Rhythm Pharmaceuticals, Inc. · NASDAQ:RYTM
Rhythm Pharmaceuticals — Investor Presentation (January 2020)
51 slides from Rhythm Pharmaceuticals's investor presentation, Jan 10, 2020
Slide 1: Rhythm Pharmaceuticals: Targeting MC4R pathway
© Rhythm Pharmaceuticals, Inc. All rights reserved. © Rhythm Pharmaceuticals, Inc. All rights reserved. January 2020 Rhythm Pharmaceuticals Targeting MC4R pathway and transforming the care of patients with rare genetic disorders of obesity
Slide 2: Forward Looking Statements
2 This presentation contains certain statements that are forward - looking within the meaning of Section 27A of the Securities Act of 1933, as amended, and Section 21E of the Securities Exchange Act of 1934, as amended, and that involve risks and uncertainties, including statements regarding Rhythm'
Slide 3: Meet Katy: Living with HET Obesity
3 Meet Katy: Living with HET Obesity “It causes extreme unrelenting hunger and excessive eating. As a child…the fridge and food was controlled massively…but nobody could understand that I was desperately hungry and just wanted to stop that feeling.” Genetic Disorders of Obesity Impact Every Aspect o
Slide 4: Rhythm's Focus in 2020 is Expanding the Opportunity for Setmelanotide
4 Rhythm’s Focus in 2020 is Expanding the Opportunity for Setmelanotide in Rare Genetic Disorders of Obesity 1 Secure FDA approval for POMC or LEPR deficiency obesities 4 Drive disease understanding through genetic sequencing and community building 2 Deliver on the potential of setmelanotide to pati
Slide 5: Setmelanotide has Potential to Address Multiple MC4R Pathway Disorders
5 Setmelanotide has Potential to Address Multiple MC4R Pathway Disorders Activation MC4R expressing neuron MSH Appetite Energy expenditure Weight Genetic targets added to Phase 2 Basket study Sept, 2019 Setmelanotide BBSx Other potentially relevant gene targets Genetic targets in Phase 3 Alström syn
Slide 6: MC4R Pathway Disorders: Genetic or Syndromic Diagnosis
6 MC4R Pathway Disorders: Genetic or Syndromic Diagnosis *Based on company estimates; Images are for illustrative purposes only and not intended to imply or suggest actual prevalence es timates or patient identification yields. ** Estimated prevalence of U.S. patients with addressable variants of th
Slide 7: POMC and LEPR Deficiency Obesities
7 POMC and LEPR Deficiency Obesities Secure FDA approval for POMC or LEPR deficiency obesities
Slide 8: Setmelanotide Met all Primary and Key Secondary Endpoints in Phase 3 Trials
8 Demonstrated statistically significant and clinically meaningful reductions of weight and hunger Setmelanotide Met all Primary and Key Secondary Endpoints in Phase 3 Trials for POMC and LEPR POMC Phase 3 Topline* 80% p<0.0001 - 25.4% p<0.0001 - 27.8% p=0.0005 31.9kg 70.2lbs >10% weight loss mean w
Slide 9: Bardet-Biedl & Alström Syndromes
9 Bardet - Biedl & Alström Syndromes Deliver on the potential of setmelanotide to patients with Bardet - Biedl and Alström syndromes and advance disease understanding ahead of pivotal Phase 3 data
Slide 10: Strong Phase 2 Data in BBS Shows Substantial Weight Loss and Hunger Control
10 Strong Phase 2 Data in BBS Shows Substantial Weight Loss and Hunger Control at ~Two Years, Supporting Advancement into Phase 3 *Pt. has cognitive impairment, so Food Problem Diary (FPD) score maintained by caregiver; **Pt. did not have baseline hunger mea sure. The first score was a 7, which was
Slide 11: BBS & Alström Phase 3 Trial: Enrollment in Pivotal Cohort Complete
11 Bardet Biedl & Alström Syndromes Phase 3 Trial: Enrollment in Pivotal Cohort Complete Setmelanotide 3 mg Placebo Double - blind treatment period 14 weeks Long - term e xtension Screening and 1:1 randomization Setmelanotide 3 mg Open - label treatment Primary Endpoint : Proportion of patients (>12
Slide 12: Partnering with the Patient Community to Build Awareness
12 Ongoing relationships with patient advocacy groups to drive awareness, disease understanding and build support for regulatory pathway • Bardet - Biedl Syndrome Foundation • BBS Family Foundation • BBS UK • Alström Syndrome UK • Alström Syndrome International (ASI) Existing patient cohorts allow f
Slide 13: Engaging with Physicians to Advance Disease Understanding
13 Engaging with Physicians to Advance Disease Understanding for BBS and Alström Syndrome *Assessment of numbers of patients relies on HCP recall, which may result in over or under reporting Rhythm field medical teams have engaged with more than 275 physicians in the U.S. and EU who are involved in
Slide 14: Rhythm Engine & Basket Study
14 Rhythm Engine & Basket Study Establish proof - of - concept in new indications
Slide 15: Rhythm Engine is the Foundation of Future Growth
15 Rhythm Engine is the Foundation of Future Growth through Patient Finding and Clinical Development TRACING THE EFFECT OF THE MC4R PATHWAY IN OBESITY UNCOVERING RARE OBESITY Sponsored genetic testing program Biobanks 101 - gene panel Phase 2 Basket Study Six indications
Slide 16: Rare genetic disorders of obesity affect upwards of 85,000 people in the U.S.
16 Rhythm is initially studying 10 rare genetic disorders of obesity, estimated to affect upwards of 85,000 people in the United States Approximately 5.7M People in the U.S. Have Severe, Early - onset Obesity Rhythm has sequenced 13,567 ** individuals with severe obesity * These calculations assume
Slide 17: Rhythm's Approach Enables Deep Understanding of Rare Genetic Disorders of Obesity
17 Rhythm’s Approach Enables Deep Understanding of Rare Genetic Disorders of Obesity and Optimizes Registration/Commercial Strategy Rhythm’s Sequencing Database Optimized strategy for clinical development, registration and commercialization Translational research informs classification of genetic va
Slide 18: Sequencing Yield Points to Significant Opportunity
18 Sequencing Yield for Genetically - identified Indications Points to Significant Opportunity Individuals with severe obesity sequenced 13,567 * MC4R n = 269; 2.0% SH2B1 n = 245; 1.8% SRC1 n = 335; 2.5% Yield for genetically - identified indications ** : High - impact HETs n = 97; 0.7% * As of June
Slide 19: Translating Rhythm Sequencing Data to U.S. Prevalence Estimates
19 Translating Rhythm Sequencing Data to U.S. Prevalence Estimates * PolyPhen : Adzhubei IA, et al. Nat Methods 7(4):248 - 249 (2010); SIFT : Vaser R, et al. Nat Protocol 4:1073 - 1081 (2009); Mutation Taster : Schwarz J.M., et al. Nat. Methods 11(4):361 - 362 (2014) Functional and computational fil
Slide 20: Stratifying Patients Based on Loss of Function Variant
20 Stratifying Patients Based on Loss of Function (LOF) Variant – HET Example * Calculated based on the following assumptions: US pop 327 million; 1.7% has early onset, severe obesity; High impact HET al lel e frequency based on Rhythm genetic sequencing (Feb 2019) U.S. prevalence approximately 1 mi
Slide 21: Basket Study Key to Proof of Concept
21 • Improve understanding of interplay of genetic variation and MC4R pathway function • Aim for seamless integration with sequencing efforts • Rapid proof - of - concept in new indications • Delivers pivotal indications into phase 3 trials Basket Study Key to Proof of Concept, Advancing Indications
Slide 22: Phase 2 Basket Study Indications Have Significant Patient Populations
22 Phase 2 Basket Study Indications Have Significant Patient Populations Smith - Magenis syndrome ~2,400 * MC4R deficiency obesity ~10,000 * POMC and LEPR heterozygous deficiency obesities >20,000 * SRC1 deficiency obesity >23,000 * SH2B1 deficiency obesity >24,000 * * Company estimates calculated b
Slide 23: Setmelanotide Generally Well-tolerated Across Development Program
23 Setmelanotide has been evaluated in more than 400 patients with obesity, with individual patient treatment duration now exceeding four years Setmelanotide has been generally well - tolerated Most AEs are mild: • Mild injection site reactions • Darkening of skin (tanning) and skin lesions, mediate
Slide 24: Setmelanotide Once-weekly Subcutaneous Injection in Development
24 • Setmelanotide delivered through gel - like depot with slow diffusion o Mean pharmacokinetic half - life of 123 hours o Formulation intended to be more patient - friendly • Currently being evaluated in more than 70 healthy obese volunteers o Trial includes daily cohort receiving doses higher tha
Slide 25: RM-853: Oral GOAT Inhibitor for Prader-Willi Syndrome
25 RM - 853: Potent, Orally Available GOAT Inhibitor for Prader - Willi Syndrome (PWS) • Ghrelin O - Acyltransferase (GOAT) is key enzyme involved in producing active ghrelin • Blocking GOAT results in: o L ower levels of active ghrelin, and o Increased levels of des - acyl - ghrelin ( DAG ), a ghre
Slide 26: Rhythm Achieved Key Milestones in 2019
26 x Announced positive topline data from POMC and LEPR pivotal Phase 3 trials: met all primary and key secondary endpoints x Announced positive updated data from Phase 2 Basket Study in BBS and Alström syndrome x Completed pivotal enrollment in BBS and Alström syndrome Phase 3 study x Announced pro
Slide 27: Rhythm Expects Transformational Progress in 2020
27 Rhythm Expects Transformational Progress in 2020 1 First potential approval for setmelanotide in POMC or LEPR deficiency obesities 1Q: NDA submission 2Q: MAA submission 2 Bardet - Biedl and Alström syndromes Phase 3 4Q or 1Q21 : Topline data from Phase 3 trial 3 New indications 2020: Proof - of -
Slide 28: U.S. Prevalence Estimates Suggest >85,000 Patients
28 U.S. Prevalence Estimates Suggest >85,000 Patients with MC4R Pathway - driven Rare Genetic Disorders of Obesity Pivotal Indications = > 5,000 POMC deficiency obesity LEPR deficiency obesity Bardet - Biedl syndrome Alström syndrome New indications > 60,000 SRC1 deficiency obesity SH2B1 deficiency
Slide 29: Cash Expected to be Sufficient Through at Least End of 2021
29 Cash Expected to be Sufficient to Fund Operations Through at Least End of 2021 Raised $ 161.3 M in estimated net proceeds in October 2019 follow - on offering of 9.3 million shares of common stock SHARES OUTSTANDING as of 9/30/2019 34,578,564 (basic share count) CASH, CASH EQUIVALENTS AND SHORT -
Slide 30: Living with the Insatiable Hunger and Obesity that Characterize BBS
30 Living with the Insatiable Hunger and Obesity that Characterize BBS “As our daughter Lucy grows older, the weight obstacle of BBS looms more ominously before us, hindering much of what we do. Lucy measures most of her activities and much of her happiness around when her next meal is, what food is
Slide 31: Appendix
31 Appendix
Slide 32: Strong Leadership Team with Broad Biopharma Experience
32 Keith M. Gottesdiener, MD Chief Executive Officer Hunter Smith Chief Financial Officer Nithya Desikan Chief Commercial Officer Murray Stewart, MD Chief Medical Officer Simon D. Kelner Chief Human Resources Officer 10 - plus marketed products and NDAs 200 - plus INDs Financial leadership for Otezl
Slide 33: Setmelanotide: Investigational MC4R agonist
33 Setmelanotide: Investigational MC4R agonist FDA Breakthrough Therapy Designation ▪ POMC deficiency obesity ▪ LEPR deficiency obesity ▪ Bardet - Biedl syndrome ▪ Alström syndrome FDA Orphan Drug Designation ▪ POMC deficiency obesity ▪ LEPR deficiency obesity ▪ Bardet - Biedl syndrome Setmelanotide
Slide 34: Rhythm Pipeline Focused on MC4R Pathway Disorders
34 * Rhythm is currently assessing setmelanotide in additional disorders, including POMC epigenetic disorders and LEP and CPE de fic iency obesity, as part of investigator - initiated protocols within the basket study. Given the recent discovery of these rare disorders of the MC4R pathway, there is
Slide 35: Primary and Key Secondary Endpoints
35 Primary endpoint Three key secondary endpoints (after ~52 weeks of treatment) Proportion of patients (≥12 years old) who achieve ≥10% reduction in body weight after ~52 weeks of treatment Proportion of patients (≥12 years old ) who achieve a ≥25% improvement in daily hunger score Body weight perc
Slide 36: POMC and LEPR Phase 3 Trials Achieve Statistically Significant Results
36 POMC and LEPR Phase 3 Trials Achieve Statistically Significant and Clinically Meaningful Results in Reductions of Weight and Hunger Endpoint Result Proportion of Participants Achieving at Least 10% Change in Body Weight 80% p<0.0001 Mean Percent Change from Baseline in Body Weight* - 25.4 % p<0.0
Slide 37: Taking a Closer Look at POMC
37 ▪ 8 of the 10 POMC participants achieved the primary endpoint threshold of 10% weight loss vs. baseline ▪ These individuals achieved between 25.8% – 35.6% weight loss ▪ Of the participants who did not meet the primary endpoint: ▪ One participant had confounding comorbidities making their response
Slide 38: POMC Phase 3 Trial: Change in Weight and Hunger Over Year
38 POMC Phase 3 Trial – Change in Weight and Hunger Over 1 Year with Substantial Weight Gain and Hunger Increase During Placebo Withdrawal 0 - 10 - 30 - 40 BL V2 V3 V4 V5 V6 V7 V8 V9 V10 V11 V12 - 20 0 10 20 30 40 50 60 10 9 8 7 6 5 4 3 2 1 0 Daily Hunger Score (Most in 24 hours) During Placebo Peri
Slide 39: Taking a Closer Look at LEPR
39 ▪ 5 of the 11 LEPR participants achieved the primary endpoint threshold of 10% weight loss vs. baseline ▪ These individuals achieved between 15.2% - 23.3% weight loss ▪ Of the participants who did not meet the primary endpoint: ▪ Three participants showed initial meaningful responses but after th
Slide 40: LEPR Phase 3 Trial: Change in Weight and Hunger Over 1 Year
40 Change in Weight (kg) 0 Final Visit V12 V11 V10 V9 V8 V7 V6 V5 V4 V3 V2 BL - 5 - 15 - 10 - 20 - 25 Week 0 Week 10 Week 20 Week 30 Week 50 Week 60 0 - 2 - 4 - 6 Daily Hunger Score - (Most in 24 hours) Week 40 LEPR Phase 3 Trial – Change in Weight and Hunger Over 1 Year with Substantial Weight Gain
Slide 41: POMC and LEPR Participant Demographics
41 POMC and LEPR Participant Demographics – Phase 3 Trials POMC Deficiency Obesity Age at Trial Enrollment (years) Mean (range) 18.4 (11 - 30) <12 years old (n) 2 Gender, M,F 5, 5 Weight (kg) Mean 118.7 Range 55.9 - 186.7 BMI (kg/m 2 ) Mean 40.4 Range 26.6 - 53.3 Most Hunger (≥12 years old) Most hun
Slide 42: Updated Phase 2 Data in Alström Syndrome
42 Updated Phase 2 Data in Alström Syndrome * Age at enroll ment/ Sex Baseline Weight (kg) Treatment, weeks % Weight Change from Baseline % Hunger Score Change from Baseline † 12/M 78.6 95 - 20% - 25% 15/F 70.7 84 1% - 38% 16/F 91.6 68 - 6% 0% • Patient 1 has reached healthy body weight • Patient 3
Slide 43: Phase 2 Data in HET Patients Based on LOF Variant
43 High - Impact LOF Group: ▪ All patients ongoing; fourth patient, still very early in dose titration, showing promising weight loss and hunger score decr eas es. Other Subgroups: ▪ Five patients ongoing 1 ▪ Four patients discontinued treatment: ▪ One patient due to lack of efficacy at 14 weeks 3 .
Slide 44: New MC4R Pathway Indications Based on Supported Scientific Rationale
44 New MC4R Pathway Indications Based on Supported Scientific Rationale DOWNSTREAM ACTIVATION MC4R - EXPRESSING NEURON Appetite Weight Energy expenditure POMC NEURON UPSTREAM LEPR Leptin Satiety Signals (Leptin) MSH MC4R POMC SRC1 SH2B1 RAI1 PCSK1
Slide 45: SRC1 is a Transcriptional Coactivator that Drives POMC Expression
45 SRC1 is a Transcriptional Coactivator that Drives POMC Expression Pathway Relevance: Drives POMC Expression • Transcriptional coactivator activated downstream of LEPR • Found in POMC neurons Autosomal Dominant • Obesity arises due to heterozygous gene variants Clinical Presentation • Early onset
Slide 46: SH2B1 is an Adapter Protein that Regulates LEPR Activity
46 SH2B1 is an Adapter Protein that Regulates LEPR Activity POMC NEURON Satiety Signals (Leptin) MSH MC4R POMC LEPR Leptin + PCSK1 Pathway Relevance: Regulates LEPR activity • Adapter protein • Found in POMC neurons Autosomal Dominant • Obesity arises due to heterozygous gene variants or chromosomal
Slide 47: MC4R: Receptor for POMC Ligand MSH
47 MC4R: Receptor for POMC Ligand MSH ACTIVATION MC4R - EXPRESSING NEURON Appetite Weight Energy expenditure MC4R Pathway Relevance: Receptor for POMC ligands • Required for satiety effects of α / β - MSH Autosomal Dominant • Obesity arises due to heterozygous gene variants Clinical Presentation • E
Slide 48: Smith-Magenis Syndrome: RAI1 Affects POMC Expression
48 Smith - Magenis Syndrome: RAI1 Affects POMC Expression RAI1 POMC NEURON Satiety Signals (Leptin) MSH MC4R POMC LEPR Leptin PCSK1 RAI1 Pathway Relevance: Decreased Pathway Function Upstream of MC4R • Causal gene is RAI1 • Transcription factor for a number of pathway genes Autosomal Dominant • Gene
Slide 49: POMC and LEPR Deficiency Obesities Characterized by Early-onset Obesity
49 POMC and LEPR Deficiency Obesities Characterized by Early - onset Obesity, Unrelenting Hunger Hyperphagia Early - onset, severe obesity Hypoglycemia Light, pale skin Hypocortisolism and ACTH deficiency POMC Deficiency Obesity Results from loss - of - function homozygous or biallelic variants in t
Slide 50: Bardet-Biedl and Alström Syndromes Associated with Severe Obesity
50 Bardet - Biedl and Alström Syndromes Associated with Severe Obesity and Hunger Hyperphagia Early - onset, severe obesity Polydactyly (extra finger or toe) Renal disease Bardet - Biedl syndrome 1 Rare ciliopathy disorder resulting from genetic variants within BBS family of genes Alström syndrome 2
Slide 51: Rhythm Pharmaceuticals
PHARMACEUTICALS
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