Em­maus re­scinds EU mar­ket­ing ap­pli­ca­tion, fol­low­ing neg­a­tive re­view

Two years ago, Em­maus Life Sci­ences se­cured FDA ap­proval for its sick­le cell dis­ease (SCD) ther­a­py — mark­ing the first new ap­proval for pa­tients af­fect­ed by the group of in­her­it­ed red blood cell dis­or­ders that typ­i­cal­ly af­flict those of African an­ces­try in two decades. But the Eu­ro­pean reg­u­la­tor was not sat­is­fied with the dataset sup­port­ing the ther­a­py  — prompt­ing its mak­er on Thurs­day to re­scind its ap­pli­ca­tion.

En­dari is a high­ly pu­ri­fied (phar­ma­ceu­ti­cal grade) ver­sion of the amino acid L-glu­t­a­mine and was ap­proved in Ju­ly 2017 to re­duce the se­vere com­pli­ca­tions that come with SCD. (Non-med­ical grade L-glu­t­a­mine is avail­able as a sup­ple­ment over the counter).

The US ap­proval was based large­ly on a 230-pa­tient place­bo-con­trolled study that ran for 48 weeks. Da­ta showed pa­tients on En­dari ex­pe­ri­enced 25% few­er sick­le cell crises, as well as a 33% drop in hos­pi­tal­iza­tions, com­pared to place­bo. Ad­di­tion­al­ly, pa­tients on En­dari spent few­er cu­mu­la­tive days in the hos­pi­tal and ex­pe­ri­enced a low­er in­ci­dence of acute chest syn­drome.

In its as­sess­ment, the Eu­ro­pean reg­u­la­tor took is­sue with the num­ber of dropouts in the study. The EMA’s Com­mit­tee for Med­i­c­i­nal Prod­ucts for Hu­man Use (CHMP) said the main study on the ther­a­py — chris­tened Xyn­dari in Eu­rope — did not show it was ef­fec­tive at re­duc­ing the num­ber of sick­le cell crises or hos­pi­tal vis­its, due to the high­er num­ber of dropouts in the drug arm.

“(I)nfor­ma­tion on how the med­i­cine worked for those pa­tients (who dropped out) was not avail­able. The CHMP con­sid­ered that the way da­ta from these pa­tients were dealt with was not ap­pro­pri­ate,” the agency said ear­li­er this year.

A to­tal of 156 pa­tients com­plet­ed the tri­al — 97 of 152 pa­tients (63.8%) in the L-glu­t­a­mine group and 59 of 78 pa­tients (75.6%) in the place­bo group, ac­cord­ing to da­ta pub­lished by Em­maus. “The rea­sons for dis­con­tin­u­a­tion were sim­i­lar in the two tri­al groups; the most com­mon rea­sons were with­draw­al of con­sent, ‘oth­er’ rea­sons, and non­ad­her­ence,” the com­pa­ny wrote.

The EMA went on to flag con­cern about a small study used to sup­port the ap­pli­ca­tion for the drug. Once again, many pa­tients in this study dropped out ear­ly, the reg­u­la­tor un­der­scored. “(I)n this study more of the pa­tients tak­ing Xyn­dari had re­ceived a med­i­cine for sick­le cell dis­ease called hy­drox­yurea than pa­tients tak­ing place­bo. This could have in­flu­enced the re­sults.”

Af­ter its ini­tial neg­a­tive rec­om­men­da­tion in May, Em­maus asked the EMA to re­view its da­ta again in June, but the reg­u­la­tor stood by its orig­i­nal stance.

On Thurs­day, Em­maus — which was delist­ed from the Nas­daq ear­li­er this month — dis­closed it was with­draw­ing its Eu­ro­pean mar­ket­ing ap­pli­ca­tion.

Yu­ta­ka Ni­ihara Busi­ness Wire

“Be­cause we have demon­strat­ed the ef­fi­ca­cy of Xyn­dari, as sup­port­ed by the da­ta from the tri­als con­duct­ed, we are dis­ap­point­ed in the CHMP’s po­si­tion,” chief Yu­ta­ka Ni­ihara said in a state­ment.

How­ev­er, Xyn­dari is cur­rent­ly sup­plied through ear­ly ac­cess pro­grams based on named pa­tient use in a num­ber of EU mem­ber states, Turkey and the Mid­dle East.

Mean­while, Em­maus’ ri­vals in the Unit­ed States are scram­bling to get their SCD prod­ucts on the mar­ket.

Glob­al Blood Ther­a­peu­tics $GBT un­veiled pos­i­tive piv­otal da­ta on its sick­le cell dis­ease drug in June — the once-dai­ly pill vox­elo­tor is de­signed to work by in­creas­ing he­mo­glo­bin’s affin­i­ty for oxy­gen. No­var­tis’ $NVS ther­a­py for the blood dis­or­der was grant­ed a speedy re­view by the FDA in Ju­ly — the mon­o­clon­al an­ti­body, called crizan­l­izum­ab,  is ad­min­is­tered in­tra­venous­ly and en­gi­neered to bind to a mol­e­cule called P-se­lectin, one of the ma­jor dri­vers of the va­so-oc­clu­sive process. Oth­er drug­mak­ers, in­clud­ing Blue­bird Bio, Imara, and part­ners CRISPR Ther­a­peu­tics and Ver­tex, are al­so work­ing on their own drugs.

Sick­le cell dis­ease pa­tients have atyp­i­cal he­mo­glo­bin mol­e­cules, which can dis­tort red blood cells in­to a sick­le, or cres­cent, shape. Symp­toms such as ane­mia, re­peat­ed in­fec­tions and pe­ri­od­ic episodes of pain called va­so-oc­clu­sive crises (VOC) when sick­le-shaped red blood cells get stuck in­side blood ves­sels be­gin to ap­pear in ear­ly child­hood. These episodes de­prive the body of oxy­gen-rich blood, which can cul­mi­nate in wide­spread tis­sue and or­gan dam­age — par­tic­u­lar­ly in the lungs, kid­neys, spleen, heart, and brain — and dras­ti­cal­ly di­min­ish life ex­pectan­cy.

For now, bone mar­row trans­plants of­fer the on­ly po­ten­tial cure for sick­le cell ane­mia — but the pro­ce­dure is not safe enough for pa­tients old­er than 16 — be­sides se­cur­ing a healthy donor is dif­fi­cult and the risks can be life-threat­en­ing. There­fore, treat­ment is typ­i­cal­ly lim­it­ed to avoid­ing crises, re­liev­ing symp­toms and pre­vent­ing com­pli­ca­tions. Hy­drox­yurea, a drug be­lieved to stim­u­late the pro­duc­tion of fe­tal he­mo­glo­bin, is of­ten giv­en dai­ly to re­duce the fre­quen­cy of painful crises — but it in­creas­es the risk of in­fec­tion, and the risks as­so­ci­at­ed with long-term use are un­clear.

Lessons for biotech and phar­ma from a doc­tor who chased his own cure

After being struck by a rare disease as a healthy third year medical student, David Fajgenbaum began an arduous journey chasing his own cure. Amidst the hustle of this year’s JP Morgan conference, the digital trials platform Medable partnered with Endpoints Studio to share Dr. Fajgenbaum’s story with the drug development industry.

What follows is an edited transcript of the conversation between Medable CEO Dr. Michelle Longmire and Dr. Fajgenbaum, and it is full of lessons for biotech executives charged with bringing the next generation of medicines to patients.

Jim Scholefield via PR Newswire

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Two months before the outbreak, Moderna CMO Tal Zaks traveled from Cambridge, MA to Washington DC to meet with Anthony Fauci and the leaders of the National Institutes of Health.

For two years, Moderna had worked closely with NIH researchers to build a new kind of vaccine for MERS, one of the deadliest new viruses to emerge in the 21st century. The program was one test for a new technology designed to be faster, cheaper and more precise than the ways vaccines had been made for over a century. They had gathered evidence the technology could work in principle, and Fauci, the longtime head of the National Institute of Allergy and Infectious Diseases and a longtime advocate for better epidemic preparedness, wanted to see if it, along with a couple of other approaches, could work in a worst-case scenario: A pandemic.

“[We were] trying to find a test case for how to demonstrate if our technology could rapidly prepare,” Zaks told Endpoints News.

Zaks and Fauci, of course, wouldn’t have to wait to develop a new test. By year’s end, an outbreak in China would short circuit the need for one and throw them into 24/7 work on a real-world emergency. They also weren’t the only ones with new technology who saw a chance to help in a crisis.

An ocean away, Lidia Oostvogels was still on vacation and relaxing at her mother’s house in Belgium when her Facebook started changing. It was days after Christmas and on most people’s feeds, the news that China had reported a novel virus to the World Health Organization blurred into the stream of holiday sweaters and fir trees. But on Oostvogels’s feed, full of vaccine researchers and virus experts, speculation boiled: There was a virus in China, something contained to the country, but “exotic,” “weird,” and maybe having to do with animals. Maybe a coronavirus.

Lidia Oostvogels

“I was immediately thinking like, ‘Hey, this is something that if needed, we can play a role,'” Oostvogels told Endpoints.

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Christos Kyratsous (via LinkedIn)

He built a MERS treat­ment in 6 months and then the best Ebo­la drug. Now Chris­tos Kyrat­sous turns his sights on Covid-19

TARRYTOWN, NY — In 2015, as the Ebola epidemic raged through swaths of West Africa, Kristen Pascal’s roommates sat her down on their couch and staged an intervention.

“Are you sure this is what you want to be doing with your life?” she recalls them asking her.

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Pascal, a research associate for Regeneron, had been coming home at 2 am and leaving at 6 am. At one point, she didn’t see her roommate for a week. For months, that was life in Christos Kyratsous’ lab as the pair led a company-wide race to develop the first drug that could effectively treat Ebola before the outbreak ended. For Pascal, that was worth it.

“I’m ok, I don’t have Ebola,” Pascal told them. “I see that death toll rising and I can’t not do something about it.”

Last August, Regeneron learned they had succeeded: In a large trial across West Africa, their drug, REGN-EB3, was vastly more effective than the standard treatments. It was surprise news for the company, coming just 10 months into a trial they thought would take several years and a major victory in the global fight against a deadly virus that killed over 2,000 in 2019 and can carry a mortality rate of up to 90%.

For Kyratsous and Pascal, though, it brought only fleeting reprieve. Just four months after the NIH informed them REGN-EB3 worked, Kyratsous was back in his office reading the New York Times for updates on a new outbreak on another continent, and wondering alongside Pascal and senior management whether it was time to pull the trigger again.

In late January, as the death toll swelled and the first confirmed cases outside China broke double digits, they made a decision. Soon they were back on the phone with the multiple government agencies and their coronavirus partners at the University of Maryland’s Level 3 bio lab. The question was simple: Can Kyratsous and his team use a process honed over two previous outbreaks, and create a treatment before the newest epidemic ends? Or worse, if, as world health experts fear, it doesn’t vanish but becomes a recurrent virus like the flu?

“Christos likes things immediately,” Matt Frieman, Regeneron’s coronavirus collaborator at the University of Maryland, told Endpoints. “That’s what makes us good collaborators: We push each other to develop things faster and faster.”

Kristen Pascal (Regeneron)

Click on the image to see the full-sized version

The first time Regeneron tried to respond to a global outbreak, it was something of a systems test, Kyratsous explains from his office at Regeneron’s Tarrytown headquarters. Kyratsous, newly promoted, has crammed it with photos of his family, sketches of viral vectors and a shark he drew for his 3-year-old son. He speaks rapidly – an idiosyncrasy his press person says has only been aggravated this afternoon by the contents of his “Regeneron Infectious Diseases”-minted espresso glass – and he gesticulates with similar fluidity, tumbling through antibodies, MERS, the novel coronavirus, Ebola-infected monkeys.

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Today, it’s another I/O bust.

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