Karyopharm shares tank af­ter FDA in­sid­ers slam their case on the ef­fi­ca­cy of a can­cer drug with “sig­nif­i­cant tox­i­c­i­ty”

Karyopharm’s at­tempt to gain an ac­cel­er­at­ed ap­proved for se­linex­or as a treat­ment for drug-re­sis­tant cas­es of mul­ti­ple myelo­ma is in se­ri­ous jeop­ardy. And in­vestors know it.

Their stock $KP­TI plum­met­ed 46% as an­a­lysts ab­sorbed a high­ly crit­i­cal as­sess­ment of their drug — an oral XPO1 in­hibitor — ahead of next Tues­day’s ex­pert pan­el re­view.

Giv­en the his­to­ry of the FDA with these kinds of re­views, Tues­day’s as­sess­ment will like­ly be harsh.

Bat­ting back the op­ti­mistic as­sess­ment the biotech gave se­linex­or, the in­ter­nal FDA re­view con­cludes that there’s pre­cious lit­tle ev­i­dence that the drug has any sig­nif­i­cant val­ue on its own. Just as bad, the drug has been tied to high rates of tox­i­c­i­ty and a high­er death rate when it was test­ed in a ran­dom­ized con­trolled study for acute myeloid leukemia.

“Treat­ment with se­linex­or is as­so­ci­at­ed with sig­nif­i­cant tox­i­c­i­ty,” the re­view states un­am­bigu­ous­ly. The sin­gle arm study that is be­ing used to seek ac­cel­er­at­ed ap­proval demon­strat­ed a 60% rate of se­ri­ous ad­verse events. Al­most 9 out of 10 pa­tients re­quired a dose mod­i­fi­ca­tion due to serous drug re­ac­tions. And a quar­ter of the pa­tients bowed out of the study.

The com­bi­na­tion drug that was used in their pro­posed piv­otal — dex­am­etha­sone — has a his­tor­i­cal re­sponse rate of 10-27% at high dos­es, says the FDA. They could see no re­sponse for the drug when used as a monother­a­py, and even as a com­bo they could see on­ly “lim­it­ed ef­fi­ca­cy.” 

As for the claimed over­all re­sponse rate of 25%, most of those were on­ly par­tial re­spons­es.

An­oth­er chal­lenge: There are 9 drugs ap­proved for treat­ing mul­ti­ple myelo­ma — 4 in the last 4 years. The im­plic­it ques­tion there is, why should the agency ap­prove this drug as num­ber 10?

Giv­en the lim­it­ed ef­fi­ca­cy and sig­nif­i­cant tox­i­c­i­ty demon­strat­ed in this pop­u­la­tion, it is un­clear whether treat­ment with se­linex­or-dex­am­etha­sone pro­vides a clin­i­cal­ly mean­ing­ful ben­e­fit that out­weighs the risks of treat­ment. The lim­i­ta­tions of in­ter­pret­ing safe­ty and ef­fi­ca­cy from a sin­gle arm tri­al, and lack of sin­gle agent ac­tiv­i­ty of se­linex­or cou­pled with his­tor­i­cal da­ta show­ing ac­tiv­i­ty of dex­am­etha­sone in RRMM, add to the chal­lenges in in­ter­pret­ing the re­sults of the piv­otal study in sup­port of the pro­posed in­di­ca­tion.

That’s not good.

An­oth­er black eye was earned for the com­pa­ny’s at­tempt to sup­ply some re­al world ev­i­dence to back up their pitch — which the FDA es­sen­tial­ly re­ject­ed. And an­a­lysts didn’t over­look the vot­ing ques­tion: Should the agency wait for the piv­otal Phase III da­ta from the BOSTON study be­fore the drug hits the mar­ket?

It doesn’t take a ge­nius to fill in the blank on that one.

Jonathan Chang at SVB Leerink notes:

While we were ful­ly ex­pect­ing the tox­i­c­i­ties of se­linex­or to be a key dis­cus­sion point, we view ques­tion­ing the in­ter­pretabil­i­ty of se­linex­or’s ef­fi­ca­cy da­ta as a neg­a­tive sur­prise. Our MEDA­Corp KOL checks have in­di­cat­ed that ef­fi­ca­cy da­ta from the STORM study sug­gest that se­linex­or is an ac­tive drug. No­tably, some of the ef­fi­ca­cy da­ta cit­ed by the FDA for dex alone are gen­er­at­ed in an ear­li­er-line pa­tient pop­u­la­tion (our da­ta ta­bles at­tached). The draft vot­ing ques­tion for the pan­el is “Should ap­proval of se­linex­or be de­layed un­til re­sults of the ran­dom­ized phase 3 tri­al, BOSTON, are avail­able?”. Re­call the Phase III BOSTON study is eval­u­at­ing se­linex­or + Vel­cade + dex (SVd) vs. Vel­cade + dex (Vd) in re­lapsed/re­frac­to­ry mul­ti­ple myelo­ma with da­ta ex­pect­ed by YE19. Ul­ti­mate­ly, po­ten­tial de­lay of ap­proval un­til the BOSTON re­sults are avail­able would be a neg­a­tive up­date vs. our as­sump­tions.

Secretary of health and human services Alex Azar speaking in the Rose Garden at the White House (Photo: AFP)

Trump’s HHS claims ab­solute au­thor­i­ty over the FDA, clear­ing path to a vac­cine EUA

The top career staff at the FDA has vowed not to let politics overrule science when looking at vaccine data this fall. But Alex Azar, who happens to be their boss’s boss, apparently won’t even give them a chance to stand in the way.

In a new memorandum issued Tuesday last week, the HHS chief stripped the FDA and other health agencies under his purview of their rule making ability, asserting all such power “is reserved to the Secretary.” Sheila Kaplan of the New York Times first obtained and reported the details of the September 15 bulletin.

#ES­MO20: Push­ing in­to front­line, Mer­ck and Bris­tol My­ers duke it out with new slate of GI can­cer da­ta

Having worked in parallel for years to move their respective PD-1 inhibitors up to the first-line treatment of gastrointestinal cancers, Merck and Bristol Myers Squibb finally have the data at ESMO for a showdown.

Comparing KEYNOTE-590 and CheckMate-649, of course, comes with the usual caveats. But a side-by-side look at the overall survival numbers also offer some perspective on a new frontier for the reigning checkpoint rivals, both of whom are claiming to have achieved a first.

President Donald Trump (via AP Images)

Signs of an 'Oc­to­ber Vac­cine Sur­prise' alarm ca­reer sci­en­tists

President Donald Trump, who seems intent on announcing a COVID-19 vaccine before Election Day, could legally authorize a vaccine over the objections of experts, officials at the FDA and even vaccine manufacturers, who have pledged not to release any vaccine unless it’s proved safe and effective.

In podcasts, public forums, social media and medical journals, a growing number of prominent health leaders say they fear that Trump — who has repeatedly signaled his desire for the swift approval of a vaccine and his displeasure with perceived delays at the FDA — will take matters into his own hands, running roughshod over the usual regulatory process.

#ES­MO20: Bris­tol My­ers marks Op­di­vo's sec­ond ad­ju­vant win — eye­ing a stan­dard of care gap

Moving into earlier and earlier treatment lines, Bristol Myers Squibb is reporting that adjuvant treatment with Opdivo has doubled the time that esophageal or gastroesophageal junction cancer patients stay free of disease.

With the CheckMate-577 data at ESMO, CMO Samit Hirawat said, the company believes it can change the treatment paradigm.

While a quarter to 30% of patients typically achieve a complete response following chemoradiation therapy and surgery, the rest do not, said Ronan Kelly of Baylor University Medical Center. The recurrence rate is also high within the first year, Hirawat added.

Clay Siegall (Life Science Washington via YouTube)

#ES­MO20: Seat­tle Ge­net­ics eyes 4th ap­proval with new da­ta in a crowd­ed field

Does Seattle Genetics have another approval on its hands?

The last 12 months, not so great for the world, has been great for Seattle Genetics. The company landed two separate FDA approvals, signed a $4.5 billion deal with Merck and watched antibody-drug conjugates — the technology they spent years developing to broad industry skepticism — emerge suddenly as one of the most popular approaches in oncology. And on Monday at ESMO, the company and their partners at Genmab unveiled the data behind the ADC it hopes will provide its next major FDA approval.

Jonathan Rigby, Immune Regulation group CEO

Im­mune Reg­u­la­tion, tak­ing two clin­i­cal pro­grams to 're­set' the im­mune sys­tem, nets $53M+ Se­ries B

A little under two years after a company rebranding, Immune Regulation is taking an even bigger step toward advancing its goals.

Formerly known as Peptinnovate, the British biotech announced a $53.4 million Series B early Monday morning, helping to further advance two clinical programs in rheumatoid arthritis and asthma. Though those are the two initial indications the company is focusing on, CEO Jonathan Rigby told Endpoints News he hopes the candidates can be applied to a broad swath of autoimmune disorders.

Israel Lowy (Regeneron)

#ES­MO20: 'As good as any PD-1 out there': Re­gen­eron flash­es PD-(L)1 lung can­cer da­ta to ri­val Mer­ck

Regeneron entered the PD-(L)1 game late, so they devised a two-pronged strategy to catch up with Big Pharma rivals: They would push it into cancers where PD-1s had yet been tested, and they would prove that it’s as powerful in the big indications as any other on the market.

They cleared a hurdle on the first goal Friday, showing a 31% response in patients with the rare skin cancer basal cell carcinoma. And with the data they’re rolling out Monday, Regeneron cancer chief Israel Lowy is ready to declare success on the second.

Eli Lilly CSO Dan Skovronsky (file photo)

UP­DAT­ED: #ES­MO20: Eli Lil­ly shows off the da­ta for its Verzenio suc­cess. Was it worth $18 bil­lion?

The press release alone, devoid of any number except for the size of the trial, added nearly $20 billion to Eli Lilly’s market cap back in June. Now investors and oncologists will get to see if the data live up to the hype.

On Sunday at ESMO, Eli Lilly announced the full results for its Phase III MonarchE trial of Verzenio, showing that across over 5,000 women who had had HR+, HER2- breast cancer, the drug reduced the odds of recurrence by 25%. That meant 7.8% of the patients on the drug arm saw their cancers return within 2 years, compared with 11.3% on the placebo arm.

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Greg Friberg (File photo)

#ES­MO20: Am­gen team nails down sol­id ear­ly ev­i­dence of AMG 510’s po­ten­tial for NSCLC, un­lock­ing the door to a wave of KRAS pro­grams

The first time I sat down with Amgen’s Greg Friberg to talk about the pharma giant’s KRAS G12C program for sotorasib (AMG 510) at ASCO a little more than a year ago, there was high excitement about the first glimpse of efficacy from their Phase I study, with 5 of 10 evaluable non-small cell lung cancer patients demonstrating a response to the drug.

After decades of failure targeting KRAS, sotorasib offered the first positive look at a new approach that promised to open a door to a whole new approach by targeting a particular mutation to a big target that had remained “undruggable” for decades.

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