Ralph Mechoulam. EPM via YouTube

Start­up EPM launch­es, high off cannabi­noid acid in­no­va­tion

When Sue Sis­ley opened the first bag of her Wash­ing­ton-li­censed weed, she knew some­thing was wrong. It came with the verisimil­i­tude of gov­ern­ment cheese, a bu­reau­crat­ic knock-off that nei­ther looked nor smelled like the re­al thing.

“It was this green pow­der with lit­tle sticks and leaves,” Sis­ley, head of the Scotts­dale Re­search Group, told End­points News ear­li­er this month.”So di­lut­ed.”

Sue Sis­ley

Two years ago, Sis­ley gained ap­proval for a PhII study on the ef­fects of mar­i­jua­na on vet­er­ans with PTSD. Since the 1960s, though, the DEA has on­ly al­lowed one lab in the coun­try, at the Uni­ver­si­ty of Mis­sis­sip­pi, to grow mar­i­jua­na. That meant that when Sis­ley and oth­er re­searchers be­gan some of the first mod­ern stud­ies on med­ical mar­i­jua­na, they were forced to use a prod­uct that looks more like oregano than weed. Al­so, it ap­peared to be moldy.

It was just one of sev­er­al prob­lems that have plagued cannabis re­search and kept the drug in­dus­try from fol­low­ing the stri­dent changes in the na­tion­al view of a once-taboo drug. More broad­ly, re­search in­to mar­i­jua­na and de­riv­a­tives such as cannabi­noids has suf­fered from a lack of pre­ci­sion: The un­der­ly­ing prob­lem be­hind the gov­ern­ment weed is that weed doesn’t come with a stan­dard dose of THC, or stan­dard­ized at all, as you’d want for a drug tri­al. And cannabi­noids might have more pre­ci­sion, but they’re plant ex­tracts — not the chem­i­cal com­pounds the FDA and drug com­pa­nies want for clin­i­cal tri­als.

Which is why Raphael Me­choulam, the 88-year-old Is­raeli “grand­fa­ther” of cannabis re­search, was so ex­cit­ed about the launch of the start­up EPM yes­ter­day and the sig­na­ture tech­nol­o­gy he helped pro­duce: The dis­til­la­tion, sta­bi­liza­tion and in­dus­tri­al-lev­el pro­duc­tion of cannabi­noid acids, the po­tent mol­e­cules that give rise to the plant’s psy­chotrop­ic ef­fects and that, com­pa­ny founders say, could move soon to the clin­ic.

“Here we have a new fam­i­ly of cannabi­noid that are prob­a­bly par­al­lel or even bet­ter than CBD it­self,” he told End­points.

Reshef Swisa

Me­choulam and CEO Reshef Swisa are care­ful to dis­tance them­selves from the plant and re­search done di­rect­ly on its con­sump­tion. But at its root, the point of the new mol­e­cules is to un­lock for the clin­ic the leaf and oil based ef­fects ad­vo­cates have boast­ed about for years and that orig­i­nal­ly drove Me­choulam to start study­ing mar­i­jua­na in the ear­ly 1960s, when as a young re­searcher at the Re­hovot-based Weiz­man In­sti­tute, he man­aged to con­vince a lo­cal po­lice of­fi­cer to il­le­gal­ly hand him five ki­los of Lebanese hashish and then prompt­ly car­ried the pun­gent par­cel from the sta­tion to his lab on a crowd­ed bus of pas­sen­gers ask­ing “What the hell is this smell?”

Me­choulam’s re­search then was to dis­till the ac­tive in­gre­di­ent in mar­i­jua­na, THC. This new sci­ence goes a cou­ple steps fur­ther, iso­lat­ing and sta­bi­liz­ing the acids that give rise to cannabi­noids in the first place.

The prob­lem with look­ing in­to these acids has al­ways been that while they ap­pear on the plant alive, they dis­ap­pear off the plant it­self as it be­gins to dry. This earned them the movie-style moniker “the mys­tery com­pounds,” Swisa told End­points. You could smoke weed your whole life with­out en­coun­ter­ing them.

But by tak­ing the acid from the plant and us­ing a par­tic­u­lar es­ter, EPM re­searchers were able to sta­bi­lize it, cre­at­ing a po­tent com­pound they can take in­to the lab as you would ibupro­fen. Swisa said they’ve spo­ken with the FDA, and their prod­uct would be treat­ed not as cannabis, with­out all its at­ten­dant rules and stig­mas, but as any oth­er drug in de­vel­op­ment.

“You can look at this com­pound as in­spired by cannabis,” Swisa said. “But it is a se­mi-syn­thet­ic com­pound.”

The im­pli­ca­tions are about as man­i­fold as the wild promise med­i­c­i­nal weed has some­times held, and on­ly tri­als will tell what in­di­ca­tions bear fruit. EPM has done re­search on hu­man cells and rats in­to the com­pounds’ ef­fect on IBD, skin dis­eases and meta­bol­ic dis­eases, find­ing sim­i­lar rates of ef­fec­tive­ness to steroids and oth­er drugs with­out the steep side ef­fects those drugs can bring. They hope to move in­to the clin­ic on a cou­ple in­di­ca­tions soon.

But the crux is that this puts the drug in a form — dis­crete, patentable and con­sis­tent — that makes them at­trac­tive to phar­ma, Swisa said. They hope to li­cense their prod­uct out to oth­er phar­ma­ceu­ti­cal com­pa­nies, and he not­ed that there was en­thu­si­as­tic in­ter­est when they pre­sent­ed the re­sults Mon­day in LA — but then again, they were pre­sent­ing at a cannabis con­fer­ence.

“Peo­ple chas­ing our re­searchers; peo­ple fol­low­ing them; peo­ple com­ing to ask what can be done; peo­ple com­ing to our booths, ask­ing ques­tions, see­ing what we can do and how we can col­lab­o­rate,” he said. “The in­ter­est is big.”

The field is in­deed hot right now de­spite on­go­ing con­cerns from some re­searchers, in­clud­ing Me­choulam, that the pub­lic is em­brac­ing CBD be­fore it’s been prop­er­ly test­ed. Re­sults from Sis­ley’s tri­al are forth­com­ing; oth­er tri­als are un­der­way or al­ready back with pos­i­tive re­sults and sci­en­tists are now mak­ing ef­forts to bio­engi­neer THC through CRISPR. This morn­ing, the EU OK’d a cannabis-based epilep­sy drug al­ready ap­proved by the FDA.

But for a re­searcher who’s been in the game as long as Me­choulam, there still aren’t enough clin­i­cal tri­als and there’s a bit­ter­sweet tinge to some of these new pro­nounce­ments. Me­choulam’s lab con­duct­ed a small clin­i­cal tri­al on CBD and epilep­sy in 1980, find­ing it all but elim­i­nat­ed seizures in 4 of 8 pa­tients and curbed them in three hours. But it was decades be­fore any­one took up that work.

“This was a pity,” Me­choulam said. “We could have saved thou­sands of pa­tients, in par­tic­u­lar chil­dren.”

BY­OD Best Prac­tices: How Mo­bile De­vice Strat­e­gy Leads to More Pa­tient-Cen­tric Clin­i­cal Tri­als

Some of the most time- and cost-consuming components of clinical research center on gathering, analyzing, and reporting data. To improve efficiency, many clinical trial sponsors have shifted to electronic clinical outcome assessments (eCOA), including electronic patient-reported outcome (ePRO) tools.

In most cases, patients enter data using apps installed on provisioned devices. At a time when 81% of Americans own a smartphone, why not use the device they rely on every day?

Chris Gibson (Photo By Vaughn Ridley/Sportsfile for Web Summit via Getty Images)

Re­cur­sion founders gin for­tunes as IPO back­ers show­er $436M on one of the biggest boasts in AI -- based on some very small deals

In the AI drug development world, boasting often comes with the territory. Yet few can rival Recursion when it comes to claiming the lead role in what company execs like to call the industrialization of drug development, with promises of continued exponential growth in the number of drugs it has in the pipeline.

On Friday, the Salt Lake City-based biotech translated its unicorn-sized boasts into a killer IPO, pricing more than 24 million shares at the high end of its range and bringing in $436 million — with a large chunk of that promised by some deep-pocket backers.

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Covid-19 vac­cine halt drags on, an FDA ap­point­ment at long last, the great CRO con­sol­i­da­tion, and more

Welcome back to Endpoints Weekly, your review of the week’s top biopharma headlines. Want this in your inbox every Saturday morning? Current Endpoints readers can visit their reader profile to add Endpoints Weekly. New to Endpoints? Sign up here.

Conference season is upon us, and while we’d much prefer to be wandering down the hallways and presentation rooms in person, the team is ready to cover the most consequential data coming out of these scientific meetings. Get in touch early if you have news to share.

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Image: Shutterstock

Eli Lil­ly asks FDA to re­voke EUA for Covid-19 treat­ment

Eli Lilly on Friday requested that the FDA revoke the emergency authorization for its Covid-19 drug bamlanivimab, which is no longer as effective as a combo therapy because of a rise in coronavirus variants across the US.

“With the growing prevalence of variants in the U.S. that bamlanivimab alone may not fully neutralize, and with sufficient supply of etesevimab, we believe now is the right time to complete our planned transition and focus on the administration of these two neutralizing antibodies together,” Daniel Skovronsky, Lilly’s CSO, said in a statement.

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Ex­clu­sive in­ter­view: Pe­ter Marks on why full Covid-19 vac­cine ap­provals could be just months away

Peter Marks, director of the FDA’s Center for Biologics Evaluation and Research, took time out of his busy schedule last Friday to discuss with Endpoints News all things related to his work regulating vaccines and the pandemic.

Marks, who quietly coined the name “Operation Warp Speed” before deciding to stick with his work regulating vaccines at the FDA rather than join the Trump-era program, has been the face of vaccine regulation for the FDA throughout the pandemic, and is usually spotted in Zoom meetings seated in front of his wife’s paintings.

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Near­ly a year af­ter Au­den­tes' gene ther­a­py deaths, the tri­al con­tin­ues. What hap­pened re­mains a mys­tery

Natalie Holles was five months into her tenure as Audentes CEO and working to smooth out a $3 billion merger when the world crashed in.

Holles and her team received word on the morning of May 5 that, hours before, a patient died in a trial for their lead gene therapy. They went into triage mode, alerting the FDA, calling trial investigators to begin to understand what happened, and, the next day, writing a letter to alert the patient community so they would be the first to know. “We wanted to be as forthright and transparent as possible,” Holles told me late last month.

The brief letter noted two other patients also suffered severe reactions after receiving a high dose of the therapy and were undergoing treatment. One died a month and a half later, at which point news of the deaths became public, jolting an emergent gene therapy field and raising questions about the safety of the high doses Audentes and others were now using. The third patient died in August.

“It was deeply saddening,” Holles said. “But I was — we were — resolute and determined to understand what happened and learn from it and get back on track.”

Eleven months have now passed since the first death and the therapy, a potential cure for a rare and fatal muscle-wasting disease called X-linked myotubular myopathy, is back on track, the FDA having cleared the company to resume dosing at a lower level. Audentes itself is no more; last month, Japanese pharma giant Astellas announced it had completed working out the kinks of the $3 billion merger and had restructured and rebranded the subsidiary as Astellas Gene Therapies. Holles, having successfully steered both efforts, departed.

Still, questions about precisely what led to the deaths of the 3 boys still linger. Trial investigators released key details about the case last August and December, pointing to a biological landmine that Audentes could not have seen coming — a moment of profound medical misfortune. In an emerging field that’s promised cures for devastating diseases but also seen its share of safety setbacks, the cases provided a cautionary tale.

Audentes “contributed in a positive way by giving a painful but important example for others to look at and learn from,” Terry Flotte, dean of the UMass School of Medicine and editor of the journal Human Gene Therapy, told me. “I can’t see anything they did wrong.”

Yet some researchers say they’re still waiting on Astellas to release more data. The company has yet to publish a full paper detailing what happened, nor have they indicated that they will. In the meantime, it remains unclear what triggered the events and how to prevent them in the future.

“Since Audentes was the first one and we don’t have additional information, we’re kind of in a holding pattern, flying around, waiting to figure out how to land our vehicles,” said Jude Samulski, professor of pharmacology at UNC’s Gene Therapy Center and CSO of the gene therapy biotech AskBio, now a subsidiary of Bayer.

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J&J faces CDC ad­vi­so­ry com­mit­tee again next week to weigh Covid-19 vac­cine risks

The CDC’s Advisory Committee on Immunization Practices punted earlier this week on deciding whether or not to recommend lifting a pause on the administration of J&J’s Covid-19 vaccine, but the committee will meet again in an emergency session next Friday to discuss the safety issues further.

The timing of the meeting likely means that the J&J vaccine will not return to the US market before the end of next week as the FDA looks to work hand-in-hand with the CDC to ensure the benefits of the vaccine still outweigh the risks for all age groups.

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Osman Kibar (Samumed, now Biosplice)

Os­man Kibar lays down his hand at Sa­mumed, step­ping away from CEO role as his once-her­ald­ed an­ti-ag­ing biotech re­brands

Samumed made quite the entrance back in 2016, when it launched with some anti-aging programs and a whopping $12 billion valuation. That level of fanfare was nowhere to be found on Thursday, when the company added another $120 million to its coffers and quietly changed its name to Biosplice Therapeutics.

Why the sudden rebrand?

“We did that for obvious reasons,” CFO and CBO Erich Horsley told Endpoints News. “The name Biosplice echoes our science much more than Samumed does.”

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Pascal Soriot (AstraZeneca via YouTube)

Af­ter be­ing goad­ed to sell the com­pa­ny, Alex­ion's CEO set some am­bi­tious new goals for in­vestors. Then Pas­cal So­ri­ot came call­ing

Back in the spring of 2020, Alexion $ALXN CEO Ludwig Hantson was under considerable pressure to perform and had been for months. Elliott Advisers had been applying some high public heat on the biotech’s numbers. And in reaching out to some major stockholders, one thread of advice came through loud and clear: Sell the company or do something dramatic to change the narrative.

In the words of the rather dry SEC filing that offers a detailed backgrounder on the buyout deal, Alexion stated: ‘During the summer and fall of 2020, Alexion also continued to engage with its stockholders, and in these interactions, several stockholders encouraged the company to explore strategic alternatives.’

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