LONDON, UK (GlobalData), 30 April 2012 - Earlier this month, AVI BioPharma of Bothell, Washington announced that eteplirsen, its lead therapeutic candidate for Duchenne Muscular Dystrophy (DMD), met the primary efficacy endpoint of a key Phase IIb study, significantly increasing levels of the muscle fiber protein dystrophin in boys with the disease as compared to a placebo. The company hailed the positive finding as a “major advance” in the field of DMD research, noting that eteplirsen represents the first drug candidate to demonstrate the production of novel dystrophin in a “robust and consistent manner.”
Unfortunately, the increase in dystrophin levels with eteplirsen failed to translate into any significant clinical benefit in the study patients, which led to a precipitous 25% drop in the company’s shares. This finding was a disappointment to investigators and shareholders alike, especially after the positive primary endpoint result. However, GlobalData believes it is far too early to simply give up on on this potentially promising therapy for a disease that has a significant unmet treatment need and is ultimately fatal.
Duchenne Muscular Dystrophy
DMD is a devastating, incurable, and fatal muscle-wasting disease. It is one of the most common fatal genetic disorders seen in children throughout the world. DMD is inherited in an X-linked recessive pattern, which means that the disease almost always strikes males and rarely affects females. Presently, DMD affects approximately one in every 3,500 boys worldwide.
DMD is caused by specific inborn errors in the gene that codes for dystrophin, which plays a key structural role by acting as a shock absorber during muscular contraction. The most common genetic defects seen in DMD are missing pieces of DNA (deletions) that are essential to the production of dystrophin. These pieces of DNA are called exons and they are joined together like links in a chain. The dystrophin gene is the largest in the human body, consisting of 79 exons. When one or more exons are missing, dystrophin cannot be synthesized.
Signs and symptoms of DMD typically appear by the time a child is 3 years of age and include fatigue, muscle weakness, and difficulty in walking that worsens over time. Progressive muscle weakness in the legs and pelvis eventually spreads to the arms, neck, and other areas of the body. Breathing becomes increasingly difficult as a result of respiratory muscle dysfunction. Cardiac muscle dysfunction leads to heart failure and ultimately death, which usually occurs before the age of 30.
Significant Unmet Treatment Need in DMD
There is a significant unmet need for effective, life-saving therapies for patients with DMD. At present, there is no cure or treatment that is specifically indicated for the disease. Treatments that are currently used for symptomatic management (e.g., steroids) are merely palliative and completely fail to address the needs of these patients.
Eteplirsen: A Novel Gene Therapy for the Treatment of DMD
For the first time, promising new disease-modifying therapies such as eteplirsen are being developed that can bring potentially life-saving treatments to subpopulations of DMD patients with different deletions in the dystrophin gene. These therapies have the potential to fulfill the significant unmet need for these patients.
A particularly promising approach to the treatment of DMD involves the use of a technique known as exon-skipping, which was developed by scientists as a way to potentially restore the functionality of the dystrophin gene. Eteplirsen uses AVI BioPharma’s proprietary exon-skipping technology. This involves realigning the genetic information in the defective dystrophin gene by “skipping over” the missing piece of DNA (i.e., exon 51) so that protein synthesis can proceed. It results in the production of a shortened, yet functional, version of dystrophin. Researchers at the company believe that promoting synthesis of a shortened dystrophin protein might improve, stabilize, or significantly slow the progression of DMD. It may also prolong and improve the quality of life for specific patients with the disease. In addition to eteplirsen, AVI BioPharma is currently evaluating other exon-skipping drug candidates for the treatment of DMD.
The FDA and the EMA granted etelplirsen orphan drug status in November 2007 and December 2008, respectively. The FDA also granted eteplirsen fast track status in December 2007.
AVI’s Phase IIb Trial Demonstrates Rise in Dystrophin with Eteplirsen
AVI BioPharma’s Phase IIb trial of eteplirsen is the first reported placebo-controlled study to assess the disease-modifying effects of exon-skipping technology in patients with DMD. The trial, which was conducted at the Nationwide Children’s Hospital in Columbus, Ohio, was a 24-week, randomized, double-blind, placebo-controlled study that enrolled 12 boys with DMD between the ages of 7 and 13 years. All of these patients had an error in the gene for dystrophin that could be treated by skipping exon 51.
The study patients were randomly assigned to one of three treatment groups: 30 mg/kg or 50 mg/kg IV infusions of eteplirsen once weekly, or IV infusions of placebo once weekly for 24 weeks. The primary endpoint of the study was the change in dystrophin levels between baseline and 24 weeks, as measured by muscle biopsy. Biopsies were taken after 12 weeks in the 50 mg/kg group, and after 24 weeks in the 30 mg/kg group.
On April 2, 2012, AVI BioPharma announced that the study met its primary efficacy endpoint. It showed that eteplirsen administered at a dose of 30 mg/kg once weekly for 24 weeks resulted in a statistically significant increase in new dystrophin (22.5% dystrophin-positive fibers as a percentage of normal), compared to no increase in the placebo group (p < 0.02). Eteplirsen was also well tolerated at both doses through 24 weeks of treatment. There were no serious or treatment-related adverse events, and no drug-related treatment discontinuations. Also, no treatment-related changes were detected on any of the safety laboratory parameters, including several biomarkers for renal function.
At the same time, however, eteplisen administered at a higher dose for a shorter duration (50 mg/kg over 12 weeks) did not result in a significant increase in new dystrophin (0.79% dystrophin-positive fibers as a percentage of normal; p = NS).
On April 30, 2012, AVI BioPharma expects to release unblinded data from the results of the Phase IIb study of eteplirsen.
In addition, the company has already completed enrollment in a continuous dosing extension study that is designed to evaluate the long-term safety and efficacy of eteplirsen over a period of 48 weeks. All patients from the Phase IIb study have been rolled over to treatment with open-label drug. The results of this study will be announced later this year.
No Significant Improvement in Clinical Outcomes with Eteplirsen
Although eteplirsen did significantly increase dystrophin levels in the 30 mg/kg dosing group, this positive result did not translate into an improvement in clinical outcomes in either active treatment group. Specifically, performance on a standard 6-minute walk test and other outcome measures were generally stable across most of the study patients, including those who received placebo.
Upon hearing this disappointing news, investors immediately became skittish, and AVI BioPharma’s stock plummeted about 25%. Researchers, however, have a far more optimistic outlook. They expect that eteplirsen will show a clinical benefit if it is used for a longer period of time and are awaiting the release of additional data from the 48-week follow-up study. AVI BioPharma contends that the positive endpoint result of the Phase IIb study supports advancing eteplirsen into a pivotal Phase III study, which the company plans to initiate in 2013.
Future Research and Market Implications for Eteplirsen
DMD is presently incurable and current treatment is aimed at symptomatic management of the disease, which has resulted in a significant unmet treatment need. Therefore, GlobalData believes the market is virtually wide open for the development and marketing of gene therapy products such as eteplirsen, which target the underlying cause of DMD, as well as for other products specifically indicated for the treatment of the disease. GlobalData expects that this need will be the major driver in the future DMD market.
GlobalData expects that the approval of eteplirsen will be largely contingent upon the ability of the upcoming Phase III trial to demonstrate a rise in dystrophin levels that correlate with improvements in clinical outcomes. Approval of eteplirsen will also be more likely if the long-term (48-week) study is able to demonstrate this result. Furthermore, the fact that eteplirsen has received fast track status from the FDA may increase the likelihood of approval.
However, even if the FDA ultimately does approve eteplirsen, the drug will only benefit the small population of patients with deletions in exon 51, since it is specific for that exon. GlobalData expects that this could create a barrier that significantly limits the potential market impact of eteplirsen.
AVI BioPharma claims that approximately 85% of all DMD patients are potential candidates for treatment with exon-skipping drugs. The challenge, however, is that there are deletions in the dystrophin gene that involve more than one exon. Since each drug is specific for only one exon, more than one agent may be needed in order to produce a beneficial effect. For this reason, AVI BioPharma is developing several additional exon-skipping drug candidates intended to help DMD patients. This includes one called AVI-5038, which is intended to skip exon 50. It is currently in preclinical development in the US. The EMA granted AVI-5038 an orphan drug designation in February 2010. If preclinical studies show that AVI-5038 is safe, it will proceed to evaluation in clinical trials.
GlobalData expects exon-skipping drugs with different specificities, if approved, will collectively have a significantly greater impact on the DMD market compared to a single product.
Since the disappointing clinical outcome of the Phase IIb trial, AVI BioPharma is reconsidering its initial go-it-alone strategy and may seek a partner to assist in moving eteplirsen through development. Although such a partnership could result in the company giving up partial ownership of eteplirsen, GlobalData predicts that it may ultimately prove valuable in bringing the product to market following approval.
*AVI BioPharma’s Eteplirsen Conundrum
This expert insight was written by GlobalData's senior analyst for the genitourinary, genetic and hormonal disorders segment, Denise Lymperis, MS. If you would like an analyst comment or to arrange an interview, please contact us on the details below.
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