UNITED STATES
SECURITIES AND EXCHANGE COMMISSION
Washington, D.C. 20549
FORM 8-K
CURRENT REPORT
Pursuant to Section 13 or 15(d)
of the Securities Exchange Act of 1934
Date of Report (Date of earliest event reported): September 25, 2019
RHYTHM PHARMACEUTICALS, INC.
(Exact name of registrant as specified in its charter)
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Delaware |
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001-38223 |
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46-2159271 |
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(State or other jurisdiction |
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(Commission |
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(IRS Employer |
222 Berkeley Street
12th Floor
Boston, MA 02116
(Address of principal executive offices, including Zip Code)
Registrant’s telephone number, including area code: (857) 264-4280
Check the appropriate box below if the Form 8-K filing is intended to simultaneously satisfy the filing obligation of the registrant under any of the following provisions:
o Written communications pursuant to Rule 425 under the Securities Act (17 CFR 230.425)
o Soliciting material pursuant to Rule 14a-12 under the Exchange Act (17 CFR 240.14a-12)
o Pre-commencement communications pursuant to Rule 14d-2(b) under the Exchange Act (17 CFR 240.14d-2(b))
o Pre-commencement communications pursuant to Rule 13e-4(c) under the Exchange Act (17 CFR 240.13e-4(c))
Securities registered pursuant to Section 12(b) of the Act:
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Title of each class |
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Trading Symbol(s) |
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Name of each exchange on which |
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Common Stock, $0.001 par value per share |
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RYTM |
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The Nasdaq Stock Market LLC (Nasdaq Global Market) |
Indicate by check mark whether the registrant is an emerging growth company as defined in Rule 405 of the Securities Act of 1933 (§230.405 of this chapter) or Rule 12b-2 of the Securities Exchange Act of 1934 (§240.12b-2 of this chapter). Emerging growth company x
If an emerging growth company, indicate by check mark if the registrant has elected not to use the extended transition period for complying with any new or revised financial accounting standards provided pursuant to Section 13(a) of the Exchange Act. x
Item 7.01 Regulation FD Disclosure.
On September 25, 2019, Rhythm Pharmaceuticals, Inc. (the “Company”) issued the attached press release providing an update on its research and development efforts and providing updated data for its Phase 2 Basket trial. Further, the Company reviewed a slide presentation during a webcast on September 25, 2019. Copies of the press release and the presentation slides are furnished as Exhibits 99.1 and 99.2, respectively, to this Current Report on Form 8-K and a replay of the webcast will be available on the Company’s website at www.rhythmtx.com under “Investors & Media” for 30 days following the event. The Company undertakes no obligation to update, supplement or amend the materials attached hereto.
The information contained in this Item 7.01 and in the accompanying Exhibits 99.1 and 99.2 shall not be incorporated by reference into any filing of the Company, whether made before or after the date hereof, regardless of any general incorporation language in such filing, unless expressly incorporated by specific reference to such filing. The information in this Item 7.01 and the exhibits hereto shall not be deemed to be “filed” for purposes of Section 18 of the Securities Exchange Act of 1934, as amended, or otherwise subject to the liabilities of that section or Sections 11 and 12(a)(2) of the Securities Act of 1933, as amended.
Item 9.01 Financial Statements and Exhibits.
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Exhibit No. |
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Description |
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99.1 |
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99.2 |
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SIGNATURES
Pursuant to the requirements of the Securities Exchange Act of 1934, as amended, the registrant has duly caused this report to be signed on its behalf by the undersigned hereunto duly authorized.
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RHYTHM PHARMACEUTICALS, INC. | |
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Date: September 25, 2019 |
By: |
/s/ Hunter Smith |
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Hunter Smith |
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Chief Financial Officer |
Rhythm Pharmaceuticals Provides Update on Research and Development Programs
— Four new MC4R pathway obesity indications added to Phase 2 Basket Study and enrolling patients —
— Genetic sequencing of 13,567 individuals with severe obesity yields 11.7 percent (1,584 individuals) who have a rare genetic variant within MC4R pathway eligible for Phase 2 Basket Study —
— Sequencing results supports ultra-rarity of POMC and LEPR deficiency obesity —
— Sequencing results suggest U.S. prevalence estimates for four new indications of greater than 60,000 —
— Updated data from continuing patients with Bardet-Biedl syndrome in Phase 2 Basket trial demonstrate 22.2 percent mean weight loss following approximately two years on therapy —
— Rhythm R&D event in New York City; Live webcast begins at 8:15 a.m. today —
Boston, MA — September 25, 2019 — Rhythm Pharmaceuticals, Inc. (Nasdaq:RYTM), a biopharmaceutical company aimed at developing and commercializing therapies for the treatment of rare genetic disorders of obesity, today will announce an update on its Research & Development (R&D) programs, genetic sequencing efforts and patient finding initiatives at its R&D event in New York City.
During the event, the Company will provide a comprehensive overview of the four new melanocortin-4 receptor (MC4R) pathway-driven disorders that it has added to its Phase 2 Basket Study, as well as updated U.S. prevalence estimates for all of the MC4R pathway-driven rare genetic disorders of obesity for which it is currently evaluating setmelanotide. The Company also will share updated data from its Phase 2 Basket Study of setmelanotide in Bardet-Biedl syndrome (BBS) and Alström syndrome and provide details on ongoing community building and patient-finding efforts related to those two indications. Together, the presentations will highlight how the Rhythm Engine is working to discover disease-causing genetic variants and sequence patients to identify those living with MC4R pathway-driven disorders of obesity and potentially provide these patients with the first disease-modifying therapeutic option.
“In collaboration with partners, patients and health care providers, Rhythm is advancing toward our goal of changing the paradigm for rare genetic disorders of obesity,” said Keith Gottesdiener, M.D., Chief Executive Officer of Rhythm. “We are committed to advancing the science underlying MC4R-pathway obesity disorders and expanding our clinical development and community-building efforts. Through these initiatives, we aim to provide patients with severe obesity and unrelenting hunger a potential new therapeutic option, and to equip physicians and caregivers with the knowledge and resources to better manage these disorders.”
Expansion of the Rhythm Basket Study into Four Additional Indications
Rhythm is expanding its Phase 2 Basket Study into four new indications: SRC1 deficiency obesity, SH2B1 deficiency obesity, MC4R deficiency obesity and Smith-Magenis syndrome obesity. The Company is evaluating setmelanotide for the treatment of severe obesity and unrelenting hunger, or hyperphagia, associated with these diseases.
· SRC1 deficiency obesity: SRC1 is a transcriptional coactivator that drives pro-opiomelanocortin (POMC) expression.
· SH2B1 deficiency obesity: SH2B1 is an adapter protein that regulates leptin receptor (LEPR) activity.
· MC4R deficiency obesity: The MC4R is the receptor for POMC ligands, and is responsible for the satiety effects of α/β-MSH. The Company plans to focus its development efforts on patients with potentially rescuable variants in the MC4R.
· Smith-Magenis syndrome (SMS) obesity: SMS is caused by dysfunction of the RAI1 gene, a transcription factor for a number of MC4R pathway genes, which affects POMC expression.
“We are taking an exciting step toward our foundational goal of translating our understanding of the MC4R pathway into treatments for people living with rare genetic disorders of obesity,” said Alastair Garfield, Ph.D., Vice President of Translational Research and Development of Rhythm. “Leveraging our extensive scientific expertise, genetic sequencing initiatives and variant interpretation capabilities, we selected additional rare genetic disorders of obesity to include in our Phase 2 Basket Study, each with a strong scientific tie to the MC4R pathway and, we believe, a larger target population than certain other indications that we are currently evaluating in clinical trials. We look forward to evaluating setmelanotide in these indications in the months and years ahead. We are also committed to continuing to probe the numerous other MC4R pathway genes that may be implicated in rare genetic disorders of obesity and may provide additional opportunities for setmelanotide.”
Genetic Sequencing Provides Updated U.S. Prevalence Estimates for Genetically-identified MC4R Pathway-driven Indications
Rhythm has been collaborating with partners to advance its own initiatives to sequence individuals living with early-onset, severe obesity to uncover more rare genetic disorders of obesity, and develop a better understanding of those disorders currently under study in its pivotal trials and Phase 2 Basket Study. As of June 2019, the Company collected samples from 13,567 individuals with severe obesity, and those samples have yielded 11.7 percent, or 1,584 genetically-identified individuals, who have a rare genetic variant of the MC4R pathway and who may be eligible for inclusion in Rhythm’s Phase 2 Basket Study or Rhythm’s pivotal Phase 3 trials.
Rhythm’s genetic sequencing results have identified samples from 29 patients with POMC or LEPR deficiency obesity. This result supports that these conditions are ultra-rare, even among the portion of the population with severe, early-onset obesity. These results are consistent with Rhythm’s clinical epidemiology estimates of 100-500 POMC deficiency obesity and 500-2,000 LEPR deficiency obesity patients living in the U.S.
Additionally, Rhythm believes the sequencing yield in this cohort supports the Company’s prior estimates of greater than 20,000 people living with high-impact heterozygous obesity of the POMC, PCSK1 or LEPR genes in the U.S.
For the genetically-defined MC4R pathway indications that the Company has not previously included in prior clinical trials, the Company applied well-established functional and computational filtering processes to refine this yield and provide estimated U.S. prevalence(1):
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Indication |
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Estimated U.S. Prevalence |
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SRC1 deficiency obesity |
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>23,000 |
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SH2B1 deficiency obesity |
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>24,000 |
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MC4R deficiency obesity |
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>10,000 |
Syndromic conditions, such as SMS, BBS and Alström syndrome, are often clinically identified and confirmed by genetic testing. Rhythm estimates that there are greater than 2,400 people living with severe obesity and SMS in the U.S.
Update on Clinical Data from Phase 2 Basket Study in BBS and Alström Syndrome, and Community Building and Patient-Finding Efforts in these Two Indications
Rhythm provided an update on data from its Phase 2 Basket Study of setmelanotide in patients with BBS and Alström syndrome. As previously disclosed in January 2019, six of nine enrolled patients with BBS showed weight loss of greater than 10 percent on setmelanotide treatment. As of August 2019, all of these patients either continued to maintain, or increased, their weight loss following approximately two years of treatment, with a mean weight reduction of 22.2 percent. Additionally, five of six patients continued to show a substantial decrease in hunger from baseline.
In patients with Alström syndrome, the three patients on treatment at the Company’s last update in November 2018 have continued on treatment. One of these patients has demonstrated 20 percent weight loss and a 25 percent reduction in hunger score at greater than one year. One patient has not lost weight but has demonstrated a 38 percent decrease in hunger and improved diabetes control at greater than one year, and the third patient achieved 6 percent weight loss without a change in hunger. All three patients plan to continue setmelanotide therapy in the long-term extension trial.
“Rhythm is working to build a community to better understand the substantial, long-term burden of rare genetic and syndromic disorders of obesity on the lives of patients and their families. Both BBS and Alström syndrome are typically diagnosed via clinical presentation, which requires an informed healthcare-provider community, capable of recognizing and managing the care of these patients,” said Nithya Desikan, Chief Commercial Officer of Rhythm. “We believe we may have identified nearly one third of the estimated BBS and Alström patients living in the U.S., providing a foundation as we continue to enroll our pivotal Phase 3 trial in BBS and Alström syndrome, and begin to build the infrastructure to support the potential commercialization of setmelanotide in these indications.”
Webcast Information:
The live audio webcast of today’s R&D event can be accessed under “Events & Presentations” in the Investors & Media section of the Company’s website at www.rhythmtx.com. A replay of the webcast will be available on the Rhythm website for 30 days following the event.
(1) SRC1 and SH2B1 deficiency obesity epidemiology estimates include patients with high-impact loss-of-function variants, screened through three computational algorithms applied for newly-observed variants. These calculations assume a U.S. population of 327 million, of which 1.7% have early-onset, severe obesity (Hales et al in Jama — April 2018: Trends in Obesity and Severe Obesity Prevalence in US Youth and Adults by Sex and Age, 2007-2008 to 2015-2016); allele frequency based on Rhythm genetic sequencing (June 2019).
About Rhythm
Rhythm is a biopharmaceutical company focused on the development and commercialization of therapies for the treatment of rare genetic disorders of obesity. The company recently announced positive topline results from pivotal Phase 3 clinical trials of setmelanotide, its MC4R agonist, in patients with POMC deficiency obesity and LEPR deficiency obesity, and Rhythm expects to share the full data in forthcoming publications and medical meeting presentations. The company plans to complete its first rolling new drug application (NDA) submission to the U.S. Food and Drug Administration in the fourth quarter of 2019 or the first quarter of 2020. Rhythm is also evaluating setmelanotide in a pivotal Phase 3 study in patients with Bardet-Biedl syndrome and Alström syndrome, and expects to complete enrollment in the second half of 2019. The company is leveraging the Rhythm Engine — comprised of its Phase 2 basket study, TEMPO Registry, GO-ID genotyping study and Uncovering Rare Obesity program — to improve the understanding, diagnosis and potentially the treatment of rare genetic disorders of obesity. For healthcare professionals, visit www.UNcommonObesity.com for more information. For patients and caregivers, visit www.LEADforRareObesity.com for more information. The company is based in Boston, MA.
Forward-Looking Statements
This press release 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’s anticipated timing for enrollment of patients in clinical trials and submission of an NDA, its ongoing efforts related to patient identification, estimates of treatable patient populations, the timing of the release of results of clinical trials, the efficacy of setmelanotide in patients with POMC deficiency obesity, LEPR deficiency obesity, Bardet-Biedl Syndrome, Alström Syndrome, POMC heterozygous deficiency obesity, or POMC epigenetic disorders, as well as new indications that we may pursue. Statements using word such as “expect”, “anticipate”, “believe”, “may”, “will” and similar terms are also forward looking statements. Such statements are subject to numerous risks and uncertainties, including but not limited to, our ability to enroll patients in clinical trials, the design and outcome of clinical trials, the impact of competition, the ability to achieve or obtain necessary regulatory approvals, risks associated with data analysis and reporting, and expenses, and other risks as may be detailed from time to time in our Annual Reports on Form 10-K and quarterly reports on Form 10-Q and other reports we file with the Securities and Exchange Commission. Except as required by law, we undertake no obligations to make any revisions to the forward-looking statements contained in this release or to update them to reflect events or circumstances occurring after the date of this release, whether as a result of new information, future developments or otherwise.
Corporate Contact:
David Connolly
Head of Investor Relations and Corporate Communications
Rhythm Pharmaceuticals, Inc.
857-264-4280
dconnolly@rhythmtx.com
Investor Contact:
Hannah Deresiewicz
Stern Investor Relations, Inc.
212-362-1200
hannah.deresiewicz@sternir.com
Media Contact:
Adam Daley
Berry & Company Public Relations
212-253-8881
adaley@berrypr.com
Rhythm Researchand DevelopmentEvent RESEARCH & DEVELOPMENT UPDATE SEPTEMBER 2019 1 CONFIDENTIAL
Forward Looking Statements 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's expectations for 2019 and 2020, anticipated timing for enrollment, design and completion of clinical trials, the timing for filing of an NDA, the release of results of clinical trials, estimates of treatable patient populations, the efficacy of setmelanotide in patients with new indications, and Rhythm’s strategy, prospects and plans. Statements using word such as "expect", "anticipate", "believe", "may", "will" and similar terms are also forward-looking statements. Such statements are subject to numerous risks and uncertainties, including but not limited to, our ability to enroll patients in clinical trials, the outcome of clinical trials, the impact of competition, the ability to achieve or obtain necessary regulatory approvals, risks associated with data analysis and reporting, our expenses, and other risks as may be detailed from time to time in our Annual Reports on Form 10-K and quarterly reports on Form 10-Q and other reports we file with the Securities and Exchange Commission. Except as required by law, we undertake no obligations to make any revisions to the forward-looking statements contained in this presentation or to update them to reflect events or circumstances occurring after the date of this presentation, whether as a result of new information, future developments or otherwise. 2 RESEARCH & DEVELOPMENT UPDATE SEPTEMBER 2019
Today’s Agenda Introductions Hunter Smith, Chief Financial Officer Welcome and Overview Keith Gottesdiener, M.D., Chief Executive Officer Science Behind New Indications Alastair Garfield, Ph.D., Vice President of Translational Research and Development Update on Epidemiology Estimates Keith Gottesdiener, M.D., Chief Executive Officer Rhythm Engine, Basket Study and Update on Phase 2 Bardet-Biedl Syndrome Patients Murray Stewart, M.D., Chief Medical Officer Bardet-Biedl and Alström Syndromes Community Building and Patient Finding Nithya Desikan, Chief Commercial Officer Closing Remarks and Q&A 3 RESEARCH & DEVELOPMENT UPDATE SEPTEMBER 2019
Welcome Keith Gottesdiener, M.D. Chief Executive Officer 4 RESEARCH & DEVELOPMENT UPDATE SEPTEMBER 2019
Welcome to Rhythm’s Fall 2019 R&D Event Growing database now with 4 new indications being added to Phase 2 Basket Study sequences of 13,567 people with early-onset, severe obesity Sequencing yield and updated epidemiology for pivotal and basket indications Rhythm Engine and what it’s designed to accomplish Progress in programs for Bardet-Biedl and Alström syndromes 5 RESEARCH & DEVELOPMENT UPDATE SEPTEMBER 2019
Rhythm Achievements on the Road to Changing the Paradigm with a Much-needed Therapy for Rare Genetic Disorders of Obesity Added high-impact heterozygous (HET) obesity to Basket Study and presented preliminary clinical data demonstrating consistent weight and hunger responses Secured Breakthrough Therapy and EMA PRIME designations for POMC, LEPR, BBS & Alström Completed enrollment in POMC Phase 3 trial Completed enrollment in LEPR Phase 3 trial Initiated Phase 2 trial for once-weekly formulation of setmelanotide Achieved positive Phase 2 Bardet-Biedl & Alström syndromes results Launched Uncovering Rare Obesity, a free genetic testing program Enrolled first patient in pivotal Phase 3 study in BBS & Alström Launched TEMPO registry and GO-ID trial 6 RESEARCH & DEVELOPMENT UPDATE SEPTEMBER 2019 Expand Basket Study and provide update on genetic sequencing and patient finding Met all primary and key secondary endpoints for weight loss and reduction in hunger in POMC and LEPR Phase 3 trials Clinical Advancement Translational Research and Genetics
Today’s Focus is on New Indications and Patient Finding These Rhythm initiatives remain on track • POMC and LEPR deficiency obesities pivotal data and registration •Presentations of data at major medical meeting expected during 4Q2019 •U.S. New Drug Application submission on track to be completed 4Q2019/1Q2020 • High-impact HETs progressing in Rhythm Basket Study; update coming in 2020 • Commercialization approach for POMC/LEPR - 1H2020 7 RESEARCH & DEVELOPMENT UPDATE SEPTEMBER 2019
RAI1 Setmelanotide has Potential to Address Disrupt MC4R Pathway Function Multiple Genetic Disorders that MC4R pathway genes BBSx SRC1 deficiency SRC1 SH2B1 deficiency SH2B1 Bardet-Biedl syndrome BBSx Setmelanotide POMC deficiency Appetite PCSK1 POMC High-impact heterozygous and epigenetic dysfunction Energy expenditure MC4R Activation LEPR deficiency LEPR MSH Weight MC4R Alström syndrome ALMS1 expressing neuron Smith-Magenis syndrome RAI1 Genetic targets currently under investigation Genetic targets identified today Other potentially relevant gene targets 8 RESEARCH & DEVELOPMENT UPDATE SEPTEMBER 2019 SRC1 deficiency obesity SH2B1 deficiency obesity Smith-Magenis syndrome MC4R deficiency obesity High-impact heterozygous deficiency obesity Epigenetic disorders POMC deficiency obesity LEPR deficiency obesity Bardet-Biedl syndrome Alström syndrome
Rhythm Genetic Engine Drives Understanding and Treatment Disorders of Obesity of Rare Clinical Advancement Translational Research and Genetics Rhythm Scientific Expertise Treat Patients • Pivotal-ready indications • Community building • Identified patient population • Sequencing to drive patient finding Phase 2 Basket Trial TEMPO Registry Learn and adapt • Largest obesity DNA sequencing initiative Variant discovery and interpretation Epidemiology Pathway mapping • • • • • • Academic Scientific Community 9 RESEARCH & DEVELOPMENT UPDATE SEPTEMBER 2019
ScienceBehind NewIndications Alastair Garfield, Ph.D., Vice President of Translational Research and Development 10 RESEARCH & DEVELOPMENT UPDATE SEPTEMBER 2019
Numerous MC4R Pathway Disorders of Obesity Genes Implicated in Rare Genetic BDNF PCSK1 POMC SRC1 SH2B1 OTP SIM1 TUB TBX3 ADCY3 ALMS1 BBS1-21 MC4R RAI1 NTRK2 Semaphorins (~13 genes) GNAS LEPR LEP CPE MRAP2 ?? ?? ?? ?? ?? 11 RESEARCH & DEVELOPMENT UPDATE SEPTEMBER 2019
MC4R Pathway Disorders: Genetic or Syndromic Diagnosis POMC, LEPR deficiency obesities; High-impact HETs BBS and Alström syndrome Patients diagnosed after genetic screening Patients often known to the medical system Smith-Magenis syndrome SRC1 deficiency obesity MC4R deficiency obesity SH2B1 deficiency obesity Images are for illustrative purposes only and not intended to imply or suggest actual prevalence estimates or patient identification yields. 12 RESEARCH & DEVELOPMENT UPDATE SEPTEMBER 2019 Genetically-identified Clinically-identifiable, syndromic
New MC4R Pathway Indications Based on Proven Scientific Rationale UPSTREAM DOWNSTREAM NEURON MC4R Weight ACTIVATION 13 RESEARCH & DEVELOPMENT UPDATE SEPTEMBER 2019 POMC NEURON Leptin LEPRRAI1 MC4R-EXPRESSING Appetite Energy expenditure PCSK1 SH2B1 Satiety SignalsSRC1 (Leptin)MSH POMC
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 obesity and hyperphagia • Hyperleptinemia C4R Citations • Yang et al 2019, Nat Comm. 10, Article 1718 14 RESEARCH & DEVELOPMENT UPDATE SEPTEMBER 2019 POMC NEURON Leptin LEPR M (Leptin)MSH PCSK1 + Satiety SignalsSRC1 POMC
SH2B1 is an Adapter Protein that Regulates LEPR Activity Pathway Relevance: Regulates LEPR activity • Adapter protein • Found in POMC neurons Autosomal Dominant • Obesity arises due to heterozygous gene variants or chromosomal deletions Clinical Presentation • Early onset obesity and hyperphagia • Hyperinsulinemia + C4R Citations • Doche et al 2011, JCI, 122; 4732 • Ockukova et al 2010, Nature, 463; 666 15 RESEARCH & DEVELOPMENT UPDATE SEPTEMBER 2019 POMC NEURON Leptin LEPR M PCSK1 SH2B1 Satiety Signals (Leptin)MSH POMC
MC4R: Receptor for POMC Ligand MSH Pathway Relevance: Receptor for POMC ligands • Required for satiety effects of /-MSH Autosomal Dominant • Obesity arises due to heterozygous gene variants Clinical Presentation • Early onset obesity and hyperphagia Setmelanotide • Pharmacological target for setmelanotide • Rhythm conducted small, 4-week PhIb study in MC4R deficiency obesity • Rhythm biochemical studies indicate that setmelanotide can rescue specific MC4R variants • Current indication is focused on rescuable MC4R variant carriers MC4R Citations • Farooqi et al 2003, NEJM, 348; 1085 • Collett et al 2017, Molecular Metabolism, 6; 1321 16 RESEARCH & DEVELOPMENT UPDATE SEPTEMBER 2019 MC4R-EXPRESSING NEURON Appetite ACTIVATION Weight Energy expenditure
Smith-Magenis Syndrome Obesity: RAI1 Affects POMC Expression Pathway Relevance: Decreased Pathway Function Upstream of MC4R • Causal gene is RAI1 • Transcription factor for a number of pathway genes Autosomal Dominant • Gene variants and chromosomal deletions Clinical Presentation • Adolescent obesity and hyperphagia C4R • Sleep disturbance, cognitive impairment, craniofacial anomalies, low energy expenditure Citations • Edelman et al 2007, Clin Genet; 71: 540–550 • Burns et al 2010, Hum. Mol. Gen; 19; 4026 RAI1 17 RESEARCH & DEVELOPMENT UPDATE SEPTEMBER 2019 POMC NEURON Leptin LEPRRAI1 M (Leptin)MSH PCSK1 Satiety Signals POMC
Leveraging Sequencing of Genetics Underlying Data to Build Obesity a Better Understanding 18 RESEARCH & DEVELOPMENT UPDATE SEPTEMBER 2019 101 Gene Panel for Obesity •Clinically relevant obesity genes •Research based genes •Not all associated with MC4R pathway
There’s an Art to the Science of Rhythm’s Genotyping Strategy growing DNA a rare genetic contributes to Rhythm has established a deep for functional testing of genetic pathway obesity disorders 19 RESEARCH & DEVELOPMENT UPDATE SEPTEMBER 2019 Biochemical Screening biochemical screening strategy variants in trial eligible MC4R-Individuals with variant that their severe obesity Rhythm’s sequencing database for clinically obese individuals Severe obesity + rare genetic variants Epidemiology Rhythm’s robust internal infrastructure drives epidemiological analysis of MC4R-pathway obesity disorders based on clinically relevant cohort data (obese and lean)
Epidemiology Estimates for MC4R Pathway-driven Disorders Keith Gottesdiener, M.D. Chief Executive Officer 20 RESEARCH & DEVELOPMENT UPDATE SEPTEMBER 2019
Building the Largest Genetic Database for Severe Obesity Rhythm’s growing database has 13,567 samples** Clinical Characteristics: Early-onset obesity Obesity is severe BMI> 40* as adults * For children under 12, included those who are 1.4 X 95th percentile for weight; ** As of June 2019. 21 RESEARCH & DEVELOPMENT UPDATE SEPTEMBER 2019
Sequencing Focused Disorders of Obesity on Genetically-identified Rare Individuals with severe obesity sequenced 13,567 + variant 22 RESEARCH & DEVELOPMENT UPDATE SEPTEMBER 2019 Severe obesity rare genetic Number of genetically-identified individuals who may be eligible for Rhythm Basket Study: 1,584 Yield = 11.7% With ‘rarity filter’ of <1% frequency applied
Sequencing Yield Supports Deficiency Obesities Ultra-rare Populations in POMC and LEPR Individuals with severe obesity sequenced 13,567 23 RESEARCH & DEVELOPMENT UPDATE SEPTEMBER 2019 Consistent with Rhythm’s U.S. clinical epidemiology estimates of 100-500 for POMC deficiency obesity and 500-2,000 for LEPR deficiency obesity n = 21; 0.15% LEPR PCSK1 n = 3; 0.02% POMC n = 5; 0.04% Patients with bi-allelic POMC or LEPR genetic variants: n = 29, Yield =0.2%
Sequencing Yield for New Significant Opportunity Basket Indications Points to Individuals with severe obesity sequenced 13,567 *Basket yield includes 683 individuals with other variants; some patients have more than one variant. 24 RESEARCH & DEVELOPMENT UPDATE SEPTEMBER 2019 HETs 0.7% Syndromic indications, which are diagnosed based on clinical presentation, not included here High-impact n = 97; SH2B1 n = 245; 1.8% SRC1 n = 335; 2.5% MC4R n = 269; 2.0% Yield for new genetically-identified Basket indications*:
Obesity Affects a Meaningful Smith-Magenis Syndrome Portion of Patients with U.S. epidemiology estimate of SMS patients living with severe obesity: 10% of patients have RAI1 variants 67% of SMS patients with RAI1 variant live with obesity* Smith-Magenis Syndrome 1:25,000 People in the United States 13% of SMS patients with 17p11.2 deletion live with obesity * 90% of patients have 17p11.2 chromosomal deletion U.S. epidemiology estimate of SMS patients living with severe obesity > 2,400 * Elsea and Girirajan, European Journal of Human Genetics, 16;412-421 (2008) 25 RESEARCH & DEVELOPMENT UPDATE SEPTEMBER 2019
Translating Rhythm Sequencing Data to U.S. Prevalence Estimates Individuals with obesity SRC1 SH2B1 MC4R and rare variant Variant of interest Variant of interest Functional and High-impact loss-of-functionOR variant 3 computational algorithms* Biochemical assay computational filters >23,000** patients with SRC1 deficiency obesity >24,000** patients with SH2B1 deficiency obesity >10,000** patients with MC4R deficiency obesity with a potentially rescuable variant Prevalence estimates: Obesity associated with variant *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) ** Company estimates calculated based on the following assumptions: US pop 327 million; 1.7% has early onset, severe obesity (Hales et al in JAMA – April 2018: Trends in Obesity and Severe Obesity Prevalence in US Youth and Adults by Sex and Age, 2007-2008 to 2015-2016); Allele frequency based on Rhythm genetic sequencing (June 2019) 26 RESEARCH & DEVELOPMENT UPDATE SEPTEMBER 2019
U.S. Prevalence Estimates for Genetic Disorders Obesity MC4R Pathway-driven Rare * Company estimates calculated based on the following assumptions: US pop 327 million; 1.7% has early onset, severe obesity (Hales et al in JAMA – April 2018: Trends in Obesity and Severe Obesity Prevalence in US Youth and Adults by Sex and Age, 2007-2008 to 2015-2016); Allele frequency based on Rhythm genetic sequencing (June 2019); Company also estimates that EU prevalence is similar for each indication. 27 RESEARCH & DEVELOPMENT UPDATE SEPTEMBER 2019 Pivotal indications: up to 5,000* POMC deficiency obesity LEPR deficiency obesity Bardet-Biedl syndrome Alström syndrome High-impact HETs: > 20,000* New indications > 60,000* SRC1 deficiency obesity SH2B1 deficiency obesity Smith-Magenis syndrome MC4R deficiency obesity
RhythmEngineand theBasketStudy Murray Stewart, M.D., Chief Medical Officer 28 RESEARCH & DEVELOPMENT UPDATE SEPTEMBER 2019
Rhythm Engine: Identifying and Advancing a Therapy Patients, Discovering Diseases RARE OBESITY Sponsored genetic testing program Phase 2 Basket Study TRACING THE EFFECT OF THE MC4R PATHWAY IN OBESITY 29 RESEARCH & DEVELOPMENT UPDATE SEPTEMBER 2019 Biobanks UNCOVERING
Uncovering Rare Obesity Program Broadens Access to Genetic Testing and Facilitates Diagnosis of Rare Genetic Disorders of Obesity Raise Awareness Elevate awareness and increase suspicion of rare genetic disorders of obesity (RGDO) Increase Frequency of Genetic Testing Providing simple and efficient genetic testing program Improve Access to Genetic Testing Offering no-cost genetic testing option 30 RESEARCH & DEVELOPMENT UPDATE SEPTEMBER 2019
Biobanks Providing Large Data Sets for Patient Identification and Furthering Disease Understanding Established collaborations with 9 well-known biobanks giving Rhythm access to sequencing data from 23,000 individuals with severe obesity 31 RESEARCH & DEVELOPMENT UPDATE SEPTEMBER 2019 • Identification of eligible patients for potential trial enrollment and treatment • Data for variant characterization • Evaluation of clinical features that may be predictive of genotypes of interest
GO-ID Driving and Enriching Genetic Testing and Patient Distinct Patient Subsets Finding while Evaluating Early-onset obesity and hyperphagia MC4R pathway deficient variants High BMI Bariatric surgery Basket Study Improved clinical algorithm 32 RESEARCH & DEVELOPMENT UPDATE SEPTEMBER 2019 81 sites 9 countries Significant overlap with
Community Building Through the TEMPO Registry TEMPO is for individuals with specific variants in the MC4R pathway genes, that include at least one of the following: POMC PCSK1 RPS6KA3 TRACING THE EFFECT OF THE MC4R PATHWAY IN OBESITY SH2B1 LEPR AFF4 NTRK2 Designed to complement existing patient registries (e.g. CRIBBS for BBS) and to facilitate better understanding of rare genetic disorders of obesity in the medical community BBS 1-20 PMCH ALMS1 RAI1 RAB23 PROK2 CPE GNAS BDNF HTR2C INPP5E THRB SRC1 IRS2 KSR2 MRAP2 SIM1 LEP MAGEL2 NHLH2 MC3R MC4R 33 RESEARCH & DEVELOPMENT UPDATE SEPTEMBER 2019 • Target enrollment of ~1,000 patients • Genetic screening through GO-ID • Potential enrollment in Phase 2 basket studies
Basket Study Key to Proof of Concept, Advancing Indications to Phase 3 • 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 • Multiple cohorts of HETs patients enrolled Enrolling patients • • • • in new indications Images are for illustrative purposes only and not intended to imply or suggest actual prevalence estimates or patient identification yields. 34 RESEARCH & DEVELOPMENT UPDATE SEPTEMBER 2019
Updated Phase 2 Data in BBS Show Continued Responses at ~Two Years • Six of nine pts responded - All maintain weight loss at ~two years Mean percent weight reduction of responders = 22.2% after ~two years on therapy Three patients discontinued treatment • • – Patient 5 (pediatric patient with BBS1 variant and type 1 diabetes) experienced 53.3% reduction in hunger and reduction in hemoglobin A1c (10.1% to 7.6%) before withdrawing. Pt subsequently entered long-term extension study Two patients (one non-genetically confirmed) withdrew due to lack of weight loss – *Pt. has cognitive impairment, so Food Problem Diary (FPD) score maintained by caregiver; **Pt. did not have baseline hunger measure. The first score was a 7, which was not recorded until after the patient had received treatment. Current score is a 6. 35 RESEARCH & DEVELOPMENT UPDATE SEPTEMBER 2019 WeightHunger Score GeneTreatment,Change fromChange from weeksBaselineBaseline Patient 1BBS1123-36.7%-33% Patient 2BBS2119-15%-71% Patient 3BBS10121-28%-100%* Patient 4BBS12108-25%67% Patient 6BBS583-10.8%-38% Patient 7BBS473-17.9%-14%**
Updated Phase 2 Data in Alström Syndrome Show Variable Responses • Patient 1 showed strongest response and HCP started decreasing the dose after 32 weeks of treatment; currently 0.5 mg/day and has reached healthy body weight Patient 3 maintaining weight and reduced hunger – HbA1c decreased by 3% from 11% to 8% All 3 continuing patients plan to enter long-term extension trial • • *As previously disclosed, patient 2 (data not shown) discontinued at ~14 weeks 36 RESEARCH & DEVELOPMENT UPDATE SEPTEMBER 2019 Age atBaseline% Weight% Hunger enrollWeightTreatment,ChangeScore Change ment/(kg)weeksfromfrom SexBaselineBaseline† Patient 112/M78.695-20%-25% Patient 3* 15/F70.7841%-38% Patient 416/F91.668-6%0%
Community Building and Patient Finding Nithya Desikan, Chief Commercial Officer 37 RESEARCH & DEVELOPMENT UPDATE SEPTEMBER 2019
Community Building Off and Running 38 RESEARCH & DEVELOPMENT UPDATE SEPTEMBER 2019 Disease Journey • Reducing barriers to diagnosis Established Registries • CRIBBS (Bardet-Biedl syndrome registry) • Large cohorts of known patients Advocacy Relations • Building relationships with multiple advocacy groups in US and EU Field Medical Outreach • GOLD academies building awareness and community • Field team members connecting with HCPs
Mapping the BBS Patient Journey to Diagnosis and Beyond Working to Reduce Barriers to Diagnosis Variability: Variability of presentation and progression of the disease Initial concerns dismissed: Caregivers collect “proof ” to raise HCP suspicion Medical Team: Specialists brought in as symptoms increase and worsen with no coordinated care Specialists may include: Pediatricians, ENTS, ophthalmologist, endocrinologist, nephrologist and/or therapist Discovering BBS: Happens by chance for most via an encounter with someone familiar with BBS; or someone diagnosed with it. Solomon, Living with BBS 39 RESEARCH & DEVELOPMENT UPDATE SEPTEMBER 2019
Patient Advocacy Collaborations Advance Common Mission to Improve Lives of Patients, Families Affected by Bardet-Biedl, Alström Syndromes • Increase disease awareness and reduce barriers to diagnosis Gain feedback on clinical trial design and materials • • Support pathway to regulatory approval 40 RESEARCH & DEVELOPMENT UPDATE SEPTEMBER 2019 CMO Murray Stewart at the 2019 9th Alstrom Syndrome International Family Conference and Scientific Symposium
Community Building: Genetic Network Development Obesity Leadership and Established education modules on rare genetic disorders of obesity, hyperphagia, clinical characteristics, potential diagnosis and management strategy Launched in 2019 to educate health care providers, develop management strategies and build a peer-to-peer network 20 GOLD Academy faculty 20 >500 programs completed or in process Health care providers have or are expected to participate 41 RESEARCH & DEVELOPMENT UPDATE SEPTEMBER 2019
Patient Finding Efforts have Resulted in Many Identified Patients with BBS and Alström syndrome* Field Medical teams survey of physicians confirms original prevalence of estimates for Bardet-Biedl, Alström syndromes 2,500 in U.S. 2,500 in EU Bardet-Biedl syndrome 224 physicians who treat BBS patients 500-800* in U.S. 1,000 - 1,500* in EU 500 in U.S. 500 in EU Alström syndrome 93 physicians who treat patients with Alström syndrome 50-70* in U.S. 200-225* in EU *Assessment of numbers of patients relies on HCP recall, which may result in over or under reporting 42 RESEARCH & DEVELOPMENT UPDATE SEPTEMBER 2019 Patients with Alström Syndrome Identified BBS Patients Identified Rhythm Physician Interactions Estimated Clinical Epidemiology
Conclusion 43 RESEARCH & DEVELOPMENT UPDATE SEPTEMBER 2019
Rhythm Expects Significant Progress in 2019 and 2020 Updated interim data for HET obesity Positive topline data from both POMC and LEPR Phase 3 studies Expand Phase 2 basket studies into four additional MC4R pathway disorders 2H19 Complete pivotal enrollment in BBS and Alström Phase 3 study 4Q19-1Q20 Initial NDA submission for setmelanotide in POMC and LEPR 2020 Additional data in high impact HETs obesity and additional Basket indications 2020 Topline data from BBS and Alström Phase 3 study 44 RESEARCH & DEVELOPMENT UPDATE SEPTEMBER 2019
Rhythm Is Transforming the Care for Patients with Rare Genetic Disorders of Obesity Driven by deficiencies within the MC4R Pathway Discovering MC4R pathway disorders that cause obesity and identifying patients Study into 4 new indications, all MC4R pathway substantial 45 RESEARCH & DEVELOPMENT UPDATE SEPTEMBER 2019 Rhythm Engine is executing on a scientific approach to identifying patients with rare genetic disorders of obesity related to the MC4R pathway Rhythm has expanded the Basket with strong scientific ties to the Sequencing has improved our understanding of: •POMC and LEPR •New indications, for which the estimated prevalence is Significant progress in Bardet-Biedl and Alström syndromes programs • Patients in Phase 2 trial showing deepening of response over longer-term • Patient finding efforts are exceeding expectations
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RAI1 Setmelanotide has Potential to Address that Disrupt MC4R Pathway Function Multiple Genetic Disorders MC4R pathway genes BBSx SRC1 deficiency SRC1 SH2B1 deficiency SH2B1 Bardet-Biedl syndrome BBSx Setmelanotide POMC deficiency Appetite PCSK1 POMC High-impact heterozygous and epigenetic dysfunction Energy expenditure MC4R Activation LEPR deficiency LEPR MSH Weight MC4R Alström syndrome ALMS1 expressing neuron Smith-Magenis syndrome RAI1 Genetic targets currently under investigation Genetic targets identified today Other potentially relevant gene targets 47 RESEARCH & DEVELOPMENT UPDATE SEPTEMBER 2019 SRC1 deficiency obesity SH2B1 deficiency obesity Smith-Magenis syndrome MC4R deficiency obesity High-impact heterozygous deficiency obesity Epigenetic disorders POMC deficiency obesity LEPR deficiency obesity Bardet-Biedl syndrome Alström syndrome
