Why commercialization of gene therapy stalled;
examining the life cycles of gene therapy
technologies
Supplementary Information
Fred D. Ledley, Laura M. McNamee, Vedat Uzdil, Irvin W. Morgan, Jr.
Bentley University, 175 Forest Street, Waltham, MA 02452
Supplementary information
A. Bibliometric analysis
Supplemental Table 1a. Boolean terms for publication search
Supplemental Table 1b. Boolean terms for patent search
B.
Multivariate statistical analysis
Supplemental Table 2a. Correlation Table
Supplemental Table 2b. Multivariate regression performed with annual Capital Investment,
cumulative publications, NASDAQ Composite Index, and the number of gene therapy
companies
Supplemental Table 2c. Multivariate regression performed with annual Capital Investment,
cumulative patents, NASDAQ Composite Index, and the number of gene therapy companies
C. Companies and financing totals
Supplemental Table 3. Companies and financing totals used in this study.
References
A. BIBLIOMETRIC ANALYSIS
Bibliometric methods involve quantifying the number of research publications or number of patents as a
measure of scientific activity or progress.1-6 These methods posit that each peer-reviewed research
report or patent embodies a quantum of new information about a specific topic. Integrated over large
numbers of papers, representing a distribution of major (large), minor (small), or even erroneous
(negative) findings, the total number of publications on a particular technology provides a metric for
progress. For this analysis, Boolean search terms are used to identify relevant citations in the PUBMED
database of the National Center for Biotechnology Information (NCBI) (www.pubmed.gov) or the US
Patent and Trademark (USPTO) (www.uspto.gov). The annual number of publications is determined by
the publication date, and the annual number of patents is determined by the date of issuance.
Table 1a. Boolean terms for publication search. Actual search terms in the Query Translation vary.
Technology
Search terms
Gene therapy Gene therapy not review
Non-viral Gene therapy and (nonviral or non-viral or liposome or lipofection or particle or
formulation or "gene gun" or particle or particulate or electroporation) not review
Retroviral gene therapy and murine and (retrovirus or retroviral)
Adenoviral gene therapy and (adenovirus or adenoviral) not review
Lentiviral gene therapy and (lentivirus or lentiviral) not review
AAV gene therapy and (adenoassociated or adeno-associated or "adeno associated") not
review
Table 1b. Boolean terms for patent search. Search was performed on specifications (SPEC/)
Technology
Adeno
Retro
AAV
Lenti
Non-viral
Search terms
(((("gene therapy") or ("genetic therapy")) and ("adenovirus" or "adenoviral")) andnot
((((adenoassociated or adeno-associated) or AAV)or lentivirus) or retrovirus))
((("gene therapy") or ("genetic therapy")) and (("retrovirus" or "retroviral")) andnot
(("adenovirus" or "adenoviral") or lentivirus))
((("gene therapy") or ("genetic therapy")) and (((adenoassociated or "adenoassociated") or AAV)) ANDNOT (murine and (retrovirus or retroviral)))
((("gene therapy") or ("genetic therapy")) and lentivirus )
((("Gene therapy" or "genetic therapy") AND (((((((((("nonviral" OR "non-viral") OR
"liposome") OR "lipofection") OR "particle") OR "formulation") OR "gene gun") OR
naked) OR "polymer") OR "particulate") OR "electroporation")) ANDNOT
((((((((((Herpes OR "adeno-associated") OR polynoma) OR papilloma) OR sv40) OR
lentivirus) OR lentiviral) OR adenovirus) OR adenoviral) OR retrovirus) OR retroviral))
B.
MULTIVARIATE STATISTICAL ANALYSIS
Multivariate regressions were performed to examine the relationship between annual capital
investment in gene therapy companies and: (a) metrics for the maturation of gene therapy, either the
cumulative number of publications or cumulative number of patents; (b) market conditions reflected in
the NASDAQ Composite Index; (c) the number of gene therapy companies. Multivariate analysis was
performed in Microsoft Excel.
Two models are shown, each of which has an R2=0.88, indicating that the model statistically accounts for
~88% of the annual variation in investment. In both models, annual capital investments in gene therapy
significantly correlate with the NASDAQ Composite Index and number of companies, but negatively
correlate with the maturation of gene therapy, as measured either by the cumulative number of
publications or cumulative number of patents.
Supplemental Table 2a. Correlation Table
Annual Capital investment
Cumulative Papers
Cumulative Patents
NASDAQ Composite Index
# Companies
Investment
1
Papers
0.49
1
Patents
0.52
0.99
1
NASDAQ
0.87
0.71
0.73
1
Companies
0.81
0.84
0.87
0.86
1
Supplemental Table 2b. Multivariate regression performed with annual Capital Investment,
cumulative publications, NASDAQ Composite Index, and the number of gene therapy companies.
Regression Statistics
Multiple R
0.94
R Square
0.88
Adjusted R Square
0.86
Standard Error
36.59
Observations
25
ANOVA
Regression
Residual
Total
Intercept
Papers
NASDAQ
# Companies
Coefficients
-18.34
-0.01
0.07
3.85
df
3
21
24
Standard
Error
17.41
0.00
0.02
0.94
SS
202884
28121
231006
t Stat
-1.05
-4.39
4.09
4.10
MS
67628
1339
P-value
0.30
0.0003
0.0005
0.0005
F
51
Significance F
8.90E-10
Lower 95%
-54.54
-0.01
0.03
1.90
Upper 95%
17.85
-0.0027
0.10
5.80
Supplemental Table 2c. Multivariate regression performed with annual Capital Investment,
cumulative patents, NASDAQ Composite Index, and the number of gene therapy companies.
Regression Statistics
Multiple R
0.94
R Square
0.88
Adjusted R Square
0.86
Standard Error
36.33
Observations
25
ANOVA
Regression
Residual
Total
Intercept
Patents
NASDAQ
# Companies
Coefficients
-23.35
-0.01
0.07
4.18
df
3
21
24
Standard
Error
17.75
0.002
0.02
0.98
SS
203289
27717
231006
t Stat
-1.31
-4.46
4.06
4.28
MS
67763
1320
P-value
0.20
0.0002
0.0006
0.0003
F
51
Significance F
7.65E-10
Lower 95%
-60.27
-0.015
0.03
2.15
Upper 95%
13.58
-0.005
0.10
6.22
C. COMPANIES AND FINANCING TOTALS
Clinical trials of gene therapy were identified in the Wiley database on Gene Therapy Trials Worldwide.7
Companies engaged in gene therapy were identified in the “gene/cell therapy” category of BioCentury’s
BCIQ database, the biotechnology database described by Morgan and Abetti,8 and in Jain.9 Each
company’s technology was characterized from reports in BioCentury, press releases, company web sites,
or regulatory filings, as well as patents or publications citing the company as the “institution.”
Companies developing cell therapies, stem cells, non-therapeutic products (e.g., platforms, devices,
diagnostics) as well as companies that were developing other classes of products in addition to gene
therapies were excluded from this analysis. Capital financings were identified in the BioCentury BCIQ
database, the Moran and Abetti database,8 or CapitalIQ. This analysis did not include other forms of
financing such as non-convertible debt, non-capital investments by non-profit or government
organizations, grants, or revenues from contract research, products or services.
Supplemental Table 3. Companies and financing totals included in study.
Company
#
Financings
total raised founded
Amsterdam Molecular Therapeutics N.V.
AnGes MG Inc./Medgene Bioscience
Applied Genetic Technologies Corp.
Ark Therapeutics Group plc
Asklepios BioPharmaceutical Inc
Avigen
Avior Therapeutics Inc.
Calydon Inc.
Cardiogene AG
Cardion AG
Ceregene Inc.
Chatham
Cobra Therapeutics Ltd. (fka Therexsys Ltd.)
Copernicus Therapeutics Inc.
Corautus Genetics Inc.
Danbiosyst
Epeius Biotechnologies
Eurogene Ltd.
Eurogene Ltd. (aka Ark Therapeutics)
Expression Genetics
FKD Therapies Oy
Geneart AG
GeneMedicine Inc.
Genetic Therapy Inc.
Genetix Pharmaceuticals Inc./ Buebird bio. Inc.
Genovo
GenStar Therapeutics Inc./ Urogen
Genteric Inc.
5
3
5
0
11
0
3
5
5
6
0
3
4
7
0
0
4
4
2
2
2
9
13
5
4
0
3
22
$
$
$
$
$
$
$
$
$
$
$
$
$
$
$
$
$
$
$
$
$
$
$
$
$
$
$
$
132,636,544
88,419,037
27,100,000
250,652,869
249,960,155
22,000,000
83,575,000
83,575,000
88,370,000
43,500,000
13,649,900
46,510,680
28,695,000
28,695,000
12,000,000
16,000,000
22,500,000
75,600,000
100,689,000
78,900,000
26,200,000
31,000,000
1998
1999
1999
1997
2003
1992
2001
1994
1996
1996
2001
2012
1992
1997
1994
1989
2000
1997
1997
1998
2011
1999
1992
1986
1992
1992
1995
1997
Technology
(primary)
AAV
Nonviral
AAV
Adeno
AAV
AAV
Adeno
Adeno
Adeno
Nonviral
AAV
AAC
Nonviral
Nonviral
Nonviral
Nonviral
Retroviral
Nonviral
Nonviral
Nonviral
Adeno
Nonviral
Nonviral
Retro
Lenti
Adeo
Adeno
Nonviral
Supplemental Table 3 (continued). Companies and financing totals included in study.
Company
#
Financings
total raised
GenVec Inc
Ichor
Introgen Therapeutics Inc.
IntroGene B.V.
Intronn Inc./Proteome
Lentigen
Medgenics Inc.
Medigene AG
Megabios Corp.
Mirus Bio Corp.
Mologen AG
NanoCor
Neozyme II
Neurologix Inc.
Oxford BioMedica plc
PolyMasc Pharmaceuticals plc
Prizm/Selective Genetics Inc.
ReGenX Biosciences LLC
Somatix Therapy
Targeted Genetics Corp.
Therexsys
Transgene S.A. (fka Ribogene)
UroGen Corp.
Valentis
Vascular Genetics Inc.
Via Pharmaceuticals
Vical Inc.
VimRx Pharmaceuticals Inc
VirRx
Virxsys Corp.
0
12
4
5
0
12
3
7
2
7
0
2
6
12
2
0
9
0
16
10
3
2
5
11
4
13
15
0
8
0
$
$
$
$
$
$
$
$
$
$
$
$
$
$
$
$
$
$
$
$
$
$
$
$
$
$
$
$
$
$
236,090,000
157,055,200
46,700,000
22,932,485
41,685,055
146,500,000
70,400,000
5,400,000
32,819,897
85,000,000
42,165,885
216,109,601
7,000,000
92,171,999
185,351,228
33,900,000
558,849,527
19,300,000
105,350,000
54,750,000
28,250,000
318,331,498
80,050,000
94,500,000
founded
Technology
(primary)
1992
1994
1993
1993
1993
2004
2001
1994
1992
1995
1998
2005
1992
1999
1995
1995
1992
2008
1988
1992
1992
1979
1995
1998
1994
1994
1987
1986
1999
1998
Adeno
Nonviral
Adeno
Adeno
Lenti
Lenti
Adeno
AAV
Nonviral
Nonviral
Nonviral
AAV
Adeno
AAV
Lenti
Nonviral
Adeno
AAV
Retro
AAV
Nonviral
Adeno
Adeno
nonviral
Nonviral
Nonviral
Nonviral
Retro
Adeno
Lenti
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