Rhythm Pharmaceuticals, Inc. · NASDAQ:RYTM
Rhythm Pharmaceuticals — Investor Presentation (April 2022)
59 slides from Rhythm Pharmaceuticals's investor presentation, Apr 6, 2022
Slide 1: Rhythm Pharmaceuticals
© Rhythm® Pharmaceuticals, Inc. All rights reserved. ® April 2022 Rhythm Pharmaceuticals Targeting MC4R pathway and transforming the care of patients with rare genetic diseases of obesity
Slide 2: Forward Looking Statements
® 2 This presentation contains certain forward - looking statements within the meaning of the Private Securities Litigation Reform Act of 1995, and that involve risks and uncertainties, including without limitation statements regarding the potential, safety, efficacy, and regulatory and clinical pro
Slide 3: Transforming Care of Patients with Rare Genetic Diseases of Obesity
® 3 Transforming Care of Patients with Rare Genetic Diseases of Obesity Commercial availability in U.S. meeting expectations and market access advancing in key international markets Poised to deliver on Bardet - Biedl in the near - term: PDUFA June 16, 2022 Clinical development meaningfully expands
Slide 4: Early-onset, Hyperphagia and Severe Obesity Have Significant Impact on BBS Patients
® 4 Early - onset, Hyperphagia and Severe Obesity Have a Significant Impact on Patients with Bardet - Biedl Syndrome and their Families “My weight is my biggest challenge, and it affects every aspect of my daily activities. When I’m hungry, I can’t stop it because I don’t have the signal from my sto
Slide 5: MC4R Pathway Biology is Clear and Strong
® 5 MC4R Pathway Biology is Clear and Strong: Regulates Hunger, Caloric Intake, Energy Expenditure and, Consequently, Body Weight DOWNSTREAM ACTIVATION MC4R - EXPRESSING NEURON Appetite Weight Energy expenditure POMC NEURON UPSTREAM LEPR Leptin Satiety Signals (e.g. Leptin) MSH MC4R POMC SRC1 SH2B1
Slide 6: Executing on Gene-by-gene Strategy to Expand Reach of Setmelanotide
® 6 Executing on Gene - by - gene Strategy to Expand Reach of Setmelanotide BBS ( all ) ALMS1 U.S. and EU Regulatory Submissions Filed Setmelanotide lifecycle advancements Pediatric patients (2 - 6 years old) and weekly formulation Genes in Clinical Development DAYBREAK Phase 2 10 additional genes r
Slide 7: Clinical Development Programs Designed to Expand the Setmelanotide Opportunity
® 7 Phase 3 EMANATE Trial € 2,000 – 3,000 ** 600 – 2,500 ** Clinical Development Programs Designed to Expand the Setmelanotide Opportunity * 1.7% of the US population (328M; 2019 US census) presents with severe early onset obesity (Hales et al 2018Ɨ); ~95% of individuals with severe early onset obes
Slide 8: Bardet-Biedl Community is Established and Patients are Identified
® 8 Bardet - Biedl Community is Established and Patients are Identified U.S. prevalence estimated to be 1,500 to 2,500 patients More than 600 individuals living with BBS are enrolled in CRIBBS registry Estimated European prevalence estimated to be ~2,500 patients More than 1,500 individuals identifi
Slide 9: Sequenced Individuals with Severe Obesity Carry Variants in MC4R Pathway Genes
® 9 URO: >20%Sequenced Individuals with Severe Obesity Carry Variants in MC4R Pathway Genes Targeted for EMANATE, DAYBREAK or BBS * Represents a weighted yield from 8,599 URO samples collected as of July 12, 2021. Prior to May 2021, Rhythm’s URO panel test ed for variants in 40 obesity - related gen
Slide 10: Synergistic Strategy Drives Patient Identification for Trials and Commercialization
® 10 Synergistic Strategy Drives Patient Identification for Clinical Trials and Commercialization • Disease state education and awareness • Field teams • HCP education programs • Digital outreach efforts • Uncovering Rare Obesity • Genetic counseling services Genetic Sequencing Community Building 3
Slide 11: Rhythm Leadership – Strong Team with Broad Biopharma Experience
® 11 David Meeker, MD Chair, President and Chief Executive Officer Hunter Smith Chief Financial Officer Linda Shapiro Manning, MD, PhD Chief Medical Officer Jennifer Chien Executive Vice President, Head of North America Yann Mazabraud Executive Vice President, Head of International Joe Shulman Senio
Slide 12: IMCIVREE (setmelanotide)
® 12 IMCIVREE® (setmelanotide) Commercial availability in U.S. meeting expectations and market access advancing in key international markets
Slide 13: U.S. and EU Approvals of IMCIVREE Based on Phase 3 Data
® 13 Mean % Change in Body Weight Visit BL V2 V3 V4 V5 V6 V7 V8 V9 V10 V11 V12 FV 0% – 5% – 10% – 15% – 20% – 25% Mean % Change in Body Weight BL V2 V3 V4 V5 V6 V7 V8 V9 V10 V12 FV 0% – 2% – 4% – 6% – 8% – 12% – 10% U.S. and EU Approvals of IMCIVREE Based on Phase 3 Data from Largest Studies Conduct
Slide 14: IMCIVREE Launch
® 14 First three quarters of IMCIVREE commercial availability: • $3.2M revenue in 2021 • Positive coverage decisions, reimbursement and access • Continued focus on HCP engagement • Patient Services and Corporate Accounts teams in place and making a difference IMCIVREE Launch 38 year old : W ent from
Slide 15: International Market Access: First Commercial Sales Expected in Germany and France
® 15 International Market Access: First Commercial Sales Expected in Germany and France in Second Quarter 2022 Germany • Commercial launch anticipated in Q2 2022 • IMCIVREE exempted by Federal Joint Committee (G - BA) from Annex II (Lifestyle products) France • Paid early access granted by Haute Aut
Slide 16: Bardet-Biedl and Alström Syndromes
® 16 Bardet - Biedl and Alström Syndromes Poised to deliver on Bardet - Biedl in the near - term
Slide 17: Bardet-Biedl and Alström Syndromes Associated with Severe Obesity and Hunger
® 17 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
Slide 18: Hyperphagia's Severe Impact on Lives of Patients with BBS and Caregivers
® 18 Hyperphagia’s Severe Impact on Lives of Patients with BBS and their Caregivers Excerpted from in - depth qualitative interviews with patients with BBS and/or their caregivers who were participating in an open - label extension study of setmelanotide. I was eating pretty much whatever, whenever
Slide 19: Vast Majority of BBS Patients Had Clinically Meaningful Response at One Year
® 19 Vast Majority of BBS Patients * had Clinically Meaningful Response to Setmelanotide at One Year on Therapy in Pivotal Study *A total of 28 patients were older than 12 years old and included in the primary analysts set, 15 adults and 13 patients betw een the ages of 12 and 18; ** One patient was
Slide 20: Setmelanotide Led to Significant BMI Reduction in BBS Versus Placebo at Week 14
® 20 Phase 3 Trial: Setmelanotide Led to Significant BMI Reduction in Patients with BBS Versus Placebo at Week 14 As presented at ESPE 2021 – 59th Annual European Society for Paediatric Endocrinology Meeting, September 2021. Difference: - 3.8% P <0.05 Patients with BBS treated with setmelanotide ach
Slide 21: Clinically Meaningful Reduction in Hunger in Adults and Children with BBS
® 21 Phase 3 Trial: Setmelanotide Achieved Clinically Meaningful Reduction in Hunger in Adults and Children with BBS at Week 52 Daily most hunger score weekly average percent change from placebo - controlled period baseline by week among participants without cognitive impairment who were 12 years ol
Slide 22: U.S. and EU Regulatory Submissions for BBS and Alström Syndrome
® 22 CHMP recommendation on Type II Variation Application anticipated in June 2022** U.S. and EU Regulatory Submissions for BBS and Alström Syndrome Recently Completed sNDA Accepted by U.S. FDA; Assigned PDUFA target date of June 16, 2022 Pivotal Phase 3 trial met all primary and key secondary endpo
Slide 23: Rhythm Continues to Advance to BBS Commercial Launch
® 23 Rhythm Continues to Advance to BBS Commercial Launch Rhythm is ready to launch in BBS • Commercial foundation established • Experienced commercial team in place • >350 patients already identified Solution • Address root cause • Hunger reduction • Weight loss • Established safety profile Unmet n
Slide 24: Roadmap to Identifying Patients with BBS
® 24 Roadmap to Identifying Patients with BBS Identified and diagnosed Diagnosed patients Suspected Undiagnosed U.S. prevalence estimated to be 1,500 to 2,500 patients* >350 Identified and diagnosed patients * Company estimate based on published prevalence estimates of one in 100,000 in North Americ
Slide 25: Clinical Development
® 25 Clinical Development Meaningful Expansion of Addressable Patient Population
Slide 26: Clinical Programs Designed to Achieve Label Expansion on Track
® 26 Clinical Programs Designed to Achieve Label Expansion on Track Denotes study complete, Denotes study underway; Denotes planned study Patient Population Phase 2 Phase 3 Market Authorization Approved POMC, PCSK1 or LEPR deficiency x x x US, EU, Great Britain Setmelanotide daily formulation Bardet
Slide 27: EMANATE and DAYBREAK Studies to Drive Significant Expansion of Addressable Market
® 27 Phase 3 EMANATE Trial € EMANATE and DAYBREAK Studies to Drive Significant Expansion of Setmelanotide’s Potential Addressable Market *† Estimated U.S. patients based on population* with early - onset, severe obesity who may benefit from setmelanotide based on seq uencing results, current estimat
Slide 28: Proof of Concept in HETs, SRC1 and SH2B1 Established in Phase 2 Basket Study
® 28 Proof of Concept in HETs, SRC1 and SH2B1 Established in Exploratory Phase 2 Basket Study with Clinically - meaningful Weight Loss at Month 3 34.3% of patients (12/35) achieved the primary endpoint of ≥5% weight loss from baseline at Month 3 Responses to setmelanotide were maintained through 6 a
Slide 29: Phase 3 EMANATE Trial Across Four Genetic Subtypes
® 29 Phase 3 EMANATE 3 Trial to Evaluate Setmelanotide Across Four Genetic Subtypes Four independent sub - studies : allows for independent data readouts and potential registrations Targeted patient populations: Patients with pathogenic, likely pathogenic or suspected pathogenic variants • ~ 5.1% pa
Slide 30: ACMG Variant Classification Can Inform MC4R Pathway Deficit
® 30 ACMG Variant Classification Can Inform MC4R Pathway Deficit and Potentially Setmelanotide Response Pathogenic Likely pathogenic VUS Likely benign Benign Number of variants Pathway impact science *ACMG Guidelines Richards et al, 2015 Variants of Uncertain Significance • Largest category of rare
Slide 31: Rhythm's Approach to VUS Functional Assessment
® 31 Rhythm’s Approach to VUS Functional Assessment “Low” “Mid” “High” Suspected Pathogenic Benign Likely Benign Likely pathogenic Pathogenic Uncertain Significance Increasing potential for setmelanotide response Molecular, genetic and clinical characterization of VUS variants to elucidate pathogeni
Slide 32: Phase 2 Daybreak Trial to Evaluate Setmelanotide Across 10 New Genes
® 32 Relevance to MC4R Pathway : Rhythm’s ClinGen - based framework suggests all 10 genes have very strong relevance to MC4R Pathway Efficient, two - stage trial design • 16 - week, open - label run - in in allows for fast signal - seeking in individual gene cohorts • 24 - week, double - blind treat
Slide 33: Daybreak Trial Evaluating Setmelanotide in 10 Genes
® 33 Phase 2 Daybreak Trial is Evaluating Setmelanotide in 10 Genes with Strongest Association with Severe Obesity and MC4R Pathway * The remaining 11 SEMA3 pathway genes are also listed in DAYBREAK trial protocol but are currently paused for enrollment (to get her 9 other MC4R pathway genes). Initi
Slide 34: Improved URO with Expanded Gene Panel
® 34 Improved URO with Expanded Gene Panel Launched in July 2021 URO Utilization as of Dec. 31, 2021 >2,700 U.S. health care providers with pediatric endocrinologists and pediatricians accounting for >50% >13,000 sequence samples completed ~20% 6 years old and younger ~80% 7 years old and older * As
Slide 35: Parallel Operations to Support both EMANATE and DAYBREAK
® 35 Site initiations underway • Approximately 65 trial sites in 14 countries in North America, Europe and the Middle East • Trial sites to service both EMANATE and DAYBREAK • Area Development Managers in the field building referral network Parallel Operations to Support both EMANATE and DAYBREAK Re
Slide 36: Setmelanotide Generally Well-tolerated Across Development Program
® 36 Setmelanotide has been evaluated in 639 patients with obesity, with some individual patient treatment durations now exceeding five years Setmelanotide has been generally well - tolerated Most AEs are mild: • Mild injection site reactions • Hyperpigmentation and skin lesions, mediated by the clo
Slide 37: Continued Transformational Progress Expected in 2022
® 37 Continued Transformational Progress Expected in 2022 1H 2022 ض Initiate Phase 2 DAYBREAK trial ض Initiate Phase 3 “switch study” of weekly formulation ض Initiate Phase 3 trial in pediatric patients aged 2 - 6 years old Initiate Phase 3 EMANATE trial PDUFA target date for BBS and Alström syndrom
Slide 38: Financial Snapshot: Cash Sufficient to Fund Operations into 4Q 2023
® 38 Financial Snapshot: Cash Sufficient to Fund Planned Operations into 4Q 2023 $294.9 Million * Cash, cash equivalents and short - term investments as of 12/31/2021 Guidance ** cash expected to be sufficient to fund operations into 4Q 2023 50.2 Million € Common shares outstanding As disclosed on F
Slide 39: Appendix
® 39 Appendix
Slide 40: Exclusive Licensing Agreement with RareStone Expected to Expand Reach into Asia
® 40 In December 2021, RareStone was granted an exclusive license to develop and commercialize IMCIVREE in China, including mainland China, Hong Kong and Macau RareStone agreed to: • Seek local approvals to commercialize IMCIVREE for the treatment of obesity and hyperphagia due to POMC, PCSK1 and LE
Slide 41: Results from Exploratory Phase 2 Basket Trial
® 41 Results from Exploratory Phase 2 Basket Trial
Slide 42: Phase 2 Basket Study Evaluated Response at Three Months of Therapy
® 42 Phase 2 Basket Study Evaluated Response at Three Months of Therapy Adult starting dose 2 mg Adolescent starting dose 1 mg Adult therapeutic dose 3 mg Adolescent dose titration to 2 mg Open - label dose - titration 4 weeks Final visit or bridge to extension study Screening 2 - 8 weeks 10 weeks O
Slide 43: Clinical Characteristics of Patients Enrolled in Phase 2 Basket Study
® 43 Clinical Characteristics of Patients Enrolled in Exploratory Phase 2 Basket Study N= 35 39 years old (15 - 68) 316 lbs/ 143 kgs 50 kg/m 2 HETs deficiency obesity Heterozygous POMC, PCSK1 or LEPR N= 30 a 31 years old (9 - 66) 270 lbs/ 123 kgs 45.4 kg/m 2 HETs Heterozygous POMC, PCSK1 or LEPR SRC
Slide 44: Response Rate and Weight Loss at Month 3: POMC/PCSK1/LEPR Heterozygous
® 44 Phase 2 Basket Study: Response Rate and Weight Loss at Month 3 POMC/PCSK1/LEPR Heterozygous Deficiency Obesity 34.3% of patients (12/35) achieved the primary endpoint of ≥5% weight loss from baseline at Month 3* Baseline Month 3 Percent change from baseline Mean (SD) body weight: Responders (n=
Slide 45: Long-term Extension Study: Responses Maintained Through 6 and 9 Months
® 45 Long - term Extension Study: Responses to Setmelanotide Were Maintained Through 6 and 9 Months in POMC/PCSK1/LEPR Heterozygous Deficiency Obesity -16 -12 -8 -4 0 0 3 6 9 Mean weight change, % Months A responder was defined as having ≥5% weight loss from baseline at Month 3. Data as of December
Slide 46: Approximately One-Third of Patients Respond to Setmelanotide: SRC1
® 46 Phase 2 Basket Study: Approximately One - Third of Patients Respond to Setmelanotide Treatment at Month 3 SRC1 Deficiency Obesity 30% of patients (9/30) achieved the threshold of ≥5% weight loss or ≥0.15 reduction in BMI Z score from baseline at Month 3 Full analysis set reported. In the Comple
Slide 47: Setmelanotide Decreases Body Weight in Adults: SRC1 Deficiency Obesity
® 47 -12 -10 -8 -6 -4 -2 0 2 Responders (n=6) Non-responders (n=14) Responders (n=6) Nonresponders (n=14) Mean weight change, % −7.9 (90% CI, −9.7 to −6.0) −2.3 (90% CI, −3.2 to −1.4) Full analysis set reported. In the Completers’ set, mean percent weight change for responders was −8.7% (90% CI, −11
Slide 48: Setmelanotide Decreases BMI Z Score in Children and Adolescents: SRC1
® 48 Full analysis set reported. In the completers’ set, mean BMI Z score change for responders was −0.48 (90% CI, −0.95 to −0.01; n= 3) and for nonresponders was −0.09 (90% CI, −0.11 to −0.07; n=6). A responder was defined as ≥5% weight loss in those ≥18 years old or ≥0.15 reduction in BMI Z score
Slide 49: More Than 40% of Patients Respond to Setmelanotide: SH2B1
® 49 42.9% of patients (15/35) have achieved the threshold of ≥5% weight loss or ≥0.15 reduction in BMI Z score from baseline at Month 3 Proportion of patients Responders ≥5% weight loss in those ≥18 years old, n/N (%) 8/22 (36.4) ≥0.15 reduction in BMI Z score in those <18 years old, n/N (%) 7/13 (
Slide 50: Setmelanotide Decreases Body Weight in Adults: SH2B1 Deficiency Obesity
® 50 -12 -10 -8 -6 -4 -2 0 2 4 Responders (n=8) Non-responders (n=14) −7.2 (90% CI, −8.6 to −5.8) −0.8 (90% CI, −1.9 to 0.3) Mean weight change, % Responders (n=8) Nonresponders (n=14) Phase 2 Basket Study: Setmelanotide Decreases Body Weight in Adults with Clear Separation between Responders and No
Slide 51: Additional Supporting Slides
® 51 Additional Supporting Slides
Slide 52: Phase 3 Trial in Pediatric Patients Ages 2 to 6 Years Old
® 52 International one - year, open - label study Enrollment: 10 patients • 5 with biallelic POMC, PCSK1 or LEPR deficiency • 5 with BBS Primary endpoint: Responder analysis based on proportion of patients who experience a decrease in BMI - Z of ≥0.2 Secondary endpoints : S afety and tolerability Ph
Slide 53: Phase 3 Weekly Formulation Switch and De Novo Studies
® 53 Phase 3 randomized, double - blind “switch study” initiated in 4Q 2021 • Enrollment: 30 patients with BBS or biallelic or heterozygous POMC, PCSK1 or LEPR deficiency who have who have been on open - label QD setmelanotide treatment for at least 6 months • Randomized 1:1 for 13 weeks of double -
Slide 54: Phase 3 EMANATE Trial Comprised of Four Independent Sub-studies
® 54 Design allows for independent data readouts, success in each sub - study and registration for each gene First patient: 1H 2022 Each sub - study : • Placebo - controlled: Patients randomized 1:1 (therapy vs. placebo) • Enrollment: 12 - 18 months • Treatment period is 52 weeks Endpoints • Primary
Slide 55: EMANATE Primary Endpoint: Difference in Mean Percent Change in BMI at 52 Weeks
® 55 Heterozygous POMC/PCSK1 and LEPR sub - studies are 90% powered to show >8% treatment effect vs. placebo SRC1 and SH2B1 sub - studies are 90% powered to show >7% treatment effect vs. placebo Assumption to achieve mean treatment effect v placebo: • The placebo group is not expected to lose weight
Slide 56: EMANATE Secondary Endpoints to Illustrate Effect on Weight and Hunger
® 56 EMANATE Secondary Endpoints to Illustrate Effect on Weight and Hunger Secondary endpoints • Proportion of patients who achieve at least 5% reduction in BMI at 52 weeks compared to placebo • Proportion of patients who achieve at least 10% reduction in BMI at 52 weeks compared to placebo • Differ
Slide 57: Phase 2 DAYBREAK Trial Design in 10 Genes
® 57 Phase 2 DAYBREAK Trial Designed to Evaluate Setmelanotide Therapy in 10 Genes with Strong or Very Strong Relevance to MC4R Pathway ≥12 years starting dose 2 mg 6 to <12 years starting dose 1 mg 6 to <12 years dose titration to 2 mg Open - label dose titration 2 weeks Screening 2 - 8 weeks 10 we
Slide 58: DAYBREAK Phase 2 Trial Design and Endpoints
® 58 Primary endpoint is the proportion of patients by gene who enter Stage 2 and are responders compared to placebo • Responders > 18 years who achieve 10% or greater body weight reduction from baseline • Responders <18 years who achieve BMI reduction of > 0.3 from baseline Secondary endpoints by g
Slide 59: Setmelanotide Improved Health-related Quality of Life in Patients with BBS
® 59 Phase 3 Trial Setmelanotide Achieved Clinically Meaningful Improvements in Health - related Quality of Life (HRQOL) in Patients with BBS 85% of patients reported clinically meaningful improvements or preserved non - impaired health related quality of life status Adults ( > 18 years old) Childre
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