Baby Steps To Real-World Evidence Of Efficacy: External Controls Gain Popularity In Rare Disease Trials
Executive Summary
The Pink Sheet takes a closer look at recent clinical announcements showing how rare disease therapy sponsors are already increasingly reliant on natural history studies to guide drug development.
While the US FDA grapples with its emerging regulatory framework for real-world evidence, a small wave of recent clinical announcements illustrates how rare disease therapy sponsors are already increasingly reliant on natural history studies to guide drug development.
The FDA’s January 2019 draft guidance on rare disease drug development emphasizes the role of natural history data. "The natural history of rare diseases is often poorly understood, and the need for prospectively designed, protocol-driven natural history studies initiated in the earliest drug development planning stages cannot be overemphasized," the guidance states. "Although FDA does not require natural history studies, we advise sponsors to evaluate early the depth and quality of existing natural history knowledge to determine if it is sufficient to inform their drug development programs."
However, the agency’s real-world evidence (RWE) framework, released in December, takes a cautious approach to use of observational studies to support efficacy claims, promising more study and forthcoming guidance. (Also see "US FDA Is Hesitant About Using Observational Studies In Real-World Evidence Framework " - Pink Sheet, 6 Dec, 2018.) When FDA has based approvals on single-arm interventional trials with supportive RWE of efficacy, the framework observes that the real-world data has consisted of “data on historical response rates drawn from chart reviews, expanded access, and other practice settings.”
Approvals using RWE of efficacy have occurred “when using a parallel control arm is unethical or not feasible,” the framework says, and “usually when the effect size is expected to be large, based on preliminary data.” A Pink Sheet analysis identified 13 new product approvals that relied on RWE of efficacy, all in difficult-to-study rare disease settings. (Also see "A Baker’s Dozen Of US FDA Efficacy Approvals Using Real World Evidence" - Pink Sheet, 7 Aug, 2018.)
While approvals relying on RWE of efficacy are likely to remain uncommon, increasing familiarity with the possibilities and constraints of natural history data – prospective and retrospective, for uses ranging from direct evidence of efficacy to validation of new endpoints – can only help industry and regulators alike. The FDA is reviewing Novartis AG's biologics license application (BLA) for Zolgensma, which uses a prospective observational cohort study to contextualize a single-arm efficacy trial, and is likely to see more applications incorporating natural history studies in 2019 for bluebird bio Inc.’s Lenti-D gene therapy, Ultragenyx Pharmaceutical Inc.'s UX007, and Clementia Pharmaceuticals Inc.’s palovarotene.
In the meantime, natural history studies are playing a key role in clinical programs from Moderna Inc., Biohaven Pharmaceutical Holding Co. Ltd. BioMarin Pharmaceutical Inc., Abeona Therapeutics Inc., Retrotope Inc., and Rocket Pharmaceuticals Inc.
Bluebird bio’s Lenti-D Gene Therapy For Cerebral Adrenoleukodystrophy
Observational studies of patients with the rare progressive neurodegenerative disease cerebral adrenoleukodystrophy (CALD) were fundamental to the pivotal trial of bluebird bio’s Lenti-D CALD gene therapy, the company indicated in September 2018 after reaching “general agreement” with FDA on its clinical program. A January 2019 corporate presentation predicted submission of a BLA by the end of this year. The product holds a breakthrough therapy designation from the FDA.
The pivotal trial for the gene therapy is the Phase II/III Starbeam study, which has a primary endpoint measuring the proportion of patients who are alive and free of six major functional disabilities (MFD) at month 24. “This endpoint will be compared to a clinically meaningful benchmark that is based on literature and data collected in ALD-101, a retrospective analysis that assessed the natural history of CALD as well as outcomes from allo-HSCT treatment,” bluebird said. Allogeneic hematopoietic stem cell transplantation (allo-HSCT) is the only therapeutic option for CALD, but is associated with adverse immunologic complications.
The Starbeam trial is expected to enroll 30 patients, who will all receive autologous CD34+ hematopoietic stem cells transduced with the Lenti-D lentiviral vector encoding human adrenoleukodystrophy protein.
“Due to the potential increased risk of immunological complications when randomizing subjects with a less than ideal HLA-matched donor to an allo-HSCT trial arm, an external control approach has been adopted to establish the benefit-risk profile of Lenti-D,” bluebird bio explained. “The safety results from the Phase II/III Starbeam study will be compared with data collected from ALD-103,” another observational study that is running concurrently with the Phase II/III trial.
ALD-103 is a “prospective and retrospective data collection study” that is following outcomes of allo-HSCT in up to 60 CALD patients aged 17 or younger. Bluebird bio reported initial results from the ongoing study from 41 boys in September 2018, noting that the observational data “highlight the increased risks of mortality and morbidity in boys without a matched sibling donor who undergo allogeneic HSCT.”
Ultragenyx’ UX007 For Long-Chain Fatty Acid Oxidation Disorders
Ultragenyx plans to submit retrospective medical chart review as part of an upcoming new drug application (NDA) for its pharmaceutical-grade synthetic triglyceride product UX007.
Ultragenyx plans to submit the NDA in mid-2019 for patients with a group of autosomal recessive genetic disorders known as long-chain fatty acid oxidation disorders (LC-FAOD). Patients with LC-FAOD are unable to convert long-chain fatty acids into energy, which can lead to severe depletion of glucose and then to serious liver, muscle and heart disease. About 2,000 to 3,500 people in the US have LC-FAOD, which is currently treated with dietary regimens and medium-chain triglyceride oil, a medical food. Despite medical management, “many patients have significant metabolic events including hospitalizations and mortality due to LC-FAOD,” the company said.
UX007 is a highly purified seven-carbon fatty acid triglyceride that provides patients with medium-length odd-chain fatty acids. Unlike typical even-chain fatty acids, the odd-chain product “can be converted to new glucose through the Krebs cycle,” according to Ultragenyx. The company’s clinical program aims to show that UX007 is associated with fewer and shorter major clinical events. The major clinical events of interest include hard measurements that can be captured by real-world medical chart data, “primarily comprised of hospitalizations” but also including “some emergency room visits:” duration can be measured as the number of days in hospital or emergency room.
The NDA will rest on a 29-patient Phase II study of UX007, supported by an open-label long-term efficacy and safety extension study in 75 patients, data from 70 patients treated through expanded access, and investigator-sponsored randomized controlled study of 32 patients showing an effect on cardiac function. The NDA will also include “a retrospective medical record review of 20 original compassionate use patients,” Ultragenyx said in a Jan. 22 press release.
Ultragenyx is also using RWE to generate a comparison between pre-UX007 and UX007 treatment periods for patients in the long-term extension study, which enrolled 24 patients from the company-sponsored Phase II, 20 patients who had never been treated with UX007, and 31 patients from expanded access and investigator-sponsored studies. “For the Phase II study and naïve patients, retrospective medical chart data were collected allowing comparison of the annualized major clinical event and duration rates between pre-UX007 and UX007 treatment periods,” the company said.
Clementia’s Palovarotene For Fibrodysplasia Ossificans Progressiva
A natural history study in fibrodysplasia ossificans progressiva (FOP) was “instrumental” in establishing a clinically meaningful outcome to serve as the primary endpoint for Phase III, Clementia Pharmaceuticals reported in its 2018 annual filing with the SEC. The company is developing palovarotene, a retinoic acid receptor gamma (RARγ) agonist, for treatment of FOP and other ultra-rare diseases of abnormal bone formation. The natural history cohort will also serve as an external control for the company’s Phase III MOVE trial.
The company conducted the “first of its kind natural history study” in FOP in parallel with its Phase II trials. The natural history study, which enrolled 114 patients worldwide, was designed to “characterize the progression of FOP across numerous outcomes” by tracking formation of new heterotopic ossification (HO), or bone that forms outside the normal skeleton, Clementia said. No disease-altering treatments are available for FOP, which was known to be diagnosed in only about 800 patients globally as of 2016, although the company projects a higher prevalence nearer to 9,000 patients. Clementia announced a rare pediatric disease designation for palovarotene in FOP on Feb. 11, an incentive that makes the company eligible for a priority review voucher upon approval.
The natural history study used whole body CT scans and measured range of motion across all joints to track new HO formation. “Cross-sectional data indicates a strong correlation between losses in physical function with age,” the company said. “Also, the total body volume of HO in individual patients as well as the number of joints with heterotopic ossification shows strong correlations with these functional outcomes.”
Clementia’s first Phase II study of palovarotene in FOP, Study ‘201, was a randomized, placebo-controlled adaptive design study in 40 patients. “This study showed encouraging safety and efficacy results, as well as unique insights regarding the disease in general and how to better dose patients and measure disease impact,” the company said, but it did not reach statistical significance. The results did, however, suggest that the drug reduced incidence of new HO by approximately 50% as determined by CT scan at 12 weeks. For patients who formed new HO, mean volumes were reduced by approximately 70% as compared with placebo patients.
The natural history data helped to convince the FDA that palovarotene showed substantial improvement on a clinically significant endpoint, a necessary condition for the breakthrough therapy designation awarded to the drug in 2017 for prevention of HO associated with flare-up symptoms in patients with FOP.
Phase II data, compared with the natural history study, will also support an NDA filing planned for the second half of 2019, Clementia announced in October 2018 after a meeting with FDA. “Based on clinical data generated from our Phase 2 study, open-label extensions and our natural history study, the FDA has indicated that new HO is a clinically meaningful outcome and is sufficient as a primary endpoint for a registration trial supporting approval,” Clementia said.
The agency “based its assessment on the efficacy and safety data available from the completed Phase II clinical program,” which ultimately included “92 palovarotene-treated flare-ups in 62 patients across three different dosing regimens … compared to 46 placebo or untreated flare-ups in 41 patients from the company’s natural history study.” The Phase II analysis found a >70% reduction in mean new HO volume at 12 weeks as well as a statistically significant reduction in mean new HO volume in patients treated with the episodic 20/10 mg dosing regimen.
The NDA will seek approval of the 20/10 mg episodic dosing regimen. In the meantime, Clementia continues to enroll up to 80 patients in its open-label Phase III MOVE trial, which is evaluating a chronic 5 mg daily dose for two years in addition to the episodic regimen as time of flare-up; the trial could support an sNDA for the alternate dosing regimen. The MOVE trial’s primary efficacy endpoint is the annualized change in new HO volume as assessed by whole body CT compared to untreated patients from the natural history study. Data from MOVE could be available later in 2019, the company predicted.
Novartis’ AVXS-101 For Spinal Muscular Atrophy Type 1
FDA is reviewing a BLA for AVXS-101, a one-time gene replacement therapy for spinal muscular atrophy (SMA) type 1 that also holds a breakthrough therapy designation. The user fee goal for AVXS-101, which will be known as Zolgensma (onasemnogene abeparvovec), falls in May 2019. (Also see "Keeping Track: Pfizer’s Talzenna Ensures Record Year For Novel US Approvals; Novartis Submits SMA Gene Therapy" - Pink Sheet, 21 Oct, 2018.) Novartis acquired the breakthrough-designated gene therapy with its acquisition of AveXis Inc.
SMA is one of the most common genetic diseases, according to the SMA Foundation, with about 10,000-25,000 patients in the US. About 60% of patients have the most severe type, SMA type 1, which presents in infancy. FDA approved the first drug therapy for SMA, Biogen Inc.’s intrathecal Spinraza (nusinersen), in 2016 with a sham procedure-controlled, double-blind Phase III trial after open-label Phase II studies showed benefit over historical controls.
Novartis is seeking approval of Zolgensma on the basis of the single-arm Phase I START trial, which treated 15 patients, along with data from the ongoing Phase III STR1VE trial. An ongoing observational long-term follow-up of START patients tracks performance on motor milestones.
The clinical program relies on a natural history study to provide context for the START results, Novartis indicated. Eleven of the 12 patients who received the proposed therapeutic dose could sit unassisted for five or more seconds -- “a milestone never achieved in the natural history of SMA Type 1,” the company said, citing a prospective observational cohort study of 34 SMA type 1 patients, who were followed for up to 36 months.
All Zolgensma patients in START were alive without need for permanent mechanical ventilation at 24 months, while “natural history indicates that more than 90 percent of untreated patients with SMA Type 1 will die or require permanent ventilation by 24 months of age,” Novartis added. At 24 months follow-up, all 15 patients in the START trial were event-free, “as opposed to only 8% of patients in a natural history study.”
Abeona’s EB-101 For Recessive Dystrophic Epidermolysis, ABO-101 And ABO-102 For MPS III
The rare genetic disease gene and cell therapy company Abeona has relied on natural history studies to shape its lead clinical programs: EB-101 for the inherited connective tissue disease recessive dystrophic epidermolysis bullosa (RDEB), which has received both FDA breakthrough therapy and regenerative medicine advanced therapy (RMAT) designations; another RMAT product, ABO-102 for the lysosomal storage disorder mucopolysaccharidosis type IIIA, also known as Sanfillipo Syndrome type A; and ABO-101 for MPS IIIB/Sanfillipo type B. All three products have rare pediatric disease designations.
Abeona is currently preparing for a pivotal Phase III trial of EB-101 (engineered autologous dermal sheets) according to a recent company investor presentation. A natural history study is helping to “shape the clinical program,” Abeona said.
The company also has completed a Phase I/II trial that compared safety and wound healing with gene-corrected skin grafts compared with the patient’s baseline. The data also were compared with untreated wounds from a supporting natural history study. (Also see "Keeping Track: A Little Bit Of (Nearly) Everything" - Pink Sheet, 2 Feb, 2018.)
The natural history study included 128 RDEB subjects with a total of 1,436 wounds, Abeona reported. All patients had a history of either chronic open wounds or recurrent wounds with no healing >12 weeks. In the natural history study, 13 patients (15 chronic wounds) had been treated with the approved allograft products Apligraf and Dermagraft, but the allografts “demonstrated lack of efficacy in healing RDEB wounds” during the natural history study, Abeona said.
The company’s MPS III gene therapy candidates are both in Phase I/II studies. The clinical program has been influenced by a 25-patient natural history study of Sanfillipo Syndrome types A and B conducted by Nationwide Children’s Hospital in Cleveland.
When the Nationwide natural history study was announced in 2013, the investigators and supporting research foundations highlighted their efforts “to ensure that data collected from this study would be available to other qualified institutions” to speed development of therapeutic candidates for Sanfillipo Syndrome.
BioMarin’s Tralesinidase Alfa For MPS IIIB And Vosoritide For Achondroplasia
BioMarin is one of the few companies that have received FDA approval for a novel product that used RWE of efficacy. Brineura (cerliponase alfa) was approved in 2017 for late infantile ceroid lipofuscinosis type 2 on the basis of a non-randomized single-arm trial compared with patients from an independent external control group. (Also see "A Baker’s Dozen Of US FDA Efficacy Approvals Using Real World Evidence" - Pink Sheet, 7 Aug, 2018.) Brineura is designated a breakthrough therapy.
BioMarin continues to compare Brineura patients against external controls. On Feb. 7, the company announced new data from its open-label extension study of Brineura patients compared with CLN2 patients enrolled in the DEM-CHILD NCL natural history database. “Natural history patients were 12 times more likely on average to have experienced an unreversed two-point decline in ML score [a motor-language scale] than treated patients at three years,” BioMarin reported.
The orphan disease specialty company has long incorporated natural history studies into its clinical programs to design trials and justify endpoints. (Also see "BioMarin’s Orphan Drug Clinical Strategy Is Rooted In Natural History" - Pink Sheet, 22 Jan, 2015.)
To prepare for and complement BioMarin’s development of the peptide therapeutic vosoritide to treat achondroplasia, the company identified gaps in knowledge about the natural history of growth velocity and height of people with the disorder, an inherited short-stature skeletal dysplasia. “We have undertaken a natural history program to augment our clinical understanding of outcomes of untreated patients for comparison to patients treated with vosoritide,” the company’s 2018 10-K filing states.
A prospective natural history study, Study 111-901, started in 2012 to collect consistent growth measurements every three months in 350 achondroplasia patients under age 17, with enrollment open at birth. The study also served to collect baseline data on patients being considered for enrollment in a vosoritide trial, company materials note.
The company is also collecting contemporaneous natural history data on height into adulthood. “In collaboration with the leading skeletal dysplasia centers in the United States, BioMarin is conducting a multi-center, natural history study in 1,377 people with achondroplasia,” the company announced at a November 2018 R&D Day. “This natural history study will make it possible to compare the final adult height of people treated with vosoritide in our clinical studies and those not treated. These data will support the assessment of efficacy of vosoritide.”
BioMarin’s natural history data did not, however, allow the company to submit vosoritide without a conventional Phase III trial. When FDA convened its Pediatric Drugs and Endocrine and Metabolic Drugs Advisory Committees to discuss general issues in achondroplasia trial design in May 2018, most panelists said randomized, placebo-controlled trials would be necessary because the currently available natural history data do not appear adequate to allow for the use of historical controls in a single-arm study. (Also see "Achondroplasia Trial Design: US FDA Panel Moves Patient-Centered Development To The Forefront " - Pink Sheet, 16 May, 2018.)
Despite the challenges of rare disease trial recruitment, BioMarin’s placebo-controlled Phase III trial of vosoritide is “(over)enrolled” with 121 patients, the company told the JP Morgan health care conference in January. Phase III data is expected by year-end.
BioMarin has woven natural history studies of mucopolysaccharidosis IIIB (MPS IIIB, or Sanfilippo B syndrome) into its clinical program for the enzyme replacement therapy tralesinidase alfa (BMN 250). The candidate is being evaluated in a Phase I/II treatment trial (study ‘201) and two complementary real-world investigations: Study ‘901 is an observational study of the progression of MPS IIIb in children aged 1 to 10 with relatively preserved cognitive function, and Study ’902 is a natural history study of the progression of the disease in children from birth to age 18 with all levels of cognitive function. “Efficacy will be assessed by comparing changes in disease progression in the observational BMN 250-901 study vs. changes observed in Part 2” of the ‘201 study, the company reported last year.
The ‘901 study is a longitudinal study “to quantify the progression of MPS IIIB over time and to correlate changes in clinical features of the disease, in particular cognitive decline, with both MRI characteristics and biochemical markers of disease burden,” BioMarin’s web site says. “This information may help inform the design and interpretation of subsequent intervention studies.” The observational study will prospectively collect data from 20 to 30 pediatric patients aged one to 10 years old.
Study ‘902, another prospective natural history study, will enroll 60 pediatric patients up to 18 years old. The ‘902 study aims “to quantify the progression of cognitive decline in pediatric patients with MPS IIIB over time,” BioMarin said. Primary outcome measures include neurocognitive function, behavioral function, sleep habits, and quality of life assessments along with disease-specific biomarkers.
Biohaven’s Troriluzole For Spinocerebellar Ataxia
Biohaven is gearing up for a new randomized Phase III trial of its troriluzole for treatment of spinocerebellar ataxia (SCA), according to clinicaltrials.gov. While the Phase III trial has a conventional placebo-controlled design, the pivotal clinical program is indebted to a natural history-based analysis conducted after the drug failed to statistically differentiate from placebo in topline Phase II/III results released in late 2017.
“We engaged in discussions with the FDA regarding the potential for further development of troriluzole in ataxias, and the FDA expressed willingness to consider a modification of our trial’s primary endpoint, the Scale for Assessment and Rating of Ataxia, or SARA, as an acceptable registrational endpoint,” company investor materials report.
Biohaven’s post hoc analysis of the Phase II/III data suggested that “certain of the eight items measured by SARA were strongly susceptible to a placebo effect,” the company said, so Biohaven “proposed use of a modified SARA scale in future clinical evaluation of troriluzole.”
To support the modified SARA scale, Biohaven applied the same modified scale both to data from the long-term open-label extension of Phase II/III and data from a published natural history study, which followed the disease progression of 345 US patients for up to two years. “At one year, the mean change in the modified SARA score in the natural history reference cohort was an increase of +0.79, compared to a mean change in the troriluzole cohort of a decrease of −0.44,” Biohaven said. “We believe these observed changes with troriluzole suggest a clinically meaningful benefit relative to the natural history reference cohort.” However, the company observed, “comparisons to historical controls are generally not accepted by the FDA as the basis for approval.”
The analysis was persuasive to FDA, which advised Biohaven in November 2018 that “it agreed to a modified SARA scale, including a reduction in the number of domains measured.”
Rocket’s RP-A501 For Danon Disease
Rocket Pharmaceuticals’ RP-A501 is “the first investigational gene therapy for a monogenic heart failure syndrome,” according to the company. It is designed to treat patients with Danon disease, a rare neuromuscular and cardiovascular disease caused by mutations in the gene encoding lysosome-associated membrane protein 2 (LAMP-2). RP-A501 uses an adeno-associated virus (AAV) vector to deliver a LAMP2B transgene.
The gene therapy is in early clinical development, with a first-in-human Phase I trial expected to start in the second quarter of 2019, Rocket said in its Jan. 22 announcement that the FDA had cleared the RP-A501 investigational new drug (IND) application. The company sees a quick path to registration for RP-A501, with a goal of starting a Phase II registrational study in 2020 to support accelerated approval.
Between 15,000 and 30,000 patients in the US and Europe have Danon disease, Rocket estimates. “In parallel with the Phase I clinical trial, the company plans to publish a comprehensive literature review and conduct a retrospective chart review,” Rocket stated. The company is also planning a prospective natural history study of Danon disease, with enrollment expected to start in second quarter 2019.
Moderna’s mRNA-3704 And mRNA-3927 For Organic Acidemias
Moderna is enrolling patients in a longitudinal exploratory natural history study to support the development of its “systemic intracellular therapeutics” for organic acidemias, mRNA-3704 for methylmalonic acidemia (MMA) and mRNA-3927 for propionic acidemia (PA). The products, both of which hold rare pediatric disease designations from FDA, deliver mRNA to cells within target organs.
The MMA and PA Natural History Study (MaP) is “designed to identify and correlate clinical and biomarker endpoints for these disorders,” Moderna said. The company enrolled the first patients in the observational cohort study in mid-2018; the MaP study aims to enroll up to 60 patients with confirmed diagnosis of MMA due to methylmalonyl-CoA mutase (MUT) deficiency and 60 PA patients in the US and Europe. Patients will be followed prospectively for one to three years, Moderna said, and “retrospective data will be collected as available.”
The MaP study will look at plasma levels of MUT for MMA patients and the biomarkers 2-MC and 3-HP for PA patients, as well as the frequency of disease-related clinical events, according to clinicaltrials.gov.
Moderna has submitted an IND for a Phase I/II study of mRNA-3704, the company announced Jan. 8. The company hopes to start the 34-patient Phase I/II study in May 2019, clinicaltrials.gov indicates. The clinical trial will start by characterizing baseline biomarker levels, followed by a dose-escalation treatment phase.
Retrotope’s RT001 For Infantile Neuroaxonal Dystrophy
Retrotope started enrolling the first of what will be 15 to 20 patients with the ultra-rare neurodegenerative disease infantile neuroaxonal dystrophy (INAD) in an open-label Phase II/III trial of its fatty acid candidate RT001 in late 2018. “Due to the paucity of publicly available natural history of the progression of the disease, Retrotope is also enrolling a prospective natural history study in a matched group of INAD patients who are not participating in the trial,” the company reported Dec. 13. “These trials will be the first interventional and prospective natural history clinical trials of classical INAD,” which affects “only a few hundred patients worldwide.”
The drug, the first of a new category of drugs known as deuterated polyunsaturated fatty acid products (D-PUFAs), is “designed to protect against free radical damage resulting in cell death that is a hallmark of numerous neurodegenerative diseases including INAD,” Retrotope said. “Observational data in expanded access trials in several indications support the possible slowing or halting of progression in neurodegenerative diseases,” including two expanded access patients with INAD.
For its primary endpoint, the Phase II/III trial measure the “effectiveness of treatment as measured by a quantitative scale of both Activities of Daily Living (ADLs) and deficits in vital functions affecting INAD children compared to natural history progression,” Retrotope said.