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.”

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Alice Shaw, Lung Cancer Foundation of America

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Sean Parker, AP

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Medical animation has in recent years become an increasingly important tool for conveying niche information to a varied audience, particularly to those audiences without expertise in the specialist area. Science programmes today, for example, have moved from the piece-to-camera of the university professor explaining how a complex disease mechanism works, to actually showing the viewer first-hand what it might look like to shrink ourselves down to the size of an ant’s foot, and travel inside the human body to witness these processes in action. Effectively communicating a complex disease pathophysiology, or the novel mechanism of action of a new drug, can be complex. This is especially difficult when the audience domain knowledge is limited or non-existent. Medical animation can help with this communication challenge in several ways.
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Hal Barron, GSK's president of R&D and CSO, speaks to Endpoints News founder and editor John Carroll in London at Endpoints' #UKBIO19 summit on October 8, 2019

[Video] Cel­e­brat­ing tri­al fail­ures, chang­ing the cul­ture and al­ly­ing with Cal­i­for­nia dream­ers: R&D chief Hal Bar­ron talks about a new era at GSK

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This is one discussion you won’t want to miss. Insider and Enterprise subscribers can log-in to watch the video.

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Flu Virus (Source: CDC)

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