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 / Search terms
Adeno / (((("gene therapy") or ("genetic therapy")) and ("adenovirus" or "adenoviral")) andnot ((((adenoassociated or adeno-associated) or AAV)or lentivirus) or retrovirus))
Retro / ((("gene therapy") or ("genetic therapy")) and (("retrovirus" or "retroviral")) andnot (("adenovirus" or "adenoviral") or lentivirus))
AAV / ((("gene therapy") or ("genetic therapy")) and (((adenoassociated or "adeno-associated") or AAV)) ANDNOT (murine and (retrovirus or retroviral)))
Lenti / ((("gene therapy") or ("genetic therapy")) and lentivirus )
Non-viral / ((("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
Investment / Papers / Patents / NASDAQ / Companies
Annual Capital investment / 1 / 0.49 / 0.52 / 0.87 / 0.81
Cumulative Papers / 1 / 0.99 / 0.71 / 0.84
Cumulative Patents / 1 / 0.73 / 0.87
NASDAQ Composite Index / 1 / 0.86
# Companies / 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
df / SS / MS / F / Significance F
Regression / 3 / 202884 / 67628 / 51 / 8.90E-10
Residual / 21 / 28121 / 1339
Total / 24 / 231006
Coefficients / Standard Error / t Stat / P-value / Lower 95% / Upper 95%
Intercept / -18.34 / 17.41 / -1.05 / 0.30 / -54.54 / 17.85
Papers / -0.01 / 0.00 / -4.39 / 0.0003 / -0.01 / -0.0027
NASDAQ / 0.07 / 0.02 / 4.09 / 0.0005 / 0.03 / 0.10
# Companies / 3.85 / 0.94 / 4.10 / 0.0005 / 1.90 / 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
df / SS / MS / F / Significance F
Regression / 3 / 203289 / 67763 / 51 / 7.65E-10
Residual / 21 / 27717 / 1320
Total / 24 / 231006
Coefficients / Standard Error / t Stat / P-value / Lower 95% / Upper 95%
Intercept / -23.35 / 17.75 / -1.31 / 0.20 / -60.27 / 13.58
Patents / -0.01 / 0.002 / -4.46 / 0.0002 / -0.015 / -0.005
NASDAQ / 0.07 / 0.02 / 4.06 / 0.0006 / 0.03 / 0.10
# Companies / 4.18 / 0.98 / 4.28 / 0.0003 / 2.15 / 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.
Financings / Technology (primary)
Company / # / total raised / founded
Amsterdam Molecular Therapeutics N.V. / 5 / $ 132,636,544 / 1998 / AAV
AnGes MG Inc./Medgene Bioscience / 3 / $ 88,419,037 / 1999 / Nonviral
Applied Genetic Technologies Corp. / 5 / $ 27,100,000 / 1999 / AAV
Ark Therapeutics Group plc / 0 / $ 250,652,869 / 1997 / Adeno
Asklepios BioPharmaceutical Inc / 11 / $ - / 2003 / AAV
Avigen / 0 / $ 249,960,155 / 1992 / AAV
Avior Therapeutics Inc. / 3 / $ - / 2001 / Adeno
Calydon Inc. / 5 / $ 22,000,000 / 1994 / Adeno
Cardiogene AG / 5 / $ 83,575,000 / 1996 / Adeno
Cardion AG / 6 / $ 83,575,000 / 1996 / Nonviral
Ceregene Inc. / 0 / $ 88,370,000 / 2001 / AAV
Chatham / 3 / $ - / 2012 / AAC
Cobra Therapeutics Ltd. (fka Therexsys Ltd.) / 4 / $ 43,500,000 / 1992 / Nonviral
Copernicus Therapeutics Inc. / 7 / $ 13,649,900 / 1997 / Nonviral
Corautus Genetics Inc. / 0 / $ 46,510,680 / 1994 / Nonviral
Danbiosyst / 0 / $ - / 1989 / Nonviral
Epeius Biotechnologies / 4 / $ - / 2000 / Retroviral
Eurogene Ltd. / 4 / $ 28,695,000 / 1997 / Nonviral
Eurogene Ltd. (aka Ark Therapeutics) / 2 / $ 28,695,000 / 1997 / Nonviral
Expression Genetics / 2 / $ 12,000,000 / 1998 / Nonviral
FKD Therapies Oy / 2 / $ 16,000,000 / 2011 / Adeno
Geneart AG / 9 / $ 22,500,000 / 1999 / Nonviral
GeneMedicine Inc. / 13 / $ 75,600,000 / 1992 / Nonviral
Genetic Therapy Inc. / 5 / $ 100,689,000 / 1986 / Retro
Genetix Pharmaceuticals Inc./ Buebird bio. Inc. / 4 / $ 78,900,000 / 1992 / Lenti
Genovo / 0 / $ - / 1992 / Adeo
GenStar Therapeutics Inc./ Urogen / 3 / $ 26,200,000 / 1995 / Adeno
Genteric Inc. / 22 / $ 31,000,000 / 1997 / Nonviral
Supplemental Table 3 (continued). Companies and financing totals included in study.
Financings / Technology (primary)
Company / # / total raised / founded
GenVec Inc / 0 / $ 236,090,000 / 1992 / Adeno
Ichor / 12 / $ - / 1994 / Nonviral
Introgen Therapeutics Inc. / 4 / $ 157,055,200 / 1993 / Adeno
IntroGene B.V. / 5 / $ 46,700,000 / 1993 / Adeno
Intronn Inc./Proteome / 0 / $ 22,932,485 / 1993 / Lenti
Lentigen / 12 / $ - / 2004 / Lenti
Medgenics Inc. / 3 / $ 41,685,055 / 2001 / Adeno
Medigene AG / 7 / $ 146,500,000 / 1994 / AAV
Megabios Corp. / 2 / $ 70,400,000 / 1992 / Nonviral
Mirus Bio Corp. / 7 / $ 5,400,000 / 1995 / Nonviral
Mologen AG / 0 / $ 32,819,897 / 1998 / Nonviral
NanoCor / 2 / $ - / 2005 / AAV
Neozyme II / 6 / $ 85,000,000 / 1992 / Adeno
Neurologix Inc. / 12 / $ 42,165,885 / 1999 / AAV
Oxford BioMedica plc / 2 / $ 216,109,601 / 1995 / Lenti
PolyMasc Pharmaceuticals plc / 0 / $ 7,000,000 / 1995 / Nonviral
Prizm/Selective Genetics Inc. / 9 / $ - / 1992 / Adeno
ReGenX Biosciences LLC / 0 / $ - / 2008 / AAV
Somatix Therapy / 16 / $ 92,171,999 / 1988 / Retro
Targeted Genetics Corp. / 10 / $ 185,351,228 / 1992 / AAV
Therexsys / 3 / $ 33,900,000 / 1992 / Nonviral
Transgene S.A. (fka Ribogene) / 2 / $ 558,849,527 / 1979 / Adeno
UroGen Corp. / 5 / $ 19,300,000 / 1995 / Adeno
Valentis / 11 / $ 105,350,000 / 1998 / nonviral
Vascular Genetics Inc. / 4 / $ 54,750,000 / 1994 / Nonviral
Via Pharmaceuticals / 13 / $ 28,250,000 / 1994 / Nonviral
Vical Inc. / 15 / $ 318,331,498 / 1987 / Nonviral
VimRx Pharmaceuticals Inc / 0 / $ 80,050,000 / 1986 / Retro
VirRx / 8 / $ - / 1999 / Adeno
Virxsys Corp. / 0 / $ 94,500,000 / 1998 / Lenti

References

1. Agarwal, P. & Searls, D.B. Can literature analysis identify innovation drivers in drug discovery? Nat Rev Drug Discov 8, 865-878 (2009).

2. Garfield, E. & Melino, G. The growth of the cell death field: an analysis from the ISI-Science citation index. Cell Death Differ 4, 352-361 (1997).

3. McNamee, L.M. & Ledley, F.D. Patterns of technological innovation in biotech. Nat Biotechnol 30, 937-943 (2012).

4. Marshall, A. Trends in biotech literature 2008. Nature Biotechnology 27, 789-789 (2009).

5. Taroncher-Oldenburg, G. & Marshall, A. Trends in biotech literature 2007. Nat Biotechnol 26, 1062 (2008).

6. Taroncher-Oldenburg, G. & Marshall, A. Trends in biotech literature 2006. Nat Biotechnol 25, 961 (2007).

7. Ginn, S.L., Alexander, I.E., Edelstein, M.L., Abedi, M.R. & Wixon, J. Gene therapy clinical trials worldwide to 2012 - an update. J Gene Med 15, 65-77 (2013).

8. Morgan Jr, I.W. & Abetti, P.A. Private and Public “Cradle to Maturity” Financing Patterns of US Biotech Ventures (1970-2001). The Journal of Private Equity 7, 9-25 (2004).

9. Jain, K. A Special Report on Gene Therapy. (Wiley, 2000).