Gene therapy developers have been ringing out 2020 with a series of announcements about new manufacturing facilities, or at least production agreements with CDMOs. This month, Thermo Fisher said it will build a cGMP plasmid production site at its campus in Carlsbad, CA, while Taysha Gene Therapies disclosed plans for an $85 million cGMP facility in Durham, NC.
Also, this month, Passage Bio has announced two manufacturing developments. The company began operations to support adeno-associated virus (AAV) production for its lead gene therapy product candidates at a dedicated manufacturing suite at Catalent Cell & Gene Therapy’s Harmans/BWI campus in Harmans, MD, near Baltimore/Washington International Airport.
A week later, Passage Bio revealed plans for a second site at the Princeton West Innovation Campus, the former Bristol-Myers Squibb property in Hopewell, NJ, to support Chemistry, Manufacturing and Controls (CMC) lab operations for its gene therapy programs. The company has entered into a long-term lease for approximately 62,000 square feet at Princeton West, a 1.2 million-square-foot, multi-purpose R&D and biologic/pharmaceutical manufacturing campus. Passage Bio plans to create more than 20 new positions at the new lab in 2021.
Passage Bio said the CMC lab is a key component of its strategy of expanding internal manufacturing capabilities to support its lead programs as they advance into the clinic and toward commercialization. The company develops gene therapies for rare, monogenic central nervous system (CNS) disorders through a strategic collaboration and licensing agreement with the University of Pennsylvania’s Gene Therapy Program (GTP) to conduct discovery and IND-enabling preclinical work. Passage Bio’s co-founders include GTP Director and gene therapy pioneer James M. Wilson, MD, PhD.
Passage Bio’s pipeline is led by PBGM01, designed to treat GM1 gangliosidosis by targeting the lysosomal enzyme β-galactosidase (GLB1), which is set to dose its first patient in 2021. Two other gene therapy candidates are also headed for the clinic in 2021: PBFT02, designed to treat frontotemporal dementia by targeting the gene encoding the lysosomal protein progranulin (PGRN); and PBKR03, aimed at treating Krabbe disease by targeting the gene encoding the hydrolytic enzyme galactosylceramidase (GALC).
Rounding out Passage Bio’s pipeline are 14 preclinical programs, including:
- PBML04 for metachromatic leukodystrophy (MLD) patients who have mutations in the ARSA gene;
- PBAL05 for amyotrophic lateral sclerosis (ALS) patients who have a gain-of-function mutation in the C9orf72 gene;
- PBCM06 for Charcot-Marie-Tooth Type 2A (CMT2A) patients who have a mutation in the MFN2
Bruce Goldsmith, PhD, President and CEO of Passage Bio, recently discussed the company’s approach to manufacturing and its progress in developing its pipeline of gene therapies with GEN Edge (This interview has been lightly edited for length and clarity).
GEN Edge: The new CMC lab in Hopewell, NJ. will be one of two manufacturing facilities for Passage Bio. Why has Passage Bio opted to run its own facilities for manufacturing?
GOLDSMITH: We optimized all the SOPs [standard operating procedures] in the suite that Penn was using that we were in. Having our own suite, though, allows us to control all the scheduling. For example, with a fee-for-service suite that Penn has, if Catalent has to schedule another run in between, or switch for example between one of our programs and one of Penn’s other relationships, there has to be a takedown of capsid X and a switch over for cleaning etc. to capsid Y. So we can’t run, for example, if we feel we need two FTD runs or two GM1 runs — we can now do that back to back, which is a huge efficiency. And we control all the scheduling.
We also have more people in the plant, and we’ve been hiring. We’ve grown from 20 people at the beginning of the year to at the time of the IPO to over 60 now. A lot of that has been manufacturing, so we can control the SOPs etc.
GEN Edge: Passage Bio was launched in 2019 to commercialize gene therapies developed by Penn’s Gene Therapy Program (GTP). How has GTP helped in the manufacturing effort?
GOLDSMITH: GTP is about 300 people under Jim [Wilson]. It’s not your typical academic collaboration. They have everybody from a vector core, which optimizes capsid promoter transgene selection, all the way through IND-enabling studies, and even a regulatory group that has filed multiple INDs and supported us in our IND filings as well. In between that is also a manufacturing group that does all the scale-up at Penn in their facilities, but also a relationship with Catalent, where we also do our manufacturing. It really is an integral part of the company.
One thing that we’ve been doing, focusing first on that relationship, is we have a joint steering committee, joint research committees. This year, we have established a lot of connections, and strengthened those connections between GTP and Passage Bio. We’ve not only manufactured all of the drug for our lead indication, GM1, but also for FTD and Krabbe [disease], which are manufactured and awaiting release.
We have worked with Penn very closely and Catalent on manufacturing to optimize that whole process, hand-in-hand with them. And all of those SOPs and workaround manufacturing are now transferred into our wholly-owned cGMP suite at Catalent.
GEN Edge: How has the Passage Bio-GTP relationship evolved since the company went public earlier this year?
GOLDSMITH: In late spring, we changed the agreement to expand the number of options. We had 12 at the time of IPO; we went to 17. We also expanded the duration to a five-year total duration. All of that is great and expands the collaboration. But we also expanded into supporting Jim [Wilson]’s work in research. Previously, when we had a program, if there were advances, for example, a new capsid or a new formulation, etc. at the time of candidate selection and IND-enabling studies, we could apply all of that. But if there were continuous improvements, we would have had to renegotiate the application of these improvements into the compounds.
Now with this research collaboration, if Jim and his team present work that show some advances, which they recently did on the DRG toxicity, that is known as a class effect on AAVs, not just on a specific serotype. We can apply it across our entire program. And there are other advances that Jim and his team are working on—such as formulation, new capsids, manufacturing improvements, etc—which we can also apply to our program. So it’s really become our research arm, if you will. We do things very heavily in collaboration. That’s another change from pre-IPO to the execution of the company.
GEN EDGE: When it went public, Passage Bio projected that at least some of the clinical work for your lead candidate PBGM01 would start this year. Now, clinical studies are set to begin in 2021. Is that delay related to the pandemic? Or to the clinical hold?
GOLDSMITH: No, it wasn’t. It would be convenient to point to COVID-19. However, we want to be really upfront with that. We filed the IND in June, as we said we would. Unfortunately, we got put on clinical hold based on the medical device. The good news is that there were no other clinical hold issues identified.
The device itself is quite simple. It’s a syringe, a tube, and a needle. Essentially what the FDA asked us to do was conduct bio-compatibility risk assessments and testing because no devices have been approved specifically for ICM (although there are some in use)…
We had assumed, in consultation with Jim and regulatory experts, that the risk benefit, especially in GM1, was such that if there was any neurotoxicity, which we had not seen in the animal studies (except for the DRG toxicity that’s been disclosed), was going to be very positive in the assessment. However, the FDA raised a concern. We then collaborated with them to identify exactly what tests were needed, what risk assessment as needed. We’ve been working on that. We updated our guidance from what we thought was going to be fourth quarter first patient in, to first quarter 2021 first patient.
GEN Edge: For GM1, Passage Bio recently announced a partnership with Invitae for testing and diagnosis. How much will that collaboration serve as a model for PBFT02 and PBKR03 going forward?
GOLDSMITH: Invitae can look at their historic database and look for physicians that have identified a patient in the past who have had these diseases, and they can provide educational material as well as identification of clinical trials opportunities, etc. As patients are suspected of having a potential diagnosis of GM1, we essentially fund and Invitae provides a free genetic test to those children. That’s not newborn screening, that’s a little bit different.
Basically this is the Detect Lysosomal Storage Disorders program that Invitae helps add to their existing panel. There’s information that’s provided around our clinical studies and potentially others that are available. This is really a diagnostic identification and support program. Yes, you’re right that can be scaled and supported for Krabbe (PBKR03) as well. And we would think about doing that going forward.
The other piece that’s important is the validation of a heel stick. As children are born, the Recommended Uniform Screening Panel (RUSP) essentially recommends a bioassay–in this case, of beta galactosidase expression or enzymatic activity. The issue with getting it on the screening panels is that the test needs to be validated.
We are supporting New York ScreenPlus, which is a pilot program that is going to include both DNA testing as well as a GM1 enzymatic essay, and that will provide support for validation that then can get incorporated more broadly into newborn screening… We are going to work with various states to get this adopted for GM1 as well. But the biggest issue here is a gap between diagnosis and second, getting patients into therapy. That’s why we’re supporting all of these different efforts to move these forward.
GEN Edge: Given the rarity of the diseases, any thought as to how many patients will be studied in the trial?
GOLDSMITH: It’s a great question. If we look at known incidence rates that are reported in the literature, there are probably around 50 babies a year that are diagnosed with GM1. About two thirds of those patients will manifest the disease as infantile disease, which is a very early onset. Krabbe is probably in the hundred to 150 newborns, a year.
Those are very rough estimates, and because a lot of these children may not be appropriately diagnosed, the instance may be higher. And this is just the United States. We are going to multiple countries for the studies. For the GM1 study, we are only enrolling two patients at once for each cohort at the beginning, so we’re not looking for a huge number of patients.
GEN Edge: Passage Bio in October announced the publication in Human Gene Therapy of positive preclinical data for PBGM01 and PBFT02. Can you discuss those results?
GOLDSMITH: Yes, absolutely. What we announced was a more comprehensive data set for GM1 essentially. That data showed that beta-galactosidase was effectively expressed. Interestingly, if delivered in the mouse into the CNS, there is a form of AAV9 that we’re using. It’s a naturally occurring variant called hu68, which is a novel capsid, but similar to AAV9, it does cross the blood-brain barrier. We delivered this into the brain.
We saw a very good expression of beta-galactosidase and we also saw peripheral expression in target organs. We also saw then a dose-dependent rescue of the neurologic phenotype, as well as overall survival in mice. That was all presented in the GM1 paper [Human Gene Therapy is published by GEN publisher Mary Ann Liebert Inc.]. That’s important because GM1 and Krabbe express both peripherally and centrally.
We selected a dose that’s over the minimally effective dose, because we want to make sure that even the low dose has the possibility of having a positive effect on outcomes.
GEN Edge: Dosing of gene therapies has been an issue in several recent clinical trials which have seen setbacks, some of them tragic. How is Passage Bio addressing dosing?
GOLDSMITH: The patient deaths and very severe liver toxicity have unfortunately come mostly from systemic delivery. We are only going [to use the] ICM, which allows us a smaller volume, a lower overall viral load and genocopy that we’re delivering. It’s not systemic. There’s a number of reasons for that, but we think that that should hopefully avoid some of those toxicities. We didn’t see systemic tox in our non-human primate studies.
Having said that, we’re obviously very concerned and certainly going to monitor those carefully. There have been some CNS toxicities observed.
For example, there was a report of a study in Parkinson’s disease with GBA1 mutations by Prevail [Therapeutics, to be acquired by Eli Lilly], where there appeared to be exacerbation of symptoms, that was using an ICM delivery. It is not really clear whether that was related to abrupt steroid discontinuation or an immune reaction. But because of that, we’re also very closely monitoring our steroid use, and we are adjusting the flexibility around either steroids or other immunosuppressive regimens.
There has been a recognition and adaptation, because not only we but obviously Jim Wilson, with his background, is absolutely critical to us. Every time there are any reports, we consult with Jim and his group. We’re taking those very, very seriously, because patient safety is absolutely paramount.
GEN Edge: Passage Bio has projected advancing the FTD (PBFT02) and Krabbe (PBKR03) programs into the clinic during 2021. What is the status of those candidates?
GOLDSMITH: FTD and Krabbe, we have guided towards first half of next year. The IND work has been completed. The manufacturing has been done. We’re waiting for release of that material, so there is some work to do. But we’re only going to file those once the clinical hold is lifted, because it does use the same ICM device. There’s no reason to file if we’re going to go directly on hold again because of the same device. They will be filed sequentially after the hold is lifted…
GEN Edge: PBML04 is further into preclinical development, in the candidate selection phase, compared with discovery-phase candidates PBAL05 and PBCM06. Will ‘04 be the next candidate to be ramped up into clinical development in 2021?
GOLDSMITH: Yes, that’s a fair interpretation. As we get clarity on our timelines around next steps, like IND and clinical initiation, we will give some updates on the timelines for those programs. That’s likely to come in our annual report.
GEN Edge: Any thought to expanding Passage Bio’s pipeline beyond the GTP platform and programs?
GOLDSMITH: Yes, we certainly can. It’s an interesting question, and we certainly have been thinking about this, Stephen Squinto and myself, and obviously Tachi [Tadataka Yamada, MD, Passage Bio’s Chairman]. I was at Deerfield Management before coming here. At Deerfield, we looked at a lot of different academic programs. Dave has as well. And the challenge is always that the translation between an academic idea, which is a research stage, and really moving forward to the IND, is a unique set of proficiencies, and Jim has really built that.
I’d say the answer is yes, it’s possible. But the hurdle rate that we’d have to look at for investing in those areas where we do not have investment in research right now, it would be a heavier lift. I could also see the possibility of later-stage programs that fit well with the CNS strategy as a possible approach. I think there’s a two-sided piece to that: One is research, maybe, but the hurdle is very hard. Later stage that maybe in the clinic would be potentially of interest.
GEN Edge: Beyond the GTP platform candidates, what does Passage Bio see as the potential for expanding its pipeline beyond gene therapy?
GOLDSMITH: While we certainly are keeping our eye on other approaches for genetic medicines—CRISPR or mRNA knockdown, etc.—the primary focus of the first six programs is all gene therapy. Certainly, that’s the near-term focus. And we get some synergies because Krabbe and GM1 are using the same vector. All three of the lead programs are using the same injection. They’re also taking advantage of cross correction, in which the protein or enzyme can get taken up by neighboring cells, But you may see an evolution of this over time.