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.”

Biotech Half­time Re­port: Af­ter a bumpy year, is biotech ready to re­bound?

The biotech sector has come down firmly from the highs of February as negative sentiment takes hold. The sector had a major boost of optimism from the success of the COVID-19 vaccines, making investors keenly aware of the potential of biopharma R&D engines. But from early this year, clinical trial, regulatory and access setbacks have reminded investors of the sector’s inherent risks.

RBC Capital Markets recently surveyed investors to take the temperature of the market, a mix of specialists/generalists and long-only/ long-short investment strategies. Heading into the second half of the year, investors mostly see the sector as undervalued (49%), a large change from the first half of the year when only 20% rated it as undervalued. Around 41% of investors now believe that biotech will underperform the S&P500 in the second half of 2021. Despite that view, 54% plan to maintain their position in the market and 41% still plan to increase their holdings.

Covid-19 vac­cine boost­ers earn big thumbs up, but Mod­er­na draws ire over world sup­ply; What's next for Mer­ck’s Covid pill?; The C-suite view on biotech; 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.

You may remember that at the beginning of this year, Endpoints News set a goal to go broader and deeper. We are still working towards that, and are excited to share that Beth Snyder Bulik will be joining us on Monday to cover all things pharma marketing. You can sign up for her weekly Endpoints MarketingRx newsletter in your reader profile.

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No­var­tis de­vel­op­ment chief John Tsai: 'We go deep in the new plat­form­s'

During our recent European Biopharma Summit, I talked with Novartis development chief John Tsai about his experiences over the 3-plus years he’s been at the pharma giant. You can read the transcript below or listen to the exchange in the link above.

John Carroll: I followed your career for quite some time. You’ve had more than 20 years in big pharma R&D and you’ve obviously seen quite a lot. I really was curious about what it was like for you three and a half years ago when you took over as R&D chief at Novartis. Obviously a big move, a lot of changes. You went to work for the former R&D chief of Novartis, Vas Narasimhan, who had his own track record there. So what was the biggest adjustment when you went into this position?

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Susan Galbraith, Executive VP, Oncology R&D, AstraZeneca

As­traZeneca on­col­o­gy R&D chief Su­san Gal­braith: 'Y­ou're go­ing to need or­thog­o­nal com­bi­na­tion­s'

 

Earlier in the week we broadcast our 4th annual European Biopharma Summit with a great lineup of top execs. One of the one-on-one conversations I set up was with Susan Galbraith, the oncology research chief at AstraZeneca. In a wide-ranging discussion, Galbraith reviewed the cancer drug pipeline and key trends influencing development work at the pharma giant. You can watch the video, above, or stick with the script below. — JC

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Susan Galbraith speaking at Endpoints News' virtual EUBIO21 summit

Imfinzi/treme­li­mum­ab com­bo scores As­traZeneca an­oth­er OS win — this time in liv­er can­cer

Is the tide turning on AstraZeneca’s battered PD-L1/CTLA4 combo?

A single priming dose of the experimental tremelimumab, followed by Imfinzi every four weeks, beat Nexavar (sorafenib) in helping a group of liver cancer patients live longer in a Phase III study, the company reported, meeting the primary endpoint.

Specifically, the two drugs extended overall survival for patients with unresectable hepatocellular carcinoma who had not received prior systemic therapy and were not eligible for localized treatment.

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Roche's Tecen­triq cross­es the fin­ish line first in ad­ju­vant lung can­cer, po­ten­tial­ly kick­ing off gold rush

While falling behind the biggest PD-(L)1 drugs in terms of sales, Roche has looked to carve out a space for its Tecentriq with a growing expertise in lung cancer. The drug will now take an early lead in the sought-after adjuvant setting — but competitors are on the way.

The FDA on Friday approved Tecentriq as an adjuvant therapy for patients with Stage II-IIIA non small cell lung cancer with PD-(L)1 scores greater than or equal to 1, making it the first drug of its kind approved in an early setting that covers around 40% of all NSCLC patients.

Amit Etkin, Alto Neuroscience CEO (Alto via Vimeo)

A star Stan­ford pro­fes­sor leaves his lab for a start­up out to re­make psy­chi­a­try

About five years ago, Amit Etkin had a breakthrough.

The Stanford neurologist, a soft-spoken demi-prodigy who became a professor while still a resident, had been obsessed for a decade with how to better define psychiatric disorders. Drugs for depression or bipolar disorder didn’t work for many patients with the conditions, and he suspected the reason was how traditional diagnoses didn’t actually get at the heart of what was going on in a patient’s brain.

Rahul Singhvi, Resilience CEO

A Bob Nelsen start­up turns to Har­vard to help sharp­en its tech, in­spir­ing first spin­out

One of Bob Nelsen’s latest projects is headed to Harvard.

Resilience, a company started with the goal of establishing itself as a “one-stop-shop” for companies looking to scale manufacturing, including for hard-to-develop cell and gene therapies, is less than a year old. Friday, it announced a five-year R&D deal with Harvard University that includes $30 million to develop biologics, including vaccines, nucleic acids and cell and gene therapies.

Tillman Gerngross, Adagio CEO

Q&A: Till­man Gern­gross ex­plains why his Covid mAb will have an edge over an al­ready crowd­ed field

If anyone knows about monoclonal antibodies, it’s serial entrepreneur, Adimab CEO, and Dartmouth professor of bioengineering Tillman Gerngross.

Even the name of Gerngross’ new antibody startup Adagio Therapeutics is meant to reflect his vision behind the development of his Covid-19 mAb: slowly, he said, explaining that “everyone else, whether it’s Regeneron, Lilly, or AstraZeneca, Vir, they all valued speed over everything.”

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