Gene Editing: A Powerful, Growing Modality In Regenerative Medicine
Executive Summary
Regenerative medicine has made advances in recent years to emerge as one of the key fields with a chance of addressing, and even curing, diseases that until now had few or no treatment options.
These regenerative methods have far-reaching potential and mark an important next wave of research targeting genetically defined diseases, as well as chronic or life-threatening disorders that are underserved or not yet addressed.
Broadly defined, the regenerative medicine market encompasses a wide range of treatment modalities that help to repair, replace or regenerate lost functionality in tissue that has been damaged because of disease, injury or aging. How regenerative medicine is specifically characterized can vary, but it generally includes therapeutic- or pharmaceutical-based treatments, devices or types of engineered materials.
Government initiatives have been helping to move the regenerative medicine field forward, including the 2007 regulation introduced in the EU to govern advanced therapy medicinal products (ATMPs), and most recently, the creation of the regenerative medicine advanced therapy (RMAT) designation in the US under the 21st Century Cures Act.
In parallel, there has been exponential growth in the regenerative medicine therapy pipeline. In 1995, there were 114 drugs from preclinical through to pre-registration phases in development; by 2017, that figure had increased to over 1,000. The volume has been steadily growing year on year since 2010. A sharp uptick starting in 2015 was the result of an investment resurgence in this area, particularly in gene therapy, which had dropped off following patient deaths in clinical trials at the end of the 1990s. This revival was also prompted by the promise of the field following several product launches outside of the US.
Exhibit 1. Growth In Regenerative Medicine Pipeline, 1995–2017
Source: Pharmaprojects
The regenerative medicine pipeline is led by in vivo gene therapies, which account for 30% of the volume. The next generation of these products has improved in safety over initial treatments. Gene therapy developers have become more targeted when it comes to the patient populations being treated and more niche indications, and by focusing in on parts of the body that are somewhat separated from the immune system and antibodies that might attack. There have also been improvements in the delivery vectors used. Altogether, the potential for gene therapies to offer single-treatment cures of genetically defined diseases will ultimately continue to move this class forward.
Exhibit 2. Pipeline Therapies By Product Type
Source: Pharmaprojects
In the current pipeline, only approximately 3% of the volume of candidates are gene editing therapies. While the proportion is small, gene editing presents a unique and potentially paradigm-changing opportunity in the regenerative medicine market. The underlying principle of gene editing is to make precise changes to DNA in a cell. As opposed to gene therapy – which essentially provides a gene or genetic instructions for the cell to use – gene editing permanently and more precisely changes a cell's genome. There are high hopes this modality will provide a way to radically impact how diseases are targeted. The technologies in place to perform gene editing take varying approaches but ultimately the goal is to improve treatment, and possibly generate cures for thousands of inherited disorders caused by genetic defects.
Across the gene editing therapy pipeline, the most active companies range from discovery-stage biotechs to large pharmaceutical companies. The key clustered regularly interspaced short palindromic repeats (CRISPR)/CRISPR associated protein 9 (Cas9) companies are well represented, including Editas Medicine Inc. and CRISPR Therapeutics AG, which each have 10 candidates in development (either as an originator or licensee). Among the big pharma (companies with annual revenues in excess of $15bn) and mid pharma peer sets, Shire PLC, Pfizer Inc. and Bayer AG have stakes in gene editing.
Exhibit 3. Most Active Gene-Editing Companies
Source: Pharmaprojects
The pipeline of gene editing drug candidates is dominated by clustered regularly interspaced short palindromic repeats (CRISPR)/CRISPR associated protein 9 (Cas9) technology. There are nearly 60 gene editing therapies currently in development from preclinical through Phase II (the most advanced stage for any gene-edited candidate in the pipeline presently), and 74% of them use the CRISPR/Cas9 method. It is a clear indicator of the interest and investment in this latest generation of gene editing technologies for the long term, and companies' vision that it has the most potential for producing new therapies as a result. At much smaller proportions, zinc-finger nuclease (ZFN) therapies account for 14% of the pipeline (all of these exclusively owned by Sangamo Therapeutics Inc.), and transcription activator-like effector nuclease (TALEN) candidates take a 10% share (sourced solely from Cellectis SA, which has been the most advanced with TALENs programs in the pipeline).
While CRISPR/Cas9 candidates are the most abundant in the gene editing pipeline by volume, they are further back in development, reflecting the relative newness of this method in gene editing drug development. All of the CRISPR/Cas9 therapies are in preclinical studies, although there is ongoing academic research to test the application of CRISPR/Cas9 in humans. In contrast, ZFN, which has been in practice a lot longer by Sangamo, is incorporated into more advanced programs. The majority of ZFN candidates (those from Sangamo) are in Phase II.
Similar to CRISPR/Cas9, there is a higher volume of TALEN therapies in the preclinical setting, although Cellectis has two candidates in Phase I, including programs partnered with Pfizer and Servier.
Rare diseases, many of which are genetically defined, are the primary targets for gene editing candidates in the pipeline. The same holds true when filtering down to most gene editing methods. For both CRISPR/Cas9 and ZFN technologies, the volume of therapies in development is higher for rare diseases than for any other therapy area. Other primary therapy areas where overall gene editing is active include oncology, blood and clotting diseases, and infectious diseases. (It is worth noting that these therapy area categories also include rare diseases that are counted in the separate "rare disease" category.) CRISPR/Cas9 therapies have a broader reach, with development in several other areas. In contrast, TALEN editing candidates to date have been focused on cancers, many of which are rare diseases themselves.
Exhibit 4. More Gene-Editing Therapies For Rare Diseases
Source: Pharmaprojects
Within the broad category of rare diseases are several unique indications that are active in development. Leading that group of rare disorders is thalassemia, for which four preclinical therapies are in the pipeline. Both Poseida Therapeutics Inc. and Editas are working on candidates themselves, while CRISPR Therapeutics and Sangamo Therapeutics have secured bigger partners: Vertex Pharmaceuticals Inc. and Bioverativ Inc., respectively.
In addition to thalassemia, sickle cell anemia and Duchenne muscular dystrophy are being pursued within rare diseases via a high volume of gene editing therapies. Various cancer indications are also the subject of multiple gene editing candidates in the pipeline. Among the specified cancers, lymphomas are the most active (including Hodgkin's lymphoma and myeloma, which are considered rare diseases), with this development exclusively being done by Cellectis. For many of the other oncology candidates, the tumor types at this point have not yet been identified because of the early-stage nature of the work being done.
Within the commercial biotech community, both Intellia Therapeutics Inc. and Editas could be the next to initiate Phase I trials in CRISPR/Cas9 therapies, and would be the first development-stage companies to do so. Intellia and Editas may file their IND applications within the next couple of years.
Intellia is potentially the closest to reaching the clinic with a CRISPR/Cas9 therapy for transthyretin amyloidosis, an abnormal build-up of amyloid deposits in organs and tissues. The company presented preclinical data at the American Society of Gene & Cell Therapy Annual Meeting in May 2017 showing a high reduction of serum transthyretin protein levels in two animal models. Intellia may submit its IND in early 2018. Since 2016, Regeneron Pharmaceuticals has been co-developing the transthyretin amyloidosis candidate and holds co-promotion rights.
Editas may have been ahead of Intellia in starting its human trials, but a manufacturing issue disclosed in May 2017 has delayed Editas's IND filing to mid-2018. Editas's lead CRISPR/Cas9 candidate aims to treat leber congenital amaurosis 10, a retinal disorder that causes severe visual impairment. Editas optioned this program, among others for ocular diseases, to Allergan in March 2017. Editas is still gathering preclinical data and now must contend with the manufacturing delay, which the company says is related to quality control around the input materials needed to produce the adeno-associated viral vectors. Editas' CEO Katrine Bosley said the company had lost its time slot with its contract manufacturing organization.
Not to be outdone by the other two, CRISPR Therapeutics could be beginning its own human studies soon in Europe. In May 2017, the company said that it was planning to file a clinical trial authorization by the end of 2017 for its beta-thalassemia therapy CTX001, to which Vertex holds a licensing option under a 2015 deal. The manufacturing process has already been vetted by Germany's Paul-Ehrlich Institute and the UK's Medicines and Healthcare Products Regulatory Agency.