Lachlan MacKinnon (L) and Adrian Woolfson (Replay)

With AAV al­ter­na­tive and DNA writ­ing tech, a new hub-and-spoke start­up wants to ‘de­moc­ra­tize’ gene ther­a­pies

When Adri­an Woolf­son was head of R&D at Sang­amo, he be­gan con­tem­plat­ing start­ing his own com­pa­ny. His goal? Solve some of the key chal­lenges plagu­ing ge­nom­ic med­i­cine he’d seen while work­ing on a wide spec­trum of Sang­amo’s pro­grams.

Then, he met Lach­lan MacK­in­non, a biotech in­vestor, in Lon­don, and the two re­al­ized they shared a sim­i­lar vi­sion, de­spite their “or­thog­o­nal” back­grounds, he told End­points News.

Re­play, their new hub-and-spoke start­up, looks to change the way gene ther­a­pies are made. With $55 mil­lion in seed mon­ey, the biotech has col­lect­ed a se­ries of plat­forms, in­clud­ing an HSV vec­tor, pro­tein rewrit­ing al­go­rithm and a DNA writ­ing tool from George Church’s lab.

“We iden­ti­fied es­sen­tial­ly three key chal­lenges that we’re solv­ing for, which we think will de­fine the fu­ture,” Woolf­son, who is the chair­man and pres­i­dent, said. “The first of those is pay­load ca­pac­i­ty; the sec­ond is the need for an off-the-shelf, low cost scal­able, and ex­ten­sive­ly ge­nom­ic en­gi­neered cell ther­a­py plat­form; and the third is the abil­i­ty to as­sem­ble big DNA.”

Re­play’s pri­ma­ry tech­nol­o­gy is its HSV de­liv­ery sys­tem. While AAV vec­tors can gen­er­al­ly on­ly hold about 4.7 kilo­bas­es of a gene, HSV vec­tors can hold about 150 kilo­bas­es. With that in­creased ca­pac­i­ty, ther­a­pies us­ing the vi­ral vec­tor could ex­tend to dis­eases with big­ger genes, like mus­cu­lar dy­s­tro­phy, and genes with their in­trons (and reg­u­la­to­ry parts) in­tact, Woolf­son not­ed.

Woolf­son added Re­play has two class­es of HSV vec­tors. “We’ve got our gene-delet­ed HSV, but we’ve al­so got what we call an am­pli­con — which is an HSV in which we’ve stripped out vir­tu­al­ly all of the genes — and this is al­most a non-vi­ral vec­tor,” Woolf­son said. “And we think that will ac­tu­al­ly be prob­a­bly the most com­pelling of all.”

How­ev­er, the ju­ry re­mains out on whether an HSV-based ther­a­py will be safer than the stan­dard AAV, as the vi­ral vec­tor trig­gers a dan­ger­ous im­mune re­sponse. Woolf­son ac­knowl­edged that like for AAV, the body has neu­tral­iz­ing an­ti­bod­ies against HSV, though he added that HSV has evolved to bet­ter evade the im­mune sys­tem.

A suite of biotechs has grown out of the ef­fort to solve the var­i­ous prob­lems re­lat­ed to gene ther­a­pies. Splice­Bio is try­ing to solve the pay­load lim­i­ta­tion through pro­tein splic­ing, and Aper­tu­ra is work­ing on cus­tom-de­signed AAV vec­tors that it hopes can get AAVs to dif­fi­cult-to-ac­cess ar­eas.

Re­play has al­so li­censed a DNA writ­ing tech­nol­o­gy, used for build­ing syn­thet­ic strands of DNA. “We think we can re­ca­pit­u­late what we’re see­ing with DNA se­quenc­ing and dra­mat­i­cal­ly bring down the cost of writ­ing to help to pi­o­neer a new era of genome writ­ing,” Woolf­son said.

So far, the plat­form com­pa­ny has spun out five dif­fer­ent prod­uct com­pa­nies — four HSV gene ther­a­py com­pa­nies fo­cused on mono­genic dis­or­ders, in­clud­ing one for Parkin­son’s and one for Duchenne mus­cu­lar dy­s­tro­phy, and one en­zyme writ­ing com­pa­ny.

Re­play’s seed round was led by KKR and OMX Ven­tures, and al­so in­clud­ed AR­TIS Ven­tures and Lans­downe Part­ners, SALT, DeciBio Ven­tures, and Ax­i­al.

Has the mo­ment fi­nal­ly ar­rived for val­ue-based health­care?

RBC Capital Markets’ Healthcare Technology Analyst, Sean Dodge, spotlights a new breed of tech-enabled providers who are rapidly transforming the way clinicians deliver healthcare, and explores the key question: can this accelerating revolution overturn the US healthcare system?

Key points

Tech-enabled healthcare providers are poised to help the US transition to value, not volume, as the basis for reward.
The move to value-based care has policy momentum, but is risky and complex for clinicians.
Outsourced tech specialists are emerging to provide the required expertise, while healthcare and tech are also converging through M&A.
Value-based care remains in its early stages, but the transition is accelerating and represents a huge addressable market.

Clay Siegall, Morphimmune CEO

Up­dat­ed: Ex-Seagen chief Clay Sie­gall emerges as CEO of pri­vate biotech

Clay Siegall will be back in the CEO seat, taking the helm of a private startup working on targeted cancer therapies.

It’s been almost a year since Siegall resigned from Seagen, the biotech he co-founded and led for more than 20 years, in the wake of domestic violence allegations by his then-wife. His eventual successor, David Epstein, sold the company to Pfizer in a $43 billion deal unveiled last week.

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Zhi Hong, Brii Biosciences CEO

Brii Bio­sciences stops man­u­fac­tur­ing Covid-19 an­ti­body com­bo, plans to with­draw EUA re­quest

Brii Biosciences said it will stop manufacturing its Covid-19 antibody combination, sold in China, and is working to withdraw its emergency use authorization request in the US, which it started in October 2021.

The Beijing and North Carolina biotech commercially launched the treatment in China last July but is now axing the work and reverting resources to other “high-priority programs,” per a Friday update. The focus now is namely hepatitis B viral infection, postpartum depression and major depressive disorders.

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FDA ad­vi­sors unan­i­mous­ly rec­om­mend ac­cel­er­at­ed ap­proval for Bio­gen's ALS drug

A panel of outside advisors to the FDA unanimously recommended that the agency grant accelerated approval to Biogen’s ALS drug tofersen despite the drug failing the primary goal of its Phase III study, an endorsement that could pave a path forward for the treatment.

By a 9-0 vote, members of the Peripheral and Central Nervous System Drugs Advisory Committee said there was sufficient evidence that tofersen’s effect on a certain protein associated with ALS is reasonably likely to predict a benefit for patients. But panelists stopped short of advocating for a full approval, voting 3-5 against (with one abstention) and largely citing the failed pivotal study.

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Sergio Traversa, Relmada Therapeutics CEO

Rel­ma­da makes 'crit­i­cal changes' to PhI­II tri­al to try and save de­pres­sion drug

Relmada Therapeutics is making changes to its Phase III study of its lead drug for major depressive disorder, in an attempt to avoid problems with a prior trial that showed little difference between the drug and a placebo.

That failure in October wiped 80% from Relmada’s stock price, and was followed by another negative readout a few months later. In both cases, the company said that there had been trial sites that were associated with what it called surprising placebo effects that skewed the results compared with the drug, REL-1017.

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Paul Song, NKGen Biotech CEO

NK cell ther­a­py-fo­cused biotech eyes SPAC deal

A small, Santa Ana-based biotech created in 2017 is looking to enter a SPAC deal as it lays out plans to begin trials in its lead cell therapy candidates and bring on new executives.

Graf Acquisition Corp. IV and NKGen Biotech announced Thursday, with few other details, that the two companies signed a non-binding letter of intent to “pursue a business combination.” Graf Acquisition II and III withdrew their IPOs last year.

In­cyte hit by CRL on ex­tend­ed-re­lease JAK tablets, mud­dy­ing plans for Jakafi fran­chise ex­pan­sion

The FDA has rejected Incyte’s extended-release formulation of ruxolitinib tablets, in a surprise setback for the company’s plans to build on its blockbuster Jakafi franchise.

The ruxolitinib XR tablets are designed to be taken once a day, whereas Jakafi is indicated for twice daily dosage (although some patients can take it once daily).

According to Incyte, the FDA acknowledged in its complete response letter that the study submitted in the NDA “met its objective of bioequivalence based on area under the curve (AUC) parameters but identified additional requirements for approval.”

Peter Hecht, Cyclerion Therapeutics CEO

Hard pressed for cash, Cy­cle­ri­on looks for help fund­ing rare dis­ease drug

Cyclerion Therapeutics may have the design of a Phase IIb study ready to go, but it’s scrambling for a way to fund it.

The company said in a press release that it’s “actively evaluating the best combination of capital, capabilities, and transactions available to it to advance the development of zagociguat,” its lead candidate for a rare, genetic mitochondrial disease known as MELAS.

In a separate SEC filing, Cyclerion once again flagged “substantial doubt about (its) ability to continue as a going concern.” As of the end of 2022, it had cash and cash equivalents of only $13.4 million.

Quince Ther­a­peu­tics faces takeover bid from share­hold­er Echo Lake Cap­i­tal

A bid to take over the biotech Quince Therapeutics has been put forward by one of its shareholders.

On Tuesday, Echo Lake Capital sent a letter to Quince’s board of directors putting forth a proposal to acquire all the biotech’s stock for $1.60 per share, which would value a takeover at around $58 million.

In the letter, Echo Lake said that it believes Quince’s stock is severely undervalued and that no drugs are being actively marketed or developed that require cash expenditures. It’s trading below the value of its assets, Echo Lake said.

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