Rocket Pharmaceuticals’ CEO Talks Gene Platforms and Spiritual Leadership

The trajectory of Rocket Pharmaceuticals, a clinical-stage gene therapy company, has been marked by a series of impressive milestones. At least partial credit for those accomplishments goes to CEO Gaurav Shah, who co-founded the company in 2015 and has combined scientific, business and managerial savvy to progress the company through two regulatory filings this year. Shah recently spoke to In Vivo about the company and his own leadership style.

Source: Alamy

In classical Indian music, the raga song structure provides a framework for soloists to improvise and 'tinge' (one meaning of 'raga') the composition with their own flavor. But while each soloist explores their own tonality, they do so within a set of rules, limiting them to the notes allowed by that particular raga.

 

This balance of freedom and rigidity is what Gaurav Shah, CEO of Rocket Pharmaceuticals Inc., has been perfecting since co-founding the company in 2015, both in his own life and as a corporate leader. Shah, a board-certified oncologist, is focused on running a growing publicly-traded gene therapy company, while also being a GRAMMY-award winning artist.

Starting From Seed

Shah co-founded the company with initial funding from RTW Investments and a follow-up Series A financing round and steered Rocket to the launch of its two first programs in 2016, with series B fundraising completely shortly thereafter. That was followed by an IPO in early 2018 and since then, the company’s trajectory has been marked by a steady stream of clinical, operational and regulatory milestones.

 

Gaurav Shah, CEO of Rocket Pharmaceuticals Rocket Pharmaceuticals

The company, which grew from 12 employees in 2015 to roughly 225 at last count, expanded its research and manufacturing sites to include a 20,000-square foot drug discovery facility in Cranbury, New Jersey, and a 104,000 square-foot facility where its follows Current Good Manufacturing Practices (cGMP). Most recently, the company added to its AAV-based cardiovascular gene therapy portfolio with its PKP2 arrhythmogenic cardiomyopathy program and acquisition of Renovacor Inc., gaining access to its lead program, which targets BAG3-associated dilated cardiomyopathy.

 

In addition to that acquisition, Rocket has four clinical-stage gene therapy programs, all of which have received orphan drug designation and fast track approval status, as well as a number of pre-clinical programs.

 

The company is approaching two possible regulatory filings this year with each of their lead candidates, RP-L102 and RP-L201. The former targets Fanconi anemia subtype A, which is a rare DNA repair disorder that affects 5500-7000 people in the US and EU and is characterized by bone marrow failure as well as a predisposition to cancer and, frequently, death by age 30. Positive safety and efficacy data from an international, open-label and registration-enabling Phase II trial of that drug have led to an anticipated regulatory filing in the fourth quarter of 2023.

 

The second anticipated regulatory filing would occur in Q2 2023 for RP-L201, which is undergoing a registration-enabling Phase II study. That treatment targets the much rarer leukocyte adhesion deficiency-type I (LAD-I), a disorder that affects 800-1000 people in the US and EU and predisposes them to recurrent infections that often lead to death within the first two years of life.

 

The company has two other late-stage programs, including one that targets Danon disease, which affects 15000-30000 people in the US and EU and is characterized by thickening and weakening of the heart muscle. RP-A501, its experimental treatment for Danon disease, is in a Phase I trial in both pediatric patients and adults. Meanwhile, the company announced positive discussions with the FDA regarding a single-arm, open-label trial design for a pivotal study for RP-A501, given the challenges of performing a randomized controlled trial in Danon disease.

 

The fourth clinical program, RP-L301, targets Pyruvate Kinase Deficiency (PKD), a blood disorder with a prevalence of 4000-8000 people in the US and EU and is characterized by excessive rupture of red blood cells resulting in frequent, chronic anemia that may be severe or life-threatening. The company is conducting a Phase I open label trial of that agent, which it in-licensed from Spanish firm Ciemat-Ciberer in 2019.

 

During his tenure at the company, Shah has cultivated partnerships with over a dozen academic and medical centers and several industry partnerships to study multi-drug regimens and developed a licensing agreement with Regenxbio Inc. for its NAV AAV9 vector and a lentiviral vector manufacturing contract with MolMed.

 

Shah recently sat down in a video call with In Vivo and shared his thoughts on the role of gene therapies in addressing devastating pediatric diseases as well as the company’s unique R&D approach and his own leadership style, which blends spirituality and openness with managerial rigor.

 Can you tell us about the role gene therapies play in ameliorating rare pediatric diseases?

The majority of the more than 7000 known rare diseases have some onset in early years of life, so they can be considered pediatric. I think that much like antibiotics, which came into play more than a century ago for treating infectious diseases, gene therapies for rare disease have similar potential to eradicate rare diseases, including pediatric-onset illnesses. This is not medicine as we conventionally think of it; it is actually intended to be a cure at the deepest level of who we are, just like anti-infective agents eradicate disease by addressing bacteria directly. So, it has that profound transformation potential for our species. 

At the moment, most gene therapies target diseases that are monogenic in nature, but I think we’re not far from addressing polygenic diseases. We have to perfect some of the technology and develop viral vectors and nonviral techniques for gene therapy that might allow for bigger cassette sizes that allow us to pack in more genes.

What is unique about the R&D process at Rocket?

Starting a research team and a company around a platform or program has been a very common strategy in the gene therapy field. That could be the development of an AAV in vivo platform for a heart disease using a certain capsid, or it might be using the ex vivo lentiviral approach for certain bone marrow diseases. Companies that start off this way and develop platform technologies largely center around scientific research.

 That approach was particularly critical in the early days of the gene therapy field, but Rocket developed its platform based on existing proof of concepts using the ex vivo lentiviral approach and the in vivo AAV approach. This allowed us to build on great work already done and focus our talent and efforts on selecting diseases with the highest unmet needs and moving quickly with available platforms to achieve results, with potential for broader disease application.

In terms of our research-guiding principles, we select diseases where we can ideally be not only first and best in class, but only in class. That allows us to do things the right way without worrying about what another company is doing. The second guiding philosophy is to have a clear on-target mechanism of action, a protein or a cell of interest with a validated gene target. On the business end, we identify high-impact indications to address and we work with patient communities so that we can ensure their input is reflected as we advance our programs and grow the company. We've been blessed to have access to some very scientifically direct and validated disease targets.

 We also worked hard to build the right team with experience not only in gene therapy, but in complex biologics, and with experience in the clinical, regulatory and commercial aspects of operating a gene therapy company. This was very important for us to be strategic and think many steps ahead of what is crucial to success in our field. We've also been very lucky to have some highly supportive long-term investors, like RTW, who have stayed with us and helped us on our great journey over this recent couple of years. That puts us in a strong position to continue growing beyond the four current clinical-stage programs we have into many other rare diseases and to choose from the large number of monogenic rare diseases in a platform-agnostic way.

Can you tell us about your platform-agnostic approach?

We leverage and build upon platforms that already exist, which allows us to focus on harnessing their power for the express purposes of addressing diseases that are currently not addressed. For example, we’ve built upon some of bluebird’s work in ex vivo lentiviral therapy and also on some of Luigi Naldini’s work at San Raffaele University in Milan, using ex vivo lentiviral vectors.

 One thing we’ve done is refine the viral backbone of gene therapy. We did that by improving a replication-incompetent virus that's regulatory-friendly and continues to improve yields and titers. We also refined the cell processing aspect of gene therapy and found ways to enrich stem cells. Our corrected stem cells are more effective now than they were five to 10 years ago when we started.

 By building upon existing platforms, we can move more quickly to get treatment into the real world. That creates a strong business case because we can start developing therapies that will be approved sooner, as opposed to basing our operations on a scientific development that may or may not work and will take a lot longer to prove.

Tell us about the company’s financial successes to date?

We’ve had a series of successful financings based on milestones, most of which have been related to clinical data. Our formula for fundraising success has been to show investors that our therapy is working. The more people it works for, the better it works and the longer the duration of efficacy, the more excitement there is about it.

 Early milestones that led to financial raises included positive data for our experimental treatment for Fanconi anemia that demonstrated clinical proof of concept. And in 2020, our data for Danon disease allowed us to execute a very large late-stage raise.

 Moving forward into our next stage of development as a company, we will need to demonstrate an approval pathway, which we hope to do this year, and to start showing that the FDA is open to these approvals. We’re also simultaneously working on building a path to commercialization and to generating revenue. Those are the forward-looking milestones that will not only lead to more financing but also to financial independence for the company.

What regulatory and commercialization challenges do you anticipate moving forward?

On the regulatory side, we’re holding detailed discussions with the FDA around the ongoing clinical development of our AAV gene therapy in Danon disease. Given how rare the disease is and the absence of other treatments, we need to build an approval pathway. We completed a Phase I trial as planned and demonstrated that out of six appropriately treated patients, most had improvements -- and at the very least, stabilization -- across almost every parameter that we measured. It’s a devastating heart disease that kills patients, mostly males, by the age of 20, on average. We treated our patients as early as 11 or 12 years old and saw reductions in vacuoles. A build-up of vacuoles in the heart is the cause of this disease. Additionally, we saw improvements in lab markers of heart failure like BNP [B-type natriuretic peptide], and troponin, as well as improvements in echocardiogram imaging and other measures.

 We’ve taken this package to the FDA and are in talks about what a registration path might look like for a Phase II pivotal study. We’ve had positive discussions about the use of a single-arm, open-label trial design with a natural history comparator arm, using a biomarker-based composite endpoint supported by functional and quality-of-life assessments. In addition to Danon disease, we are also diligently preparing regulatory filings for our two late-stage lenti programs. We expect to submit regulatory filings for LAD-I and Fanconi anemia in the second quarter and fourth quarter of 2023, respectively.

In terms of the success of commercialization, I would say it starts with the right selection of the disease, its severity and unmet need. Novartis AG’s success with Zolgensma for SMA1 [spinal muscular atrophy type 1] is a good case study. Novartis exceeded commercial forecasts in the US and Europe, in large part because there's nothing else available for patients with SMA1 that really works. These kids would otherwise die by two years of age. When you have something that's potentially curative, the value story – and the patient story - is enormous. All the programs that we have address diseases that are as severe as SMA1, or cause death, or severe sickness if left untreated, so the value story of our treatments is strong and we think we are set up for success.

Clinical and regulatory success are the first steps in our roadmap to commercial success. We are already working to develop and lead the therapeutic areas in context by identifying and developing clinical centers of excellence, educating physicians, engaging with patient communities, promoting getting genetic testing and working alongside payors to ensure our groundbreaking science reaches all patients that can benefit from it. We are crafting launch plans to be ready by the time our first program comes out. All this comes to life as we have hired a best-in-class team, some from Novartis, and some from elsewhere.

Describe your own leadership style and the origin story of the company?

 

My leadership style is to a large extent about empowering others, based highly on trust and on making sure that whoever comes into the company has a chance to find their absolute best self and to develop not only professionally, but personally. I’ve always wanted everyone to not just grow their career, but to grow and enrich their lives while they're part of this company.

 I've grown a lot myself, even spiritually, from understanding who I really am, the roles one plays in the world, what I am  good at and not good at, learning to trust yourself, to trust my instincts, and learning how to engender the same confidence in others. And to shift my focus from the inward to the outside world, that's been my journey, and I want others to participate in that journey as well.

 My leadership style has also been informed by my music, which has been a whole parallel stream in my life. I've been in a band since eighth grade. Growing up in Texas in a traditional Indian family, I grew up influenced by Indian classical music and 80s and 90s rock. I lived blending two different worlds at any given time and I was able to see the world in multiple ways. The music I perform exudes that same global identity and blends a mix of styles. I am proud to say we were nominated for our first Grammy three years ago and then won in 2022. 

 I used to say that I learned more about leadership by playing and leading bands than I did during my medical training and experience in drug development, but today I would also say that being CEO at Rocket has made me a better musician. I’ve grown thanks to this frame of mind that emphasizes spiritual growth and a leadership style that empowers others, and that has ultimately revealed itself in the music in a deep and revelatory way.