Fanconi anaemia is a rare condition caused by genetic mutations in FA genes, meaning cells are unable to repair damage to their DNA. This eventually leads to bone marrow failure once bone marrow stops producing blood cells; leukaemia and head and neck cancer are other common complications of Fanconi.

Rare disease-focused Rocket Pharma is developing lentiviral-based gene therapy RP-L102 for Fanconi with the aim of overcoming and resolving the complications from the standard-of-care allogeneic stem cell transplant. In data published in Nature Medicine, RP-L102 was both effective and safe in patients without the need for conditioning using Process A to culture the cells.

As the company moves towards testing its updated, more efficient Process B method in Fanconi patients, Rocket CEO Gaurav Shah discusses RP-L102 and why it is so effective in Fanconi patients, as well as the remaining risk factors associated with the gene therapy and how the company plans to overcome these in the future.

Allie Nawrat: What are the current treatment approaches for Fanconi and why are they insufficient?

Gaurav Shah: The only potentially curative treatment for the haematologic, or the bone marrow, part of Fanconi anaemia is an allogeneic stem cell transplant. So harvesting good stem cells from another person, then wiping out the bone marrow in the patient with chemotherapy, then infusing the donor cells into the patient in the hope that stem cells will eventually help create new bone marrow for the patients and therefore restore the hematologic part of the body and, also, maybe prevent leukaemia.

Allogeneic transplant does work for the haematologic aspect [of the disease]; it helps prevent bone marrow failure, and prevents leukaemia; those are main things that patients die of in their teens and 20s.

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[However,] it is insufficient because having a transplant increases the risk of head and neck cancer, especially if they have transplant followed by graft-versus-host disease; 100% of patients with a chronic version of graft-versus-host disease develop head and neck cancer. In this day and age, even though transplants work, almost everybody with Fanconi passes away in their 30s.

The second reason is that a transplant itself still has about a 10% to 20% one year mortality, which is high and, I think, unacceptable.

AN: How did you discover that haematopoietic gene therapy could be effective against FA?

GS: We knew that in Fanconi there is a phenomenon called somatic mosaicism, where if even a single cell in the bone marrow for some reason normalises, that stem cell has a proliferative advantage in the bone marrow. [This means] the [normal] stem cell outcompetes other diseased stem cells, and over many years the stem cell eventually takes over the whole marrow. There is a subset of Fanconi patients – less than 5% called somatic mosaics – whose cells actually spontaneously revert to normal or near-normal.

That led our investigator, Juan Bueren, who is the senior author on the Nature Medicine paper, to postulate that maybe if you infuse a lot of gene-corrected cells with gene therapy, without chemotherapy conditioning, maybe those could proliferate over time and outcompete the original bad stem cells in the marrow.

When he first had this theory, people laughed it off as science fiction. [But] what happened is exactly as predicted; the [genetically] corrected stem cells do take over, so in patients treated with this gene therapy and followed for at least a year, you see engraftment [where the cells are accepted by and incorporated into the patient’s body].

AN: What are the differences between Process A and Process B? Which one will be chosen to move towards commercialisation?

GS: There are three processes. The natural process is the somatic mosaicism concept; that’s the template by which this gene therapy approach was envisioned by Juan Bueren and which we are now sponsoring.

Process A was Bueren’s original process; just trying to get the maximum number of cells of gene corrected cells re-infused into the patient so that instead of taking many, many, many years, like a somatic mosaic would, you could potentially achieve it in a couple of years. Process A is what is reported in the Nature Medicine paper, and it works.

Process B, however, is Rocket’s collaboration with [Spanish Centre for Energy, Environment and Technology] CIEMAT in which we discovered ways to get more gene-corrected cells re-infused, potentially by a many-fold factor, to make this process occur even faster.

The hope is that if you can treat patients early enough in life and you get in engraftment without any chemotherapy conditioning, these patients will never have to have a bone marrow transplant. Process B will be the registration process as both FDA and EMA have approved it as a commercialisable process.

AN: What were the most exciting parts of the recent data announcement from the FANCOLEN-I trial published in Nature Medicine?

GS: There are two key questions when thinking about Fanconi. The first is: can you truly genuinely get long-term, durable, engraftment without chemotherapy? This paper unequivocally answers that as an affirmative; and the whole point of Process B is to make that happen faster.

For the first time, in gene therapy, we’re achieving something without conditioning. Conditioning is chemotherapy – typically busalfan – that wipes out the stem cells and other cells in the bone marrow, so it allows new donor cells to take over the patient’s marrow. You have to do that with most transplants, as well as with most gene therapies, but not for Fanconi [or RP-L102] as this paper suggests.

Chemotherapy is toxic to the whole body; it can cause mucositis, gastro-intestinal issues, skin issues, hair loss. As Fanconi is a disorder of DNA repair, chemotherapy is especially toxic for Fanconi patients, even at low doses. So avoiding it was a huge victory for Fanconi patients and their families.

Also, without the conditioning and the need for a stem cell transplant, these patients potentially won’t get head and neck cancer and could live much longer.

The second question is sure, you can engraft, but does engraftment really mean anything in terms of benefiting patients? Here we’re showing that the patients who are treated with the highest doses of gene corrected stem cells over the course of two or three years are seeing a stabilisation and a trend toward improvement in blood counts. Later this year, and next year, we’ll have even more updated data that potentially supports this second point.

Now that those questions have been answered in the affirmative, we’re starting to see a lot more patients and families, as well as physicians who typically treat this disease with transplant, view gene therapy as a way to address Fanconi early in life as a preventative therapy, so they never need bone marrow transplants.

AN: What are the remaining risk factors associated with the condition following treatment with Rocket’s gene therapy?

GS: Let’s say that the treatment essentially mimics allogeneic transplant and the patients do not develop bone marrow failure, they do not develop leukaemia, they don’t have this graft-versus-host disease and this highly increased risk of head and neck cancer. If that is all true, what still remains is that Fanconi patients, in general, have a higher risk of head and neck cancer anyway above the normal population. So that’s something that that this gene therapy will not address. But it’s not going to increase the risk nearly as much as if they had had an allogeneic transplant.

But our commitment is to the whole life cycle of the Fanconi patients, not just the haematologic aspect. So as we move our gene therapy forward, we’re also committed to developing other gene therapy approaches to potentially address head and neck cancer [risk in Fanconi].