Cell and gene therapies

Cell and gene therapies are a burgeoning market expected to reach $106 billion by 2033. But critical bottlenecks still obstruct the way forward to the field’s full potential, said Fran Gregory, vice president of emerging therapies at Cardinal Health. 

Cutting-edge treatments offer the possibility of a one-and-done cure if the industry can overcome access and information issues and sky-high sticker prices that have thrown the traditional pharma payment model for a loop and put treatments out of reach for many patients. Gene therapies such as Orchard Therapeutics’ $4.2 million Lenmeldy and CSL Behring and UniQure’s $3.5 million Hemgenix, now two of the highest-cost drugs in the world, are forcing payers to rethink traditional payment models.

While cell and gene therapies are often associated with cancer treatment, the more than two dozen FDA-approved treatments also include products in hematology and neuromuscular conditions, including rare diseases with no other treatment options, Gregory said. 

A Tufts Medicine consortium estimated the FDA could sign off on as many as 66 more product-indication approvals by 2032, and there could be 41 conditions with a cell and gene treatment option by 2027. Potential new technologies, such as off-the-shelf, allogeneic and in vivo CAR-T options are progressing and may offer advantages over traditional CAR-T cell therapies. 

To make this happen, manufacturers need provider and patient buy-in, which will require safety, access and affordability guarantees.

Barriers to uptake

Many cell and gene therapy treatments are only available through manufacturer-certified providers or facilities — typically academic medical centers in cities that may be far from prospective patients. Gregory said access is limited because it’s often too hard for patients to travel to the treatment site. 

To make matters more complicated, local doctors may sometimes be reluctant to give up a patient, preferring to treat them in-house. In other instances, doctors and patients don’t know the therapies are an option.

Patient out-of-pocket costs also vary dramatically. 

“It’s really all over the board,” Gregory said. “Sometimes patients have low out-of-pocket costs, and some patients face huge financial burdens.”

Affording treatment may be impossible for some, depending on their insurance coverage, although some foundations offer financial assistance. 

Manufacturer-sponsored programs help others, but not those with government-funded insurance, such as Medicare or Medicaid, Gregory said. For example, because Medicaid coverage is determined independently by states, two Medicaid patients with the same condition might have different treatment access. 

Solutions on the rise

“As this market evolves, we're finding a lot of solutions to a lot of these problems,” Gregory said. 

Among them, the Centers for Medicare and Medicaid Services has instituted the Cell and Gene Therapy Access Model, which is slated to roll out in January, aiming to forge value-based agreements between states and cell and gene therapy companies to reduce prices and create outcome-based payment incentives. 

Gregory supports asking manufacturers to clarify medical necessity guidelines. Individual companies such as Kite aim to certify more community oncology practices, where most cancer patients seek treatment.

Cardinal Health is taking steps to help manufacturers work with payers earlier in the process, giving them information about cost, risks and benefits to prepare products hitting the market, Gregory said. 

“If you look online and try to figure out if these products are covered for certain payers or certain health plans, it's very difficult to determine,” she said. “Clarifying treatment guidelines and medical necessity guidelines would save healthcare providers and patients a lot of time.” 

Innovative payment models could permit installment payments or offer warranties or rebates if the treatment fails. 

“We've got to figure out how manufacturers and payers can work together to mitigate that huge one-time cost to their health plan,” Gregory said.

The field will likely make big strides in the next few years. 

“I think we'll continue to see the FDA supporting cell and gene therapy products, which is exciting,” she said, but progress will depend on investors, payers and healthcare community backing. 

“These are amazing products, life changing and life-saving in many cases, so they’re something we want to continue to support,” Gregory said.

CAR-T cell therapies offer many cancer patients a shot at a cure, but the technology comes with some critical drawbacks. Treatments are complex, costly, time-intensive and often inaccessible. They require invasive procedures and present serious risks.

In vivo CAR T-cell therapy could be a game-changer in a global market projected to reach $88.5 billion by 2032. The investigational technology sidesteps external manufacturing, instead using a gene vector to modify immune cells inside the body. This could eliminate many drawbacks of both autologous CAR-T and experimental off-the-shelf allogeneic treatments, enabling cell therapy to reach more patients and new indications including autoimmune diseases, where it has shown significant promise.

“If in vivo CAR-T pans out and we're able to retain all the all the positives, particularly the powerful efficacy of a living drug . . . but do away with all the limitations, autologous and even allogeneic CAR-T could become obsolete, and should become obsolete,” said Dr. Ramin Farzaneh-Far, chief medical officer of Capstan Therapeutics. “That’s really the vision, to retain all the pros and do away with all the cons.”

The field is moving ahead quickly, with as many as four companies rumored to publicly disclose an IND this year or next, according to David Fontana, chief operating officer at Umoja Biopharma, an early-stage CAR-T cell therapy company. 

“I'd like to believe we’ll be first,” Fontana said. “We are confident we're going to be in the clinic this year.”

Rethinking the approach

Since 2017, the FDA has approved six autologous CAR-T cell therapies for blood cancers. Treatments require a multi-step process of harvesting T cells from the patient, reprogramming them to find and destroy cancer cells, and then multiplying and reinfusing them. 

Due to the slow manufacturing process and capacity bottlenecks, some patients die before the treatment can reach them, and quality varies, depending on the health of extracted cells. Patients undergo chemotherapy to eliminate existing T-cells before infusion, which provides a fresh canvas for the new cells but raises the potential for complications, including life-threatening infections.  

Avoiding chemo could help in vivo CAR-T improve outcomes, Fontana said. Eliminating the need for chemotherapy could also expand CAR-T’s applications. 

There’s rising interest in using the technology to treat autoimmune diseases, such as lupus, triggered by a malfunctioning immune system that mistakenly attacks healthy tissues. CAR-T has shown dramatic results in calling off this immune system attack in some patients, putting the disease into a drug-free remission. 

However, due to its risks, traditional CAR-T will likely only be an option for people with severe illness. Capstan aims to change this and treat more patients with its lead in vivo CAR-T therapy, CPTX2309, an autoimmune candidate, which recently secured $175 million in a series B financing.

In vivo CAR-T could also democratize treatment access and allow developers to tap into a large underserved patient population, said Fontana. Only 20% of U.S. hospitals offer autologous CAR-T, which means the vast majority of cancer patients, even those who could benefit, go without. In vivo treatments could be manufactured and stored in hospitals or distribution centers and may be easier to administer, allowing more sites to offer treatment within and outside the U.S. 

At least one autologous company has made moves to overcome some of these logistical challenges. Gilead’s Kite Pharma, which manufactures Yescarta and Tecartus, is working to speed up manufacturing times and bring CAR-T into more community oncology practices. Others, such as TG Therapeutics, which recently acquired an allogeneic CAR-T candidate from Precision Biosciences, are pursuing off-the-shelf therapies, using donor cells to hasten treatment and improve quality. Still, allogeneic treatments face unique challenges, such as keeping the patient’s immune system from attacking foreign cells. 

Facing challenges

In vivo CAR-T also faces challenges that include scaling the production of treatment components such as engineered viruses and synthetic genetic material. The field also needs to sort out the best technological approach. 

A handful of startups including Ensoma and Exuma Biotech are testing in vivo CAR- technology using gene vectors such as lentiviral or adeno-associated viruses, and non-viral platforms such as lipid nanoparticles or nanocarriers, according to Fran Gregory, vice president of emerging therapies at Cardinal Health.

Farzaneh-Far believes Capstan’s delivery method, using a lipid nanoparticle similar to those used in COVID-19 vaccines, may have an advantage over companies using adeno-associated viral vectors, which he said carry potential safety concerns. Using AAVs in vivo could be toxic to the liver or brain and could potentially cause thrombotic microangiopathy, a condition marked by blood clots in small arteries and capillaries, Gregory said. 

“Non-viral vectors like lipid nanoparticles or nanocarriers may help but this is still being studied,” she said.

The success of in vivo technologies will also hinge on whether developers can find ways to mitigate adverse events, including those common to CAR-T, such as neurotoxicity and cytokine release syndrome, Gregory said. 

“Developers also need to prevent off-target transduction and ensure only target cells are affected,” she said.

Umoja decided to focus on the CD-22 molecule to test its technology and avoid the additional risk related to an unfamiliar target. This molecule has shown efficacy in people who have failed to respond to CD-19 targeting CAR-T treatments, such as Kymriah, Fontana said. 

“There’s clearly an unmet medical need because there is nothing available for those patients,” he said. Once the technology is proven, the doors can swing open to new in vivo CAR-T indications, Fontana said, including solid tumors.

For now, the most formidable barrier for in vivo CAR-T is the unknown. While companies have seen promising early results in non-human primates, monkeys aren’t people. 

“The field will change dramatically if one of us shows that this can work,” Fontana said. “This field has progressed probably quicker in the last two years than anything I've seen.”

Next year may be pivotal, showing whether in vivo CAR-T cell therapy holds transformational potential or needs more tweaking, Fontana said. 

“I feel pretty confident by this time next year, there's going to be at least a couple of us out there with data,” he said.

Setbacks and controversies have dogged the search for treatments for Duchenne muscular dystrophy, a degenerative muscle-wasting disorder. 

Last week, Pfizer axed its program for the DMD drug Ciffreo, which failed in phase 3. 

Sarepta Therapeutic’s drug, Elevidys, the first approved gene therapy for the condition, has had brisk sales of $334 million since the FDA approved it in June 2023 and recently granted it a substantial label expansion. But it’s also beleaguered by controversy such as underwhelming trial data, which raised questions about the efficacy of the treatment that carries a $3.2 million price tag for a single infusion.

There is a bright spot amidst the tumult, however. Capricor Therapeutics, a California-based biotech, recently announced its investigative treatment, deramiocel (CAP-1002), slowed Duchenne progression by almost 50% in patients who had taken the treatment for three years as part of its ongoing phase 2 HOPE-2 open-label extension study, according to Linda Marbán, Capricor’s CEO. Notably, the drug improved heart function in patients who developed an often-fatal form of cardiomyopathy that currently has no approved treatments. Patients in the trial saw a global improvement in ejection fraction, which is the gold standard of cardiac function, she said. And patients with the healthiest hearts at the start of the trial saw the most significant improvement.

The DMD challenge

A gene mutation that triggers a deficit in the muscle-protecting protein dystrophin causes DMD. Because the mutation is on the X chromosome, the disease predominantly affects boys who are usually slower to meet movement milestones than their peers and start to lose abilities around their second or third birthday. The condition also leads to progressive, often fatal, heart and respiratory problems.

The FDA has approved several DMD drugs since 2016 in a market anticipated to reach $18 billion by 2030. Many of them are exon-skipping drugs, which bridge sections of faulty genetic code to help restore some dystrophin protein production. 

Regenxbio is also testing a gene therapy, RGX-202, which recently produced positive findings in its ongoing phase 1/2 trial. The treatment appeared to prompt the expression of a shorter but similar version of dystrophin called microdystrophin. Some treated patients saw expression increase as much as 77% compared with controls after three months. It’s not clear, however, if that increase will translate into functional improvements. The company plans to release strength and functional assessment data in the second half of 2024.

Slowing progression

Unlike many of these treatments, Capricor’s phase 3 allogeneic cell therapy doesn’t target the underlying cause of DMD but still aims to slow disease progression. The treatment modulates the immune system to soothe inflammation, reduces fibrosis and helps cells replicate and repair damaged tissues. It could also bolster other therapies and offer an advantage over steroids because it appears to produce few, serious side effects, giving it potential as a long-term treatment. 

“One of the best things about this therapeutic is how safe it is,” she said. 

Even after multi-year doses, most patients report mild symptoms such as body soreness or headaches following infusions. The treatment, which Marbán said will likely be priced around $1 million a year, similar to exon-skipping drugs, could help keep patients healthier longer. 

“We're treating patients that are already on maximal steroid dosing, and we're still seeing additional benefits. We're seeing additional preservation of function, ability to maintain and perform tasks that they either have lost or were in the process of losing,” she said. “That's because with [the] breakdown of the proteins from the cellular destruction you need something to attenuate that inflammation and prevent fibrosis.”

The company is now awaiting phase 3 data for the allogeneic cell therapy, expected at the end of 2024. If all goes as planned, company leaders could apply for a biologics license application by mid-2025, Marbán said. Capricor is also exploring similar conditions that could benefit from the treatment, Marbán said. 

“We're looking very closely at Becker muscular dystrophy as our next target,” she said. 

The company’s second-generation DMD product, CAP-2003, which Marbán hopes will produce better results than current technology, is in preclinical development. 

While cell and gene therapies represent some of the most exciting scientific breakthroughs in pharma, they’re not always a commercial success. 

One of the biggest obstacles to uptake has been cost, with each new gene therapy out-doing the last in terms of price. For a successful launch, a game-changing innovation isn’t always enough, and developing a sound commercial strategy is critical even when therapies are still in development. 

Internal alignment across the organization during clinical development and nimbleness in the growth stage should be top priorities, according to executives from Bayer, Kite Pharmaceuticals and Orca Bio, who shared their best practices during a virtual discussion at the ThinkLive Cell and Gene Therapy Summit 2024 last week.

Commercial considerations from the top

In the last few years, Bayer has jumped headfirst into the cell and gene therapy space, laying down $600 million to acquire BlueRock Therapeutics in 2019 and picking up Asklepios BioPharmaceutical in a $4 billion deal in 2020. 

“We're focusing on Parkinson's disease and chronic heart failure,” Doug Danison, head of commercial for the cell and gene therapy unit, said during the panel. “And as you can imagine, those are relatively large indications for a large number of patients. So that impacts how we think about preparing our commercial strategies.”

When there are treatments with “reasonable outcomes” available, Bayer centers on therapies “that will change [a] person’s life.”

“You need to understand those patients, look at what their current outcomes are, and then design a robust evidence generation package around selling both within a clinical trial and outside the clinical trial,” he said. 

Understanding the costs, profit potential and value proposition to a larger indication, and zeroing in on that business model early is the best bet, he said. 

Engaging payers and providers

Orca Bio, which is currently in mid- and late-stage studies for cell therapies targeting blood cancers, is concentrated on trial design with commercialization in mind. Namely, Dan Kirby, lead commercial at the biotech, is much more hands-on in his approach. He tapped Orca’s external stakeholders, seeking feedback on what endpoints are most valuable in randomized trials that would ensure coverage for patients. The commercial team also asked physicians what is needed from a clinical standpoint to justify cell therapy over standard care.

“We took all of that feedback as we renegotiated with the FDA on our trial design,” Kirby said. “As you think about registrational trials … it's making sure you're going to prove the right points with your trial, because when you get to the other side of commercialization, that's going to make a successful launch.”

The company is currently balancing its phase 3 leukemia candidate, Orca T, with newer assets within the academic community. Getting feedback from the academic community and other stakeholders is crucial to understanding the capabilities of the provider, as well.

“We feel like we've been around for a while, but you're introducing change into their system, and no two cell or gene products are identical,” he said. “But you need to get the feedback from them early from the provider standpoint and of course, the payers, the advocacy groups and the physicians.” 

Danison echoed the importance of connecting with payers and understanding how treatments will be administered.

“We all engage with payment centers differently based on what's required for our products … [to] understand how they will bring that treatment through the treatment center,” Danison said.“The more you can understand that early on, you should have a better chance to be able to get the market in a better circumstance where they know how things work.” 

Leadership at Kite Pharmaceuticals, which is owned by Gilead Sciences and has a pipeline of CAR-T cell therapies in oncology, puts science at the forefront for commercial discussions.

“I would encourage folks to avail themselves of early scientific advice wherever possible, so that you're going into your payer discussions clear-eyed,” Ted Slocomb, vice president of global commercial strategy, value and access at Kite Pharma, said during the discussion.

Internal best practices

Internal alignment has been essential for Orca Bio, which focused on goal-setting on a quarterly basis with the leadership team in addition to longer-term planning meetings. As it’s grown from a small, close-knit group, the meetings have covered each function of the expanding leadership team, tracking progress of their objectives and remaining nimble.

“In this market, and being a smaller company, you always have to make sure you're doing trade-offs and managing your cash burn,” Kirby said. “That really helps visibility across the organization that we're not spending too much in commercial but then letting operation sacrifice. It's a very good way … to align to our priorities and make sure that we're spending our resources where we need to bring these products to patients.”

Beyond keeping company leaders close, Orca is also delivering on differentiation.

“As you look at the emerging number of companies and what they're working on, there's tremendous tech out there,” Kirby said. “And you have to make sure [you’re] focused on what you're doing to commercialize, what's in front of you.”

For a company like Bayer, managing wholly owned subsidiaries is a different ballgame, according to Danison, who identifies which decision makers are needed to ensure commercial input is involved in the treatment and clinical trial plans. Creating one aligned voice between Bayer and its subsidiaries is the goal.

“In a bigger company, there's a tendency to have everything functionally led,” he said. “For us, it's constantly trying to bring the cell and gene therapy team together cross-functionally and providing a uniform perspective on what needs to happen with medical marketing, market access and actually with selling gene therapy.”

In addition, Danison said his job is to ensure that teams can “make decisions among themselves” while allocating resources within their budgets. 

“If [the product team doesn’t] get that money early on, they're not going to be set up for success in the future,” he said.

Kite has found that leveraging a team approach is best for launching cell therapies. The biotech has two approved therapies — Yescarta and Tecartus — that treat lymphoma, in addition to the candidates in its pipeline.

“We like to say cell therapy is a team sport,” Slocomb said. “It's critically important to have your commercial people coordinating well with your medical people.”

CAR-T cell therapy makers are on their way to finding a footing in the autoimmune disease space, and companies like Kyverna Therapeutics are targeting rare disorders with limited treatment options.

After winning several approvals in oncology, an arms race is underway to bring the technology to the autoimmune diseases with several companies, including CRISPR Therapeutics and Novartis, developing therapies for lupus. While CAR-T comes with several challenges in cancer, researchers are hopeful that autoimmune patients will fare better with fewer side effects.

“CAR-T therapy as a scientific approach is completely the right way to look at autoimmune disease, to just eliminate those B cells that are making antibodies against you and causing all these autoimmune diseases,” said Dr. Sham Dholakia, business unit head of rare disease at Kyverna. “And it's the perfect target by using your own cells to get rid of the problem.”

But Kyverna is venturing into a more obscure autoimmune disease — stiff person syndrome — as well. The disorder causes muscles to lock up and become stiff, as well as painful spasms and other symptoms, and is extremely rare, affecting around 5,000 people in the U.S. There are currently no therapies that target the underlying disease, and only treatments for symptoms. The most commonly used options include painkillers, anti-inflammatories, muscle relaxers and intravenous immunoglobulin, according to Dholakia, who said more options for autoimmune diseases are needed.

“If you take Infliximab for long enough, or if you're taking kinase inhibitors for long enough, if you read the labels of all of these drugs that are approved for inflammation as a result of autoimmune disease, their side effects are pretty terrible,” he said.

The disease gained media attention after popular singer Celine Dion announced her diagnosis in 2022. More recently, Dion shared how the disease impacts her life in a documentary released on Amazon Prime in June.

Kyverna is planning a phase 2 trial of its CAR-T cell therapy KYV-101 to treat stiff person syndrome, which was given fast track and regenerative medicine advanced therapy designations from the FDA. All told, KYV-101, Kyverna’s lead candidate, is being tested across eight designations, including multiple sclerosis and myasthenia gravis. Kyverna aims to enroll 20 to 30 patients in the trial for stiff person syndrome, according to Dholakia.

We caught up with Dholakia to dig deeper into the autoimmune CAR-T pipeline and what the company has learned from the oncology space.

This interview has been edited for brevity and style.

PHARMAVOICE: Why is Kyverna targeting stiff person syndrome given its very small patient population?

DR. SHAM DHOLAKIA: A lot of CAR-T therapy has been developed on the wings of oncology, but what we found is that with that approach, there are a lot of side effects. Patients' immune systems [are] very fatigued once you've had therapy, once you've had cancer — the normal cells that you have in your body don't work so well and they're exhausted. When you now look at the autoimmune patient overall, apart from the era targeting your own cells, the rest of the immune system is OK. And so this creates an opportunity to get all of the cells that you need at much lower volumes, but also much healthier. We can now use that same sort of immune reset approach to create significant impact. 

A lot of the diseases currently are treated with drugs that are looking at symptoms or symptomatic care, trying to reduce pain, trying to improve ability to move muscles, or trying to reduce inflammation. But the underlying problem is the antibody that's being made by your body [works] against your body, and no one's really addressing that. We feel this is an overdue approach. 

Right now, there isn't any CAR-T therapy approved for any autoimmune disease, and that's across any company around the world. So we want to set a precedent [that] this is possible. 

Commercialization plans are considered much earlier in the process these days, including in clinical trial design. How are you thinking about commercialization at this stage?

The great thing is that we have a playbook from oncology. There are several approved CAR-T therapies in oncology, [which gives] a sense of cost effectiveness [and] payer strategies. It creates a landscape for us to curate and optimize. 

We also think [there are] some similarities and synergies to what we're doing in terms of the approach of resetting an immune system and creating significant improvement for a patient that would otherwise be chronically ill. Those thoughts are all working in parallel, and being embedded into the protocol to make sure we're collecting data that's going to support not only the approval of KYV-101, but make sure it’s accessible to patients.

What are some of the lessons from the oncology playbook you’re using in drug development?

The oncology patient is in a completely different starting position in terms of what they're dealing with, and the amount of side effects that people have seen on oncology is different, and the outcomes for patients are also different. Overall, compared to oncology patients, [our patients are] much healthier, apart from that autoimmune disease we're targeting. That gives us a massive ability to create a lot of benefit for patients and [minimize] adverse outcomes.

All CAR-T therapy patients are being surveyed for the longer term. What's really important here is that we've done a lot of work understanding the right dose to get a benefit without giving too much [while not] giving too little and then having to re-dose. That fine tuning is really important, because that now creates a one-and-done approach.

What’s the impact of Celine Dion’s public diagnosis?

Overall, it's a good thing for patients. It's a very heterogeneous disease. A lot of patients have been hanging on the wayside, waiting for a formal diagnosis and are not sure how to go for help with the right medical providers. [Dion] has given a lot of visibility to the disease, which is a good thing. 

What’s the future of CAR-Ts in the autoimmune space?

We used to treat rheumatoid arthritis with gold injections, and now there are 56 drugs approved for rheumatoid arthritis. It's still a multi-billion dollar opportunity because people are having progressive disease, because they keep failing all of these biologics. The science is finally good enough that diseases like that and now other autoimmune diseases, where the primary driver is this error in antibody production, can be reset. I think that's an amazing opportunity. It's going to change medicine forever. 

In the longer arc, we'd love to be able to say that the incidence and prevalence of these diseases are not going to be as bad as they are today because [CAR-T] therapies are going to make a significant dent and help a lot of people.

After decades being known for its work in the reproductive health space, Ferring Pharmaceuticals has spent the past year expanding its focus and reach after the approval of two “firsts” in high-profile areas: gene therapy and the microbiome.

The privately held Swiss company scored two big FDA approvals at the tail end of 2022. There was the recurrent Clostridioides difficile (C. diff) treatment Rebyota, which became the first FDA-approved fecal microbiota product. A few weeks later came the nod for the vector-based gene therapy Adstiladrin, the first approved for bladder cancer.

Despite these two new products, Ferring’s current late-stage pipeline is otherwise focused on reproductive medicine and maternal health. According to Ferring’s U.S. president Brent Ragans, Rebyota and Adstiladrin — and their corresponding therapeutic areas — aren’t a pivot away from those areas, but rather a broadening of focus.

“I think strategically, it’s a broadening. It gives us two new, innovative platforms to develop,” he said.

First is the microbiome platform, which Ragans said is initially focused on gastroenterology and recurrent C. diff infection. Earlier this month, Ferring announced a research and development collaboration with Zürich-based microbiome translation company PharmaBiome to develop new microbiome-based therapeutics in gastroenterology.

However, Ragans said the microbiome “extends far beyond the initial proof of concept indication” for Rebyota, with potential future focus areas for Ferring in the vaginal microbiome and “applications as adjunctive therapy, potentially in different types of cancer.”

Similarly, Ragans called Adstiladrin a “beachhead in uro-oncology” for Ferring.

PharmaVoice spoke with Ragans about Ferring’s expanded strategy for new products and its ongoing focus on maternal and reproductive health.

This interview has been edited for brevity and style.

PHARMAVOICE: How is Ferring continuing its reproductive health focus?

BRENT RAGANS: We are steadfastly committed to reproductive medicine. Our products are in over 100 countries, so this is an area that is of continuous interest for us. We continue to develop better therapies [and] a broader portfolio in what is already a very complete portfolio for most stages of IVF and infertility care.

But as we look to the future, we will continue to invest in this new research. For example, male infertility is an area that has had very little attention, and male factor infertility represents, as you might expect, about 50% of the infertility patients in the country. We’ve begun some trials in this area for idiopathic infertility with men and improving sperm quality.

On the other side, I would say it is about things that are unrelated to just innovating therapies. We consider ourselves the leader in reproductive medicine. It's important for us to continue to innovate in areas beyond just the therapeutic. So for example, things like Fertility Out Loud, which is helping people navigate their family-building journey. This is really a program that has nothing to do with brands and was launched in conjunction with Resolve: The National Infertility Association. It’s a social community platform for aspiring parents to speak out, to get information, to learn and to support them through their journey.

Can you talk about the commercialization strategies for Rebyota and Adstiladrin?

We launched [Rebyota] right around a year ago. Really, the commercialization strategy was very much about education and access at the beginning, and continues to be to some extent. Any time you’re first in an orphan indication there's a whole lot of simply educating the community. We spent a lot of the first part of last year and into the middle of last year doing just that and ensuring reimbursement and access to care was there, as well as educating the provider network. Today, we have much more focus, both in institutional and hospital settings as well as in community practices, of what I would call a more traditional commercial approach.

For Adstiladrin, the manufacturing of gene therapy-based products is not simple, and in and of itself is high risk. So while we did receive approval last year, this was not made commercially available to patients until the end of the third quarter of 2023. So it's still quite early in the game. Our commercial approach has been very much to focus specifically on urologists and uro-oncologists who are treating these patients.

How has the reimbursement landscape been for those products?

The good news for us on Adstiladrin is in the intervening period between approval and making the product commercially available … because it was included in the NCCN guidelines, we've been able — both commercially as well as from a Medicare viewpoint — to establish very strong reimbursement from launch.

With Rebyota it took a little more time. But today I would say yes, we have both the commercial as well as Medicare's support of this product in a good way.

These were both firsts following fast-track and breakthrough indications, so as one would expect, making those available to patients who are clearly in need is a priority for us, and I think we've been able to accomplish that.

How has being a private company worked to Ferring’s advantage with these and other products?

As a privately owned biopharmaceutical company, it does enable us to do things that we otherwise wouldn't be able to necessarily do and to pursue therapeutic areas for development projects that may take longer than the market might tolerate for a publicly traded company.

Adstiladrin had several setbacks. It was not approved the first time around, and we had lots of work to do to get this product, from a CMC [chemistry, manufacturing and controls] standpoint, ready for market. So I think we have a very current example where other [companies] may not have elected to continue. But we have this relentlessness and this long-term view. This is not about the next quarter or the next month. This is really about building a sustainable company that is committed to developing these life-changing therapies.

Astellas Pharma is gearing up for the grand opening of a $70 million, 154,00-square-foot research hub in San Francisco to streamline the company’s infrastructure as it dives deeper into R&D for cancer and rare diseases. 

The move is apt for Astellas — one of the largest pharmas in Japan — as it extends its reach into new modalities like gene therapies.

“Ten years ago, we didn’t work on gene therapies,” said Yoshi Shitaka, the company’s chief scientific officer. “Now we are expanding the modality scope beyond small molecules and biologics.”

Like many major pharma companies, Astellas has evolved with the industry’s shifting tides into more complicated and specialized therapeutics — a journey that’s led them to deliver a number of recent wins.

Last year was particularly fruitful, Shitaka said, pointing to a positive phase 3 readout for zolbetuximab, an investigational cancer therapy aimed at HER2-negative, CLDN18.2-positive tumors. CLDN18.2 has become a particularly sought-after target among drug developers, and the demonstration of progression-free survival for zolbetuximab in combo with chemotherapy has put Astellas at the front of the pack to receive an FDA nod for the first-in-class monoclonal antibody.

But the company hit a snag in January when the regulatory agency rejected Astellas’ BLA due to “unresolved deficiencies” with a third-party manufacturer.

“We remain confident in zolbetuximab’s clinical profile and potential to fill a significant therapeutic gap for those diagnosed with advanced gastric or GEJ cancer whose tumors are CLDN18.2 positive,” Astellas’ senior vice president and head of immuno-oncology development, Moitreyee Chatterjee-Kishore, said in a release which noted that the rejection was not due to safety or efficacy reasons.

Astellas also made a splash in the women’s health space last May when its drug Veozah became the first NK3 receptor antagonist approved to treat hot flashes and night sweats in menopausal women.

Moving forward, Shitaka said the company’s pipeline development will focus on five core areas: immuno-oncology, gene therapy, targeted protein degradation, cell therapies and mitochondrial biology.

And through its bustling R&D efforts and a flurry of deals, Astellas is aiming to close any remaining holes in its development plans.

The gene factor

Astellas is looking beyond its cancer focus to forge into gene therapies, but the journey hasn’t all been smooth sailing. 

In 2021, four patients died in a study testing its gene therapy AT132 for X-linked myotubular myopathy, a rare neuromuscular illness, prompting an FDA hold on the trial. Late last year, the company said an investigation found an underlying liver condition in the four patients and that it’s working with the agency to get the hold lifted.

Rather than being deterred, Astellas is leaning into its gene therapy plans. In addition to the new research hub in San Francisco, the company opened a large-scale gene therapy manufacturing facility in North Carolina in 2022.

“Most gene therapy companies are outsourcing clinical trials and manufacturing [but we] made a decision to internalize it,” Shitaka said. “That differentiates us.”

With these development plans in place, Shitaka said the remaining gaps Astellas wants to fill are related to technology capabilities — a challenge it’s tackling through partnerships.

In 2019, Astellas acquired Audentes Therapeutics, which handed the company AT132, alongside an AAV gene therapy technology platform and manufacturing know-how.

More recent deals are aimed at bolstering capabilities in the company’s other focus areas, such as its match-up with Cullgen, announced last year, which will advance R&D into targeted protein degraders.

On a personal level, Shitaka said he is focused on using emerging technologies to enhance drug development, especially after the company was able to shorten the optimization period for small molecule development from one and a half years to seven months using AI.

“I’d like to [advance a] new stage of the AI and digital transformation in the R&D process,” Shitaka said.

On a roll in oncology

While venturing into new areas like gene therapy, Astellas has continued to fuel its growth engine with blockbusters and innovative oncology treatments.

In November, the FDA signed off on a significant label extension for Xtandi, which Astellas developed with Pfizer, that made it the only androgen receptor inhibitor approved for patients with nonmetastatic castration-sensitive prostate cancer — and the only novel hormone therapy that treats three kinds of prostate cancer. The nod could elevate Xtandi, which pulled in about $5.9 billion in 2022, to the new standard-of-care option, the company said in a release.

April marked another oncology score when Astellas won an FDA nod for the antibody-drug conjugate enfortumab vedotin (sold under the brand name Padcev) it developed with Seagen to treat bladder cancer. 

Later in the year, the companies also released results from a trial testing the ADC in combination with Merck & Co.’s Keytruda in urothelial cancer, which they called “groundbreaking” for achieving progression-free survival rates not previously seen in a “broad population of patients.” 

“We got a standing ovation at ESMO,” Shitaka said of Astellas’ results presentation at the European Society of Medical Oncology meeting.  

For its next oncology act, Astellas is advancing selective KRAS degraders leveraging targeted protein degradation technology for “aberrant proteins” in cancer once deemed undruggable. The company’s lead asset using targeted protein degradation, ASP3082, is in early-stage clinical trials for pancreatic, colorectal and lung cancers with the KRAS G12D mutation.

The race to bring KRAS-targeting drugs to market has intensified in recent years, and in 2021, Amgen got across the finish line first with an accelerated approval for non-small cell lung cancer.

But those drugs inhibit KRAS, Shitaka said, pointing out that the beauty of Astellas’ KRAS degraders is that they could trigger “fewer adverse events.” Proving the technology, he said, is a holy grail.

Gene editing technologies have come a long way in a short period of time. 

After about a decade in development, CRISPR is now widely known as a revolutionary gene editing tool potentially offering a wide range of curative treatments. And with the first-ever FDA approval for a CRISPR-based treatment today — Vertex Pharmaceuticals and CRISPR Therapeutics’ Casgevy for sickle cell disease — it’s also one of the buzziest sectors of pharma, already raking in billions in investments and triggering a new drug development heyday. 

The roots of this biotech bonanza trace back to the 1980s when Japanese scientists studying E. coli discovered the DNA sequences now known as CRISPR, which stands for clustered regularly interspaced short palindromic repeats. Decades passed, however, before researchers learned how to harness the discovery to develop therapeutics. 

One of the critical step changes in this scientific saga came from insights derived from a common refrigerator item: yogurt. In the early 2000s, researchers at the dairy company Danisco attempted to understand why some yogurt cultures were attacked by viruses and observed that the DNA sequence within the CRISPR of the resistant bacteria matched that of the invading virus. The discovery that CRISPR was part of the bacteria’s “adaptive immune system” also illuminated how a CRISPR-associated protein (Cas) could “remember” past viral invaders and attack them when they reappear. 

In the years of research that followed, two molecular biologists — Jennifer Doudna and Emmanelle Charpentier — discovered that the protein Cas9 could be used to snip DNA with precision. They published their Nobel Prize-winning work in 2012, giving rise to the CRISPR era. 

While other gene editing technologies such as zinc finger nucleases were already in development when CRISPR hit the R&D scene, the newcomer offered a less expensive and more efficient approach. 

“CRISPR is a phenomenal technology,” said Jen Klarer, partner and head of cell and gene therapy at The Dedham Group, a consulting agency focused on oncology and specialty therapies. “There is a lot of promise [with CRISPR] and it comes down to how genes are edited with such high specificity.”

Dozens of companies have now sprung up to leverage CRISPR, including Editas Medicine, Caribou Biosciences, Intellia Therapeutics, Beam Therapeutics and CRISPR Therapeutics, which won U.K. approval for Casgevy last month. 

Researchers are also investigating many high-profile disease targets for CRISPR, including AIDS, Huntington’s disease, several types of cancer, cystic fibrosis, autoimmune conditions and infectious diseases like COVID-19. 

After Casgevy, the next most advanced candidate in the pipeline is Regeneron and Intellia’s treatment for ATTR amyloidosis, greenlighted for a phase 3 trial in the U.S. in October.

Some companies are exploring how different enzymes such as Cas12 and Cas13 could overcome challenges in delivery and off-target effects. Others are advancing candidates that work in vivo as opposed to ex vivo therapies like Casgevy.

And even though CRISPR has revolutionized the field, several gene editing approaches are still being investigated. 

“There are a lot of technologies being studied that are medically and clinically impressive,” Klarer said. “We need a lot of years of exploration in this space. There’s not one turnkey solution for all the diseases. The human genome is complex so certain modalities will work better and time will tell which modality works for which disease.”