ELEVIDYS (DELANDISTROGENE MOXEPARVOVEC-ROKL)

Condition (Therapeutic Area):

Duchenne muscular dystrophy (DMD)

Year of Approval (by Agency):

Approved by FDA in June 2023 (FDA, 2023a);

Not yet submitted to EMA.

Context of Approval (e.g., Standard of Care):

Elevidys was approved for the treatment of ambulatory patients, aged 4 through 6 years of age with DMD with a confirmed mutation in the DMD gene (FDA, 2023a). It was the first approval of a gene therapy for DMD (FDA, 2023c).

Regulatory Pathway Used:

Elevidys was approved under FDA’s accelerated pathway (FDA, 2023a).

Designations/Expedited Programs Used:

FDA granted the drug Orphan Product designation and Fast Track (FDA, 2023a).

Novel Trial Design Elements:

Approval relied on three separate studies submitted: two were open-label studies and one was a randomized, placebo-controlled cross-over trial (cross-over trial formed the primary base of the decision). The studies used of a surrogate endpoint of expression of ELEVIDYS micro-dystrophin; correlated to North Star Ambulatory Assessment score (FDA, 2023a).

“Supplemental Data” Used:

Open Label Extension Study and use of natural history data used as the external control (FDA, 2023a).

Advisory Committee and Patient Community Engagement:

A virtual Advisory Committee was held on May 12, 2023. FDA expanded the public hearing to 90 minutes, allowing for public testimony as well as videos of individuals who had participated in studies. Parents, clinicians, and others presented what they referenced as real world data to demonstrate benefit of Elevidys. Individuals who had received Elevidys demonstrated the increased ability to jump, climb and ride bikes, activities that were impossible prior to receiving the therapy. The advisory committee voted 8 to 6 in favor of Elevidys (FDA, 2023a).

Regulatory Flexibilities Deployed:

FDA:

FDA approval demonstrated flexibility expressed in FDA guidance allowing for submissions based on “one adequate and well controlled study with confirmatory evidence.” That “confirmatory evidence” included the use of natural history data used as an “external control” in comparison to subjects in the open label extension of the single study. Despite the Review Committee’s determination, that there was insufficient evidence to use micro-dystrophin as a surrogate endpoint, the Center Director overrode the decision leading to approval of Elevidys (FDA, 2023a).

MEPSEVII (VESTRONIDASE ALFA)

Condition (Therapeutic Area):

Mucopolysaccharidosis (MPS) VII, Sly Syndrome

Year of Approval (by Agency):

Approved by FDA November 2017 (FDA, 2017);

Recommended for authorization by EMA in April 2018 (EMA, 2018b);

Authorized by European Commission in August 2018 (EMA, 2018b).

Context of Approval (e.g., Standard of Care):

First treatment approved for MPS VII. Prior to approval of Mepsevii, there were no disease-modifying treatments available; treatment consisted of supportive care and management of disease complications (FDA, 2017).

Regulatory Pathway Used:

FDA granted Mepsevii standard approval (FDA, 2017).

EMA used Exceptional Circumstances approval to approve Mepsevii (EMA, 2018b).

Designations/Expedited Programs Used:

FDA granted Mepsevii Orphan and Fast Track designation as well as Priority Review (FDA, 2017).

EMA had designated the drug an orphan product (EMA, 2018b).

Novel Trial Design Elements:

FDA: Approval based on totality of evidence approach on a per subject basis. There was no pre-specified primary endpoint for the study (FDA, 2017)

EMA: Approval based on a surrogate biomarker uGAG (EMA, 2018b)

“Supplemental Data” Used:

FDA: Natural history (informal)—no organized natural history data collection, but consideration of the known chronic progressive nature of the disease, disease complications/manifestations, and extrapolation of findings from other related MPS’s and ERT approvals for these conditions. FDA also considered pharmacologic effect of the drug from nonclinical studies (FDA, 2017).

EMA: relied upon knowledge of the disease, severity and life-threatening nature of the illness, lack of available treatments, and reliance upon a biomarker for clinical outcome (EMA, 2018b).

Advisory Committee and Patient Community Engagement:

There are no advisory committees or patient engagement documented for this drug

Regulatory Flexibilities Deployed:

Both FDA and EMA relied upon efficacy and safety data from 17 patients exposed to Mepsevii.

FDA:

Although limitations in the clinical program were noted relating to the quantity of the evidence, FDA considered that given the rarity of the disease and the limited patient availability, it was not feasible to conduct a traditional parallel group, placebo-controlled trial (FDA, 2017).

EMA:

EMA considered the limited amount of data from clinical studies, the life-threatening and debilitating nature of MPS7, and lack of authorized medicines available to treat the disease, all of which supported an MA under “exceptional circumstances” (EMA, 2018b).

NEXVIAZYME® (AVALGLUCOSIDASE ALFA)

Condition (Therapeutic Area):

Late-onset Pompe disease

Year of Approval (by Agency):

Approved by FDA August 2021 (FDA, 2021b);

Recommended for authorization by EMA in November 2021 (EMA, 2024b);

Authorized by European Commission in June 2022 (EMA, 2024b).

Context of Approval (e.g., Standard of Care):

First treatment.

Regulatory Pathway Used:

FDA granted Nexviazyme approval using priority review (FDA, 2021b); EMA used standard approval to approve Nexviazyme (EMA, 2024b).

Designations/Expedited Programs Used:

FDA granted Nexviazyme Breakthrough Therapy, Fast Track, and Orphan designations (FDA, 2021b).

EMA had originally granted Nexviazyme an orphan designation. However, at the time of authorization, the dug was not found to provide a significant benefit over an existing treatment. Thus, the orphan designation was removed (EMA, 2022a)

Novel Trial Design Elements:

FDA: Approval based on totality of evidence approach which included open label data and g an analysis of covariance (ANCOVA) model (FDA, 2021b) EMA: Approval based on a benefit risk analysis (EMA, 2024b)

“Supplemental Data” Used:

Open label data was used to support approval in both FDA and EMA (EMA, 2024b; FDA, 2021b).

Advisory Committee and Patient Community Engagement:

There are no advisory committees or patient engagement documented for this drug

Regulatory Flexibilities Deployed:

Both FDA and EMA relied on open label data

FDA:

Despite a non-statistically significant analysis, FDA reviewed the totality of evidence

OGSIVEO (NIROGACESTAT)

Condition (Therapeutic Area):

Progressing, unresectable, recurrent or refractory desmoid tumors

Year of Approval (by Agency):

Approved by FDA in November 2023 (FDA, 2023e);

Submitted to EMA – no opinion yet. EMA validated the Marketing Authorization Application in February 2024 (SpringWorks Therapeutics, 2024).

Context of Approval (e.g., Standard of Care):

First product approved for desmoid tumors (FDA, 2023e)

Regulatory Pathway Used:

FDA granted Ogsiveo standard approval (FDA, 2023e)

Designations/Expedited Programs Used:

FDA granted Orphan designation, Breakthrough Therapy, Fast Track, and Priority Review (FDA, 2023e).

EMA granted Orphan designation (EMA, 2019a)

Novel Trial Design Elements:

Phase 3 randomized (1:1), double-blind, placebo-controlled trial with 142 patients in an international multicenter setting (FDA, 2023e).

“Supplemental Data” Used:

Patient-reported outcomes such as pain, physical functioning, health-related quality of life, and desmoid tumor specific symptoms (FDA, 2023e)

Advisory Committee and Patient Community Engagement:

There are no advisory committees or patient engagement documented for this drug

Regulatory Flexibilities Deployed:

FDA:

The program utilized the real-time oncology review (RTOR) pilot program; it entails a rapid-cycle and streamlined data submission process prior to the application filing. The approval also included a post-marketing requirement for the presence of ovarian toxicity risk increase. Risk-benefit profile was in favor of an approval, and this is why a REMS or risk management plan was not indicated (FDA, 2023e).

QALSODY (TOFERSEN)

Condition (Therapeutic Area):

Amyotrophic lateral sclerosis (ALS)

Year of Approval (by Agency):

Approved by FDA April 2023 (FDA, 2023g);

Recommended for authorization by EMA in February 2024 (EMA, 2024c); Not yet authorized by European Commission (EMA, 2024c).

Context of Approval (e.g., Standard of Care):

Qalsody is the first drug specific to SOD1 mutation; progressive disease with rapid morbidity and mortality with standard of care (FDA, 2023f).

Regulatory Pathway Used:

FDA used Accelerated Approval (based on surrogate endpoint) to approve Qalsody (FDA, 2023g).

EMA recommended marketing authorization under exceptional circumstances (EMA, 2024d).

Designations/Expedited Programs Used:

FDA granted Qalsody orphan designation and Priority Review (FDA, 2023g). EMA granted orphan designation (EMA, 2024d).

Novel Trial Design Elements:

One randomized, double-blinded, placebo-controlled trial; post-hoc analyses; open-label extension study (post-hoc exploratory analyses); use of novel surrogate endpoint (NfL)

“Supplemental Data” Used:

Open-label extension study (FDA, 2023g)

Advisory Committee and Patient Community Engagement:

FDA advisory committee which unanimously voted in favor of Qalsody (FDA, 2023g).

Regulatory Flexibilities Deployed:

FDA:

Qalsody failed its primary endpoint in the one pivotal trial. FDA accepted the significant reduction of NfL, a marker of neuronal degeneration and a secondary endpoint in the study as a reasonably likely surrogate endpoint to predict clinical benefit and thus support accelerated approval (FDA, 2023g).

EMA:

The CHMP positive opinion was “based on a reduction in the levels of SOD1 in the cerebrospinal fluid, a reduction in the levels of plasma neurofilament light chain (a marker of neuronal damage), and a numerically favorable effect on the ALSFRS-R physical ability scale” (EMA, 2024d)

RELYVIO (SODIUM PHENYLBUTYRATE AND TAURURSODIOL) KNOWN AS ALBRIOZA IN EU

Condition (Therapeutic Area):

Amyotrophic lateral sclerosis (ALS)

Year of Approval (by Agency):

Approved by FDA September 29, 2022 (FDA, 2022b);

Negative opinion for authorization by EMA in December 2023 (EMA, 2024a);

Refusal of marketing authorization by European Commission in May 2024 (EMA, 2024a).

Context of Approval (e.g., Standard of Care):

Two other drugs approved in United States (FDA, 2022b);

One other drug approved in EU (EMA, 2023).

Alternative products offer only modest clinical benefits. Patients have rapid morbidity and mortality on existing therapy (EMA, 2023; FDA, 2022b).

Regulatory Pathway Used:

FDA granted Relyvrio standard approval (FDA, 2022b).

Designations/Expedited Programs Used:

FDA granted Relyvrio orphan designation and Priority Review (FDA, 2022b). EMA granted orphan designation (EMA, 2023).

Novel Trial Design Elements:

Phase 3, double-blind, placebo-controlled trial—post-hoc long-term analysis (FDA, 2022b).

“Supplemental Data” Used:

Open-label extension study and Natural History Database (FDA, 2022b).

Advisory Committee and Patient Community Engagement:

United States: Two Advisory Committees. First AC voted down approval. Reconvened AC to discuss a major amendment to application, and committee voted in favor of the drug (FDA, 2022b).

EU: Scientific Advisory Group Review (EMA, 2023)

Regulatory Flexibilities Deployed:

FDA and EMA analyzed the same data from a Phase II study with open label extension; both sought input from outside scientific advisors and both received extensive input from patient groups. FDA and EMA both assessed that there were limitations in the clinical dataset.

FDA:

FDA noted that although these limitations were greater than usually were seen in drugs that meet the approval standard, they considered that the serious nature of the disease and the un-met need warranted use of regulatory flexibility. Applying this flexibility, they found that the benefits outweighed the risk and approved the drug (FDA, 2022b). In 2024, Relyvrio failed a Phase 3 trial. The company has withdrawn the drug from U.S. market (Amylyx Pharmaceuticals, 2024).

EMA:

EMA rejected the application based on its assessment that the efficacy data was neither robust nor statistically compelling (EMA, 2023)

SKYCLARYS (OMAVELOXOLONE)

Condition (Therapeutic Area):

Friedreich’s ataxia

Year of Approval (by Agency):

Approved by FDA February 28, 2023 (FDA, 2023h);

Recommended for authorization by EMA in December 2023 (EMA, 2024e); Authorized by European Commission in February 2024.

Context of Approval (e.g., Standard of Care):

SkyClarys is the first approved treatment for Friedreich’s ataxia in the United States (FDA, 2023d) and in Europe (Biogen Inc., 2024).

Regulatory Pathway Used:

Both agencies granted SkyClarys a standard approval (EMA, 2024e; FDA, 2023h).

Designations/Expedited Programs Used:

FDA granted the drug Orphan Product designation, Rare Pediatric Disease Priority Review Voucher program, Expedited Review, and Fast Track (FDA, 2023h).

EMA had designated it an Orphan Product (EMA, 2024e).

Novel Trial Design Elements:

External control in comparison to subjects in the open-label extension (OLE) (FDA, 2023h)

“Supplemental Data” Used:

Open-label extension study and use of natural history data used as the external control (Biogen Inc., 2024; FDA, 2023h)

Advisory Committee and Patient Community Engagement:

A patient advocacy organization, the Friedreich’s Ataxia Research Alliance (FARA), engaged with both FDA and EMA during the drug development process.

Regulatory Flexibilities Deployed:

FDA:

FDA approval demonstrated flexibility expressed in FDA guidance allowing for submissions based on “one adequate and well controlled study with confirmatory evidence.” That “confirmatory evidence” included the use of natural history data used as an “external control” in comparison to subjects in the Open Label Extension (OLE) of the single study (FDA, 2023h).

EMA:

EMA received the same clinical study data and supplemental data/confirmatory evidence as FDA, assessed them very similarly, and reached the same conclusion—recommending market approval 10 months after submission (EMA, 2024e).

TAFLINAR (DABRAFENIB) & MEKINIST (TRAMETINIB)

Condition (Therapeutic Area):

Unresectable or metastatic melanoma with a BRAF V600 mutation

Year of Approval (by Agency):

Approved by FDA in June 2022 (FDA, 2022a);

FDA indication update to include pediatric patients with low-grade glioma in March 2023 (FDA, 2023b);

EMA adopted a positive opinion to a change in the marketing indication for the combination therapy for resected Stage III melanoma (adjuvant treatment) in July 2018 (EMA, 2018a).

Context of Approval (e.g., Standard of Care):

This combination therapy was also approved as first-line therapy for pediatric patients with low-grade glioma driven by BRAF V600E mutation (FDA, 2023b).

Regulatory Pathway Used:

FDA used Accelerated Approval to approve the combination treatment (FDA, 2022a).

Designations/Expedited Programs Used:

FDA granted the drugs Priority Review (FDA, 2022a).

Novel Trial Design Elements:

Notable for the use of a basket trial design (NCI-MATCH and ROAR trials) inclusive or rare and non-rare cancer across 24 indications. Three trials and supporting evidence from 2 studies (FDA, 2022a).

“Supplemental Data” Used:

Patient reported outcomes specifically PROMIS Parent Proxy Global Health 7+2 were also used in the FDA approval process (FDA, 2022a).

Advisory Committee and Patient Community Engagement:

There are no advisory committees or patient engagement documented for this drug

Regulatory Flexibilities Deployed:

FDA:

This FDA approval is a first-in-class tumor agnostic indication for BRAF V600E mutation in solid tumors and expands the pool of biomarker targeted therapies in the marketplace. Additionally, this approval was facilitated by leveraging “Project Orbis,” an initiative designed by FDA Oncology Center of Excellence that entails a pathway for simultaneous review of oncology-focused therapies with international partners (FDA, 2023b)

EMA:

EMA approval is limited to a single-disease (melanoma) as opposed to the tumor agnostic framework of FDA and based on the results of a single Phase 3 RCT (EMA, 2018a)

WAKIX® (PITOLISANT)

Condition (Therapeutic Area):

Excessive daytime sleepiness (EDS) or cataplexy in adults with narcolepsy.

Year of Approval (by Agency):

Approved by FDA in October 2020 (FDA, 2021a);

Recommended for authorization by EMA on November 19, 2015 (EMA, n.d.);

Authorized by European Commission on March 31, 2016 (EMA, n.d.).]

Context of Approval (e.g., Standard of Care):

Wakix, which was approved in the United States and Europe to treat narcolepsy, is now being trialed in United States for a rare disease, Prader-Willi syndrome. Ten families in the United States obtained the medication at FDA’s discretion via personal importation and documented their experiences of improved sleep profiles and cognitive indicators (Pullen et al., 2019). The drug is now in clinical trials as a treatment for Prader Willi syndrome.

Regulatory Pathway Used:

FDA used priority review to approve Wakix (FDA, 2021a)

Designations/Expedited Programs Used:

FDA granted the drug orphan status for treatment of narcolepsy and Prader-Willi syndrome (FDA, n.d.). FDA also granted the drug Fast Track and Breakthrough Therapy designations for the cataplexy indication, but only Fast Track designations for the EDS indication (FDA, 2021a). EMA granted the drug Orphan Product designation (EMA, n.d.)

Novel Trial Design Elements:

A study of Pitolsant in patients with Prader-Willi Syndrome began in April, 2024. The study is a “Phase 3, randomized, double-blind, placebo-controlled, multicenter, global clinical study” (NIH, 2024). The study will include an open-label extension period (NIH, 2024).

“Supplemental Data” Used:

None

Advisory Committee and Patient Community Engagement:

There are no advisory committees or patient engagement documented for this drug (FDA, 2021a).

Regulatory Flexibilities Deployed:

FDA allowed for personal importation of the treatment for off-label use before the drug was approved in the United States.

WAYLIVRA (VOLANESORSEN)

Condition (Therapeutic Area):

Familial Chylomicronemia Syndrome (FCS)

Year of Approval (by Agency):

Not approved – complete response letter from FDA in August 2018 (Ionis Pharmaceuticals, 2018);

Recommended for authorization by EMA on February 28, 2019 (EMA, 2022b);

Authorized by European Commission on May 3, 2019 (EMA, 2022b).

Context of Approval (e.g., Standard of Care):

Waylivra was approved for patients in whom other medicines to reduce triglycerides have not worked (EMA, 2022b).

Regulatory Pathway Used:

EMA used conditional approval to approve Waylivra (EMA, 2022b).

Designations/Expedited Programs Used:

EMA granted the drug Orphan Product designation (EMA, 2022b).

Novel Trial Design Elements:

One pivotal controlled study in conjunction with open label extension and additional control from a previous study (EMA, 2022b).

“Supplemental Data” Used:

Open-label extension study (EMA, 2019b).

Advisory Committee and Patient Community Engagement:

An ad hoc expert group was convened to address questions raised by the CHMP on June 19, 2018. The CHMP considered the views of the ad hoc expert group as presented in the minutes of that meeting and, between June 28, 2018, and November 15, 2018, sent three additional lists of outstanding issues to the applicant (EMA, 2019b).

Regulatory Flexibilities Deployed:

EMA:

EMA stated “The overall safety database is therefore relatively limited but acceptable in the context of a rare and orphan disease like FCS” when discussing the limited data available (EMA, 2019b).

ZOLGENSMA (ONASEMNOGENE ABEPARVOVEC-XIOI)

Condition (Therapeutic Area):

Spinal muscular atrophy (SMA)

Year of Approval (by Agency):

Approved by FDA May 24, 2019 (FDA, 2019b);

Recommended for authorization by EMA in March 2020 (EMA, 2022c);

Authorized by European Commission in May 2020 (EMA, 2022c).

Context of Approval (e.g., Standard of Care):

Zolgensma was the first approved gene therapy to treat SMA in children younger than 2 years old (FDA, 2019a).

Regulatory Pathway Used:

FDA used priority review to approve Zolgensma (FDA, 2019b).

EMA used Conditional approval to approve Zolgensma (EMA, 2022c).

Designations/Expedited Programs Used:

FDA designated the drug an Orphan Product, a Rare Pediatric Disease, and Fast Track (FDA, 2019b).

EMA had designated it an Orphan Product and an Advanced therapy medicinal product (EMA, 2022c).

Novel Trial Design Elements:

External control in comparison to subjects in the open-label extension (FDA, 2019b).

“Supplemental Data” Used:

Open-label extension study and use of natural history data used as the external control (FDA, 2019b).

Advisory Committee and Patient Community Engagement:

There are no advisory committees or patient engagement documented for this drug

Regulatory Flexibilities Deployed:

FDA:

FDA granted approval based on a Phase 1 trial evaluating safety and preliminary efficacy and an ongoing Phase 3 trial evaluating the efficacy and safety. Both studies were open-label extension studies with 15 patients in the first study and 21 in the second. FDA demonstrated flexibility by approving Zolgensma based on increase in survival when compared with a natural history control (FDA, 2019b).

EMA:

EMA used the same data to approve Zolgensma but provided a conditional approval pending the final outcome of the Phase 3 trial (EMA, 2022c).

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