Where is Gene Therapy Heading?

Where is Gene Therapy Heading?

By Niki Gallo, RAC – Associate Principal Consultant, Regulatory Affairs

Within the next decade, I expect to see ground-breaking, innovative changes in the way gene therapy products are developed, regulated, reimbursed and launched. Our industry is quick to analyze, repair and implement learnings from the current trailblazers to bring curative therapies to patients in need sooner. However, the present development and commercialization strategies will be a thing of the past when we encroach upon 2030 given our industry’s nature to continually improve upon prior methodologies. For starters, a transition from developing gene therapies for rare genetically defined diseases to pursuing larger patient populations is underway and has been for a few years. Although there is still a lot of work to be done in the orphan disease space, gene therapy developers are stepping further into oncology indications, musculoskeletal disorders and central nervous system / neurological disorders including multiple sclerosis, Alzheimer’s Disease, and Parkinson’s Disease. where the patient populations are much larger, and for the some, the root cause of the disease is not genetic. This leap into larger patient populations and non-genetically defined diseases result from our understanding of the inherent mechanisms at play for gene therapy products and the improved methods to evaluate tropism, biodistribution and immunomodulatory effects.

With this shift, there are pluses and minuses to pursuing a larger patient population. For example, on the manufacturing front, larger quantities of product will be needed from a complex biological (living) manufacturing process, manufacturing materials, and resources. Additionally, timelines will need to be closely scrutinized to maintain supply and demand. Platform technologies, such as delivery or vector platforms, will become a must and ultimately the preferred method for developing these innovative therapies to allow for expedited manufacturing development. The way gene therapies are prepared (freeze/thaw, wash, dilutions, etc.) and subsequently administered/delivered to patients will need to be streamlined for larger patient populations. Given the expedited development pathways applicable to gene therapy products, clinical development will not proceed in the traditional path, instead innovative clinical trial designs and the pooling of clinical data across studies will become the standard approach to developing these products.

Market access and reimbursement policies will need to be revamped if gene therapies are approved to treat large patient populations. This laundry list is just the tip of the “gene therapy” iceberg, and it is likely many other issues lie beneath the surface that will show themselves as we progress forward. We’ve all heard the buzz words “regulatory framework”, “market access and value”, and “manufacturing hurdles” fly around the gene and cell therapy sector for the past couple of years. These buzzwords and the effort behind them, while evoking images of a dynamic, entrepreneurial gene therapy ecosystem, has not produced much actual change. However, I anticipate more action from all sides, to implement change across these areas that become visible in 2020 and continue to impact the way gene therapies are developed throughout the next decade.

In 2019, the U.S. Food and Drug Administration’s (FDA) Center for Drug Evaluation and Research (CDER) approved 48 novel drugs (Advancing Health Through Innovation: New Drug Therapy Approvals 2019. FDA CDER January 2020) which is not as many as 2018 but still progressing on a nice upward trend since 2016.

Image removed.

Reference: Advancing Health Through Innovation: New Drug Therapy Approvals 2019. FDA CDER January 2020

According to the FDA’s Center for Biologics Evaluation and Research (CBER) website 2019 Biological License Application Approvals, current as of October 28, 2019, there have been 21 biological product approvals consisting of vaccines, biological assays, blood products, and one gene therapy, Zolgensma®. Instead of having 1 gene therapy product approved per year, that number will double if not quadruple as we progress into the next decade. Prior FDA Commissioner Scott Gottlieb and CBER Director Peter Marks were quoted a year ago stating that by 2020 they expect an upwards of 200 INDs for cell and gene therapy products each year, and by 2025 they expect to be approving between 10-20 cell and gene therapy products annually. I believe we are on track to meeting that mark given the strong gene therapy pipeline currently under development, supported by the Alliance for Regenerative Medicine (ARM) Quarterly Regenerative Medicine Sector Report Q3 2019 which states that there are 1,052 clinical trials underway worldwide involving gene therapy, gene-modified cell therapy, cell therapy, and tissue engineering. Specifically, the report states there are a total of 370 clinical trials ongoing with a gene therapy product, (Phase 1 =115, Phase 2 = 223 and Phase 3 = 32). And given the 2019 end of the year push, the number of Phase 1 trials has likely significantly increased with new INDs being activated.

The regulatory framework in the U.S. is evolving through recent FDA press releases, guidance documents, and FDA sponsored workshops focused on 1) developing therapies for specific indications in need or that are complex too, and 2) recommended methodologies that are dependent on product type to produce data. The traditional way of developing drugs does not fit the development innovations we are witnessing with gene therapy products. Conducting standalone Phase 1, Phase 2 and Phase 3 trials are rare for a gene therapy product. Given the expedited development programs of gene therapy products, the FDA welcomes dialogue and considers the use of alternative strategies to bring these targeted products to patients sooner. Whether it be from a single-arm trial to an open-label randomized trial, to pooling clinical data sets, both Sponsors and the FDA are exploring these alternative avenues to generate data to support a substantial claim of efficacy and safety.

As we progress into 2020 and the next decade, I expect to see many headlines regarding the partnership or acquisition of small gene therapy biotech companies or academic centers with big pharma, as big pharma continues to carve out or further supplement their cell and gene therapy product pipeline. To this end, I expect to see big pharma taking matters into their own hands by building their manufacturing facility(s) to try and avoid the excruciating long manufacturing timelines and overhead cost to hurry up and wait. For example, Novartis has opened a manufacturing facility for innovative cell and gene therapies in Switzerland in November 2019 and Bluebird Bio opened its first wholly-owned manufacturing facility in Durham, North Carolina for their cell and gene therapies in March 2019. ElevateBio in Waltham Massachusetts has developed a new business model to accelerate innovation of cell and gene therapies by creating and operating portfolio companies to which centralized research and development, integrated process development support and cGMP manufacturing capabilities are provided to accelerate product manufacturing timelines and reduce costs. Additionally, more and more big pharma is getting into the cell and gene therapy space, as was seen in the recent news with BioPharma Dive reporting that Roche has established itself as the biggest global players in gene therapy following a massive $1.2 billion collaboration with Sarepta Therapeutics and the Federal Trade Commission’s clearance to acquire Spark Therapeutics and Bristol-Myers Squibb (BMS) making a $100 million deal with UniQure to invest in their gene therapies for cardiovascular diseases.

The one aspect of gene therapy that both Sponsors, regulators, and insurers are presently working through is the cost of these innovative gene therapies and their reimbursement. The cost of developing and commercializing gene therapy products needs to be aligned with the regulators, insurers and reimbursement agencies earlier in the product development life-cycle, such as in parallel with achieving clinical proof of concept and maybe as early as pre-IND for a rare genetically defined inherited disease. Health regulators and reimbursement agencies need to harmonize and find common ground to provide Sponsor’s advice that is aligned to enable streamlined development of these cell and gene therapy products to produce data that satisfies both agency’s requirements. Joint scientific regulatory advice and health technology assessment (HTA) meetings will become a standard milestone meeting in product development.

Market access and value will likely take baby steps into this next decade, but I am hopeful that as we approach 2030, new systems and incentives will be in place to allow these innovative, potentially curative therapies to reach those patients in need without the sky-high price tag and bureaucratic obstacles. Presently, new pricing and reimbursement paradigms are being proposed and rolled out, Centers for Medicare and Medicaid Services (CMS) issued a final national coverage determination for CAR-T therapies, and large insurers are continuing to work with Sponsors on the amount of coverage and novel payment plans, particularly for Luxtrana and Zolgensma® the two most recently FDA approved gene therapies.

Gene therapy is red hot and will continue to be throughout the next decade. As we continue to develop these innovative products and learn more about their capabilities, we become more comfortable with their benefit-risk profile and have a deeper understanding how these products behave and their duration of effect. If we continue with this trend, perhaps gene therapies will become as commonplace as proteins or antibodies within the next decade or so.

Author Note: Niki Gallo is a strategic consultant to ElevateBio where she provides regulatory leadership and development strategy. Niki has more than 13 years of experience in regulatory affairs and drug development covering cell and gene therapies, small molecules, and therapeutic biologics with an emphasis on the disease areas of CNS, immuno-oncology, and oncology. Her experience spans multiple stages of drug development from executing early development strategies to supporting and executing marketing applications. Through partnering with clients, Niki leads early key milestone development activities such as generating the overall program development strategy, initial interactions with the U.S FDA (INTERACT and Pre-IND Meetings), original IND applications and subsequent FDA milestone meetings and expedited pathways discussions following the generation of clinical data.