Henry Klassen (UC Irvine via YouTube)

Can prog­en­i­tor cells go fur­ther than gene ther­a­py in reti­nal dis­or­ders? A biotech's an­swer shines in PhI­Ib

By the time the FDA ap­proved Lux­tur­na — the pi­o­neer­ing gene ther­a­py for an in­her­it­ed reti­nal dis­ease — Hen­ry Klassen had been re­search­ing and treat­ing the group of dis­eases known as re­tini­tis pig­men­tosa for more than 20 years.

Spark Ther­a­peu­tics’ suc­cess there had not just in­spired a $4.3 bil­lion takeover by Roche, it had al­so em­bold­ened oth­er biotechs pur­su­ing a ther­a­py that would de­liv­er one of the genes tied to dif­fer­ent vari­a­tions of the dis­or­der. Night­star Ther­a­peu­tics sub­se­quent­ly scored its own buy­out with Bio­gen, and MeiraGTx re­cent­ly post­ed ear­ly but “ex­cit­ing da­ta” on its J&J-part­nered pro­gram.

But Klassen went a dif­fer­ent way.

Catch­ing on the stem cell craze right at the turn of the mil­len­ni­um, he took in­spi­ra­tion from sci­en­tists who trans­plant­ed neur­al prog­en­i­tor cells in­to the reti­na and de­vel­oped a method to grow reti­nal prog­en­i­tor cells in­stead as a ther­a­py. Start­ing out as the di­rec­tor of stem cell re­search at the Chil­dren’s Hos­pi­tal of Or­ange Coun­ty, he con­tin­ued the work at the Uni­ver­si­ty of Cal­i­for­nia, Irvine, even­tu­al­ly spin­ning out a biotech dubbed jCyte in 2012.

Paul Bres­ge

Over the week­end jCyte re­port­ed pos­i­tive Phase IIb re­sults from what they call one of the largest stud­ies ever con­duct­ed in RP, sug­gest­ing that pa­tients on the treat­ment saw im­proved func­tion­al vi­sion com­pared to the place­bo group.

“The cred­it to the gene ther­a­pies is that they’re ac­tive­ly try­ing to fix the gene un­der­ly­ing the prob­lem. That’s very com­mend­able, and we’re not do­ing that,” Klassen told End­points News. “But our treat­ment as it stands should have im­pact across a va­ri­ety of dif­fer­ent geno­types.”

The study en­rolled a to­tal of 84 pa­tients, of whom 74 were in­clud­ed for the fi­nal analy­sis. For each pa­tient on the pri­ma­ry end­point of best cor­rect­ed vi­su­al acu­ity (mea­sured with glass­es on), the mean change from base­line to month 12 for the sham, low dose and high dose arms were +2.81, +2.96, and +7.43 let­ters, re­spec­tive­ly.

In a post hoc analy­sis for a tar­get sub­group, the dif­fer­ence was even more promi­nent: +1.85, -0.15, and +16.27 let­ters, re­spec­tive­ly.

There was one se­ri­ous ad­verse event in the low dose arm, but jCyte said the grade 3 oc­u­lar hy­per­ten­sion re­solved with treat­ment and oth­er side ef­fects were gen­er­al­ly mi­nor.

CEO Paul Bres­ge not­ed that the tar­get sub­group analy­sis was in­tend­ed to ham­mer out the cri­te­ria they might use to re­cruit pa­tients in­to Phase III — which would like­ly have a sim­i­lar de­sign and use the same pri­ma­ry end­point of BC­VA, the “gold stan­dard in the con­text of FDA.” The late-stage tri­al is slat­ed for 2021.

“We did en­roll a very wide pa­tient pop­u­la­tion in­to our Phase IIb, in­clud­ing pa­tients that had vi­sion any­where from 20/80 to 20/800, just to learn which pa­tients would po­ten­tial­ly be the best re­spon­ders,” he said.

The tar­get sub­group is char­ac­ter­ized by hav­ing re­li­able fix­a­tion on the study eye, and a study eye that does not have sig­nif­i­cant­ly worse BC­VA (≤15 let­ters) than the fel­low eye.

He added that in­ves­ti­ga­tors al­so ob­served en­cour­ag­ing re­sults with the sec­ondary end­points such as low light mo­bil­i­ty, con­trast sen­si­tiv­i­ty ki­net­ic vi­su­al fields and a vi­sion func­tion ques­tion­naire, al­though the da­ta weren’t dis­closed.

“Typ­i­cal­ly peo­ple think about the dis­ease as a nar­row­ing of this pe­riph­er­al vi­sion in a very nice gran­u­lar way, but that’s ac­tu­al­ly not what hap­pens,” he said about the vi­su­al fields find­ing. “What hap­pens in the dis­ease is that pa­tients lose like is­lands of vi­sion. So what we’re do­ing in our tests is ac­tu­al­ly mea­sur­ing […] is­lands that the pa­tients have at base­line, and then what we’re see­ing af­ter treat­ment is that the is­lands are ex­pand­ing. It’s sim­i­lar to the way that one would track, let’s say a tu­mor, in on­col­o­gy of course we’re look­ing for the op­po­site ef­fect. We’re look­ing for the is­lands of vi­sion to ex­pand.”

The ther­a­py works pri­mar­i­ly by pre­serv­ing pho­tore­cep­tors, Klassen posits, not by gen­er­at­ing new ones. But what he thinks is hap­pen­ing is that pho­tore­cep­tors are re­gen­er­at­ing the out­er seg­ment — if pho­tore­cep­tors are ra­dios, these would be the an­ten­na — there­by re­gain­ing some func­tion.

That could po­si­tion it as a treat­ment for a dif­fer­ent stage of the dis­ease than Spark’s or Night­star’s. Klassen, who’s al­so re­search­ing reti­nal re­con­struc­tion us­ing stem cells, is hap­py to not view it through the com­pet­i­tive lens.

“If you look in­to the fu­ture, one could imag­ine that gene ther­a­pies will be most ef­fec­tive very ear­ly in the course of a dis­ease be­fore pho­tore­cep­tors are lost,” he said. “Then as pho­tore­cep­tors be­gin to be lost any­way, if that hap­pens, then a ther­a­py like ours would be­come ex­treme­ly valu­able. And if ours starts to lose pow­er late in the course of a dis­ease, maybe cell trans­plan­ta­tion un­der the reti­na could have a role.”

2023 Spot­light on the Fu­ture of Drug De­vel­op­ment for Small and Mid-Sized Biotechs

In the context of today’s global economic environment, there is an increasing need to work smarter, faster and leaner across all facets of the life sciences industry.  This is particularly true for small and mid-sized biotech companies, many of which are facing declining valuations and competing for increasingly limited funding to propel their science forward.  It is important to recognize that within this framework, many of these smaller companies already find themselves resource-challenged to design and manage clinical studies themselves because they don’t have large teams or in-house experts in navigating the various aspects of the drug development journey. This can be particularly challenging for the most complex and difficult to treat diseases where no previous pathway exists and patients are urgently awaiting breakthroughs.

Dipal Doshi, Entrada Therapeutics CEO

Ver­tex just found the next big ‘trans­for­ma­tive’ thing for the pipeline — at a biotech just down the street

Back in the summer of 2019, when I was covering Vertex’s executive chairman Jeff Leiden’s plans for the pipeline, I picked up on a distinct focus on myotonic dystrophy Type I, or DM1 — one of what Leiden called “two diseases (with DMD) we’re interested in and we continue to look for those assets.”

Today, Leiden’s successor at the helm of Vertex, CEO Reshma Kewalramani, is plunking down $250 million in cash to go the extra mile on DM1. The lion’s share of that is for the upfront, with a small reserve for equity in a deal that lines Vertex up with a neighbor in Seaport that has been rather quietly going at both of Vertex’s early disease targets with preclinical assets.

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Christian Itin, Autolus CEO (UKBIO19)

Au­to­lus tips its hand, bags $220M as CAR-T show­down with Gilead looms

The first batch of pivotal data on Autolus Therapeutics’ CAR-T is in, and execs are ready to plot a path to market.

With an overall remission rate of 70% at the interim analysis featuring 50 patients, the results set the stage for a BLA filing by the end of 2023, said CEO Christian Itin.

Perhaps more importantly — given that Autolus’ drug, obe-cel, is going after an indication that Gilead’s Tecartus is already approved for — the biotech highlighted “encouraging safety data” in the trial, with a low percentage of patients experiencing severe immune responses.

Rami Elghandour, Arcellx CEO

Up­dat­ed: Gilead, Ar­cel­lx team up on an­ti-BC­MA CAR-T as biotech touts a 100% re­sponse rate at #ASH22

Gilead and Kite are plunking down big cash to get into the anti-BCMA CAR-T game.

The pair will shell out $225 million in cash upfront and $100 million in equity to Arcellx, Kite announced Friday morning, to develop the biotech’s lead CAR-T program together. Kite will handle commercialization and co-development with Arcellx, and profits in the US will be split 50-50.

Concurrent with the deal, Arcellx revealed its latest cut of data for the program known as CART-ddBCMA, ahead of a full presentation at this weekend’s ASH conference — a 100% response rate among patients getting the therapy. Investors jumped at the dual announcements, sending Arcellx shares $ACLX up more than 25% in Friday’s morning session.

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WIB22: Am­ber Salz­man had few op­tions when her son was di­ag­nosed with a rare ge­net­ic dis­ease. So she cre­at­ed a bet­ter one

This profile is part of Endpoints News’ 2022 special report about Women in Biopharma R&D. You can read the full report here.

Amber Salzman’s life changed on a cold, damp day in Paris over tiny plastic cups of lukewarm tea.

She was meeting with Patrick Aubourg, a French neurologist studying adrenoleukodystrophy, or ALD, a rare genetic condition that causes rapid neurological decline in young boys. It’s a sinister disease that often leads to disability or death within just a few years. Salzman’s nephew was diagnosed at just 6 or 7 years old, and died at the age of 12.

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Ahead of ad­comm, FDA rais­es un­cer­tain­ties on ben­e­fit-risk pro­file of Cy­to­ki­net­ic­s' po­ten­tial heart drug

The FDA’s Cardiovascular and Renal Drugs Advisory Committee will meet next Tuesday to discuss whether Cytokinetics’ potential heart drug can safely reduce the risk of cardiovascular death and heart failure in patients with symptomatic chronic heart failure with reduced ejection fraction.

The drug, known as omecamtiv mecarbil and in development for more than 15 years, has seen mixed results, with a first Phase III readout from November 2020 hitting the primary endpoint of reducing the odds of hospitalization or other urgent care for heart failure by 8%. But it also missed a key secondary endpoint analysts had pegged as key to breaking into the market.

Ab­b­Vie slapped with age dis­crim­i­na­tion law­suit, fol­low­ing oth­er phar­mas

Add AbbVie to the list of pharma companies currently facing age discrimination allegations.

Pennsylvania resident Thomas Hesch filed suit against AbbVie on Wednesday, accusing the company of passing him over for promotions in favor of younger candidates.

Despite 30 years of pharma experience, “Hesch has consistently seen younger, less qualified employees promoted over him,” the complaint states.

WIB22: Lead­ing NK cell re­searcher re­flects on roots in Iran, the UK and Texas

This profile is part of Endpoints News’ 2022 special report about Women in Biopharma R&D. You can read the full report here.

In a small but widely-cited 11-person study published in NEJM in 2020, seven patients saw signs of their cancer completely go away after getting a new therapy made from natural killer cells. The study was one of the earliest to provide clinical proof that the experimental treatment method had promise.

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Philip Astley-Sparke, Replimune CEO

Replimune looks to rope in $225M on the back of melanoma da­ta

The Massachusetts-based, oncolytic virus biotech Replimune is feeling bullish now that it has lifted the cover on data for its lead product.

Replimune said Thursday it looks to nab about $225 million from a public offering after giving a snapshot of some initial data from its IGNYTE clinical study earlier this week. The trial is investigating RP1 in combination with Opdivo, for patients with melanoma and who did not have a response when being treated with a PD-1.