Many gene therapy companies seek to exploit a platform technology or leverage a specific vector. Rocket Pharmaceuticals is pursuing a multi-platform pipeline of treatments that directly target the genetic mutation underlying rare, childhood disorders. We spoke to Gaurav Shah, CEO of Rocket, about the companies approach to gene therapy, the conditions it’s targeting, and how it determines what gene therapies it will pursue.


Daniel Levine: Gaurav, thanks for joining us.

Gaurav Shah: Thanks for having me, Danny.

Daniel Levine: We’re going to talk about Rocket Pharma, it’s pipeline of gene therapies, and its agnostic approach to these medicines. Before we discuss some of the specific indications Rocket is pursuing, I wanted to start with a more general question about the company’s approach. Many companies in this space are leveraging a platform technology, specific set of vectors, or some other basic technology. That’s not the case with Rocket. What’s the thinking behind that and does it require a different skill sets or expertise from one therapeutic candidate to another?

Gaurav Shah: Yeah. Great question. So, first of all, the company was started six years ago by a group of health providers, physicians, and scientists, most importantly folks who are focused on the clinical side of things rather than early discovery. As a result, just the lens through which we look at developing a pipeline is going to be clinical focused, right? So we start with the end in mind, which is what are diseases where there is a large unmet need and a large number of patients who don’t have available treatment options? That’s how we start. Then we look back and we ask the question, what is the appropriate enabled technology? What technology makes sense to address this disease in the field of gene therapy? And in those efforts, we found two technologies, which were advanced enough to support these patients in the near term and at most medium term. And those two were the in vivo AAV platform and the ex vivo lentiviral platform. So, in some sense, we’re platform agnostic, but in some sense, it’s not about a platform approach, but more of a clinical disease approach.

Daniel Levine: Given that Rocket is not tied to a platform technology, what drives the selection of programs that rocket chooses to pursue?

Gaurav Shah: The way we select assets and pick diseases to try to potentially cure is three ways. One, we want to have a clear, clean on-target mechanism of action that predicts a good response with gene therapy. What does that mean? You want to hit the cell of interest and the protein of interest directly. For example, Danon disease is a disease of the heart in which a certain protein called LAMP2 is missing. And because of the missing protein, these patients build debris in their cells and therefore going into heart failure. So what we do is we correct the LAMP2 problem in cardiomyocytes, heart cells. So, we insert the correct version of LAMP2 into cardiomyocytes to attempt to reverse the disease at the core, at the root. That is how we start looking at assets.

Secondly, we want to look for achievable endpoints. What does that mean? Endpoints sometimes take time. So just because you can restore a protein and make these cardiomyocytes, these heart cells, better doesn’t mean you can do it in a relatively short amount of time. It could take a decade or more, right? So we find diseases where the preclinical data, the preclinical models suggest that we can reverse the disease course in a reasonable amount of time, meaning say one to two years. And then third, we want to go after diseases where we can have a sizable population. So, the resource investments we make into these technologies and these diseases can benefit a large number of patients. And we try to be first, best, and only-in-class, which is also important. We think it’s important to be only-in-class in this field, because that way we are pursuing drug development methodically, strategically, and not rushing to certain endpoints just because certain stakeholders want them. I think that’s an important part of our thesis as well. Out of the 7,000 or so rare diseases that we know about today that affect 300 million people we try to carve out large segments of the population so we can address them one by one, as we grow our pipeline.

Daniel Levine: You’re pursuing both lentiviral vector therapies and AAV therapies. What determines the appropriate vector for a particular condition?

Gaurav Shah: Excellent question. So, as I mentioned before, we start with the disease in mind first and then apply the correct platform or technology AAV versus lenti. The ex-vivo lenti programs are best suited for bone marrow-derived diseases. That’s because when you remove stem cells from the marrow, you are able to insert a correct gene and those stem cells, when reinfused into the body, automatically hone to the bone marrow. In other words, there’s a word called tropism. They have tropism for the bone marrow. So you can take the stem cells and put them outside the body, but when you correct them, they go back to the bone marrow, right? So in other words, we can treat these stem cells outside the body. That’s why it’s called ex vivo and we use a vector called a lentivirus vector, which works very well in the ex vivo setting to correct these stem cells. So, for bone marrow-derived disorders, ex vivo lentiviral is a commonly preferred approach.

for other organs like heart, liver, CNS, eye, an in vivo AAV approach may work better. And that’s because the AAV vector—it’s a viral vector just like lenti—has tropism directly for those organs. For example, AAV9, which is our program in Danon disease, is a AAV9-based gene therapy. It’s the ninth version of that AAV—it’s a capsid called AAV9, right? That has a direct tropism for heart tissue, more so than most other organs. So, when we infuse that directly into the vein, just like the stem cells go to the bone marrow, the AAV9 directly goes to the heart. So that’s how we select the platform. Starting with the disease in mind first.

Daniel Levine: You have two lead experimental therapies that are in phase 2 studies. The first is RP-L102, which is in development for the rare genetic condition. Fanconi anemia. What is Fanconi anemia?

Gaurav Shah: Fanconi anemia is a rare disorder. It affects mostly children, but also continues to affect these children as they grow into adults. It’s a disorder of DNA repair that results in bone marrow failure and a predisposition to cancer, especially leukemia and head and neck cancer. And without a bone marrow transplant, these patients have bone marrow failure by the age of 10 in most cases, and go on to develop leukemia and pass away in their teens and twenties, but even with a bone marrow transplant, these patients later get head and neck cancer and live longer, but still tend to pass away, unfortunately, in their thirties. So really a devastating disorder.

Daniel Levine: And how does the condition manifest itself in progress?

Gaurav Shah: Two thirds of Fanconi anemia cases are caused by genetic defects in a gene called FANC A and the rest one-third are other FANC subtypes, such as C, G and others. These subtypes are known as Fanconi anemia complementation groups. So as mentioned before, most patients unfortunately have bone marrow failure. Actually this occurs in about 80 percent of patients by the time they’re age 10.

Daniel Levine: What treatment options exist today? What is the prognosis for patients with the condition?

Gaurav Shah: An allogeneic bone marrow transplant can work. It can potentially cure patients of the hematologic, meaning the blood manifestations of the disease, but the issue with allogeneic transplant is that one is not always available. In fact, we’ve learned that only one third of patients who actually need a bone marrow transplant with Fanconi anemia are getting a bone marrow transplant. But it’s also a limited by toxicities, including graft versus host disease and graft-versus-host disease can be painful for the patient and also result in some early death.  What’s even worse is that graft-versus-host disease increases the risk of head and neck cancer in some cases by 30-fold or more. So, patients who get a bone marrow transplant do potentially have a cure of the blood disorder, which is the bone marrow failure and the leukemia, but they have much higher incidence later for head and neck cancer.

Daniel Levine: What is RP-L102? How was it prepared and how does it work?

Gaurav Shah: RP-L102 is our ex vivo lentiviral gene therapy candidate, which is now in a phase 2 registration study for the treatment of Fanconi anemia. It contains stem cells that have been genetically modified. They’ve been, uh, apheresed from patients via basically taking circulating blood and extracting it from the body. These cells are then bathed with the lentiviral vector that contains a correct version of either the FANC A gene for now, but eventually all the FANC compliment types, like I mentioned before, and then reinfuse them into the body. So that drug product that’s genetically modified but derives from the patient’s own marrow is reinfused into the marrow. And it potentially, if given early enough in life, can treat ongoing bone marrow failure, but it can also prevent future bone marrow failure. There’s something interesting in Fanconi anemia—the cause of the disorder is also the key to curing it. What do I mean by this? The disease is caused by disorders in DNA repair and because of DNA repair damage, these stem cells fizzle away and lead to bone marrow failure, right? So, DNA repair issues lead to bone marrow failure. The correction of the disease relies on that same process. When you reinfuse the gene corrected cells, the old disease cells die off on their own. So, we actually don’t need to use conditioning or chemotherapy to wipe out diseased cells that are existing in the bone marrow. Now, all we have to do is reinfuse. These corrective cells that I just mentioned were corrected outside the body. They go to the bone marrow and over time they replace the diseased cells because they have selective advantage over those diseased cells. And this has actually set up quite an upside for patients and caregivers, because you’re not subjecting patients to traditional chemotherapy yet. They’re still able to undergo a transplant with gene corrected cells.

Daniel Levine: What’s known about the approach from studies that have been done to date?

Gaurav Shah: So, we’ve treated nine patients with RP-L102 and of these nine patients, six at least are now showing some evidence of engraftment without any chemotherapy and this is because of the selective advantage being manifest. In fact of the six, four have now shown chimeric marrow, meaning that some of their stem cells in the bone marrow are no longer looking like Fanconi anemia cells. In fact, the way we diagnose Fanconi anemia is looking at stem cells in the bone marrow and evaluating them in the presence of chemotherapy, such as mytomycin C. And if all those cells don’t survive, if those cells die, that patient has Fanconi anemia. If the cells survive that patient doesn’t have Fanconi anemia. Some of the marrow of the patients we’ve treated looks like their cells survive mytomycin C, so at the root diagnostic modality available for Fanconi anemia, these patients don’t look like Fanconi anemia patients anymore, which is a remarkable testament to the power of the selective advantage here.

Daniel Levine: The other phase 2 program you have is for leukocyte adhesion deficiency. What is LAD-1?

Gaurav Shah: Yeah. LAD-1 is, in some ways, very near and dear to our hearts at Rocket. It’s a rare, devastating disease. In fact, I would say that it defines the word or redefines the word devastating. This is a disease caused by mutations in a gene encoding a protein called CD18. You need CD18 on certain white cells for those white cells to get out of the bloodstream and fight infection. Without that CD18, these patients have recurrent pneumonia and other infections, and they can be very fatal early in life.

Daniel Levine: What happens to someone who has LAD-1? What is the prognosis for them and how are they treated? Are there any available therapies today?

Gaurav Shah: Sadly, some of these infections like pneumonia and other infections can lead to early death. In fact, two thirds of these children pass away by the age of two. So again, redefining the word devastating. An allogeneic transplant can also treat LAD-1 effectively, but because the disease is so rapid and rapidly fatal, often it’s not possible to find marrow or a match in time. So we see a lot of patients die without even being evaluated for a transplant. Very sad.

Daniel Levine: You’re developing RP-L201 to treat this condition. Is it similar to what you’re doing with Fanconi anemia?

Gaurav Shah: It is very similar. In fact, it’s also an ex vivo lentiviral gene therapy, treated much like we had just mentioned on Fanconi anemia. And in this case, we do have to employ chemotherapy conditioning to wipe out the old diseased marrow stem cells and replace them with the new gene corrected stem cells. And once this drug product, RP-L102 is reinfused, it naturally homes to the bone marrow and we’re finding in patients that it is working.

Daniel Levine: And what’s known about that from studies that have been done to date?

Gaurav Shah: So most recently we reported data at ESGCT, which the European Society for Gene and Cell Therapies, just recently in October. And these data demonstrated that in the patients that we had treated, in fact seven out of seven patients who have been followed for at least three months after this gene therapy infusion have had restoration of CD18 levels between 25 and 80 percent of normal. So, a normal person would have a hundred percent and these patients have had restored CD 18 25 to 80 percent. We’ve learned from natural history, the history of patients who go untreated that less than 2 percent is severe LAD and those patients pass away by the age of two, in many cases. In fact, in most cases, levels of CD18 of 10 percent or higher are associated with a normal lifespan. So 25 to 80 percent, we believe, should confer a normal lifespan on these patients. And many of them are very much clinically improved. Some of them are off of all prophylactic antibiotics at this point. So in some ways, this is the sort of disease that gene therapy was invented for. And for LAD-1, like for Fanconi anemia, we’ll be reporting updates at ASH in December.

Daniel Levine: Earlier in the conversation, you had mentioned that in Danon disease, you are developing a gene therapy for this condition, which is a cardiomyopathy that involves intellectual disability. This is an AAV program, is it not?

Gaurav Shah: Correct, in vivo AAV.

Daniel Levine: What’s the prognosis today for patients with this condition and what treatment options exist, if any?

Gaurav Shah: Danon disease is an X-linked disorder so it does affect boys earlier and more severely than females. For boys are their median age of longevity is 19 years old. So by age 19, unfortunately, these boys either pass away or in some cases, which is also not very common, they can receive a heart transplant. There are about 30,000 patients in the U.S. and Europe with Danon disease. That’s our current estimate.

Daniel Levine: What is RP-A501? And how does it work?

Gaurav Shah: RP-A501 is our AAV gene therapy. And potentially, by the way, it could be the first gene therapy for a monogenic, meaning a single gene cause, of heart failure. It contains an AAV9 capsid, which as I’ve mentioned loves the heart, combined with a restored LAMP2, in this case the LAMP2b isoform of the transgene. LAMP2 is a protein that is important in something called autophagy, which is like the vacuum cleaner of a cell. As I mentioned earlier, without this protein debris starts building up in the cell and these patients rapidly progress to heart failure. RP-A501, we just presented data earlier this week. We’ve seen now sustained clinical benefit in all four patients who have long-term follow-up. Three of these four patients also received closely monitored immunosuppressive therapy, including steroids and other immunosuppressive agents, and in these three patients, not only are we seeing stabilization, like we are in a fourth patient who did not have close monitoring of this immunosuppression, but in these three patients, we’re actually seeing potential evidence of remodeling of the heart as early as 12 to 18 months after therapy. And we see, number one, improvements and New York Heart Association class from 2 to 1 in those three patients, meaning that they are asymptomatic with regard to their heart failure after this treatment, again as early as 12 to 18 months out. We also saw concomitant drops in a protein marker that circulates in the blood called BNP brain natriuretic peptide. BNP drops are also associated with improving heart failure. In fact, patients who are worsening with Dannon disease have increases in NYHA class as well as BNP. And then finally, and importantly, we’re seeing physical evidence of remodeling because the thickness of the ventricle walls is going down in these patients. These data are early;, they’re limited in terms of number of patients and time for follow-up, but highly encouraging at this early phase 1 data point.

Daniel Levine: And does this cross the blood-brain barrier? How was it delivered?

Gaurav Shah: This is delivered through intravenous infusion and it gets straight to the heart, just any IV agent would. AAV9, however, is also known to potentially cross the blood-brain barrier. A systemic AAV9 was used for the AveXis Zolgensma program, which is a CNS disorder. So there are CNS manifestations of Danon as well that could be affected positively with this therapy.

Daniel Levine: As you think across the pipeline here, what’s the regulatory path forward, and when might you be in a position to seek an approval for the first therapy?

Gaurav Shah: So, for Danon disease our regulatory path is as follows. We will finish our phase 1. We’ve started a pediatric cohort. We recently initiated dosing in pediatric, in our case it’s age eight to 14. Ultimately these are patients who may benefit the most from gene therapy because it’s almost preventative in these patients. And we will finish the phase 1 with two to four patients in this cohort. Hopefully only two, if there are no safety events, which there have not been so far. And then we’ll approach FDA after a reasonable amount of follow-up from these patients to design what we anticipate could be a pivotal phase 2 trial with one or more of the endpoints that I discussed above as being potential registration endpoints. We anticipate that we could start having those discussions with the FDA as early as toward the end of 2022.

Daniel Levine: And how about for either of the lentiviral therapies that we had discussed?

Gaurav Shah: So, Fanconi anemia and LAD-1 are both in pivotal registration trials now in agreement with both FDA and EMA. They are enrolling rapidly. In fact, LAD-1 has completed enrollment of nine patients and FA enrollment is ongoing but progressing pretty quickly. At some point in 2022, we do think that we’ll reach what we would call top-line data, meaning data that is ready to present for BLA and MMA filings. So both of those programs are on track for potentially the first commercialization for Rocket

Daniel Levine: Rocket in August completed a $26.4 million private placement. How is that money being used and how far will that funding take you?

Gaurav Shah: So, this was added on to funding that we already had. We currently have about $420 million in cash, and that cash gets us into the second half of 2023. We’re well-funded to advance all five of our current gene therapy programs and also to support both R&D development and manufacturing in our Cranberry, New Jersey facility, where I’m sitting now. It’s a 100,000 square foot space. Our hope is that we could have five potentially curative therapies available to rare disease patients in the U.S. and EU by 2025. In addition to that, we hope to have more programs in the clinic in new indications that we find through the mechanism that we discussed earlier.

Daniel Levine: Gaurav Shah, CEO of Rocket Pharma. Gaurav, thanks for your time today.

Gaurav Shah: Thank you, Danny. Great chatting.