Full Press Release Details
Conference Call July 26, 2023
On Today's Call Welcome Lindsey Allen, Head, Investor
Relations and Communications, Amylyx Opening Remarks Josh Cohen and Justin Klee, Co-CEOs, Amylyx AMX0035 Scientific Rationale in PSP Dr. Jamie Timmons, Head, Global Medical Strategy and Communications, Amylyx PSP Treatment
Landscape Prof. Dr. G nter H glinger, Director of the Department of Neurology at LMU Hospital, Ludwig-Maximilians-University (LMU) in Munich, Germany Primary Investigator for Phase 3 ORION Clinical Trial of AMX0035 in PSP Overview
of Phase 3 PSP Trial Dr. Lahar Mehta, Head, Global Clinical Development, Amylyx Q&A Session 2
Disclaimer Statements contained in this presentation regarding matters
that are not historical facts are "forward-looking statements" within the meaning of the Private Securities Litigation Reform Act of 1995, as amended. Because such statements are subject to risks and uncertainties, actual results may
differ materially from those expressed or implied by such forward-looking statements. Such statements include, but are not limited to, statements regarding the potential of AMX0035 as a treatment for ALS and the Company's plans to explore the
use of AMX0035 for other neurodegenerative diseases, including progressive supranuclear palsy (PSP) and expectations around the timing of initiation of a Phase 3 clinical trial in PSP and the geographic sites for enrollment; expectations about the
market size for PSP; and expectations regarding our longer-term strategy. Any forward-looking statements in this presentation are based on management's 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. Risks that contribute to the uncertain nature of the forward-looking statements include: the
success, cost, and timing of Amylyx' program development activities, including ongoing and planned clinical trials, Amylyx' ability to execute on its commercial and regulatory strategy, regulatory developments, Amylyx' ability to
fund operations, and the impact that the COVID-19 pandemic may have on Amylyx' operations, as well as the risks and uncertainties set forth in Amylyx' United States Securities and Exchange Commission (SEC) filings, including
Amylyx' Annual Report on Form 10-K for the year ended December 31, 2022, and subsequent filings with the SEC. All forward-looking statements contained in this presentation speak only as of the date on which they were made. Amylyx undertakes no
obligation to update such statements to reflect events that occur or circumstances that exist after the date on which they were made. 3
AMX0035 Scientific Rationale in PSP Dr. Jamie Timmons Head, Global
Medical Strategy and Communications, Amylyx 4
Our mission is to one day end the suffering caused by neurodegenerative
Neurodegenerative Diseases Share Interconnected, Hallmark Pathological
Pathways Pathological Protein Aggregation Amyotrophic Lateral Sclerosis (ALS) TDP43, tau, SOD1, FUS, DPRs Tauopathies; e.g., Progressive Supranuclear Palsy (PSP) tau Alzheimer's Disease tau, A The
interconnectedness of these pathways highlights the need for multi-pathway therapy Wilson DM 3rd, et al. Cell. 2023 Feb 16;186(4):693-714. 6
AMX0035 (Sodium Phenylbutyrate and Taurursodiol) Acts on Several Shared
1-9 Hallmark Pathways to Reduce Neuronal Cell Death Pathological Neuronal Cell Death Protein Aggregation In vitro evidence of protecting 2 Reduces tau in neurons from death neurodegenerative Affects key pathways leading
disease cell and to cell death, including mouse models and intrinsic apoptosis via the in Alzheimer's mitochondria and unfolded 3-5 disease clinical protein response 6-9 trial Altered Energy Homeostasis Stabilizes mitochondrial
membrane, improves mitochondrial function, increasing energy production 4,5 of the cell 1. Wilson DM 3rd, et al. Cell. 2023 Feb 16;186(4):693-714. 2. Cohen J, et al. Poster presented at: 28th International Symposium for ALS/MND; December 4-10, 2017;
Boston, MA. 3. Zhou W. J Biol Chem. 2011;286(17):14941-14951. 4. Rodrigues CM, Steer CJ. Expert Opin Investig Drugs. 2001;10(7):1243-1253. 5. Rodrigues CM, et al. Biochemistry. 2003;42(10):3070-3080. 6. Ricobaraza A, et al. Neuropsychopharmacology.
2009;34(7):1721-1732. 7. Bondulich MK, et al. Brain. 2016;139(8):2290-2306. 8. van der Harg JM, et al. 7 Cell Death Dis. 2014;5(8):e1393. 9. Arnold SE, et al. Poster presented at: 15th Clinical Trials on Alzheimer's Disease; November
29-December 2, 2022; San Francisco, CA.
PSP is a Rare, Progressive and Fatal Tauopathy Rare neurological
disorder affecting ESTIMATED PREVALENCE: body movements, walking and 1,2 balance, and eye movement. 7 in 100,000 worldwide Lack of disease modifying therapies ESTIMATED INCIDENCE: creates significant unmet need. 2 0.81 in 100,000 worldwide
PSP is a tauopathy associated with tau dysfunction, tau aggregation and widespread neurodegeneration. PSP is typically fatal within 3-6 6-8 years from symptom onset 1. Swallow DMA, et al. Mov Disord Clin Pract. 2022 Jun 28;9(5):604-613. doi:
10.1002/mdc3.13489. 2. Lyons S, et al. J Neurol.2023;June 8. epub ahead of print. 3. Stamelou M, et al. Nat Rev Neurol. 2021;17(10):601-620. 4. Viscidi E, et al. Front Neurol. 8 2021;12:571800. 5. Golbe and Ohman-Strickland. Brain.
2007;130(6):1552-65. 6. Swallow and Counsell. J Neurol. 2023;270(7):3464-3474
Pathophysiologic Changes Underlying PSP Provide Multiple Pathways to
Target M MO OB BP P,, S ST TX X6 6,, E EIIF F2 2A AK K3 3,, M MA AP PT T G Ge en ne e M Mu ut ta at tiio on ns s T Ta au u D Dy ys sf fu un nc ct tiio on n T TR RIIM M1 11 1 G Ge en ne e M Mu ut ta at tiio on ns s O Ox xiid da at tiiv ve e IIn njju
ur ry y/ / T Ta au u C Clle ea ar ra an nc ce e D De ec cr re ea as se ed d E En ne er rg gy y a an nd d R Re ep pa aiir r T Ta au u A Ag gg gr re eg ga at tiio on n Ubiquitin-Proteasome System Autophagy-Lysosome System M Miit to oc
ch ho on nd dr riia all Unfolded Protein Response D Dy ys sf fu un nc ct tiio on n N Ne eu ur ro on na all C Ce ellll D De ea at th h a an nd d N Ne eu ur ro od de eg ge en ne er ra at tiio on n N Ne eu ur ro oiin nf flla am mm ma at tiio on
n D Dy ys sm my ye elliin na at tiio on n PSP Park HK, et al. J Mov Disord. 2021; 14(2):103-113. 9
1-9 AMX0035 May Influence PSP Tau Pathology through Multiple Mechanisms
M MO OB BP P,, S ST TX X6 6,, E EIIF F2 2A AK K3 3,, M MA AP PT T G Ge en ne e M Mu ut ta at tiio on ns s T Ta au u D Dy ys sf fu un nc ct tiio on n T TR RIIM M1 11 1 G Ge en ne e M Mu ut ta at tiio on ns s O Ox xiid da at tiiv ve e IIn njju ur ry
y/ / T Ta au u C Clle ea ar ra an nc ce e D De ec cr re ea as se ed d E En ne er rg gy y a an nd d R Re ep pa aiir r T Ta au u A Ag gg gr re eg ga at tiio on n Ubiquitin-Proteasome System Autophagy-Lysosome System M Miit to oc ch ho
on nd dr riia all Unfolded Protein Response D Dy ys sf fu un nc ct tiio on n N Ne eu ur ro on na all C Ce ellll D De ea at th h a an nd d N Ne eu ur ro od de eg ge en ne er ra at tiio on n N Ne eu ur ro oiin nf flla am mm ma at tiio on n D
Dy ys sm my ye elliin na at tiio on n PSP 1. Park HK, et al. J Mov Disord. 2021; 14(2):103-113. 2. Cohen J, et al. Poster presented at: 28th International Symposium for ALS/MND; December 4-10, 2017; Boston, MA. 3. Zhou W. J Biol Chem.
2011;286(17):14941-14951. 4. Rodrigues CM, Steer CJ. Expert Opin Investig Drugs. 2001;10(7):1243-1253. 5. Rodrigues CM, et al. Biochemistry. 2003;42(10):3070-3080. 6. Ricobaraza A, et al. Neuropsychopharmacology. 2009;34(7):1721-1732. 7. Bondulich
MK, et al. Brain. 2016;139(8):2290-2306. 10 8. van der Harg JM, et al. Cell Death Dis. 2014;5(8):e1393. 9. Arnold SE, et al. Poster presented at: 15th Clinical Trials on Alzheimer's Disease; November 29-December 2, 2022; San Francisco, CA.
Preclinical Data Support Sodium Phenylbutyrate (PB) for Potential
Treatment of PSP MOBP, STX6, EIF2AK3, MAPT Gene Mutations Tau Dysfunction PB is Effective in PSP Mouse Model, TRIM11 Gene Mutations Reduced Tau in AD Mouse Model O O Oxx xiiid d da a att tiiiv v ve e e IIIn n njjju u ur rry yy/ / / Tau Clearance D
De ec cr re ea as se ed d E En ne er rg gy y Decreased Energy and Repair Tau Aggregation PB reduced tau pathology and improved cognitive and motor function Ubiquitin-Proteasome System 5,6 Autophagy-Lysosome System Mitochondrial
measures in relevant mouse models M Miit to oc ch ho on nd dr riia all Unfolded Protein Response DD D ys y yf s su f fu u nn n cc c tit to iio o n n n Neuronal Cell Death and Neurodegeneration Alzheimer's APP/PS1 mouse model:
reduced tau phosphorylation 5 and improved cognition Neuroinflammation Dysmyelination Tau35 PSP mouse model (shown): reduced tau phosphorylation and 6 improved cognition and motor function PSP 6 6 Morris Water Maze Grip Strength Sodium
phenylbutyrate upregulates and recruits chaperone proteins, stabilizes protein folding, and reduces ER stress and the 1-4 unfolded protein response (UPR) in vitro 1. Zhou W. J Biol Chem. 2011;286(17):14941-14951. 2. Wiley JC, et al. PLoS One.
2010;5:e9135. 3. Mimori S, et al. Biol Pharm Bull. 2012;35:84-90. 4. Cho JA, et al. PLoS One 2014;9:e110086. 5. Ricobaraza A, et al. Neuropsychopharmacology. 11 2009;34(7):1721-1732. 6. Bondulich MK, et al. Brain. 2016;139(8):2290-2306.
Preclinical Data Support Taurursodiol (TURSO) for Potential Treatment
of PSP MOBP, STX6, EIF2AK3, MAPT Gene Mutations Tau Dysfunction TURSO reduced p-tau in cellular model of TRIM11 Gene Mutations 3 metabolic stress Oxidative Injury/ Tau Clearance T Ta au u C Clle ea ar ra an nc ce e Decreased Energy a a an n nd d d R
R Re e ep p pa a aiiir r r Tau Aggregation 3 Taurursodiol (TURSO) reduced tau phosphorylation in vitro Ubiquitin-Proteasome System Autophagy-Lysosome System Mitochondrial Unfolded Protein Response Dysfunction Neuronal Cell
Death and 3 Reduced p-tau with TURSO Neurodegeneration Neuroinflammation Dysmyelination PSP Taurursodiol stabilizes the mitochondrial 2 deoxy glucose (2DG) induced metabolic stress in neuronal cell 3 model resulting in increased p-tau levels
membrane by reducing the translocation of cell 3 death regulator Bax, improving mitochondrial TURSO (T) reduced increase in p-tau levels function and energy production and increasing 1,2 cell apoptotic threshold 12 1. Rodrigues CM, Steer CJ.
Expert Opin Investig Drugs. 2001;10(7):1243-1253. 2. Rodrigues CM, et al. Biochemistry. 2003;42(10):3070-3080. 3. van der Harg JM, et al. Cell Death Dis. 2014;5(8):e1393.
Numerous Preclinical Studies Show that AMX0035 Combination Targets
Multiple Pathways Simultaneously to Prevent or Slow Cell Death 2 Dose-Matrix Study: Profilin Mouse Model of ALS 1 Primary Cortical Neuron Damage Model I In n v viit tr ro o,, A AM MX X0 00 03 35 5 c co om mb biin na at tiio on n d de em mo on ns st
tr ra at te ed d s sy yn ne er rg giis st tiic c I In n m mo ou us se e m mo od de ell o of f A AL LS S,, A AM MX X0 00 03 35 5 c co om mb biin na at tiio on n d de em mo on ns st tr ra at te ed d p pr ro ot te ec ct tiio on n o of f c co or rt tiic
ca all n ne eu ur ro on ns s a ag ga aiin ns st t p pe er ro ox xiid de e--m me ed diia at te ed d n ne eu ur ro on na all s sy yn ne er rg giis st tiic c d de ec cr re ea as se e iin n m mo ot to or r f fu un nc ct tiio on n d de ec clliin ne e c
ce ellll d de ea at th h A AM MX X0 00 03 35 5 c co om mb biin na at tiio on n s siig gn niif fiic ca an nt tlly y d de ec cr re ea as se ed d m mo ot to or r f fu un nc ct tiio on n d de ec clliin ne e E Eiit th he er
r P PB B o or r T TU UR RS SO O a ad dm miin niis st tr ra at tiio on n a allo on ne e p pr re ev ve en nt te ed d a a m mo od de er ra at te e iin n a a m mo ou us se e m mo od de ell o of f A AL LS S p pe er rc ce en nt ta ag ge e o of f n ne eu
ur ro on na all c ce ellll d de ea at th h iin n v viit tr ro o T Th hiis s b be en ne ef fiit t w wa as s o on nlly y s se ee en n w wh he en n c co om mb biin niin ng g P PB B a an nd d T TU UR RS SO O a an nd d n no ot t
A AM MX X0 00 03 35 5 c co om mb biin na at tiio on n p pr re ev ve en nt te ed d n ne ea ar rlly y 1 10 00 0% % o of f n ne eu ur ro on na all d de ea at th h w wiit th h iin nd diiv viid du ua all P PB B o or r T TU UR RS SO O t tr
re ea at tm me en nt t iin n v viit tr ro o 1. Cohen J, et al. Clinical trial design for a phase II, randomized, placebo-controlled trial of AMX0035 in amyotrophic lateral sclerosis (CENTAUR). Poster presented at: 28th International Symposium for
ALS/MND; December 4-10, 2017; Boston, MA. 2. Timmons J, 13 et al. Efficacy of Sodium Phenylbutyrate and Ursodoxicoltaurine Combination in Transgenic Mice Displaying Progressive Motor Neuron Degeneration Phenotype. Poster presented at ENCALS
Meeting 2023; July 12-14, 2023; Barcelona, Spain.
Numerous Preclinical Studies Show that AMX0035 Combination Targets
Multiple Pathways Simultaneously to Prevent or Slow Cell Death 2 Dose-Matrix Study: Profilin Mouse Model of ALS 1 Primary Cortical Neuron Damage Model 2 26 6 p pr riim ma ar ry y p ph ha ar rm ma ac co od dy yn na am miic c s st tu ud diie es s o of
f A AM MX X0 00 03 35 5 s su up pp po or rt t e ef ff fe ec ct t iin n r re elle ev va an nt t m me ec ch ha an niis st tiic c p pa at th hw wa ay ys s f fo or r 3 3 o ot th he er r n ne eu ur ro od de eg ge en ne er ra at tiiv ve e d diis se ea as
se es s 3 3.. D Da at ta a o on n F Fiille e I In n v viit tr ro o,, A AM MX X0 00 03 35 5 c co om mb biin na at tiio on n d de em mo on ns st tr ra at te ed d s sy yn ne er rg giis st tiic c I In n m mo ou us se e m mo od de ell o of f A AL LS S,,
A AM MX X0 00 03 35 5 c co om mb biin na at tiio on n d de em mo on ns st tr ra at te ed d p pr ro ot te ec ct tiio on n o of f c co or rt tiic ca all n ne eu ur ro on ns s a ag ga aiin ns st t p pe er ro ox xiid de e--m me ed diia at te ed d n ne
eu ur ro on na all s sy yn ne er rg giis st tiic c d de ec cr re ea as se e iin n m mo ot to or r f fu un nc ct tiio on n d de ec clliin ne e c ce ellll d de ea at th h A AM MX X0 00 03 35 5 c co om mb biin na at tiio on n s siig gn
niif fiic ca an nt tlly y d de ec cr re ea as se ed d m mo ot to or r f fu un nc ct tiio on n d de ec clliin ne e E Eiit th he er r P PB B o or r T TU UR RS SO O a ad dm miin niis st tr ra at tiio on n a allo on ne e p pr re ev ve en
nt te ed d a a m mo od de er ra at te e iin n a a m mo ou us se e m mo od de ell o of f A AL LS S p pe er rc ce en nt ta ag ge e o of f n ne eu ur ro on na all c ce ellll d de ea at th h iin n v viit tr ro o T Th hiis s b be en ne ef
fiit t w wa as s o on nlly y s se ee en n w wh he en n c co om mb biin niin ng g P PB B a an nd d T TU UR RS SO O a an nd d n no ot t A AM MX X0 00 03 35 5 c co om mb biin na at tiio on n p pr re ev ve en nt te ed d n ne ea ar rlly y
1 10 00 0% % o of f n ne eu ur ro on na all d de ea at th h w wiit th h iin nd diiv viid du ua all P PB B o or r T TU UR RS SO O t tr re ea at tm me en nt t iin n v viit tr ro o 1. Cohen J, et al. Clinical trial design for a phase II, randomized,
placebo-controlled trial of AMX0035 in amyotrophic lateral sclerosis (CENTAUR). Poster presented at: 28th International Symposium for ALS/MND; December 4-10, 2017; Boston, MA. 2. Timmons J, 14 et al. Efficacy of Sodium Phenylbutyrate and
Ursodoxicoltaurine Combination in Transgenic Mice Displaying Progressive Motor Neuron Degeneration Phenotype. Poster presented at ENCALS Meeting 2023; July 12-14, 2023; Barcelona, Spain.
AMX0035 Significantly Lowered CSF Tau and p-Tau in Randomized Placebo
Controlled Trial in People with Alzheimer's Disease Week 24 Mean (SE) CSF t-tau Week 24 Mean (SE) CSF p-tau181 Change From Baseline Change From Baseline 40 Placebo AMX0035 Placebo AMX0035 20 0 0 8.8 -20 -0.27 (15.2) -10 (2.9) -40 -60
Difference Difference -20 -14.6 - -7 73 3..7 7 p pg g/ /m mL L - -1 14 4..4 4 p pg g/ /m mL L (3.0) -80 -64.9 P P< <0 0..0 00 00 01 1 P P= =0 0..0 00 00 02 2 (15.5) -30 -100 Arnold SE, et al. Cerebrospinal
Fluid Biomarker Effects From a Fixed-Dose Combination of Sodium Phenylbutyrate and Taurursodiol in Alzheimer's Disease:Results From the PEGASUS Trial. Poster presented at: 15th Clinical Trials on Alzheimer's Disease CTAD, November
29-Dec2; California. AMX0035 met the primary endpoint of safety and tolerability in the PEGASUS trial of AMX0035 for the treatment of Alzheimer's disease. The 6-month trial was not powered to evaluate differences between groups in efficacy
outcomes and no differences were seen 15 in the primary efficacy outcome, a newly developed composite outcome of cognitive, functional, and imaging measures, or secondary efficacy outcomes of cognition, function, and imaging. CSF concentration,
pg/mL CSF concentration, pg/mL
AMX0035 Shown to Reduce Tau Protein in Proteomic Analysis Tau Protein
288 Of 288 proteins measured in CSF and plasma, Tau protein was the most significantly changed protein 1 by AMX0035 1. Data on File 16 The Proteomic analysis was a pre-specified, exploratory analysis in the PEGASUS trial of AMX0035 for the treatment
of Alzheimer's disease.
1,2 AMX0035 Slowed Disease Progression and Prolonged Survival in ALS
3-5 ALS and PSP Share Several Phenotypic Features and Shared Disease Mechanisms 3 Suggests that a Drug Effective for ALS May be Effective for PSP 3 4,5 Shared Disease Mechanisms Shared Phenotypic Features Unfolded protein response Swallowing
difficulty Mitochondrial dysfunction Respiratory dysfunction Neuroinflammation Speech disturbance Protein misfolding and aggregation Impaired cognition 1. Paganoni S, et al. N Engl J Med. 2020;383(10):919-930. 2. RELYVRIO. Prescribing information.
Amylyx Pharmaceuticals, Inc.; 2022. 3. Wilson DM 3rd, et al. Cell. 2023 Feb 16;186(4):693-714. 4. Viscidi E, et al. Front Neurol. 2021;12:571800. 5. Brown RH, Al- 17 Chalabi A. N Engl J Med. 2017;377(2):162-172.
Key Takeaways PSP is a tauopathy associated with tau
dysfunction, tau aggregation and widespread neurodegeneration. Multiple pathways, are implicated in tau pathology in PSP. AMX0035 is proposed to mitigate tau pathology in PSP through multiple pathways. Pre-clinical and
clinical evidence supports that AMX0035 can reduce tau pathology. 18
ORION Phase 3 PSP Trial Design Dr. Lahar Mehta Head, Global Clinical
Development, Amylyx 19