ly have el­e­vat­ed pro­tein lev­els in their urine, or pro­tein­uria.

Shares of the Texas-based drug de­vel­op­er $RE­TA slipped about 4.4% to $204.25 in Tues­day pre­mar­ket trad­ing.

But both an­a­lysts were large­ly con­vinced by the ev­i­dence sup­port­ive of the drug’s use in this pa­tient pop­u­la­tion.

“Nev­er­the­less, in light of the high ef­fi­ca­cy bar that RE­TA had set in Ph.3 CAR­DI­NAL as well as the high un­met need in a mo­ti­vat­ed pt. pop­u­la­tion, we con­tin­ue to think that bar­dox­olone of­fers a valu­able ther­a­peu­tic ben­e­fit for pts. in pre­serv­ing kid­ney func­tion,” Schwartz said.

Rea­ta, which is test­ing bar­dox­olone in a range of rare kid­ney dis­eases, should be able to repli­cate sim­i­lar re­sults across these in­di­ca­tions, Sko­r­ney said, be­stow­ing the ther­a­py block­buster po­ten­tial.

CAR­DI­NAL is a Phase II/III tri­al — the mid-stage por­tion of the tri­al was un­veiled last year. On the safe­ty front, Rea­ta said the drug was well tol­er­at­ed showed a sim­i­lar safe­ty pro­file to the Phase II por­tion of the tri­al.

“Im­por­tant­ly, treat­ment emer­gent SAEs were ac­tu­al­ly worse for place­bo-treat­ed pa­tients. Con­cerns about flu­id over­load or MACE seem to be put to bed with this re­sult,” Sko­r­ney added.

Bar­dox­olone en­gages with the Keap1/Nrf2 path­way, which is piv­otal in the res­o­lu­tion of in­flam­ma­tion by sta­bi­liz­ing mi­to­chon­dr­i­al func­tion, restor­ing re­dox bal­ance, and sup­press­ing cy­tokine pro­duc­tion. In Oc­to­ber, Ab­b­Vie re­lin­quished its li­cense to Rea­ta’s omavelox­olone, bar­dox­olone and oth­er Nrf2 ac­ti­va­tors in a $330 mil­lion deal.

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The most widely anticipated and perhaps most widely watched meeting in the FDA’s 113-year history ended late Thursday night with a score of questions and very few answers.

For nearly 9 hours, 18 different outside experts listened to public health agencies and foundations present how the United States’ Covid-19 vaccine program developed through October, and they debated where it should go from there: Were companies testing the right metrics in their massive trials? How long should they track patients before declaring a vaccine safe or effective? Should a vaccine, once authorized, be given to the volunteers in the placebo arm of a trial?

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A top drug pro­gram at Bay­er clears a high bar for CKD — open­ing the door to an FDA pitch

Over the past 4 years, Bayer has been steering a major trial through a pivotal program to see if their drug finerenone could slow down the pace of chronic kidney disease in patients suffering from both CKD as well as Type 2 diabetes.

Today, their team jumped on a virtual meeting hosted by the American Society of Nephrology to offer a solid set of pivotal data to demonstrate that the drug can delay dialysis or a kidney replacement as well as cardio disease, while also adding some worrying signs of hyperkalemia among the patients taking the drug. And they’re hustling it straight to regulators in search of an approval for kidney disease and cardio patients — one of the toughest challenges in the book, as demonstrated by repeated past failures.

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Michel Vounatsos, Biogen CEO (via YouTube)

UP­DAT­ED: Bio­gen spot­lights a pair of painful pipeline set­backs as ad­u­canum­ab show­down looms at the FDA

Biogen has flagged a pair of setbacks in the pipeline, spotlighting the final failure for a one-time top MS prospect while scrapping a gene therapy for SMA after the IND was put on hold due to toxicity.

Both failures will raise the stakes even higher on aducanumab, the Alzheimer’s drug that Biogen is betting the ranch on, determined to pursue an FDA OK despite significant skepticism they can make it with mixed results and a reliance on post hoc data mining. And the failures are being reported as Biogen was forced to cut its profit forecast for 2020 as a generic rival started to erode their big franchise drug.

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Biond­Vax stock im­plodes af­ter a big PhI­II gam­ble for its uni­ver­sal flu vac­cine fails

After flying high on Wall Street for the last few months of a pandemic, BiondVax’s stock and dreams of getting approval for its universal flu vaccine hit the windshield.

The Jerusalem-based biotech announced on Friday that its only clinical candidate, M-001, failed both primary and secondary endpoints in a Phase III study. There was no statistically significant difference in reduction of flu illness and severity between the vaccine and placebo groups, according to the company. The vaccine did prove safe, if ineffective, BiondVax said.

Pascal Soriot, AstraZeneca CEO (Zach Gibson/Bloomberg via Getty Images)

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Ul­tragenyx in­jects $40M to grab Solid's mi­crody­s­trophin trans­gene — while side­step­ping the AAV9 vec­tor that stirred up safe­ty fears

Since before Ilan Ganot started Solid Bio to develop a gene therapy for kids like his son, who has Duchenne muscular dystrophy, Ultragenyx CEO Emil Kakkis has been watching and advising the former investment banker as he navigated the deep waters of drug development.

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Stephen Hahn, FDA commissioner (AP Images)

As FDA sets the stage for the first Covid-19 vac­cine EUAs, some big play­ers are ask­ing for a tweak of the guide­lines

Setting the stage for an extraordinary one-day meeting of the Vaccines and Related Biological Products Advisory Committee this Thursday, the FDA has cleared 2 experts of financial conflicts to help beef up the committee. And regulators went on to specify the safety, efficacy and CMC input they’re looking for on EUAs, before they move on to the full BLA approval process.

All of this has already been spelled out to the developers. But the devil is in the details, and it’s clear from the first round of posted responses that some of the top players — including J&J and Pfizer — would like some adjustments and added feedback. And on Thursday, the experts can offer their own thoughts on shaping the first OKs.

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Adam Koppel and Jeffrey Schwartz, Bain

Bain ex­ecs Adam Kop­pel and Jef­frey Schwartz line up $125M for their first blank check deal as Wall Street con­tin­ues to em­brace biotech

Adam Koppel and Jeffrey Schwartz have jumped into the blank check game, raising $125 million for a stock listing in search of a company.

Their SPAC, BCLS Acquisition Corp, raised $125 million this week, with a line on $25 million more as it scouts for a biotech in search of money and a place on Wall Street.

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Researchers for the German biotech say they got the high antibody titers and T cell activation they were looking for, lining up a hamster challenge to demonstrate — in a simple model — that the vaccine could protect the furry creatures. Like the other mRNA vaccines, the drug sends instructions to spur cells to decorate themselves with the distinctive spike on the virus to elicit an immune response.