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One of the most complex areas in disease management, is the ailments related to genetic disorders. As these were incurable, over the last four decades, medical researchers are engaged in understanding the complex and intricate process to modify human DNA, using viruses for treatment. This painstaking initiative led to the evolution of ‘gene therapy’ which, according to Mayo Clinic, ‘involves altering the genes inside human body’s cells in an effort to treat or stop the disease.’ In that process, ‘gene therapy’ replaces a faulty gene or adds a new gene, to cure a disease or improve the human body’s ability to safely and effectively treat dreaded ailments, such as cancer, cystic fibrosis, heart disease, diabetes, hemophilia and AIDS, it further added.

Several studies, e.g., one titled ‘Gene therapy on the move,’ published in the EMBO Molecular Medicine highlighted, the first gene therapy clinical trials were initiated more than two decades ago. However, initially many of these were impeded by the occurrence of severe side effects in a few treated patients. Nevertheless, over a period of time, ‘highly efficient gene targeting strategies and site-directed gene editing technologies have been developed and applied clinically.’ With over hundreds of clinical trials to date, gene therapy has moved from a vision to clinical reality – offering a powerful treatment option for the correction of monogenic disorders.

It is believed that in the new millennium, ‘gene therapy’ has emerged as one of biotech’s momentous success stories for curing many genetic disorders, which were once considered incurable. But, the cost of ‘gene therapy’ treatment is indeed jaw-dropping – ranging ‘from about US$ 500,000 to US$ 1.5m. And for treatment over a lifetime, some drugs can cost as much as US$ 750,000 in the first year, followed by US$ 375,000 a year after that – for life.

Since, I have already deliberated on ‘gene therapy’ price and associated moral dilemma that it causes, in this article, I shall focus on different concerns that could pose a threat to its ongoing commercial model. Nevertheless, let’s start with the current scenario on ‘gene therapy,’ for better understanding of the issue.

The current scenario:

According to McKinsey & Company’s October 2019 article - ‘Gene therapy coming of age’ - till 2019, the primary focus in development of ‘gene therapy’ has been on monogenic rare diseases with all currently approved therapeutics falling into this category. It is worth noting, rare diseases tend to have clear genomic targets, as well as, high unmet need in a very small patient population, who have generally been under-served by other, more traditional, therapeutic modalities (including monoclonal antibodies)—making them ideal targets for gene therapies.

More than 150 investigational new drug applications were filed for gene therapy in 2018 alone. With this in mind, McKinsey & Company expects this market to grow significantly, with ten to 20 cell and gene therapy approvals per year over the next five years.

Major ‘gene therapy’ launched:

If one takes a broad look at the ‘gene therapy’ treatments launched so far, which I have compiled from different sources, it may appear as follows.

The latest being Zolgensma of Novartis. It was approved by USFDA on May 24, 2019 for ‘patients less than 2 years of age with spinal muscular atrophy (SMA) with bi-allelic mutations in the survival motor neuron 1 (SMN1) gene.’ It costs US$ 2.125 million in the US for a one-time treatment.

However, to get a better idea on the industry focus in this area, let us look at the current ‘gene therapy’ pipeline.

Current ‘gene therapy’ pipeline:

To fathom the extent of industry interest in ‘gene therapy’ let’s have a glance at the depth of its pipeline – both in terms of phase-wise clinical study, as well as therapy areas covered. This will help understand the concerns that could pose a threat to its ongoing commercial model.

Adapted from: McKinsey article – ‘Gene therapy coming of age’, October 2019

Both large and small companies are entering into the fray:

Besides Novartis and GSK, as mentioned above, other Big Pharma constituents, such as Pfizer, Roche, Gilead and Bristol-Myers Squibb - are also putting their money in developing ‘gene therapy.’ This includes Mergers and Acquisitions too. For example:

• Pfizer’s ‘gene therapy’ deals with Bamboo and Sangamo,
• Novartis buying AveXis Inc,
• Roche acquires Spark Therapeutics,
• Gilead buys Kite Pharma,
• Bristol-Myers Squibb takes over Celgene.

Alongside, newer ‘gene therapy’ platforms continue to come up, many funded by venture capitals – further enriching the ‘gene therapy’ pipeline. In tandem, fresh concerns that could pose a serious threat to the ongoing commercial model of ‘gene therapy’ are also being realized. Mainly, the impact of the one-time or curative version of such avant-garde therapy on current pharma business models.

Also facilitates a giant leap towards personalized medicine:

‘Gene therapy’ is also believed to be a giant leap of medical science towards personalized medicine. This is because, in addition to repairing and replacing defective or missing genes of a human body, this therapy can use body’s own cellular immune system to treat the disease. This is because, CAR-T cell therapy can fall in the category of personalized medicine, where a patient’s T cells are changed in the laboratory, empowering them to attack cancer cells.

Concerns that could threaten its ongoing commercial model:

Despite its significant patient-value offerings with long-term benefits, ‘gene therapies’ that have been approved and are already in the market had to confront with tough unforeseen challenges, both from fresh regulatory questions - to therapy withdrawal for commercial reasons. These developments, coupled with a very low and difficult to identify patient population, and affordability related low market access, prompt the need of a transformed marketing model for novel ‘gene therapy.’ This is important for financial sustainability of current ‘gene therapies’ in most pharma markets, globally, including the United States.

Some critical areas:

An article on ‘gene therapy’ by the Managing Directors of L.E.K Consulting, published by Cell & Gene on May 16, 2019, also pointed to some of these critical areas. Even this paper articulated, the fundamental value proposition of ‘gene therapy’, its long-term efficacy with a single-dose treatment, gives rise to a number of unique challenges for its manufacturing companies. Let me paraphrase below just three of those, as I understand, to drive home this point.

Declining number of eligible patients for most doctors: 

The promise of a functional cure is expected to limit ‘gene therapies’ to a single dose per patient, in most cases. Thus, inability to re-treat would lead such therapies to deplete their addressable prevalent populations, for most doctors. This is primarily because, as the number of treated patient accumulates – the number of potential patients who could be treated in a given year is reduced. This leads to demand that would peak early before steadily declining. Once the prevalent population is depleted, the demand for a gene therapy would be driven by incident patients.

However, research has now been initiated targeting larger populations – e.g., those suffering from leukemia and lymphomas. But, the greatest revenue potential for ‘gene therapy’, is expected to be its success in delivering life-changing treatment outcomes in multiple myeloma. When such patients will get to experience better outcomes from cell and gene therapies, the incremental approach the industry has been taking in this area, will be more than justified.

Till then, it could pose a challenge to business sustainability:

As discussed, the ‘gene therapy’ sales curve with an early peak and then steady decline, caused by a depleted addressable patient population within a few years after launch, could pose a serious challenge to business sustainability. This would require launching, possibly another ‘gene therapy’ product before the revenue of the first ‘gene therapy’ starts waning. Consequently, the timing of its life cycle management efforts and subsequent launches would be a critical success factor.

Intricacy of market access dynamics:

Optimal market access of ‘gene therapy’ will call for working in unison with virtually all stakeholders, including regulators, governments, and at the same time, effectively disseminating the real-life treatment-success stories. However, both in the developed countries and also in the emerging markets, such as India, its treatment cost will continue to remain a key barrier, sans some disruptive pricing strategy.

How this tough task remains unresolved, can be sensed from the Wall Street Journal (WSJ) report of December 19, 2019 titled, ‘Novartis to Offer World’s Most Expensive Drug for Free Via Lottery.’ For this purpose, Novartis launched a lottery-style program to provide doses of its pricey gene therapy for Zolgensma, a one-shot ‘gene therapy’ cure, for free of charge. But, this approach drew criticism from patient groups that called it – an inappropriate way to distribute a lifesaving treatment aimed at babies for a deadly inherited disease whose victims cannot control their muscles. At a price of US$ 2.1 million, Zolgensma, is the world’s most expensive drug.

Conclusion:

As I discussed above, ‘gene therapy’, also known as ‘human gene transfer,’ has been one of biotech’s momentous success stories in the new millennium, paving the way for a cure of many genetic disorders – once considered incurable. However, the number of patients on ‘gene therapy’ remains small compared to other therapeutic regimens, mainly because of two factors. One – this therapy, mostly targets rare diseases, and the second – even among those small patient populations, only very few can afford such pricey therapy.

Nevertheless, current research in this complex area, is now targeting larger populations – suffering from leukemia, lymphomas and multiple myeloma. Success in these areas will open the door of significantly greater revenue potential for ‘gene therapy’ by delivering life-changing treatment outcomes. Till then, its current business model, I reckon, would continue to pose a high commercial risk to this venture.

By: Tapan J. Ray   

Disclaimer: The views/opinions expressed in this article are entirely my own, written in my individual and personal capacity. I do not represent any other person or organization for this opinion.