RARE Daily

Bringing Regenerative Medicine to a Rare Bone Condition in Children

June 8, 2023

Congenital pseudarthrosis of the tibia is a rare condition that can cause spontaneous fractures, mobility problems, and impede proper growth. It is treated surgically, but because the bone often breaks again, it can lead to amputation. Novadip is developing an autologous cell therapy to allow tissue regeneration of large bone defects. We spoke to Denis Dufrane, co-founder and CEO of Novadip, about the rare pediatric bone disorder, the company’s cell therapy to address the condition, and how it works.

Daniel Levine: Denis, thanks for joining us.

Denis Dufrane: Thank you for your invitation.

Daniel Levine: We’re going to talk about Novadip and its efforts to develop cell therapies to accelerate bone and tissue regeneration. Novadip is working in both rare and common indications including trauma, spinal fusion, cancer, and tissue regeneration. We’re going to focus on the work in a rare pediatric bone disorder you’re doing, which is your lead indication. Let’s start there. What is congenital pseudoarthrosis of the tibia?

Denis Dufrane: It’s a specific and pediatric disease and it’s associated with a genetic disease in young kids. It can be associated with a disease called neurofibromatosis type 1. It’s a spontaneous deformation of bowing of the bone leading to breakage of the bone. And unfortunately, we are in this type of kids with a special disease in which we have a lack of bone formation and in parallel we have spontaneous bone reductions; therefore you have a defect and the defect is growing progressively by the progressive restrictions of the bone. It is a very ultra rare disease.

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

Denis Dufrane: You have firstly the tibia, which is broken. You have a lot of pain on the kids. The kids cannot walk on the tibia due to the pain and unfortunately you have a very high frequency of surgical interventions, which can lead finally at the teen age to amputations because you are in a specific physiological context and the bone cannot heal spontaneously.

Daniel Levine: And how soon after birth does the condition become apparent?

Denis Dufrane: That can appear at two years old when you begin to walk because finally it’s really in these conditions that you realize that your kids cannot walk due to the pain and you can see that there is a fracture due to the disease.

Daniel Levine: And is anything done to detect the condition prior to a fracture developing?

Denis Dufrane: No, you can detect before, but unfortunately, these spontaneous interventions, currently we have no surgical procedure in view to cure because you try to maintain the angle of the tibia in view to avoid the fracture, but unfortunately in most cases that still leads to fractures. But it’s difficult to prevent.

Daniel Levine: So how successful are treatments for the breaks once they occur?

Denis Dufrane: Currently you can estimate that at one year after a fracture in this type of kid you have more than 70 percent of refractures leading to multiple surgeries. And currently we can estimate that we have a risk of amputations over 60 percent due to the lack of bone formation.

Daniel Levine: Novadip has developed platform technology that uses differentiated adipose derived stem cells. You’ve spent a large part of your career as a researcher and have been doing work in diabetes on adipose stem cell therapies to improve the production of insulin. How did your work lead to the area of bone and tissue regeneration using these cells?

Denis Dufrane: That’s an excellent question. Before, as you mentioned, I spent 15 years at the University Hospital St Luc in Brussels where I proposed an alternative view to improving insulin producing cells in case of type 1 diabetes. And by studying this approach with my PhD students, we realized that finally the adipose stem cells have a property to perform a newborn’s formations, but also to resist in a very hypoxic environment with a very low oxygen tension. And in this context, finally a bone defect is exactly what we need. We have a bone defect, so, fibrotic tissue, no vascularization, very low oxygen tension. And we realized that finally the adipose stem cells can overcome the pathophysiology by restoration of oxygen, new vascularization, and finally new bone formation. That was really based on the biological properties of the adipose stem cells that can mimic the pathophysiological context of a bone defect. It’s why really that was a biological combination.

Daniel Levine: Walk me through the process of how this works. You start with the patient’s own adipose cells. These are fat cells. How do you take these and get them to convert to stem cells that differentiate into bone or skin cells? Does this happen naturally through their application?

Denis Dufrane: Yeah, the idea is to not only to use the adipose stem cells is why we developed the 3M³ platform because we’re really ex vivo outside the body. From the fat tissue we isolate the adipose stem cells by combinations with particles. We promote the cells to an extracellular matrix and you obtain real three-dimensional structures. Cells are a microscopical structures, our product is a microscopical structure. Therefore that’s really the beauty of the technology. We have a real mature product by asking the cells to promote the synthesis of a matrix in view to cure the pathophysiology. Therefore, it seems simple, but biologically it is more complex.

Daniel Levine: Well, walk me through the process of the 3M³ platform. What do you start with? What does it go through and what’s the final output?

Denis Dufrane: It’s very easy. From the cells combined, as I’ve mentioned, with particles, we have a spontaneous prediction of an extracellular matrix and when the cells are included inside the extracellular matrix, they begin to secrete a highly specific profile of bioactive agents involved in the tissue healing, but also in the control of the cellular proliferations, for example, in case of a tumor. And based on these three-dimensional structures, we have the autologous product for critical size defect because we need the active role of the cells. We have the off-the-shelf, it’s an allogeneic matrix and therefore, the growth factors and bioactive agents are passively released by the matrix. And finally, we have the exosome, nanovesicles, secreted by the three and three platform.

Daniel Levine: Once you have the cells ready, how are they used to treat a patient and what do they do within the body?

Denis Dufrane: In the case of the autologous program, you restore exactly the bone physiology in the defect of the congenital pseudarthrosis of the tibia. Those cells and the matrix play the roles of a bone biological bandage. It is really fully integrated and restores the bone physiology to grow normally.

Daniel Levine: Well, how do you apply them and how do you get them to stay where they need to be active?

Denis Dufrane: Oh, they remain active because that’s the properties of the adipose stem cells. They have the resistance to hypoxic stress, to low oxygen stress. And by the fact that they are fully integrated in their matrix, you have a real bone phenotype playing the role of the restoration of the bone. The beauty of the technology is really the combination of the matrix and the cells, which play a major role in bone physiological restoration.

Daniel Levine: What’s known about your experimental therapy NVD003 from studies that have been done to date?

Denis Dufrane: NVD003 was developed now three years before and we developed the first approach in adult patients with a very severe trauma to demonstrate that the cells and the product, the 3M³, can restore new bone formation in very severe patients. And based on that, we transferred the technology to congenital pseudoarthrosis of the tibia in young kids. Therefore, we have already now nine patients transplanted and up to now, more than two years after the implantations, we have full restoration of the bones’ continuity and people can work easily without any pain. That was the most beautiful demonstration—to transfer to young populations of patients.

Daniel Levine: What’s the development path forward?

Denis Dufrane: NVD003. Clearly we want to go into the market with the product for rare pediatric indications. We now are in phase 1b/2a trials, the pilot trials, the trials is granted by the FDA. We have an IND open and the study is now ongoing both in the U.S. and also in Belgium. And the first patient was implanted now two weeks before and now we are starting to recruit the last three patients in view to plan the pivotal trials next year. And we hope that we could be on the market in 2026 and therefore available for the patients.

Daniel Levine: We mentioned you’re developing a range of regenerative medicine products. Why start with this indication?

Denis Dufrane: Why? Because that was the worst severe condition and when I was in my university hospital, my mentors in the past told me, if you can cure this disease, you can cure everything in bone defect. And I like the challenge. That is why I perform now first to treat the worst case patients and after that to propose our technology for our broader populations of patients.

Daniel Levine: The company is developing both autologous and allogeneic therapies. I’m always curious what determines whether it would be best to use an autologous or allogeneic therapy for a given indication?

Denis Dufrane: It’s an excellent question. For the autologous product, you need the active role of the cells. You are in a critical size bone defect in a severe patient. You have a big defect. Therefore you need a product which is active by the role of the cells inside the defect. That’s the role of NVD003 in the congenital pseudoarthrosis of the tibia or after a severe trauma. For the off-the-shelf matrix, the matrix is releasing passively to stimulate the cells of the host. Therefore, it’s more as a first line [therapy] for every type of small bone defect such as spine surgery, maxillofacial, after a trauma or in case of [indecipherable] surgery. Therefore it’s really the size. You have a big defect, you need the roles of the cells, you need the autologous product. You have a small defect, you need to stimulate passively. You use the off-the-shelf matrix.

Daniel Levine: And in creating the off-the-shelf matrix, is there any challenge in the preparation to ensure it doesn’t trigger some kind of an immune response?

Denis Dufrane: No, that’s the beauty of the technology because it’s an allogeneic matrix derived from the cells, but inside the product you have no viable cells and therefore we demonstrated in our models, which were really strong animal models, that we never elicited any cellular humoral response. Therefore, we have no immune cell reaction and no antibody production.

Daniel Levine: In late November, Novadip raised about $54 million in a series B round. How far will existing funds take you and what’s the plan for additional fundraising?

Denis Dufrane: That’s an excellent question. We have a plan now with the fundraising of the series B to go up to the end of 2024, start of 2025. Our objective is really to go for the trials with the autologous and also the off-the-shelf. And it’s why we are planning a new round, a series C crossover investment. If we can go to IPO certainly for the start of 2025 end of 2024, that’s the major goal of the company.

Daniel Levine: We’ve certainly seen big change in the capital markets and investors’ attitudes. I’m wondering from sitting on the other side of that table, have the conversations changed at all from your series A to your B to C round?

Denis Dufrane: Yes. The capital market is completely changed. Currently it’s clear that VCs ask to focus efforts with a view to be sure that we can deliver clinical data. That’s the main aim in view to the risk and environment this completely different. And before that was a less risky environment and investors could put more risk on early stage companies. I think that this time, currently, is gone and it’s why our objective for the B round is to deliver three clinical trials in parallel with data to be sure that we can go for the next step, an IPO, a C round, or also eventually a strategic partner because that’s the possibility of and the beauty of our platform. We have a different type of product and in terms of bone healing we are really unique and it’s why we have all the free possibilities currently, which are remaining open for the next refinancing run of the company.

Daniel Levine: Denis Dufrane, co-founder and CEO of Novadip. Denis, thanks so much for your time today.

Denis Dufrane: It was a pleasure. Thank you so much.


This transcript has been edited for clarity and readability.

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