RARE Daily

Buying and Building a Gene Therapy Presence

March 28, 2024

Ha Tran, medical head of cell and gene therapy for Astellas Pharma, discusses the company’s vision for cell and gene therapies, its efforts to restart trials for its X-linked myotubular myopathy gene therapy, and how it is looking to other programs beyond that.

Daniel Levine: Thanks for joining us.

Ha Tran: Thanks so much for having me again.

Daniel Levine: We’re going to talk about gene therapies, the challenges with developing these therapies for small populations with progressive conditions, and the work of Astellas Gene Therapies. Perhaps we can go back a few years. Astellas made a big move into gene therapies when it announced a $3 billion acquisition of Audentes at the end of 2019. What was the thinking driving the acquisition?

Ha Tran: Yeah, the acquisition of Audentes represented a key step in the expansion of the Astellas focus area approach. This is an approach where Astellas tries to create innovative medicines for diseases with high unmet medical needs by identifying unique combinations of biology and therapeutic modality based on emergent science. So, with the acquisition of Audentes, the company added a primary focus area in genetic regulation under which gene therapy is a key driver of the company’s future growth. So the complimentary capabilities and resources of the two organizations of Audentes and Astellas would create an industry leading gene therapy company.

Daniel Levine: Astellas is a large, well-established commercial biopharma with about 15,000 people headquartered in Japan. Audentes, based in San Francisco, had just under a hundred employees at the time it was acquired. It’s operating as a wholly owned subsidiary. The company was acquiring not just the programs, but people with important expertise that could walk out the door. To what extent has Astellas been protective of the culture of Audentes or blended it with Astellas, or remade it?

Ha Tran: Yeah, great question. So Audentes had been relatively independent for some time following the acquisition back in 2019, but with legacy Audentes leaders departing, which naturally occurs following acquisitions, there was a natural desire to integrate, and it happened quite slowly over time. So, in that sense, the Audentes culture has been well preserved. It was very natural for many employees to start referring to themselves as AGT or Astellas Gene Therapy shortly after the acquisition. I think the biggest challenge was for employees to start calling themselves Astellas versus AGT. We have a mix of team members who have been with Audentes since 2017 when the company formed, some who joined right during the acquisition or shortly after when Audentes became AGT. And then more recently, people like myself, who are what we call legacy Astellas employees, who started to join the gene therapy programs. So it’s been a nice blend and the culture and vibe is unique and distinctive within the company, and that’s quite special. And just to shed a little bit of light on it, mainly you can think of the people working on gene therapy as West Coasters. We have the South San Francisco biotech mover and shaker mentality, the people who love rare diseases and are driven by passion, and really just huge advocates to get things done for rare disease populations that have very limited therapies in place.

Daniel Levine: The company just completed construction on a 154,000 square foot state of the art facility in South San Francisco. This will be the West Coast hub for cell and gene therapy research and bring together what’s now been more than 20 geographically dispersed teams. Are you opened yet? Is it officially open? And how do you see that changing the way the company operates?

Ha Tran: Yeah, we actually had our soft opening at the end of December. Since I live in the San Francisco Bay area, I’ve been coming in every week or so, sometimes multiple days a week. But the grand opening will be in May. It’s an absolutely gorgeous state-of-the-art space that comes with great lighting, plenty of parking, open space, as well as plenty of conference room and private workspace that allows for collaboration as well as one-on-one meetings. And it’s super exciting. I think the deal sealer is the plethora of parking, as we know can be limited in the Bay Area, especially in San Francisco. And I’ve noticed people coming into the office more since December. Before the development and research teams were scattered. So, most of the development and business strategy folks were coming into the city while the research teams were spread across three different buildings in South San Francisco. Now being under one roof really enhances our connectivity. We have now larger size lecture style rooms so that we can give and listen to talks, and boardroom style conference rooms, which is effective for external business meetings. So, all in all this compliments our end-to-end infrastructure capabilities with manufacturing GMP compliant drug substance and drug product materials, our ability to commercially scale our manufacturing capabilities, the ability to perform quality control testing with our lab space and warehousing for our pipeline of our AVG therapy programs and studies, which can all be done in parallel. So, I’m not sure if you’re also aware that we have a 135,000 square foot manufacturing facility in Sanford, North Carolina that was completed in 2022. This is a GMP compliant facility that also expands our Astellas manufacturing capabilities.

Daniel Levine: At a time when development stage biotechs are being so protective of their cash and doing what they can to extend the runway, I take it it’s also a reminder on the upside of being acquired by a large pharmaceutical company.

Ha Tran: Yeah, absolutely. I think that’s a big hurdle for some small biotech gene therapy companies. So it’s nice to have this wealth of capabilities that we’re so fortunate to have.

Daniel Levine: The company’s lead gene therapy and development is AT132, a gene therapy for X-linked myotubular myopathy. For listeners not familiar with the condition, what is it?

Ha Tran: Yeah, X-linked myotubular myopathy is also known shortly as XLMTM, or some groups also call it MTM. MTM is a serious life-threatening rare neuromuscular disease, and it’s characterized by extreme muscle weakness, respiratory failure, and early death. So overall, the mortality rates are estimated to be approximately 50 percent in the first 18 months of life. Now that’s without any sort of therapeutic intervention. And for patients who do survive past infancy, approximately 75 percent will live to the age of 10. It’s caused by a mutation in that MTM1 gene, and that leads to a lack or dysfunction of myotubular, which is a protein that is needed for normal development, maturation, and function of skeletal muscle cells. It’s a rare disease and it affects approximately one in 40,000 to 50,000 newborn males.

Daniel Levine: How does the condition manifest itself and progress?

Ha Tran: So, the specific symptoms and severity of XLMTM can vary from one person to another. However, the majority of individuals with XLMTM have severe presentation. So, one classification subdivides XLMTM into different forms. There’s a severe classic form, which is what Astellas is developing a gene therapy for, and then there are also less common moderate or mild forms. In the severe form, the affected male infants exhibit extreme muscle weakness and hypotonia or floppiness shortly after birth. These are the patients who have really weak muscles and that affects their ability to breathe and swallow so they have problems like breathing and feeding difficulties shortly after birth or right at birth and it’s really noticeable. And these patients usually have really low Apgar scores. It becomes a medical emergency in the neonatal ICUs, and they will need intervention to stay alive. Those interventions include putting in a breathing tube initially and eventually converting over to a tracheostomy to allow for ventilation and then insertion of a gastrostomy tube for feeding. These infants typically stay in the hospital for approximately three months of their lives, so they continue to have this usually for lifelong, and if they do survive the infancy period, they typically will be ventilator feeding and wheelchair dependent.

Daniel Levine: And for those who survive, are there treatment options and what’s the prognosis?

Ha Tran: Sure. The treatment options are symptomatic, right? And so, for breathing, again, as I mentioned, it’s respiratory therapy dependency on the ventilator and all the medications that come with that, but it doesn’t change or reverse their condition. For the feeding difficulties that is G-tube feeding, nutritionist or dieticians can help with to meet some of those dietary demands, which these patients will have more of because of the need to use artificial ventilation. And physical therapy can be helpful. However, for prolonged periods of time you’re not able to sit, stand, or walk, it does take a toll on the architecture. And so, a lot of these patients may have scoliosis, contractures, and whatnot. With artificial ventilation over time, these patients can be subject to life-threatening infections such as pneumonia that could become either antibiotic resistant or antifungal resistant, et cetera, so that you can put a big dent on not just their mortality, but also the quality of life. These patients also have what’s reported in the literature as something called peliosis of the liver, abnormal vascular formations in the liver that can cause life-threatening liver bleeds as well.

Daniel Levine: What’s AT1 32 and how does it work?

Ha Tran: It’s a gene therapy. And to back up, I can briefly explain how AAV-based gene therapies work—that’s adeno-associated virus-based gene therapies. So, these are a method to treat patients if you have a missing or dysfunctional gene. In general, it’s difficult to insert DNA into cells so AAV is used as a vector to direct DNA into cells, and the genome of the AAV is replaced with the functional copy of the gene that is missing or dysfunctional, so that comes as a transgene. And once the functional gene is delivered into the cell’s nucleus, the AAV is broken down and the single stranded DNA transgene is copied to form double stranded DNA, and then the therapeutic transgene is converted into an episode. So, this remains separate from the patient’s genomic DNA, it doesn’t alter or integrate into the patient’s genome, but the transgene now provides information to the cells to produce the functional protein. In XLMTM, the myotubulin is the protein that is required for normal development and for normal function of skeletal muscle that’s, again, missing or not functional in XLMTM. So AT132 is comprised of AAV8 capsid that carries that functional copy of the MTM1 gene designed to express the myotubular protein, and it’s used under a muscle specific promoter called Dismen. So, after the gene transfer, the MTM1 gene produces functional myotubular. So, that has the potential to improve the respiratory motor development, and that hopefully leads to increased function and improved survival.

Daniel Levine: This is a program that has been on a clinical hold since late 2021. There were a total of four patients in the clinical study who had died. More recently, a publication in the journal Lancet Neurology has shed some light on what happened to the patients in the study who died, and how the other patients in the study have fared. What’s now known about the therapy.

Ha Tran: Yeah, so we’ve been updating the health authorities, scientific community, and patient groups about the status of the program and high level results of the study data to date. The Lancet Neurology article allows for a much more detailed look into the details, and it’s also peer reviewed. So the article itself is really well done. It has a lot of appendixes for people who really want to dig into data. But what’s new here, or what is more informative, is that it highlights the commonalities of the clinical trial participants who experienced the hepatobiliary serious adverse events. So, four out of the four participants who died and four out five participants with a serious adverse event of the hepatobiliary abnormalities did show that they had some abnormal liver or gallbladders prior to dosing with AT132. On the flip side, the journal article also highlights the transformational promise that many patients and families hope for, such as meeting ventilatory benchmarks that are not typically observed in the natural history. More than half of the participants with gene therapy achieved ventilator independence, meaning they came off the ventilator. This is something that is, again, not seen typically in a natural history. And then eight out of 24 participants dosed were able to walk independently versus none in the control group. And aside from walking independently, which is a huge feat, sitting independently for 30 seconds and pulling to stand were also seen more frequently in participants dosed with AT132 compared to control. So, these are quite remarkable as, again, it’s not seen with the symptomatic care that I’ve discussed previously, like with respiratory therapy, physical therapy, feeding therapy you wouldn’t expect to see these types of improvements in your respiratory or your motor milestones.

Daniel Levine: One of the challenges with this therapy is the need to deliver high doses of it. You’ve also identified that the patients who died all had progression of disease to the liver. Is Astellas planning any changes for the study or the patient selection criteria?

Ha Tran: Yes. Well, we have been looking into enrichment of the investigational product, and this is in line with industry trends and a desire for Astellas to constantly improve the product quality, the desire to further remove empty capsids from our investigational product, and thus reduce the total capsid load, which gives the ability to reduce the total dose. The development of a new clinical protocol is something that we’re continuing to discuss internally as well as with our stakeholders, including the health authorities, the principal investigators, our KOLs, and the patient community. So we continue to review the nonclinical and clinical data and to help identify the study population with a lower risk for these types of hepatobiliary cholestatic events after AAV gene therapy.

Daniel Levine: Where is Astellas with regards to discussions with regulators on starting up the trial again?

Ha Tran: So, we initially submitted our responses back in 2022, and we did also submit a clinical hold response in March of 2023. The hold remains in place to date, and as stated before, we continue to work through the complexities of the protocol and the program and continue to interact with the health authorities and the patient and scientific community.

Daniel Levine: In June 2023, the company entered into a licensing deal with Kate Therapeutics for KT430, a next generation XLMTM gene therapy. What makes this next generation?

Ha Tran: Sure. So AT132, our current technology in which this study was described in the Lancet Neurology publication, is designed to deliver the functional copy of human MTM1 gene with AAV8 as previously described. So KT430 is next generation, meaning that it is expected to deliver a functional copy of the MTM1 one gene via a novel MyoAAV capsid. So, it’s an engineered AAV capsid, more specifically, Myo-AAV is a new group of adeno-associated viruses and it uses a modified outer protein shell of AAV known as the capsid to deliver genetic therapies with greater efficiency and low doses. So, there’s an article that was published in the journal Cell in 2021, and the data shows that in mouse models of Duchenne muscular dystrophy and X-linked myotubular myopathy, the MyoAAV demonstrated more efficient delivery of the gene therapy and gene editing payloads. So, their preclinical data resulted in complete restoration of muscle function and improved survival, and in the preclinical data from non-human primates they also did a comparison between the natural AAV serotypes. Then what they showed or reported was that MyoAAV delivered 25 to 50 times greater gene expression in multiple skeletal muscles and 10 to 15 times greater gene expression in cardiac muscle. So, they demonstrated the ability to reduce delivery to the liver by 50 percent and showed lower accumulation of the transgene in the liver. That’s really encouraging news because what you can expect is to be able to dose at a log lower and then also to have increased efficiency. All in all, it’s really the hope that you can deliver the functional copy of the gene at a log lower dose with greater efficiency.

Daniel Levine: This is a preclinical program. Would the expectation be that this would replace AT132? Would you use it as a backup or would you move them both as fast as you can?

Ha Tran: Yeah, I mean, this licensing agreement is an important opportunity for Astellas to demonstrate our ongoing commitment to developing therapies for XLMTM. And so I think this really demonstrates our commitment to this patient and caregiver community. And I think it’s also important for us to invest in newer AAV capsid that can potentially help bring benefits to patients at lower doses that can be achieved with naturally occurring serotypes.

Daniel Levine: So, do you think you’ll develop both programs, or do you expect the newer program to replace the existing one?

Ha Tran: That’s a great question, and I think that’s a lot of, as stated before, the licensing agreement. The data currently only exists in the preclinical model. So, there’s a lot of assessment that needs to be done internally before even beginning to evaluate that specific situation.

Daniel Levine: Astellas has a number of other programs in development, including ones for Pompe disease, Friedreich’s ataxia, and myotonic dystrophy. What has the company learned about developing gene therapies from its experiences to date, and are there challenges you’ve learned to address through the XLTMTM program that you’re applying to the other programs?

Ha Tran: Yeah, absolutely. We’re extra conscientious about balancing risk and benefits—so the starting dose for any new programs, the decision to dose escalate and when are all topics we take very seriously and have hearty debates about. Expanding your selection criteria is also something that we think carefully about. Most companies start enrolling patients who meet a very narrow and specific inclusion exclusion criteria. But as time goes on, many companies are tempted to loosen that criteria to speed up enrollment. And when we do that, there’s always a risk that the new participants may not respond in the same manner as previous ones. And that can lead to either a safety risk or a risk where the efficacy won’t be the same. For example, if the disease has progressed too much or if the disease is not severe enough yet to detect a clinical meaningful benefit. So we’ve gained the ability to have more standardized approach to assessing the situation and gathering key stakeholder input to help gather information so that we can make an informed decision. And I think really before we make a decision, it’s important to get the opinions of our investigators, our key opinion leaders, external committees, and patient groups to really help us with that.

Daniel Levine: And what have you learned about working with the patient community through the program?

Ha Tran: Well, they are our biggest stakeholders and much of what we are doing or all of what we’re doing is for the patients and the families. And so what we’ve learned is they really like to hear from us. And often, and we need to remember that for some of us it’s work, but for them it’s their livelihood, their families, their children, their future. So when we think, oh, we just met with them last month, it may seem like years to them. And so, if we don’t have an update that we can share, just for them to see us on video, to know that we’re here, we’re working, we care. And I think that does help a little bit. I know the families are always wanting to find out additional information. They want to know what it means for them and their families. They want to know the timelines. They want to know when we’ll be back in clinic, will we be back in clinic in time for their loved ones? So, there’s quite a bit of education that needs to be provided on behalf of the sponsor and really setting or resetting expectations as well. Drug development is really challenging, even for your common every day run of the mill family doctor. So they may not know what it takes to bring a drug to market. If that’s the case, there’s just so much more education and close discussion that needs to be done with the patient community,

Daniel Levine: Ha Tran, medical head of cell and gene therapy for Astellas Pharma. Thanks so much for your time today.

Ha Tran: Thank you so much.

This transcript has been lightly edited for clarity and readability.


The RARECast podcast is made possible through support from the Global Genes’ Corporate Alliance. The members of the Corporate Alliance support Global Genes’ mission and programs, work to meet the vital needs of people with rare diseases, and address inequities they face. To learn more about the Corporate Alliance or how your organization can become a member, click here.




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