In pharma, disruptive innovations often strike in waves. In the late 80s, the introduction of approved monoclonal antibodies (mAbs), which offered a new method for taking aim at specific defects in protein structures, triggered a revolution in drug development. After the landmark approval of Roche’s Rituxan in 1997 — the first of its kind in cancer — mAbs became the fastest growing therapeutic in the industry, particularly for oncology and inflammatory diseases.
Yet, pharma companies also faced challenges associated with scaling up production of the novel therapies and spent years ironing out the kinks. A similar situation is now unfolding in the world of cell and gene therapies.
More than 25 cell and gene therapy products have been approved by the FDA, and this burgeoning class of treatments is experiencing its own explosive growth. Over 1,200 experimental cell and gene candidates are in the industry’s pipeline — more than half of which have reached phase 2. And the market for these therapies is expected to swell from about $9 billion in 2023 to over $42 billion by 2030.
Late last year, the FDA also gave its first-ever approval of a CRISPR-based drug. As momentum for gene editing approaches picks up, interest and R&D dollars are flooding into the space.
While more potentially curative therapies are reaching patients, the industry is still grappling with growing pains.
The complexity of producing CAR-T cell therapies, for example, has given rise to production bottlenecks that can create harrowing wait times for patients. Facilities are also struggling at times to find needed staff for lab and manufacturing roles.
And the multi-million dollar price tags for several of these approved rare disease gene therapies have pressured the payer system and industry to innovate new ways of ensuring access — a challenge that will grow more pressing if one of these treatments is approved for an indication with a larger patient population.
In response, the industry is pushing for next-generation solutions to overcome many of these hurdles while unleashing a new wave of technologies that could make the field more transformative than ever before.
The FDA just approved the first CRISPR drug. Here’s what’s next in gene editing.
A look at the fast-evolving pipeline for gene editing therapies.
By: Meagan Parrish• Published Dec. 8, 2023
Gene editing technologies have come a long way in a short period of time.
After about a decade in development, CRISPR is now widely known as a revolutionary gene editing tool potentially offering a wide range of curative treatments. And with the first-ever FDA approval for a CRISPR-based treatment today — Vertex Pharmaceuticals and CRISPR Therapeutics’ Casgevy for sickle cell disease — it’s also one of the buzziest sectors of pharma, already raking in billions in investments and triggering a new drug development heyday.
The roots of this biotech bonanza trace back to the 1980s when Japanese scientists studying E. coli discovered the DNA sequences now known as CRISPR, which stands for clustered regularly interspaced short palindromic repeats. Decades passed, however, before researchers learned how to harness the discovery to develop therapeutics.
One of the critical step changes in this scientific saga came from insights derived from a common refrigerator item: yogurt. In the early 2000s, researchers at the dairy company Danisco attempted to understand why some yogurt cultures were attacked by viruses and observed that the DNA sequence within the CRISPR of the resistant bacteria matched that of the invading virus. The discovery that CRISPR was part of the bacteria’s “adaptive immune system” also illuminated how a CRISPR-associated protein (Cas) could “remember” past viral invaders and attack them when they reappear.
Casgevy at a glance
100,000
Americans impacted by sickle cell disease according to the CDC. Around 1 in every 365 Black Americans develops SDC.
Estimated annual revenue for Casgevy by 2028, according to Evaluate.
In the years of research that followed, two molecular biologists — Jennifer Doudna and Emmanelle Charpentier — discovered that the protein Cas9 could be used to snip DNA with precision. They published their Nobel Prize-winning work in 2012, giving rise to the CRISPR era.
While other gene editing technologies such as zinc finger nucleases were already in development when CRISPR hit the R&D scene, the newcomer offered a less expensive and more efficient approach.
“CRISPR is a phenomenal technology,” said Jen Klarer, partner and head of cell and gene therapy at The Dedham Group, a consulting agency focused on oncology and specialty therapies. “There is a lot of promise [with CRISPR] and it comes down to how genes are edited with such high specificity.”
The growing gene editing ecosystem
>460
Companies developing and using CRISPR nucleases including Cas9, Cas12, etc. These companies include startups, pharmas, vendors and more.
$900 million
The upfront investment Vertex paid CRISPR Therapeutics in 2021 to advance their candidate for sickle cell.
Dozens of companies have now sprung up to leverage CRISPR, including Editas Medicine, Caribou Biosciences, Intellia Therapeutics, Beam Therapeutics and CRISPR Therapeutics, which won U.K. approval for Casgevy last month.
Researchers are also investigating many high-profile disease targets for CRISPR, including AIDS, Huntington’s disease, several types of cancer, cystic fibrosis, autoimmune conditions and infectious diseases like COVID-19.
After Casgevy, the next most advanced candidate in the pipeline is Regeneron and Intellia’s treatment for ATTR amyloidosis, greenlighted for a phase 3 trial in the U.S. in October.
The gene editing pipeline
279
Gene editing therapies in development, according to a Citeline analysis provided to PharmaVoice. Of those, 239 are preclinical. So far, 136 clinical trials for gene editing therapies have been announced.
26
Clinical trial starts for gene editing therapies in 2022 — a record. This year is on track to at least match that number, according to Klarer.
55
Discrete diseases being evaluated with gene editing technologies, according to Citeline.
>3/4
The portion of the gene editing pipeline based on CRISPR/Cas9 technology, according to IQVIA in mid-2023.
27%
Portion of the gene editing pipeline devoted to blood disorders. The next largest slices of the pie are oncology (18%), CNS disorders (16%), infections (13%) and ophthalmology (11%).
Some companies are exploring how different enzymes such as Cas12 and Cas13 could overcome challenges in delivery and off-target effects. Others are advancing candidates that work in vivo as opposed to ex vivo therapies like Casgevy.
And even though CRISPR has revolutionized the field, several gene editing approaches are still being investigated.
“There are a lot of technologies being studied that are medically and clinically impressive,” Klarer said. “We need a lot of years of exploration in this space. There’s not one turnkey solution for all the diseases. The human genome is complex so certain modalities will work better and time will tell which modality works for which disease.”
Article top image credit: Stock via Getty Images
One biotech’s 3 gene therapy hurdles: delivery, delivery and delivery
4DMT’s David Kirn is looking to the future of gene therapy with delivery methods that change the paradigm.
By: Michael Gibney• Published Jan. 10, 2024
Welcome to today’s Biotech Spotlight, a series featuring companies that are creating breakthrough technologies and products. Today, we’re looking at 4D Molecular Therapeutics, a company that uses a cutting-edge evolutionary method to usher in the next stage of gene therapy.
Even a few years ago, gene therapy was an up-and-coming part of the biopharma industry. Now, the trajectory seems almost limitless, and biotechs like 4D Molecular Therapeutics are on the path of developing treatments that could change how we view genetic medicine.
With the recent hiring of UCSF professor Dr. Noriyuki Kasahara and a partnership with fellow gene therapy pioneer Arbor Biotechnologies, 4DMT is carving a new foothold in the gene therapy cliffside by coming up with novel delivery methods based on viral vectors.
4DMT’s advanced computational discovery system picks the tiny nits from a genome that cause conditions like diabetes and heart disease. To get to the root of these complicated diseases, the company has used a method called “directed evolution,” finding needles in the haystack and directing gene therapy to correct them.
Gene therapy is all about the delivery, says 4DMT CEO Dr. David Kirn, and 4DMT’s technology is designed to bring delivery methods up to speed. Here, we talk to Kirn about the future of gene therapy and why improving delivery is so important.
This interview has been edited for brevity and style.
PHARMAVOICE: Why is it important that the industry finds new ways to leverage gene therapy?
DR. DAVID KIRN: In the simplest way, people think of gene therapy as treating a disease where there’s a missing gene, whether it’s muscular dystrophy or cystic fibrosis, where there’s a single gene that’s mutated and you’re going to put a normal copy of a gene into a vector and deliver it to the tissues and cells that need it. When you describe it that way, it sounds very simple — and the beauty of the concept is that it is very simple, but it goes beyond replacement of genes that are mutated in monogenic, recessive diseases. We believe you can also use it for a large market beyond rare inherited diseases with a flexible approach.
When I entered the field, I asked a colleague what the big problems in gene therapy were. They said there are only three: delivery, delivery and delivery. The concept is simple, but what’s difficult is how to deliver it. There was a sort of naive start to the field where people thought they could just take these things and throw them into a cell, and that was very inefficient. So the limitations remain in delivery, and our platform is designed to overcome those limitations.
How did your platform come about to address those problems?
We use what’s called directed evolution. This is a technology that’s used to create or invent customized biologics that have the features you want and was awarded the Nobel Prize in Chemistry back in 2018 to Francis Arnold at CalTech, who did it with enzymes. She said, if I generate a massive number of different versions of an enzyme and then screen and select for the one that matches the phenotype I want, then I could invent a new optimized factor for any condition that I want to optimize for. And then others like Greg Winters and George Smith did it with monoclonal antibodies and bacteriophages. That was the beginning of this idea that we can move beyond the biologics that are present in nature and invent brand new ones with the features we want. And so we’re the first to do it with the [adeno-associated virus] vectors.
What does the future of gene therapy look like to you?
It’s about using technology like directed evolution to keep optimizing and improving the approach such that it can go beyond a handful of rare diseases and begin to impact countless patients. The starting point was these very rare niches where you didn’t need very good delivery and you could still get a product approved, and what we’re trying to do is take it to a whole new level to make it a central pillar of medical care. The future of gene therapy is funneling down from a billion options to a needle in a haystack that is optimal for a target vector.
As you prepare for your FDA discussions, what do your days look like?
It’s a super exciting time — an inflection point. In 10 years, we’ve gotten five products into the clinic and discovered and filed patents on hundreds of different optimized vectors. So now we’ve shown that these vectors behave the way we hoped they would, and it’s the creation of a superior vector that solves limitations we had with the old vectors.
Article top image credit: Permission granted by 4DMT
This biotech aims to expand the CRISPR toolkit for more disease targets in the liver and brain
Arbor Biotechnologies is looking past CRISPR’s recent regulatory wins and into the next stage of gene editing.
By: Michael Gibney• Published Dec. 19, 2023
The technology behind CRISPR gene editing is one of the most cutting edge areas of biopharma, and recent regulatory approvals have demonstrated how far it has come in a relatively short period of time.
Arbor Biotechnologies is setting itself up for the next stage of the gene editing revolution by developing tools that could shape and hone current strategies to reach more disease targets. The preclinical-stage company, co-founded by CRISPR pioneer Feng Zhang and Illumina founder David Walt, is starting with diseases of the liver and central nervous system.
CRISPR is used to modify DNA, and is often paired with the protein Cas9 to locate the correct spots on a gene. Arbor is looking to expand that toolbox with additional proteins to target different genes in pursuit of treatments for more diseases. Its lead program in hyperoxaluria is close to an IND filing next year, CEO Devyn Smith said. The company is also targeting ALS in its earlier pipeline and plans three filings over the next three years.
“There is a kind of horizon coming at some point where gene editing will be able to do things that no other modality can do,” Smith said. “In simple genetics, there’s a mutation in a gene and you need to fix it — and as we understand disease biology more, it becomes a factor of becoming more sophisticated in how we think about the other elements.”
"If we think about the long term, someday I would love to see editing integrated into our worldview."
Here, Smith discusses what sets Arbor apart in the CRISPR crowd and how the space is evolving.
This interview has been edited for brevity and style.
PHARMAVOICE: Tell me a little about the origins of Arbor and how it stands out in the gene editing landscape.
DEVYN SMITH: One of the key differences of Arbor versus many other companies is that Arbor was founded on an idea as opposed to intellectual property — and that ideas was that everyone was using Cas9 at the time, and it was clear that there’s probably a need to identify other approaches that allow you to do more and have more functionality to treat disease. That was the founding principle, and the company has subsequently built a deep discovery tool engine that allows us to discover novel editing approaches. We’ve taken this broad swath of nucleases we’ve discovered, and those have underpinned our technology, which allows us to cover everything you’d want to do with DNA.
For small molecules, you need six million molecules in a library to screen against antibodies. Now, we don’t need six million tools in gene editing, but you need enough tools to cover the broad target set that you have. And the other important piece is making sure we can rapidly translate these discoveries into therapeutics, so we’re very focused on what we call a gateway indication strategy — picking an indication and going deep as soon as possible. Our focus is the central nervous system (CNS) and liver diseases.
CRISPR technology has cleared regulatory hurdles in the last couple months, and it’s an exciting time for gene editing. What does this mean for you and the future of the field?
It’s amazing to me that in 10 years we’ve gone from the original publications from Feng [Zhang]’s lab to an approved product — that’s really fast. And it will make a great difference in patients’ lives. It also allows a pathway and more comfort with these novel approaches that edit DNA. From Arbor’s perspective, we celebrate this. There’s work still to be done as we move to in vivo approaches. Our view is that Cas9 does a lot and is a well-used and well-understood tool. But it has limitations, and you can only do so much. So there is an opportunity to bring to bear a range of tools that allow you to do more. We’re very encouraged by the CRISPR approval and hope it’s the vanguard of many, many more in our space.
How do you see Arbor evolving over time as you grow into the market with these new tools?
If we think about the ex vivo space, we’re not doing executable cell therapy — there, it’s about partnering with folks to give them the tools to do what they need to do. In vivo, we’re very focused on developing our own therapies in liver disease and CNS, starting with ALS. Our goal is to have three filings over the next three years, and what’s important is the breadth of our toolbox. Making sure we have the right technologies and tools that we’ve built and making sure we have the right team of dedicated, knowledgeable drug developers. And by focusing on a single gateway indication, we can be successful there and then expand into other indications. We’re very disciplined in how we think about our pipeline and don’t try to do too much, but learn to walk before we run.
Why did you choose to focus on liver disease and the central nervous system? How did you decide these initial targets?
We wanted to find disease areas where delivery is clear and also an area where we could be the first editor to go into that disease. In liver, we’re making sure we can differentiate and do something that others can’t. CNS is a different profile, and the industry has struggled with it over the last gazillion years because the biology hasn’t been well understood. Now, we’re just starting to understand the underlying genetic impacts on disease pathology and we’ve got a host of genetic targets that are open and accessible for gene editing. There’s real opportunity there and the potential can be life changing.
What are the major shifts you see coming as gene editing technology advances?
Near-term, I think we’ll begin to see more clinical data emerge from in vivo therapeutics. There are only a couple companies in the clinic today, but other companies will join. And we’re beginning to understand the breadth of capabilities for the technology today and hopefully beginning to see one-and-done solutions for patients.
In the mid-term, you’ll see a shift from knockdown approaches to more sophisticated editing, like rewriting and inserting bigger pieces of DNA to achieve more specific results.
And then if we think about the long term, someday I would love to see editing integrated into our worldview. You go to the physician, your DNA is sequenced, they identify 10 things we want to fix now to solve any potential issues. It’s a little like a vaccine. When that occurs, maybe for my great grandchildren, it’s such a different world where, rather than trying to treat ALS once you have it, we’re preventing it from happening in the first place. It’ll be a long road to get there, but that to me is exciting and revolutionary for healthcare.
Article top image credit: iStock via Getty Images
Can Sarepta’s Duchenne gene therapy still deliver on its promise?
For Sarepta — and DMD patients — there’s a lot riding on the treatment’s next steps.
By: Kelly Bilodeau• Published Nov. 14, 2023
Since its initial approval, the industry and patients have eagerly awaited news from a confirmatory trial for Elevidys, the first marketed gene therapy for Duchenne muscular dystrophy (DMD).
Even so, company officials are undeterred and believe the treatment for the devastating degenerative muscle-wasting disorder caused by a faulty dystrophin gene can still deliver on its promise to help patients.
Sarepta is now working with the FDA to request a label expansion for all age groups. Although the trial fell short of its main goal, patients did show improvement on individual motor function tests, and the study period might not have been long enough to demonstrate the treatment’s full benefit.
“The totality of evidence in Embark supports the conclusion that Elevidys modifies the trajectory of Duchenne, demonstrating a treatment benefit that is clinically meaningful and similar regardless of age; therefore, we believe all patients with Duchenne can benefit from treatment with Elevidys,” said company officials in an email to PharmaVoice.
But will the FDA agree?
A challenging disorder
The stakes are high for Elevidys because there are limited treatment options for DMD and no cure. Sarepta developed three of the four approved exon-skipping drugs, which form a bridge over faulty parts of the dystrophin gene, allowing it to regain some function. But these drugs each target specific mutations, limiting efficacy.
DMD, which primarily affects boys, starves the muscles of the crucial dystrophin protein that keeps them healthy, triggering a slow deterioration. People with the condition often need a wheelchair by the time they reach their teens and can face life-threatening heart and breathing problems in their 30s. Elevidys delivers a gene that codes for a shortened form of dystrophin to muscle cells to improve strength and function.
The FDA signed off on a controversial accelerated approval of Elevidys in June to treat 4- and 5-year-old patients with a confirmed DMD gene mutation. Initially, FDA review teams appeared to be on the verge of rejecting the treatment after weighing the benefits against risks of the treatment, which can cause liver damage, myocarditis and a condition called immune-mediated myositis that damages muscle fibers. But Dr. Peter Marks, who oversees the agency's review of gene therapies, reportedly stepped in to intervene, stating in a memo that he disagreed with the efficacy findings from the review teams. Following an advisory committee vote, the FDA signed off on the approval but narrowed the patient population to 4- and 5-year-olds.
Where Sarepta saw benefit
The phase 3 confirmatory trial results showed that children who received the treatment noteched a 2.6-point increase on the North Star Ambulatory Assessment (NSAA), a standardized motor function test, compared to a 1.9-point increase in the placebo group, which wasn’t statistically significant. On individual motor function tests, such as time to rise and 10-meter walk, some fared better.
“It was clear in the results that the NSAA was not sensitive to meaningful changes that were occurring in the study population and weren’t capturing the full treatment effects that were evident and consistent across multiple key secondary outcomes,” said company officials in the email.
Because the study enrolled a mild patient population, 52 weeks might not have been long enough for the untreated group of patients to show the expected decline in function, affecting the comparison, they said.
“Even though the primary endpoint was not met, we are pleased with the consistency, the magnitude of response and the clinical meaningfulness of the results from Embark and from the body of evidence supporting Elevidys,” said company officials.
Sarepta officials are now working with the FDA to prepare its submission for the label expansion as soon as possible.
“We have shared the Embark topline results with FDA leadership and they have confirmed that, based on the totality of the evidence, they are open to such label expansion if supported by review of the data, and that they intend to proceed rapidly with consideration of the submission,” Sarepta officials stated in the email.
Article top image credit: Courtesy of Sarepta
This biotech’s ‘Microsoft’ approach could change how we see gene therapy
The company’s using a unique component-based platform to develop functional cures for diseases, including HIV.
By: Karissa Waddick• Published March 20, 2023
Welcome to Biotech Spotlight, a series featuring companies that are creating breakthrough technologies and products. Today, we’re looking at American Gene Technologies and its “software development” approach to developing gene therapies.
In focus with: Jeff Galvin, CEO, American Gene Technologies (AGT)
AGT’s vision: After a brief retirement from the tech sector in the early 2000s, Galvin founded AGT with the goal of harnessing genetic medicine to develop a one-dose functional cure for HIV and other diseases. He also sees the company filling a niche in the gene and cell therapy world as a sort of “software developer” with a platform of reusable components from which its therapies are developed.
“Nobody's really focused on the middleware (in cell and gene therapy development),” he said. “My whole concept was gene and cell therapy is so broad, and it's so much like the software industry, that the most important thing to do is develop these middleware components that you can mix and match to create efficiencies and that you can later leverage when the market is ready, when pharmas are ready (and) when the FDA is ready.”
Its strategy: Over the last 15 years of developing its HIV therapy, the company has patented 25 processes — from how it isolates certain T cells to its lentivirus viral vectors — that Galvin believes could be “valuable building blocks that will eventually be in 1000s of drugs” either developed by AGT or at other companies licensing AGT’s technology. That side of the business is still growing, he said, noting that AGT has mainly “been approached by “really small companies without any money” for such deals.
Many biotech companies are built on similar types of platform technologies, but Galvin argued that AGT’s component-focused approach is different. Other companies typically “do one thing,” he said, whereas AGT’s platform approach includes smaller components that build into an entire proprietary operating system, like Apple’s patented iOS.
At a glance: In a recent phase 1 trial of seven patients, the company’s HIV candidate AGT103-T, met primary and secondary endpoints. The drug, a single dose autologous cell therapy, uses a lentivirus vector to deliver modified HIV-specific CD T cells, which is a type of white blood cell that is often depleted in HIV patients. If effective, it could reduce the depletion of CD4 T cells and restore the body’s ability to kick-start an antiviral immune response to naturally control HIV.
“We pulled those out and we can modify them with viruses, so they are impermeable. Now (the cells) can survive the HIV attack (and) stick around and do their job. When they do their job, then they can clear HIV just like you clear a cold,” Galvin said of the approach.
The company is in the midst of an analytic treatment interruption study which takes patients off their regular antiretroviral therapies to better gauge the efficacy of the cell therapy in suppressing HIV. It’s also in talks with the FDA over protocols for a phase 2 trial, which Galvin said will enroll 24 patients.
AGT is also conducting preclinical work on a drug to treat the rare, inherited monogenic disease phenylketonuria, as well as an immuno-oncology program, dubbed ImmunoTox, to deliver therapy to solid tumors using lentiviral vectors. Down the line, Galvin sees potential for treating a range of monogenic diseases.
Why it matters: Existing antiretroviral therapies for HIV allow patients to live fairly normal lives and, when taken every day, can act as a functional cure by bringing the viral load so low that it cannot be transmitted or progress into AIDS. But an actual one-and-done functional cure has remained elusive for drug developers since HIV was first discovered more than 40 years ago.
One of the latest attempts at a cure was with an anti-inflammatory antibody in 2018 that proved successful in monkeys but failed to show any efficacy in humans. Since then, many HIV trials have focused on developing a prophylactic vaccine for the virus. AGT is one of just a few companies, including Gilead, working on a functional cure for the virus. Currently, Gilead has several ongoing proof-of-concept studies testing new therapy combinations to tackle the virus in novel ways.
If validated, AGT’s therapy could provide a more convenient option for HIV patients to manage their disease, and could decrease the stigma of regular dosing, Galvin argued.
“We're making a cell therapy that would take somebody who has HIV, and it would suppress it for life in a way where they wouldn't need any medication,” he said. “They (would) go from daily medication or whatever type of regimen they're on for viral suppression to essentially living a normal life.”
However, there’s a long list of promising HIV cure strategies that, in the end, yielded no results. And although AGT’s therapy is one of the most advanced candidates at the moment, it still faces a long road ahead before it can be clinically validated.
AGT’s progress
When Galvin, who spent his early career as a Silicon Valley software engineer turned marketing executive at the likes of Apple and Hewlett-Packard, founded AGT, he saw parallels between gene therapy development and the tech industry.
“We're making a cell therapy that would take somebody who has HIV, and it would suppress it for life in a way where they wouldn't need any medication."
Jeff Galvin
CEO, AGT
“Coming from the software industry, I had an immediate epiphany,” he said. “I was like wait a minute, viral vectors are diskettes for the organic computer, the human cell. Now that we can modify your operating system, your DNA, what can’t we do?”
He created AGT to develop cures and the elements of cures that other scientists could build from, in the vein of major companies like Apple and Microsoft.
“I thought, somebody is going to be the Microsoft of this business one day,” he said, noting that many people build software using Microsoft’s operating system. “I took my whole retirement, dumped it into starting this company. It was a really perilous journey for 10 years.”
Now, based on phase 1 data from the company’s first trial of its autologous gene therapy for HIV, Galvin said he believes that the “journey was not in vain.”
In the case of the phase 1 study in which patients have stopped taking antiretroviral treatment, Galvin admits that aspirations were somewhat subdued because when a gene therapy is administered in combination with antiretrovirals for a prolonged period of time, the body sheds the unnecessary immune cells created by the therapy. So far, however, three of the seven patients tested in the study showed “significant suppression of their virus without antiretrovirals,” and one patient’s virus remained undetectable six months after.
“This was a really good finding, considering that the number of cells in (the patients’) bodies by the time we took them off antiretrovirals was only 2% to 5% of their original (count),” Galvin said.
The next step will be much more telling, though. In a phase 2 study, AGT hopes to be able to conduct the analytic treatment interruption earlier after administering the treatment — at 14 days, 30 days and 60 days — to see if the efficacy improves.
“We also want to gather more data from these 24 patients to see if we can find a correlation between aspects of their disease and the outcomes, because if we find that a subgroup gets cured, that's a drug,” Galvin said. “That would be a sustainable business model if that group is 3% of the population or better.”
Several challenges also remain. For instance, taking patients off antiretrovirals poses the risk that they may develop a new strain of HIV and that old drugs will no longer work to treat them. It will require close monitoring, ensuring that the disease doesn’t “run amok,” and putting patients back on antiretrovirals if their viral loads increase too much, Galvin said.
Another issue is funding and pricing dynamics. Though investment in cell and gene technologies has picked up in recent years as more therapies are approved by the FDA, it remains a fairly nascent space.
“I think that the major challenge in what we're doing is that gene and cell therapy is really new and historically, let's say over the last 10 years, there hasn't been a lot of interest in it,” Galvin said of AGT, which raised $69 million in its first six rounds of financing, according to Andrew Miller, AGT’s vice president of finance.
“The key is that we were able to go wherever the science took us because we are not a VC-backed company,” he said. “A technology company just goes as fast as they can, (while) a visionary company is in it because they believe it is going to lead to something great. That is what AGT is attempting to do. This place reminds me more of Apple than any other company I’ve seen.”
Article top image credit: Stock via Getty Images
Boosting the cell and gene therapy workforce with a skilled, localized approach
Experts provide a roadmap for how the industry can work with academia to ensure a robust talent pipeline for the burgeoning field.
By: Karissa Waddick• Published June 15, 2023
As the market for cell and gene therapies gains steam — the FDA is expected to approve as many as 12 new treatments in 2023 — workforce shortages caused by a lack of adequate entry-level training in areas like manufacturing are straining development in the space. And without increased investment from industry and academia in new education programs, experts warn that the promise of the technology to treat large patient populations could be stunted.
Already, industry leaders are having trouble filling positions. In a recent report by the Alliance for Regenerative Medicine, most respondents said they have more than six open roles and an average talent search timeline of two to three months.
The problem is most acute in technical laboratory, manufacturing and quality control positions, where more staff is needed to scale up cell and gene therapy production. While all FDA-approved therapies in the space are currently used to treat rare diseases, nearly 60% of ongoing clinical trials are testing applications for more prevalent disorders, the Alliance’s report found. And as these drugs progress through the pipeline and potentially enter the market, companies will need to ramp up production to meet the larger demand.
Natalie Fekete, manager of science and industry affairs at the Alliance, argued that the workforce bottleneck “speaks to the rapidness of the evolution that's taking place in cell and gene therapy.”
“Because the industry is still growing and maturing, you can expect to see new equipment, new ways of automated processes and data collection, and all of these topics need a new way of teaching as well,” Fekete, who co-authored the Alliance’s report, said.
But because complexities and technical modalities in cell and gene therapy production require additional training beyond what’s needed for other areas of drug development, most existing training programs aren’t preparing students to enter the space.
“There are a few initiatives — basically community colleges — that are providing credentialed training,” Fekete said, noting that it’s far from widespread. And the ones that do provide training often need to update their curriculum on “a yearly or bi-yearly basis to keep up with the new technologies.”
To create a more robust pipeline of workers for the future, more partnerships between industry and academic institutions are needed, and current collaborations could provide a framework to get there.
Local training programs
One idea gaining traction is the creation of a national biotechnician credential program that could be implemented at training centers around the U.S. The Biotechnician Assistant Credentialing Exam, an industry-recognized assessment launched in 2012 by the University of Florida, is being touted as a potential standardized test on which to base a program, as it’s already approved in 12 states and the District of Columbia.
But researchers and leaders in the field have expressed skepticism about the feasibility and utility of a national standard.
“It would be really hard to come up with a national curriculum because not all institutions, whether they be high school, or colleges and universities, are going to have the same resources to carry that out,” said Kristy Shuda McGuire, dean of biomedical studies at The Wistar Institute in Philadelphia. “They also don't all have the same needs.”
In 2000, Wistar began a Biomedical Technician Training program in partnership with the Community College of Philadelphia to allow students at different academic stages to prepare for careers as laboratory technicians, and eventually apprentice in industry facilities. Since then, the program has grown to include community college students from across the state but is still one of only a few programs of its kind in the U.S.
The local focus is key to the program’s success, McGuire said. While the academic portions of the program are meant to provide students with a “solid foundation” in biomedical laboratory skills, the integrated internships at area biotechs like Chimeron Bio and Integral Molecular give students more targeted skills that often lead directly to jobs at the companies.
The program’s structure helps solve one of the key challenges of training regenerative medicine technicians that a nationalized curriculum likely wouldn’t account for — the varying techniques and skills required by each drug developer to create individual products.
“When we talk about workforce development, it's very local,” McGuire argued. “You've got to make sure the training that you're offering is meeting the needs of the employers in your area. People from Philadelphia don't really want to leave Philadelphia, so we've always been training a workforce that is going to stay in the region.”
Industry partnership
The local approach may also allow biopharma companies to create more hands-on partnerships with academic institutions that could lead to direct pipelines of highly specialized talent. For instance, Fekete suggested that a company could reach out to schools in its area, offer funding, and ask for specific skills or disciplines to be taught
Wistar implements a version of that strategy and views it as a win-win situation, McGuire said, because it allows them to seek advice from industry experts and gives their internship partners piece of mind that students will be trained in the skills they need. Its workforce council, which includes industry partners, meets quarterly to update the training structure and curriculum as needed.
"You've got to make sure that the training that you're offering is meeting the needs of the employers in your area."
Kristy Shuda McGuire
Dean of biomedical studies, The Wistar Institute
And when sussing out new partnerships McGuire cautioned that Wistar avoids any company with large bureaucratic processes that require “lots of input from legal” to get anything done. Often that’s led to more partnerships with smaller pharma companies.
On the opposite side, academic and government institutions lack the highly-trained faculty needed to educate the next generation of students because of the low pay rates compared to industry positions.
Precigen, a clinical-stage biopharma focused on immuno-oncology, created a unique postdoc program with the potential to help address this problem. Students who enter the program are given direct access to the company’s immuno-oncology and autoimmune drug development platforms and after the fellowship become eligible for a grant from Precigen to continue their research in academia.
“It becomes very important that the industry and academia come together and play a role in putting some of these programs in place and creating these bridges,” Precigen CEO Helen Sabzevari said. “One without the other, and we will not be serving the patients correctly.”
The retention of existing talent is another issue the industry faces, Fekete said. Once trained workers enter the field, it’s up to the company to create a meaningful environment where they can grow.
“It needs to be clear that this is an industry that's growing, that there are opportunities for growth, and to keep the career path interesting inside the companies that they're working with,” Fekete said. “That's where company culture can be really helpful in driving motivation for each and every individual that is working there.”
Article top image credit: Adene Sanchez via Getty Images
A biotech ‘tuning’ the genome for a potentially safer gene therapy
Tune Therapeutics is hoping to overcome the pitfalls of CRISPR-style treatments with epigenetic editing.
By: Kelly Bilodeau• Published Oct. 9, 2023
Welcome to today’s Biotech Spotlight, a series featuring companies creating breakthrough technologies and products. Today, we’re looking at Tune Therapeutics, a preclinical biotech pioneering a next-generation genetic therapy by tuning the epigenome.
In focus with: Lucas Thompson, senior director of the ex vivo program at Tune Therapeutics
Tune Therapeutics’ vision: Tune launched in 2021 with $40 million in funding and is one of several companies — including Chroma Medicine and Epic Bio — riding a wave of investor enthusiasm for epigenetic editing. The approach modifies gene expression using the epigenome, a system of marks that provide instructions for how DNA is read and used. By modifying these marks, epigenetic editing can alter gene expression while leaving the underlying DNA untouched. Touted as a safer and more precise way to carry out genetic therapy, it could help treat a broad variety of diseases, from cancer and autoimmune diseases to chronic health conditions.
“The premise of our vision is to leverage our genetic tuning technology platform in ways that uniquely address unmet medical needs across various indications,” Thompson said. “We have the potential to address a large number of disease settings.”
Why it matters: Epigenetic editing is an alternative to CRISPR-enabled gene editing, which has some critical drawbacks. Gene editing technologies that snip and splice strands of DNA may accidentally insert dangerous, permanent errors into a patient’s genetic sequence. Genetic tuning through epigenetics could wield similar power with less risk.
Tune’s Tempo platform adjusts the epigenome, not just turning genes on or off but acting as a dimmer switch, turning down genes stirring up trouble or amplifying others to reverse a deficiency.
“Instead of addressing genetic issues in disease by causing DNA breaks, we can go in and tune the genes using natural mechanisms — we harness endogenous gene regulatory networks in a controlled, targeted manner,” Thompson said. “This means we can avoid unintended consequences of some of the other modalities of either knocking in are knocking out genes that can break DNA and cause issues with recombination and other sort of mutational genomic toxicities.”
“It is really difficult or impossible to achieve these types of outcomes with other modalities.”
Lucas Thompson
Senior director, ex vivo program, Tune Therapeutics
A more precise mechanism also allows the company to simultaneously target multiple gene pathways, opening the door to treating complex conditions that were previously out of reach, Thompson said. Other technologies can also carry out multiple modifications, but this increases the risk of potentially dangerous translocations. Tune’s process does not.
“This is really unique, this ability to go up and down with genes in the same cell, and this can unlock some very complex mechanisms that control cellular behavior,” Thompson said. “It is really difficult or impossible to achieve these types of outcomes with other modalities.”
A major milestone: Tune’s technology cleared a major hurdle in May when the company revealed its success modifying a well-known gene target called PCSK9, which can elevate levels of artery-clogging LDL-cholesterol in the blood. The goal was to show that epigenetic editing could alter this gene’s expression and lower cholesterol in animal models.
Researchers performed a single infusion of the Tempo epi-repressor targeting the gene using a lipid nanoparticle and not only dropped cholesterol levels by 56% but still showed repression of the PCSK9 gene at seven months. Company officials said this provided validation for the field by showing that epigenetic editing can durably modify gene expression in non-human primates. However, researchers are still tracking how long this effect will last.
How the technology will be used: “We're still in a range of discovery and preclinical stages across multiple programs. At this point, we aren't disclosing our pipeline,” Thompson said, noting that although Tune yet to announce clinical targets, the company is hoping to move rapidly toward a preclinical development candidate.
“Once we start working toward candidates for any kind of indication, the process of discovery, and getting to develop a candidate is pretty quick,” he said. “We do have candidates that are fairly advanced in that process.”
The program will likely use two major therapeutic approaches, including direct gene modulation in patients.
“That's where an epi-editor product would be infused into the patient to target certain organs and other cells that have an inborn error in gene expression and address it,” Thompson said. “The other major modality is using this for ex vivo therapies. And that's the CAR-T cell-type approach where we take cells, program them to our liking in vitro using gene tuning and other methods and then infuse them back into the patient as a drug.”
This approach could boost the therapeutic potency and clinical durability of CAR-T cell therapy and reduce detrimental side effects for patients, possibly enabling earlier treatment, Thompson said.
Navigating the obstacles ahead: One of the main challenges will be hitting the right notes with the gene-tuning technology.
“I think probably the most significant hurdle is trying to understand what kind of durability of effect we need for our epi-editors to achieve the outcome in vivo,” Thompson said.
In cancer treatments for instance, the therapy may need to maintain an effect long enough to destroy tumor cells but not so long it produces dangerous side effects. But the payoff could be big if they get the timing right.
“We believe that we can precision target key epigenetic modalities, and this unlocks a pretty large untapped resource for some of these next-generation therapeutic strategies,” Thompson said.
Distinguishing themselves in a crowded market: Tune is not the only company looking to harness the power of the epigenome.
“But I think our outlook here is that this is a great time to be in this field,” he said. There are a lot of really smart people working here and investors are excited.”
Tune hopes to distinguish itself from competitors through its unique approach to tuning genes by turning them up or down, its ability to modulate genes in different ways and to target and combine epigenetic editors to achieve unique outcomes.
“We're really excited to be at the forefront of this,” Thompson said.
Article top image credit: Stock via Getty Images
Google for genes? This AI company aims to curate the entire human genome.
Genomenon’s acquisition of their contract scientific partner Boston Genetics will help them unlock the potential of genetic knowledge.
By: Michael Gibney• Published July 20, 2023
As researchers understand more about genetics and the human genome, the sheer amount of data can be overwhelming. The vast landscape of genetic information from past publications holds a wealth of knowledge — if it can be unlocked in an organized way.
Genomenon is a software company based in Ann Arbor, Michigan, that has created one of the leading search engines for finding scientific publications with genetic content. And with about 15,000 peer-reviewed articles published every week, that’s a big undertaking.
To help hone its AI system — called Mastermind — Genomenon last month acquired contract genomics company Boston Genetics, a longtime science partner of theirs. The goal is to improve curation of their human genome database to help pharma companies and researchers review past studies more thoroughly and quickly.
For Genomenon CEO Mike Klein, the move was a no-brainer.
“We had already decided we’re going to go all in on curating the genome — I think Boston Genetics looked at that as being very intriguing, as well as the opportunity to scale that part of the business much faster by combining forces,” Klein said.
"By acquiring Boston Genetics, we can start building off-the-shelf datasets by curating the entire genome that can be available for researchers."
Mike Klein
CEO, Genomenon
We spoke to Klein about how Genomenon started as a genetic research search engine, what the Boston Genetics acquisition will mean for the companies moving forward, how pharma clients use the vast databases of genetic information and what the future has in store with tools like this.
This interview has been edited for brevity and style.
PHARMAVOICE: Before we talk about the acquisition, can you tell me a little about Genomenon and how AI fits into the genomics equation?
MIKE KLEIN: The basic premise behind Genomenon is that there’s millions of years of genomics research that’s locked into publications, and from either the clinical side or the pharma side, the question is, how do you take all of that research and organize that into a something that is easy for a genetic researcher to leverage? Of the 30 million plus articles that are in PubMed, about 9.2 million of those have genetic content. So what we’ve done is build an AI engine that allows us to go in, find that genomic information, find the associations to disease and therapies across publications and normalize it so there is a search capability.
How do you combine that with Boston Genetics’ contract genomics business?
Essentially, we’ve built an in-house team that has the scientific expertise to do this original curation work that we’ve been delivering. Boston Genetics has been a contractor providing additional resources, and so it lays really easily into our operations. A lot of the variant science and interpretation work they were doing was for clinical labs, so we’re going to expand that capability to address the needs of pharma companies, as well. And we’re leveraging more and more of those resources to bring that into our focus on curating the genome.
We had been one of Boston Genetics’ first customers and then over the last three and a half years we became their biggest customer. And when they approached us and said they were thinking of selling the company, it made sense to bring those two pieces together.
You’ve worked with some big pharmas, including AstraZeneca as of 2021. How does that type of partnership work and how will Boston Genetics play into that?
What we’ve typically done with our pharma customers is deliver what we call genomic landscapes as they build clinical trials or companion diagnostics — an understanding of every gene and every variant, the pathogenicity of those variants, the functionality or loss of function and the drivers behind those variants. By acquiring Boston Genetics, we can start building off-the-shelf datasets by curating the entire genome that can be available for researchers.
A lot of what researchers are asking very early on is, what are the genetic drivers of the disease? So we take all this knowledge and past research that’s been done, and we can get a deeper insight into the process of drug discovery efforts. The first step is understanding what they’re looking for, such as specific genomic biomarkers or a very rapid natural history study showing every patient that’s ever given insight into the disease. We’ve worked with pharma companies to better understand disease prevalence out there from a genetic perspective to get a better scientific basis.
AI is a very buzzy word at this point, and sometimes we gloss over some of the details of how an AI system actually works. Can you talk about how your Mastermind program came about?
We had to create our own genomic language processing — natural language processing doesn’t work very well, we found, when you’re trying to leverage it for genomic data because there’s nothing natural about the way it is described in the literature. So we had to build our own bespoke set of algorithms to drive and continue to refine that.
And on the other hand, we’re leveraging some of the machine learning models on the curation side to help us better organize the data that scientists will review. I’m sure you’ve seen some of the challenges where ChatGPT can make stuff up — well, the beauty of having an expert on the other side is you cut through that. You really get to say, ‘OK, we need to look at the literature and the scientific evidence and put it at the fingertips of our scientists,’ but we’re not asking it to put together narratives that may or may not be true.
What is the measure of success of your AI? How do you know that it’s getting better and going in the right direction?
One of the tools we have inside our search engine is a feedback capability so that our customers are telling us, ‘Hey, I found this and it doesn’t make sense.’ They can identify false positives and false negatives. And that information goes right back to our development team to tweak the algorithms and make sure we’re not missing those in the future. And when we’re going through and leveraging machine learning to identify and queue up articles, researchers from Boston Genetics can give us a very tight closed-loop on that side as well.
More broadly, tell me what you see as the future of genetic medicine. What’s in store?
As we look more and more at precision medicines, you’re seeing this play out on the oncology side, on the rare disease side, as well as with other well-known genetic diseases — just understanding every piece of innovation that’s out there helps identify which patients are going to be served by particular treatments.
Another interesting and exciting opportunity is in newborn screening. Today, they’re only looking for a couple dozen different biomarkers, but with genome sequencing, it will be possible to look across thousands of rare diseases and change the trajectory of that baby’s life and the family’s going forward. We’re working with the Rady Children’s Institute for Genomic Medicine on a couple of pilot programs to be able to pre-adjudicate every variant that’s ever been seen in the publications and be able to use that for screening. So you don’t need a scientist in the middle, which can be very expensive.
Article top image credit: iStock via Getty Images
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