Category Archives: Genetic Therapy

When all else fails, some patients trying to overcome alcoholism, severe depression or anxiety, and even cluster headaches, turn to psychedelic drugs, which clinical research has shown can help treat individuals with these conditions, sometimes with dramatically positive results. But sometimes, as with any therapy, the psychedelic treatment does not work. It just takes a patient on a long strange trip.

Now, UNC School of Medicine researchers led by Dr. Bryan Roth, the Michael Hooker Distinguished Professor of Pharmacology, report that one reason for treatment disparity could be common genetic variations in one serotonin receptor.

Published in the journal ACS Chemical Neuroscience, the lab research in cells shows that seven variants uniquely and differentially impact the receptors response to four psychedelic drugs psilocin, LSD, 5-methoxy-N, N-dimethyltryptamine (5-MeO-DMT) and mescaline.

Based on our study, we expect that patients with different genetic variations will react differently to psychedelic-assisted treatments, said Roth, who leads the NIH Psychotropic Drug Screening Program. We think physicians should consider the genetics of a patients serotonin receptors to identify which psychedelic compound is likely to be the most effective treatment in future clinical trials.

Site of the 5-HT2A serotonin receptor.

After decades of taboo regarding potential therapeutic benefit of psychotropic drugs, there has been renewed interest and research in using such compounds to treat neuropsychiatric disorders, such as major depression disorder, because the drugs stimulate serotonin receptors in the brain. These receptors bind the neurotransmitter serotonin and other similar amine-containing molecules, helping regulate peoples mood and emotions, as well as their appetite. In particular, the 5-hydroxytryptamine receptor known as 5-HT2A is responsible for mediating how a person reacts to psychedelic drugs. However, there are several naturally occurring, random genetic variations, known as single nucleotide polymorphisms, or SNPs, that can affect the function and structure of the 5-HT2A receptor.

Roth and colleagues wanted to explore how variations in this one serotonin receptor changes the activity of four psychedelic therapies.

UNC Graduate student Gavin Schmitz and postdoctoral researchers Manish Jain and Samuel Slocum used a series of experimental assays to measure the effect that seven different SNPs had on in vitro binding and signaling of the 5-HT2A serotonin receptor when in the presence of one of the four drugs. Their results indicated that some gene variations even ones far from the exact location where the drug binds to the receptor alter the way that the receptor interacts with the psychedelic drugs.

For example, the SNP Ala230Th had decreased response to one of the four drugs (psilocin the active metabolite of psilocybin) while the Ala447Val mutation showed only reduced effects to two of the drugs.

This is another piece of the puzzle we must know when deciding to prescribe any therapeutic with such dramatic effect aside from the therapeutic effect, Roth said. Further research will help us continue to find the best ways to help individual patients.

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Carolina research reveals role of genetic variants on psychedelics' therapeutic effects | UNC-Chapel Hill - University of North Carolina

Item 2.02 Results of Operations and Financial Condition.

On August 3, 2022, Poseida Therapeutics, Inc. (the "Company," "we," "us" and"our") filed a preliminary prospectus supplement with the Securities andExchange Commission (the "SEC") in which we disclosed that, based on currentlyavailable information, we expect our cash, cash equivalents and short-terminvestments as of June 30, 2022 to be approximately $142.6 million.

The preliminary results set forth above are based on management's initial reviewof our operations for the quarter ended June 30, 2022 and are subject tocompletion of financial closing procedures. The preliminary financial results inthis Item 2.02 have been prepared by, and are the responsibility of management.Actual results may differ materially from these preliminary results as a resultof the completion of financial closing procedures, final adjustments, and otherdevelopments arising between now and the time that our financial results arefinalized. In addition, these preliminary results are not a comprehensivestatement of our financial results for the quarter ended June 30, 2022, shouldnot be viewed as a substitute for full financial statements prepared inaccordance with generally accepted accounting principles, and are notnecessarily indicative of our results for any future period.PricewaterhouseCoopers LLP has not audited, reviewed, compiled, or appliedagreed-upon procedures with respect to the preliminary financial results.Accordingly, PricewaterhouseCoopers LLP does not express an opinion or any otherform of assurance with respect thereto.

Item 8.01 Other Events.

We are filing the following information for the purpose of supplementing andupdating certain disclosures contained in our prior filings with the SEC,including those discussed under the heading "Risk Factors" in our most recentQuarterly Report on Form 10-Q for the quarter ended March 31, 2022, filed withthe SEC on May 12, 2022 (the "Quarterly Report") and certain aspects of ourpublicly disclosed description of our business contained in our other filingswith the SEC.

Company Overview

We are a clinical-stage biopharmaceutical company dedicated to utilizing ourproprietary genetic engineering platform technologies to create next-generationcell and gene therapeutics with the capacity to cure. We have discovered and aredeveloping a broad portfolio of product candidates in a variety of indicationsbased on our core proprietary platforms, including our non-viral piggyBac DNADelivery System, Cas-CLOVER Site-specific Gene Editing System and nanoparticleand AAV-based gene delivery technologies. Our core platform technologies haveutility, either alone or in combination, across many cell and gene therapeuticmodalities and enable us to engineer our portfolio of product candidates thatare designed to overcome the primary limitations of current generation cell andgene therapeutics.

Within cell therapy, we believe our technologies allow us to create productcandidates with engineered cells that engraft in the patient's body and drivelasting durable responses that may have the capacity to result in singletreatment cures. Our CAR-T therapy portfolio consists of both autologous andallogeneic, or off-the-shelf, product candidates. We are advancing a broadpipeline and have multiple CAR-T product candidates in the clinical phase inboth hematological and solid tumor oncology indications. Within gene therapy, webelieve our technologies have the potential to create next-generation therapiesthat can deliver long-term, stable gene expression that does not diminish overtime and that may have the capacity to result in single treatment cures.

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CAR-T for Oncology

The following table summarizes our current CAR-T for oncology product candidateportfolio, including a representation of programs that we partnered with F.Hoffmann-La Roche Ltd and Hoffmann-La Roche Inc. (collectively "Roche") in July2022:

Our most advanced investigational clinical programs are:

We manufacture these product candidates using our non-viral piggyBac DNADelivery System. Our fully allogeneic CAR-T product candidates are developedusing well-characterized cells derived from a healthy donor as starting materialwith the goal of enabling treatment of potentially hundreds of patients from asingle manufacturing run. Doses are cryopreserved and stored at treatmentcenters for future off-the-shelf use. In addition, our allogeneic productcandidates use our proprietary Cas-CLOVER Site-specific Gene Editing System toreduce or eliminate reactivity, as well as our booster molecule technology formanufacturing scalability.

Our most advanced preclinical cell therapy program is:

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Gene Therapy

Our gene therapy product candidates have been developed by utilizing ourpiggyBac technology together with AAV to overcome the major limitations oftraditional AAV gene therapy. We believe that our approach can result inintegration and long-term stable expression at potentially much lower doses thanAAV technology alone, thus also conferring cost and tolerability benefits. Oureventual goal is to completely replace AAV with our non-viral nanoparticletechnology, freeing future product development in gene therapy of AAVlimitations.

The following table summarizes our current gene therapy product candidateportfolio including a representation of programs that we partnered with TakedaPharmaceuticals USA, Inc. (Takeda) in October 2021:

Our most advanced gene therapy programs are:

We expect our expenses and losses to increase substantially for the foreseeablefuture as we continue our development of, and seek regulatory approvals for, ourproduct candidates, including P-PSMA-101 and P-MUC1C-ALLO1, and begin tocommercialize any approved products. While we anticipate an overall increase indevelopment costs as we continue to expand the number of product candidates inour pipeline and pursue clinical development of those candidates, we expect adecrease in our development costs on a per program basis as we are transitioningto our allogeneic platform. In addition, all or some of the development costsrelated to partnered gene therapy programs and cell therapy programs will bereimbursed by Takeda and Roche, respectively. We also expect our general andadministrative expenses will increase for the foreseeable future to support ourincreased research and

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development and other corporate activities. Our net losses may fluctuatesignificantly from quarter-to-quarter and year-to-year, depending on the timingof our clinical trials and our expenditures on other research and developmentactivities.

We do not expect to generate any revenues from product sales unless and until wesuccessfully complete development and obtain regulatory approval for P-PSMA-101and P-MUC1C-ALLO1, or any other product candidates, which will not be for atleast the next several years, if ever. If we obtain regulatory approval for anyof our product candidates, we expect to incur significant commercializationexpenses related to product sales, marketing, manufacturing and distributionactivities. Accordingly, until such time, if ever, as we can generatesubstantial product revenue, we expect to finance our operations through equityofferings, debt financings or other capital sources, including potential grants,collaborations, licenses or other similar arrangements.

However, we may not be able to secure additional financing or enter into suchother arrangements in a timely manner or on favorable terms, if at all. Therecan be no assurances that we will be able to secure such additional sources offunds to support our operations, or, if such funds are available to us, thatsuch additional financing will be sufficient to meet our needs. Our failure toraise capital or enter into such other arrangements when needed would have anegative impact on our financial condition and could force us to delay, reduceor terminate our research and development programs or other operations, or grantrights to develop and market product candidates that we would otherwise preferto develop and market ourselves.

The manufacturing process for our allogeneic product candidates is nearlyidentical to the process for our autologous product candidates, except for thegene editing and related steps. We work with a number of third-party contractmanufacturing organizations for production of our product candidates. We alsowork with a variety of suppliers to provide our manufacturing raw materialsincluding media, DNA and RNA components. We have completed construction of aninternal pilot GMP manufacturing facility in San Diego, California adjacent toour headquarters to develop and manufacture preclinical materials and clinicalsupplies of our product candidates for Phase 1 and Phase 2 clinical trials inthe future. We commenced GMP activity in the third quarter of 2021, however weexpect that we will continue to rely on third parties for various manufacturingneeds. In the future, we may also build one or more commercial manufacturingfacilities for any approved product candidates.

An investment in our common stock is speculative and involves a high degree ofrisk. Our business, reputation, results of operations and financial condition,as well as the price of our common stock, can be affected by a number offactors, whether currently known or unknown, including those described under theheading "Risk Factors" of our Quarterly Report. If any of such risks occur, ourbusiness, financial condition, results of operations and future growth prospectscould be materially and adversely affected. In these circumstances, the marketprice of our common stock could decline, and you may lose all or part of yourinvestment. Below are certain changes to our risk factors included in theQuarterly Report.

Risks Related to Our In-Licenses and Other Strategic Agreements

We may not realize the benefits of any acquisitions, in-license or strategicalliances that we enter into or fail to capitalize on programs that may presenta greater commercial opportunity or for which there is a greater likelihood ofsuccess.

Our business depends upon our ability to identify, develop and commercializeresearch programs or product candidates. A key element of our business strategyis to discover and develop additional programs based upon our core proprietaryplatforms, including our non-viral piggyBac DNA Delivery System, Cas-CLOVERSite-specific Gene Editing System and nanoparticle- and AAV-based gene deliverytechnologies. In addition to internal research and development efforts, we arealso seeking to do so through strategic collaborations, such as ourcollaborations with Roche and Takeda, and may also explore additional strategiccollaborations for the discovery of new programs. We have also entered intoin-license agreements with multiple licensors and in the future may seek toenter into acquisitions or additional licensing arrangements with third partiesthat we believe will complement or augment our existing technologies and productcandidates.

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These transactions can entail numerous operational and financial risks,including exposure to unknown liabilities, disruption of our business anddiversion of our management's time and attention in order to manage acollaboration or develop acquired products, product candidates or technologies,incurrence of substantial debt or dilutive issuances of equity securities to paytransaction consideration or costs, higher than expected development ormanufacturing costs, higher than expected personnel and other resourcecommitments, higher than expected collaboration, acquisition or integrationcosts, write-downs of assets or goodwill or impairment charges, increasedamortization expenses, difficulty and cost in facilitating the collaboration orcombining the operations and personnel of any acquired business, impairment ofrelationships with key suppliers, manufacturers or customers of any acquiredbusiness due to changes in management and ownership and the inability to retainkey employees of any acquired business. As a result, if we enter intoacquisition or in-license agreements or strategic partnerships, we may not beable to realize the benefit of such transactions if we are unable tosuccessfully integrate them with our existing operations and company culture, orif there are materially adverse impacts on our or the counterparty's operationsresulting from COVID-19, which could delay our timelines or otherwise adverselyaffect our business. Further, because we have limited resources, we must chooseto pursue and fund the development of specific types of treatment, or treatmentfor a specific type of cancer, and we may forego or delay pursuit ofopportunities with certain programs or products or for indications that laterprove to have greater commercial potential. Our estimates regarding thepotential market for our program could be inaccurate, and if we do notaccurately evaluate the commercial potential for a particular program, we mayrelinquish valuable rights to that program through a strategic collaboration,licensing or other arrangements in cases in which it would have been moreadvantageous for us to retain sole development and commercialization rights tosuch program. Alternatively, we may allocate internal resources to a program inwhich it would have been more advantageous to enter into a partneringarrangement. If any of these events occur, we may be forced to abandon or delayour development efforts with respect to a particular product candidate or failto develop a potentially successful program.

Our collaborators may not devote sufficient resources to the development orcommercialization of our product candidates or may otherwise fail in developmentor commercialization efforts, which could adversely affect our ability todevelop or commercialize certain of our product candidates and our financialcondition and operating results.

We have, with respect to our collaborations with Roche and Takeda, and willlikely have, with respect to any additional collaboration arrangements with anythird parties, limited control over the amount and timing of resources that ourcollaborators dedicate to the development or commercialization of our productcandidates. For example, while we expect to collaborate with Takeda on thedevelopment of up to six in vivo gene therapy programs, only two such programshave been designated by Takeda and we cannot guarantee that Takeda will elect topursue development of additional gene therapy programs under the collaboration.Similarly, while we expect to collaborate with Roche on the development of up toten allogeneic CAR-T cell therapy programs and have granted to Roche an optionto acquire licenses under certain of our intellectual property to develop,manufacture and commercialize products for up to three solid tumor targets, onlytwo such programs have been designated by Roche and we cannot guarantee thatRoche will elect to pursue development of additional cell therapy programs underthe Roche Collaboration Agreement. In each case, a decision by Roche or Takedato pursue less than the maximum number of targets or programs available forcollaboration under their respective collaboration agreements will limit thepotential payments we may receive under such collaboration agreements, delay ourdevelopment timelines or otherwise adversely affect our business. In general,our ability to generate revenues from these arrangements will depend on ourcollaborators' abilities to successfully perform the functions assigned to themin these arrangements and otherwise to comply with their contractualobligations.

Any of our existing or future collaborations may not ultimately be successful,which could have a negative impact on our business, results of operations,financial condition and growth prospects. In addition, the terms of any suchcollaboration or other arrangement may not prove to be favorable to us or maynot be perceived as favorable, which may negatively impact the trading price ofour common stock. In some cases, we may be responsible for continuingdevelopment or manufacture of a product or product candidate or research programunder collaboration and the payment we receive from our partner may beinsufficient to cover the cost of this development or manufacture. For example,under the Takeda Collaboration Agreement, we are obligated to perform certainplatform development activities at our own cost. In addition, under the RocheCollaboration Agreement, while Roche is obligated to reimburse us for aspecified percentage of certain costs incurred in performance of developmentactivities relating to P-BCMA-ALLO1 and P-CD19CD20-ALLO1, we will be responsiblefor the balance and the amount Roche is obligated to reimburse us is subject toa maximum cap.

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Conflicts may arise between us and our collaborators, such as conflictsconcerning the interpretation of clinical data, the achievement of milestones,the division of development responsibilities or expenses, development plans, theinterpretation of financial provisions, or the ownership of intellectualproperty developed during the collaboration. If any such conflicts arise, acollaborator could act in its own self-interest, which may be adverse to ourbest interests. Any such disagreement between us and a collaborator could delayor prevent the development or commercialization of our product candidates.

Further, we are subject to the following additional risks associated with ourcurrent and any future collaborations with third parties, the occurrence ofwhich could cause our collaboration arrangements to fail:

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Forward-Looking Statements

Statements contained in this Current Report regarding matters that are nothistorical facts are "forward-looking statements" within the meaning of thePrivate Securities Litigation Reform Act of 1995. Such forward-lookingstatements include statements regarding development activities under thecollaboration agreements; our expectations regarding the timing, scope andresults of our development activities, including our ongoing and plannedclinical trials; the timing of and plans for regulatory filings; the potentialbenefits of our product candidates and technologies; our expectations regardingthe use of our platform technologies to generate novel product candidates; themarket opportunities for our product candidates and our ability to maximizethose opportunities; our business strategies and goals; estimates of our cashbalance, expenses, capital requirements, any future revenue, and need foradditional financing; our expectations regarding manufacturing capabilities andplans; the performance of, and reliance on, our third-party suppliers andmanufacturers; our ability to attract and/or retain new and existingcollaborators with development, regulatory, manufacturing and commercializationexpertise and our expectations regarding the potential benefits to be derivedfrom such collaborations; the sufficiency of our existing cash and cashequivalents to fund our operations; and future events and uncertaintiesdescribed under the "Risk Factors" heading of this Current Report. In somecases, you can identify forward-looking statements because they contain wordssuch as "anticipate," "believe," "contemplate," "continue," "could," "estimate,""expect," "intend," "may," "plan," "potential," "predict," "project," "should,""target," "will" or "would" or the negative of these words or other similarterms or expressions. Because such statements are subject to risks anduncertainties, actual results may differ materially from those expressed orimplied by such forward-looking statements. These forward-looking statements arebased upon our current expectations and involve assumptions that may nevermaterialize or may prove to be incorrect. Actual results could differ materiallyfrom those anticipated in such forward-looking statements as a result of variousrisks and uncertainties, which include, without limitation, the fact that theRoche Collaboration Agreement may not become effective based onHart-Scott-Rodino Antitrust Improvements Act of 1976, as amended, clearance, orthe effectiveness may be substantially delayed; our collaboration agreements may. . .

Edgar Online, source Glimpses

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POSEIDA THERAPEUTICS, INC. : Results of Operations and Financial Condition, Other Events (form 8-K) - Marketscreener.com

Venture capital firms have poured tens of billions of dollars into new drug startups over the past several years, greatly expanding the ranks of biotechnology companies both private and public.

But some argue theres still room for more. Specifically, theres room for more young biotechs led and run by the scientists and researchers that founded them. While the idea of the scientific entrepreneur isnt a foreign one, increasingly the highest-profile and best-funded biotech startups are launched from inside the walls of major venture funders like Flagship Pioneering, Third Rock Ventures and Atlas Venture.

These firms often form and incubate young drugmakers around ideas developed in-house and equip them with the tools, funding and executives they need to advance their research. Its a controlled approach thats led to high-profile successes like Moderna as well as a host of other well-resourced companies advancing new drugmaking technologies. But its birthed similar companies, too, which can struggle to stand out, some argue.

Jake Becraft, the CEO and cofounder of Strand Therapeutics, is one of those advocating for more founder-led biotech companies, as well as for an ecosystem thats more conducive to funding and supporting their development.

Theres still good science that goes unfunded, and theres bad science that gets funded, he said in an interview.

Becraft founded Strand in 2017 to build medicines from messenger RNA, years before the strips of genetic code would power the COVID-19 vaccines from Moderna and Pfizer partner BioNTech. Its raised $58 million to date in seed and venture funding, but its investors are from outside the familiar circle of East Coast biotech backers. The company, which now employs about 75 staff, aims to bring its first therapy into clinical testing next year.

BioPharma Dive spoke with Becraft about the founder-led biotech movement, the ongoing public market downturn for drugmakers and the appeal of platform companies. The following interview has been lightly edited and condensed for clarity.

BIOPHARMA DIVE: There's this idea of founder-led biotech, which is sometimes mentioned in contrast to some of the venture capital models that are out there. As a founder and CEO, what does that idea mean to you? What does it mean for how biotech companies are created?

JAKE BECRAFT: To me, it's not really an either/or thing. Venture-created companies will continue to be a thing. I think the biotech ecosystem would be healthier and we'd probably get more revolutionary companies if we had more founder-supported ecosystems.

The playbook for venture creation for classic drug development, [where you] take an asset out of an academic group, discover some novel biology, then take that out into a company and run traditional drug development became sort of formulaic. Not to besmirch the challenge, but essentially that formula was more reproducible and so a lot of funds started to run these companies.

What we're seeing from people throughout the industry is those sorts of companies ended up being ... there is just less identity when a fund makes it and the leadership is also sometimes rapidly changing. You'll see CEOs and management teams cycle in every two years. I think that generally leads to a very different sort of experience for your employees.

Founder-led biotech, to me, just means the founders and the creators of the technology are given a voice and a position at steering the company. I does not necessarily means that the scientist who does the work has to be the CEO of a company. Certainly, that won't be the case for everyone. Not every scientist is going to have the ability or even the want to take up a CEO role.

You mentioned you thought the biotech ecosystem would be healthier if we had more founder-led biotechs. What are some of the challenges preventing that from happening?

BECRAFT: It was a bias that emerged because of the way that people were doing things. When I started Strand, before there was a founder-led biotech movement, there simply weren't any biotech founders that I knew here in Boston. There were more in San Francisco, but the idea that you would both found a company and run that company was pretty foreign. I remember having a lot of investor meetings where people would completely dismiss the idea, almost rudely. The general nature of that not being the case, leads to people saying, Well, the ends justify the means.

I don't believe that I'm such an intelligent person that I'm a standout for the ability to start and lead a company. The fact that I did it is more luck and being given the opportunity. What's stopping more people is that opportunity. It certainly isn't the ability to do it.

With more capital being put behind founders now in the biotech space, especially as capital from the West Coast came in and had more openness to this idea, we're seeing people be very successful.

So much of what big biotech venture firms are creating are companies that they've incubated in their own labs, that they've funded and maybe put in their own executives. Is biotech venture capital open to ideas coming from outside their walls?

BECRAFT: Again, it becomes like a playbook that you know. The problem, let's say five years ago in the Boston biotech ecosystem, was that people mistook what was happening with what was the best. They said, This is working and this is how it's happening, so this is the only way that it should be done.

I'm trying to advocate for something that's less common, because that's what needs the advocacy. I don't think that venture funds starting their own companies need the advocacy. They seem to be doing just fine doing that themselves.

We're hopefully seeing a trend of people continuing to [found and run companies] and, obviously, more wins on the board help everyone get more comfortable with it as well.

Theres been a downturn in biotech markets recently. Yet there's still been an enormous infusion of capital into the sector over the past few years. What effect has that had in terms of which ideas get funded?

BECRAFT: Prior to this downturn, there was a lack of discipline. There's still a lack of discipline. Things still to this day seem to be getting funded that I'm all for go out and fund your innovation, right? I mean, it's capitalism at its best. However, I think a lot of those were not great ideas.

There's still good science that goes on unfunded, and there's bad science that goes funded. Do we really need another AAV [gene therapy] for Duchenne muscular dystrophy? No. We should focus on Duchenne, but there's like 20 companies trying to do the same approach and it just seems unnecessary.

You see it with new fancy platforms that sometimes come out of the venture creation arena. Then you look at their development plan and they say We're going to start with liver disease, prove it out there and then we'll be able to solve all these other things. I just bang my head against the wall. The liver delivery problem is the problem. It's wonderful that another liver disease is going to be targeted. But the hard part is going to be not going to the liver and getting to the other tissues. This doesn't open up the platform directly. You're just a liver disease company unless you have a real idea for how to not get there.

The idea of a platform has become a buzzword that's often used to describe why a company might have a lower risk of failure. Over the past year, though, I've heard that maybe people are less inclined to invest in that premise. Has there been a shift in how people view platforms?

BECRAFT: People have abused [the idea of] platforms to raise money. Because how many companies actually intelligently develop a platform that will make a difference? How many of them have then, over time, translated that into actual drug approvals? You've got like six companies, probably, that have gotten multiple drug approvals in different diseases Alnylam, Regeneron, etc.

You have companies that have platforms, and you have companies that have a single asset and a dream. If a company has a Phase 2 clinical trial and then there is a bunch of discovery work, that was never really a platform company. It's more the story that they're using.

Unfortunately, investors have been burned by that and so now, what they would like to do is pull back from the idea of platforms. But more so, it's not that investors are even pulling back from platforms right now, it's just that they don't care about the story as much. They want to talk to you less about the platform and more about the drug.

What impact has this biotech downturn had on Strand? Has the retrenchment in public markets gone through to the private side, or shut any paths that were previously open to you?

BECRAFT: It doesn't directly affect us. You really only feel the effect if you go out and try to raise funds. We're always talking to investors. I have CEO friends who are in similar stages and there's been a big pullback, especially in Series B rounds as well. The problem in the biotech ecosystem is, over time, the private market investors have swum upstream all the way to start their own companies. The later-stage guys have just become crossovers, rather than actual growth-stage private capital.

What's happening now is the early-stage, private market guys are just continuing to start new companies and trying to go real early. If they're far enough from the public market, then they feel safe that the market will rebound in the next two or three years and they won't have to worry about it.

We've seen from other companies private valuations drop with the public markets, and just a lack of capital to invest into this area because people are scared. Its a weird time.

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Strand CEO on founder-led biotech, venture capital and the market's retreat - BioPharma Dive

WAKEFIELD, Mass.--(BUSINESS WIRE)--Myrtelle Inc. (Myrtelle or the Company), a clinical stage gene therapy company focused on developing transformative treatments for rare genetic diseases, today announced that it has entered into a worldwide exclusive licensing agreement with Rescue Hearing Inc. (RHI) to develop a novel gene therapy for DFNB8 genetic hearing loss. The low-dose recombinant adeno-associated virus (rAAV) gene therapy is intended to deliver a therapeutic TMPRSS3 (transmembrane protease, serine 3) gene by local administration directly to the inner ear. Mutation in the TMPRSS3 gene is the underlying cause of DFNB8 genetic hearing loss in humans. Across its gene therapy programs, Myrtelle utilizes direct administration of low-dose gene therapy to target key cell types involved in the disorder, thereby avoiding immune-related and off-target effects that can arise with high-dose gene therapy administration delivered systemically. This strategy, currently being developed for Myrtelles central nervous system (CNS) programs, can be leveraged to other therapeutic areas outside the CNS, including adjacent and related areas such as the ear where local gene therapy delivery is potentially advantageous for hearing loss disorders such as DFNB8.

We are excited to partner with RHI on this important potential gene therapy for patients with DFNB8 genetic hearing loss. The program will leverage Myrtelles core capabilities and augment our product opportunities to build on the proof-of-concept demonstrated by RHI and move toward the clinic to advance a novel therapeutic approach for patients with DFNB8 genetic hearing, said Mark Pykett, Myrtelle CEO, adding, The potential significance of this new therapeutic hearing loss strategy for patients and families is high.

Preclinical studies in the mouse model of DFNB8-mediated deafness have demonstrated that delivery of a wild type TMPRSS3 gene was able to promote hair cell and neuron survival and improve hearing function. Recently, a successful meeting was held with German health authorities and the Paul Ehrlich Institute to discuss clinical trial authorization (CTA) requirements for starting a first-in-human study. CTA-enabling nonclinical work is currently planned to start later this year to meet these requirements.

RHI is a private, preclinical stage gene therapy company focusing on diseases affecting human hearing. The DFNB8 program targets a common form of genetic hearing loss caused by a mutation in the TMPRSS3 gene. TMPRSS3 mutation is the most common form of genetic deafness in the adult cochlear implant population. DFNB8 patients experience progressive hearing loss usually starting in late teens and early 20s which can lead to complete deafness. RHIs initial preclinical research has demonstrated positive proof-of-concept data enabling entrance to the IND development phase.

We are pleased to partner with Myrtelle on this exciting program. Myrtelles team and their drug development experience are an outstanding fit for the TMPRSS3 AAV-based gene therapy program for DNFB8-related genetic hearing loss. The groundbreaking proof-of-concept data generated by our scientific team lead by Dr. Hinrich Staecker (University of Kansas Medical Center), Dr. Zheng Yi Chen (Mass Eye and Ear Infirmary), and Dr. Xue Zhong Liu (University of Miami Health System) provide a strong foundation for further development. The RHI team is proud to have brought the TMPRSS3 program to this exciting stage and look forward to advancing the program into the clinic with Myrtelle with the goal of developing a novel therapy to positively impact unmet medical needs of the genetic hearing loss community, said Jim Ayala, CEO/Founder Rescue of Hearing.

ABOUT MYRTELLEMyrtelle Inc. is a clinical stage gene therapy company focused on developing transformative treatments for neurodegenerative diseases. The company has a proprietary platform, intellectual property, and portfolio of programs and technologies supporting innovative gene therapy approaches for neurodegenerative diseases. Myrtelle has an exclusive worldwide licensing agreement with Pfizer for its lead gene therapy program in Canavan Disease. For more information, please visit the Companys website at: http://www.myrtellegtx.com.

RESCUE HEARING INCRescue Hearing Inc (RHI) is a private, preclinical stage gene therapy company focused on the genetic forms of hearing loss. RHIs initial product (RHI100) has produced positive proof of concept data and is entering the IND development phase. RHI100 targets a common form of genetic hearing loss caused by a mutation in the TMPRSS3 gene. TMPRSS3 mutation is the most common form of genetic deafness in the cochlear implant population. RHI has two additional gene therapy assets in development. For more information, please visit the companys website at: http://www.rescuehearing.com.

DFNB8Individuals with mutations in TMPRSS3 present with two phenotypes: DFNB10-associated hearing impairment that is pre-lingual and DFNB8-associated hearing impairment that is typically late-onset and post-lingual. TMPRSS3 mutations can be divided into mild or severe; the combination of two severe mutations causes profound pre-lingual hearing loss, whereas milder mutations lead to less severe post-lingual hearing loss.

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Myrtelle Enters into a Worldwide Exclusive License Agreement with Rescue Hearing to Develop and Commercialize Gene Therapy for the Treatment of...

In a few months, a daring clinical trial may fundamentally lower heart attack risk in the most vulnerable people. If all goes well, it will just take one shot.

Its no ordinary shot. The trial, led by Verve Therapeutics, a biotechnology company based in Massachusetts, will be one of the first to test genetic base editors directly inside the human body. A variant of the gene editing tool CRISPR-Cas9, base editors soared to stardom when first introduced for their efficiency at replacing single genetic letters without breaking delicate DNA strands. Because its safer than the classic version of CRISPR, the new tool ignited hope that it could be used for treating genetic diseases.

Verves CEO, Dr. Sekar Kathiresan, took note. A cardiologist at Harvard University, Kathiresan wondered if base editing could help solve one of the main killers of our time: heart attacks. It seemed the perfect test case. We know one major cause of heart attackshigh cholesterol levels, particularly a version called LDL-C (Low-density lipoprotein cholesterol). We also know several major genes that control its level. Andmost importantlywe know the DNA letter swap that can, in theory, drastically lower LDL-C and in turn throttle the risk of heart attacks.

Theres just one problem: we dont know how base editors will behave inside a living human body.

LDL-C is like a fatty piece of chewing gum with a smattering of protein mixed in. It normally swirls in the blood, and is eventually pulled inside cells in bubble-like ships and eaten up in an acid-filled compartment (yeah, cell biology is awesomely weird). Voilthe bloodstream has less fatty gunk.

For this to happen, LDL-C needs to dock onto the cell. The docking point is aptly named LDLR, with R for receptor. Like an efficient shipping yard, the cell controls how many docks are available depending on the level of the LDL-C. If there isnt enough cholesterol, the cell directs a handler, PCSK9, to destroy the docks.

But PCSK9 can get overzealous at times. Without a sufficient number of docks, LDL-C has nothing to grab onto and accumulates inside the bloodstream. Eventually it tacks onto blood vessel walls and builds up a nasty crust, narrowing the bloods supply infrastructure and increasing risk of a heart attack or stroke. The whole process gets thrown into high gear in familial hypercholesterolemia (HeFH), where DNA letter changes in PCSK9 ramp it up, in turn skyrocketing cholesteroloften to a life-threatening level.

PCSK9 has been in scientists crosshairs for decades. Statins are a popular choice, but they only target the symptomhigh cholesterolwithout tackling the underlying genetic issue. Several drugs, such as antibodies that inhibit its actions, were approved by the FDA in 2015. Another option to shut down gene expression is small interfering RNA, which went to market in 2021. Yet both treatments require frequent injectionssome at the doctors officemaking them a lifelong struggle. Theyre also not designed for the greater population of people with heart attack risk.

Instead of a lifetime investment, is there a way to go for one shot and done for heart disease?

In 2021, Kathiresan made a radical move: forget transient therapieslets target the source.

Tapping into CRISPR base editors, his team built on previous work in mice and showed that a single injection of a base editor, dubbed ABE8.8, can reduce both PCSK9 and LDL cholesterol levels in healthy macaque monkeys.

The therapy is a work of art. It contains two easily and cheaply synthesized components: an mRNA that makes the base editor inside the body, and a guide RNA (gRNA) to direct the base editor to the correct DNA spot. The components were then encased inside a lipid nanoparticleessentially, a fatty bubbleand injected into monkeys bloodstreams.

Unlike classic CRISPR treatments, which usually require a virus to hitchhike on, lipid nanoparticles are far safer in that they dont carry the risk of integrating into the genome. Theyre also readily taken up by the liver. As a major source of cholesterol metabolism, the liver is the perfect candidate for testing the gene editor and the delivery mechanism.

With just one infusion, the therapy had 63 percent frequency at editing the PCSK9 gene. After two weeks, the monkeys cholesterol levels fell by more than half. Its not just a blip, but an obviation: after eight months, the monkeys had just 10 percent of their former PCSK9 levels and consistently low cholesterol. Biopsies and blood tests also showed that the monkeys experienced few side effects.

The gene editor was also shockingly specific. In one screen, only one DNA site popped up for off-target editing. However, the site may be monkey-specific, and was never flagged as a problem in tests with human liver cells.

Its an exciting example of the tremendous therapeutic potential of CRISPR base editing, said Dr. Eva van Rooij at the Hubrecht Institute in the Netherlands, who was not involved in the study, at the time. Of course, concerns regarding off-target mutations, immunogenicity, and organ targeting must be addressed. Even so, with the rapid progress in CRISPR-based systems, it seems just a matter of time before the advantages of precise genome editing outweigh the disadvantages in moving to clinical translation.

Directly editing genes inside the human body to prevent heart attacks may seem extreme. But the team has a reason for pursuing a one-and-done strategy.

The main type of liver cells have a relatively long life. This means a one-time administration of gene editing components to permanently inhibit PCSK9 function in the liver could therefore be effective for decades, improving quality of life and reducing healthcare costs, said van Rooij.

Verve isnt the only company eyeing a paradigm shift for heart disease. Another study at the same time, led by Dr. Gerald Schwank at the University of Zurich, took a similar CRISPR base editing approach and found a 26 percent reduction in PCSK9 levels a month later, which increased in efficacy after a second dose. One more study targeting PCSK9 took a different route with antisense oligonucleotides (ASO), a string of DNA letters that block a gene. Here, the treatment was ingested orally rather than injected, with rates of shutting off PCSK9.

For Verve, much is riding on the clinical trial, set to take place in New Zealand in mid-2022. If successful, itll be the first foray of using base editors directly inside the body, and a potentially permanent solution for managing heart attacks. To start, the trial will only recruit people with HeFH, the genetic disorder that causes extremely high levels of cholesterol. The first phase is mainly focused on safety, though improvementsif anymay also show up after analysis. Verve expects initial results around 2023. Meanwhile, the company is also asking the UK and US for the clinical trial green light.

The company has a struggle ahead. Though it was deemed safe in preclinical trials in mice and monkeys, the human immune system may still attack the delivery vehicle. The treatment may also face reluctance from patients as it directly edits the genome. Long-term treatment and side effects remain unknown. And finally, the cost of the treatmentestimated at $50,000 to $200,000would make it unattainable for some. Statins, for example, can be as low as $29 a month, but do require long-term treatment.

Verve is already eyeing the future. We will first focus on adults with life-threatening atherosclerotic cardiovascular disease (ASCVD) and will then expand to broader patient populations with disease, they said.

Meanwhile, legal and reimbursement gears need to swing into action. To Drs. Coen Paulusma and Piter Bosma at the University of Amsterdam, who previously commented on the monkey studies, To make these life-changing therapies available to patients in the near future is a task for regulators, health insurance companies, and governments. In view of the pace of these exciting technical developments, it will be challenging for them all to keep up.

Image Credit: Jolygon/Shutterstock.com

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A One-and-Done CRISPR Gene Therapy Will Aim to Prevent Heart Attacks - Singularity Hub

EVRY, France--(BUSINESS WIRE)--Atamyo Therapeutics, a biotechnology company focused on the development of new-generation gene therapies targeting neuromuscular diseases, today announced multiple major milestones for ATA-100 and ATA-200, its one-time gene-replacement therapies for the treatment of limb-girdle muscular dystrophy types 2I/R9 and 2C/R5 (LGMD2I/R9 and LGMD2C/R5 respectively), as well as the reinforcement of its management team.

Authorization of Clinical Trial Application in France for ATA-100

A third authorization of a Clinical Trial Application (CTA) in Europe was granted by the French National Medicines Health Agency (ANSM) for ATA-100. Two CTA approvals had previously been granted respectively by the United Kingdom Medicines & Healthcare products Regulatory Agency (MHRA) and by the Denmark Danish Medicines Agency (DKMA). ATA-100, a single-administration gene therapy candidate for LGMD2I/R9, delivers a normal copy of the gene for production of FKRP proteins. LGMD2I/R9 is a rare genetic disease caused by mutations in the gene that produces fukutin-related protein (FKRP) and affects an estimated 5,000 people in the US and Europe.

Orphan Drug Designation awarded from European EMA for ATA-200

ATA-200, Atamyos one-time gene replacement therapy for the treatment of LGMD 2C/R5, has been granted Orphan Drug Designation by the European Medicines Agency (EMA) for the treatment of LGMD. Orphan Drug Designations by the EMA grants a ten-year market exclusivity in Europe and provides with other benefits such as tax credits, protocol assistance and research grants.

The therapy is based on the research of Atamyo Chief Scientific Officer Isabelle Richard, Ph.D., Research Director at CNRS who heads the Progressive Muscular Dystrophies Laboratory at Genethon.

We are thrilled by this additional approval for our first-in-human trial with ATA-100 and by the Orphan Drug Designation in Europe for ATA-200. These single-administration treatments bring hope to patients with LGMD2I/R9 and LGMD2C/R5, said Stphane Degove, CEO of Atamyo Therapeutics.

Forthcoming presentation of ATA-200 at ASGCT annual meeting on May 16, 2022

The ATA-200 construct, as well as unveiled in vivo results and GLP-biodistribution and toxicology study, will be presented at the forthcoming ASGCT 25th Annual Meeting, Washington (DC) on May 16-19, 2022. The poster presentation details are:

We are looking forward to presenting to the community ATA-200/GNT008 our first-in-class one-time gene replacement therapy for LGMD2C/R5, said Isabelle Richard, Chief Scientific Officer at Atamyo Therapeutics.

LGMD 2C/R5 affects an estimated 2,000 people in the US and Europe. Symptoms usually appear during early childhood. Patients suffer from progressive muscular weakness leading to loss of ambulation before adulthood. They also are prone to respiratory impairment and myocardial dysfunction. There are currently no curative treatments for LGMD2C/R5.

Appointment of Catherine Cancian MSc, MEng, MBA, as CTO

Atamyo also announced the appointment of Ms. Catherine Cancian, MSc, MEng, MBA as Chief Technical Officer overseeing all pharmaceutical development, clinical and future commercial supply. Ms Cancian has an extensive career as a senior manager in the industry, particularly in regard to pharmaceutical development of biologicals.

Before joining Atamyo, Ms. Cancian was Vice President Pharmaceutical Operations for GenSight Biologics where she developed and executed the strategy for CMC and Supply Chain activities to support the clinical development and commercial readiness of AAV-based gene therapies. Previously, Catherine was Industrialization Project Director for the setup of a new Gene and Cell Therapy manufacturing facility at YposKesi and served at Sanofi Pasteur during 18 years at various management positions including Manufacturing, Project Management, Process Science & Technology and Quality for various marketed vaccines.

About Atamyo Therapeutics

Atamyo Therapeutics is focused on the development of a new generation of effective and safe gene therapies for neuromuscular diseases. A spin-off of gene therapy pioneer Genethon, Atamyo leverages unique expertise in AAV-based gene therapy and muscular dystrophies from the Progressive Muscular Dystrophies Laboratory at Genethon. Atamyos most advanced programs address different forms of limb-girdle muscular dystrophies (LGMD). The name of the company is derived from two words: Celtic Atao which means Always or Forever and Myo which is the Greek root for muscle. Atamyo conveys the spirit of its commitment to improve the life of patients affected by neuromuscular diseases with life-long efficient treatments. For more information visit http://www.atamyo.com

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Atamyo Therapeutics Announces Significant Milestones for ATA-100 and ATA-200, its Gene Therapy Programs to Treat Limb-Girdle Muscular Dystrophy 2I/R9...