FDA Releases Draft Guidance on Duchenne Muscular Dystrophy Drug Approval

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by Charles Moore |

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The US Food and Drug Administration (FDA) this week released a new draft guidance document intended to clarify the development process for new Duchenne Muscular Dystrophy drug treatments.

The purpose of this guidance is to assist sponsors in clinical development of drugs treatment of Duchenne muscular dystrophy (DMD) and related dystrophinopathies including Becker muscular dystrophy (BMD), DMD-associated dilated cardiomyopathy (DCM), and symptomatic carrier states in females. Specifically, this guidance addresses FDA’s current policy thinking regarding the clinical development program and clinical trial designs for drugs to support an indication for the treatment of one or more of these dystrophinopathies.

Duchenne Muscular Dystrophy is a progressive, fatal disease for which there is currently no cure. The most prominent pathology in DMD and related dystrophinopathies is degeneration of skeletal and cardiac muscle leading to progressive loss of muscle function, respiratory and cardiac failure, and ultimately premature death.

DMD and other dystrophinopathies result from genetic mutations in the dystrophin gene that decrease the amount of dystrophin in the body and/or cause dystrophin protein dysfunction which leads to muscle degeneration and, in many patients, additional opportunistic downstream pathologies including inflammation and fibrosis that interfere with muscle regeneration and cause loss of movement, orthopedic complications, and, ultimately, respiratory and cardiac failure. Persons afflicted will usually experience progressively more severe muscle weakness which will eventually confine them to a wheelchair in early adolescence and lead ultimately to full paralysis. DMD is the most common dystrophinopathy, with a birth prevalence of about 1 in 3,500 to 6,000 males born in the United States. DMD also generally has the most severe phenotype of the dystrophinopathies, manifesting as failure to reach developmental milestones, functional losses in the first decade of life, and greatly decreased life expectancy.

Duchenne muscular dystrophy sufferers are nearly always boys because of the dystrophin gene’s being located on the X chromosome. A girl would need to inherit two faulty dystrophin gene copies, highly improbable because male carriers often die in early adulthood. However, while dystrophinopathies are considered to be diseases afflicting males only, the guidance notes that some female carriers of dystrophin mutations experience muscle degeneration similar to that in males.

Becker muscular dystrophy (BMD) is similar to DMD but generally has later onset of symptoms, slower progression, and is characterized by wide inter-patient variability in severity. BMD’s clinical course resembles that of DMD in some patients, while others will remain nearly — or in some cases completely — asymptomatic. Birth prevalence of BMD is about 1 in 20,000 males.

DMD-associated dilated cardiomyopathy (DCM) is caused by dystrophin mutations that primarily affect cardiac muscle, and is even less common than BMD.

The FDA’s draft guidance is intended to serve as a focus for continued discussions among the Division of Neurology Products, pharmaceutical sponsors, the academic community, and the public. It does not address the development of drugs to treat secondary complications of muscle degeneration in dystrophinopathies (e.g., drugs specifically for heart failure or for pulmonary infections).

The guidance has been prepared by the Division of Neurology Products in the Center for Drug Evaluation and Research (CDER) at the FDA, and for the purposes of the guidance, all references to drugs include both human drugs and therapeutic biological products unless otherwise specified. In addition to consulting guidances, sponsors are encouraged to contact the division to discuss specific issues that arise during development of drugs for treatment of dystrophinopathies.

Development of the guidance was preceded by submission to the FDA of a proposed draft guidance independently prepared by a consortium of stakeholders including patients, parents and caregivers, clinicians, scientific experts, and industry representatives. The proposed draft guidance submitted by the consortium was made available through a Federal Register notice seeking public comment. Both the independently prepared proposed draft guidance and the public comments received in response to the Federal Register notice were considered in writing the draft guidance released this week.

Note that the guidance doesn’t contain discussion of general issues of statistical analysis or clinical trial design, which are addressed in the ICH guidances for industry E9 Statistical Principles for Clinical Trials and E10 Choice of Control Group and Related Issues in Clinical Trials, respectively.

Also, in general, the FDA’s guidance documents do not establish legally enforceable responsibilities, but describe the Agency’s current thinking on a topic and should be viewed only as recommendations unless specific regulatory or statutory requirements are cited. The use of the word “should” in Agency guidances means that something is suggested or recommended, but not mandated.

The document notes that for a variety of reasons, communication about issues associated with both drug safety and efficacy between drug developers and those affected by dystrophinopathies is important during the development of drugs to treat these diseases. The FDA says it recognizes that those affected by life-threatening and severely debilitating illnesses with unmet medical need are generally willing to accept greater risks and greater uncertainty regarding potential risks associated with new treatments.

Nevertheless, the agency insists that it is important that drug developers understand from affected individuals how treatment goals and risk tolerance are related to specific patient circumstances, such as age, disease stage, and phenotype, among others. For example, the guidance observes that tolerance for risk may differ between patients with the more severe dystrophinopathy phenotypes and those with less severe phenotypes. As development proceeds and the potential benefits and risks of a drug become more clearly understood, the Agency recommends that input from patients and caregivers be further elicited.

The guidance also recognizes that many patients with dystrophinopathies are children, and that special ethical considerations apply to conduct of studies in children and types and contexts of risks that are considered acceptable for juvenile trial participants. However, it notes that within the bounds of these ethical considerations, even if risk of serious or irreversible harm is possible, drug development studies may be allowed to proceed under the FDA s regulatory framework if the risks are not deemed unreasonable in the context of the the disease phenotype’s seriousness. However, patients and caregivers can only make appropriate decisions about children’s participation in clinical trials if provided with clear information about potential risks and benefits.

The guidance indicates that in addition to informed consent based on information available at the beginning of the study, it is critical that emerging safety information be communicated rapidly and efficiently to study patients and/or their caregivers on an ongoing basis in order to allow them to reassess the patient’s continued participation.

Treatment goals similarly may also differ depending on patient-specific circumstances such as age and disease stage, and those patients most affected by the disease can provide insight into the outcomes that are most appropriate to designate as primary endpoints, how best these outcomes might be assessed, as well as the overall effect of a treatment on the disease.

The guidance document also acknowledges a need to understand the safety and efficacy of investigational drugs for dystrophinopathy treatments across disease stages and phenotypes, noting that patients should not be unnecessarily excluded from enrolment based on characteristics such as age or disease stage unless scientifically justified, observing that broad inclusion criteria might also allow more rapid study enrolment, thereby accelerating drug development.

Observing that vetting the safety and efficacy of an investigational drug generally involves several stages of development and a number of clinical trials, increasing the feasibility of including patients across different disease stages and phenotypes, the guidance recognizes a strong rationale for treatment of patients at an early age because drugs that preserve muscle, in particular, may have the greatest effect on prognosis before muscle health has deteriorated. Nevertheless, there is a balancing need to understand safety and efficacy of drugs at later stages of disease, including stages when respiratory and cardiac pathology is more pronounced.

A concrete example of what obtains in practical terms is Sarepta Therapeutics, Inc.’s New Drug Application (NDA) for approval of its lead product candidate candidate eteplirsen — a DMD treatment currently in clinical trials, is designed for treatment of some mutations that cause DMD. Sarepta and the FDA are agreed on Sarepta’s initiation of a rolling NDA submission for eteplirsen (AKA AVI-4658) toward the objective of being able to submit the final NDA component by mid-year 2015.

Sarepta has been in discussion with the regulatory agency since November 2013 when the FDA ruled that accelerated approval for eteplirsen was premature. Since the end of last year, Sarepta participated in several meetings with the FDA to discuss the path forward for eteplirsen and based on these discussions formal guidance was outlined, with the agency ruling that with additional data to support eteplirsen’s efficacy and safety of for treatment of DMD, an NDA should be fileable. Furthermore, the regulatory agency provided clear guidance on an open-label, historically controlled confirmatory study of eteplirsen, as well as initial guidance on a placebo-controlled study of one or more follow-on exon-skipping compounds.

Sarepta Therapeutics began dosing in the confirmatory eteplirsen study in the third quarter of 2014; and has been opening additional trials in younger and older boys living with Duchenne.

In a statement the FDA says it recognizes the unmet medical need in Duchenne muscular dystrophy (DMD), the devastating nature of the disease for patients and their families, and the urgency to make new treatments available, and that it remains committed to working with all companies to expedite development and approval of safe and effective drugs to treat these diseases, and that over the past several years, the Agency has worked extensively with Sarepta on development of eteplirsen, and provided guidance with respect to the data that would be necessary to determine whether it is effective and support filing of an NDA.

The FDA says it has been working intensively to help Sarepta provide the additional data and analyses needed to support an NDA, and that the agency understands the considerable disappointment in the Duchenne community following Sarepta’s October 27, 2014 announcement that the previous time frame for submitting the NDA for eteplirsen could not be met.

The FDA explains that in its advice to Sarepta, the agency has consistently stated it would be necessary to include data in its NDA demonstrating that eteplirsen increases production of the muscle protein dystrophin. (eteplirsen’s proposed mechanism of action is through increasing production of this muscle protein), and that the need for additional data and analyses to support the NDA was reinforced by an FDA inspection of the clinical site where dystrophin analyses had been conducted.

The FDA says it understands the dire urgency of the situation, that the importance of the agency’s actions to the DMD community, and it will continue to work with Sarepta in their efforts to provide the data it considers critical to FDA’s ability to review the NDA and reach a decision on approvability.

The guidance document observes that the FDA has long stressed that statutory standards for effectiveness apply to drugs for dystrophinopathies just as they do for all other approved drugs, and it is appropriate to exercise flexibility in applying the statutory standards to drugs for serious diseases with important unmet needs, while preserving appropriate guarantees for safety and effectiveness.

Consequently, trials in drug treatments for dystrophinopathies generally should be conducted under the oversight of a safety assessment committee (SAC) with access to real-time unblinded safety data, and the SAC should look at frequent intervals for emerging safety signals and, if necessary, take appropriate measures to ensure that patients are not placed at unreasonable risk of harm.

Also, to support marketing approval, drug safety must be supported by an adequate number and duration of patient exposures to characterize drug risks, and the FDA generally will consider the serious and life-threatening nature of DMD and other severe dystrophinopathies when determining the minimum number and duration of patient exposures needed, with drugs shown to provide an important benefit possibly needing less safety data to provide adequate assurance that risks associated with its use are commensurate with benefits. TOward that end, during drug development, as much safety data as possible should be collected from patients across the spectrum of disease stages and severities, including, whenever possible, data from patients who may not have been included in efficacy studies.

The guidance notes that safety data from a reasonable number of patients exposed to the drug for at least 1 year generally is considered appropriate to support approval of drugs intended for chronic use in treating DMD and other severe dystrophinopathies, with the caveat that adverse events of special interest for drugs for the treatment of dystrophinopathies include exacerbation of autoimmunity to dystrophin or other muscle components. Exacerbation of cardiac disease may be a concern for drugs that increase physiological stress on the heart by increasing the amount or activity of skeletal muscle, or for drugs that could directly affect cardiac dystrophin.

The document’s authors also say randomized placebo-controlled trials are strongly recommended, and generally are the most efficient way to demonstrate efficacy for drugs for dystrophinopathies. In some circumstances, however, they observe that trials using external controls, such as historically controlled trials, may be considered adequate and well-controlled, and may provide or contribute to evidence of efficacy to support approval, but they stress that it should be noted that historically controlled trials lack important design features that reduce bias, such as randomization and masking of treatment assignment, and generally are persuasive only when drug effects are large on objective endpoints that are less susceptible to bias, and that for externally controlled studies to be persuasive, detailed evidence should be presented that the study design and conduct adequately controlled for bias.

Sponsors of drug candidates are encouraged to propose, and, if necessary, develop, endpoints that can be used to validly and reliably assess patients with a wide spectrum of symptoms and disease stages, and the guidance says the FDA should be engaged by a sponsor early during the selection and/or development of efficacy endpoints — with assessment of multiple efficacy endpoints included when feasible, to characterize the breadth of effects on dystrophin-related pathologies, including skeletal, respiratory, and cardiac muscle function, even if the study primary endpoint is only one of these measures. It is noted that efficiency endpoints that can measure change of function over a wide range of deficits may offer a number of advantages in the development of drugs for dystrophinopathies.

The guidance notes that when making regulatory decisions regarding drugs for dystrophinopathies, the FDA will consider patient and caregiver tolerance for risk, and the serious and life-threatening nature of these conditions, and that patients and/or their caregivers may be willing to tolerate substantial risk of harm if a drug might delay loss of important abilities such as ambulation. However, tolerance for risk may vary among individuals, and be affected by disease stage and severity, and accordingly the FDA will consider this heterogeneity of risk-tolerance in making regulatory decisions.

The entire FDA Guidance on Duchenne Muscular Dystrophy document can be downloaded (PDF format)here.

U.S. Food and Drug Administration
Sarepta Therapeutics, Inc.