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.

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.

Here is a look at the other technologies on the Mass General Brigham’s Disruptive Dozen list:

• 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.

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.

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."

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.

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.

“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.”

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.

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.

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."

In focus with: Sandy Macrae, CEO of Sangamo Therapeutics 

Sangamo Therapeutics’ breakthrough technology: Zinc finger (ZF) technology is a gene-editing technique with the potential to cure severe and rare diseases. Zinc finger technologies are made up of a DNA-binding domain, which can be applied with precision to any sequence of DNA and various functional domains, including nucleases and transcription factors, according to Sangamo. Their versatility and compact size make them highly vector compatible, and therefore they work with a multitude of delivery vectors making them applicable for a range of ZF-based genomic medicines — either ex vivo for cell therapy or in vivo for genomic engineering.

Why it matters: ZF technology has been in development for several decades, but with increased industry interest in various gene editing techniques, momentum in the space is quickly growing. According to Sandy Macrae, CEO, Sangamo, ZF technologies hold several key advantages over other gene editing techniques such as CRISPR.

“We've watched with fascination as CRISPR companies pop up every week with a new version of the technology. But it’s all based on one technology. Therefore, if something goes wrong, the whole house of cards will fall,” Macrae says. “So, we think having more than one way to edit seems like a very good idea.”

And as the industry moves from gene therapies to gene editing, Macrae says Sangamo represents the future of where medicine is headed.

At a glance: Although they’ve been around for more than 25 years, Sangamo is on the precipice of becoming an overnight success as interest in gene editing takes off. With four products moving into advanced-stage clinical trials based on the company’s proprietary ZF technology, Macrae is bullish on his company’s ability to transform the genomic medicine arena by applying what he calls a “Swiss army knife” approach to gene editing.

Macrae believes that in five to 10 years the conversation will have evolved from creating gene therapies to solely being about the whole field of gene editing.

Today, the publicly traded company has three main areas of concentration: gene therapy, cell therapy and genome engineering. In addition to its four key programs, one in phase 3 for hemophilia A, and three moving into late phase trials — Fabry Disease, CAR-Treg cell therapy for renal transplant and Sickle Cell Disease — the company has a robust pipeline of wholly owned and partnered products for rare disease, neurology, oncology and autoimmune indications.

To learn more about their unique approach, we caught up with Macrae, a PharmaVoice 100 honoree, who discusses the future of gene editing, the advantage of having its own manufacturing facilities and key objectives for 2022.

PharmaVoice: What is Sangamo’s secret sauce?

Sandy Macrae. Our secret sauce is our Zinc Finger platform. We want to try and move the world increasingly into genomic medicine and allogeneic cell therapy. We use the term genomic medicine broadly because our zinc finger platform can do a whole range of things with DNA. Many think of editing as cutting out a bit of DNA, but we can also use our ZF transcription factors to repress, or activate targets based on therapeutic need. We can do base editing where we take out a single letter, or we can do recombinase editing where we take out a whole paragraph. We can do all of this because the zinc finger platform is modular.

Gene therapy continues to be a hot area of interest for investors, what does Sangamo offer that’s different? 

We're blessed that we have three late-phase assets, which is all some analysts want to talk about, but we also have so many other riches. We have our cGMP AAV manufacturing facility and our CNS platform, so there’s something for everyone.

First-generation gene therapy companies, which only put simple gene therapy in the liver, are trying to find ways to get to editing technology, because that is the future. In five to 10 years, we will only be talking about gene editing – it won't be gene therapy.

Our zinc finger platform can do multiple things — I use the analogy of a Swiss army knife. Our zinc finger technology is small, it’s modular, it’s reliable, it’s been used in patients and it’s proven to be safe.

And we have an expertise that has been built over 26 years. We're sometimes poked at being an old company, but sometimes being old is a good thing in that we have years and years of experience. Some of our scientists have been with us for decades; their whole life has been dedicated to zinc finger technology, it's a total passion. They believe zinc fingers are the right way to go forward. Now we need to apply it to important problems.

The genomic medicine space is really interesting because many companies are going after the same targets as that is where we can deliver the technology – whether that’s CRISPR or Zinc Fingers. The future is all about delivery, and we’ve got to be able to deliver to a wider variety of tissues. I know that ZF always works in test tubes, always, and I know ZF works in animals. This is about engineering, not biology. We know if we can get it to the lung, we could address cystic fibrosis. We know if we can get it to the kidney, we could address polycystic kidney disease. But those vectors don't exist at the moment. And so we're limited in going to the liver and increasingly to the brain. Hopefully, eventually, soon, other ways of delivery will come about, and when that does a whole rush of genomic medicines will be developed.

One might say you have an embarrassment of riches…

Be careful what you wish for. Because most companies have a single asset and one or two candidates that are pre-IND steam, their choices are obvious in terms of their focus. Whereas I have four disparate assets either in phase 3 or moving into phase 3, all of which have good and compelling data. There are some investors who only value the company on these assets, therefore we need to be very aware of the benefits of our program and what the competition is doing.

The company recently completed the build out of a manufacturing facility, what advantages does that provide?

Why do we do manufacturing? As a product developer there is a huge advantage in having the research team and manufacturing team working side by side. When the research team comes up with something innovative and thinks the process can be easily converted to GMP, the manufacturing team can weigh in. That’s an advantage we have, particularly with cell therapy and autologous cell therapy. It's not just about the editing, the editing should be quite standard, and shouldn't be the thing that everything pivots on.

I don't think the world understands that the product is the process. What's really important, is how to take the cells from the patient, how to look after them, how to expand them, and which cells to choose to give to give back. This is one of the key areas we are working on with our Sickle Cell asset. We worked with Sanofi last year on this and we got great results. We think this process will lead to more long-term progenitors and a greater effect for patients. There are a number of cell therapy companies spinning out from academia that don't have manufacturing and their challenge is going to be ways to think about GMP manufacturing.

This is an investment; it's taken us 12-15 months to set up the facilities in our Brisbane, Calif., where we have AV manufacturing and cell therapy, and in France where we also have cell therapy manufacturing capabilities. It was a great investment and I’m glad we did it.

What are your key objectives for 2022?

It's very clear, we need to drive our Fabry trial forward and complete the phase 1/2 study. We also will do everything to help Pfizer restart the hemophilia A study, and we now need to find a good solution for our Sickle Cell asset. We will dose the first-ever patient in our CAR-Treg cell therapy for renal transplant very soon. Excitement is palpable, there are no less than seven other CAR-Treg companies behind us. But firstly, it’s about safety and we hope to share results about this trial in 2022 and 2023. These are the things that we need to do, and we must not drop the ball. It's about delivery in the scientific sense, it's also delivery in the operational sense. We are building a genomic medicine company to last so it's important that we continue to drive forward that basic science and fine tuning and improving our platform as well.

It’s only been a handful of years since the FDA issued its landmark first approval of an adeno-associated virus gene therapy. But up-and-comers in biotech have already been looking to improve upon the first wave of gene therapies and overcome its limitations with next-gen tech.

Among those generating buzz is Switzerland-based Anjarium Biosciences, who crowned Stephen Yoo as its new CEO in June. Drawing on his medical training and extensive background in helping to build growth stage biotech companies, including others in the gene therapy space, Yoo is now laser-focused on unlocking the full potential of gene therapies with the company’s non-viral delivery platform that offers several key advantages over existing tech.

Traditionally, the use of viral vectors in gene therapies has been beset by challenges associated with payload capacity, immunogenicity, targeted delivery and scalable manufacturing. Yet, Anjarium’s platform was developed to overcome these hurdles by using proprietary DNA-based gene vectors, and natural and synthetic nanoparticle delivery modalities. By combining genetic medicine, synthetic biology and nanoparticle engineering, the company says it can more effectively and durably address the underlying causes of many genetic diseases.

The prospect of Anjarium’s success excited investors enough that it raised $61 million in series A financing last year — a thick purse that Yoo is now looking to leverage wisely as the company works to expand its platform and advance its preclinical pipeline.

Before joining Anjarium, Yoo was the chief medical officer and head of R&D for Third Harmonic Bio, a clinical-stage company focused on severe allergy and inflammation. He also spent four years at Regenxbio working on recombinant adeno‐associated virus (AAV) gene therapy, as well as many years at larger biopharma companies including AstraZeneca and MedImmune.

PharmaVoice spoke to Yoo as he began establishing early objectives and getting to know the team, which he says is one of his top priorities.

“We're only going to go as far as our talent takes us, so it’s important to build a positive and empowering culture,” he says. “It all starts with communication and transparency and setting the compass for the kind of culture we want as the company grows.”

Here, Yoo shares his goals and vision for the next stage of Anjarium’s growth, what he brings to the role of CEO and the challenges that lie ahead.

PharmaVoice: What do you believe makes you a good fit to lead Anjarium?

Stephen Yoo: There are a lot of synergies from my last two roles. I’m leaning on a lot of my previous experiences of successfully building those two companies, and I believe that fits what Anjarium needs. Most recently at Third Harmonic, I was the second employee and helped to build the company from the ground up. And at Regenxbio, I was one of the first 10 employees and today that company is a leader in the AAV gene therapy space. When I started at Regenxbio, prior experience in gene therapy wasn't a prerequisite because no one had it, but now there’s so much going on in the space, so I think having the experience of working with this unique modality of therapeutics helps in terms of strategic focus and understanding where to take the company.

At both those companies, the focus was on developing preclinical or research-stage assets and transitioning them into the clinic to show whether or not they could become effective medicines. Again, at both we received approval to start clinical trials, and were able to generate positive clinical data. I also have a lot of experience in taking products from non-clinical through all stages of clinical development, and that helps us to set the compass of how to effectively use our platform to create therapeutics. It’s about building the plane as it flies.

In what direction are you looking to take Anjarium, and what steps are you taking to achieve those goals?

With Anjarium’s gene therapy platform we’re aiming to leverage gene therapy in a more predictable, effective and lasting way, for a range of genetic diseases. We have the luxury of having multiple platforms under one roof: our proprietary DNA-based gene vectors, natural and synthetic nanoparticle delivery modalities — including our novel Hybridosome delivery technology —and our manufacturing solutions.

We want to address the limitations of current gene therapy platforms and tackle more diseases more precisely. Ultimately, we’re in the drug-making business and we need to make therapeutics for patients, so we need to figure out how we’re going to take advantage of this incredible biology that we have in all our different platforms and translate that into effective and compelling medicines for patients.

Innovative, agile thinking is obviously important at a company like Anjarium. But how does your experience help you take that innovation and ensure it achieves desired outcomes?

Innovative people tend to join companies like Anjarium because they enjoy the reduced bureaucracy, the quick decision making and the ability to be in the middle of the action. At the same time, you need the proper amount of intention to help the company build the necessary infrastructure to support effective decision-making without stifling that innovative spirit. It’s a yin and yang of fostering innovation while maintaining the required processes to help build a strong foundation. It can be a tricky balance and the center changes as the company grows. Having lived through this type of growth twice helps me manage that at Anjarium.

What do you regard as the most important skill set for a leader to keep teams focused, motivated and engaged?

I’ve always focused on empowering people to do their jobs, and that starts with establishing a positive culture. Really, the two most important assets that a company has are its time and its people. How do we hire the best people and enable them to do their jobs? And then, we really have to have a sense of urgency, because patients are waiting for us to unlock this potential.

When you're a young company, maintaining alignment in the middle of the chaos that goes with growth is really important. So, we have regular conversations with everyone in the company on what's important to us. How do we want to operate? How do we put this into practice? How do we hold people accountable to our values? Transparency is essential to building a positive culture. Everyone has to know the why, not just the what or the how so everyone believes in the mission, and that tends to be very empowering.

What hurdles does Anjarium face in its quest to achieve breakthroughs in tackling genetic disease?

With the platform we have, there is a feeling that we can do anything. But the key to managing growth is developing focus. We have to balance developing a robust understanding of the capabilities of our platforms, while also defining our strategy, and how we're going to develop new medicines that will make it to patients. There will be initial drugs we develop based on the current status of our platform, but as the science continues to evolve, and we continue to expand the capabilities of our platforms, we're going to have the privilege of taking on more disease biology as we continue to expand those capabilities. It’s a balance of developing the platform to open up future opportunities and focusing on the here and now.

We’re exploring new frontiers with the technology at Anjarium. It's exciting to be at the forefront of science, to help grow the organization and to help develop and advance its pipeline strategy. Ultimately, I believe this technology will translate into really meaningful medicines for patients in the future.