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Proof-Of-Concept Study* T op Line Data Report of a Phase 1 Clinical Study in Healthy Volunteers November 8, 2021 * Joint study with AskBio
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arket opportunity for the com pany's gene therapy programs, the potential of any com pany gene therapy product candidate to address unm et m edical needs including b ut not lim ited to the ab ility to re-treat gene therapy disease indications
or enhance transgene expression, the potential treatment applications and regulatory and clinical development of the com pany's product candidates utilizing the Im mTOR platform in areas such as enzyme therapy and gene therapy and related tim
ing, the potential of the Im m TOR technology platform generally and the com pany's ab ility to grow its strategic collab orations, upcoming events and presentations, including with respect to the presentation of the SEL-399.101 em pty capsid
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forward-looking statements included in this presentation. 2
The Ability to Inhibit The Development of AAV-Specific Antibodies Has
The Potential to Enable Re-Dosing of AAV Gene Therapy Adeno-associated virus (AAV) vectors are the most widely used in-vivo gene therapy vectors AAV is non-self replicating and over time transgene expression may wane, particularly in
growing tissues such as liver in childhood, suggesting that re-dosing of gene therapy may be necessary Gene therapy with AAV induces a robust immune response in recipients, resulting in high level anti-AAV neutralizing antibodies (NAb) which
precludes re-dosing of the gene therapy Because NAb can reduce the efficiency of gene therapy, treatment with AAV gene therapy is restricted to patients with low levels of pre-existing NAb. For example, Zolgensma NAb titers must be
1:50 to be eligible for treatment In addition to induction of anti-AAV NAb, the immune response to AAV gene therapy may be involved in observed gene therapy associated toxicities such as hepatotoxicity and thrombotic microvascular
angiopathy As a proof-of-concept study, we studied the ability of ImmTOR, an immune tolerizing drug, to inhibit anti-AAV8 NAb formation in healthy volunteers to evaluate the potential of ImmTOR for gene therapy re-dosing 3
AAV Gene Therapy Induces an Immune Response That Precludes Redosing,
Inhibits Efficacy, And Causes Adverse Events Lower efficacy Prevention of re-dosing Adverse events Loss of efficacy 4
Potential for ImmTOR to Enhance AAV Gene Therapy Potential to enable
re-dosing of AAV gene therapy Prevention of AAV antibody production Potential to re-dose Inhibition of liver inflammation Enhanced efficacy More durable efficacy Improved safety 5
Long-Term Inhibition of Anti-AAV8 Antibodies With 3 Monthly Doses of
ImmTOR in Animals Single And Multiple Dose ImmTOR Data AAV-EC + AAV-EC + 1 Mice AAV8 Empty capsid 2e13 vp/kg Single dose ImmTOR 3 monthly doses ImmTOR 2.0 2.0 1.5 1.5 1.5 1.0 1.0 1.0 0.5 0.5 0.5 0.0 0.0 0.0 Day Day Day BL = baseline AAV-SEAP +
AAV-SEAP + Nonhuman AAV8-SEAP 2e12 vg/kg Single dose ImmTOR 3 monthly doses ImmTOR 1.5 1.5 1.5 2 primates 1.0 1.0 1.0 0.5 0.5 0.5 0.0 0.0 0.0 BL 7 14 28 56 84 BL 7 14 28 56 84 BL 7 14 28 56 84 Day Day Day BL = baseline 1 2 ESGCT 2021 Poster P010 /
ESGCT 2021 Poster 003 6 BL 7 12 19 27 42 55 70 84 112 140 168 BL 7 12 19 27 42 55 70 84 112 140 168 BL 7 12 19 27 42 55 70 84 112 140 168 Anti-AAV8 IgG (OD ) 450-570 Anti-AAV8 IgG OD 450-570
SEL-399 Phase 1 Dose-Escalation Study: Objectives and Endpoints
General Objectives To determine the immune response to AAV8 empty capsids (EMC-101), which contain no DNA payload, in healthy volunteers To determine whether single escalating doses of ImmTOR can reduce the immune response to AAV8
empty capsids in healthy volunteers 8
SEL-399 Phase 1 Dose-Escalation Study: Subjects and Design Total
healthy volunteers enrolled: 23 (14 males and 9 females) All subjects with anti-AAV8 NAb titers <1:5 at baseline Randomized, placebo controlled and double-blind study Drug Infusions 30 45 60 75 90 Study Day 0 15 Placebo* + Empty
Capsid (2E12 vp**/kg) n=3 Placebo + Empty Capsid (2E12 vp/kg) n=3 ImmTOR (0.15 mg/kg) + Empty Capsid (2E12 vp/kg) n=9 Placebo + Empty Capsid (2E12 vp/kg) n=2 ImmTOR (0.3 mg/kg) + Empty Capsid (2E12 vp/kg) n=6 Neutralizing antibodies (NAb)
measurement * Placebo=saline infusion ** vp=viral particles 9
SEL-399 Phase 1 Dose- Escalation Study 10
Single Dose ImmTOR Inhibited Formation of Anti-AAV8 NAb at Day 30 100%
of subjects dosed with 0.3 mg/kg ImmTOR had NAb titers 1:25 at Day 30 67% of subjects dosed with 0.3 mg/kg ImmTOR had NAb titers 1:5 at Day 30 Linear Scale Log Scale 10 2000 2000 1000 1500 100 1000 Titer 1:25 10 500 Titer 1:5 1 0 Empty
Capsid (n=8) Empty Capsid + 0.15 mg/kg ImmTOR (n=9) Empty Capsid + 0.3 mg/kg ImmTOR (n=6) 11 NAb Titers Log NAb Titers 10
Single Dose ImmTOR Inhibited Formation of Median Anti-AAV8 NAb in a
Dose- Dependent Manner at Day 30 1:5 Median NAb titers in subjects dosed with 0.3 mg/kg ImmTOR at Day 30 250-fold lower median NAb titers in subjects dosed with 0.3 mg/kg ImmTOR at Day 30 100000 Median 10000 Titer 1:1250 1000 50-Fold 250-Fold
Difference 100 Difference 1:25 10 1:5 1 0 10 20 30 Days Empty Capsid (n=8) Empty Capsid + 0.15 mg/kg ImmTOR (n=9) Empty Capsid + 0.3 mg/kg ImmTOR (n=6) 12 Median Log NAb Titers 10
Subjects Treated With a Single Dose of ImmTOR Developed Delayed NAb
Formation by Day 90 Two additional doses of ImmTOR may be required to maintain control beyond Day 30 2 of 6 subjects dosed with 0.3 mg/kg ImmTOR had NAb titers 1:25 at Day 90 1 of 6 subjects dosed with 0.3 mg/kg ImmTOR had NAb titers
1:5 at Day 90 Day 90 Day 30 Titer 1:25 Titer 1:5 Empty Capsid (n=8) Empty Capsid + 0.15 mg/kg ImmTOR (n=9) Empty Capsid + 0.3 mg/kg ImmTOR (n=6) 13
Empty Capsid Data In-Line With Single Dose ImmTOR NHP Data at Day 90 1
Human Nonhuman Primate Target For Redosing Single dose Single Dose Three Doses 1000000 100000 Titers too high for re-dosing 100000 10000 200+ 10000 Failure 1000 1000 Antibody levels may interfere 50-200 Intermediate with efficient re-dosing** 100
100 Patients eligible for re-dosing* 10 1-50 10 (Zolgensma eligibility: 1:50) Target 1 1 AAV8-SEAP AAV8-SEAP * May be dependent on gene therapy dose AAV8-EC + + + ** Ancillary approaches such as IgG protease ImmTOR ImmTOR ImmTOR pre-treatment
may be required for re-dosing D0 D0, 28, 56 D0 1 14 ESGCT 2021 Poster 003 Log NAb Titers 10 Log NAb Titers 10
Safety All treatment-related adverse events were expected for ImmTOR,
readily monitorable, and transient There were no Serious Adverse Events (SAEs) Adverse events related to ImmTOR were expected based on previous clinical trials Stomatitis (mouth ulcers, redness, or pain) was most common 3
of 9 subjects in 0.15 mg/kg group and 6 of 6 subjects in 0.3 mg/kg group, all mild to moderate Average start of stomatitis was on day 11 with an average duration of 8 days Symptoms were ameliorated with steroid mouth wash Rash
was next most common 3 of 9 subjects in 0.15 mg/kg group and 3 of 6 subjects in 0.3 mg/kg group, all mild to moderate Average start of rash was day 12 and resolved after an average of 23 days No therapy was required
Asymptomatic and transient laboratory AEs in subjects receiving ImmTOR were seen in 2 subjects with mild to moderate thrombocytopenia and 1 subject with grade 3 hypertriglyceridemia 15
Summary and Conclusions AAV8 empty capsids elicited a strong
immune response with peak median anti-AAV8 NAb titers of 1:6875 ImmTOR inhibited the formation of anti-AAV8 NAb in a dose-dependent manner at Day 30 After Day 30, 2 of 6 subjects treated with 0.3 mg/kg ImmTOR maintained NAb titers
1:25, while remaining ImmTOR- treated subjects showed delayed formation of NAb reaching control levels by Day 90 Animal studies suggest that, if NAb are inhibited at Day 30, administration of two additional monthly doses of ImmTOR may
maintain control of NAb beyond 90 days Safety findings included AEs previously observed with ImmTOR This promising study in healthy volunteers provides support for the potential use of ImmTOR for the inhibition of neutralizing
antibodies to AAV8 in gene therapy clinical trials 17