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).

Then, in late October, the topline results revealed that Elevidys failed to meet its primary goal in the pivotal phase 3 study called Embark — sending Sarepta Therapeutics' stock into a more than 40% tailspin.

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.

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.

“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.”

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By Guidehouse

Cell therapy — a rapidly advancing class of medicines that modify and administer a patient’s immune system cells to fight diseases — has already proven highly effective in treating cancer. Given that success, academic researchers and industry players are increasingly looking more broadly at cell therapy’s potential applications in other therapeutic areas, particularly in immunological and autoimmune diseases. 

Beyond CAR-T, other therapies such as CAAR-T (chimeric autoantibody receptor T cell) and CAR-Treg (chimeric antigen receptor T regulatory cell), which have yet to be proven in oncology, appear to have high potential in immunological diseases. As a more specific cell therapy option for fighting autoimmune diseases, CAAR-T therapy works by re-engineering T cells to specifically target autoreactive cells that produce autoantibodies (antibodies that react with self-antigens). 

Trends in cell therapy development

CAR-T has shown promise in autoimmune diseases due to its ability to destroy autoantibody-producing cells, which are the drivers of many autoimmune diseases. Recent studies have demonstrated positive results of CAR-T treatment in prominent immunological diseases such as systemic lupus erythematosus (SLE).

Cartesian Therapeutics, Inc., has been conducting a CAR-T therapy trial for myasthenia gravis (MG), a rare autoimmune disease. Interim results from Cartesian’s Phase 1/2 trial showed sustained efficacy over 10 weeks. These results indicate a positive outlook of expanding CAR-T technology in immunology.

CAAR-T can also be a promising application for diseases with a clearly characterized autoantibody-mediated mechanism driving pathogenesis. 

Three key considerations for cell therapy manufacturers

The ability to successfully deliver cell therapies to patients suffering from autoimmune disease will require: 1) disrupting the right cell mediators of autoantibody production; 2) delivering clinically meaningful benefits that will support a sufficient value proposition for market access; and 3) ensuring patients can access these therapies.

1. The importance of pathophysiology in clinical development

As manufacturers look to address the current unmet needs in the immunology space with cell therapies, specific characteristics of inflammatory and autoimmune diseases will be highly influential to achieving clinical development success. Some autoimmune diseases, such as SLE and ulcerative colitis, have multiple immune cell types and autoantibodies involved in driving clinical manifestations of disease. Other diseases have well-defined autoantibodies as a driver of disease pathogenesis, such as DSG3+ in pemphigus vulgaris. Different CAR technologies (e.g., CAR-T, CAAR-T, CAR-Treg) can be employed to target autoimmune diseases, depending on the specific drivers of pathogenesis.

Recent development of CAAR-T and CAR-Treg therapies in autoimmune diseases have shown promise that CAR technologies, beyond traditional CAR-T therapies with broad B cell targets (e.g., CD19, CD20), can be successful in these diseases. As there will likely be rapid development and heightened interest in this area as these technologies demonstrate early clinical trial success, manufacturers can utilize the latest research on disease pathogenesis to drive decisions on where to focus their drug development. 

2. Strategies to ensure patient access

CAR-Ts to date have a high price relative to conventional therapeutics in immunology such as molecules and biologics. The pricing potential of CAR-Ts in immunology and the subsequent market access strategy to enable patient access will depend on several factors, including (but not limited to) the strength of the clinical profile, the size of the target patient population, and the need for repeated dosing. Given the number of variables at play and the complexities associated with launching this new therapy class in a new therapeutic area, early market access input into clinical development and overarching strategy becomes even more crucial.

Consideration of market access perspectives early on in clinical development will ensure the highest likelihood of appropriate patient access. Key aspects influencing patient access include patient populations with proven biomarkers expected to drive efficacy outcomes based on mechanism of action, (e.g., PV patients with autoantibodies against DSG3) as well as patient previous treatment status, (e.g., refractory to immunosuppressants). 

3. Advocacy, customer engagement and support

Manufacturer-provided patient support programs (PSP) have been a central element of CAR-T therapies in oncology due to the high costs and burdens associated with receiving treatment. Current manufacturers of approved oncology CAR-T therapies offer care coordinators and educational resources to support patients in finding a suitable treatment center in their area and becoming comfortable with what to expect from therapy. 

Manufacturers entering the cell therapy space in immunological indications should have a strong understanding of what support services are required to assist patients logistically, financially and emotionally as they undergo treatment. To date, advanced therapies in these indications have not required the same sophisticated efforts to support the ecosystem of patient access to treatment. They must therefore consider how existing PSPs for other biologic and small molecule brands may need to be adapted, given the higher level of support required for cell therapy.

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.

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.”

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.”

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.

“This is a pretty exciting new field, so it’s a fruitful area for competition,” Thompson said. Other companies in the space include Modalis Therapeutics, Rejuvenate Bio, Navega Therapeutics, and Sangamo Therapeutics, among others.

“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.

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. 

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. 

Unlocking the potential of human genetics is key to many advances in the biopharma industry. From immunotherapies that treat cancer to potential cures for rare diseases to mapping the genome for incredible medical discoveries, researchers have still only scratched the surface of what is possible in gene science. 

The FDA recently approved the first-ever gene therapy that can be applied directly to the skin to treat patients known as "butterfly children" because of how fragile their skin can be. These kinds of forward-thinking medicines have come about due to the ever more advanced understanding of how genetics cause certain conditions. And early research in the genetic space — even that which might not appear directly related to medicine — has given scientists the tools to make better treatments down the road.

Some of those treatments are on their way to helping patients soon. One cell therapy in late-stage trials could change the landscape of Duchenne muscular dystrophy. An understanding of how certain genes affect cardiovascular disease could lead to better breakthroughs. The promise of mRNA beyond COVID-19 vaccines is vast.

Here, we're looking at some recent discoveries in genetics that could bring major shifts in the future — medical and otherwise.

Ancient DNA provides a clue to human evolution

What we know about human genetics comes from studying the genome and the many complex interactions therein — and that is only at the current state of human evolution. Imagine being able to look back thousands of years to prehistoric humans and understanding how their genes differ from our own, perhaps granting clues to the connections between the genetic code and disease.

Researchers at Germany's Max Planck Institute for Evolutionary Anthropology have developed a way to isolate DNA from a deer tooth worn by a woman who lived as far back as 25,000 years ago — her DNA is a time capsule that helped researchers learn more about where the ancient woman came from and potentially how she lived.

"It is amazing that this is still possible after 20,000 years," said geneticist Matthias Meyer in a release from the institute.

This isn't the first time anthropological research has made use of DNA to understand our biological history. A study from 2019 found that ancient pathogens could provide clues to infectious diseases, potentially helping researchers overcome emerging threats to public health.

Making the genetic connection

In many cases, we know how to diagnose an illness and we know how to read the human genome — but making a connection between the two is the most important part of using genetics to treat those diseases.

Researchers at New York University and the New York Genome Center have discovered a new way to find causal links between genes and physical conditions. This new method uses large-scale genome studies along with the gene-editing tool CRISPR to target specific regions of the genetic code, helping to understand which locations play a part in causing diseases, according to a release from NYU.

The scientists used the method, called STING-seq, to identify particular genes that contribute to sickle cell disease. But the future could be limitless in scope and there is still much to learn, the researchers said.

"The huge success in (genome-wide association studies) has highlighted the challenge of extracting insights into disease biology from these massive data sets," said NYGC senior associate faculty member and the study's co-author, Tuuli Laapalainen. "Despite all of our efforts during the past 10 years, the glass was still just half full — at best. We needed a new approach."

Using DNA as data storage

DNA contains the genetic information that make living organisms what they are, and as we understand more about how that code works, those building blocks can be used to store information like a biological supercomputer, researchers at the Eindhoven University of Technology in the Netherlands have found.

Professor Tom de Greef worked with Microsoft to develop synthetic DNA that could someday be scalable to solve a big problem: too much data in the world. De Greef said in a university release that in only three years, there will be so much information that current data centers wouldn't be able to store half of it.

The idea for using DNA to store data began in the 1980s, according to the release, but the technology had not reached a point where it was feasible. Fast forward to 2023, when genetic research has advanced to allow tiny microcapsules to contain bits of information that can be searchable on a large scale.

And with the technology catching up to the original concept, the only piece of the puzzle left to fall into place is the cost.

"Now it's just a matter of waiting until the costs of DNA synthesis fall further," de Greef said. "The technique will then be ready for application."

Until recently, most people with Duchenne muscular dystrophy (DMD) only lived into their teens. But drugs, including steroids and advances in heart and respiratory therapy, have slowly pushed the needle on life expectancy for people with the devastating genetic disorder into their 30s, sometimes beyond.

Capricor Therapeutics, a California-based biotechnology company is hoping to add another tool to the growing arsenal of treatments for DMD with its phase 3 allogenic cell therapy, CAP-1002.

“It works in a similar fashion as a CAR-T (cell therapy) might, which is in the modulation of the immune system. So, it's actually calming down inflammation, reducing fibrosis, allowing cells to replicate and to drive repair,” Capricor CEO Linda Marbán, said.

While CAP-1002 is not a cure for the underlying disease, it aims to slow disease progression.

For patients with DMD, which causes muscles to slowly waste away, the mutated DMD gene is located on the X-chromosome so the disease predominantly affects boys. People with DMD are usually slower to sit, stand and walk than their peers, and start to show progressive signs of the disease around their second or third birthday.

A phase 2 trial of CAP-1002 found that the cell therapy was able to slow down muscle deterioration in patients with late-stage DMD by 71% over 12 months compared with a placebo.

“It basically takes a two-year decline in a typical patient and turns it into a less than one year decline, about nine months,” Marbán said. “So, you are seeing a very significant delay.”

Unlike steroid medications, which are also used to slow DMD disease progression, CAP-1002 appears to have fewer serious side effects. Only one person in the phase 2 trial had to discontinue the drug due to an allergic reaction, but there were no other serious problems reported. Slowing the rate of decline can offer hope for DMD patients.

“It's just like with oncology, every day you're alive, there's one more chance to get a better therapy,” she said.

A burgeoning market

Drugmakers have triggered a surge in new treatments for DMD in recent years and the global market for DMD drugs is anticipated to grow from $1.1 billion in 2022 to $18 billion in 2030.

Since 2016, the FDA has approved several DMD drugs, many of them in a category called exon skipping drugs, which help the body to resume some dystrophin protein production. The drugs are essentially able to create a bridge over faulty exons, or sections of the genetic code used to make protein, to link healthy sections. The drugs in this category, all approved by the FDA under its accelerated approval pathway, include three therapies from Sarepta Therapeutics and one from NS Pharma.  

Other treatments are also being explored, such as gene repair and gene therapy. In a narrow eight to six vote, an FDA advisory committee recently recommended approval of the first gene therapy, SRP-9001, from Sarepta. Based on the advisory board recommendation, the FDA could approve the treatment using its accelerated pathway by the end of May.

Another treatment called ataluren is being tested through a partnership between PTC Therapeutics and Genzyme, and aims to overcome a stop codon in the middle of a gene sequence that interferes with protein production.

Marbán said CAP-1002 could play a valuable role even amidst other emerging treatments.

“We consider our cell therapy to be one of the most important opportunities for Duchenne patients, because no matter what disease-modifying or dystrophin modifying technologies come to bear, CAP-1002 will be a good partner for those therapies. That’s why we call it a backbone therapy in our own vernacular,” Marbán said. “There is nothing that does as good of a job at calming inflammation and driving muscles into endogenous repair as CAP-1002, at least as has been evidenced in current clinical trials.”

Capricor is currently enrolling patients in its phase 3 trial. If all goes well, Marbán said they hope to apply for a biologics license application and ask the FDA for approval by mid-2025.

“That seems like tomorrow and a long time in the future all at the same time,” she said.