Cell and gene therapies

For patients in need of revolutionary CAR-T cell therapies, time is not a luxury. And even though they offer a shot at a cure, the time it takes to manufacture a treatment can be a matter of life and death. 

To speed delivery of its personalized immunotherapy Yescarta, Kite Pharma recently got the FDA to sign off on a new manufacturing process that will shave two days from its median turnaround time. 

“It’s really exciting because these patients have an aggressive disease, and every day matters,” said Cindy Perettie, executive vice president at Kite, which is a part of Gilead Sciences.

The manufacturing process for CAR-T therapies is complex. It starts by extracting the patient’s white blood cells, which are then modified to produce surface proteins called chimeric antigen receptors that help immune cells target the patient’s cancer. It takes upwards of 18 people to carry out the various manufacturing steps, Perettie said.

Kite officials expect it will now take around 14 days from a patient’s cell collection to infusion — a reduced timeline that not only helps patients, but gives the company an edge over competitors. It may also position the lymphoma therapy to withstand competition from a crop of “off the shelf” allogeneic treatments working their way through the pipeline, said Perettie. Allogeneic treatments use donor cells to create a less expensive option that don’t require cell collection from the ill patient, but can trigger an immune reaction, which has hampered development.

Even with an off-the-shelf option, patients can still wait weeks for a scheduled treatment, and Kite aims to further whittle down the turnaround time, Perettie said. 

“There’s this sense of urgency. Every patient matters. Every day matters. And that's allowed us to get to this industry-leading manufacturing turnaround time and we're not going to stop here,” Perettie said. “We have another set of efforts ongoing and I hope by the end of the year, we're able to announce again that we can shorten it even further.”

Innovating next-gen approaches

Gilead acquired Kite in 2017 for $11.9 billion to bolster its market position in cell therapy. Perettie said the deal gave Kite the best of both worlds, allowing it to remain separate but giving it access to Gilead’s extensive resources. The company kept its singular focus on CAR-T, sparing it from having to make portfolio tradeoffs that detract from its mission. 

“We have the opportunity to solely focus on CAR-T, and I think that has allowed us to serve more patients,” she said. In addition to Yescarta, Kite has a second approved CAR-T therapy, Tecartus, for patients with relapsed or refractory mantle cell lymphoma and acute lymphoblastic leukemia.

To date, Kite has treated more than 19,500 patients with its CAR-T therapies. The goal now is not only speed but broadened access. Currently, only 2 in 10 American patients who could benefit from CAR-T get the treatment, Perettie said. 

“This is a potentially curative therapy for almost half of the patients. It’s insanity to me that we’re unable to reach more patients,” she said. 

Because CAR-T treatments are only administered in authorized facilities — there are 135 in the U.S. and 400 worldwide — oncologists sometimes don’t offer it. Most authorized centers are academic medical centers, but the majority of people with cancer — 70% to 80% are treated in community practices, Perettie said. 

Kite is building partnerships with hospitals that are affiliated with community oncology practices to give more patients access and to encourage treatment referrals.

New disease targets

Kite officials also want to improve their existing CAR-T treatments and broaden their applications. 

“The last five years have been absolutely amazing,” Perettie said, adding that the company aims to maintain its market leadership and serve more patients. 

“Part of that has been focused on expanding both our Yescarta and Tecartus labels so that we can move into earlier lines,” she said. 

Data shows survival rates rise when the treatment is started sooner, possibly because harvested cells and the patients are healthier, so gaining approval to start treatment earlier is a goal. 

Kite is also working to improve its existing therapeutics and is exploring three modified versions of Yescarta aimed at improving safety and efficacy, Perettie said. 

“We have three constructs that are in phase one right now and we're going to pick the winner at the end of the year, and rapidly advance it,” she said. “The early data looks quite promising.”

CAR-T therapy safety recently got additional scrutiny when the FDA moved to require a black box warning on CAR-T treatments to alert patients that they may trigger secondary T cell cancers. Perettie said this is something the company will monitor, but so far, hasn’t seen evidence its drugs triggered T cell malignancies, and the risk of these cancers appears to be lower in CAR-T than from traditional chemotherapy. 

Initially there were some concerns the FDA warning would scare patients from taking these treatments. 

“But we haven't seen that,” Perettie said. 

She does see room to expand CAR-T to other areas. 

“We’re also doing a lot of work in solid tumors and beginning to look at autoimmune approaches,” Perettie said, pointing to compelling data related to autoimmune diseases. 

“We’re seeing patients with highly refractory diseases like lupus, myositis and multiple sclerosis having profound responses from CAR-T,” she said. 

The company also recently inked a $285 million deal with Arcellx to exercise its rights to the ACLX001 ARC-SparX program and expand into multiple myeloma, which affects about 180,000 patients in the U.S. 

“We expect to have pivotal data at the end of this year,” she said. 

About 20% of multiple myeloma patients are Black, so the company is working to ensure that clinical trials enroll the right mix of people and to establish treatment centers in communities with the greatest need, Perettie said.

“Our purpose really is about using that singular focus to advance care for patients and making sure that we have a transformative option,” Perettie said.

Even a few years ago, gene therapy was an up-and-coming part of the biopharma industry. Now, the trajectory seems almost limitless, and biotechs like 4D Molecular Therapeutics are on the path of developing treatments that could change how we view genetic medicine.

With the recent hiring of UCSF professor Dr. Noriyuki Kasahara and a partnership with fellow gene therapy pioneer Arbor Biotechnologies, 4DMT is carving a new foothold in the gene therapy cliffside by coming up with novel delivery methods based on viral vectors.

4DMT’s advanced computational discovery system picks the tiny nits from a genome that cause conditions like diabetes and heart disease. To get to the root of these complicated diseases, the company has used a method called “directed evolution,” finding needles in the haystack and directing gene therapy to correct them.

Gene therapy is all about the delivery, says 4DMT CEO Dr. David Kirn, and 4DMT’s technology is designed to bring delivery methods up to speed. Here, we talk to Kirn about the future of gene therapy and why improving delivery is so important.

This interview has been edited for brevity and style.

PHARMAVOICE: Why is it important that the industry finds new ways to leverage gene therapy?

DR. DAVID KIRN: In the simplest way, people think of gene therapy as treating a disease where there’s a missing gene, whether it’s muscular dystrophy or cystic fibrosis, where there’s a single gene that’s mutated and you’re going to put a normal copy of a gene into a vector and deliver it to the tissues and cells that need it. When you describe it that way, it sounds very simple — and the beauty of the concept is that it is very simple, but it goes beyond replacement of genes that are mutated in monogenic, recessive diseases. We believe you can also use it for a large market beyond rare inherited diseases with a flexible approach.

When I entered the field, I asked a colleague what the big problems in gene therapy were. They said there are only three: delivery, delivery and delivery. The concept is simple, but what’s difficult is how to deliver it. There was a sort of naive start to the field where people thought they could just take these things and throw them into a cell, and that was very inefficient. So the limitations remain in delivery, and our platform is designed to overcome those limitations.

How did your platform come about to address those problems?

We use what’s called directed evolution. This is a technology that’s used to create or invent customized biologics that have the features you want and was awarded the Nobel Prize in Chemistry back in 2018 to Francis Arnold at CalTech, who did it with enzymes. She said, if I generate a massive number of different versions of an enzyme and then screen and select for the one that matches the phenotype I want, then I could invent a new optimized factor for any condition that I want to optimize for. And then others like Greg Winters and George Smith did it with monoclonal antibodies and bacteriophages. That was the beginning of this idea that we can move beyond the biologics that are present in nature and invent brand new ones with the features we want. And so we’re the first to do it with the [adeno-associated virus] vectors.

What does the future of gene therapy look like to you?

It’s about using technology like directed evolution to keep optimizing and improving the approach such that it can go beyond a handful of rare diseases and begin to impact countless patients. The starting point was these very rare niches where you didn’t need very good delivery and you could still get a product approved, and what we’re trying to do is take it to a whole new level to make it a central pillar of medical care. The future of gene therapy is funneling down from a billion options to a needle in a haystack that is optimal for a target vector.

As you prepare for your FDA discussions, what do your days look like?

It’s a super exciting time — an inflection point. In 10 years, we’ve gotten five products into the clinic and discovered and filed patents on hundreds of different optimized vectors. So now we’ve shown that these vectors behave the way we hoped they would, and it’s the creation of a superior vector that solves limitations we had with the old vectors.

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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.

The six CAR-T therapeutics with U.S. approval have transformed blood cancer treatment, eliminating cancers in some patients or preventing recurrence. But the FDA is now requiring these therapies to include a black box warning on the label after 22 patients went on to develop secondary T-cell cancers.

The FDA sent letters out on Jan. 19 to Bristol Myers Squibb, Gilead Sciences’ Kite Pharma, Johnson & Johnson and Novartis, spelling out the changes companies will need to make following an investigation into cancers that occurred in patients treated with five of the six approved BCMA- and CD19-directed genetically modified autologous T cell immunotherapies. Post-marketing surveillance identified the cases, which represent a small portion of the 27,000 patients treated with FDA-approved CAR-T therapies — although it’s unclear if it flagged all cases.

All six treatments — Abecma, Breyanzi, Carvykti, Kymriah, Yescarta and Tecartus —will carry the warning. However, the FDA sent a revised letter to Kite for its therapy, Tecartus, removing the requirement to state that secondary cancers have occurred in patients who took the therapy because it hasn’t identified any cases. It’s unclear how or if the newly identified risk will affect the burgeoning CAR-T market, which is poised to expand beyond oncology and may generate $35.9 billion by 2032. 

Drugmakers weigh next steps

Some of the companies affected by the FDA decision said they are now determining how to proceed.

“Bristol Myers Squibb has received the letters from the FDA and is evaluating next steps on the labels for Abecma and Breyanzi,” the company said in an emailed statement. “Bristol Myers Squibb has treated more than 5,000 patients with hematologic malignancies across clinical and commercial settings with Abecma and Breyanzi. To date, BMS has not observed any CAR-positive T-cell malignancy cases and therefore, we have not found a causal relationship between our products and secondary T cell malignancies.” 

Even so, the company said it will continue to focus on patient safety. 

“We remain confident in the safety profile and clinical value of our cell therapies and are committed to ongoing transparency with all stakeholders,” BMS said.

Johnson & Johnson officials said it’s clear the benefits of CAR-T, and its treatment, Carvykti, outweigh the risks.

“We remain focused on the clinical development of Carvykti in our commitment to improving outcomes for patients living with multiple myeloma, a disease where unmet needs continue to persist,” Johnson & Johnson officials said in an emailed statement. “While the FDA determined that the risk of T-cell malignancies is applicable to all currently approved BCMA-directed and CD-19 directed CAR-T therapies, it’s important to note that the agency did communicate that the overall benefits of these products continue to outweigh their potential risks.” 

To date, more than 2,000 patients have been treated with Carvykti worldwide.

While the risk/benefit profile remains in favor of CAR-T products, it’s unclear how the safety warning will impact FDA reviews of expanded approvals for the therapies as earlier line treatments. Last June, J&J submitted a supplemental BLA seeking approval of Carvykti for patients who’ve received just one prior line of therapy rather than four. A decision on the application will be taken up by the FDA’s Oncologic Drugs Advisory Committee at a still undetermined date. BMS is similarly slated to face the same adcomm for its bid to expand the use of Abecma into earlier lines of care. For patients who have undergone CAR-T treatment, experts suggest ongoing monitoring to identify new cases.

“It is important for clinicians caring for people who have received CAR-T cells to report the occurrence of any new cancer,” states a NEJM perspective. “At this time, we recommend that patients and clinical trial participants who receive treatment with these products be monitored for new cancers throughout their lives, since — owing to the relatively recent widespread introduction of CAR-T products into clinical care — we don’t yet know how long after treatment people remain at risk for these adverse events.”

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.”

The technology behind CRISPR gene editing is one of the most cutting edge areas of biopharma, and recent regulatory approvals have demonstrated how far it has come in a relatively short period of time.

Arbor Biotechnologies is setting itself up for the next stage of the gene editing revolution by developing tools that could shape and hone current strategies to reach more disease targets. The preclinical-stage company, co-founded by CRISPR pioneer Feng Zhang and Illumina founder David Walt, is starting with diseases of the liver and central nervous system.

CRISPR is used to modify DNA, and is often paired with the protein Cas9 to locate the correct spots on a gene. Arbor is looking to expand that toolbox with additional proteins to target different genes in pursuit of treatments for more diseases. Its lead program in hyperoxaluria is close to an IND filing next year, CEO Devyn Smith said. The company is also targeting ALS in its earlier pipeline and plans three filings over the next three years.

“There is a kind of horizon coming at some point where gene editing will be able to do things that no other modality can do,” Smith said. “In simple genetics, there’s a mutation in a gene and you need to fix it — and as we understand disease biology more, it becomes a factor of becoming more sophisticated in how we think about the other elements.”

Beyond developing its own therapies, Arbor has also teamed up with Vertex Pharmaceuticals — which, along with CRISPR Therapeutics, was behind the FDA’s first approval this month — to provide more precise tools for gene editing.

Here, Smith discusses what sets Arbor apart in the CRISPR crowd and how the space is evolving. 

This interview has been edited for brevity and style.

PHARMAVOICE: Tell me a little about the origins of Arbor and how it stands out in the gene editing landscape.

DEVYN SMITH: One of the key differences of Arbor versus many other companies is that Arbor was founded on an idea as opposed to intellectual property — and that ideas was that everyone was using Cas9 at the time, and it was clear that there’s probably a need to identify other approaches that allow you to do more and have more functionality to treat disease. That was the founding principle, and the company has subsequently built a deep discovery tool engine that allows us to discover novel editing approaches. We’ve taken this broad swath of nucleases we’ve discovered, and those have underpinned our technology, which allows us to cover everything you’d want to do with DNA.

For small molecules, you need six million molecules in a library to screen against antibodies. Now, we don’t need six million tools in gene editing, but you need enough tools to cover the broad target set that you have. And the other important piece is making sure we can rapidly translate these discoveries into therapeutics, so we’re very focused on what we call a gateway indication strategy — picking an indication and going deep as soon as possible. Our focus is the central nervous system (CNS) and liver diseases.

CRISPR technology has cleared regulatory hurdles in the last couple months, and it’s an exciting time for gene editing. What does this mean for you and the future of the field?

It’s amazing to me that in 10 years we’ve gone from the original publications from Feng [Zhang]’s lab to an approved product — that’s really fast. And it will make a great difference in patients’ lives. It also allows a pathway and more comfort with these novel approaches that edit DNA. From Arbor’s perspective, we celebrate this. There’s work still to be done as we move to in vivo approaches. Our view is that Cas9 does a lot and is a well-used and well-understood tool. But it has limitations, and you can only do so much. So there is an opportunity to bring to bear a range of tools that allow you to do more. We’re very encouraged by the CRISPR approval and hope it’s the vanguard of many, many more in our space.

How do you see Arbor evolving over time as you grow into the market with these new tools?

If we think about the ex vivo space, we’re not doing executable cell therapy — there, it’s about partnering with folks to give them the tools to do what they need to do. In vivo, we’re very focused on developing our own therapies in liver disease and CNS, starting with ALS. Our goal is to have three filings over the next three years, and what’s important is the breadth of our toolbox. Making sure we have the right technologies and tools that we’ve built and making sure we have the right team of dedicated, knowledgeable drug developers. And by focusing on a single gateway indication, we can be successful there and then expand into other indications. We’re very disciplined in how we think about our pipeline and don’t try to do too much, but learn to walk before we run.

Why did you choose to focus on liver disease and the central nervous system? How did you decide these initial targets?

We wanted to find disease areas where delivery is clear and also an area where we could be the first editor to go into that disease. In liver, we’re making sure we can differentiate and do something that others can’t. CNS is a different profile, and the industry has struggled with it over the last gazillion years because the biology hasn’t been well understood. Now, we’re just starting to understand the underlying genetic impacts on disease pathology and we’ve got a host of genetic targets that are open and accessible for gene editing. There’s real opportunity there and the potential can be life changing.

What are the major shifts you see coming as gene editing technology advances?

Near-term, I think we’ll begin to see more clinical data emerge from in vivo therapeutics. There are only a couple companies in the clinic today, but other companies will join. And we’re beginning to understand the breadth of capabilities for the technology today and hopefully beginning to see one-and-done solutions for patients.

In the mid-term, you’ll see a shift from knockdown approaches to more sophisticated editing, like rewriting and inserting bigger pieces of DNA to achieve more specific results.

And then if we think about the long term, someday I would love to see editing integrated into our worldview. You go to the physician, your DNA is sequenced, they identify 10 things we want to fix now to solve any potential issues. It’s a little like a vaccine. When that occurs, maybe for my great grandchildren, it’s such a different world where, rather than trying to treat ALS once you have it, we’re preventing it from happening in the first place. It’ll be a long road to get there, but that to me is exciting and revolutionary for healthcare.