Leading Expert Insights on Drug Development and Immunology

Dr Narendra Chirmule

Director of Biological Sciences at Symphony Technology

In this exciting blog, we have the privilege of hearing from a seasoned expert, Dr Narendra Chirmule, PhD who has dedicated decades to advancing our understanding of immunology and pushing the boundaries of drug development. Dr Chirmule is a Director of Biological Sciences at Symphony Technology, a data analytics company focused on engineering solutions to biology and engineering, and an adjunct professor at University of Pennsylvaia, IIT-D, IIT-B and Shoolini University. He was former Head of R&D at Biocon (Bangalore), and previously at Amgen (Thousand Oaks, CA) and Merck Vaccines (West Point, PA). He has worked on clinical development of vaccines and biopharmaceuticals. Join us as we explore pivotal moments, groundbreaking discoveries, and the promise of exploring the fascinating world of drug development and immunology.

Please tell us about your professional journey and how you got involved in the field of drug development and immunology.

My journey in immunology commenced during my Ph.D. studies at the Cancer Research Institute, Mumbai, India, with Padmashri Dr M.G. Deo, MD-PhD, and Dr Rita Mulherkar, focusing on the immunology of leprosy. Since then, I have been immersed in various facets of immunology, including infectious diseases, gene therapy, and autoimmune conditions.

I feel privileged to have sustained my involvement in immunology over an extended period. The field holds a captivating allure, particularly in the realm of drug development. My inaugural foray into drug development occurred during my tenure at the University of Pennsylvania in the mid-nineties, where we pioneered gene therapy, with Dr James Wilson and colleagues, employing adenoviral vectors to address rare diseases.

Afterward, I joined Merck, where I played a role with amazing teams in development of vaccines for Rotavirus (Dr James Drummond), HPV (Dr Mark Esser), Varicella Zoster (Dr Rocio Marchese), HIV (Dr Lisa Kierstead), among others. Later, I moved on to Amgen to work on biologics such as Nplate (Dr Vibha Jawa), denosumab (Dr Mike Moxness), EPO (Dr Dan Mytych), Enbrel (Dr Arunan Kaliyaperumal), and then Biocon (Dr Ramkrishnan Melarkode, Dr Anuj Goel), where I had an opportunity to work on biosimilars. My journey in drug development was a gradual one, spanning 40 years during which I acquired valuable insights into regulatory strategy. I also honed my ability to cultivate personal relationships with regulators, academics, and industry experts in this collaborative arena dedicated to advancing drug development. Above all, I came to recognize the paramount importance of prioritizing the patient's well-being.

In your opinion, what are some of the most exciting recent advancements in immunology that are shaping the field of drug development, especially in oncology?

The promise of gene therapy and cell and gene therapy in various diseases, particularly in oncology, is truly exciting. I've observed the progressive development of our understanding of immune responses over the five decades that I've been immersed in the field. Starting around five decades ago, significant discoveries such as the identification of immune cells like CD4 and CD8, along with the functions of other predominant cells, have proven immensely fruitful.

For instance, Dr Max Cooper's discovery of B cells and their role in generating antibodies, and Dr Jacques Miller's elucidation of the timeless role of the thymus in T cell development, both from around 50 years ago were honored with the Lasker Award. This recognition underscores the pivotal role of the immune response in various aspects of disease. This significance was especially apparent during the pandemic, with immunologists and virologists playing central roles in enabling communities to understand the devastatic effects of the virus.

One of the most exciting recent advances in immunology is the comprehension of checkpoint inhibitors, which merited the Nobel Prize for Dr Jim Allison and Dr Tasuku Honjo a few years back. This marked a pivotal moment in our understanding of immunology. Since then, numerous other remarkable discoveries in immunology have emerged, fundamentally altering how drugs are developed based on our understanding of immunological processes.

Please share an example of a particularly challenging project you've worked on in drug development and how you overcame these challenges?

This question had been bothering me for quite some time, and it's likely the reason why I wrote the book 'Good Genes Gone Bad' by Penguin publishers. Each chapter in the book delves into a specific challenge in development and highlights the outcomes and solutions that arose from those challenges.

What's striking is that every solution born from these trials and challenges has brought about fantastic advancements in the development of new drugs for various diseases. One key takeaway for me in this journey of learning from failures is that failures often provide more valuable lessons than successes. It's a powerful message. Another insight is that without experiencing failure, one cannot unearth a new path.

This understanding has remained a constant in my approach. Consider, for example, the study on the development of a vaccine against HIV. Creating an effective HIV vaccine has posed a significant challenge over the past few decades. A notable instance was about a decade ago, when an Adenoviral vector was employed to elicit an immune response.

The STEP trial not only showed that the vaccine didn't work, but it actually made individuals more susceptible to contracting HIV. This was a monumental setback in the quest for an HIV vaccine. Even now, the field is grappling with how to engineer a more effective HIV vaccine. I often share this story because it encapsulates the progressive evolution of our knowledge in immunology and vaccinology, and the valuable lessons gleaned from failures along the way.

Please can you highlight any promising areas of research that have the potential to revolutionize the development of new drugs and therapies?

As I mentioned earlier, developing gene therapy certainly hinges on a thorough understanding of the human genome sequence. I believe that the progress in computational technologies, encompassing both increased computational power and the emergence of technologies like general AI, machine learning, and modeling, plays a pivotal role. Additionally, advancements such as quantum computing and enhanced computing speed further contribute to this.

The synergy between biological understanding and computational prowess will undoubtedly lead to the discovery of numerous 'needles in the haystack', ultimately facilitating the development of more effective drugs. This provides a high-level response to your question. There are, of course, numerous specific examples along the way that can be elucidated.

The next question What do you see the role of emerging technologies such as AI and machine learning playing a role in the future of drug development in immunology?

These technologies are poised to play a significant role in uncovering valuable insights from the vast amounts of available data in genomics, proteomics, transcriptomics, and other 'omics' fields. These disciplines generate extensive datasets. Our task is to sift through this data to discern patterns in genes, proteins, and signatures. This enables us to either diagnose diseases or gauge their progression. Additionally, it aids in identifying promising targets for therapies against such conditions.

In terms of specific examples, this is an emerging field. The US FDA has extensively referenced the use of AI and machine learning in drug discovery on their website. This endorsement encompasses various facets of discovery, including pharmacology, where it helps understand the dosage-response relationships crucial in treating specific diseases, as well as toxicology, where it assists in predicting potential safety concerns and adverse events for a particular drug.

How important is collaboration between industry, academia, regulatory bodies in advancing drug development and immunology?

Well, we've really homed in on a very important question that I feel is, is probably central to every question that I can answer. This collaboration has been pivotal, and I'm fortunate to work alongside some exceptional colleagues and partners. Shilpa Bhat, Sabyasachi Mondal (both now in Mu-Sigma, Bangalore) and I even authored an article on this topic, which was published in the Indian Journal of Science under the National Science Academy Journal, emphasizing the critical nature of this collaboration.

I believe the key factors in enabling such collaborations are straightforward. Each group involved has distinct needs. Academics might require financial support, industry seeks innovative ideas, and regulatory bodies necessitate quality control, processes, and oversight. So, there's a unique set of needs for each group, and the intersection, or the 'Venn diagram', for each of these entities centralizes around common elements where everyone can contribute. Figuring out these Venn diagrams, understanding what each party requires, and finding common ground presents a fantastic opportunity for transformation in India.

Another noteworthy point I'd like to make is that India, in general, has witnessed a series of leapfrog technologies since gaining independence. Whether it's the advent of telecommunication, advancements in the banking system, or the introduction of the UPI system for seamless access to payments, there's a history of immense learnings in this rapid exponential progress.

All of these technologies have been transformational And so I think healthcare transformation is the next big thing. I don't know precisely what it is going to be, but it will be a combination of many small things that is going to change. Digital Heath, a focus of the government, will be central to the transformation to access affordable healthcare.

What advice would you give young scientists and researchers aspiring to make a meaningful impact in the field of drug development?

Yeah, very difficult to give one piece of advice. There are many small elements to consider. One thing that comes to mind, albeit somewhat clichéd, is to 'follow your passion'. However, I often emphasize the importance of determining your life's purpose.

While identifying one's purpose can be a formidable task, there are various avenues and methods to explore it. Engage in activities and pursuits with fervor a clear sense of purpose. Discovering this can be a challenging journey. So, while there are many facets to consider, I would say, seek out a mentor or a group of mentors with whom you can have ongoing discussions.

Looking ahead, what do you believe will be the key challenge and opportunity in the field of drug development in the next decade?

I believe the primary challenge will be finding the right drug for the right patient at the right time. Achieving this will necessitate extensive data analytics. It's crucial to recognize that not all drugs will have the same impact on all the individuals. Therefore, tailoring treatments to the specific patient and stage of the disease will likely be a major advancement for the future—embracing the concept of personalized medicine.

Another aspect I find intriguing is the emergence of what's known as 'hallmarks' in the last decade, as published by the Journal Cell. They have covered 'Hallmarks of Cancer' and 'Hallmarks of Aging'. In 2021, they released a comprehensive review article on what they term 'Hallmarks of Health' by Drs Carlos Lo´ pez-Otı´n and Guido Kroemer. What struck me was the realization that, for centuries, medicine has predominantly focused on understanding and treating diseases. However, it's high time we shifted our attention to comprehending the factors that sustain health. It's truly remarkable that the majority of us remain in good health most of the time. Understanding the biology of health is arguably as, if not more, crucial than understanding the biology of disease.

From an immune response perspective, there's a growing interest in fundamental immunology concepts like the “hygiene hypothesis”. These areas, including the systematic study of the gut microbiome and an understanding of how our brain, nervous system, social interactions, and mental well-being influence our overall health, are now being explored with greater precision and depth.

Please provide a brief overview of your book Good Genes, Gone Bad, and what inspired you?

When I started writing the book, I didn't have a clear plan about its content. I began by recounting my experiences in developing various drugs. Over time, I assembled these stories, which eventually formed the book. It's been close to four years since the book was written and then published. Looking back, if I were to rewrite it, I would likely emphasize a theme that has become more apparent in retrospect. This concept will be central to the next edition.

The overarching theme of the book, I believe, is that we derive more significant lessons from our failures than our successes. Furthermore, the successes that follow failures may not have materialized without those initial setbacks. That, I think, would encapsulate the essence of the book and what motivated me to write it.

I've always felt compelled to write a book. While I've authored numerous papers over the years, I've also maintained a fervent habit of daily writing. On average, I write about 100 to 200 words on various subjects each day. So, for me, writing comes naturally.

The “art” of this “science” is s, about how to bring all of it together.

Please share an example or two from the book that illustrates how genetics can play a role in health and disease.

One I particularly appreciate involves a gene called PCSK9, which codes for a protein involved in lipid metabolism. This protein serves as a chaparone toushering LDL cholesterol, often dubbed 'bad' cholesterol, to be cleared through the liver. Surprisingly, in the absence of the PCSK9 protein, cholesterol levels are markedly reduced at a significantly faster rate.

The validation of this biological process came through the discovery of a few rare disease patients who possess a mutation in the PCSK9 gene, resulting in remarkably low cholesterol levels. This serves as a compelling genetic confirmation of a target for effective cholesterol reduction. While there are many other examples, this one stands out to me as a vivid illustration of how genetics intricately intertwined with health, disease, and the development of pharmaceutical interventions.

And finally, could you give me a little glimpse of your vision of the future of drug development and how it can benefit patients and health care as a whole?

Well, it's a formidable task to articulate a vision like this. I've had the privilege of engaging with numerous individuals in both the U.S. and India. I've been fortunate to teach in both countries, at the University of Pennsylvania in Philadelphia and in Delhi and Solan. I am grateful for my colleagues' support, and I hope to extend these opportunities to Mumbai soon, with the help of Dr Ashutosh Kumar and others.

The future of drug development, in my view, encompasses several crucial elements. As I mentioned earlier,

• Understanding the factors contributing to good health will be of paramount importance.
• Personalized medicine through the process of data analytics is set to play a significant role.
• The application of advanced technologies will be pivotal in addressing debilitating diseases.

I am deeply passionate about working on rare diseases. Individuals afflicted with rare diseases, along with their families, face incredibly challenging times. Society has a collective responsibility to strive for the treatment for these conditions. Large pharmaceutical companies often lack the incentive to invest in the development of drugs for rare diseases, making it even more crucial to focus on them. I have had the fortune of working closely with the Indian Association of Muscular Dystrophy (IAM:D), in Solan, with Sanjana Goyal, and with Ambrish Kapadia, in Mumbai. They have taught me so much about focus, hard-work, collaboration, and societal support in bringing much needed medicines to patients.

There are over 7000 recognized rare diseases, possibly affecting more than 100 million patients worldwide. While collectively it constitutes a substantial healthcare challenge, it's imperative to approach each rare disease individually and work towards its development.

On-Demand Webinar: Risk Mitigation in Gene Therapy Clinical Trials Development

Dr Narendra Chirmule co-hosted a webinar. Listen to our On-demand webinar as our subject matter experts explores key themes regarding

• Risk Mitigation in Gene Therapy Clinical Trials
• Gene Therapy in Diabetes
• Opportunities and Challenges in Gene Therapy Clinical Trials

Dr Narendra Chirmule

CEO
SymphonyTech

Dr Kirk Hammond

Professor of Medicine,
UC San Diego and Founder
Renova Therapeutics

Dr Atul Gupta

Associate Vice President, Medical & Scientific Affairs
Navitas Life Sciences

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