Sunday, October 27, 2024

US Approved Gene Therapies and Summary Basis for Approvals

The FDA presentation by Dr Gopa Raychaudhuri, "Facilitating Development of Gene Therapies for Rare Diseases," summarized all Gene Therapies approved by the US FDA. There were 19 approved gene therapies: 6 stem cell therapies, 6 T cell therapies, and 7 directly administered therapies.  



Gene therapy therapies are reviewed and approved by FDA Center for Biologicals Evaluation and Research (CBER), especially the Office of Therapeutic Products (OTP) - Approved Cellular and Gene Therapy Products are listed here

For each approved gene therapy, FDA publishes the product approval and review information on their website by year. The clinical evidence of effectiveness is provided to the public for transparency. For those 19 approved gene therapies, "Summary Basis for Regulatory Action" documents were reviewed and some basic information was summarized in the table below. 

Sponsor

Product & Indication

Study Design

Sample Size

FDA approval date/Brand Drug Name

Pfizer

Adeno-associated virus vector-based gene therapy.

 

Adults with moderate to severe hemophilia B.

Phase 1/2a Study C0371005 (Safety)  - open-label, single-dose, single-arm, multi-center.

 

Phase 3 Study C0371002 (Efficacy and Safety), open label, single-dose, multi-national study .

 

https://www.fda.gov/vaccines-blood-biologics/cellular-gene-therapy-products/beqvez

 

15 subjects

 

 

45 subjects

April 2024

Beqvez

 

Orchard Therapeutics

Stem cell-based gene therapy.

 

Children with pre-symptomatic late infantile, pre-symptomatic early juvenile, or early symptomatic early juvenile, metachromatic leukodystrophy.

Data from an adequate and well-controlled investigation comprised of two single arm, single-center, open-label studies, a European Union Expanded Access Program (EAP), and one ongoing long-term follow-up study and a natural history study.

https://www.fda.gov/vaccines-blood-biologics/cellular-gene-therapy-products/lenmeldy

 

Study OTL-200-201222 (n=18) and Study 205756 (n=10)

March 2024

Lenmeldy

Vertex

Stem cell-based gene therapy-genome editing using CRISPR/Cas9 and SPY101.

Patients aged 12 years and older with transfusion-dependent β-thalassemia (TDT).

Multinational, single-arm, open-label, phase 1/2/3 study.

https://www.fda.gov/vaccines-blood-biologics/casgevy


52 dosed,

35 evaluable.

Jan 2024

Casgevy

Vertex

Stem cell-based gene therapy -genome editing using CRISPR/Cas9/SPY101 technology.

Sickle cell disease in patients aged 12 years or older with recurrent vaso-occlusive crises.

Multinational, single-arm, phase 1/2/3 study.

 

 

https://www.fda.gov/vaccines-blood-biologics/casgevy

44 treated,

31 evaluable.

Dec 2023

Casgevy

Bluebird Bio

LVV gene therapy.

Sickle cell disease in patients aged12 years or older with a history of vaso-occlusive events.

Study Hgb 206, an ongoing Phase 1/2, open label, multicenter.

https://www.fda.gov/vaccines-blood-biologics/lyfgenia

 

Safety: 54 subjects.

 

Efficacy: 32 subjects.

Dec 2023

Lyfgenia

BioMarin 

Adeno-associated virus vector-based gene therapy.

 

Adults with severe hemophilia A.

Open-label, single-dose, single-arm, multinational phase 3 study.

 

https://www.fda.gov/vaccines-blood-biologics/roctavian

112 subjects dosed and constituted the rollover population evaluated.

June 2023

Roctavian

Sarepta

Adeno-associated virus vector-based gene therapy.

Ambulatory pediatric patients aged 4 through 5 years with Duchenne muscular dystrophy (DMD) with a confirmed mutation in the DMD gene.

Open-label study 101.

Randomized, double-blind, placebo-controlled study 102.

Open label study 103.

 https://www.fda.gov/vaccines-blood-biologics/tissue-tissue-products/elevidys

Safety: 85 subjects.

73 subjects received intended dose and 12 received lower doses.

 

 

June 2023

Elevidys

Krystal Biotech

Vector-based gene therapy.

 

Wounds in patients 6 months of age and older with dystrophic epidermolysis bullosa with mutation(s) in the collagen type VII alpha 1 chain (COL7A1) gene.

First-in-human, single-center, open-label, randomized, intra-subject, placebo (vehicle) controlled phase 1/2 study (KB103-001).

Multicenter, intra-subject randomized, placebo-controlled, double-blind open-label phase 3 study (B-VEC-03).

https://www.fda.gov/vaccines-blood-biologics/vyjuvek

 

9 subjects.

 

 

 

 

 

Safety: 31 subjects.

May 2023

Vyjuvek

Ferring Pharmaceuticals A/S

Vector-based gene therapy.

Adult patients with high-risk Bacillus Calmette-Guérin unresponsive non-muscle invasive bladder cancer with carcinoma in situ with or without papillary tumors.

Single-arm trial study (CS-003).

 

https://www.fda.gov/vaccines-blood-biologics/cellular-gene-therapy-products/adstiladrin

 

107 subjects enrolled.

98 subjects evaluable.

Efficacy: 55 subjects.

Dec 2022

Adstiladrin

CSL Behring

Adeno-associated virus vector-based gene therapy.

 

Adults with Hemophilia B (congenital Factor IX deficiency).

Open-label, single-dose, single-arm, multi-center phase 2b study.

Open-label, single-dose, multi-center, multinational phase 3 study.

https://www.fda.gov/vaccines-blood-biologics/vaccines/hemgenix

 

3 subjects.

 

 

54 subjects.

Nov 2022

Hemgenix

 

Bluebird bio

Stem cell-based gene therapy.

Slowing the progression of neurologic dysfunction in boys 4-17 years of age with early, active cerebral adrenoleukodystrophy.

 

Open-label, multicenter, single-arm phase 2/3 study.

Open-label, multicenter, single-arm phase 3 study.

 

https://www.fda.gov/vaccines-blood-biologics/skysona

 

Safety: 67 subjects.

Efficacy: 61 subjects.

Sept 2022

Skysona

Bluebird Bio

LVV Gene Therapy

Beta-thalassemia.

B cell maturation antigen-directed genetically modified.

Adult and pediatric patients with ß-thalassemia who require regular red blood cell (RBC) transfusions.

Two open-label, multicenter, single-arm phase 3 studies.

https://www.fda.gov/vaccines-blood-biologics/zynteglo

 

18 in HGB-212 study and 23 in HGB 207 study.

Aug 2022

Zynteglo

Janssen Biotech

Autologous T cell immunotherapy.

Adult patients with relapsed or refractory multiple myeloma who have received at least one prior line of therapy.

Single-arm, phase 1b-2 multicenter study.

 

https://www.fda.gov/vaccines-blood-biologics/cellular-gene-therapy-products/carvykti

 

Efficacy: 97 subjects.

Feb 2022

Carvykti

Celgene Corporation

B cell maturation antigen-directed genetically modified autologous T cell immunotherapy.

Adult patients with relapsed or refractory multiple myeloma after two or more prior lines of therapy including an immunomodulatory agent, a proteasome inhibitor, and an anti-CD38 monoclonal antibody

Single-arm, multicenter phase 2 study.

 

https://www.fda.gov/vaccines-blood-biologics/abecma-idecabtagene-vicleucel

 

Safety: 127 subjects.

Efficacy: 100 subjects.

March 2021

Abecma

Juno Therapeutics

CD19-directed genetically modified autologous T cell immunotherapy.

Adult patients with large B-cell lymphoma, including diffuse large B-cell lymphoma (DLBCL) not otherwise specified (including DLBCL arising from indolent lymphoma), high-grade B cell lymphoma, primary mediastinal large B-cell lymphoma, and follicular lymphoma grade 3B.

Single-arm, multicenter phase 1 study.

 

https://www.fda.gov/vaccines-blood-biologics/cellular-gene-therapy-products/breyanzi-lisocabtagene-maraleucel

 

Safety: 268 subjects.

Efficacy: 256 subjects.

Feb 2021

Breyanzi

Kite Pharma

CD19-directed genetically modified autologous T cell

Immunotherapy.

 

Adult patients with relapsed or refractory

Mantle Cell Lymphoma.

Single-arm, multicenter, phase 2 study.

 

https://public4.pagefreezer.com/browse/FDA/27-12-2021T03:59/https://www.fda.gov/vaccines-blood-biologics/cellular-gene-therapy-products/tecartus-brexucabtagene-autoleucel

 

68 subjects treated.

Efficacy: 60 subjects.

July 2020

Tecartus

AveXis

Adeno-associated virus vector-based gene therapy. 

Pediatric patients less than 2 years of age with spinal muscular atrophy (SMA) with bi-allelic mutations in the survival motor neuron 1 gene.

Open-label, single-arm, ascending-dose, phase 1 study.

Open-label, single-arm, phase 3 study.

https://public4.pagefreezer.com/browse/FDA/29-01-2023T09:49/https://www.fda.gov/vaccines-blood-biologics/zolgensma

 

15  subjects.

 

 

44 subjects.

May 2019

Zolgensma

Spark Therapeutics

Adeno-associated virus serotype 2 vector gene therapy.

 Confirmed biallelic RPE65 mutation-associated retinal dystrophy.

Open-label, dose-escalation, phase 1 study.

Open-label, randomized, controlled, cross-over, phase 3 study.

https://public4.pagefreezer.com/content/FDA/29-01-2023T09:49/https://www.fda.gov/vaccines-blood-biologics/cellular-gene-therapy-products/luxturna

 

12 subjects.

 

29 subjects.

Dec 2017

Luxturna

Kite Pharma

CD19-directed genetically modified autologous

T cell immunotherapy.

Adult patients with large B-cell lymphoma that is refractory to first-line chemoimmunotherapy or that relapses within 12 months of first-line chemoimmunotherapy

Single-arm, open-label, multicenter phase 1/2 study.

 

https://public4.pagefreezer.com/content/FDA/29-01-2023T09:49/https://www.fda.gov/vaccines-blood-biologics/cellular-gene-therapy-products/yescarta-axicabtagene-ciloleucel

 

Safety: 108 subjects.

Efficacy: 101 subjects.

Oct 2017

Yescarta

Novartis Pharmaceuticals

CD19-directed genetically modified autologous T cell immunotherapy.

Adult patients with relapsed or refractory follicular lymphoma after two or more lines of therapy.

Multicenter, open-label, single-arm, trial.

 

https://public4.pagefreezer.com/content/FDA/29-01-2023T09:49/https://www.fda.gov/vaccines-blood-biologics/cellular-gene-therapy-products/kymriah-tisagenlecleucel

 

63 subjects.

Aug 2017

Kymriah


The clinical evidence for the effectiveness of gene therapies often comes from multi-center, open-label, single-arm studies with relatively small sample sizes, as shown in the table above. In some cases, phases of clinical development are combined.

Monday, October 21, 2024

FDA Office of Scientific Investigations (OSI) Requests for Bioresearch Monitoring (BIMO) Data for NDA/BLA Submission

FDA has a Bioresearch Monitoring (BIMO) program and the BIMO program is managed by the Office of Scientific Investigations (OSI). 

BIMO program is a comprehensive, FDA-wide program of on-site inspections and data audits, designed to monitor all aspects of the conduct and reporting of FDA-regulated research. 

Objectives of the BIMO program includes: 

  • Protect the rights, safety, and welfare of human research subjects
  • Verify the accuracy, reliability, and integrity of clinical and non-clinical trial data submitted to FDA
  • Assess compliance with FDA's regulations governing the conduct of clinical and non-clinical trials, including regulations for informed consent and ethical review

BIMO program has become a cornerstone of the FDA preapproval process for new medicines, medical devices, food and color additives, veterinary products and, tobacco products introduced to the U.S. consumer.

The BIMO program also takes part in pharmacovigilance activities for postmarketing drug products. These activities serve to detect, understand, and prevent drug-related problems.

The BIMO program is managed and executed differently at different review centers (namely CDER and CBER). CBER's BIMO program was described in a FDA presentation by Dr Triet Tran "The Center for Biological Evaluation and Research (CBER) Bioresearch Monitoring (BIMO) Program". CDER's BIMO program was described in a Youtube video by Dr Kelly Nolen "Center for Drug Evaluation and Research (CDER) Bioresearch Monitoring (BIMO) Program - A General Overview".

For NDA or BLA submissions to CDER, sponsors are often asked to provide site-specific information to support the FDA’s Bioresearch Monitoring (BIMO) program and aid in selecting sites for inspection. The FDA typically includes standard language about this (see below) in their communications, such as in letters to the sponsor or the minutes of pre-NDA or pre-BLA meetings.
OFFICE OF SCIENTIFIC INVESTIGATIONS (OSI) REQUESTS

The Office of Scientific Investigations (OSI) requests that the items described in the draft guidance for industry, Standardized Format for Electronic Submission of NDA and BLA Content for the Planning of Bioresearch Monitoring (BIMO) Inspections for CDER Submissions, and the associated conformance guide, Bioresearch Monitoring Technical Conformance Guide Containing Technical Specifications, be provided to facilitate development of clinical investigator and sponsor/monitor/CRO inspection assignments, and the background packages that are sent with those assignments to the FDA ORA
investigators who conduct those inspections. This information is requested for all major trials used to support safety and efficacy in the application (i.e., phase 2/3 pivotal trials). Please note that if the requested items are provided elsewhere in submission in the format described, the Applicant can describe location or provide a link to the requested information.

Please refer to the draft guidance for industry Standardized Format for Electronic Submission of NDA and BLA Content for the Planning of Bioresearch Monitoring (BIMO) Inspections for CDER Submissions (February 2018) and the associated Bioresearch Monitoring Technical Conformance Guide Containing Technical Specifications.
Sponsor's statistical programming group will need to prepare the BIMO related data sets and data listings - all by sites. 
  • A data set containing general study related information and comprehensive clinical investigator information
  • Subject level data listing by site
  • Site level dataset
Details about BIMO datasets and data listings can be found in the FDA CDER guidance titled Bioresearch Monitoring Technical Conformance Guide Containing Technical Specifications (see the table of contents below). It’s important to note that this guidance applies only to CDER and not to other FDA review divisions like CBER. Since the BIMO technical conformance guide is regularly updated, the statistical programming team must ensure they are following the most current version when preparing the BIMO package for NDA or BLA submissions.

There has been extensive discussion about using SAS programming to generate the BIMO package, including the creation of BIMO datasets and data listings:

Saturday, September 28, 2024

Crossover design in confirmatory therapeutic trials

This week, FDA approved a new drug called Aqneursa (levacetylleucine) for the treatment of neurological symptoms associated with Niemann-Pick disease type C (NPC) - a rare disease - in adults and pediatric patients. FDA approval was based on the confirmatory phase 3 study using a crossover design. "The safety and efficacy of Aqneursa for the treatment of NPC were evaluated in a randomized, double-blind, placebo-controlled, two-period, 24-week crossover study. The duration was 12 weeks for each treatment period. The study enrolled 60 patients." The study design was discussed in the paper by Fields et al "N-acetyl-L-leucine for Niemann-Pick type C: a multinational double-blind randomized placebo-controlled crossover study" and the crossover study design was depicted as below. Patients were assessed during a baseline period and then randomized (1:1) to one of two treatment sequences: IB1001 (levacetylleucine) followed by placebo or placebo followed by IB1001 (levacetylleucine). Each sequence consists of a 12-week treatment period. The primary efficacy endpoint is based on the Scale for the Assessment and Rating of Ataxia


The advantages of the crossover design includes:
  • It allows a within-patient comparison between treatments. Each patient serves as his/her own control
  • Treatment contrasts estimated as a within subject effect
  • Fewer subjects (smaller sample size) required for the study

The disadvantages of the crossover design includes: 
  • Carryover effect of previous treatment to the next treatment
  • Time dependent changes
  • Increased time length of the trial
  • Drop out issue, too many visits
  • May require complicated statistical modeling - for example, mixed model to analyze the data
The crossover design is very common and almost the default design for bioequivalence studies. As stated in FDA's guidance for industry "Bioequivalence Studies With Pharmacokinetic Endpoints for Drugs Submitted Under an ANDA", crossover design was recommended in most of situations. 
"For most dosage forms that release a drug intended to be systemically available, FDA recommends that applicants perform a two-period, two-sequence, two-treatment, single-dose,crossover study using either healthy subjects or other populations, as appropriate. In this design, each subject should receive each treatment (the test and the reference product) in a random order. 
A replicate crossover study design (either partial or fully replicate) is appropriate for drugs  whether the reference product is a highly variable drug or not. A replicate design can have the advantage of using fewer subjects compared to a non-replicate design, although each subject in a replicate design study would receive more treatments."

However, crossover designs are seldom employed in confirmatory therapeutic clinical trials, which typically use clinical endpoints rather than pharmacokinetic ones. The most common design for these trials is the traditional randomized controlled trial (RCT) with parallel groups, where patients are randomly assigned to either an experimental treatment group or a placebo.

In some special situations such as the rare disease drug development, the crossover design may be employed in the phase 3 confirmatory clinical trials. Here are some examples: 

ICH E9 "STATISTICAL PRINCIPLES FOR CLINICAL TRIALS" have a section discussing crossover design:


FDA's Good Review Practice: Clinical Review of Investigational New Drug Applications" also discussed the advantages and disadvantages of the crossover design:



In confirmatory therapeutic trials using a crossover design, an additional concern is the potential for unblinding. As the same patient receives both the experimental drug and the placebo, the patient might be able to identify or guesstimate the treatment group they are assigned to based on slight differences in taste, smell, or side effects.

Monday, September 23, 2024

The Role of Radiolabeling in Clinical Studies: Exploring Lung Deposition and Mass Balance Studies

Radiolabeling is an advanced and valuable technique in clinical research that enables scientists to trace the journey of drugs through the human body. By attaching a radioactive isotope to a drug molecule (usually a small molecule), researchers can track its absorption, distribution, metabolism, and excretion (ADME). This technique provides precise, real-time data and is especially useful for two types of clinical studies: lung deposition studies and mass balance studies.

What Are Lung Deposition Studies?

Inhaled medications are commonly used to treat respiratory diseases like asthma, chronic obstructive pulmonary disease (COPD), alpha-1 antitrypsin deficiency, and cystic fibrosis. However, the efficacy of these treatments largely depends on how much of the drug reaches the target area in the lungs.

Lung deposition studies assess the distribution of inhaled drugs within the lungs. The primary goal of these studies is to ensure that the drug particles deposit in the right lung regions for optimal therapeutic effect. Radiolabeling plays a crucial role in these studies by enabling researchers to visualize and quantify how inhaled drugs spread through the respiratory system.

Radiolabeling in Lung Deposition Studies

Radiolabeling in lung deposition studies involves attaching a radioactive isotope, such as technetium-99m (99mTc), to the drug formulation. After inhalation, the radioactive emissions from the drug particles are detected using imaging techniques like gamma scintigraphy or positron emission tomography (PET). These images provide a detailed map of drug distribution within the lungs.

Key advantages of using radiolabels for lung deposition studies include:

  • Accurate Measurement: Researchers can measure how much of the drug reaches the lungs and where exactly in the lungs it settles (central airways, peripheral airways, alveoli, etc.).
  • Device Optimization: By studying how well different inhaler devices (e.g., dry powder inhalers, metered-dose inhalers, nebulizers) deliver the drug, researchers can refine device designs to improve drug delivery to the lungs.
  • Personalized Treatment: Lung deposition patterns vary across individuals due to differences in lung anatomy, disease severity, and inhaler technique. Radiolabeling helps researchers tailor treatments to individual needs.

Imaging Techniques in Lung Deposition Studies

  1. Gamma Scintigraphy: This is the most commonly used imaging method in lung deposition studies. It detects gamma radiation emitted from radiolabeled drug particles and generates detailed images showing how much of the drug is deposited in different parts of the lungs.

  2. Positron Emission Tomography (PET): PET is a more advanced imaging technique that uses isotopes like carbon-11 to provide high-resolution, three-dimensional images of drug distribution in the lungs. While more expensive and complex than gamma scintigraphy, PET can offer more precise data on drug uptake and metabolism in the lungs.

Why Lung Deposition Studies Matter

  • Efficacy: Lung deposition studies help determine if a drug reaches the specific areas of the lungs (for example, the peripheral part of the lung versus central part of the lung) where it's needed most. For example, drugs intended for deep lung penetration must reach the alveoli to be effective.
  • Safety: By ensuring that a drug is delivered directly to the lungs and not to other parts of the body, these studies minimize systemic side effects.
  • Regulatory Compliance: Regulatory agencies like the FDA and EMA often require data on drug deposition patterns to ensure safety and efficacy, especially for inhaled drugs.

Some Examples of the Lung Deposition Studies: 



What Are Mass Balance Studies?

Mass balance studies, also known as absorption, distribution, metabolism, and excretion (ADME) studies, track the fate of a drug from administration to elimination. These studies are essential for understanding how much of the drug is absorbed into the bloodstream, how it is metabolized, and how it is excreted from the body.

Radiolabeling is critical in mass balance studies as it enables precise quantification of the drug and its metabolites in different biological samples, including blood, urine, feces, and sometimes breath.

Radiolabeling in Mass Balance Studies

In mass balance studies, radiolabeling involves attaching a radioisotope (such as carbon-14 or tritium) to the drug molecule. Once the drug is administered, researchers can track its movement through the body by measuring radioactive emissions in collected biological samples. The use of radiolabels allows for accurate and complete recovery of the drug and its metabolites, making it easier to determine:

  • Total absorption: How much of the drug is absorbed into systemic circulation.
  • Metabolic pathways: How the drug is broken down in the body and the metabolic products formed.
  • Elimination: The routes through which the drug is excreted (e.g., urine, feces) and how much is removed from the body over time.
According to FDA guidance for industry (2024) "Clinical Pharmacology   Considerations for  Human Radiolabeled Mass Balance Studies", the following were stated:
A human radiolabeled (most commonly 14C or 3H) mass balance study is the single most direct method to obtain quantitative and comprehensive information on the absorption, distribution, metabolism, and excretion (ADME) of the drug in the human body.  
The mass balance study can provide information to: 
  • Determine the overall pathways of metabolism and excretion of an investigational drug 
  • Identify circulating metabolites 
  • Determine the abundance of metabolites relative to the parent drug or total drug-related exposure 
The results from mass balance studies help to: 
  • Provide information on which metabolites should be structurally characterized and which metabolites should undergo nonclinical safety assessment or drug-drug interaction (DDI) evaluation 
  • Assess whether renal or hepatic impairment studies or certain DDI studies are recommended for the investigational drug 
  • Assess the extent of absorption of the investigational drug 

Importance of Mass Balance Studies

  1. Drug Safety: Mass balance studies help identify any potentially harmful metabolites that could lead to side effects. By understanding how a drug is metabolized, researchers can predict interactions with other medications.

  2. Dose Optimization: These studies provide critical information for determining appropriate dosage levels by understanding how much of the drug remains in the system over time.

  3. Regulatory Approval: Mass balance data is essential for regulatory submissions, providing authorities with a full picture of the drug’s pharmacokinetics and safety profile.

Challenges in Radiolabeled Mass Balance Studies

Although radiolabeling offers precise tracking of drugs, mass balance studies present a few challenges:

  • Complexity: Preparing radiolabeled drugs requires specialized equipment and expertise, which can increase the cost and time required for studies.
  • Radiation Safety: Even though radiolabels use minimal radiation doses, strict safety protocols must be followed to minimize exposure risks for study participants and researchers.
  • Variability: Individual differences in metabolism can lead to variability in study results, requiring large sample sizes for accurate interpretation.

Combining Lung Deposition and Mass Balance Studies

Radiolabeling enables researchers to link data from both lung deposition and mass balance studies. For inhaled drugs, this combined approach provides a complete picture of how the drug behaves after delivery: from deposition in the lungs to its absorption into the bloodstream and eventual elimination.

Conclusion

Radiolabeling plays a pivotal role in both lung deposition and mass balance studies, providing detailed, real-time insights into the distribution and metabolism of drugs within the body. These studies are indispensable for the development of safe and effective therapies, particularly for inhaled medications and other drugs that require precise delivery to target tissues.

By combining data from lung deposition studies with mass balance studies, researchers can optimize drug formulations, refine delivery devices, and ensure that new drugs meet regulatory requirements, all while enhancing patient outcomes.