Road to a Cure: Sarepta Therapeutics' Eteplirsen

Sarepta press releases were used as references for this essay. Because these announcements typically had similar names, they will be noted by (Sarepta Date of announcement) for in-text citations.
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On June 26, 2015, Sarepta Therapeutics completed rolling submission of a New Drug Application for the drug Eteplirsen, reflecting an exciting moment for Duchenne muscular dystrophy patients.  Eteplirsen acts by targeting the genetic code of the dystrophin protein to skip exon 51, a mutation found in 13% of all Duchenne muscular dystrophy (DMD) patients. Skipping exon 51 results in a protein that is shorter but functional, improving patient outcomes (Sarepta 29 Jun 2015). Therefore, this drug treats DMD, offering solace to some of these patients. With time, Eteplirsen can be drawn upon to treat a greater variety of DMD patients and potentially aid patients with other neuromuscular disorders. Though potentially a powerful therapy, Eteplirsen faced a variety of regulatory concerns over the past couple years and still has drastic technical limitations in treating DMD.

Exon-skipping is considered a powerful technique due to its experimental success, as shown through clinical trials (Nakamura and Takeda 2011). At the same time, it faces a smaller regulatory and practical barrier to clinical use, making it less daunting than gene therapy or cell therapy. Though this drug is capable only of targeting this group of patients, Sarepta hopes to expand this technology to target other DMD mutations (Sarepta 29 Jun 2015). This drug has received much attention because it is believed capable of addressing Duchenne, a serious condition to most of its patients. Clinical trials have suggested that this drug is quite beneficial. A significant treatment benefit has emerged for a 6-minute walk test with patients treated with weekly intravenous Eteplirsen compared to a placebo control group. (Douglas and Wood 2013)

This product makes use of phosphorodiamidate moropholino oligomers (PMO), which are neutrally charged and therefore more difficult to degrade by the body, to achieve exon skipping. This oligomer contains modified phosphates and morpholinos rather than the sugar groups typically found in a nucleic acid backbone, enhancing the oligomer’s stability inside the body.  The PMO is a type of antisense oligonucleotide (AO) – this strategy uses AOs to target splicing or other elements in the dystrophin pre-mRNA; then one or more exons can be skipped during RNA processing to restore the correct reading frame. The resulting protein loses a relatively small internal region but contains the vital C-terminal domain and is at least partially functional (Wood 2010). This internal region is termed the rod of the dystrophin protein and is not as critical to protein function as the N- and C-terminal domains. Therefore, a Becker’s type of mutation is expected, which represents improved life outcomes for the patients.

Completing the regulatory process requires an Investigational New Drug application and a New Drug Application; only then can a company market and sell a drug. The IND essentially gives the company permission to ship the drug across state lines so that it can be independently investigated in clinical trials. However, an IND itself requires preclinical trials using animals, which often must stem from proof of concept studies.  Proof of concept studies have suggested that PMOs are capable of restoring dystrophin in a widespread manner, at least as far as skeletal muscle is concerned; muscle pathology and locomotor activity were noted to improve as a result of this therapy (Douglas and Wood 2013). Studies were performed using PMOs to skip Exon 51 in a mdx-mouse model, resulting in an open reading frame and the recovery of dystrophin expression without a toxic response. These results suggest both safety and efficacy for using PMOs for this purpose. Sarepta performed preclinical trials in Duchenne animal models including mouse, monkey, and rat; these trials provided insight into the safety of the drug, which is critical for the preclinical trails (“Preclinical Safety Assessment”).

Once approved for the IND, the company then moved onto establishing information towards the NDA, which must be approved before a drug can reach market. Clinical trials were then performed with human subjects to supplement the NDA. In 2009, the drug was first tested in the foot of seven patients in a controlled study, suggesting that the PMOs were well tolerated and dystrophin protein was generated (Wood 2010).  The 2011 phase II clinical trials are notable because the researchers were able to treat ambulatory Duchenne muscular dystrophy patients with a mutation that can be treated by skipping exon 51. Most prominently, the proportion of fibers containing dystrophin increased from 5% pre-treatment to 55% post-treatment, indicating a successful outcome (Nakamura and Takeda 2011). However, Sarepta, despite this clinical research, met resistance from the FDA during the regulatory process. This step of filing the NDA was the most significant barrier because the FDA requested much more information than Sarepta had obtained through trials. Furthermore, the FDA found the research methods used behind clinical trials to be inconclusive and inconsistent.  

In April 2014, Sarepta claimed that it would submit an NDA for Eteplirsen by the end of 2014 based on a guidance letter by the FDA proposing a strategy using the potential Accelerated Approval pathway (Sarepta 21 Apr 2014). However, the FDA stipulated that more information was needed to assess whether dystrophin production was improved. In Oct 2014, Sarepta announced that the FDA still requested more data, meaning that they could not submit the NDA by the end of 2014 (Sarepta 27 Oct 2014). Mainly, the FDA was concerned that clinical site inspection uncovered marked disparities in the immunohistochemistry methodology and concerns about the data reproducibility, indicating that ongoing clinical trials had to lend support to the application.

In response, many DMD patients, families, and advocacy groups wrote to the FDA, prompting a response in a news release (“Duchenne Muscular Dystrophy Statement”). Understandably, these patients were frustrated that a drug that actually treated the disorder rather than simply alleviating its symptoms was not passing regulatory burdens. In this release, the FDA emphasized that they worked extensively with Sarepta and they were concerned that their research methods were not robust enough to support an NDA, which delayed the process. The FDA also suggested a willingness to conduct a rolling review of Sarepta’s NDA. At the same time, the agency emphasized that Sarepta needed to start enrolling patients as soon as possible to furnish novel data to support the NDA.

Finally, in May 2015, Sarepta held a pre-NDA meeting with the FDA and the two parties agreed to do a rolling submission process (Sarepta 19 May 2015). The nonclinical portion of the application was submitted to the FDA later in the month. Only a month later, Sarepta was able to complete the submission of the NDA and request Priority Review, which would make the drug available sooner (Sarepta 29 Jun 2015). Edward M. Kaye, new head of Sarepta, described the submission as meeting Sarepta’s desire to treat Duchenne Muscular Dystrophy and help the patients and families of DMD patients. Furthermore, Priority Review would allow the drug to come to market more quickly and help patients who need this therapy. The drug etiplirsin could be approved by 2016 due to Priority Review.

One must wonder why the regulatory process was so delayed. Potentially Sarepta and its seemingly contentious ex-CEO Chris Garabedian poorly coordinated with the FDA. Garabedian was replaced by Edward M. Kay, as interim CEO, in April 2015, which may provide insight into why the company was suddenly capable of convincing the FDA to do a rolling submission despite months of disagreements (“Sarepta CEO Quits”). This process may have simply been hampered regardless of who led Sarepta but the introduction of Kay appeared to enhance the FDA’s cooperation.  Sarepta’s regulatory pathway serves to reinforce the necessity of working with the FDA and properly following medical regulations. In particular, clinical trials must have a reliable and consistent methodology while ensuring that research methods can provide strong support for an NDA.

Though the regulatory process for the drug was difficult, there are other barriers to using Eteplirsen as a means to treat DMD. Currently, Eteplirsen only targets exon 51, only aiming to treat 13% of all DMD cases; the PMO technology used by Sarepta must be expanded so that it can treat numerous other kinds of genetic mutations leading to DMD. For example, deletions can occur over exons 45-55, which includes 60% of deletion mutations in patients. Therefore, this drug does not target the majority of DMD patients. (Nakamura and Takeda 2011) This region, because the deletions in this area tend to result in mild BMD phenotypes - can be potentially used to enhance the activity of exon-skipping therapies by allowing for the skipping of multiple exons (Douglas and Wood 2013). This result is logical because that expanse of exons apparently does not play a large role in the functionality of the dystrophin protein.  One major limitation of exon-skipping is that the DMD-causing mutation needs to be limited to a deletion and that only one exon can be skipped (Douglas and Wood 2013). These aspects of exon-skipping must be improved before the existing technology can benefit the majority of patients with DMD.

This drug also only substantially improves dystrophin production in skeletal muscle even though Duchenne impacts the heart and the brain as well (Nakamura and Takeda 2011; Douglas and Wood 2013; Wood 2010). Therefore, this exon-skipping technology using PMOs has to improve as a whole to encourage the production of dystrophin in other affected parts of the body. This concern is especially critical because cardiac (Kaspar et. al 2009) and neurological (Cyrulnik and Hinton 2008) components are intrinsic to the disease phenotype of DMD. One possible solution is to use microbubble ultrasound technology – which entails attaching the AO to gas-filled microbubbles and using ultrasound to activate the release of the AO – to deliver the oligonucleotides to the heart, thereby enhancing cardiac dystrophin restoration (Wood 2010).

Though Eteplirsen is limited in its ability to truly alleviate DMD, the drug is potentially quite beneficial to DMD patients. Many of the currently existing therapies seek to only heal symptoms of DMD without tackling the root problem, which makes this drug unique on the market. Thus, Sarepta’s regulatory woes presented a grave concern to the DMD community. The lessons from this drug are twofold: 1) collaborating in a respectful and effective manner with the FDA is necessary to get a drug onto market, especially if that drug must go through special avenues such as Priority Review; and 2) though Eteplirsen does not treat a wide population of afflicted patients, it can lead to other drugs that can treat other conditions through exon-skipping. Currently, Sarepta is at work, developing other potential drug candidates in order to treat a plethora of DMD phenotypes and expand into treating other neuromuscular disorders.

References

Chen, Caroline and Danielle Burger. “Sarepta CEO Quits; Successor Pledges to Work Better With FDA.” Bloomberg. 31 Mar 2015.  Web. 4 Jul 2015.

Cyrulnik, Shana E. and Veronica J. Hinton. “Duchenne muscular dystrophy: A cerebellar disorder?” Neuroscience and Biobehavioral Reviews 32 (2008): 486-496. Print.

Douglas, Andrew G.L, and Matthew J.A. Wood. “Splicing therapy for neuromuscular disease.” Mol Cell Neurosci 56.100 (2013): 169-185. Print.

“Duchenne Muscular Dystrophy Statement.” U.S. Food and Drug Administration. 30 Oct 2014. Web. 4 Jul 2015.

Kaspar, Rita Wen, Hugh D. Allen, and Federica Montanaro. “Current understanding and management of dilated cardiomyopathy in Duchenne and Becker muscular dystrophy.” J Am Acad Nurse Pract 21.5 (2009): 241-249. Print.

Nakamura, Akinori and Shin’ichi Takeda. “Exon-skipping therapy for Duchenne muscular dystrophy.” The Lancet 378 (2011): 546-547. Print.

“Preclinical Safety Assessment of Phosphorodiamidate Morpholino Oligomers (PMO): Everylife Foundation Scientific Workshop 2014.” Sarepta Therapeutics. 16 Sept 2014. Web. 4 Jul 2015.

“Sarepta Therapeutics Announces Plans to Submit New Drug Application to FDA for Eteplirsen for the Treatment of Duchenne muscular Dystrophy by Year End 2014.” Sarepta Therapeutics. 21 Apr 2014. Web. 4 Jul 2015.

“Sarepta Therapeutics Announces Plans to Submit Rolling NDA for Eteplirsen following Today’s Pre-NDA Meeting with the FDA.” Sarepta Therapeutics. 19 May 2015. Web. 4 Jul 2015.

“Sarepta Therapeutics Announces Regulatory Update on Eteplirsen.” Sarepta Therapeutics. 27 Oct 2014. Web. 4 Jul 2015.

“Sarepta Therapeutics Completes NDA Submission to FDA for Eteplirsen for the Treatment of Duchenne Muscular Dystrophy Amenable to Exon 51 Skipping.” Sarepta Therapeutics. 29 Jun 2015. Web. 4 Jul 2015.

Wood, Matthew J.A. “Toward an Oligonucleotide Therapy for Duchenne Muscular Dystrophy: A Complex Development Challenge.” Sci. Transl. Med 2.25 (2010). Print.

Acknowledgements
Thank you to my friend Macy and my father Nasir for providing feedback.