Bobby Gaspar, MD, PhD, is relatively new to his position as CEO of Orchard Therapeutics, having been appointed in March. But with more than 25 years’ experience in gene therapy, he’s a pioneer in the field who was early to grasp the potential of blood-forming or hematopoietic stem cells (HSCs) as an investigator in several early clinical trials.

Orchard is drawing on Gaspar’s background in HSCs as the gene therapy developer’s co-founder and previous chief scientific officer, and as a researcher—he remains a professor of pediatrics and immunology at the University College London (UCL) Institute of Child Health—as the company advances its lead programs through clinical studies to regulatory filings it hopes will yield approvals starting this year. Gaspar’s promotion followed cash, cash equivalents, and investments that dipped 3% last year to $325 million and tumbled 19% to $264 million as of last March.

Gaspar made his presence felt at Orchard in May, leading the company in carrying out a strategic plan that included eliminating about 25% of its workforce, or 60 jobs—generating $125 million in savings through the end of 2021 and extending Orchard’s cash runway into 2022. Orchard also ended its development of a manufacturing site in Fremont, CA; shut down a lab-office site in Menlo Park, CA; shifted its manufacturing approach to investing in next-generation technologies; and narrowed its near-term R&D pipeline programs to four:

  • Lead program OTL-200 for metachromatic leukodystrophy (MLD), for which a decision by European regulators is expected by year’s end, to be followed by launch in the first half of 2021.
  • OLT-103 in Wiskott-Aldrich syndrome (WAS), for which Orchard is preparing U.S. BLA and European marketing authorization application (MAA) filings next year.
  • OLT-201 in MPS Type IIIA (MPS-IIIA), which is expected to generate interim data from a proof-of-concept study in five patients in 2021.
  • OLT-203 in Mucopolysaccharidosis Type I (MPS-I), set to report interim proof-of-concept data later this year and one-year follow-up results in the first half of next year, followed by a registrational study.

A week later, Orchard announced interim data of OLT-203 from an ongoing proof-of-concept trial showing that the study’s first primary endpoint was met: All eight patients achieved hematologic engraftment in less than 45 days. The eight showed supraphysiological levels of alpha-L-iduronidase (IDUA) lysosomal enzyme in the blood, while the first two patients followed up at 12 and 18 months showing promising preliminary clinical effects on motor skills, IQ, and growth.

“This early data provides strong proof of mechanism for OTL-203, and we believe the consistency demonstrated across all treated patients bodes well for the transition to pivotal trial in 2021,” Yaron Werber, MD, MBA, managing director, Health Care-Biotechnology with Cowen, and colleagues wrote in an investor note.

Earlier in May, Werber praised Orchard’s strategic plan: “The new business plan represents a smart reprioritization of its commercial strategy to focus on higher-yield opportunities and conserve cash. This should remove any need for near-term financings.”

Anupam Rama, who specializes in coverage of small- and mid-sized biotechs for J.P. Morgan, and colleagues also shared a favorable view of Orchard in June:  “ORTX shares are undervalued given the spectrum of de-risked/late-stage programs in areas of high unmet need,” with the company’s first potential launch on track for 2021 for OTL-200 in MLD in the EU. “In our view, the broader pipeline, specifically WAS, is underappreciated.”

Orchard Therapeutics has extended its collaboration with Italian CDMO MolMed—whose Milan facility is shown—to develop and manufacture vectors and drug products for several pipeline programs. MolMed was acquired by AGC Biologics on July 31. [ACG Biologics]
A month later, Orchard moved on the manufacturing front by extending its collaboration with Italian CDMO MolMed—acquired July 31 by AGC Biologics for €240 million ($282 million)—to develop and manufacture vectors and drug products for several pipeline programs; and inking royalty-bearing license agreements with GlaxoSmithKline (GSK) to use its lentiviral stable cell line technology (LV-SCLT) for OTL-103 and a therapy in development for transfusion-dependent beta thalassemia (TDT), OTL-300. GSK took a 20% stake in Orchard in 2018 after transferring to the gene therapy developer its rare disease portfolio, including Strimvelis™, approved in Europe for adenosine deaminase severe combined immune deficiency (ADA-SCID).

Orchard has its own candidate for ADA-SCID (OTL-101)—but cut investment in that and OTL-300 as part of its strategic refocus.

Gaspar recently discussed Orchard’s strategic refocus, its pipeline, and approach to HSC gene therapy, and the company’s approaches to manufacturing and technology with GEN Edge, in an interview lightly edited for length and clarity.


GEN: Why did Orchard refocus its R&D portfolio in May? And what is the current size of the company staff as a result?

GASPAR: We went from just over 250 to around 200. And a lot of that was associated with some decisions we made around manufacturing and our technical operations. We had a very extensive portfolio of programs at Orchard. We had three late-stage clinical programs, all moving towards approval in the EU and the U.S. We had programs that were in proof-of-concept that were then going to go to pivotal studies, and we had some early stage programs as well.

As a company of just over 200 people, we had to make some decisions about what we prioritized, where we put focus and emphasis as Orchard. So when I took over, I felt we really needed to create a sharpened focus for the company. And that’s where we thought about the programs that we had, and what choices we would make.

GEN: One of Orchard’s choices was continuing to move ahead with its lead program, OTL-200 for MLD. What is the mechanism behind OTL-200?

GASPAR: The concept there is that gene-modified hematopoietic stem cells (HSCs) can actually cross the blood brain barrier, secrete enzyme in the brain, and correct a very severe neurological disorder.

This has shown tremendous clinical potential. That mechanism, I think, allows HSC gene therapy to really offer benefits in these severe neurometabolic disorders. And so, we wanted to place emphasis in that portfolio program that we have, MLD, which is quite advanced and going to approval in the EU.

GEN: In the U.S., Orchard has talked publicly about filing an IND for OTL-200 in MLD and seeking RMAT designation from the FDA this year. How long would a clinical program take in the U.S., let alone being able to apply for a BLA?

GASPAR: We would be submitting the IND, ready to use the data that we already have. So our plan is to go to the FDA with the data we already have on patients who have already been treated, and to analyze the patients in a way that the FDA have directed us to do in some conversations that we’ve had with them. So ideally, we would not anticipate treating further patients. The IND is really an opportunity to have a discussion—a detailed discussion with the FDA about the data that we already have, and what a BLA submission might look like.

Just a bit of background on MLD: The first patient was treated 10 years ago. And so, there’s over 30 patients that have been treated. We’ve been comparing the treated patients against untreated patients. We’ve shown data that shows a significant improvement in motor and cognitive outcome that has been–that has lasted for eight years in the first patients that have been treated, So, a significant durability of effect.

That program has been submitted to the EMA [European Medicines Agency], and we’re going through the approval process now. And if all goes well, then we would look forward to an approval toward the end of this year. So that would be very exciting for that program.

At the same time, we’re going forward with an IND submission to the FDA and also seek RMAT designation at the same time. So again, we’re planning to do that before the end of this year.

GEN: Is the unique ability of HSC to treat MLD and other conditions, which Orchard is working to develop, simply the ability to cross the blood brain barrier? Or are there are other factors that make those HSCs unique?

GASPAR: There is a natural ability for a subset of HSCs to cross the blood brain barrier. But also, once they enter the CNS space, they’re able to distribute very broadly into all brain structures.

And so we’ve seen this in mouse models where you can target these cells, and you can introduce them into the neuron brain. You can see them distribute throughout the mouse brain, so they’re able to distribute broadly throughout all brain structures. They also naturally then differentiate into these microglial-like cells, and again there’s strong evidence that they can do that.

Then, you can then engineer the cells to overexpress enzyme, so that you’re now having these cells migrating into the brain, differentiating into microglial cells, and then overexpressing enzyme to correct these neurons.

There are a number of features of HSC gene therapy that allows correction or potential correction of neurons and then prevent the neurodegeneration effect associated with these conditions.

GEN: The one non-neurometabolic program in which Orchard opted to prioritize investment is OTL-103 in Wiskott Aldrich syndrome (WAS). Why such focus on WAS, and what is the company’s timeframe for pursuing approvals?

GASPAR: We chose to prioritize the Wiskott-Aldrich syndrome program, again on the base of unmet need, and also because of the larger commercial opportunity in Wiskott-Aldrich syndrome.

Again, it’s another very long-standing program. The first patients were treated nearly 10 years ago. Now, there’s a registrational study that has completed with patients that have been followed up. There have been patients treated on a compassionate use basis, and also patients treated with a cryopreserved formulation. So all of that data has been gathered together.

We’ve opened an IND in the U.S. We have RMAT designation for Wiskott-Aldrich syndrome. We’ve had a multidisciplinary meeting with the FDA. We’re looking forward to addressing some of the issues that were raised our first meeting, working through that, and then preparing for a pre-BLA meeting with them, with the intention of submitting a BLA in 2021.

At the same time, we are going starting the process with the EMA as well, looking to submit an MAA submission in 2021.

GEN: Orchard has also said it will focus more going forward on high need, high value diseases. What are examples of such diseases that the company is looking into?

GASPAR: One is a form of neurodegenerative condition which is a genetic subset of frontotemporal dementia (FTD). We believe that what we’ve seen in the ability to treat neurodegeneration in ultra rare conditions can also be applied to larger indications as well, such as frontotemporal dementia.

And similarly, we’ve seen some very exciting results in an ultra rare form of colitis, in a program that we have in chronic granulomatous disease where there was a myeloid defect, these patients have significant colitis. And when you give HSC gene therapy, the colitis goes away.

I’ve seen that clinically myself. I’ve treated a patient who had very severe colitis. He was treated with HSC gene therapy, and then he was able to stop all his immunosuppressive therapy and his colitis resolved. And that’s because a population of HSCs can cross into the gut, give rise to corrected macrophages, which can sense bacterial invasion, and prevent the abnormal immune response that leads to colitis.

The learnings from that can be applied to a larger form of colitis, and that’s a genetic subset of Crohn’s disease where it is a defect of macrophages. And again, by giving gene modified cells, you can correct those macrophages in the tissue and protect against this colitis. So, it’s a similar parallel: the learnings that we have in ultra rare diseases can be translated into larger indications.

So some prioritization of our clinical portfolio, emphasizing the ability of HSCs to correct the neurometabolic space, and also going from small indications and using HSC gene therapy for large indications—that is all part of our strategic reorientation.

GEN: Is it fair to conclude that Orchard will reorient its clinical programs toward neurometabolic disorders going forward?

GASPAR: Not exclusively. HSC gene therapy has a unique ability to address these neurometabolic conditions and some forms of neurodegeneration in a way that other modalities and other gene therapies, I think, will find challenging…HSCs have a natural ability to cross the blood brain barrier. By introducing genes into those HSCs, you can, therefore, have a route to express those genes and proteins in the brain, and have those proteins being taken up by neurons and prevent neurodegeneration.

If you can find appropriate targets where that mechanism works, then you have this ability to modulate and correct neurodegenerative conditions. So I think that’s a very exciting prospect. And as you know, these conditions have very few therapeutic options. MLD, for example, has no approved therapies, and bone marrow transplantation is associated with significant complications.

We’re really offering something for a devastating disease that has very high unmet need. And this is the same for other neurometabolic disorders as well. So, I think it can offer great benefit to patients with these kinds of conditions. And so, it is an area where we will put significant emphasis. But we also believe HSC gene therapy has potential in other areas as well: Immune deficiencies—Crohn’s disease is another exciting prospect. It comes down again to this unique ability of HSCs to enter tissues.

GEN: In reducing investment in the ADA-SCID and TDT programs, is Orchard’s plan to eventually sell those programs, or just advance them at a later date?

GASPAR: We chose to make some strategic priorities. It did mean that we reduce investment at this stage in these other programs. But that’s not to say that they’re not clinically valuable or important programs. It’s just where we chose to focus at this particular moment of time.

As far as TDT is concerned, what we announced with the LV-SCLT stable cell line development does have significant potential. It gives an advantage to us for the TDT program, and it may help with any kind of partnership, as far as TDT is concerned, because I think this is a potentially large indication. And if you change the way you make your lentiviral vector in a more scalable and efficient fashion, then it could have significant advantages for a large indication like TDT.

Similarly with ADA-SCID, that’s not to say that there is not significant potential value in the ADA-SCID program.

GEN: Orchard also ended construction of its manufacturing facility in Fremont, California. Is the facility for sale? Does Orchard plan to rent it out to another company?

GASPAR: We’re looking at a number of options…We are leaving the Fremont site. But when the time is right, we will be looking to build in-house manufacturing. I think it will be at a time when we have a greater need for capacity, already we have the expanded relationship with MolMed. As we get into larger indications and have more of a global footprint, we may invest in a manufacturing facility at that time.

GEN: Why did the company give up on Fremont?

GASPAR: At capacity, it was going to be way beyond our capacity needs. So, we chose to defer investment in in-house manufacturing to a later date. And we chose to expand our CDMO relationships. The MolMed agreement is part of that strategic change in direction.

We also chose to invest in manufacturing innovation, because we believe that for HSC gene therapy to be successful on a commercial scale, you need to have innovations that give you consistency, reliability, and efficiency as well. For example, the LV-SCLT [lentiviral stable cell line technology] license is an example of that investment in manufacturing innovations. So that’s where we’re going as far as manufacturing.

GEN: What makes the LV-SCLT technology unique and attractive to Orchard?

GASPAR: That’s a great question and I think it’s a really interesting technology. So, remember when we make our products, there are really two important components: The lentiviral vector, and then the gene modified cells.

The way everyone currently makes lentiviral vector is that the different components of the vector are placed on different plasmids, and also the gene of choice. So you have four different plasmids carrying the different components of the lens of our vector plus your gene of choice. And then you introduce those four plasmids into your producer lines where those components recombine to make lentiviral particles, and then the particles are shared from the cells and you collect the particles.

This is how we’ve made lentiviral vectors for a long time, but it’s a very inefficient process. First of all, you have to make plasmid on a regular basis to GMP, and that is quite an expensive process in itself. You then have to transfect the cells into your producer cells and then you collect your viral particles.

Some cells make lots of particles. Some cells make no particles. Some cells make intermediate numbers of particles, and then you collect those particles. When you’ve run out of using your vector, you have to make another batch of vector. You have to make a plasmid, you have to transfect it. You don’t know how many particles you’re going to get the next time around, because there’s no consistency.

So, it’s inefficient. It’s expensive. And is it’s not always reliable or consistent in the titer of vector that you get. So for a long time, people would think about: Can you make a cell line where all the components are stably integrated into that cell line. That’s what the LV-SCLT technology that we’ve licensed will do.

GEN: How does LV-SCLT work?

GASPAR: All the four components are introduced to a giant plasmid, a bacterial artificial chromosome, including your gene of choice. And you then introduce that bacterial artificial chromosome into your cells. The components integrate stably into the cells, and then you select a cell, a clone that is able to give recombination and give rise to viral particles and high titer.

You might screen several hundred or even 1000 different clones, select the one that is making high titer functional vector. And then you grow up that cell and you bank it. Every time you want to now make vector, you just grow up that cell that clonal one. You know that you’re going to always get back to have a consistently high titer because you’ve selected for that. There’s no need for plasma regeneration on a regular basis. Your clonal high titer line is going to give you a constant supply of vector.

As it makes it more consistent, reliable, and efficient and significantly reducing the cost of goods as well. As I think it is a significant advance in the technology of making lentiviral vector. I think it gives us an advantage as we go into diseases with large numbers of patients and larger indications.

GEN: Would LV-SCLT enable some sort of future expansion of manufacturing activity or return to that in-house philosophy?

GASPAR: We’ll go through a period of development work when now that we have that technology, we’ll start to put the process in to make these lentiviral vectors, and then we’ll have to look at when we want to make them to commercial–to clinical grade then whether we partner that or we have our own in-house manufacturing facility that will be able to make these lentiviral vectors.

GEN: Does this stem cell agreement with GSK auger a different model for Orchard in terms of assembling innovations by licensing them, as opposed to building them in-house?

GASPAR: I think it’s a combination of things for us. We have a whole range of innovations. We have innovative programs in FTD and Crohn’s disease. We have innovations in other parts of manufacturing as well. So stable cell line is one is one, but also looking at things like transduction enhancers to enhance the way lentiviral vectors get into stem cells. So that’s another improvement in the manufacturing process that we’re working on at an early stage, and then we’ll come into the clinic at a later time point.

Then we’re also looking at how you can automate the transduction process as well. So there’s all kinds of innovations, I think, that can happen in the manufacturing space that will lead to a more efficient and consistent process as we you know commercialize these HSC gene therapies.

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