Are gene therapies the ‘David’ in an industry of Goliaths?

In the gene therapy space, small biotechs can make a lot of noise. But all players ultimately face challenges at least as important as hopes they crystallize.



The release of the first draft of the human genome sequence in 2001 was supposed to kick off an era of precision medicine and curative gene therapies (GTs)(1,2). Only recently has that promise started to become a reality: the first curative, in vivo gene therapy (Luxturna) was approved by the FDA in December 2017, and several therapies are now on the market.

In this article, we define GT as a therapy seeking to treat or cure a disease by introducing new nucleic acid code to the patient, removing a faulty part of their code or editing genes to correct a defective sequence. We distinguish the in vivo approach – modifications made in specific cells while inside the body –, and ex vivo methods – modifications made to cells that have been removed from the patient for that purpose, also known as cell-and-gene therapy.(3)

GTs represent a tremendous opportunity in the pharma industry, with the captivating promise of turning the once-miraculous into clinical reality – making the blind see, the lame walk – hence hope for cure for patient groups where unmet need is high.

Figure 1

Fig. 1 – Quote summarizing the essence of gene therapy

Recognizing their potential, most of the world’s largest biopharma companies(4) now have GT assets. Yet, they are moving cautiously: only 2 of the top 20 have GTs making up more than 20% of their pipelines(5). In the meantime, smaller biotechs are leading innovation, and some are commanding disproportionate attention despite their size. As an example, our AI algorithm(6) highlighted Sarepta as 5th company mentioned by healthcare professionals with regards to precision medicine (grey bars in Fig. 2) and 2nd for GTs (colored bars in Fig. 2), while Sarepta being 100+ times smaller than Novartis in terms of revenues.

Fig. 2 – In the gene therapy space, small biotechs can make a lot of noise

Although the first approved therapies offer significant benefit, their real challenge is to prove themselves on the market. Usually, GTs run into four major challenges:


Ability to meet customers’ requirements and needs

Some therapies may only be available in a limited number of facilities (e.g., ex vivo therapies due to administration/delivery complexities), requiring patients to travel for treatment, possibly diagnosis and follow up. In addition, this could lead to capacity issues at launch, given the expected bolus of initial patients. Finally, many of the current treatments that GTs could replace (e.g., blood transfusions for hemophilia) are “buy and bill” and provide substantial long-term revenue for providers and hospitals. Meanwhile, a single high-priced dose via “buy and bill” presents risk to the hospital and distribution system.


Value recognition by payors

More often than not, health systems are not set up to handle large, one-time payments associated with GTs and their delivery. Most therapies also have limited long-term efficacy data, which can make the long-term cost effectiveness argument challenging. Therefore, payors tend to restrict eligibility, and innovative payment agreements are required to allow broad access. While such deals are starting to shape up in the space (e.g., Kymriah® in Italy and Spain), payors may wonder whether those deals are sustainable in the long-run.


Uncertainty associated with clinical outcomes

Long-term safety (e.g., liver toxicity due to viral load for in vivo GT) and efficacy (e.g., relevance of surrogate endpoints and durability) have yet to be established for stakeholders to recognize the therapy’s value. For instance, AAV-based(7) GTs can be confronted to a mechanism of resistance due to AAV-directed antibodies arising in the patient following the first injection and preventing subsequent dosing.


Ability to effectively meet the demand

Certain modalities, especially viral vectors, still suffer from capacity constraints, high cost of goods due to low and variable yields, and significant upfront investment requirements. In addition, demonstrating safety, quality, and potency of the final product can be a major challenge. This has implications for smaller players who might not be able to secure long-term capacity.

Fig. 3 – Market Access and Clinical challenges commonly linked to GT; Selected quotes

Thanks to recent advancements, we are beginning to realize the promise of GTs. However, the above challenges call for a paradigm shift across the ecosystem, requiring investment and buy-in from multiple stakeholders. Looking forward, yet-to-be-established ethical frameworks will also need to evolve to keep up with the science (e.g., CRISPR gene editing(8)). Biopharma and biotech companies will have a key role in empowering those changes to ensure their therapeutic advances are reaching those in need.

(1) International Human Genome Consortium. Initial sequencing and analysis of the human genome. Nature, 409: 860-921. 2001.
(2) Venter, J.C. Adams,  M.D., Myers, E.W., Li, P.W., Mural, R.J., et al. The sequence of the human genome. Science, 291: 1304-1351. 2001.
(3) In vivo = modifications usually made in somatic cells (e.g., lung, blood or muscle cells); Ex vivo = modifications usually made to bone marrow or blood cells
(4) By revenues
(5) EvaluatePharma World Preview 2018.
(6) Social listening conducted at Quadrant by training an artificial intelligence (AI) and natural language processing algorithm. Our final analysis examines ~51,000 conversations identified using 20 key terms from this pool of online dialogues between March ‘18 and March ’20.
(7) Adeno-associated virus (AAV) vectors are the leading platform for gene delivery
(8) Technique in molecular biology by which genomes of living organisms may be modified. It is based on a simplified version of the bacterial CRISPR-Cas9 antiviral defense system