Advanced therapies are assimilating into the core of mainstream healthcare at an ideal pace. To gain insight into the current landscape, we recently conducted a Q&A session with Dr. Ali Ghanem, a multidisciplinary scientist and an advisor on different projects and products that aim to improve human health longevity. Let's discover what Dr. Ali has to say.

#LBS: Your Visualized Report on FDA-approved Gene and Cell Therapies emphasizes the recent acceleration of approvals in the field. What are the driving factors behind this accelerated pace?

Dr Ali: The current surge in Gene and Cell Therapy Approvals is mostly attributable to gene therapies coming of age, for the first time since 2011 (when the first cell therapy was approved) gene therapy approvals in the first half of 2023 have overtaken cell therapies. Additionally, the first half of 2023 has counted up to 5 approvals, reaching the benchmark of 2022 and 2021, with more awaited approvals expected to reach 13 approved therapies by the end of 2023.

The approval of two new AAV gene therapies in 2023 is very reassuring regarding safety concerns associated with high-dosed AAV therapies, underscored by the unfortunate incidents during the trials of Astellas’s AT123. Despite safety concerns around hepatotoxicity and adverse immune reactions, AAV vectors remain the preferred choice for gene replacement therapies targeting congenital and inherited conditions in both pediatric and adult patients. The continued favorable research insights ensuring the safety and tolerability of properly dosed AAV-based gene therapies in addition to the dire nature of the conditions, against which the

On the macro scale, the unprecedented rapid approval and roll-out of the Covid19 vaccine has opened the door to challenge the prior status-quo of innovative therapies taking over a decade to reach patients. This especially reflected upon cell and gene therapies as both the mRNA and vectorized DNA vaccines essentially entail delivering genetic material to immune cells in-vivo, hence approximating gene therapies in many ways. These vaccines- if imperfect in preventing infections- still served as the largest global post-approval safety proof-of-concept in over 70% of the global population.

On the regulatory side, the orphan drug designation is a steady enabler of gene therapies advancing through the clinical pipeline to patients in need, due to the financial upside, expedited procedure, in addition to community and patient advocacy support it entails. Consistently, 9 out of the 10 gene and cell therapies approved in 2022 and 2023 have benefited from an orphan-drug designation.

#LBS: In light of recent authorizations of various advanced therapeutic remedies, could you elaborate on the current available options and provide insights into potential developments on the horizon?

Dr Ali: To the most part, in-vivo gene therapy is focused on monogenic diseases, where delivering the correct copies of the missing or faulty gene can cure the disease. Mostly, this requires precision delivery of the therapeutic gene, and a lasting durable expression in the target cells. Adeno associated viruses have demonstrated enormous efficacy as the go-to vector for such application, successful examples including Spark/Roche‘s Luxturna, and Novartis’s Zolgensma, both approved in 2017. The first treats a devastating condition named LCA, which is a form of hereditary blindness (retinopathy) with very early onset in the first year of life, and the second treats a SMA, a paralyzing childhood neuromuscular condition that is fatal when left untreated. The landmark approvals were followed by a 5-year gap, influenced by the concerns surrounding the safety of AAV vectors. These have been gradually dispelled, as marked by the promising approvals of Hemgenix, and Roctavian in years 2022, and 2023, for the treatment of hemophilia B and A, respectively, and the remarkable approval of ELEVEDIS as the first gene therapy for DMD, another genetic fatal condition.

Other than AAV vectors for gene replacement therapies, originally pathogenic viruses can be vectorized for the topical treatment of certain cancers, or topical superficial genetic conditions, these include AV and HSV. Examples are the newly approved Vyjuvek, an HSV based therapy for the topical treatment of genetic epidermal condition, which very recently restored sight in an affected teenage patient. The 2022 approval of the AV-based Adstiladrin for the treatment of bladder cancer is another example of effectively turning viral pathogenicity against cancer cells.

CAR-T therapies are the most promising cell therapies of our time, with proven efficiency against various blood cancers. While solid tumors remain recalcitrant, the accelerating improvements of understanding of the tumor microenvironment, and the interactions between cancer and immune cells hold a great promise to unlock the power of these therapies against solid tumors as well. In my opinion, seeking to preserve the immune system while treating cancer -especially when chemotherapy is used- will turn into a major game changer in harnessing the superior efficacy of CAR-T cells against a wider variety of malignancy. The other more “conventional” large branch of existing gene therapies is represented by cord blood, and its derivatives, all used in the replenishment of the bone marrow, following ablation, which represents another winning approach against blood cancers.

As an enthusiast for the potential of cell and gene therapies in extending the healthy life span, and eventually enhancing and improving the functioning of healthy humans I am thrilled about the emergence of functional cell therapies. This is defined by replacing a particular cell type by cells that can achieve the same physiological function, and therefore reversing the pathogenic degeneration. The first of these therapies to be approved is Lantidra, the first cell therapy for patients with type 1 diabetes. Just yesterday, as I write these words, an experimental functional stem cell therapy by Bayer/BlueRock’s has shown promise following the first year of an open label phase 1 trial. And this is just the beginning of a new era in human medicine, as successful targeted replacement of human cells in vivo holds the promise of preventing all types of degeneration, both pathological and “age related”, enhancement of healthy functions -while still medically and ethically questionable- is becoming increasingly imaginable, to put it mildly.

Another general trend is that ex-vivo cell and gene therapies have the advantage of lowering the risk, as cells can be modified and controlled ex-vivo, prior to in-vivo delivery. With that said, precision in-vivo gene therapy vectors (both or viral or purely synthetic origin) can also catch up both in efficacy and safety, enabled by the unlimited theoretical and practical variety of vector libraries, and the groundbreaking acceleration of single-cell tracing technologies. Once there, these have some advantages over cell therapies, including easier manufacturing, distribution, and administration.

#LBS: What trends or factors do you believe contribute to the growing appeal of cell and gene therapies as an investment opportunity? How do you foresee these trends shaping the future of the sector?

Dr Ali: Cell and gene therapy have seen a tremendous increase in venture capital and private equity investment with a CAGR of 18% between 2010 and 2021, enabling a staggering growth rate of 59% and 63% in Gene and Cell therapy sectors over the same period, respectively.

Amid the pandemic and the unprecedented acceleration of approval for various vaccines, the majority of which depend on novel technologies, and the realization of the potential to reduce the turnover rate of biotech innovation has increased investments and attracted new classes of investors to the space, especially from the tech space. Year 2020 saw the overall investment raised by Cell and Gene Therapy developers jump by $10 B to reach $19.9 B, the upward trend continued in 2021 to reach $23.1 B. This funding peak has coincided with a surge in approvals in years 2021, and 2022 and the trend continues strongly into 2023 and beyond. Following 2022 the shifting market conditions and increased interest rates have placed significant financial strain on early stage biotech companies, akin to other tech start-ups. Under these frugal conditions the acquisition market will offer a lifeline for promising early stage therapies, while developers with more matured therapies in phase II and III are expected to continue to raise the necessary funding to get their therapies to patients, as seen already in the increased number of trials and increased financial runway allowing more therapies to progress from the pre- and early clinical space to advanced clinical trials and eventual approvals. Currently in the foreseeable future, the acquisition market will continue to provide the funding to ensure that most promising experimental therapies will still get a chance to reach the patients.

#LBS: In your opinion, what are the primary challenges that cell and gene therapies face in moving from the fringes to mass production for widespread patient use? How can these challenges be addressed to accelerate progress in this area?

Dr Ali: High cost remains the main hurdle to be overcome to allow access to much needed gene and cell therapies. The soaring manufacturing costs, combined with a relatively small patient population for the majority of cell and gene therapy are the driving factor of the astronomical price tags for most cell and gene therapies. To overcome this bottleneck, developers, manufacturers, regulators, insurers, and societies at large, must all embrace a combination of pragmatism, flexibility, and creativity, to enable the continued innovation in this sector, and ensure the democratized access by patients.

One example to shed light on the enormous cost challenge, is that of the newly approved Hemgenix for the treatment of Hemophilia. The list price of the treatment at $3.5M exceeds the cumulative share of a US citizen over 50 years, and that of a German citizen for over 68 years of their current respective countries’ GDPs. This is a stark example highlighting the dilemma facing healthcare payers, policy makers, and societies at large when it comes to democratizing access to such groundbreaking therapies. The situation gets only more unrealistic in the developing countries with lower GDPs per capita than that of the US or Germany.

On the regulatory front, further facilitations should be made that go beyond the advantages of orphan-drug designation. For example, monogenic hereditary diseases of the same organ can all be treated by delivering a correct copy of the faulty or missing gene to the target cells, once the developer shows success in safely treating such a disease using a particular vector, swapping the transgene to treat other monogenic deficits of the same tissue is a fairly simple and straightforward process that should not necessarily require the developer to go through the complete approval lifecycle. While caution and rigor must be kept regarding the transgenes in questions, simplifying the process of further gene therapy approvals using an already approved vendors would give an enormous boost to the field, as developers and manufacturers will be vying to gain access to much larger patient pool based on the same initial investment in ensuring their vector’s safety and efficacy.

Another important trend is the point of care manufacturing of cell and gene therapies; this is in part necessitated by the autologous nature of many cell therapies, most prominently CAR-T therapies. University hospitals and research institutes are bound with gene vector, and transgenic cell production capabilities, innovation in upgrading these capabilities and validating their quality to get on par with GMP facilities has enormous potential to add to the currently limited and overbooked GMP production capacities.

It is also promising to see big pharma actively getting into the field of gene and cell therapy manufacturing, the experience and efficiency of big pharma in streamlining manufacturing, gaining approvals, and marketing therapies all hold huge potential in synergy with the capabilities developed by cell and gene therapy platform companies. A prominent example is the fresh news of the $401 M series D funding invested by Novo Nordisk in ElevateBio.

#LBS: The London Biotechnology Show offers a platform to explore and present various cutting-edge therapeutic solutions. How significant are these gatherings for the emerging and expanding field of medical biotechnology?

Dr Ali: At this uniquely pivotal time for cell and gene therapy and the biotech sector in general and all types of platforms, conferences, and events bringing together biotechnology specialists with different backgrounds will increasingly become the catalyst for the advancement of the field due to the unique opportunities presented from the cross-pollination of ideas between specialists with different scientific and medical backgrounds. As biotech gets beyond the research labs and seeks to positively reshape our world, wider platforms going way beyond academia to include investors, policy makers, patient advocacy groups, healthcare providers and other stakeholders will increasingly shape the future of biotech, medicine, and the human experience all in all. In this age and era, openness to collaboration, agility in embracing good solutions, and creativity in implementing them in a sustainable and equitable manner will make the difference between failure and success for individuals, companies, and societies, all alike.