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. 

Welcome to the Biotech Spotlight, a series featuring companies creating breakthrough technologies and products. Today, we’re looking at Tessera Therapeutics, a preclinical biotech from Flagship Pioneering developing a new class of genetic medicines.

In focus with: Michael Severino, CEO, Tessera Therapeutics

Severino’s vision: As the former president and chief scientific officer of AbbVie, Severino is one of many Big Pharma execs who’ve jumped aboard a Flagship Pioneering-affiliated company in the past year. He took the helm of genetics-focused Tessera in June 2022 and said the switch felt like a “homecoming.”

“When I was thinking about what made sense for the next chapter, it was about opportunities — where I could do cutting-edge basic science that can be applied to patient care and develop important new drugs,” he said.

At the preclinical biotech Tessera, he’s aiming to develop a new class of genetic medicines that harness mobile genetic elements — pieces of genetic material that transport DNA and code for enzymes and proteins — to potentially “make any type of genomic alteration needed to treat or cure disease.”

At a glance: Tessera’s gene writing platform includes three systems — DNA gene writers, RNA gene writers and RNA gene rewriters — that can swap base pairs, insert DNA sequences or rewrite portions of the genome, all within the body.

The company is testing the technology in mice and nonhuman primates for liver, blood and immunology indications. This spring, it presented primate data for treatment of the rare inherited condition phenylketonuria caused by a genetic mutation. After one injection, the drug altered base pairs in up to 45% of animal cells, far surpassing the 10% curative threshold required.

Additionally, in a sickle disease study, the technology reversed the mutation that misshapes red blood cells to.

Why it matters: Unlike other genetic platforms like CRISPR-Cas9, Tessera’s technology could one day rewrite genes in the body, eliminating potential manufacturing hurdles and bottlenecks, Severino said. If it is shown to be effective in humans, Tessera’s MGE approach would let scientists swap or edit any base pairs, opening the door for treatment of many genetic diseases.

“Nobody has the technology to truly correct that mutation of wild type …outside the body without a stem cell transplant to readminister,” Severino said. “If we can put all those pieces together, we can have a game-changing opportunity not only for our company, but for patients.”

Here, Severino discusses his decision to join Tessera, his vision for curing any genetic disease with the company’s technology and how he’s charting a path to get there. 

This interview has been edited for brevity and style.

PHARMAVOICE: You're one of many Big Pharma execs to have joined Flagship in the past year. What's in the water at Flagship? What is it about the company that made you want to join?

MICHAEL SEVERINO: I think it's the level of innovation that goes on around the Flagship ecosystem. Flagship doesn't think of itself as a traditional venture capital company — it doesn't invest in other people's ideas. It looks for ways to create completely novel platforms that have the potential to produce important new drugs or meet other needs in either biomedical sciences or other related areas, and that focus on innovation really resonates with me. I think that's the attraction for many of my peers who've joined Flagship as well. They have that focus and the commitment to see it through and the experience from having done it before. It's hard to find all those features in one place. And when you do, it's something special.

You said earlier this year that Tessera aims to “cure nearly any genetic disease, reduce the risk of common disease and do this broadly and efficiently across patient populations.” Why are you confident that you’ll reach these lofty goals?

That potential exists because we're developing the toolkit that's necessary to make whatever changes are needed in the human genome to address disease. We don't just have a single technology. We don't have just one approach for a certain kind of genetic alteration. If we need to change one letter in the human genome, we have the technology to do that. If we need to write longer segments into the human genome, we have the technology to do that. And so that gives us tremendous power. We leverage that power even further by developing the delivery mechanisms that are necessary to do it in living systems and, ultimately, in patients. It doesn't really matter if you have the best gene editing machinery in the world. If you can't get it where it needs to be in a patient, you can't make that kind of impact.

What about the preclinical trials you’ve conducted gives you confidence in this technology so early?

We've done work that gives us proof of concept in a number of preclinical models of disease, in mouse models and in nonhuman primates. In genetic medicine, those give a high degree of confidence for success in the clinic, and the reason is that we know unambiguously what the cause of the disease is. If we're treating a genetic disease like phenylketonuria or alpha-1 antitrypsin (AAT) deficiency, or sickle cell disease, we're not trying to use that animal model to figure out what the cause of the disease is. We're using the animal model to determine: Can we deliver in a living system and does the gene writing machinery work in the same way in a nonhuman primate, for example, as it did in all our work in cell lines and in human cells in vitro? When the answers to those questions are yes, history tells us that it has a high probability of translating into the clinic.

As a leader, how do you lay out baby steps toward that broader goal?

We're going to prioritize diseases that are the clearest fit for our technology today and look at how it can grow and evolve in the future. So, the clearest fit for the technology today might be tissues that we can deliver to —we can deliver to the liver, to bone marrow stem cells, to immune cells in particular T cells that might be relevant for cancer applications.

There are many other monogenic diseases caused by a single mutation in the genome that can fit that pattern that we’ll go after. We can look at how we might be able to reprogram immune cells in vivo so that we don't have to have a monthlong manufacturing and waiting process and the need to give chemotherapy as conditioning before we administer cell-based therapy and think about how that can be applied to cancers.

As we demonstrate value, we can also take on more biological risk. We can take on common diseases where there may not be one single cause, but we have a good idea of changes that we can make in the genome to reduce the risk of disease or to even prevent disease. So we start with the base of what we know we can do today and then continue to expand out almost in concentric circles.

What does that look like in the next year and beyond?

We want to keep developing that platform. Our platform is outstanding, but no platform is ever good enough. We want to gain more information in preclinical models, do more work in large animal models and in nonhuman primates to set ourselves up for the clinic and in the not-too-distant future, a clinical company with proof of concept in patients for our technology. Now, obviously, the goal is to get these therapies approved and help patients in clinical practice.

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The visual inspection of injectable drug product has been a regulatory requirement since 1936¹, however, successful implementation of the standard has been challenging for many organizations. The number of recall notices issued by the U.S. Food and Drug Administration (FDA) from 2010 through 2019 for injectable products due to visible particulate have reduced since 2014 but at the current trend, will be some time before it approaches zero². Between 2009 and 2019, the presence of visible particles in parenteral product was the second leading cause for product recalls.³ Patient safety is the main driver for requiring injectable products to meet the criteria of “essentially free of visible particulates.”⁴

The FDA Draft Guidance: “Inspection of Injectable Products for Visible Particulates”

Adverse events can be associated with the injection of visible particulate and are dependent on the route of administration and patient population, among other things, and can result in infection, emboli, granulomas, phlebitis and more.⁵ Control of visible particle is essential under section 501 of the Federal Food, Drug and Cosmetic Act (FD&C Act), in order to prevent a drug product from becoming adulterated. The draft guidance is titled “Inspection of Injectable Products for Visible Particulates” (hereafter referred to as the draft guidance) to clarify the various areas where controls must be in place in order to have a successful particle control strategy that meets the regulatory expectations set forth in USP <790>⁴ and the associated cGMP regulations.

The draft guidance outlines several important visual inspection considerations, which are divided into the following five categories: 100% inspections, Statistical sampling, Training and Qualification, Quality Assurance through a Life-Cycle Approach, and Actions to Address Non-Conformance. This section of the guidance should make considerable progress in demystifying some aspects of how to implement the visual inspection programs specified in USP <790>.

The draft guidance also clarifies what is needed for a risk-based approach to a visual inspection program. The approach is multi-faceted and starts with product development. The guidance also stresses the importance of a particle-control program which includes operator training and qualification. Test kits which contain representative particle types and sizes should be used for operator training and qualification. A 100% visual inspection (either manual, semi-automated, or fully automated) must be followed by statistical sampling, such as acceptance quality limit (AQL) testing. Another point stressed is that a visual inspection program alone is not enough to ensure compliance with cGMP standards. A holistic life-cycle approach to particle control is needed which includes sourcing, development and commercial manufacturing environment.²

Inherent, Intrinsic and Extrinsic particulates

The type of particles observed in the finished product must be considered when formulating the quality risk assessment. Inherent (or formulation-related) particulates do not necessitate product reaction if they are a property of the product. Intrinsic particles, or particles related to the manufacturing process, must be controlled through component selection. They can also be related to the formulation or stability in the case of particles such as glass delamination or particles from silicone oil-protein interaction. The draft guidance highlights that “a robust product design achieved through formulation optimization and container closure screening during development is critical to reduce the formation of product-related intrinsic particles.”

Extrinsic particulates are particles that are not related to the formulation, its components, or the manufacturing process contact surfaces. These particles indicate a lack of control in the manufacturing facility and “could indicate possible microbial contamination or another CGMP issue.” The draft guidance also states that “manufactures should not rely on downstream adjustments during manufacturing to justify a poorly designed product or process. Instead, quality should be built into the manufacturing process, starting with the development phase and continuing during scale-up, process qualification studies, and commercial manufacturing.” The draft guidance reiterates that applying acceptance criteria outlined in USP <790> is not enough to be in full compliance with cGMP requirements. There is a need to prepare injectable products in a manner designed to exclude visible particulates which starts in development and continues through careful selection, evaluation and continuous improvement of materials, and processes up to and including commercial manufacturing. The guidance also states, “Depending on the clinical risk profile associated with a specific product, FDA may expect that product to comply with stricter standards than those set forth in the compendia.”

Overcome the challenges of particulates

To be able to meet the holistic expectations set forth in the draft guidance, manufacturers of injectable drug products should choose components that lower the risk of the presence of visible particulate and particulate formation.  The guidance states that components and closure systems are a contributing source of visible particulate. As such, the draft guidance states that “manufacturers must have written procedures for the receipt, identification, storage, handling, sampling, testing and approval or rejection of components and product containers.” Based on two Parenteral Drug Association (PDA) conducted surveys related to visual inspection,^6,7 the major contribution of particulate from the manufacturing process is from primary packaging components.  

West offers NovaPure^® components, which reduce the presence of visible particulate using Quality by Design (QBD) principles. The product is washed, sterilized, camera-inspected and packaged using cellulose-free packaging materials. The product also has barrier film to limit drug-closure interactions. NovaPure^® products are designed to meet vial, cartridge and pre-filled syringe packaging needs and have the highest levels of manufacturing process controls around reduction of particulate in the West portfolio.  

Continuous improvement is also a factor separating NovaPure^® components from standard offerings. The NovaPure^® component platform has a dedicated particulate task force focused on identifying and implementing improvements and has annual quality and operations product reviews. Continuous improvement is achieved through implementing best practices across the West network through the process of define, measure, analyze, improve and control (DMAIC). By selecting NovaPure^® product line for vial, syringe or cartridge containment systems, the risk of product rejections due to the presence of visible particulate originating from elastomeric components can be reduced.  

NovaPure^® components and the customer experience

As an example, a major biotech company approached West while looking for a vendor to help build quality into their process. The biotech company was using a QBD approach in the development of a life-altering treatment to treat a chronic disease in older patients. The company recognized that the NovaPure^® component offering, which was also developed with a QBD approach, was a perfect fit for their product and the biotech company adopted a platform approach with the NovaPure^® product line. 

In addition to limiting the risk of visible particulate through product selection, drug product manufacturers can monitor incoming components such as stoppers and plungers for the presence of particulate.  PDA Technical Report (TR) 85⁸ “Enhanced Test Methods for Visible Particle Detection and Enumeration on Elastomeric Closures and Glass Containers” provides parenteral manufacturers with a background on the control of visible particle control in components. The TR also describes an analytical method that can be utilized to monitor the presence of visible particles and fibers on elastomeric components as well as a visual inspection method for glass containers. Tools for method training and method qualification are also described in Appendix A of the TR.

West analytical laboratory services

The Analytical Laboratory Services group at West can assist parenteral manufacturers with testing associated with product development. Additionally, West’s Technical Customer Support group can help drug product manufacturers select the best packaging system for particle-sensitive products including West’s NovaPure^® product line.

Webinar: Understanding & applying the updated FDA guidance: Inspection of injectable products for visible particulate

For those that would like to learn more about the topics discussed in this blog, West hosted a webinar titled Understanding & Applying the Updated FDA Guidance: Inspection of Injectable Products for Visible Particulate on August 16, 2022. Click here to view the recording.

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References:

1. USPNF 2022 Issue 1 General Chapter <1790> Visual Inspection of Injections
2. https://datadashboard.fda.gov/ora/cd/recalls.htm
3. Visible Particulate Contamination Control for Injectable Products: A Life-Cycle Approach, Stephen E. Langille PDA JPharm Sci and Tech 2020, 74 359-366
4. USP General Chapter <790> Visible Particulates in Injections USP 41/NF 36
5. Particulate Matter in Injectable Drug Products, Stephen E. Langille PDA JPharm Sci and Tech 2013, 67 186-200
6. PDA Survey: 2014 Visual Inspection  
7. PDA Survey Particulate Matter in Difficult to Inspect Parenterals
8. PDA Technical Report (TR) 85 “Enhanced Test Methods for Visible Particle Detection and Enumeration on Elastomeric Closures and Glass Containers” 

This document is for informational purposes only.

West’s products and solutions are sold on the basis that it is the customer’s responsibility to evaluate and test the West product or solution to determine its compatibility with other materials and fitness for any end use. WEST MAKES NO WARRANTIES, WHETHER EXPRESS, IMPLIED OR STATUTORY, INCLUDING, WITHOUT LIMITATION, THE WARRANTIES OF MERCHANTABILITY AND FITNESS FOR PARTICULAR PURPOSE, RELATING TO THE INFORMATION IN THIS DOCUMENT.

NovaPure^® and logo are trademarks or registered trademarks of West Pharmaceutical Services, Inc. in the United States and other jurisdictions.

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.”

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."

About six years ago, scientists from China's Legend Biotech landed at the annual meeting of the American Society of Clinical Oncologists (ASCO) with some truly impressive data that showed a 100% response rate in 35 multiple myeloma patients who received the company's CAR-T cell therapy candidate in an early-stage trial.

The small study garnered attention from the biggest pharma out there — J&J's Janssen — and by December the two locked arms for a long haul collaboration. Now, at the same conference, the companies are officially (after an initial data leak in April) presenting results from a phase 3 study of the cell therapy now called Carvykti, showing a 74% reduction in tumor progression or death in more than 400 patients with multiple myeloma.

"From Legend's perspective, we're very happy with how the partnership has evolved," Legend CEO Ying Huang said in an interview prior to ASCO.

The companies celebrated the first approval of Carvykti just last year for patients with four or more prior lines of therapy, and the new data is likely to allow for even earlier treatment, analysts say.

"It's been a win-win situation for Janssen and for Legend, but it's a great win also for patients because we were able to shepherd this asset from research stage to phase 1 to an FDA-approved commercial therapy in a mere four years," Ying said, adding that the company's U.S. operations grew from non-existent to more than 800 employees since the beginning of 2018.

For Janssen, the new data from the trial, which was called Cartitude-4, is an opportunity to reach more patients earlier in their disease progression, said Dr. Craig Tendler, the company's global head of late-stage clinical development in oncology.

"The key I take away from the unprecedented data coming out of Cartitude-4, and what is reinforcing our confidence, is the potential to redefine the treatment landscape across all lines of therapy in multiple myeloma," Tendler said.

The two companies have worked hand-in-hand to bring Carvykti to where it stands today, and both Ying and Tendler expressed how they owe so much to one another in realizing the potential of the cell therapy from the early stages.

The power of partnership

So often, collaboration is seen as the lifeblood of the biopharma construct — a small biotech with limited funds and a risky bet on a novel compound links up with a Big Pharma benefactor that can provide the cash runway, and regulatory and commercial expertise to bring a treatment to patients. The gamble doesn't always pay off, but in the case of Janssen and Legend, the fruits of their labor are just beginning to emerge.

"It's a great example of a biotech company having a very novel technology and approach to addressing this problem — we were at the beginning very much intrigued by how they designed their B cell maturation agent (BCMA) CAR-T using two binding domains to the target," Tendler said. "When they shared the preliminary data, we already saw evidence that this was going to be differentiated from other BCMA CAR-Ts in myeloma."

For their part, Janssen could give Legend the window to make Carvykti possible as an approved therapy in only a handful of years.

"They saw in us a real commitment to accelerate the development of Carvykti across all stages of myeloma and to make the early investments to join teams that would put together the best comprehensive development program — to essentially take their baby and work with it in a collaborative way that would get the best out of it," Tendler said.

The collaboration has paid off in other ways, as well. J&J reported $55 million in revenue from Carvykti in the fourth quarter of 2022, growing to $72 million in the first quarter of this year. And Ying said that, on the manufacturing side, the companies are on track to exit 2025 with global capacity to produce more than 10,000 doses per year.

Specifically, J&J has set its sights on $60 billion in annual pharma revenue by 2025, and forecasted peak annual sales of Carvykti at more than $5 billion would be a boon to help get them there, said Cantor Fitzgerald analyst Louise Chen in April when the Cartitude-4 results were leaked online. And with physicians expressing that they would want to give their patients the therapy even earlier in their treatment plan, Chen said there is a large market opportunity.

Earlier this year, Bristol Myers Squibb released phase 3 data for its rival multiple myeloma CAR-T cell therapy Abecma, showing that the treatment reduced the risk of disease progression or death by 51% — a good deal short of Carvykti's 74%. Although there were key differences in the trials, including the number of previous treatments patients had received, the results place Carvykti in the lead in the eyes of many analysts.

The art of precision

Personalized medicine has been the lofty goal of the pharma industry for decades. And autologous therapies like Carvykti, which use a patient's own cells to fight cancer, bring the concept to reality.

"When I was in grad school a few years back, we talked about so-called personalized medicine because everybody's genes are slightly different — the way cancer cells grow could be driven by different drivers or proteins or growth factors," Ying said. "Today, that is reality because all six commercially available CAR-T therapies today are autologous medicines — it is indeed 100% personalized medicine and it shows you the power of science and how personalized medicine can actually work to effectively treat cancer."

The concept of personalized treatments has come a long way in just a single career, Tendler said.

"We started to think about precision medicine in a very narrow way 20 some-odd years ago with Gleevec (from Novartis for chronic myelogenous leukemia) and we thought we'd never have that kind of situation again — and for the most part we don't when it comes to small-molecule targeting of single driver pathways," Tendler said. "But now, with being able to harness the immune system, we're able to do that in a very potent way, in a very selective way, and more safely than ever."

Tendler said that Cartitude-4 shows improved safety for Carvykti compared to earlier studies that were already the basis for the first approval. CAR-Ts often bring about a concern for immune-related side effects such as cytokine release syndrome.

And still, CAR-Ts are subject to long wait times and restricted patient access due to the nature of the manufacturing process — removing cells from a patient, sending them to a facility where they are engineered using the cell therapy process, and then delivering back to the patient. But with the power of Janssen and Legend combined, Ying said these barriers are becoming easier to overcome.

"It's different in terms of how we manufacture this medicine, and it's very complicated and capital-intensive," Ying said. "As a partnership, we've invested tremendously in the supply chain operation, and our goal is to ensure very reliable supply for patients who need this therapy — that includes expanding our lentivirus supply, introducing new manufacturing solutions and investing in our global footprint."

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. 

Medical treatments are only effective if they’re accessible — the best drug or procedure in the world won't help the patients who languish on a waiting list or are hindered by any number of care roadblocks.

CAR-T cell therapy is still a young breakthrough in medicine, and one that holds a good deal of promise. But the manufacturing process by which cells are engineered is lengthy and location-dependent — challenges that can be detrimental for those with the serious diseases that require the extensive intervention.

And while oncologists whose patients need CAR-T therapy for blood cancers like leukemia, lymphoma or myeloma are looking for the best treatments available, turnaround times have become a major factor in prescribing practices.

So far, all of the approved CAR-Ts are autologous therapies — for which cells are taken from the individual, engineered to express new disease-fighting antigens and then returned to the same person — and can take weeks or even months to produce. For a patient's life to hang in the balance of these manufacturing times is a frustrating aspect of an otherwise exciting and groundbreaking technology, said Dr. Fred Locke, program co-leader and immuno-oncology chair in the department of blood and marrow transplant and cellular immunotherapy at the Moffitt Cancer Center in Tampa, Fla.

"That process at its best takes about three weeks, and in some cases can take six weeks or longer, and that's not even counting the time you have to schedule the manufacturing, which in some cases could be three months from now because we have to wait to get a manufacturing slot," Locke said. "So shortening that time to get the CAR-T cell therapy is important."

For patients and their doctors, the wait is harrowing and emotional. And for oncologists who see many tough cases, feeling helplessness in the face of time is a lot to handle when the treatment is within arm's reach.

"You can't really describe that, right? You've got a patient who's out of treatment options, and you can't get them the CAR-T cell therapy that they need — it's heartbreaking," Locke said.

For patients with myeloma, for instance, the waiting list can be more than 100 patients long — and about 20% die waiting for their cell therapy, Locke said. And of those who receive it, the therapy can arrive too late to provide the benefit it could have had earlier.

But advances to CAR-T cell therapy that could alleviate some of these challenges are on the horizon. Locke is a collaborator with Allogene Therapeutics' CAR T Together, a collective of investigators and institutions helping to bring forward the next generation of cell therapies that are "off-the-shelf" ready, called allogeneic as they don't require the patient's own cells and don't require such an extensive manufacturing process.

Locke, who has been an investigator with Allogene on the first allogeneic therapy to enter phase 2 studies — ALLO-501A for patients with a certain type of lymphoma — is optimistic about the future of CAR-T cell therapy despite the challenges being faced today.

"We're hopeful that these allogeneic CAR-T cell therapy trials accrue robustly and that the results are as we expect, which is that they're going to work for our patients similar to autologous CAR-T cells," Locke said. "And that they'll become therapies that are out there for all, and I fully expect that to happen."

Next-gen breakthroughs

As with any new technology, advances are iterative and take time to develop. In the realm of cancer treatments, though, the manufacturing bottleneck is something the industry is facing for the first time, said Dr. Rafael Amado, executive vice president, head of R&D and chief medical officer at Allogene Therapeutics and a 2022 PharmaVoice 100.

The first CAR-T cell therapies approved in the U.S. came through in 2017 — Novartis' Kymriah for a type of leukemia and now-Gilead-owned Kite Pharma's Yescarta for lymphoma, both autologous therapies with well-documented wait times. Amado related the current CAR-T bottleneck to past cancer treatments that patients couldn’t access at first.

"There's been paradigms in which drugs were known to be active but they weren't really approved yet — I remember the days of (Roche's) Herceptin, for instance, when there was a lottery to see who could get access to this drug, which could be life-saving," Amado said. "So there's been situations that have been somewhat tragic in the past in oncology, and that has been done for the purpose of trying to establish the efficacy and safety of the product prior to approval."

But the issue of manufacturing delays is relatively unprecedented in the cancer space.

"In general, I think manufacturing has never been a bottleneck in oncology," Amado said.

That bottleneck is likely to persist as autologous therapies remain "a victim of their own success," and demand from patients remains high.

"It's saturated the ability to manufacture and to manufacture on time," Amado said. "So it's recognized in the field that we need to transform this into a product from what it is now — which is a process in a selective group of patients — so that this potentially curative intervention can be available to any patient in need."

Autologous CAR-T cell therapies have been available before allogeneic therapies have made it out of clinical trials because the science is more complicated. In autologous therapies, the risk of rejection in the patient is much lower because the cells are from the same person — cells from a different donor need to be prepared genetically so that they can be received by the patient, Amado said.

"A number of technologies had to come together for this to become a reality, and the technology of gene editing is now really mature," Amado said. "Gene editing technology allows us to manipulate the cells to change the genetic code so that they are tolerated and they can stay in the body of the patient long enough to exert an anti-tumor effect and therefore cure the tumor."

Allogeneic CAR-T treatments are the next logical step in cell therapy to widen the gates that have kept patients from receiving the care they need, Amado said.

"There have been hurdles, but they're no different from the hurdles that you see in the development of any other product in oncology, and little by little, we've been overcoming them," Amado said. "We're poised to come up with what we call CAR-T generation two — generation one has been fantastic and has saved the lives of many patients, but not enough patients, and not all the patients that need it."

Industry's role

Scaling up a cell therapy process isn't the same as scaling up, say, the number of drugs or chemotherapy bags a company can provide to oncologists who are treating their patients, Locke said.

"With autologous CAR-T, it's a little bit of a different equation, where they have to map out how many patients could get this therapy, how many of these clean rooms and technicians we need," Locke said. "And that's an upfront investment for a much more complex process."

Given these high barriers, Locke is worried that some companies may duck out of the CAR-T business altogether if a new generation doesn't become available.

"I am concerned that companies may look at CAR-T as something that maybe they shouldn't do," Locke said. "If the margins aren't right or it's too much of a headache or a hassle — I hope that doesn't happen at some of the Big Pharma companies, but that's a concern of mine right now."

The prospect of allogeneic options and the ability to work alongside companies like Allogene and other oncologists with the same vision are all giving Locke hope for the future of CAR-T therapy.

"Getting new CAR-T cell therapies that are manufactured more quickly or even already manufactured and given rapidly and quickly to the patient — I think that will solve a lot of these issues," Locke said.

The awareness that the collaboration of CAR T Together offers could also help bring about more comprehensive understanding of the potential of allogeneic therapies, Locke said.

"The reality is we need more of these trials and more sites so that we can find out how well they work," Locke said. "Patients who need these therapies aren't getting them."

Allogene is looking to tackle several targets outside of lymphoma, including multiple myeloma, and depends on investigators like Locke as part of the coalition to push the technology further.

"Fortunately, there's a cadre of investigators that really believe allogeneic cell therapies are required," Amado said. "It's this alliance between the investigator community who has become incredibly sophisticated in treating side effects and in really holding these patients until they're able to get therapies — the enthusiasm is there, and the problem is very well recognized."

When the first gene therapy with a price tag exceeding $1 million hit the market in 2012, the groundbreaking procedure didn’t gain traction with patients. In fact, by mid-2016, it had only been paid for and given to a patient once, according to a report in MIT Technology Review.

Part of the challenge was that the treatment, called Glybera, was approved for an ultra-rare condition with a patient population of around 1 million worldwide. Global regulators and payers also turned their noses up at the gene therapy’s price, and questions over how the healthcare system should handle the cost of a one-and-done treatment took on a sudden sense of urgency.

Despite these early hurdles, the industry kept pushing. According to the Alliance for Regenerative Medicine, 12 gene therapies have now won an FDA approval — and the agency is expected to render seven more decisions in 2023 alone. 

With each approval, a new “world’s most expensive drug” is usually crowned. CSL’s gene therapy called Hemgenix became the latest gene therapy to take this title when it was approved in November and given a $3.5 million price tag.

And while the value of these potentially curative treatments is not usually in doubt, debate continues over how the payer system should absorb the costs — a situation that is expected to intensify if and when a gene therapy is approved outside of the rare disease realm and for a condition with a larger patient population. In response, proposals for new payment models are emerging.

Recently, the Centers for Medicare and Medicaid Services (CMS) floated an experimental method that would give the agency authority to organize multistate agreements that link payments to patient outcomes. The CMS is aiming to introduce this new framework officially in 2024 or 2025 as part of a larger initiative within the Inflation Reduction Act to address drug costs, with hopes of launching the agreements by 2026.

These outcomes-based contracts are already being used by some drug companies for a range of medications. And researchers in the field are looking at other approaches as well.

Here’s a look at a few other innovative ideas for structuring payment models.

An outcomes-based contract — with a twist

In January, the U.K.-based Office of Health Economics (OHE), which says it’s the “world’s oldest independent health economics research organization,” announced the results of its first-ever OHE Policy Innovation Prize. Entrants to the contest were posed the question: Can we design a system to generate fair prices that balances access and innovation throughout the lifecycle of medicines?

The inaugural winner, Aidan Hollis, a professor at the University of Calgary, submitted a novel solution that delinks price from the payment for innovation and is similar to outcomes-based agreements. But in Hollis’ model, payers would front a much lower amount for the therapy — similar to the price of a generic drug — and then pay the drug manufacturers more over time.

“The manufacturers would receive rewards based on health benefits for a longer period — it could be 10 years, for example. And those rewards would be calculated by how much health gain was delivered,” explained Lotte Steuten, deputy chief executive at OHE. “So there would be a predictable revenue stream for the company, but not the high sticker shock impact when the product is introduced.”

During a recent presentation for drugmakers, Steuten said Hollis’ model was discussed and raised a number of questions from manufacturers. What would the initial price be? How could they be sure they’d be paid back over time? Clearly, Steuten said, there are many aspects of this model that would have to be worked out and it wouldn’t be a great fit for every type of drug. Instead, it could be a “backstop solution” where other models have failed. And, she said, it would likely work best for orphan drugs — including multimillion-dollar gene therapies.

“In that case you have the classic problem of high uncertainty — where you have to decide what to pay for that drug but you would need long-term data to know it is actually a cure,” she said. “That would be a good candidate for this type of solution because that takes away uncertainty and you only have to pay when health outcomes benefit patients.”

The ‘Netflix’ approach

Often referred to as the “Netflix model,” subscription-style approaches have been gaining traction in pharma. In this framework, payers, such as insurance companies, shell out a monthly fee to access medications if and when they need them.

It’s a model designed to delink rewards from volume sold, and could work for a number of different drugs. For example, Steuten and others wrote in an OHE blog post, that this approach was used in Louisiana to pay for hepatitis C treatments. And in 2020, the U.K. became the first country to launch this approach for antibiotics — a segment of the market where innovation has long lagged due to high R&D investments and low market potential.

“If the aggregated global subscription fees are large enough, it should attract companies to invest in antibiotic development by generating a high enough global revenue,” Steuten and others wrote.  

According to Steuten, the U.K. tested the approach on two antibiotics for “serious infections resistant to the last line of antibiotics.”

“Both companies participating in the pilot were satisfied with the result, and many experts on antibiotic resistance hailed it as a success in turning health economic theory into practice,” Steuten and others wrote.

In addition to working on lower-cost drugs like antibiotics, Grace Hampson, associate director at OHE, said the approach could help overcome payer challenges with high-cost gene therapies.

“(Payers) would pay a set fee per month and then have access to however much of that gene therapy they need,” Hampson said. “Then there is certainty for the insurer because they don’t have to worry about cash flow.”

Like other models, Hampson explained that there are lingering questions including: What would the monthly fee be? And how could manufacturers be guaranteed they’d recoup costs?

“If the manufacturer is not getting paid at the point of delivery, they have to hold the risk of not receiving those payments. So you might need a third party (such as the government or a financial institution) to finance that in the meantime,” Hampson said.

Still, as the gene therapy industry matures, more of these types of agreements could bubble to the surface in payment negotiations.

“This is the way the world is moving — toward these kinds of finance agreements,” Steuten said.