Roche Secures Ex-U.S. Rights to Sarepta’s DMD Gene Therapy SRP-9001 in $2.85 Billion Deal

Today, Roche and Sarepta Therapeutics jointly announced that they have entered into a licensing agreement, under which Roche will obtain exclusive commercialization rights for the Duchenne muscular dystrophy (DMD) gene therapy SRP-9001 in markets outside the United States. Sarepta will receive a total of $1.15 billion in upfront payments (including $750 million in cash and $400 million in equity investment) and up to $1.7 billion in potential milestone payments. According to Vantage, this is the largest licensing deal to date for an investigational asset in the cell and gene therapy sector.

Sarepta Therapeutics has recently seen a string of good news. The U.S. FDA recently approved its exon-skipping therapy Vyondys 53 for the treatment of Duchenne muscular dystrophy (DMD), significantly boosting the likelihood of approval for its third investigational exon-skipping therapy, casimersen. Although the gene therapies in Sarepta’s pipeline have received less attention than its exon-skipping drugs, they may hold greater potential for treating patients with DMD.

SRP-9001: A Potential Curative Therapy for All DMD Patients

In patients with Duchenne muscular dystrophy (DMD), mutations in the gene encoding dystrophin lead to the absence or deficiency of this protein. Dystrophin plays a critical role in maintaining tissue integrity during muscle contraction; its deficiency results in chronic damage and inflammation during muscle contraction, thereby impairing muscle regeneration. Ultimately, muscle tissue is replaced by scar tissue or fat. Muscle weakness in DMD patients becomes apparent at age 2–3 years. With progressive loss of muscle tissue and function, patients are typically confined to wheelchairs by age 12, require assisted ventilation by age 20, and suffer premature death due to respiratory or heart failure between ages 30 and 40.

Currently, although Sarepta has two exon-skipping therapies approved by the FDA, their limitation lies in being effective only for DMD patients with mutations in specific regions of the dystrophin gene. Therefore, the approved Exondys 51 can treat only about 14% of DMD patients, while Vyondys 53 can treat only 8%. The advantage of gene therapy is that it has the potential to provide therapeutic benefits regardless of where the mutation occurs in the dystrophin gene.

Gene therapy packages transgenes encoding functional dystrophin into adeno-associated virus (AAV) vectors, which are then administered to patients. These vectors deliver the dystrophin-expressing genes into patients’ muscle cells, turning them into “in vivo factories” for dystrophin production. Since the DMD gene, which encodes dystrophin, is one of the largest genes in the human genome, and AAV vectors have limited cargo capacity, the DMD transgene currently loaded into AAV vectors expresses a truncated version of dystrophin known as “micro-dystrophin.”

▲ Full-length dystrophin (a) and several micro-dystrophins expressed by gene therapy (b) (Image source: Reference [5])

Sarepta’s SRP-9001 is a gene therapy utilizing the AAVrh74 vector, which was isolated from non-human primates. The advantages of this AAV vector include its ability to drive robust transgene expression in muscle tissue without crossing the blood-brain barrier into the central nervous system. Furthermore, pre-existing immunity to this viral vector is present in fewer patients. The SRP-9001 gene therapy employs the MHCK7 promoter to drive transgene expression. This promoter not only facilitates transgene expression in skeletal muscle, cardiac muscle, and the diaphragm, but also specifically enhances transgene expression in the heart.

▲AAVrh74 viral vector (Image source: Reference [6])

Early clinical trial data released last year indicated that among the initial four Duchenne muscular dystrophy (DMD) patients treated, the SRP-9001 gene therapy not only demonstrated a favorable safety profile but also drove micro-dystrophin expression in all patients, with mean levels reaching 74.3% of normal. In comparison, Vyondys 53, which was recently approved, increases dystrophin levels to only 1% of normal. Although the two therapies express different types of protein (the protein expressed by Vyondys 53 is closer in structure to the full-length, functionally intact dystrophin), the ability of SRP-9001 to drive high-level dystrophin expression is undoubtedly a positive sign. Furthermore, preliminary trial results showed that all patients exhibited significant functional improvements in motor function scores compared to baseline. Currently, SRP-9001 is being evaluated in Phase 1/2 clinical trials.

What Messages Does Roche’s $1.15 Billion Upfront Payment for SRP-9001 Convey?

Roche’s licensing deal with Sarepta sets a record for the largest single-gene therapy asset licensing agreement. What message does this blockbuster transaction convey?

Confidence in the Safety of the AAVrh74 Viral Vector

One of the key challenges to overcome in using gene therapy for Duchenne Muscular Dystrophy (DMD) is safety. In the late 1990s, the once-booming field of gene therapy experienced a nearly decade-long stagnation due to fatal immune responses triggered by gene therapies in trial participants. Treating DMD patients requires systemic administration of high doses of viral vectors, making safety particularly critical. Encouragingly, with recent advances in adeno-associated virus (AAV) vector technology, the safety profile of gene therapies has been gradually improving. The approval this year of Novartis’ gene therapy Zolgensma for the treatment of spinal muscular atrophy (SMA), which is also an AAV-based gene therapy, serves as strong evidence of enhanced safety. Sarepta’s AAVrh74 vector may offer superior safety advantages compared to the commonly used AAV9 vector.

Dystrophin Levels as a Surrogate Endpoint for DMD Treatment Recognized by the FDA

When granting accelerated approval for Exondys 51 and Vyondys 53, the FDA recognized muscle dystrophin expression levels as a reasonably likely predictor of patient improvement in motor function. This decision has also bolstered confidence in the development of gene therapies for Duchenne muscular dystrophy (DMD). Using dystrophin levels as a surrogate endpoint can accelerate product development, facilitate earlier approval of innovative therapies, and expedite their availability to patients.

Major Pharmaceutical Companies Remain Keen on Gene Therapy

This year, not only have two gene therapies received approval from the U.S. FDA and the European Union, respectively, but several large pharmaceutical companies have also incorporated this technology platform into their R&D pipelines by acquiring biotechnology firms with expertise in gene therapy. Recently, Roche completed its $4.8 billion acquisition of Spark Therapeutics, a star player in the gene therapy sector. In addition, Astellas Pharma announced a $3 billion acquisition of gene therapy company Audentes Therapeutics. Earlier this year, Biogen completed its acquisition of Nightstar Therapeutics. According to Vantage, the total value of gene therapy product acquisitions this year has reached $17 billion.

Roche’s latest licensing deal demonstrates that large pharmaceutical companies remain highly interested in gene therapy assets. Beyond acquiring companies with gene therapy expertise, major firms that have already integrated gene therapy platforms into their R&D pipelines may shift their focus toward adding promising investigational projects.

Many rare diseases, including Duchenne muscular dystrophy (DMD), are caused by mutations in genes encoding specific proteins, which gives gene therapies that modulate gene expression a distinct advantage in treating these conditions. We look forward to Roche’s investment accelerating the delivery of gene therapies for DMD to patients, and we anticipate that this innovative therapeutic approach will also demonstrate its potential in the treatment of other diseases.

References:

[1] Roche enters licensing agreement with Sarepta Therapeutics to improve the lives of patients living with Duchenne muscular dystrophy. Retrieved December 23, 2019, from http://www.globenewswire.com/news-release/2019/12/23/1963846/0/en/Roche-enters-licensing-agreement-with-Sarepta-Therapeutics-to-improve-the-lives-of-patients-living-with-Duchenne-muscular-dystrophy.html

[2] Sarepta makes history with Roche deal. Retrieved December 23, 2019, from https://www.evaluate.com/vantage/articles/news/deals/sarepta-makes-history-roche-deal

[3] Sarepta Therapeutics Announces Partnership with Roche in Territories Outside the United States for its Investigational Micro-dystrophin Gene Therapy for Duchenne Muscular Dystrophy, SRP-9001. Retrieved December 23, 2019, from https://investorrelations.sarepta.com/news-releases/news-release-details/sarepta-therapeutics-announces-partnership-roche-territories

[4] UPDATED: Sarepta cements its DMD throne with $1B+ gene therapy deal with mighty Roche. Retrieved December 23, 2019, from https://endpts.com/sarepta-cements-its-dmd-throne-with-1b-gene-therapy-deal-with-mighty-roche/

[5] Verhaart and Artsma-Rus. (2019). Therapeutic developments for Duchenne muscular dystrophy. Nature Reviews Neurology, https://doi.org/10.1038/s41582-019-0203-3

[6] SAREPTA 2019 PPMD ANNUAL CONFERENCE PRESENTATION (gene therapy). Retrieved August 19, 2019, from https://investorrelations.sarepta.com/static-files/99d3a9d7-df9a-45dc-922a-4e6a7c6f0e41

Original Title: The Largest Gene Therapy Licensing Deal in History: What Messages Are Conveyed by Roche’s $2.85 Billion Acquisition of a DMD Gene Therapy?

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