In pharma, disruptive innovations often strike in waves. In the late 80s, the introduction of approved monoclonal antibodies (mAbs), which offered a new method for taking aim at specific defects in protein structures, triggered a revolution in drug development. After the landmark approval of Roche’s Rituxan in 1997 — the first of its kind in cancer — mAbs became the fastest growing therapeutic in the industry, particularly for oncology and inflammatory diseases.
Yet, pharma companies also faced challenges associated with scaling up production of the novel therapies and spent years ironing out the kinks. A similar situation is now unfolding in the world of cell and gene therapies.
More than 25 cell and gene therapy products have been approved by the FDA, and this burgeoning class of treatments is experiencing its own explosive growth. Over 1,200 experimental cell and gene candidates are in the industry’s pipeline — more than half of which have reached phase 2. And the market for these therapies is expected to swell from about $9 billion in 2023 to over $42 billion by 2030.
As more of these potentially curative therapies reach patients, the industry continues to grapple with growing pains.
The complexity of producing CAR-T cell therapies, for example, has given rise to manufacturing bottlenecks that can create harrowing wait times for patients.
And the multi-million dollar price tags for several of these approved rare disease gene therapies have pressured the payer system and industry to innovate new ways of ensuring access — a challenge that will grow more pressing if one of these treatments is approved for an indication with a larger patient population.
In response, the industry is pushing for next-generation solutions to overcome many of these hurdles while unleashing a new wave of technologies, such as gene editing, that could make the field more transformative than ever before.
Companies with advanced molecular therapies, oncology assets and obesity treatments could be fuel for a dealmaking fire this year.
By: Kelly Bilodeau• Published Jan. 17, 2023
In 2022, mounting economic fears led to a cautious M&A environment — and although many of those concerns persist into 2023, some areas are likely to attract the bulk of the industry’s attention and might be too irresistible to pass up as dealmaking heats up.
M&A spending dropped last year due to myriad underlying causes such as inflation, fears of a recession and drug pricing reforms passed as part of the Inflation Reduction Act, said Amanda Micklus, a senior pharma consultant for Citeline.
“There were difficult-to-access public markets for biotech companies,” she said. “The aggregate dollar value of M&A in 2022 was $87 billion.”
That number fell short of the $153 billion companies spent in 2021 — which itself was considered a stagnant performance over prior years. But the restrained M&A investment last year puts many companies in the position to spend in 2023.
“I think a lot of the larger pharma companies are actually sitting on a lot of cash on their balance sheet,” Micklus said. “So, they have power to buy companies.”
And if companies decide to open their wallets after the multi-year M&A drought, a few areas will likely draw the most interest, Micklus said.
Cutting-edge science on the table
One of these areas is advanced molecular therapies, which includes cell, gene and RNA therapies. Gene editing has taken major strides in recent years, and 2023 could see the approval of the first CRISPR-based medicine, exagamglogene autotemcel (exa-cel), to treat two rare blood disorders. The drug is the product of a partnership between Vertex Pharmaceuticals and CRISPR Therapeutics, Micklus said.
“CRISPR Therapeutics itself could be an acquisition target,” she added.
Interest in in vivo gene editing has also ticked up. In 2022, several pharma giants formed ties with companies in the burgeoning field.
“This could be the year that Genmab is actually acquired."
Senior pharma consultant, Citeline
“Bayer, Pfizer, Novartis — they all did pretty big deals in in vivo gene editing,” Micklus said. Intellia Therapeutics has a promising in vivo gene editing candidate called NTLA 2001 in the pipeline, giving it some appeal as a potential acquisition target too, Micklus said.
“I think non-viral gene delivery is going to be an area that sees increased investment and potentially M&A,” Micklus said, pointing out that many companies are looking for alternatives to gene therapy delivered by viral vectors, which bring safety and manufacturing challenges.
“One of the biggest series A rounds in this advanced molecular therapy area went to a company called SonoThera — they’re using ultrasound microbubbles to deliver gene therapy,” she said.
The diseases driving M&A interest
Oncology, a perennial favorite, will likely remain a top M&A target area. Of particular interest are newer antibody technologies such as antibody-drug conjugates, bispecific antibodies and tri-specific antibodies, Micklus said. A leader in this area is Europe’s Genmab with a highly anticipated bi-specific antibody called epcoritamab, developed through a partnership with AbbVie with an expected launch in 2023.
“This could be the year that Genmab is actually acquired,” she said.
Cardiology, obesity and ophthalmology drugs are also of interest, Micklus said. Two companies that might be M&A targets are Apellis Pharmaceuticals, which is on track to gain approval in 2023 for the first treatment for geographic atrophy, an advanced form of dry age-related macular degeneration; and Cytokinetics, a muscle biology pharmaceutical company with a cardiac myosin inhibitor in phase 3 to treat hypertrophic cardiomyopathies, a thickening of the heart muscle.
Large pharma companies might also have an eye out for small outfits working on obesity drugs that could help them compete with the success of Eli Lilly’s Mounjaro and Novo Nordisk’s Wegovy, Micklus said. One potential acquisition target might be a clinical-stage biopharma called Altimmune, which is expecting phase 2 data from an obesity drug called pemvidutide, Micklus said.
Ultimately, as the uncertainty of the last few years has shown, the real prospects for 2023 M&A remain unclear. But one thing is certain: There are plenty of opportunities for companies on the hunt.
Article top image credit: JuSun via Getty Images
Multimillion-dollar therapies are changing how payers foot the bill
With more gene therapies headed to market, novel payment methods are emerging from regulators and academia.
By: Meagan Parrish• Published Feb. 28, 2023
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.
“This is the way the world is moving — toward these kinds of finance agreements."
Deputy chief executive, OHE
“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.
Article top image credit: Stock via Getty Images
Striving for monoclonality: from antibodies to modern cell and gene therapy
Industry analysts have drawn parallels between the modality of monoclonal antibody development from two decades ago and the current rise of cell and gene therapies (C>), with tantalizing possibilities that C> could have the same or even greater transformative impact. The need for monoclonality to develop safe and effective antibody-based therapeutics spurred innovation in cell isolation and analysis. Twenty years later, the need for monoclonality is emerging again in C> products as another parallel to their antibody-based predecessors, where advancements in single cell isolation and analysis methods are needed to ensure high levels of monoclonality in modern biomanufacturing workflows.
Cell and gene therapies promise revolutionary new treatments and even cures for a broad spectrum of sever and life-threatening diseases, from cancer to genetic disorders. Cell therapy works by injecting cells from a patient or donor that are cultivated or modified outside the body to restore or alter certain sets of cells. By contrast, gene therapy delivers therapeutic transgene to cells and patient tissues to treat an inherited or developed disease, and some therapies are considered both cell and gene therapies.
As distinct yet overlapping fields of medicine, a common requirement for both cell and gene therapies is monoclonality, depending on the applications, such as when genetically modified cells are involved. Monoclonality refers to the production of cells derived from a single parental cell with identical genetic makeup. Monoclonality is essential for the safety and efficacy of these therapies. Monoclonality is achieved by expanding single cells, either from a donor or from a patient's own tissue, which reduces the risk of rejection, into clonal populations. Documentation of monoclonality is a regulatory metric for therapeutic cell lines or cell lines that are used to produce therapeutic agents, and is typically image-based, whereby an image of a single cell is recorded and included in regulatory filings.
While the source of cells, culture conditions, and the use of genetic engineering are important factors in developing clonal cell lines, single cell isolation and analysis is essential, and the method used for single cell isolation and analysis can have significant impact on achieving monoclonality with efficiency. However, current single-cell techniques like conventional FACS sorting can be expensive and time-consuming, difficult to scale up for commercial production, and can be harsh on cells, causing cellular damages that impairs cell viability and clonal outgrowth. This problem is compounded by cellular heterogeneity and rare cell types that are encountered in multi-faceted C> products.
As a result, innovation in single cell isolation and analysis is needed to meet the needs of modern manufacturing workflows to develop safe and effective C> products. Recently, Namocell became part of Bio-Techne’s portfolio of life science research and cell and gene therapy products. Namocell’s benchtop single cell dispensing technology combines microfluidics, flow cytometry and liquid dispensing to gently isolate and dispense single cells with high levels of accuracy, and precision, and speed. A strategic advantage for C> is the potential of the Namocell technology to simplify and accelerate single cell cloning workflow with high efficiency in producing monoclonal cells, thanks to the instruments’ ease-of-use and the gentle sorting. Compared to traditional methods like limiting dilution and conventional FACS sorting, Namocell instruments are cost-effective, easy to use, and can scale up to produce large quantities of cells and gene products, which is necessary for the commercialization of these therapies.
As biopharma companies face teetering investments in biotech and industry-wide labor shortages to meet biomanufacturing demand, the need for cheaper and more efficient analytical solutions is becoming even more pressing. Advances in single cell technology like Namocell can address some of the key challenges that have limited the development and commercialization of C> products, including the production of monoclonal cells and gene products that are targeted to specific cells or tissue therapies. This could help the scale-up of the production of existing therapeutics and accelerate the development of new treatments for a wide range of diseases.
Article top image credit:
Utas via Adobe Stock
Managing for resilience: Passage’s ups and downs in gene therapy
After a rocky year, Passage Bio’s CEO is focused on helping the rare disease specialist bounce back.
By: Meagan Parrish• Published Feb. 15, 2023
When Passage Bio was founded, it was a sort of comeback story for gene therapy pioneer Dr. James Wilson.
After making a name for himself as a researcher, Wilson became head of the Institute for Gene Therapy at the University of Pennsylvania. Then in 1999, a patient in a clinical study died after being dosed with a gene therapy created in Wilson’s lab. The tragic and well publicized event brought the field to a screeching halt. And in 2005, an FDA investigation into the patient’s death led to a five-year ban from clinical trials for Wilson.
Throughout that time, however, Wilson kept at his work outside the clinical arena. In 2002, he published research showing that that gene therapies could be more safely delivered using adeno-associated virus vectors. He also eventually got into the world of startups, first launching Regenxbio in 2009 and a decade later, Passage Bio, which got off the ground with $115.5 million in funding and a handful of promising gene therapy candidates.
Now, just a few years later, Passage is looking for a comeback of its own.
In March 2022, the clinical-stage company announced it was cutting about 13% of its workforce. After a 2021 IPO, the biotech’s market cap had soared to over $1 billion, but within about a year, shares for Passage plummeted about 90% amid a major downturn in the market that saw values tumble across the sector.
"The goal with these changes so soon after I started with Passage was to make all the hard decisions as soon as possible so that we can move into a rebuilding phase.”
Dr. William Chou
CEO, Passage Bio
Then in June, Passage’s CEO abruptly stepped down, opening the door for new leadership. A few months later, Dr. William Chou took the reins as Passage’s new CEO — a job he knew wasn’t going to be easy.
More job cuts followed about a month after Chou came on board along with news that Passage would have to slash its R&D efforts. The restructuring left the company with about 100 employees, two drug candidates in phase 1/2 trials — and a clear impetus among leadership to help Passage bounce back.
“I came in with eyes wide open,” Chou said. “But I had a belief in the science and in the data that has been published preclinically on these programs, so you have to believe in the fundamentals.”
There’s a lot on the line — not just for Chou and Passage, but also for patients.
One of Passage’s two remaining therapies targets GM1 gangliosidosis, a rare inherited condition that attacks nerve cells in the brain and spinal cord, and in its type 1 form, appears in babies where it is fatal before the age of 2. Right now, Passage’s gene therapy, PBGM01, is the only candidate in clinical trials for the disease.
The company’s other lead asset, PBFT02, targets frontotemporal dementia (FTD), a rare genetic mutation that can trigger early onset dementia.
Passage also has three therapies in discovery and is hoping to license out rights for two assets it had to discard — one in Krabbe disease and the other for metachromatic leukodystrophy.
“Stopping our programs had nothing to do with the science and what we think they can deliver to patients,” Chou clarified. “It was a matter of prioritizing the most advanced programs.”
After scaling back its workforce and pipeline, Chou said Passage is at the right size to move forward. The company has a cash runway that should carry it into 2025 and a unique platform developed by Wilson, who now serves as the company's chief scientific officer.
And Chou, who was formerly the CEO of gene therapy and rare disease specialist Aruvant Sciences, as well as the vice president, global disease lead for Novartis’ cell and gene therapy unit, might be just the right leader to chart its new course.
Here, Chou discusses Passage’s critical milestones for 2023 and his tips for leading through tough times.
This interview has been edited for brevity and style.
PHARMAVOICE: What have been your biggest priorities since taking the helm at Passage in October?
DR. WILLIAM CHOU: Strategic prioritization. We needed to do fewer things better. We also needed to have the financial stability to make sure we can weather this difficult market.
The second is operational focus. We have a lot of patients who need treatment so it’s important for us to deliver clinical data as quickly as possible.
The third is employee reengagement. 2022 was a difficult year for Passage. And our employees are some of the most experienced tech experts in the field, so it’s very important to me that they love being here and are inspired — and that this keeps them here.
Passage has gone through a number of changes in the last few years — from the CEO transitions to restructuring. How have these changes helped Passage?
The goal with these changes so soon after I started with Passage was to make all the hard decisions as soon as possible so that we can move into a rebuilding phase. One of the outcomes was extending our cash runway into 2025. Now we are in a much stronger position to weather the unknowns of a difficult market.
We also have two differentiated programs and having this runway gives us the time to have our clinical data mature.
Are you worried about having to do more fundraising?
In this environment, what I’ve generally heard and seen for gene therapies is that there is more of a premium on generating differentiated clinical data. We are clinical stage with two active clinical programs so I think we’re well positioned to fundraise because we will be generating more data later this year.
How are your AAV gene therapies differentiated from other gene therapies?
First is the unique discovery platform. We get to leverage the expertise of James Wilson and his discovery program at Penn to identify the best combination of mechanisms and capsids — and that combo may be different for every therapeutic area we’re in. It’s not a one-size-fits-all, but we have the best platform to identify that best combo and that is a real scientific advantage.
"Our employees are some of the most experienced tech experts in the field, so it’s very important to me that they love being here and are inspired — and that this keeps them here."
Dr. William Chou
CEO, Passage Bio
The other way we’re different is our route of administration. We target the CNS through cisterna magna at the base of the skull and we deliver directly there with a single injection. First it gets broad distribution of the vector through the CNS and then you don’t have to give as high of a dose as you would through IV systemic delivery. You also avoid other problems like liver toxicity. And then you are reducing impact of antibodies to the capsids that would neutralize the effects of the capsids.
What's nice is the whole promise of this route of administration is being borne out in the clinic.
What are the biggest milestones you’re focused on in 2023?
Let me start with our program for patients with the GRN mutation (for frontotemporal dementia). There are about 3,000 to 5,000 patients in the U.S. with this mutation and our preclinical data is the only preclinical data in this disease area that has shown super physiological levels of the missing protein. So we are in a phase 1/2 trial and in the second half of this year, we expect to share initial safety and biomarker data for the first patients treated, and we’ll get to see how this preclinical data translates into the clinic.
Our other milestone will be from our program for GM1 gangliosidosis. We’ve treated eight patients so far and shared data from the first six. In mid 2023 we will share additional data from the final two patients.
What advice would you give other executives in biotech about managing teams through a difficult stretch?
The No. 1 most important thing is keeping focus on the mission. The greatest thing we do in this industry is the impact we have on patients. That is what gets people to go above and beyond at work.
The second is togetherness. That starts from leadership to create an environment where smart people with a lot of ideas can disagree. But do they enjoy that collaboration and brainstorming? If you like the people you work with and you enjoy that work environment you’re going to want to stay.
You also have to believe your individual work makes a difference, and that the things you do on a small level make a big difference for the company. In my career, I’ve gotten a lot of personal satisfaction from that.
That is what we’re trying to accomplish from a cultural perspective.
Article top image credit: Permission granted by Dr. William Chou, Passage Bio
Cell and gene therapy advances coming fast and furious
A peek into R&D at the Mass General Brigham network reveals up-and-coming treatments pushing the boundaries of what’s possible in medicine.
By: Kelly Bilodeau• Published June 1, 2022
A treatment to restore eyesight and hearing. New hope for a devastating form of brain cancer. Cell therapies for gut diseases that affect digestion. These are just a few of the cell and gene therapy technologies that are poised to significantly improve healthcare for patients over the next decade — some of them close at hand.
Each of these innovations was recently highlighted by Mass General Brigham, a Massachusetts-based academic healthcare system and biomedical research organization, in its annual “Disruptive Dozen” list, chosen by a group of Harvard Medical School faculty members. The list showcases a small number of ongoing research projects and illustrates just how far the cell and gene therapy field has evolved from formative concepts developed as far back as the 1960s.
The first person successfully treated with gene therapy was a 4-year-old patient suffering from a rare immune system disorder in 1990. But the FDA didn’t officially approve the first gene therapy treatment, for a type of acute lymphoblastic leukemia (ALL), until 2017.
Since then, the cell and gene therapy market has seen a huge infusion of cash aimed at advancing the field. In 2019, nearly $20 billion was poured into the cell and gene therapy space, breaking the previous record of $13.5 billion set the year prior. Today, cell and gene therapy initiatives are making progress toward treating conditions such as Parkinson’s disease, sickle cell disease and even Type 1 diabetes.
But while there has been substantial investment and nearly two dozen cellular or gene therapy treatments have made it to market, the field has also had its share of setbacks ranging from disappointing trial results to safety issues, including serious complications such as inflammation, infections and even the development of certain cancers following treatment.
Despite these hurdles, cell and gene therapy research is advancing so rapidly that many of the treatments in the works today seemed unfathomable a decade ago. Ten years from now, the story could be much the same.
“When you talk to the clinicians they say, ‘We’re going to look back on this period and recognize it for how primitive it was regarding these technologies,’” says Chris Coburn, chief innovation officer at Mass General Brigham (previously known as Partners HealthCare). In the very near future, he says, the whole model is going to be different.
Here, we’re looking at some of the potentially game-changing treatments being developed in the Mass General Brigham network, which includes a number of high-profile hospitals in the Boston area.
Seeing a cure for blindness
Many of the treatments being explored target once incurable conditions, such as blindness caused by genetic disorders. A method known as CRISPR-Cas9 gene editing, which made Mass General Brigham’s list this year, repairs faulty genes in the eye by inserting healthy replacements to treat conditions like Leber congenital amaurosis type 10, a currently untreatable and severe form of childhood blindness.
Researchers are also developing cell-based therapies designed to replace lost or injured cells to restore vision in people with damage to the retina or cornea.
A suite of complementary treatments may allow doctors to treat multiple problems in different parts of the eye at once, Patrick Fortune, vice president of strategic innovation leaders at Mass General Brigham, says.
A needed therapy booster for glioblastoma
Gene therapy advances are bringing doctors closer to helping patients with glioblastoma, the devastating brain cancer with a five-year survival rate of just 6.8%. To date, precision medicine approaches have targeted proteins, but new research is focusing on a previously overlooked actor — RNA.
This treatment approach at Mass General Brigham uses molecules called microRNAs, which join to form a single unit that can be inserted into the brain using a virus. This therapy may help enhance the effectiveness of chemotherapy and other existing treatments.
Another separate approach blocks the activity of a type of microRNA called miR-10b, which prompts tumor cells to die. There has been little change in how glioblastoma has been managed over the past 50 years, Coburn says.
“Anything that gets traction in glioblastoma is almost by itself a game changer,” he says. “The idea that more advanced ability to use RNA therapeutically is emerging, and then will be applied on diseases like brain cancers, is remarkable.”
A fix for the animal organ dilemma
New technology is also furthering the field of organ transplantation. Today, performing an organ transplant is a race against time often involving middle-of-the-night phone calls and rushed surgeries. But that frenetic process may one day become a thing of the past thanks to advances in gene editing technology helping to make xenotransplantation a reality, Coburn says.
The idea of growing a steady supply of animal organs for use in human transplants isn’t new. Scientists have been working on the technology for some 20 years. What has changed is the advance in gene editing, which gives scientists the ability to camouflage transplant organs from the human immune system, which is tasked with rejecting them.
"When you talk to the clinicians they say, ‘We’re going to look back on this period and recognize it for how primitive it was regarding these technologies.’”
Chief Innovation Officer at Mass General Brigham
Molecularly engineered animal organs may help save a substantial number of lives. More than 100,000 people in the U.S. are awaiting a life-saving organ transplant and 17 people die each day before an organ becomes available. Having a predictable organ supply would allow doctors and patients to plan ahead.
“You’d have a very measured approach to optimizing when that organ will be delivered, when the surgery is going to take place, what works best for the patient,” Coburn says. “The implications here are really profound.”
Mass General Brigham researchers are not the only ones focused on this approach. This year, doctors at the University of Maryland Medical Center successfully performed a human heart transplant using an engineered pig heart supplied by Virginia-based Revivicor, a subsidiary of United Therapeutics. The patient lived with the organ for two months, and while the transplant faced a critical setback, it still represented a major step forward.
Cell transplants, not just whole organs, may also soon become a reality, Fortune says.
“Another thing that's going to go through validation very quickly, and that's approaching the clinic now, are [transplants of] pancreatic islet cells for treating Type 1 diabetes,” he says.
Cell regeneration for hearing loss
Another treatment on the horizon could help millions of Americans with hearing loss. This technology would help regrow specialized cells inside the ear called hair cells.
Most people have 16,000 of these hair cells when they’re born, but the cells may be damaged over time by loud noises or diminish with age. The destruction of these hair cells leads to permanent hearing loss.
But now, researchers are developing a process that could restore these cells and hearing along with them.
The full list
All of the technologies highlighted on Mass General Brigham’s “Disruptive Dozen” list are in various stages of preclinical and clinical trials, and expected to emerge over the next 10 years.
“I think the way these are going to be developed is going to go a little bit faster than that. But the broadest indications will not come first,” Fortune says, noting that narrower indications, such as treating people with one unique genetic defect, will likely lead the pack.
Currently, the treatments are being developed without partners in pharma, according to Mass General Brigham’s communications team.
Treating diseases related to gut motility using cell replacement therapy.
A new type of gene therapy for brain disorders that helps to overcome the challenges related to moving treatments past the blood-brain barrier.
A novel antiviral therapy to target a range of viruses using CRISPR-Cas gene editing tools.
Treatments for autoimmune disorders using CAR-T cells, a type of immune system cell. Scientists are working to use these cells to target rogue immune cells that attack the body’s own tissues in conditions like Lupus.
New types of gene therapy delivery systems, including a skin patch and a biodegradable implantable device that releases a steady infusion of medication over time, to minimize side effects.
Better options for solid tumor treatment, including the use of CAR-T cells, which are programmed to identify and target challenging types of tumors, or cancer cells that are modified to become cancer killers.
A therapeutic strategy to treat X-chromosome defects, including neurodevelopmental disorders, such as Rhett syndrome.
And more advances are right behind this batch, Fortune says.
“What you're seeing is the tip of the iceberg of things that are coming to realization in a pharmaceutical sense in the relatively near term,” Fortune says. “But the excitement that's coming several steps back in the process is at least as encouraging as what we're seeing now. So, maybe another way to put it is you're going to see more of the same on an annual basis as these things just move through the pipeline. And the things that will be here in 10 or 15 years are things we couldn't have thought of today.
Article top image credit: iStock via Getty Images
Why biomanufacturing is the next innovation frontier for genomic therapies
While cell and gene therapy research has accelerated quickly, manufacturing in the space hasn’t quite kept up, Danaher’s Chief Science Officer JC Gutiérrez-Ramos says.
By: Meagan Parrish• Published June 13, 2022
Much has changed since the first version of the complete sequence of the human genome was released in 2000.
Over the subsequent 10 years, researchers began identifying genes underlying many rare disorders, eventually characterizing about 7,000 of these markers and opening drug development up to a new world of therapeutic targets. The new understanding also triggered a shift from small molecules and biologics to disease-modifying gene therapies.
It was during this time of bustling genomic promise that Jose-Carlos “JC” Gutiérrez-Ramos helped set up the rare disease unit at Pfizer as the company’s senior vice president and head of global biotherapeutics R&D. As Gutiérrez-Ramos explains, changes in the industry have since come swiftly.
“It’s a completely different scenario now — as a drug hunter, you’re not blind,” he explains. “You not only know where you’re going, but actually how to get there. It’s a fundamental transformation.”
Since leaving Pfizer in 2015, Gutiérrez-Ramos has served as a CEO in two emerging biotechs and worked as head of global drug discovery for AbbVie. Although he’s had a front row seat to changes in drug design, he’s also seen how the manufacturing factor of this equation hasn’t fully kept up with the pace of drug development. Today, Gutiérrez-Ramos is leveraging his extensive experience to help overcome some of the lingering manufacturing challenges as the chief science officer of Danaher Corp., a global science and technology conglomerate.
According to Gutiérrez-Ramos, biomanufacturing is the next frontier in innovation for genomic medicines.
“Companies like us are considering: ‘How do we take all of our engineering, biology, automation, physics, expertise, etc., and make this process more efficient?’” he says. “There is a big push needed to get these therapies to have a positive impact on the world.”
Here Gutiérrez-Ramos discusses some hurdles biomanufacturers are looking to overcome to make cell and gene therapy manufacturing more efficient.
This interview has been edited for style, length and clarity.
PharmaVoice: What are some of the biggest challenges to manufacturing genomic medicines right now?
Jose-Carlos Gutiérrez-Ramos: First, to ease manufacturing, there has to be a standardization of the genomic payload. Meaning, how do you design your genes, or the modifications of your genes? At the moment, there is no learning from program to program. It can feel like chaos; different people do it different ways. There is no central database. Artificial intelligence (AI) helps, but could do much more.
Is there an organization that should be creating standards around genomic payloads?
I think it's going to be difficult to standardize by organization, so we have to standardize information access.
I think a lot of this will have to come from software packages that allow the design of genomic payloads, comparison learning and implications for manufacturing scale. Because these sequences have to be incorporated in the next step of the chain, and that's going to result in productivity of the cell lines.
What about the challenges associated with delivery systems?
Of course, once you have the genomic payload, then you have to get the treatment into cells. And currently, the ways of getting these genomic payloads into cells are not optimal. How we produce these delivery systems — like lipid nanoparticles, or LNPs — is not efficient … and it’s one of the biggest challenges the field of genomic medicines is facing.
We are currently working with our companies on optimizing LNP technologies … focusing specifically on the amount of genomic payload getting into the nucleus of the cell. Basically, what you want to do with genomic medicines is modify particular cells in the body. But if the drug only gets into 30% of the cells you are targeting, your therapy is not great. So, you want to make sure that you transduce as many cells as possible for your target.
If you were to pinpoint specific areas that could improve the efficiency of these delivery systems, what would they be?
One is what we call the efficiency of transfection, meaning how many cells get transduced by this virus or that LNP. And what are the mechanisms that allow this virus or that LNP to enter that cell? Are there specific receptors on those cells or on the viruses that actually get it through? Does the virus release the genomic payload or the lipid nanoparticle via the payload more efficiently?
There are a number of mechanisms that relate to the biology of that process: How many get to the surface of the cell? How many cross the surface of the cell? How many get to the nucleus, or how many get expressed? And a lot of these characteristics depend on how you have designed your genomic payload in the first place.
What are some of the tangible manufacturing goals you’re focused on right now?
Overall, our goal is to cut the time that it takes to generate any of these medicines in half, which will result in cost reductions.
We are not a pharma company, but we are enabling biomanufacturing companies with technologies, and working with our partners to make sure that from the sequence to the vial, we have technologies every step of the way that help cut the time.
How would you compare the work that you're doing now to the earlier development work you were doing at other companies?
I do think I’m having a bigger impact in this role because of the scale of Danaher. If you know the 7,000 genes, if you know their polymorphic variants, if you know that you can either generate that mRNA, or a gene editing therapy or whatever therapy for this specific disease … then suddenly, the center of gravity of the problem becomes: Can you make the medicine? Or can you make it potent enough? For enough people? And can you scale down to make sure that your vial and my vial are not different?
I think the impact that we are having at the moment is enormous.
Article top image credit: iStock via Getty Images
For Duchenne-focused Sarepta, gene therapy is the natural next step
The company with three marketed RNA drugs for Duchenne muscular dystrophy is taking the logical leap into gene therapies with a candidate under review at the FDA.
By: Michael Gibney• Published Dec. 8, 2022
Sarepta Therapeutics has followed a natural progression from its focus on RNA technology to the world of gene therapies, filing for U.S. regulatory approval of its first one-time treatment for Duchenne muscular dystrophy at the end of November.
If approved, SRP-9001, would be the first gene therapy for the muscular degenerative disease known as DMD and is slated for complete evaluation under the accelerated approval path by the end of May 2023.
The road to this potential "cure" for DMD has been a culmination of scientific persistence and a long career in incremental successes in the genetic field, said Louise Rodino-Klapac, chief scientific officer, executive vice president and head of R&D at Sarepta.
And the big step for the company is one that holds a great deal of promise for patients outside of the already groundbreaking RNA treatments Sarepta currently markets for the disease — Exondys 51, Vyondys 53 and Amondys 45. DMD is caused by a mutation that leads to the absence or dysfunction of a protein called dystrophin, which gene therapies can reset by creating functional dystrophin in patients with the disease. This gene therapy in particular adds a copy of the missing gene for potentially permanent rewiring.
"Our RNA technologies that are approved target specific exons — it's about collectively 30% of Duchenne patients with those mutations," Rodino-Klapac said. "The gene therapy approach is agnostic to mutation, and you're delivering a small functional version of the dystrophin gene to all muscle, cardiac and skeletal for a potentially lifelong benefit."
"I've been in the space for almost 20 years, and where we are today is a tremendous stride from where we were back then."
CSO, executive vice president and head of R&D, Sarepta
While the FDA reviews Sarepta's previous mid-stage data, which saw delays due to mixed results, the company is conducting a late-stage study it plans to read out at the end of 2023, months after the agency is due to make a decision.
Here, Rodino-Klapac discusses the potential for a gene therapy in the DMD treatment landscape, the development pathway the company took to get here and what persistence means for leaders of cutting-edge science where success is hard-fought.
This interview has been edited for brevity and style.
PHARMAVOICE: DMD has been your specialty with three commercial products on the market. Can you talk about the current treatment landscape?
LOUISE RODINO-KLAPAC: Duchenne is a devastating disease, where boys are often diagnosed between the ages of three and five and then progressively degenerate, often with early deaths in the mid-20s from cardiac respiratory failure. And so there's been a huge push in the biotechnology industry to find treatments for Duchenne. As far as the genetic disease, it's very well described, and we know that the DMD gene is affected. And so there's been multiple strategies to ameliorate the disease. Since Sarepta has gotten the approvals of the RNA drugs, that's led to a keen interest in the space, which is great for patients. I think there are over 50 different companies working on Duchenne right now. It's a huge treatment landscape.
What lessons did you take from your RNA medications into this gene therapy development program?
Quite a bit. From the RNA development we learned a lot about the natural history of the disease, which helps us to inform the way we design our clinical trials, but then also about levels of dystrophin. Whether you're using exon skipping or gene therapy, you're looking at how levels of dystrophin lead to clinical benefit. And so in both those ways, from the dystrophin production and natural history of the disease, we learned a lot from RNA.
Generally speaking, the development of a gene therapy is such a different beast from that of other treatments. Can you talk about the challenges there and the unique hurdles you need to overcome on your way to regulatory approval?
I've been in the space for almost 20 years, and where we are today is a tremendous stride from where we were back then. With gene therapy, one of the hurdles was being able to manufacture enough to deliver to the entire body. With Duchenne, we're trying to treat the largest system in the body, which is muscles — about 40% of the body mass is muscle. It's difficult to make enough and be able to deliver it effectively so this is a one-time treatment. After you deliver the gene therapy, patients develop antibodies and at this point you can't re-treat (the patient), although we're working on ways to do that.
We've been gradually overcoming every challenge of gene therapy and getting to a good place with overall favorable safety and, so far, very encouraging and efficacious results.
When overcoming these gene therapy challenges, do you remember any 'eureka' moments of coming up with a solution that would get you over a certain hill?
It's been a series of moments. For SRP-9001, selecting the RH74 vectors versus others and realizing that it distributes into muscle extremely well was important. There's a lot of work that went into that, and then the selection of the promoter to target the heart and skeletal muscle. So I think it's a series of those decisions and getting manufacturing on pace — it's all of those things collectively.
As you run your latest trial, what are the most important conversations you're having both internally and with the FDA?
We certainly had discussions with the FDA about the design of that trial, but importantly, we have collectively about 100 patients’ worth of data with our construct, including results showing benefits in three studies with results for some patients out to four years.. So we're in a very good place in terms of the data that we have. And we're using the accelerated approval pathway to get to patients as quickly as possible.
There were some early warning signs in terms of adverse events from early-stage trials. Those have been resolved, but can you talk about that process and how you investigate potential setbacks and then move forward?
We've seen adverse events, but they've been very manageable. The most events we've seen in terms of numbers have been nausea and vomiting. We do have some liver enzyme elevation, but once we modified our steroid protocol, those were reduced. We've been fortunate in the management of our profile, which greatly favors the benefit-risk. There have been other programs that have suffered more setbacks in terms of adverse events.
With your phase 3 pivotal study slated to read out by the end of next year, what else is next for Sarepta?
Certainly the next six months are focused on the review period with the FDA, but at the same time, we have a whole pipeline of programs we're moving along. We're using the same platform technology that we've developed for SRP-9001 in limb-girdle muscular dystrophies, so we're looking forward to additional trials there and to bring those forward as quickly as we can to patients. And we have additional RNA targets as well as gene editing, so it's obviously an exciting time. And we're balancing all of the programs as best we can to bring the biggest benefit to patients.
What are some of the most important qualities for a leader in overcoming the challenges in the development of gene therapies and the like?
These are things that are near and dear to my heart, and I think as you evolve as a leader, one of the challenges is getting good at being used to failure. Scientists for the most part are used to failure. When something doesn't go quite as you expected, being able to take it as a challenge and be able to react to it quickly and pivot and make changes is critical — things that we perceive as failures are often telling us something unique and can lead to serendipitous findings. That's the approach I've taken and try to guide my team to. As a leader, we cherish the opportunity to make sure the next generation of leaders are able to show what they can do and to give them the space to do it without micromanaging.
Article top image credit: Courtesy of Sarepta
4 ways to nail the launch of your cell therapy
A consultant’s view on how pharma companies should approach patient experience challenges when rolling out an autologous cell therapy.
By: Meagan Parrish• Published Aug. 10, 2022
Much lip service has been given to the complexities behind developing and manufacturing cell and gene therapies. But navigating those challenges don’t end once the treatment is approved — especially when it comes to autologous cell therapies, which require the patient’s own cells.
“People talk about cell and gene therapies in a bucket too much. But autologous therapies are so different — everything involved in them is very different,” explains Greg Christianson, a principal at Nuvera Life Science Consulting, which specializes in “patient-centric solutions that enhance access and adherence to rare diseases and specialty therapeutics.”
In particular, Christianson says that when rolling out an autologous cell therapy — such as a CAR-T — companies need to make critical decisions around managing team and patient management to avoid delays that could emerge.
Here are four ways Christianson says companies can help prepare for a cell therapy launch.
Know your philosophy: "First and foremost is the philosophical decision a manufacturer needs to make about whether or not they want to pursue a relationship with the patient and caregiver involved in their treatment,” Christianson says.
Unlike traditional treatments, the experience of receiving an autologous cell therapy is more arduous for patients, who produce the raw material themselves: their own cells. This begins a complex series of steps that can often require travel, longer hospital stays, and at times, participation in regulatory-required follow-up studies.
Because this creates many touchpoints with highly trained healthcare providers, the relationship that patients develop with caregivers is more involved than when receiving other types of therapies. And Christianson notes that pharma companies providing the treatment typically aim to find a balance between guiding patients through this journey, while not getting in the way of their caregivers.
“Patients [receiving cell therapies] are often in dire straits, so the greater relationship pharma companies have with patients, the greater the risk is that they’ll get in the way of the relationship the patient and treatment center have,” he says.
To help, Christianson advises that companies decide what level of involvement is a good fit for them before rollout. Often, companies start by looking at the typical pain points patients are likely to encounter and then at how they can provide assistance. For example, some companies may provide travel and lodging support. Others may create a program that walks patients through the whole process while laying out what kinds of services and support they can provide.
Either way, Christianson says that “creating that foundational view of the treatment experience provides an organizational asset that gets everyone on the same page.”
Earn a good rapport with treatment sites: Starting in the clinical trials process, manufacturers identify a number of treatment centers to administer their therapy. At first, they may only have a handful of centers in their network. But if the therapy is approved, they’ll need to expand to reach more. And when a pharma company begins negotiating with sites, its reputation could impact whether or not the site wants to form a partnership.
Therefore, it’s important to establish a streamlined and organized process in early clinical trials, Christianson says.
"There are a lot of wheels at play to manage all of [these] steps."
Principal, Nuvera Life Science Consulting
“The perception around how difficult your therapy is to use in your clinical trials and if they see disjointed processes in play, the greater the risk of hesitancy when you’re trying to encounter with getting those treatment centers on board,” he says.
Christianson points out that this was less of an issue when only a few cell therapies were approved. But now, as more treatments head to market, the competition for treatment center bandwidth has heated up.
Break down silos: “First you have clinical trials, then you have the commercial team, then billing, manufacturing and supply chain in the background,” Christianson says, describing the various groups involved in the development and launch of cell therapies. “And these teams don’t usually talk to each other.”
Henotes that at smaller biotechs this is less of an issue because the companies are “building organizations around the drug.” But at larger pharmas, a concerted effort has to be made to break down silos between departments so that everyone’s on the same page — otherwise, a disconnected approach could slow down launch.
“If your teams are not aligned internally on who’s doing what and when, where and how, then the initial certification process for treatment centers could be disjointed and not done in a timely manner,” he says. “So that could delay treatments getting to patients.”
Establish order management: Ordering an autologous cell therapy is not as easy as calling up a pharmacy. Instead, a patient has to go through screening and then cells need to be collected, a process that Christianson says can require multiple rounds of apheresis, which can take weeks depending on how many rounds they need. Once the patient receives the treatment infusion, they could then be in a center for up to four weeks for monitoring.
“There are a lot of wheels at play to manage all of those steps,” Christianson points out.
So far, he says that there are no “clean” marketplace software solutions to manage the process and organization between pharma companies and treatment centers.
“I’ve seen companies leverage the ones out there and adapt them to their needs. Some build [needed solutions] internally,” he says.
Christianson predicts that within the next decade, a “clearing house” solution will emerge that helps organize and coordinate these steps. For now, he says that companies should “bake” order management plans into their rollout to identify stumbling blocks that could arise.
“In conjunction with the blueprint for treatment management, companies need to look at the order management process — who’s involved in each step and how to enable each step,” he says. “The earlier you can map this out and figure out the underlying technologies your company needs to build for this, the better.”
Article top image credit: Stock via Getty Images
While CAR-T wait times remain ‘heartbreaking,’ researchers push for innovations that could help
Facing an unprecedented manufacturing bottleneck, a new coalition is aiming to create the next generation of CAR-T therapies.
By: Michael Gibney• Published Nov. 8, 2022
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.
"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."
Dr. Rafael Amado
Executive vice president, head of R&D and chief medical officer, Allogene Therapeutics
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."
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."
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."
Article top image credit: Amornrat Phuchom via Getty Images
Gracell Biotechnologies’ quest to unlock the CAR-T bottleneck
The biotech hopes to upend the CAR-T category by cutting manufacturing from weeks to hours and developing a first-line cell therapy.
By: Taren Grom• Published Jan. 9, 2023
Welcome to the Biotech Spotlight, a series featuring companies that are creating breakthrough technologies and products. Today, we’re looking at Gracell Biotechnologies, which is developing both autologous and allogeneic CAR-T cell therapies for solid tumors.
In focus with: William Wei Cao, CEO, chair and founder, Gracell Biotechnologies
Gracell Biotechnologies’ vision: With more than 30 years of experience in cell therapy R&D, including founding two startups and establishing more than 100 patents and applications for advanced cell therapies, Wei Cao is positioning his latest venture, Gracell Biotechnologies, to solve the biggest issues involved with CAR-T cell therapies: manufacturing time, cell quality, cost and use as a first-line therapy for solid tumors. Founded in 2017, the global clinical-stage biopharma company is pursuing the unusual path of developing both autologous and allogeneic products through its FasTCAR and TruUCAR technology platforms and Smart CART technology module.
Why it matters: Wei Cao believes the company is on its way to opening up the bottleneck that has so far limited the value and efficacy of autologous CAR-T cell therapies — the laborious manufacturing process, which can take up to six weeks. While he admits Gracell is not a manufacturing company, he said it has designed a way to increase the speed of production and reduce costs. Its FasTCAR platform automates the process in a closed-loop clean suite facility to manufacture several patient samples simultaneously “using XLenti vectors derived from lentivirus,” according to the company.
“We knew if we could technically improve the manufacturing process and make it shorter, we (could not) just cut down the time, but also reduce healthcare costs linearly,” Wei Cao said. “And, by delivering the product to patients earlier we can improve outcomes, because for late-stage patients who are waiting, their disease is progressing quickly.”
The strategy: The stem cell manufacturing market is growing at a compound annual rate greater than 9% and is expected to reach more than $18 billion by 2026.
With the booming market, Gracell has plenty of competition, which Wei Cao said is “healthy,” as the goal is to make CAR-T cell therapies available for newly diagnosed cancer patients, rather than as a last-line of defense.
In late 2022, Gracell moved one step closer to realizing its goal, presenting positive phase 1 data for GC012F, which is being investigated as a first-line therapy for newly diagnosed, high-risk multiple myeloma patients. The data shows a 100% overall response rate.
“This is probably the first time there is (evidence) of safe and efficacious CAR-T therapy for newly diagnosed cancer patients,” Wei Cao said. “All these CAR-T or TCRT or any other cell and gene therapy are designed or approved for last-line therapy. So here we are, we can give this CAR-T cell therapy to newly diagnosed patients and not just to patients who run out of options.”
At a glance: The company has nine CAR-T cell therapies — autologous and allogeneic — in the pipeline, a newly established R&D center in San Diego and plans to initiate clinical trials in the U.S. in 2023.
Since 2017, Gracell has achieved several major milestones. First, it brought the conceptual design of FasTCAR to fruition.
“When that worked, it just knocked us out. A lot of people said it’s impossible you need two weeks, but we proved we can do it overnight,” Wei Cao said. “The second milestone was our IPO after three and a half years and the Nasdaq listing. The third milestone is positive data for a first-line cell gene therapy for newly diagnosed multiple myeloma or cancer patients.”
Here, Wei Cao talks more about Gracell’s newly released data around GC012F, its lead autologous CAR-T product, moving the needle to make CAR-T therapies a first-line of cancer defense, and its dual approach to increase the efficiency and reduce the costs associated with CAR-T cell therapies.
This interview has been edited for brevity and style.
PHARMAVOICE: In late December, you received positive results for GC012F. What does this mean for the program?
WILLIAM WEI CAO: This is probably the first time, forgive me if there is data outside our reach, that a CAR-T therapy has been shown to be safe and efficacious for newly diagnosed cancer patients. All other CAR-T, TCRT or other cell and gene therapies are designed or approved for last-line therapy.
“This is probably the first time there is (evidence) of safe and efficacious CAR-T therapy for newly diagnosed cancer patients."
William Wei Cao
CEO, Gracell Biotechnologies
The reason we got approved is because of our sound safety profile, 75% of our patients actually have no CRS (cytokine release syndrome). This is unheard of and beyond our expectation. CRS is a common side effect for CAR-T therapies.
We have presented data at ASH and at other conferences, so we knew the GC012F product was safe and efficacious in late-stage multiple myeloma patients. But we did not know about the data for the newly diagnosed patients for GC012F, which shows a better safety profile and 100% MRD (multiple myeloma demonstrating) negativity response. And that was a good surprise. So, we are encouraged that this signal cell therapy could be used as a front-line therapy. Because GC012F is a FasTCAR dual targeting therapy, we are investigating beyond multiple myeloma. We also have presented data for lymphoma, non-Hodgkin lymphoma and other B cell malignancies.
And then in 2023, we’ll probably announce another very big indication. FasTCAR is a sophisticated design that could enable us to use this drug in many indications.
Most companies pursue either autologous or allogeneic products. Why are you looking at both?
There are two reasons. One, we believe allogeneic is the future. Second, there (is) still a lot of research work to be done for autologous. And for these reasons we are developing both.
Autologous is a more proven technology. The first two products or three products approved in (the) U.S. and other countries are all autologous, which brings in better efficacy. Meaning, the therapeutic effect lasts longer due to the mechanism of a patient’s own cells. It tends to stay in the patient body for a longer time and has less of a chance to be rejected.
Now, off-the-shelf allogeneic CAR-T is the future. The vision is that you can manufacture many, many doses from a healthy donor. You derive the cells from a healthy donor, deploy the cells to a hospital where they can stay in the freezer and be ready to use. That sounds great. However, off-the-shelf CAR-T, which is still developing is more challenging than autologous because its other people’s cells. So genetically, these cells will not be recognized by a patient’s body as their own. There is the potential to reject the healthy donors CAR-T cells and this means the persistence or duration of these allogeneic cells in a patient’s body may not last long.
Article top image credit: Stock via Getty Images
Inside the development of cell and gene therapies
More than 25 cell and gene therapy products have been approved by the FDA, and this burgeoning class of treatments is experiencing its own explosive growth. As more of these potentially curative therapies reach patients, the industry continues to experiment with solutions to grapple with growing pains.
included in this trendline
The M&A hunt is on — here are the prime targets
Gracell Biotechnologies’ quest to unlock the CAR-T bottleneck
Multimillion-dollar therapies are changing how payers foot the bill
Our Trendlines go deep on the biggest trends. These special reports, produced by our team of award-winning journalists, help business leaders understand how their industries are changing.