Form 8-K Dimension Therapeutics, For: Jan 31
UNITED STATES
SECURITIES AND EXCHANGE COMMISSION
Washington, D.C. 20549
FORM 8-K
CURRENT REPORT
Pursuant to Section 13 or 15(d)
of The Securities Exchange Act of 1934
Date of Report (Date of Earliest Event Reported): January 31, 2017
Dimension Therapeutics, Inc.
(Exact name of registrant as specified in its charter)
DELAWARE | 001-37601 | 46-3942159 | ||
(State or other jurisdiction of incorporation) |
(Commission File Number) |
(I.R.S. Employer Identification No.) |
840 Memorial Drive, 4th Floor Cambridge, MA |
02139 | |||
(Address of principal executive offices) | (Zip Code) |
Registrants telephone number, including area code (617) 401-0011
Not Applicable
(Former name or former address, if changed since last report)
Check the appropriate box below if the Form 8-K filing is intended to simultaneously satisfy the filing obligation of the registrant under any of the following provisions:
☐ Written communications pursuant to Rule 425 under the Securities Act (17 CFR 230.425)
☐ Soliciting material pursuant to Rule 14a-12 under the Exchange Act (17 CFR 240.14a-12)
☐ Pre-commencement communications pursuant to Rule 14d-2(b) under the Exchange Act (17 CFR 240.14d-2(b))
☐ Pre-commencement communications pursuant to Rule 13e-4(c) under the Exchange Act (17 CFR 240.13e-4(c))
Item 7.01 | Regulation FD Disclosure. |
On January 31, 2017, Dimension Therapeutics, Inc. (the Company) announced clinical trial data in a press release, a copy of which is furnished herewith as Exhibit 99.1.
In addition, on January 31, 2017, the Company posted an updated corporate presentation on its website, www.dimensiontx.com. A copy of this presentation is furnished herewith as Exhibit 99.2.
The information in this Item 7.01 and Exhibits 99.1 and 99.2 attached hereto shall not be deemed filed for purposes of Section 18 of the Securities and Exchange Act of 1934, as amended, or otherwise subject to the liabilities of that section, nor shall they be deemed incorporated by reference in any filing under the Securities Act of 1933, as amended, except as expressly set forth by specific reference in such filing.
Item 8.01 | Other Events. |
In connection with the announcement of clinical trial data described above, the Company announced preliminary topline safety and early efficacy results of the Companys multi-center phase 1/2 study of DTX101 for the treatment of adult patients with moderate/severe to severe hemophilia B. DTX101, the Companys lead AAV candidate, is designed to deliver stable expression of blood clotting Factor IX (FIX) in patients with hemophilia B, a rare genetic bleeding disorder resulting from a deficiency in FIX. The Company is reporting preliminary topline phase 1/2 results from the trials first two dose cohorts (Cohort 1: N=3, 1.6 x 1012 GC/kg; Cohort 2: N=3, 5 x 1012 GC/kg). Patients in the two cohorts have been in post-treatment follow-up ranging from 6 to 52 weeks.
In the phase 1/2 study, patients received serotype AAVrh10 vector with a codon-optimized FIX gene expressing wild-type FIX protein. Evidence of efficient liver transduction of DTX101 was observed across the two patient cohorts. Patients in the second dose cohort achieved peak FIX expression of 13%, 20%, and 12% at weeks 4, 8, and 8, respectively. FIX activity was 5% and 8% in two patients at 12-weeks follow-up, and 7% for the third patient at 7 weeks. For the low-dose cohort, expression levels achieved 10-11% peak activity, stabilizing between 3-4% at last follow-up (weeks 24, 48, and 52). The findings in the low-dose cohort are comparable to results published by Nathwani et al in the New England Journal of Medicine (2011), where patients have had measurable levels of FIX for 3-5 years or more at last follow-up (Nienhuis et al. 2016). All patients in both cohorts improved from moderate/severe-to-severe to either moderate or mild range in terms of factor levels based on World Federation of Hemophilia (WFH) criteria. In addition, none of the patients in Cohort 2 have required prophylactic or on-demand recombinant FIX transfusion for spontaneous bleeds post-dosing. According to the WFH, people with FIX levels of 5% or more usually bleed only as a result of surgery or major injury, do not bleed often and, in fact, may never have a bleeding problem.*
Elevations in alanine aminotransferase (ALT) were observed in 5 of 6 patients, with patient 3 in Cohort 2 experiencing a grade 4 adverse event due to an elevated laboratory ALT (defined as >800 IU/L). All elevated liver enzymes were clinically asymptomatic with no elevations of gamma-glutamyl transferase (GGT), alkaline phosphatase or bilirubin, and no patients experienced a drug related serious adverse event (SAE) as of the January 28, 2017 data cutoff. Preliminary Phase 1/2 findings from 2 patients in each of Cohort 1 and 2 prompted administration of a standard tapering course of corticosteroids to treat mild, asymptomatic elevations in ALTs (52-98 IU/L), similar to findings from multiple studies using other AAV serotypes, including AAV8 and AAV9. The third patient in Cohort 2 also received corticosteroids, experiencing a peak ALT of 914 IU/L, and was at 431 IU/L at 6 weeks post-dosing. The Company expects that Cohort 2 will continue to receive a standard tapering course of
corticosteroid therapy and as of the January 28, 2017 data cutoff, 2 of 3 patients ALT levels were in the normal range. Cohort 1 patients were all clinically stable and off steroids with ALT levels in the normal range. As required by the trial protocol, the Company reported the ALT levels for patient 3 in Cohort 2 to the Data Safety Monitoring Committee (DSMC), the U.S. Food and Drug Administration (FDA), and the appropriate regulatory authorities and will await their feedback prior to initiating dosing of Cohort 3.
*Information sourced from World Federation of Hemophilia
Cautionary Note Regarding Forward-Looking Statements
This Current Report on Form 8-K contains forward-looking statements within the meaning of the Private Securities Litigation Reform Act of 1995, including, but not limited to, statements regarding the development, preclinical and clinical results, and the continued progress of the Companys portfolio and programs, including the initiation, timing, scope, or likelihood of regulatory filings and approvals, and the Companys ability to develop and advance product candidates into, and successfully complete, clinical studies. All such forward-looking statements are based on managements current expectations of future events and are subject to a number of risks and uncertainties that could cause actual results to differ materially and adversely from those set forth in or implied by such forward-looking statements. These risks and uncertainties include the risks that the Companys product candidates, including its candidates, DTX101 and DTX301, will not successfully be developed or commercialized in the times indicated or at all; the impact of the observed data in Cohorts 1 and 2, including the adverse event described above and any later safety event on timing, dosing, regulatory action or patient enrollment with respect to DTX101 and DTX301; and the risks described under the caption Risk Factors in the Companys Quarterly Report on Form 10-Q for the quarter ended September 30, 2016, which is on file with the Securities and Exchange Commission, as well as other risks detailed in the Companys additional filings with the Securities and Exchange Commission. All information in this Current Report on Form 8-K is as of the date of this Current Report on Form 8-K, and the Company undertakes no duty to update this information unless required by law.
SIGNATURES
Pursuant to the requirements of the Securities Exchange Act of 1934, the registrant has duly caused this report to be signed on its behalf by the undersigned hereunto duly authorized.
Date: January 31, 2017 |
DIMENSION THERAPEUTICS, INC. | |||
By: | /s/ Jean Franchi | |||
Jean Franchi | ||||
Chief Financial Officer |
Exhibit 99.1
Dimension Announces Interim Topline Results from Ongoing Phase 1/2 Clinical Program for DTX101, Dimensions Lead AAV Product Candidate in Development for Adult Patients with Moderate/Severe to Severe Hemophilia B
Evidence of High-Efficiency Liver Transduction with AAVrh10 Vector
Sub-clinical, Asymptomatic Elevations of ALT Observed in 5 of 6 Patients
CAMBRIDGE, Mass., January 31, 2017 Dimension Therapeutics, Inc. (NASDAQ: DMTX), a biopharmaceutical company advancing novel, adeno-associated virus (AAV) gene therapies targeting the liver, a key organ for human metabolism, today announced preliminary topline safety and early efficacy results of Dimensions multi-center phase 1/2 study of DTX101 for the treatment of adult patients with moderate/severe to severe hemophilia B. DTX101, Dimensions lead AAV candidate, is designed to deliver stable expression of blood clotting Factor IX (FIX) in patients with hemophilia B, a rare genetic bleeding disorder resulting from a deficiency in FIX. Dimension is reporting preliminary topline phase 1/2 results from the trials first two dose cohorts (Cohort 1: N=3, 1.6 x 1012 GC/kg; Cohort 2: N=3, 5 x 1012 GC/kg). Patients in the two cohorts have been in post-treatment follow-up ranging from 6 to 52 weeks.
In the phase 1/2 study, patients received serotype AAVrh10 vector with a codon-optimized FIX gene expressing wild-type FIX protein. Evidence of efficient liver transduction of DTX101 was observed across the two patient cohorts. Patients in the second dose cohort achieved peak FIX expression of 13%, 20%, and 12% at weeks 4, 8, and 8, respectively. FIX activity was 5% and 8% in two patients at 12-weeks follow-up, and 7% for the third patient at 7 weeks. For the low-dose cohort, expression levels achieved 10-11% peak activity, stabilizing between 3-4% at last follow-up (weeks 24, 48, and 52). The findings in the low-dose cohort are comparable to results published by Nathwani et al in the New England Journal of Medicine (2011), where patients have had measurable levels of FIX for 3-5 years or more at last follow-up (Nienhuis et al. 2016). All patients in both cohorts improved from moderate/severe-to-severe to either moderate or mild range in terms of factor levels based on World Federation of Hemophilia (WFH) criteria. In addition, none of the patients in Cohort 2 have required prophylactic or on-demand recombinant FIX transfusion for spontaneous bleeds post-dosing. According to the WFH, people with FIX levels of 5% or more usually bleed only as a result of surgery or major injury, do not bleed often and, in fact, may never have a bleeding problem.*
Elevations in alanine aminotransferase (ALT) were observed in 5 of 6 patients with patient 3 in Cohort 2 experiencing a grade 4 adverse event due to an elevated laboratory ALT (defined as >800 IU/L). All elevated liver enzymes were clinically asymptomatic with no elevations of gamma-glutamyl transferase (GGT), alkaline phosphatase or bilirubin, and no patients experienced a drug related serious adverse event (SAE) as of the January 28, 2017 data cutoff. Preliminary Phase 1/2 findings from 2 patients in each of Cohort 1 and 2 prompted administration of a standard tapering course of corticosteroids to treat mild, asymptomatic elevations in ALTs (52-98 IU/L), similar to findings from multiple studies using other AAV serotypes, including AAV8 and AAV9. The third patient in Cohort 2 also received corticosteroids, experiencing a peak ALT of 914 IU/L, and was at 431 IU/L at 6 weeks post-dosing. We expect that Cohort 2 will continue to receive a standard tapering course of corticosteroid therapy and as of the January 28, 2017 data cutoff, 2 of 3 patients ALT levels were in the normal range. Cohort 1 patients were all clinically stable and off steroids with ALT levels in the normal range. As required by the
trial protocol, we have reported the ALT levels for patient 3 in Cohort 2 to the Data Safety Monitoring Committee (DSMC), the U.S. Food and Drug Administration (FDA), and the appropriate regulatory authorities and will await their feedback prior to initiating dosing of Cohort 3.
We are encouraged by the apparent efficiency of gene transduction and the early trend we are seeing in sustained FIX activity across both cohorts with our wild-type FIX AAVrh10 vector in patients. We continue to explore the therapeutic window for DTX101 as our data mature and in light of the ALT rises that appear to be associated with a decline in FIX activity, said Dr. Annalisa Jenkins, MBBS, FRCP, Chief Executive Officer of Dimension.
As the company pipeline and platform progresses, a broad program of translational research, conducted in partnership with the University of Pennsylvania and other academic collaborators, will continue to evaluate the evolving data. These data will add to the scientific understanding of the emerging profile for AAV gene therapy in the clinical setting and will be the subject of future presentations at academic and medical congresses.
DTX101 has received orphan drug designation from U.S. Food and Drug Administration and the European Commission.
*Information sourced from World Federation of Hemophilia
About Hemophilia B
Hemophilia B is a rare genetic bleeding disorder resulting from a deficiency in FIX. The current standard of care, chronic replacement of FIX protein through routine intravenous infusion, often does not achieve sustained, durable FIX expression, potentially putting patients at risk for spontaneous bleeds and long term joint destruction. In 2013, the World Federation of Hemophilia estimated there were more than 28,000 hemophilia B patients worldwide, including 4,000 patients in the United States.
About the Hemophilia B Phase 1/2 Program
Dimensions phase 1/2 clinical trial of DTX101 is a single arm, open-label, multi-center study, designed to evaluate the safety, dose, and early efficacy of DTX101 in adult patients with moderate/severe to severe hemophilia B. Patients enrolled in Cohorts 1 and 2 range in age from 28 to 70 years, demonstrating baseline FIX expression of £2% that requires either prophylactic or on demand recombinant FIX transfusion. Dimension is continuing to explore underlying demographics and patient characteristics to optimize dosing of DTX101.
Additional information about Dimensions Phase 1/2 study of DTX101 may be found at ClinicalTrials.gov, using Identifier NCT: NCT02618915.
About Dimension Therapeutics, Inc.
Dimension Therapeutics, Inc. (NASDAQ: DMTX) is the leader in discovering and developing new therapeutic products for people living with devastating rare and metabolic diseases associated with the liver, based on the most advanced, mammalian adeno-associated virus (AAV) gene delivery technology. Dimension is actively progressing its broad pipeline, which features programs addressing unmet needs for patients suffering from inherited metabolic diseases, including OTC deficiency, GSDIa, citrullinemia type 1, PKU, Wilson disease, a collaboration with Bayer in hemophilia A, and a wholly owned clinical
program in hemophilia B. Dimension has two phase 1/2 clinical trials for the treatment of hemophilia B and OTC deficiency. The company targets diseases with readily identifiable patient populations, highly predictive preclinical models, and well-described, and often clinically validated, biomarkers. Founded in 2013, Dimension maintains headquarters in Cambridge, Massachusetts.
For more information, please visit www.dimensiontx.com.
Cautionary Note Regarding Forward-Looking Statements
This press release contains forward-looking statements within the meaning of the Private Securities Litigation Reform Act of 1995, including, but not limited to, statements regarding the development, preclinical and clinical results, and the continued progress of Dimensions portfolio and programs, including the initiation, timing, scope, or likelihood of regulatory filings and approvals, and our ability to develop and advance product candidates into, and successfully complete, clinical studies. All such forward-looking statements are based on managements current expectations of future events and are subject to a number of risks and uncertainties that could cause actual results to differ materially and adversely from those set forth in or implied by such forward-looking statements. These risks and uncertainties include the risks that Dimensions product candidates, including its candidates, DTX101 and DTX301, will not successfully be developed or commercialized in the times indicated or at all; the impact of the observed data in Cohorts 1 and 2, including the adverse event described above and any later safety event on timing, dosing, regulatory action or patient enrollment with respect to DTX101 and DTX301; and the risks described under the caption Risk Factors in Dimension Therapeutics Quarterly Report on Form 10-Q for the quarter ended September 30, 2016, which is on file with the Securities and Exchange Commission, as well as other risks detailed in Dimension Therapeutics additional filings with the Securities and Exchange Commission. All information in this press release is as of the date of the release, and Dimension Therapeutics undertakes no duty to update this information unless required by law.
Contacts:
Jean Franchi
Chief Financial Officer
Dimension Therapeutics
617-714-0709
Burns McClellan, on behalf of Dimension Therapeutics
Media: Justin Jackson
212-213-0006, ext.327
Exhibit 99.2
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Dimension Therapeutics
Dimension Therapeutics
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Forward Looking Statements
These slides and the accompanying oral presentation contain forward-looking statements and information. The use of words such as may, might, will, should, expect, plan, anticipate, believe, estimate, project, intend, future, potential, or continue, and other similar expressions are intended to identify forward looking statements. For example, all statements we make regarding the initiation, timing, progress and results of our preclinical and clinical studies and our research and development programs, our ability to advance product candidates into, and successfully complete, clinical studies, the timing or likelihood of regulatory filings and approvals, our ability to develop manufacturing processes and engage third parties to manufacture our product candidates for late-stage clinical use or at commercial scale, the success of strategic partnerships, if any, and our expected cash, cash equivalents and marketable securities at year end are forward looking. All forward?looking statements are based on estimates and assumptions by our management that, although we believe to be reasonable, are inherently uncertain. All forward-looking statements are subject to risks and uncertainties that may cause actual results to differ materially from those that we expected. These statements are also subject to a number of material risks and uncertainties that are described under the caption
Risk Factors in Dimension Therapeutics Quarterly Report on Form 10-Q for the quarter ended September 30, 2016, which is on file with the Securities and Exchange Commission, as well as other risks detailed in Dimension Therapeutics additional filings with the Securities and Exchange Commission. Any forward?looking statement speaks only as of the date on which it was made. We undertake no obligation to publicly update or revise any forward-looking statement, whether as a result of new information, future events or otherwise, except as required by law.
The information contained in this presentation is not an offer to sell or the solicitation of an offer to buy the Companys common stock or any other securities of the Company.
© 2017 Dimension Therapeutics 2
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Dimension Therapeutics
The Leader in Gene Therapy for Rare & Metabolic Diseases
of the Liver
Broad product pipeline addressing rare & metabolic diseases with high unmet need
Leader in
discovering &
developing
new therapeutics
for people living
with devastating
rare diseases
associated with
the liver
Manufactured using mammalian process
Robust scientific AAV gene therapy platform
© 2017 Dimension Therapeutics 3
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Clade E AAV-Based Gene Therapy Product Platform
Transgene Cassette Clade E Capsid Vector Peripheral Liver Directed
Enhanced liver targeting Exclusive WW license to RGNX AAV technology*
Durable expression Up to 8 specified disease indications; 1 available**
Well established safety 2013 license & 2015 option/license
25% population NAbs Collaboration with PENN, including related IP
Source: Gao et al. 2004 J Virol; Fagiuoli et al. 2013 J Hepat
*License excludes AAV8 for hemophilia A or B; **Option to license rights to REGENXBIO AAV technology for any 1 additional disease, subject to availability (diseases not licensed in whole or in part to a 3rd party)
© 2017 Dimension Therapeutics 4
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Leveraging Mammalian Biology
Three platforms for production
HEK293 Adherent
Well-described
Regulator experience
Transient triple transfection
Serum-containing production
Limited scalability
HEK293 Suspension
Well-known
Emerging platform
Transient triple transfection
Serum-free production
Bioreactors
Scalable up to 200-500L
HeLa Producer Cell
Well-known
Clonal, high productivity
Similar to CHO platform
Serum-free production
Large scale bioreactors
Scalable up to 2000L
Sources: Martin J et al. 2013 Hum Gene Ther Meth; Grieger and Samulski 2012 Meth Enzymology; Zhang H et al. 2009 Hum Gene Ther
© 2017 Dimension Therapeutics
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Investing in Capabilities Today for Production Access Tomorrow
CMO
GMP
Cambridge
PD Engineering
Woburn
Advanced PD/ Tech Transfer
CMO: contract manufacturing organization; GMP: good manufacturing practice; PD: process development
© 2017 Dimension Therapeutics
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The Potential of AAV and Metabolic Disease
>400 Described Rare & Metabolic Diseases Associated with the Liver
Believe a Subset Well-Suited to Gene Therapy
Hem B
Proof of science
Replicate existing data
Activity supports IMD TPPs*
Learnings applied pipeline
IMDs
Known disease biology
Restore 5-10% of activity
Biomarkers, animal models
Orphan drug designation
Expansion
Leverage learning of IMDs
Harness liver biology
Bring new tools to bear
Target larger diseases
* |
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TPP: Target Product Profile |
© 2017 Dimension Therapeutics
Hem B
IMDs
Other Metabolic
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Broad Clinical
Pipeline
CANDIDATE SELECTION IND-ENABLING PHASE 1/2 PHASE 3 PARTNERS
Inherited Metabolic Disease (IMD) Portfolio
OTC Deficiency
GSDIa
PKU
Wilson Disease
Citrullinemia*
Hemophilia B
Hemophilia A
DTX301 AAV8 OTC
DTX401 AAV8 G6Pase
DTX501 AAV PAH
DTX701 AAV ATP7B
DTX601 AAV ASS1
Hemophilia Programs
DTX101 AAVrh10 FIX
DTX201 AAV FVIII
*Citrullinemia type 1
© 2017 Dimension Therapeutics
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Executing Key Milestones
ADVANCING 7 PROGRAM PORTFOLIO
Initiate OTC phase 1/2 trial
GSDIa US orphan designation
GSDIa EU orphan designation
OTC EU orphan designation
Expanded IMD portfolio
2016
Hem B available data
OTC initial data
Hem B additional data
File GSDIa and Hem A IND
PKU and Wilson Disease development candidates
2017+
© 2017 Dimension Therapeutics
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Inherited Metabolic Disease Programs
© 2016 Dimension Therapeutics
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Ornithine Transcarbamylase (OTC) Deficiency
Disease
X-linked, urea cycle disorder (UCD)
Genetic defect in ammonia detoxification
Adverse cognitive & neurological effects, coma, death
Treatments limited, non-curative
Patient Population
~10,000 patients WW ~80% late onset
Most common UCD, ~55%
Severe, early onset in males
Late onset in males & females
Sources: National Urea Cycles Disorder Foundation; NORD; Batshaw et al. Mol Gen Metab 2014; Tuchman et al 2008; Enns N Engl J Med 2007; Foschi et al. World J Gastro ESPS Manuscript no: 13209; carolguze.com/text/442-11-clinical_genetics.shtml
© 2017 Dimension Therapeutics
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DTX301: Reestablishing Ureagenesis
KNOWN DISEASE BIOLOGY; PRECLINICAL MODELS
BIOMARKERS
Serum ammonia; neurotoxic
13C-acetate; ureagenesis
carbamoyl phosphate converted to orotic acid; urinary orotic acid
PATH TO HPOC DEFINED
US/EU orphan drug designation hPOC serum ammonia
Adult males and at-risk females
Sources: DMTX-PENN data (ASGCT 2015, ECRD 2016)
© 2017 Dimension Therapeutics
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DTX301: Phase 1/2 Clinical Trial Design
DTX101
Vector capsid Clade E AAV8
Gene cassette OTC
Liver specific enhancer-promoter
HEK293 process for hPOC
TPP* targeting re-establishment of ureagenesis
Phase 1/2 Study Ongoing
Open-label, safety, dose finding study
Bayesian adaptive design
Primary endpoints safety & ureagenesis
(13C-acetate test)
Up to 9 adult males and females with late onset OTC deficiency
Dosing: 2e12-1e13 GC/kg, single peripheral venous infusion
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TPP: Target Product Profile |
© 2017 Dimension Therapeutics
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Glycogen Storage Disease Type Ia (GSDIa)
Disease
Autosomal recessive, inborn error of glucose metabolism
Deficient glucose-6-phosphatase (G6Pase)
Reduced QOL, long term risks
Strict diet and frequent feedings of uncooked starch or Glycosade®
Patient Population
~6,000 patients WW Dx at birth
Most common GSD, ~25%
No approved drug therapies
Sources: Weinstein et al. Hum Gen Ther 2010; Lee et al. Hepatology 2012; Chou et al Nat Rev Endo 2010; Boers et al. Orphanet Journal of Rare Diseases 2014; www.curegsd.org; The
Childrens Fund for GSD Research
© 2017 Dimension Therapeutics
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DTX401: Reestablishing Glucose Metabolism
KNOWN DISEASE BIOLOGY; PRECLINICAL MODELS
Improved G6Pase Activity in Canines
Single dose AAV8 gene therapy increases G6Pase
Corresponding reduction in hepatic glycogen
BIOMARKERS
Fasting blood glucose
Glycogen stores; build up in liver
Inability to release glucose, raise risk for hypoglycemia
PATH TO HPOC DEFINED
Time to hypoglycemia
Adult males and females
Sources: Weinstein et al. Hum Gen Ther 2010; Lee et al. Hepatology 2012; Chou et al Nat Rev Endo 2010; Boers et al. Orphanet Journal of Rare Diseases 2014; www.curegsd.org; The Childrens Fund for GSD Research
© 2017 Dimension Therapeutics
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Broad Inherited Metabolic Disease Portfolio
Wilson Disease
PKU
Citrullinemia Type 1
DISEASE BIOLOGY; PRECLINICAL MODELS
Autosomal recessive copper disorder
Deficiency in copper transporter P-type ATPase
Autosomal recessive disorder
Deficiency in phenylalanine hydrolase
Autosomal recessive UCD
Deficiency in argininosuccinate synthetase
BIOMARKERS
Copper
Phenylalanine
Ammonia
OPPORTUNITY
WW prevalence >50K patients
~50K prevalent patients developed world
14% of all UCDs
WW prevalence ~2K
Sources: Barends MGM 2014; Batshaw MGM 2014; Citrullinemia Type I NCBI Bookshelf; Engel et al Hum Mut 2009; Foschi World J Gastro 2015; Marti?n-Herna?ndez Orph J Rare Dis 2014; NORD; Ruder Ped Neuro 2014; Ruegger J Inherit Metab Dis 2014; Summar Acta Paediatr. 2008; Summar Crit Care Clin 2005; Tuchman et al Mol Genet Metab 2008; Berry Genet Med 2013; Hanley J Genet Disor Genet Rep 2013; Vockley Gen Med 2014; Zerjav Orph J Rare Dis 2015; Beinhardt Clin Gast Hepat 2014; Bull Nat Gen 1993; EASL Prac Guide; Gomes Ann Hum Bio 2015; Kaler Nat Rev Neurol 2011; Roberts & Schilsky Hepat 2008; Schilsky Biochimie 2009; WD Pathogenesis Semin Liver Dis 2000
© 2017 Dimension Therapeutics 16
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Hemophilia Programs
© 2016 Dimension Therapeutics
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~$6.2B WW Market for Hemophilia B and A Products
Disease
Deficiency of blood coagulation factor IX (FIX) or factor VIII (FVIII)
Joint hemorrhages, potential for severe disabilities; brain micro-bleeds
Frequent, invasive, non-curative infusions of factor replacement
Patient Population
~28,000 Hem B patients WW ~140,000 Hem A patients WW
~68% Hem B, 78% Hem A moderate/severe to severe disease
$100,000-$300,000+ annual costs per patient
Sources: Riley et al. Haemophilia 2011; National Hemophilia Foundation; World Federation of Hemophilia; www.fiercepharmamarketing.com/story/biogens-alprolix-nod-just-first-tremor-hemophilia-market-shake/2014-04-02; Stonebraker et al. Haemophilia (2011), 14; Baker et al. Haemophilia (2012); Stonebraker et al. Haemophilia (2010), 16, 2032; National Hemophilia Foundation; www.ptcommunity.com/news/2014-12-29-000000/hemophilia-market-likely-undergo-major-changes; Johnson and Zhou. ASH Annual Meeting Educational Program. 2011; Ponder. Haemophilia 2008; Manco-Johnson et al. NEJM 2007
© 2017 Dimension Therapeutics
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Goal of Hemophilia Gene Therapy
Reduce frequency of bleeds
Extend time between rFIX
Durable benefit from one infusion
Improve health outcomes and quality of life
Sources: den Uijl et al Haemophilia 2011
© 2017 Dimension Therapeutics
Consistent FIX activity confers
favorable effects on likelihood of
future bleeds, joint destruction and
need for rFIX replacement
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DTX101: Phase 1/2 Clinical Trial Design
Vector capsid Clade E AAVrh10
Gene cassette wild type factor IX
Liver specific enhancer-promoter
HEK293 process for hPOC
TPP* targeting stable FIX activity >10
Reduce dependency for on demand prophylactic rFIX therapies
DTX101
Phase 1/2 Study Ongoing
Open-label, safety, dose finding stu
Bayesian adaptive design, 3 dose c
Primary endpoints safety & FIX ac
Up to 12 males with moderate/sev severe Hem B (£2% FIX levels)
Dosing: 1.6e12-1e13 GC/kg, single peripheral venous infusion
Cohorts 1 & 2 dosing complete
* TPP: Target Product Profile
© 2017 Dimension Therapeutics
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Participant Demographics
Patient Dose Age FIX Activity
1 Low 70 <1.0%
2 Low 55 2.0%
3 Low 53 2.0%
4 Second 28 1.5%
5 Second 48 <1.0%
6 Second 48 <1.0%
All patients moderate/severe-to-severe
FIX Level Severity Description
50-150% Normal
Bleed only as a result of surgery or major injury
5-40% Mild
Do not bleed often and, in fact, may never have a bleeding problem
Less frequent bleeds, about once a month 1-5% Moderate Bleed for a long time after surgery, injury, or dental work
Rare spontaneous bleeding
Frequent bleeds into muscles/joints
May bleed 1-2 times per week
<1% Severe
Bleeding often spontaneous, and happens for no obvious reason
Sources: Information sourced from World Federation of Hemophilia, https://www.wfh.org/en/page.aspx?pid=643 (link current as of January 27, 2017)
© 2017 Dimension Therapeutics
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All Patients Improved from Moderate/Severe-to-Severe to Moderate or Mild
Patient Dose Peak FIX FIX* Severity
1 Low 11% 3% Moderate
2 Low 10% 3% Moderate
3 Low 5% 4% Moderate
4 Second 12% 5% Mild
5 Second 20% 8% Mild
6 Second 13% 7% Mild
*Data cutoff January 28, 2017; follow-up: low dose (1.6e12 GC/kg) 24-52 weeks; second dose (5e12 GC/kg) 7-12 weeks
Total Number of Bleeds
Number of Bleeds*
33
30
73%
20
15
9
10 100%
4**
0
0
Cohort 1 Cohort 2
12 Mo Prior Post-Dose All Post-Dose Spontaneous
*Data cutoff January 28, 2017; **Cohort 1 spontaneous bleeds: right shoulder, eye/conjunctivitis, right ankle (2)
© 2017 Dimension Therapeutics
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Clinically Asymptomatic Elevations in Liver Enzymes
5 of 6 patients in the normal range
Elevations in laboratory ALT* observed in 5 of 6 patients; 4 in normal range
o Patient 3 in Cohort 2 experienced a grade 4 adverse event due to an elevated laboratory ALT o Cohort 1 clinically stable, off steroids*
All elevated liver enzymes were clinically asymptomatic
o No elevations of GGT*, alkaline phosphatase or bilirubin o No patients have experienced a drug related serious adverse event (SAE) as of the January 28, 2017 cutoff date
*ALT: alanine aminotransferase; cohort 2 continues to receive a standard tapering course of corticosteroid therapy; GGT: gamma-glutamyl transferase
Patient Dose Peak ALT ALT*
1 Low 98 22
2 Low 40 21
3 Low 60 39
4 Second 52 19
5 Second 62 39
6 Second 914 431
*Data cutoff January 28, 2017; follow-up: low dose (1.6e12 GC/kg) 24-52 weeks; second dose
(5e12 GC/kg) 6-12 weeks; ALT measured in international units per liter (IU/L); normal ALT ?40
IU/L
© 2017 Dimension Therapeutics
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Summary of Interim Findings and Next Steps
Evidence of high-efficiency liver transduction with AAVrh10 vector
All patients in both cohorts improved from moderate/severe-to-severe to either moderate or mild
Notable reduction in spontaneous bleeds
Stable and durable elevations in FIX activity up to 52 weeks (range 6-52)
Sub-clinical, asymptomatic elevations of ALT observed in 5 of 6 patients; 4 currently in normal range
Explore therapeutic window in light of ALT rises & FIX decline
Broad program of translational research ongoing
Multiple hypotheses under consideration
T cell activation, general immune responses, cellular responses
Future presentations at academic and medical congresses
Await feedback from regulatory bodies prior to initiating cohort 3
© 2017 Dimension Therapeutics
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DTX201: Global Collaboration with Bayer
A LEADING GENE THERAPY COMPANY
GLOBAL LEADER IN HEMOPHILIA DRUG
DEVELOPMENT & COMMERCIALIZATION
$20M upfront, up to $232M in milestones
High single-digit to low double-digit royalties not exceeding the mid-teens
R&D expense reimbursement
DMTX responsible for preclinical activities and Phase I/II clinical trial, funded by Bayer
Bayer to fund subsequent trials and commercial activities at clinical POC
Partnered since June 2014
© 2017 Dimension Therapeutics
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DTX201: Durable FVIII Expression in NHPs
DTX201 for Hem A
hFVIII Expression in Non Human Primates
Seven male cynomolgus macaques administered IV with 1.2e13 GC/kg
Sustained FVIII expression in NHPs beyond 60 weeks
3 of 7 animals retain expression greater than 16 weeks; 2 of 7 beyond 34 weeks
Sustained RNA expression
Reduced incidence of anti-FVIII inhibitors
Sources: DMTX-PENN data (ASGCT 2016, EHA 2016)
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Dimension
A Leader in
Liver Directed
Gene Therapy
Advancing Product Portfolio Focus on Inherited Metabolic Diseases Building Gene Therapy Product Platform Highly Experienced Team Well-Capitalized
Broad 7 program pipeline; multiple near-term milestones
Addressing severe, debilitating unmet medical need
Investing in scalable, quality HeLa manufacturing
Strong R&D and manufacturing capabilities
Expected cash runway through 1Q 2018
© 2017 Dimension Therapeutics
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Thank you
January 2017
© 2016 Dimension Therapeutics
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