Regulatory environment for novel therapeutic development in mitochondrial diseases

Abstract

At present, there is just one approved therapy for patients with mitochondrial diseases in Europe, another in Japan, and none in the United States. These facts reveal an important and significant unmet need for approved therapies for these debilitating and often fatal disorders. To fill this need, it is critical for clinicians and drug developers to work closely with regulatory agencies. In the United States, mitochondrial disease patients and clinicians, the United Mitochondrial Disease Foundation, and pharmaceutical industry members have engaged with the Food and Drug Administration to educate each other about these complex and heterogeneous diseases and about regulatory requirements to obtain approvals for novel therapies. Clinical development of therapies for rare diseases has been facilitated by the 1983 US Orphan Drug Act (ODA) and similar legislation in Japan and the European Union. Further legislation and regulatory guidance have expanded and refined regulatory flexibility. While regulatory and financial incentives of the ODA have augmented involvement of pharmaceutical companies, clinicians, with patient advocacy groups and industry, need to conduct natural history studies, develop clinical outcome measures, and identify potential supportive surrogate endpoints predictive of clinical benefit, which together are critical foundations for clinical trials. Thus, the regulatory environment for novel therapeutic development is conducive and offers flexibility for mitochondrial diseases. Nevertheless, flexibility does not mean lower standards, as well-controlled rigorous clinical trials of high quality are still required to establish the efficacy of potential therapies and to obtain regulatory agency approvals for their commercial use. This process is illustrated through the authors’ ongoing efforts to develop therapy for thymidine kinase 2 deficiency.

1 |. INTRODUCTION

For more than three decades, clinical, translational, and laboratory investigators have made remarkable progress in defining the rapidly expanding spectrum of mitochondrial diseases that encompasses genetic disorders due to primary mutations in mitochondrial DNA (mtDNA) or nuclear DNA.^1,2 In contrast, the development of therapies for mitochondrial diseases has lagged behind with only one compound, idebenone, approved by the European Medicines Agency for treatment of Leber hereditary optic neuropathy,³ one amino acid, taurine, approved for prevention of stroke-like events in mitochondrial encephalomyopathy lactic acidosis stroke-like episodes⁴ and no approved therapies by the United States (US) Food and Drug Administration (FDA). Thus, there is an important unmet need for safe and effective approved therapies for mitochondrial diseases.

To ensure safety and efficacy, the regulatory approval process for novel therapies for rare disorders is inherently rigorous and challenging. The path to approval requires meticulous attention to detailed regulations and is a multistep process that includes: systematic disease characterization, identification of clinical outcomes and biomarkers (potential surrogate endpoints), preclinical development of promising therapies in cell (in vitro) and animal models (in vivo), and clinical trials. Surrogate endpoints are useful substitutes for clinical endpoints when clinical outcomes may take prolonged time to study or when the clinical benefits of improving the surrogate endpoint has been established.⁵ Clinical trials are typically necessary to establish that the surrogate endpoint predicts or correlates with clinical benefit. Surrogate endpoints may support an accelerated approval when those endpoints “are likely to predict a clinical benefit.”⁵ As of 20 August 2020, 189 surrogate endpoints were the basis for FDA drug approval or licenture.⁶ An example of a surrogate endpoint for a rare disease is globotriaosylceramide (GL-3) in blood vessels of kidneys of subjects with Fabry disease. This disorder is caused by pathogenic variants in GLA, which encodes alpha-galactosidase A. Loss of this enzyme function leads to accumulation of GL-3 in blood vessels, kidneys, heart, peripheral nerves, and other tissues manifesting as slowly progressive nephropathy, hypertrophic cardiomyopathy, arrhythmias, stroke, and early death. Efficacy of migalastat, an oral medication that increased GLA levels was demonstrated in a 6-month placebo-controlled clinical trial of 45 adults with Fabry disease using the surrogate endpoint.⁷ Based upon this evidence, the FDA granted accelerated approval. Nevertheless, to obtain full approval for treatment of Fabry disease, confirmatory clinical trials of migalastat are being conducted.⁸

Over the last decade, these issues have become particularly germane to mitochondrial diseases, as pharmaceutical industry involvement in this space has expanded dramatically. This article provides a brief summary of the historical background and overview of the regulatory environment for mitochondrial diseases with a focus on the FDA, not because the US experience is of greater or lesser importance, but rather because the authors’ predominant experiences have been in this country. Our experiences with development of a deoxynucleoside therapy for thymidine kinase 2 (TK2) deficiency are highlighted to illustrate some of the regulatory issues.

2 |. BRIEF HISTORICAL CONTEXT

In the US, the standard for FDA approval of a new drug therapy was established in 1962 by the US Federal Food, Drug, and Cosmetic Act (§ 505(d), 21USC355(d)) known as the “Drug Efficacy Amendment,” which specified that “substantial evidence of effectiveness [and safety]” must be established through “adequate and well-controlled investigations.”⁹ Effectiveness has been interpreted as a “real effect on how a patient survives, feels, or functions” as demonstrated in “two adequate and well-controlled trials.”¹⁰ Traditionally, the route to drug approvals has been through three phases of clinical studies: phase 1 with testing the drug on healthy individuals for safety and dosage; phase 2 with assessments of a group of affected subjects for safety, side-effects, dose-finding, and efficacy; and phase 3 pivotal studies to assess a larger set of affected subjects for efficacy and monitoring of adverse reactions. Data from these studies are reviewed by the FDA for potential approval. While there are concerns about costs and success rates,^11,12 this standard path to drug approval has been effective in ensuring safety and efficacy of new medications for common disorders such as diabetes,¹³ hypertension,¹⁴ and hyperlipidemia.^15–17

For rare disorders, this traditional route has not been successful given the high cost of clinical studies and small population of patients. In response to this problem, a grass-roots coalition of rare disease patients and advocates formed the National Organization of Rare Disorders (NORD) in 1983. Due to the efforts of NORD and other rare disease advocates, the US Government legislated the Orphan Drug Act (ODA), which established financial incentives for development of drugs for orphan diseases (defined as a rare condition affecting fewer than 200 000 people in the US) (Box 1).^9,10,18,19 The incentives include extended drug market exclusivity, tax credits, access to research subsidies, and new drug application fee waivers.^20,21 In practice, the ODA has successfully stimulated drug development.^20,22,23 Prior to 1983, there were only 38 FDA-approved drugs for rare diseases while in 1983 to August 2018, the FDA approved 504 orphan therapies with 731 orphan indications.²⁰ Similar policies for orphan disease were adopted in Japan in 1983 and in the European Union in 2000.²³ Further amendments to the ODA have led to further incentives and greater flexibility for regulatory approvals for rare disease therapies. To qualify for FDA consideration under the ODA regulations, the sponsor must apply for Orphan Drug Designation (ODD) as regulated by 21 CFR Part 316.²⁴

BOX 1. Key provisions in the US Orphan Drug Act of 1983.

Incentives for development for drugs for orphan diseases.

7 year market exclusivity (standard new chemical entity exclusivity is 5 years).

Tax credits = 50% of the development cost (changed to 15 year carry-forward provision and a 3-year carry back that can be applied in profitable years).

Clinical research subsidies via the Orphan Product Grant program.

Wavier of new drug application fees.

The traditional FDA standard of “two adequate and well-controlled trials” for drug approval^10,19 is often impossible for specific mitochondrial and other ultrarare diseases, which affect such small numbers of patients that single clinical trials, let alone two trials, are difficult to accomplish. The FDA Modernization Act of 1997 reinforced the general rule for “two adequate and well-controlled trials”; however, it formally opened the door to FDA “expediting study and approval of fast track drugs” for “the treatment of a serious or life-threatening condition” including approval based upon “data from one adequate and well-controlled clinical investigation and confirmatory evidence.”²⁵ The following year, the FDA provided further clarification in an Evidence Guidance document that drug approval could be granted with single studies with a statistically very persuasive finding: “In a multicenter study, a very low p-value indicates that the result is highly inconsistent with the null hypothesis of no treatment effect.”^26,27

The FDA Modernization Act of 1997 also enabled “approval of a fast track product…upon determination that the product has an effect on a clinical endpoint or on a surrogate endpoint that is reasonably likely to predict clinical benefit.”²⁵ For disorders that are slowly progressive, demonstrating effects on clinical endpoints may be a prohibitively long process. In such situations, surrogate endpoints, such as biomarkers, may be used instead of a clinical endpoint under the FDA’s Accelerated Approval program for patients with serious diseases, but post-marketing data are necessary to demonstrate that the “reasonably likely surrogate endpoint, in fact, predicts the clinical benefit.”^5,28

Although not specific for rare diseases, the FDA expanded access (also known as “compassionate use”) program is another pathway to facilitate therapy for “a patient with an immediately life-threatening condition or serious disease or condition to gain access to an investigational medical product (drug, biologic, or medical device) for treatment outside of clinical trials when no comparable or satisfactory alternative therapy options are available.”²⁹ After patient consultation, licensed physicians can apply with cross-reference to an industry Investigational New Drug (IND) (drugs or biologics) or Investigational Device Exemption (devices) and Institutional Review Board (IRB) approved protocol and consent submitted to the FDA for approval of a single-patient IND. Expanded access for intermediate-sized patient groups and widespread treatment use are also possible.^30,31 If the patient is “in a life-threatening situation, in which there is not sufficient time to obtain IRB approval,” the physician may apply for exemption from the IRB requirement and may obtain an emergency IND.^32,33

A further incentive is under the US Federal Food, Drug, and Cosmetic Act³⁴ Rare Pediatric Disease (RPD) designation, which enables the FDA to “award priority review vouchers to sponsors of certain rare pediatric disease product applications that meet the criteria specified in that section.”³⁵ Priority review vouchers shorten FDA first-cycle review deadlines for new drug applications to 6 months compared to 10 months for standard applications. Originally, the Rare Pediatric Disease Priority Review Voucher Program provided sponsors, who receive an approval for a drug or biologic for a “rare pediatric disease,” a voucher for priority review of a subsequent marketing application for a different product,³⁵ which serves as a financial incentive as this voucher may be applied to expedite review of a therapy for a common disorder. This program has been extended through September 30, 2024.

3 |. MITOCHONDRIAL DISEASE COMMUNITY INTERACTIONS WITH THE FDA

To promote the development of drugs for mitochondrial diseases in the US, the FDA has engaged in meetings with various combinations of mitochondrial disease patients, families, and caregivers; academic clinicians and investigators; patient advocacy groups; and pharmaceutical companies to identify key barriers, and paths forward toward therapeutic development. Public forums for these discussions have included: a 2014 National Institutes of Health (NIH), United Kingdom Wellcome Trust, and UMDF cosponsored workshop on nutritional interventions for primary mitochondrial disease,³⁶ a FDA Critical Pathways Innovation Meeting,³⁷ a UMDF-hosted Patient-Focused Drug Development session,³⁸ and FDA-sponsored workshop on developing therapies for mitochondrial diseases³⁹ (Table 1).

TABLE 1.

Key milestones in US regulation of drug development relevant to mitochondrial diseases

Date	Milestone	Impact
1962	US Federal Food, Drug, and Cosmetic Act (“Drug Efficacy Amendment”)	Established FDA safety and efficacy standard for approval of new drugs
1983	US Orphan Drug Act	Established incentives for development of drugs for orphan diseases
2014	US Federal Food and Drug and Cosmetic Act	Rare Pediatric Disease (RPD) designation enable FDA to award priority review vouchers to shorten FDA reviews of new drug applications upon approval for a drug or biologic for a RPD
19 October 2015	FDA Critical Pathways Innovation Meeting (CPIM) on Primary Mitochondrial Diseases	Assembled key stakeholders including: FDA, NIH, pharmaceutical industry, academic clinicians and investigators, patient advocacy groups, and representative patients to discuss the state of mitochondrial disease therapeutic development including identification of disease populations, endpoints, and trial designs
15 November 2017	FDA Inborn Errors of Metabolism on Planning Clinical Trials in Mitochondrial Diseases	Focused discussion with academic clinicians, UMDF, rare disease regulatory experts, and FDA to identify potential mitochondrial disease populations, endpoints, and trial designs
29 March 2019	UMDF Externally led Patient Focused Drug Development (PFDD) session with FDA and held at the FDA, Hyattville, MD	Patient advocacy group led meeting for patients and caregivers to voice their experiences with mitochondrial diseases
6 September 2019	FDA Workshop: Developing Therapies for Primary Mitochondrial Diseases: Bridging the Gaps	Focused meeting of academic clinicians, UMDF, rare disease regulatory experts, and FDA on key elements required for development of therapies for mitochondrial diseases

While the specific stakeholders and discussion topics in these meetings varied, several important obstacles to therapeutic development were consistently identified. They include: (a) rarity of the numerous genetically distinct disorders, which limits the number of subjects available for natural history studies and clinical trials; (b) genetic, biochemical, and clinical diversity of mitochondrial diseases, which pose formidable challenges to designing therapies, outcome measures, and clinical studies; (c) scientific challenges of identifying potent drugs that will have the large effects necessary to demonstrate significant efficacy with trials of small Ns; (d) paucity of natural history data for mitochondrial diseases; (e) few funding opportunities for natural history studies; (f) lack of outcome measures that have been assessed in mitochondrial diseases; (g) need for multiple outcome measures to capture the heterogeneity of mitochondrial diseases; (h) significant costs, labor, and expertise required for clinical trials; and (i) regulatory standards that must be met to achieve drug approval.^36–39

4 |. REGULATORY ISSUES IN DEVELOPMENT OF DEOXYNUCLEOSIDE THERAPY FOR THYMIDINE KINASE 2 (TK2) DEFICIENCY

Our ongoing development of a novel therapy for TK2 deficiency illustrates some of the regulatory issues for mitochondrial disease therapies noted above. This ultrarare autosomal recessive mitochondrial disease is due to primary pathogenic variants in TK2, a nuclear DNA encoded gene, which cause depletion and/or multiple deletions of mtDNA in muscle.^40–42 TK2 deficiency manifests predominantly or exclusively as a myopathy, with variable age-at-onset from infancy through adulthood. Due to the rarity of this disease, with fewer than 150 reported patients world-wide, a prospective natural history study has not been conducted. Nevertheless, two publications with overlapping subjects have provided documented retrospective natural history data, which clearly indicate the progressive nature of this disease, and its rapid progression and early mortality with early onset (<2 years old).^40,42

In preclinical studies, we generated the Tk2^tm1MiHi knockin mouse model of the disease, which recapitulates the infantile-onset form with early onset of weakness and growth retardation at day 10 of life with rapid progression to death mostly in the second or third week of life.⁴³ We initially demonstrated efficacy of deoxynucleoside monophosphate (thymidine monophosphate and deoxycytidine monophosphate) in delaying onset and prolonging survival twofold to threefold in a dose-dependent manner.⁴⁴ After in vitro demonstration of efficacy of deoxynucleosides in cellular models of mtDNA depletion disorders,⁴⁵ we showed that the efficacy of thymidine and deoxycytidine nucleosides and the deoxynucleoside monophosphate therapy was similar in the Tk2 knockin mutant mice.⁴⁴ We filed invention reports with the Columbia Technology Ventures office, who, in turn, obtained provisional patents, and subsequently full patents for both therapies. We also obtained ODD and RPD from the FDA for deoxynucleoside therapy.

Based on our preclinical therapy results, we began compassionate use deoxynucleoside monophosphate therapy in 2011 in a patient in Spain with local ethical committee approval, and several months later in a patient in the US. The US patient had onset at age 12 months and was severely weak at age 17 months; he had lost the ability to sit, stand, and breathe independently. Due to the severity of his condition, the FDA granted an emergency IND to begin expanded access therapy. In 2014–2015, based upon our preclinical results with deoxynucleoside therapy in Tk2 knockin mice, we transferred our patients from deoxynucleoside monophosphates to deoxynucleosides. Additional TK2 deficient patients in Spain and the US were started on deoxynucleoside therapy. In the US, patients were treated under expanded access single-patient INDs and then an intermediate IND.

We reported the result of deoxynucleoside and deoxynucleotide (deoxynuclos(t)ide) therapies in the first 16 patients.⁴⁶ Compared to historical untreated controls who displayed early mortality, five patients with early onset and severe disease showed improved survival and motor functions. In 11 childhood- and adult-onset patients, clinical measures stabilized or improved. As of 31 December 2018, 38 TK2-deficient patients worldwide were receiving deoxynucleos(t)ide therapy (Hirano and Dominguez-Gonzalez, unpublished). The challenges of an international expanded access therapeutic program include the lack of a standardized treatment protocol, variability of clinical outcome assessments, and incomplete data collection due to lack of rigorous external study monitoring.

Based upon our promising preclinical and early expanded access results, three bioincubator/pharmaceutical companies expressed interest in the therapeutic intellectual property. Columbia University licensed the ODD, RPD, and patent (US patents 10471087 and 10292996) rights to Modis Therapeutics (then Meves Therapeutics) based on the results collected under expanded access, which indicated safety and efficacy. Modis Therapeutics has produced good manufacturing practice grade deoxynucleosides (MT-1621), has sponsored a rigorous retrospective analysis of the 38 patients treated under expanded access (MT-1621-101, NCT03701568), and has transferred most of those subjects into an ongoing good clinical practice (GCP) compliant deoxynucleoside open-label continuation study (MT-1621-102, NCT03845712). The enrollment of subjects into an industry-sponsored GCP-compliant study enables rigorous assessments using standardized outcome measures with careful monitoring to ensure high data quality that will fulfill FDA requirements. While this therapeutic program has moved forward at a rapid pace, considerable work remains to be completed before applying for regulatory approval. Modis Therapeutics, now a subsidiary of Zogenix Inc, has undertaken additional clinical and nonclinical studies to support registration of pyrimidine deoxynucleosides for patients with TK2 deficiency. Modis plans to launch an international multicenter prospective open-label single-arm phase 3 clinical trial of MT-1621 (MT-1621-104) in 2021.

5 |. DISCUSSION

While the regulatory and financial incentives of the ODA have augmented involvement of the pharmaceutical industry, ODD indications still account for less than 10% of US pharmaceutical spending.²⁰ Academics should not passively follow industry initiatives, but rather continue to participate actively in therapeutic development. Academic clinicians who treat mitochondrial disease patients with support of patient advocacy groups and pharmaceutical industry need to conduct natural history studies and develop outcome measures and identify potentially supportive surrogate endpoints, which are critical foundations for clinical trials. In parallel, academic investigators need to continue to develop novel therapies, which must be protected as intellectual property, a frequently unrecognized prerequisite for successful collaborations with industry. Orphan drug and expedited programs for serious diseases provide additional benefits that can facilitate therapeutic development programs in the US and Europe which contain many distinct, but often parallel elements (Table 2).⁴⁷ Academic investigator-initiated emergency, single-patient, and intermediate INDs in the US can enable researchers to rapidly initiate an expanded access study of an unapproved drug, or of an approved drug for a new indication, or in a new patient population. As described above, deoxynucleoside therapy for TK2 deficiency was initiated under investigator INDs that enabled rapid translation from preclinical mouse studies directly to human patients on a compassionate use basis; however, further GCP-compliant industry sponsored studies are necessary to apply for regulatory approval. Thus, the regulatory environment for novel therapeutic development is favorable and offers flexibility for mitochondrial and other orphan diseases. Nevertheless, flexibility must not mean lower standards, as well-controlled rigorous clinical trials of high quality must still be required to establish the safety and efficacy of potential therapies and to obtain regulatory agency approvals for their commercial use. Finally, one must keep in mind that clinical trials are expensive and burdensome for patients and their families; therefore, it is important to judiciously move forward therapies that have been carefully vetted in preclinical studies and have a reasonable likelihood of clinically meaningful benefit with tolerable safety.

TABLE 2.

Key regulatory tools available to developers of mitochondrial disease therapeutics

Tool and key features	US FDA	EU EMA
Orphan Drug Designation: Financial incentives, regulatory flexibility and market exclusivity	US Orphan Drug Designation Application	EU Orphan Drug Designation Application
Designations: Increased interaction with FDA or EMA, expedited development, and registration	Breakthrough designation, fast track designation (Guidance for Industry Expedited Programs for Serious Conditions—Drugs and Biologics. May 2014)	PRIME designationa SME status for micro, small, and medium-sized enterprisesa
Development, protocol advice, and regulatory agency alignment	Type B, C meetings with FDA (Guidance for Industry Formal Meetings Between the FDA & Sponsors or Applications of PDUFA Products. December 2017)	National scientific advice available on an EU national level or EMA centralized scientific advice and protocol assistancea
Biomarker, surrogate, and clinical outcome regulatory acceptance	FDA Surrogate Endpoint Table Type B, C meetings with FDA	EMA scientific advicea
Pediatric access	Discuss expansion to pediatric population or initial study in pediatrics as part of Type B, C meetings with FDA	Obtain EMA scientific advice regarding proposed pediatrics development, submit and have Pediatric Investigational Plan (PIP) approved by PDCO (Pediatric Committee at EMA) prior to filing a Marketing Authorization Applicationa
Accelerated review mechanism for new drug application/BLA/marketing authorization application	Priority review (Guidance for Industry Expedited Programs for Serious Conditions—Drugs and Biologics. May 2014)	Accelerated assessmenta
Early access new drug application/BLA/marketing authorization approval with post approval development commitments	SubPart H (21CFR314) SubPart E (21CFR601)	Conditional approvala

^aGuidance available on EMA website: https://www.ema.europa.eu/en/human-regulatory/research-development