Small Molecule Inhibitors of SARM1 Prevent Chemotherapy-Induced Peripheral NeuropathyRaul Krauss*, Robert O. Hughes, Todd Bosanac, Rajesh Devraj, Thomas M. EngberDisarm Therapeutics. Cambridge, MA 02142

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SARM1 is the Central Driver of Axonal DegenerationAxons can be protected from Wallerian degeneration in PNS and CNS

Krauss, et al. Trends in Pharmacological Sciences 2020 41281-293DOI: (10.1016/j.tips.2020.01.006)

Cut Distal Axons are Protected in SARM1 KO

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SARM1 Activation Drives Rapid NAD+ Loss Leading to a Bioenergetic Crisis and Axonal Degeneration

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SARM1 KO Protects Axons in vitro and in vivo

0

50

100

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200

250

SNA

P am

plitu

de (µ

V)

WT WT SARM1HET

SARM1KO

PaclitaxelVehicle

*****

*******

WT Vehicle

1

2

3

1

2

3

SNC L Tail nerv - Stim Evotec

tail distal 3.92mA

1

20

tail distal 3.92mA

2

20

50µV 500µsWT Paclitaxel

1

2

3

1

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3

SNC L Tail nerv - Stim Evotec

tail distal 3.92mA

1

20

tail distal 3.92mA

2

20

50µV 500µs

SARM1 KO Paclitaxel

In vitro mouse DRG axotomy In vivo axonal function (SNAP) in CIPN model

Control Cut

WT

SARM1 KO

0.0

0.2

0.4

0.6

0.8

Axon

al D

egen

erat

ion

(DI)

Uncut UncutCut Cut

Wild Type SARM1 KO

****p

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Small Molecule SARM1 Inhibitors Protect Axons in vitro

10-7 10-6 10-50

20

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80

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120

cut

DSRM 6340 [M]

Deg

ener

atio

n (%

)

10X 100XX

Axo

nal D

egen

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(%)

Dose responseUncut Cut Cut + DSRM-XX

Robust protection of distal severed axons is similar to SARM1 KO

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Evaluation of SARM1 Inhibitor in Paclitaxel CIPN Mouse Model Readouts include axonal function by SNAP and intraepidermal nerve fiber density

PACLITAXEL IV 50 mg/kg

SNAP

0 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16Day

Oral dosing with vehicle or DSRM-XX at Low or High Dose

SNAP IENFHISTOLOGY

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Small Molecule SARM1 Inhibitors Protect Axons in vivo in Paclitaxel Mouse Model of CIPN

Protection of axonal structure (IENF) and function (SNAP & allodynia)

1

2

3

1

2

3

SNC L Tail nerv - Stim Evotec

tail distal 4.04mA

1

tail distal 4.04mA

2

50µV 500µsPaclitaxel

1

2

3

1

2

3

SNC L Tail nerv - Stim Evotec

tail distal 2.40mA

1

tail distal 2.40mA

2

50µV 500µsPaclitaxel + DSRM-XX

1

2

3

1

2

3

SNC L Tail nerv - Stim Evotec

tail distal 4.04mA

1

tail distal 4.04mA

2

50µV 500µsVehicle

IENF Density

0

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IENF/mm

***

**n.s.

n.s.

Vehicle Vehicle DSRM-XXLow

DSRM-XXHigh

Paclitaxel

SNAP Amplitude

Baseline Day 8 Day 13

0

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150

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SNA

P am

plitu

de (µ

V)

VehiclePTXPTX + DSRM-XX LowPTX + DSRM-XX High

****

****

**

*n.s.

n.s.

2-way ANOVA + Holm-Sidak post hoc. * p < 0.05; ** p < 0.01; **** p < 0.0001, n=10

2-way ANOVA + Holm-Sidac post hoc. *p

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§ Disarm has advanced a proprietary R&D platform to discover small molecule inhibitors of SARM1, the central driver of axonal degeneration

§ Disarm’s novel small molecule SARM1 inhibitors reproduce in vitro and in vivo the axonal protection phenotype seen in SARM1 knockout.

§ Disarm’s compounds: • Protect axons in vitro from multiple pathological insults • Prevent axonal degeneration and preserve axonal function in vivo in a rodent model of chemotherapy-

induced peripheral neuropathy (CIPN) Disarm is developing small-molecule SARM1 inhibitors for patients with neurological diseases such as CIPN, MS and ALS

Conclusions

Triggers Diseases

Axonal Degeneration Glaucoma

Multiple sclerosis

CIPN

Neurodegenerative (PD, ALS)

Peripheral neuropathies (diabetic, CMT)

CNS, Eye PNS

SARM1

Immuno/inflammatory

Metabolic / Toxins

Trauma

Mitochondrial / Other

Intraocular pressure