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FDA/EMA Approvals of Orphan Designation on Gene therapy

January 18, 2017
Gene therapy:
Gene therapy is the transfer of genetic material to dysfunctional cells to correct a deficiency in the DNA or genome of a patient. Despite numerous clinical and non-clinical research by academic institution and industries, only two gene therapy drugs are approved by EMA for market authorization. And FDA is yet to approve the commercial prescription these therapies in clinics. Progression in development of gene therapies in last decade were slower given the nature of therapy, high immunogenicity, and toxic effects on the patient. Emerging scientific understanding, technological advancement, approval of Glybera and positive outcomes on clinical trials from rare eye disease and hematological diseases, have re-focused the attention from researchers and pharmaceutical companies to pursue avenues of gene therapy for various diseases. In parallel, the regulatory agencies are also embracing the platform to provide the treatment for unmet medical needs. The FDA database showed numerous gene therapy pipeline drugs are designated as orphan status as shown in table. Although designation of orphan status does not translate to marketing authorization, it will be interesting find out how many will obtain market authorization.


Table: Pipeline gene therapy with orphan status (Based on FDA database)
Disease
Year
Encoding Gene
Vector
Company
Pompe disease
2017
Human acid alpha glucosidase gene
Non-replicating adeno associated virus
Duke University Medical Center
Mucopolysaccharidosis type I
2017
Alpha-L-iduronase (hIDUA) gene,
ZFNs
Adeno associated virus subtype 2/6 vector
Sanamo Biosciences
Retinitis pigmentosa
2016
RPGR gene
Adeno associated virus serotype 5
MeiraGTx Limited
Retinis pigmentosa due to pde6B gene mutation
2016
pde6B
Adeno-associated virus serotype 2
HORAMA, SAS
Glycogen storage disease type Ia( von Gierke disease)
2016
Glucose-6- phosphatase gene
Adeno associated virus serotype 8
Dimension Therapeutics
Inclusion body Myositis
2016
Follistatin
Adeno associate virus
Milo Biotechnology
Limb Girdle Muscular dystrophy
2016
Human dysferin gene
Adeno associated virus rhesus 74
Nationwide Children's Hospital
Hunter syndrome A (MPS II)
2016
Iduronate-2- sulfatase
Adeno-associated adenovirus  serotype 9
Nationwide Children's Hospital
Sanfiippo syndrome A (MPS IIIA)
2016
N-Sulfoglucosamine Sulfohydrolase
Adeno-associated virus serotype 9
Nationwide Children’s Hospital  
Hemophilia B
2016
Human factor 9 gene  & ZFNs
Adeno-associated virus serotypes 2/6
Sangamo Biosciences
Duchenne Muscular dystrophy
2016
Microdystrophin 5 gene under CK8 promoter(muscle specific)
Adeno-associated virus
Solid GT LLC
Friedreich’s Ataxia
2016
Frataxin
Adeno-associated virus serotype 5
Agilis Biotherapeutics
Aromatic L-amino acid decarboxylase deficiency
2016
AADC mRNA cDNA
Adeno-associated virus serotype 2
Agilis Biotherapeutics
Crigler Najjar Syndrome
2016
Bilirubin-uridine diphosphate glucouronyltransferase 1A1 isoform gene
Adeno-associated virus serotype 8
Audentes Therapeutics
Pyruvate kinase deficiency
2016
Human liver and erythroid pyruvate kinase gene
Lentivirus
Centro de Investigacion Biomedica en RED
Leber congenital amaurosis
2016
RPE65 gene
Adeno-associated virus 5
MeiaGTx Limited
Neuronal Ceroid Lipofuscinosis (NCL), CLN2 disease
2016
Tripeptidyl peptidase 1 gene
Adeno-associated virus serotype 2
Spark Therapeutics
Achromatopsia (Mutation in CNGB3 gene )
2016
CNGB3 gene
Adeno-associated virus serotype 8
Meira GTx Limited
Hemophilia A
2016
SQ variant factor VIII
Adeno-associated virus
BioMarin pharmaceutical
Ornithine Transcarbamylase deficiency
2015
Ornithine Transcarbamylase
Adeno-associated virus serotye 8
Dimension Therapeutics
MPS II
2015
Iduronate-2-sulphatase
Adeno-associated virus serotype 9
REGENXBIO Inc
Sanfilippo A sundrome (MPS IIIA )
2015
N-Sulfoglucosamine Sulfohydrolase
Adeno-associated virus serotype rh10
LYSOGENE
X-linked Retinoschisis
2015
Retinoschisin promoter & human retinoschisin cDNA
Adeno-associated virus serotype 8
Paul A. Sievig, NIH
Achromatopsia (CNGA mutation)
2015
Cyclic nucleotide gated channel alpha subunit (CNGA3)
Adeno-associated virus
Applied Genetic Technology Corporations
Angelman syndrome
2015
UBE3A- Ubiquitin ligase E3A/E6-AP
Adeno-associated virus serotype 9
Agilis Therapeutics
MPS I
2015
L-iduronidase
Adeno-associated virus serotype 9
REGENXBIO Inc
Hemophilia B
2015
High specific variant of factor IX
Adeno-associated virus
Spark Therapeutics
Hemophilia B
2015
Factor IX
Adeno-associated virus serotype rh10
Dimension Therapeutics
MPS II Hunter Syndrome
2015
Iduronate-2-sulfatase
Adeno-associated virus serotype 9
Laboratories Del Dr Esteve SA
Duchenne Muscular Dystrophy
2015
Sda gene under MCK promoter
Adeno-associated virus serotype rh74
Nationwide Children’s Hospital

FDA/EMA Approvals of Orphan Designation on Gene therapy FDA/EMA Approvals of Orphan Designation on Gene therapy Reviewed by Biotechnology on January 18, 2017 Rating: 5

FDA breakthrough designations for serious diseases: Analysis and report

January 11, 2017
Introduction
This post reviews the FDA requirement and approval history for breakthrough therapies. Based on the data from 2012-2016, a total of 59 pipeline drugs was approved for breakthrough therapies with the highest percentage being in the year 2016 as shown in Figure 1. These includes both original(n=33) and supplement (n=26) approvals. Among 59 pipeline drugs, 24 were BLA filings and 35 were NDA filing. Majorities of drugs were approved for cancer therapies followed by infectious diseases, metabolic and genetic diseases such as diabetes, cystic fibrosis, etc. The categorization of drugs based on molecular entity showed that approved drugs were small molecules, targeted monoclonal antibodies and enzyme replacement therapies(ERTs) and recombinant proteins. The list of the sponsor can be obtained on the FDA website.

Figure 1: Distribution of approved breakthrough therapy from 2012-2016. Source FDA

Table 1: Summary of disease categories for approved breakthrough therapy

What is breakthrough therapy designations?
Section 506 (a) of the FD&C Act provides the designation of a drug as breakthrough therapy “if the drug is intended, alone or in combination with 1 or more other drugs, to treat a serious or life-threatening disease or condition and preliminary clinical evidence indicates that the drug may demonstrate substantial improvement over existing therapies on 1 or more clinically significant endpoints, such as substantial treatment effects observed early in clinical development.”

It is important to consider that breakthrough therapy designation is based on the preliminary clinical evidence but not all products designated as breakthrough therapies ultimately may not have substantial improvement suggested by preliminary clinical evidence at the time of designation. For the drug approved for marketing, in contrast to the breakthrough designation, FDA reviews complete sets of data to determine whether the drugs are safe and effective for their intended use. FDA may rescind the designation when the subsequent data do not support preliminary evidence.


Summary of Breakthrough designated Molecular entity


What is the requirement of breakthrough designations?
The requirement for approval of breakthrough designation includes
i) Serious condition
ii) Existing therapy
iii)preliminary clinical evidence that shows substantial improvement, evidence generally are from phase 1 or 2 clinical trials.
iv) demonstrate substantial improvement in clinically significant endpoints.

Conclusion
To address the unmet medical need for serious medical conditions, the expedited review provision is introduced. The breakthrough designation will allow prioritizing the development of drugs for such a disease where there is no alternative therapy or the available therapy does not sufficiently improve the clinical condition of the affected subject.

Reference
FDA Breakthrough Designations
FDA breakthrough designations for serious diseases: Analysis and report FDA breakthrough designations for serious diseases: Analysis and report Reviewed by Biotechnology on January 11, 2017 Rating: 5

FDA expedited programs for serious medical conditions

January 03, 2017
This post is intended to introduce the expedite review program and help the reader understand how these are designations are provided for potential therapeutic drugs. Learning about these programs such as Fast track designation, priority reviews, etc. is important to understand the impact of these designations on the drug discovery/approval processes. These designations are more commonly encountered in rare genetic disorder domain of drug discovery since they are a serious condition with early childhood deaths and unmet medical needs. In rare diseases, these programs ensure fast-paced treatment availability with clinically meaningful data because large and extended clinical trials may not be feasible because of limited disease population and survival.

Introduction
The FDA has designated four different programs intended to facilitate and expedite the development and availability of therapies to the life-threatening medical conditions. The FDA has also outlined the threshold criteria for identifying if the potential therapeutic drug qualifies in these categories:

These designated categories include:
a) Fast track: a drug that is intended to treat a serious condition and nonclinical data demonstrate a potential to address an unmet medical need.

b) Breakthrough therapy: a drug that is intended to treat a serious condition and preliminary evidence indicate that the drug may demonstrate substantial improvement on clinically significant endpoints over available therapies.

c) Accelerated approval: a drug that treats a serious condition and generally provides a meaningful advantage over available therapies and demonstrates an effect on a surrogate endpoint that is reasonably likely to predict clinical benefit or on a clinical endpoint that can be measured earlier than irreversible morbidity or mortality.

d) Priority review designations: an application for a drug that treats a serious condition and if approved would provide a significant improvement in safety or effectiveness.

These four designations are intended to ensure the availability of the treatment to serious disease condition with unmet medical needs if the potential therapies’ benefits justify their risk. FDA defines the serious disease condition with unmet medical needs when there are no satisfactory alternative therapies. These programs expedite approval of drugs with the minimal but satisfactory clinical evidence on safety and efficacy of drugs in proposed therapeutic indications. FDA also provides continuous consultations and feedbacks with sponsors for efficient trial design, well-controlled phase 2 studies for evidence of effectiveness.

Requirements for designation into expedited programs:
Based on the guidance, FDA considers the seriousness of the disease, therapy available and unmet medical needs while reviewing and granting expedited designations. Importantly, the proposed drug/biologics should be intended to treat the disease by improving symptoms, serious manifestation and reduce the progression to an advanced stage.

Serious condition:
FDA defines a serious condition as “ a disease or condition associated with morbidity on day-to-day functioning. Short-lived and self-limiting morbidity will usually not be sufficient, but the morbidity need not be irreversible if it is persistent or recurrent. Whether a disease or condition is serious is a matter of clinical judgment, based on its impact on such factors as survival, day to day functioning, or the likelihood that disease, if left untreated, will progress from a less severe condition to a more serious one.”

Available therapy:
FDA has defined available therapy as an approved or licensed drug in the United States for the same indication considered for the same drug & is relevant to current US standard care (SOC) for the indication. While determining available therapy, FDA considers treatment option, recommendation by authoritative scientific bodies, clinical evidence and clinical practices. If any drug is granted accelerated approval based on a surrogate endpoint or an intermediate clinical endpoint and clinical benefit has not been verified by post-approval studies, FDA will not consider drug as available therapy.

Unmet Medical need:
No available therapy for the serious conditions clearly demonstrates the unmet medical need. Sometimes when there is available therapy, the new development drug is subjected to expedite review program if the later product is bio-better. Bio-betters can have an effect on serious outcomes that are not shown by an available drug, improved serious outcomes than available therapy, has an improved effect on subjects that failed to respond to available therapy, has comparable efficacy but less drug-related toxicity.

Reference
FDA guidance: Expedited Programs for Serious conditions
FDA expedited programs for serious medical conditions FDA expedited programs for serious medical conditions Reviewed by Biotechnology on January 03, 2017 Rating: 5
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