UNITED STATES
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WASHINGTON, D.C. 20549
FORM
CURRENT REPORT
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| Item 7.01 | Regulation FD Disclosure. |
On June 9, 2023, Disc Medicine, Inc. (the “Company”) issued a press release announcing initial data from its ongoing Phase 2 open-label BEACON trial evaluating bitopertin, an orally administered investigational glycine transporter 1 (“GlyT1”) inhibitor, in patients with erythropoietic protoporphyria (“EPP”) and X-linked protoporphyria (“XLP”) at the European Hematology Association 2023 Congress. The Company hosted a live webcast on June 9, 2023 at 7:30 a.m. ET. An archived webcast will be available for 30 days on the events & presentations section of the Company’s website. The Company also updated its corporate presentation. A copy of the press release and the Company’s updated corporate presentation are attached as Exhibits 99.1 and 99.2, respectively, to this Current Report on Form 8-K. The corporate presentation will also be available in the investor relations section of the Company’s website at https://ir.discmedicine.com. Information contained on the Company’s website is not incorporated by reference into this Current Report on Form 8-K, and you should not consider any information on, or that can be accessed from, the Company’s website as part of this Current Report on Form 8-K.
The information contained in Item 7.01 of this Current Report on Form 8-K (including Exhibits 99.1 and 99.2 attached hereto) is intended to be furnished and shall not be deemed “filed” for purposes of Section 18 of the Securities Exchange Act of 1934, as amended (the “Exchange Act”), or otherwise subject to the liabilities of that section, nor shall it be deemed incorporated by reference in any filing under the Securities Act of 1933, as amended, or the Exchange Act, except as expressly provided by specific reference in such filing. The Company undertakes no obligation to update, supplement or amend the materials attached hereto as Exhibits 99.1 and 99.2.
| Item 8.01 | Other Events. |
On June 9, 2023, the Company announced initial data from its ongoing Phase 2 open-label BEACON trial evaluating bitopertin, an orally administered investigational GlyT1 inhibitor, in patients with EPP and XLP.
BEACON Initial Data
The BEACON trial is a randomized, open-label, parallel-arm trial enrolling up to 22 patients with EPP or XLP at trial sites in Australia. This trial was designed to assess changes in levels of Protoporphyrin IX (“PPIX”), as well as measures of photosensitivity, quality of life, and safety and tolerability. Subjects are randomized to receive either 20 mg or 60 mg of bitopertin once-daily for 24 weeks, after which patients have the option of continuing in an open-label extension of the trial for up to an additional 24 weeks. The trial is ongoing and these data reflect initial data from 15 subjects enrolled as of the data cutoff of May 8, 2023, with a range of treatment durations from 18 days to 6 months. Due to batch processing of samples, the data cutoff for PPIX data was April 7, 2023.
Highlights of the initial data presented:
| • | PPIX levels: Significant, consistent, dose-dependent, and sustained reductions of whole-blood, metal-free PPIX; mean reduction of >40% when compared to baseline |
| • | Measures of light tolerance (individual) from two participants with the longest follow-up demonstrated substantial increases in sunlight tolerance as measured by time in sunlight without experiencing a prodrome (initial symptoms that signal a pain attack), or “sunlight challenge”: |
| • | A participant on 20 mg bitopertin reported a >80-fold increase in sunlight tolerance on day 88 of treatment, increasing from 4.5 minutes at baseline to over 6 hours; the participant did not report a prodrome during any sunlight challenge after Day 20 |
| • | A participant on 60 mg bitopertin reported a >200-fold increase in sunlight tolerance on day 74 of treatment, increasing from 1.25 minutes at baseline to over 4 hours, and did not report a prodrome during any sunlight challenge after Day 120 |
| • | Measures of light tolerance (aggregated across participants from whom data was available in the trial): |
| • | Average weekly total time spent in sunlight: increased from 344 minutes (approximately 49 minutes per day) to 1,200 minutes at Week 24 |
| • | Time to prodrome during sunlight challenge (averaged over a two-week period): increased >7-fold, from 25 minutes at baseline to 182 minutes at Week 24 |
| • | Increased proportion of days without symptoms: 75% vs. 25% (baseline) |
| • | Increased proportion of sunlight challenges without prodromes: 50% vs. 0% (baseline) |
| • | Phototoxic reactions: 96% reduction in patient-reported phototoxic reactions while on treatment compared to baseline (n=15) |
| • | Measures of patient quality of life |
| • | Patient Global Impression of Change (PGIC): All 10 patients that had completed a day 43 visit reported their disease was much better (n=8) or a little better (n=2) in the last 7 days |
| • | Patient Global Impression of Severity (PGIS): Nine out of 10 patients that had completed a day 43 visit reported their EPP was mild (n=3) or not at all severe (n=6) |
| • | EPP Impact Questionnaire (EPIQ): For patients whose most recent data was Day 43, 4/8 patients reported an improvement in the impact of EPP on quality of life and 4/8 reported no change in the impact of EPP on quality of life. For patients whose most recent data was after Day 43, 2/2 reported marked improvement in the impact of EPP on quality of life, reporting no impact of EPP on quality of life. |
| • | Bitopertin was well-tolerated at both dose levels with no reported serious adverse events, no reported discontinuations or dose reductions, no reported adverse events greater than Grade 1, and no meaningful changes observed in mean hemoglobin levels. |
Cautionary Note Regarding Forward-Looking Statements
This Current Report on Form 8-K contains “forward-looking statements” within the meaning of the Private Securities Litigation Reform Act of 1995, including, but not limited to, express or implied statements regarding the Company’s expectations with respect to its BEACON Phase 2 clinical trial of bitopertin and projected timelines for the initiation and completion of its clinical trials, the timing of additional data and other activities. The use of words such as, but not limited to, “aim,” “believe,” “expect,” “estimate,” “project,” “intend,” “future,” “potential,” “continue,” “may,” “might,” “plan,” “will,” “should,” “seek,” “anticipate,” or “could” or the negative of these terms and other similar words or expressions that are intended to identify forward-looking statements. Forward-looking statements are neither historical facts nor assurances of future performance. Instead, they are based on the Company’s current beliefs, expectations and assumptions regarding the future of the Company’s business, future plans and strategies, clinical results and other future conditions. New risks and uncertainties may emerge from time to time, and it is not possible to predict all risks and uncertainties. No representations or warranties (expressed or implied) are made about the accuracy of any such forward-looking statements.
The Company may not actually achieve the plans, intentions or expectations disclosed in these forward-looking statements, and investors should not place undue reliance on these forward-looking statements. Actual results or events could differ materially from the plans, intentions and expectations disclosed in the forward-looking statements as a result of a number of material risks and uncertainties including but not limited to: the adequacy of the Company’s capital to support its future operations and its ability to successfully initiate and complete clinical trials; the nature, strategy and focus of the Company; the difficulty in predicting the time and cost of development of the Company’s product candidates; the Company’s plans to research, develop and commercialize its current and future product candidates; the timing of initiation of the Company’s planned preclinical studies and clinical trials; the timing of the availability of data from the Company’s clinical trials; the Company’s ability to identify additional product candidates with significant commercial potential and to expand its pipeline in hematological diseases; the timing and anticipated results of the Company’s preclinical studies and clinical trials and the risk that the results of the Company’s preclinical studies and clinical trials may not be predictive of future results in connection with future studies or clinical trials and may not support further development and marketing approval; the other risks and uncertainties described in the “Risk Factors” section of our Quarterly Report on Form 10-Q for the quarter ended March 31, 2023 and other documents filed by the Company from time to time with the Securities and Exchange Commission (the “SEC”), as well as discussions of potential risks, uncertainties, and other important factors in the Company’s subsequent filings with the SEC. Any forward-looking statement speaks only as of the date on which it was made. None of the Company, nor its affiliates, advisors or representatives, undertake any obligation to publicly update or revise any forward-looking statement, whether as result of new information, future events or otherwise, except as required by law.
| Item 9.01. | Exhibits. |
(d) Exhibits
| Exhibit No. | Description | |
| 99.1 | Press release issued by Disc Medicine, Inc. on June 9, 2023, furnished herewith. | |
| 99.2 | Disc Medicine, Inc. Investor Presentation, furnished herewith. | |
| 104 | Cover Page Interactive Data File (embedded within the Inline XBRL document) | |
SIGNATURES
Pursuant to the requirements of the Securities Exchange Act of 1934, the registrant has duly caused this report to be signed on its behalf by the undersigned hereunto duly authorized.
| DISC MEDICINE, INC. | ||||||
| Date: June 9, 2023 | By: | /s/ John Quisel | ||||
| Name: | John Quisel, J.D., Ph.D. | |||||
| Title: | Chief Executive Officer | |||||
Exhibit 99.1
Disc Presents Positive Initial Data from Phase 2 BEACON Trial of Bitopertin in Patients with Erythropoietic Protoporphyria (EPP) at European Hematology Association (EHA) 2023 Congress
| • | Consistent and dose-dependent reductions of protoporphyrin IX (PPIX), the disease-causing metabolite in EPP, were observed in patients treated with bitopertin |
| • | Patients reported significant improvements in sunlight tolerance and measures of quality-of-life |
| • | Bitopertin was well-tolerated, with no meaningful changes in hemoglobin observed |
| • | Disc Medicine to host an investor conference call today at 7:30 AM ET |
WATERTOWN, Mass. (June 9, 2023) – Disc Medicine, Inc. (NASDAQ:IRON), a clinical-stage biopharmaceutical company focused on the discovery, development, and commercialization of novel treatments for patients suffering from serious hematologic diseases, today presented preliminary findings from its ongoing, Phase 2 open-label BEACON trial evaluating bitopertin, an orally administered glycine transporter 1 (GlyT1) inhibitor, in patients with erythropoietic protoporphyria (EPP) and X-linked protoporphyria (XLP) at the European Hematology Association (EHA) 2023 Congress in Frankfurt, Germany. The initial trial data demonstrated consistent decreases in PPIX, significant increases in reported sunlight tolerance and improvements in measures of patient quality of life.
“We’re delighted to share these initial, positive data from BEACON, which provide the first clinical evidence supporting our therapeutic hypothesis of bitopertin in EPP. Over the next 12 months, we plan to build on this momentum with a series of additional clinical read-outs across our portfolio,” said John Quisel, J.D., Ph.D., Chief Executive Officer and President of Disc Medicine. “This is an important moment for Disc as a company, and I want to extend my gratitude to our team, collaborators, and most importantly, the patients and families participating in BEACON.”
“We are excited to share these initial data from the BEACON trial, where we observed consistent and sustained suppression of PPIX, the disease-causing metabolite in EPP, in patients treated with bitopertin,” said Will Savage, M.D., Ph.D., Chief Medical Officer at Disc Medicine. “Importantly, this reduction translated into significant improvements in the time that patients can spend in sunlight without reporting pain or symptoms related to their disease. We’re encouraged by the data and plan to present additional data at the end of the year.”
The BEACON trial is a randomized, open-label, parallel-arm trial enrolling up to 22 patients with EPP or XLP at trial sites in Australia. This trial was designed to assess changes in levels of PPIX, as well as measures of photosensitivity, quality of life, and safety and tolerability. Subjects are randomized to receive either 20 mg or 60 mg of bitopertin once-daily for 24 weeks, after which patients have the option of continuing in an open-label extension of the trial for up to an additional 24 weeks. The trial is ongoing and these data reflect initial data from 15 subjects enrolled as of the data cutoff of May 8, 2023, with a range of treatment durations from 18 days to 6 months. Due to batch processing of samples, the data cutoff for PPIX data was April 7, 2023.
Highlights of the initial data presented:
| • | Protoporphyrin IX (PPIX) levels: Significant, consistent, dose-dependent, and sustained reductions of whole-blood, metal-free PPIX; mean reduction of >40% when compared to baseline |
| • | Measures of light tolerance (individual) from two participants with the longest follow-up demonstrated substantial increases in sunlight tolerance as measured by time in sunlight without experiencing a prodrome (initial symptoms that signal a pain attack), or “sunlight challenge”: |
| • | A participant on 20 mg bitopertin reported a >80-fold increase in sunlight tolerance on day 88 of treatment, increasing from 4.5 minutes at baseline to over 6 hours; the participant did not report a prodrome during any sunlight challenge after Day 20 |
| • | A participant on 60 mg bitopertin reported a >200-fold increase in sunlight tolerance on day 74 of treatment, increasing from 1.25 minutes at baseline to over 4 hours, and did not report a prodrome during any sunlight challenge after Day 120 |
| • | Measures of light tolerance (aggregated across participants from whom data was available in the trial): |
| • | Average weekly total time spent in sunlight: increased from 344 minutes (approximately 49 minutes per day) to 1,200 minutes at Week 24 |
| • | Time to prodrome during sunlight challenge (averaged over a two-week period): increased >7-fold, from 25 minutes at baseline to 182 minutes at Week 24 |
| • | Increased proportion of days without symptoms: 75% vs. 25% (baseline) |
| • | Increased proportion of sunlight challenges without prodromes: 50% vs. 0% (baseline) |
| • | Phototoxic reactions: 96% reduction in patient-reported phototoxic reactions while on treatment compared to baseline (n=15) |
| • | Measures of patient quality of life |
| • | Patient Global Impression of Change (PGIC): All 10 patients that had completed a day 43 visit reported their disease was much better (n=8) or a little better (n=2) in the last 7 days |
| • | Patient Global Impression of Severity (PGIS): Nine out of 10 patients that had completed a day 43 visit reported their EPP was mild (n=3) or not at all severe (n=6) |
| • | EPP Impact Questionnaire (EPIQ): For patients whose most recent data was Day 43, 4/8 patients reported an improvement in the impact of EPP on quality of life and 4/8 reported no change in the impact of EPP on quality of life. For patients whose most recent data was after Day 43, 2/2 reported marked improvement in the impact of EPP on quality of life, reporting no impact of EPP on quality of life. |
| • | Bitopertin was well-tolerated at both dose levels with no reported serious adverse events, no reported discontinuations or dose reductions, no reported adverse events greater than Grade 1, and no meaningful changes observed in mean hemoglobin levels |
These data were presented at the European Hematology Association 2023 Congress in Frankfurt, Germany and the poster is available on the EHA Congress platform at www.ehaweb.org.
Management will host a call to review the presented data on Friday, June 9th at 7:30 am ET. Please register for the event on the Events and Presentations page of Disc’s website (https://ir.discmedicine.com/).
About Bitopertin
Bitopertin is an investigational, clinical-stage, orally-administered inhibitor of glycine transporter 1 (GlyT1) that is designed to modulate heme biosynthesis. GlyT1 is a membrane transporter expressed on developing red blood cells and is required to supply sufficient glycine for heme biosynthesis and support erythropoiesis. Disc is planning to develop bitopertin as a potential treatment for a range of hematologic diseases including erythropoietic porphyrias, where it has potential to be the first disease-modifying therapy. There are currently two ongoing Phase 2 clinical trials of bitopertin in patients with erythropoietic porphyria, including an open-label trial called BEACON and a randomized, double-blind placebo-controlled trial called AURORA.
Bitopertin is an investigational agent and is not approved for use as a therapy in any jurisdiction worldwide. Disc obtained global rights to bitopertin under a license agreement from Roche in May 2021.
About Erythropoietic Protoporphyria (EPP) and X-linked Protoporphyria (XLP)
Erythropoietic protoporphyria (EPP) and X-linked Protoporphyria (XLP) are rare, debilitating and potentially life-threatening diseases caused by mutations that affect heme biosynthesis, resulting in the accumulation of a toxic, photoactive intermediate called protoporphyrin IX (PPIX). This causes severe reactions when patients are exposed to sunlight, characterized by excruciating pain, edema, burning sensations and potential blistering and disfigurement. PPIX also accumulates in the hepatobiliary system and can result in complications including gallstones, cholestasis, and liver damage in 20-30% of patients and in extreme cases liver failure. Current standard of care involves extreme measures to avoid sunlight, including restricting outdoor activities to nighttime, use of protective clothing and opaque shields, and pain management. This has a significant impact on the psychosocial development, quality of life, and daily activities of patients, particularly in young children and families. There is currently no cure for EPP and only one FDA-approved therapy, a surgically implanted synthetic hormone designed to stimulate melanin production called Scenesse® (afamelanotide).
About Disc Medicine
Disc Medicine is a clinical-stage biopharmaceutical company committed to discovering, developing, and commercializing novel treatments for patients who suffer from serious hematologic diseases. We are building a portfolio of innovative, potentially first-in-class therapeutic candidates that aim to address a wide spectrum of hematologic diseases by targeting fundamental biological pathways of red blood cell biology, specifically heme biosynthesis and iron homeostasis. For more information, please visit www.discmedicine.com.
Disc Medicine Cautionary Statement Regarding Forward-Looking Statements
This press release contains “forward-looking statements” within the meaning of the Private Securities Litigation Reform Act of 1995, including, but not limited to, express or implied statements regarding Disc’s expectations with respect to its BEACON Phase 2 clinical trial of bitopertin and projected timelines for the initiation and completion of its clinical trials, the timing of additional data and other activities. The use of words such as, but not limited to, “aim,” “believe,” “expect,” “estimate,” “project,” “intend,” “future,” “potential,” “continue,” “may,” “might,” “plan,” “will,” “should,” “seek,” “anticipate,” or “could” or the negative of these terms and other similar words or expressions that are intended to identify forward-looking statements. Forward-looking statements are neither historical facts nor assurances of future performance. Instead,
they are based on Disc’s current beliefs, expectations and assumptions regarding the future of Disc’s business, future plans and strategies, clinical data and other future conditions. New risks and uncertainties may emerge from time to time, and it is not possible to predict all risks and uncertainties. No representations or warranties (expressed or implied) are made about the accuracy of any such forward-looking statements.
Disc may not actually achieve the plans, intentions or expectations disclosed in these forward-looking statements, and investors should not place undue reliance on these forward-looking statements. Actual data or events could differ materially from the plans, intentions and expectations disclosed in the forward-looking statements as a result of a number of material risks and uncertainties including but not limited to: the adequacy of Disc’s capital to support its future operations and its ability to successfully initiate and complete clinical trials; the nature, strategy and focus of Disc; the difficulty in predicting the time and cost of development of Disc’s product candidates; Disc’s plans to research, develop and commercialize its current and future product candidates; the timing of initiation of Disc’s planned preclinical studies and clinical trials; the timing of the availability of data from Disc’s clinical trials; Disc’s ability to identify additional product candidates with significant commercial potential and to expand its pipeline in hematological diseases; the timing and anticipated data of Disc’s preclinical studies and clinical trials and the risk that the data of Disc’s preclinical studies and clinical trials may not be predictive of future data in connection with future studies or clinical trials and may not support further development and marketing approval; the other risks and uncertainties described in the “Risk Factors” section of our Quarterly Report on Form 10-Q filed with the Securities and Exchange Commission (SEC) on May 15, 2023 and other documents filed by Disc from time to time with the SEC, as well as discussions of potential risks, uncertainties, and other important factors in Disc’s subsequent filings with the SEC. Any forward-looking statement speaks only as of the date on which it was made. None of Disc, nor its affiliates, advisors or representatives, undertake any obligation to publicly update or revise any forward-looking statement, whether as result of new information, future events or otherwise, except as required by law.
Media Contact
Peg Rusconi
Verge Scientific Communications
prusconi@vergescientific.com
Investor Relations Contact
Christina Tartaglia
Stern Investor Relations
christina.tartaglia@sternir.com
Corporate Presentation June 2023 Exhibit 99.2
Disclaimer and FLS This presentation includes “forward-looking statements” within the meaning of the Private Securities Litigation Reform Act of 1995, as amended. These forward-looking statements include express or implied statements relating to Disc's management team's expectations, hopes, beliefs, intentions or strategies regarding the future. In addition, any statements that refer to projections, forecasts or other characterizations of future events or circumstances, including any underlying assumptions, are forward-looking statements. The words “anticipate,” “believe,” “contemplate,” “continue,” “could,” “estimate,” “expect,” “intends,” “may,” “might,” “plan,” “possible,” “potential,” “predict,” “project,” “should,” “will,” “would” and similar expressions may identify forward-looking statements, but the absence of these words does not mean that a statement is not forward-looking. Forward-looking statements are neither historical facts nor assurances of future performance. Instead, they are based on Disc's current beliefs, expectations and assumptions regarding the future of Disc's business, future plans and strategies, clinical results and other future conditions. New risks and uncertainties may emerge from time to time, and it is not possible to predict all risks and uncertainties. No representations or warranties (expressed or implied) are made about the accuracy of any such forward-looking statements. Disc may not actually achieve the plans, intentions or expectations disclosed in these forward-looking statements, and investors should not place undue reliance on these forward-looking statements. These forward-looking statements involve a number of risks, uncertainties (some of which are beyond Disc's control) or other assumptions that may cause actual results or performance to be materially different from those expressed or implied by these forward-looking statements. These risks and uncertainties include, but are not limited to: the adequacy of Disc's capital to support its future operations and its ability to successfully initiate and complete clinical trials; the nature, strategy and focus of Disc; the difficulty in predicting the time and cost of development of Disc's product candidates; Disc's plans to research, develop and commercialize its current and future product candidates; the timing of initiation of Disc's planned preclinical studies and clinical trials; the timing of the availability of data from Disc's clinical trials; Disc's ability to identify additional product candidates with significant commercial potential and to expand its pipeline in hematological diseases; the timing and anticipated results of Disc's preclinical studies and clinical trials and the risk that the results of Disc's preclinical studies and clinical trials may not be predictive of future results in connection with future studies or clinical trials and may not support further development and marketing approval; the other risks and uncertainties described in the “Risk Factors” section of the Quarterly Report on Form 10-Q filed with the SEC on May 15, 2023, and other documents filed by Disc from time to time with the SEC, as well as discussions of potential risks, uncertainties, and other important factors in Disc's subsequent filings with the Securities and Exchange Commission. Any forward-looking statement speaks only as of the date on which it was made. None of Disc, nor its affiliates, advisors or representatives, undertake any obligation to publicly update or revise any forward-looking statement, whether as result of new information, future events or otherwise, except as required by law.
Disc is Building a Leading Company Dedicated to Treating Hematologic Diseases Fundamental & Validated Pathways Multiple Clinical Programs with Broad Potential Multiple Near-Term Catalysts Focus on Hematologic Disorders Immense medical need across a wide spectrum of disorders Predictive, objective endpoints Fundamental to red blood cell biology: iron and heme Clinical and genetic evidence of target mechanism in humans Bitopertin in Phase 2 DISC-0974 in Phase 1b/2 MWTX-003 is Phase 1-Ready Bitopertin Phase 2 data in EPP DISC-0974 Phase 1b data in MF and NDD-CKD Initiate Phase 1 MWTX-003 EPP (Erythropoietic Protoporphyria); XLP (X-linked Protoporphyria); MF (myelofibrosis); NDD (non-dialysis dependent) CKD (chronic kidney disease)
Former CFO of Arkuda Therapeutics, Dyne Therapeutics, and Quartet Medicine; previously at WiTricity, Speedy Packets, Narrative Communications; Arthur Andersen Joanne Bryce, CPA | Chief Financial Officer Magenta Therapeutics and Shire / Takeda; Trained in Pediatric Hematology & Transfusion Medicine; Faculty at Harvard Medical School, Johns Hopkins University School of Medicine Will Savage, MD, PhD | Chief Medical Officer Qpex Biopharma (Co-founder), The Medicines Company, Acceleron Pharma, and Johnson & Johnson. Leadership roles in corporate strategy, finance and operations licensing, M&A, and commercial planning Jonathan Yu, MBA | Chief Business Officer Our Executive Team Deep experience building companies and bringing therapies to patients Former EVP & Chief Business Officer at Acceleron Pharma; 14 years through transformative Celgene partnerships, IPO and launch of Reblozyl®; led re-acquisition and positioning of sotatercept for PAH John Quisel, JD, PhD | CEO & President Former VP Legal and Chief Compliance Officer at Acceleron Pharma, supported commercial launch of Reblozyl® and eventual acquisition by Merck; Arnold & Porter, LLP; Sidley Austin LLP Rahul Khara, PharmD, JD | General Counsel Founder and former Board Member of Disc Medicine; founder and CEO of Merganser Biotech; Previously at Zelos Therapeutics, 3-Dimensional Pharmaceuticals, GlaxoSmithKline Brian MacDonald, MB, ChB, PhD | Chief Innovation Officer Agios, Millennium / Takeda, BMS. Leadership positions in DMPK and Clinical Pharmacology, including for approved therapies IDHIFA® (enasidinib), TIBSOVO® (ivosidenib) and PYRUKIND® (mitapivat) Hua Yang, PhD | SVP Nonclinical R&D Proteostasis, FORMA, Agios, AVEO Oncology. Discovery and development across range of therapeutic areas including oncology and orphan disease including AATD, CF, lysosomal storage disease and others Merck and Schering-Plough, leadership roles in discovery, manufacturing and formulation, including for Victrelis® (boceprevir), first approved HCV protease inhibitor Srikanth Venkatraman, PhD | SVP Chemistry Former Partner at CFGI, a portfolio company of The Carlyle Group and largest non-audit accounting advisory firm in US and focused on life science companies; Covidien; PwC Min Wu, PhD | VP Biology Jeremy Brinkerhoff, CPA | VP Finance
Targeting Fundamental Pathways that Impact the Biology of Red Blood Cells Erythropoietic Porphyrias ~7,500 CKD Anemia 6 Million+ (US) Sickle Cell Disease 200,000 Myelodysplastic Syndromes 200,000 Iron and heme formation play a central role in erythropoiesis Polycythemia Vera 200,000+ Critical points of intervention across multiple hematologic diseases Severe Rare (000s) Wide Spectrum of Hematologic Diseases Addressable by Disc Portfolio (US and Europe) IBD Anemia 1 Million+ (US) Anemia of Myelofibrosis 30,000 Diamond-Blackfan Anemia ~ 5,000 (WW) Hereditary Hemochromatosis 1 Million (US) Moderate Prevalence (100K+) Beta-Thalassemia 20,000+
Disc’s Portfolio Addresses Broad Spectrum of Hematologic Disorders Hepcidin Suppression Increase Iron Hepcidin Induction Reduce Iron Heme Synthesis Modulation Bitopertin (GlyT1 Inhibition) EPP, DBA, other rare blood disorders Phase 2 studies in EPP Phase 2 in DBA – init. midyear ‘23 DISC-0974 (Anti-HJV mAb) Anemia of MF, CKD, and other chronic diseases Phase 1b/2 MF Anemia - ongoing Phase 1b/2 NDD-CKD - ongoing MWTX-003 (Anti-TMPRSS6 mAb) PV, Beta-Thal, HH, other iron overload diseases IND Accepted by FDA Phase 1 in HV – init. 2H’23 Lead Program (MOA) Range of Indications Development Status EPP (Erythropoietic Protoporphyria); XLP (X-linked Protoporphyria); MF (myelofibrosis); NDD (non-dialysis dependent) CKD (chronic kidney disease); DBA = diamond blackfan anemia; PV = polycythemia vera; HH = hereditary hemochromatosis; HV = healthy volunteers
Disc’s Hematology-Focused Pipeline Multiple programs in development with pipeline-in-a-product potential Preclinical Phase 1 Bitopertin† GlyT1 Inhibitor Oral, once-daily Phase 2 Near-Term Milestones DISC-0974‡ Anti-HJV monoclonal antibody Subcutaneous, once-monthly DISC-0998‡ Anti-HJV monoclonal antibody Extended half-life Erythropoietic Porphyrias (EPP and XLP) – Initiated July ‘22 Diamond-Blackfan Anemia – IND Accepted Anemia of Myelofibrosis (MF) – Initiated June ‘22 Anemia of Non-Dialysis Dependent Chronic Kidney Disease (CKD) – Initiated Feb. ‘23 Anemia Associated with Inflammatory Diseases Heme Biosynthesis Modulator Iron Modulation Hepcidin Suppression Increase Iron Hepcidin Induction Reduce Iron Portfolio Program EPP / XLP BEACON data from all patients to be presented year-end 2023 AURORA data expected by year-end 2023, to be presented early 2024 DBA Ph 2 trial initiation expected mid-year 2023 Myelofibrosis Anemia Initial data expected by year-end 2023 CKD Anemia Initial data expected by year-end 2023 † Bitopertin in-licensed from Roche; ‡ DISC-0974 and DISC-0998 in-licensed from Abbvie; *in-licensed from Mabwell MWTX-003* Anti-TMPRSS6 Monoclonal antibody Polycythemia Vera and Diseases of Iron Overload / Ineffective Erythropoiesis Phase 1 Proof-of-Mechanism Expect to initiate Phase 1 trial 2H’23 IND accepted
Projected Upcoming Milestones and Events Multiple catalysts expected beginning mid-year and through 2024 Program Indication H1 2023 H2 2023 2024 Erythropoietic Porphyrias (EPP and XLP) Initial Ph 2 BEACON presented at EHA Phase 2 BEACON data Phase 2 AURORA data (early 2024) End of Ph 2 Meeting Diamond-Blackfan Anemia (DBA) Initiate Ph 2 DBA trial (mid-year) Initial Ph 2 DBA data Anemia of Myelofibrosis (MF) Initial Ph 1b/2 MF data Ph 2 MF data Anemia of Chronic Kidney Disease (CKD) Initiate Ph 1b/2 CKD trial Initial Ph 1b/2 CKD data Ph 2 CKD data Polycythemia Vera and Diseases of Iron Overload / Ineffective Erythropoiesis Initiate Ph 1 SAD / MAD trial Phase 1 SAD / MAD data MWTX-003 Hepcidin Induction Bitopertin Heme Synthesis Modulator DISC-0974 Hepcidin Suppression SAD = single ascending dose; MAD = multiple ascending dose
Strong Projected Growth Trajectory Towards Building a Leading Hematology Company Establish Company Build Portfolio of Clinical Programs Demonstrate Phase 2 POC in Multiple Programs 2021-2022 Licensed bitopertin and MWTX-003; DISC-0974 and bitopertin enter the clinic; Series B financing and transition to public company 2024 and Beyond Positioned to enter potentially pivotal trials; expand range of indications and pipeline Initiate Phase 3 Studies and Expand Portfolio 2020 Series A and founding technology 2023 Initial Phase 2 patient data from bitopertin and DISC-0974; Additional trial initiations for bitopertin, DISC-0974, and MWTX-003
Bitopertin GlyT1 Inhibitor Heme Biosynthesis Modulation
Bitopertin: Investigational Oral, Selective GlyT1 Inhibitor In multiple clinical trials by Roche, bitopertin was observed to modulate heme biosynthesis by blocking uptake of glycine in erythrocytes Glycine Critical and initiating precursor for heme biosynthesis and is supplied by GlyT1 transporter Hemoglobin Protoporphyrin IX (PPIX) ALAS ALAD HMBS UROS UROD CPO PPO FECH ferrochelatase Heme Bitopertin Designed to block glycine uptake in RBCs by inhibiting GlyT1 +Succinyl CoA Porphyrin Synthesis Iron Heme Biosynthesis Pathway
Erythropoietic Protoporphyria (EPP) Rare, debilitating and lifelong condition characterized by extreme pain and damage to skin caused by light Genetic condition caused by defective heme biosynthesis – deficient enzyme ferrochelatase Lifelong and presents in early childhood Caused by accumulation of toxic metabolite PPIX XLP, mechanistically similar disease, also PPIX-related Debilitating and potentially life-threatening Skin: severe, disabling pain attacks (days), edema, burning Hepatobiliary disease: gallstones, liver dysfunction or failure Psychosocial well-being (fear, anxiety) and development No cure or disease-modifying treatment Avoid sun / light, protective clothing, window tinting, Zn/Ti Oxide One FDA-approved agent, afamelanotide, a surgically-implanted tanning agent EPP and XLP Prevalence: Approximately 7-8k+ addressable patients in US and Europe; recent genetic studies suggest number may be higher Sources: Deybach et al (2009) Orphanet Journal of Rare Diseases; American Porphyria Foundation; Dickey et al (2021) Genet. Med. Image sources: Daily Mail Australia (2019); FDA Scientific Workshop on EPP (2016); Buonuomo et al. (2014) Arch Dis Child
PPIX is a Driver of Disease in EPP / XLP Patients Toxic and photo-active metabolite accumulates in RBCs and is transported to skin and other organs, causing damage Skin Porphyrin ring absorbs light and emits energy and heat Oxidative damage to endothelial capillaries and surrounding tissue, perivascular edema, complement activation Pain, burning sensation, swelling, inflammation, chronic skin lesions Protoporphyrin IX Psychosocial Issues with focus and concentration Lack of sleep, physical and social isolation Significant lifestyle modification, fear and anxiety Hepatobiliary PPIX accumulation in bile canaliculae, causing oxidative damage Cholelithiasis requiring surgery or impaired liver function (~25%) and end-stage liver disease requiring transplant (2-5%) Clinical and biochemical surveillance Other Complications Nutritional deficiency resulting in osteoporosis and propensity for fractures, chronic alterations to skin (e.g. fragile), mild anemia
Bitopertin: Potential Disease-Modifying Treatment Designed to reduce disease-causing PPIX by limiting uptake of glycine into developing erythrocytes EPP and XLP Patients High PPIX Levels Bitopertin Treatment Designed to Reduce PPIX Levels Potential first disease-modifying treatment for EPP and XLP Mutations result in reservoir of pathologically high levels of PPIX Figures adapted from Halloy et al. (2021) Cell Chem Biol FECH ALAS2 (+++) Glycine ↓ Protoporphyrin IX ↑↑↑↑ X Heme PPOX CPOX UROD UROS HMBS ALAD Protoporphyrin IX FECH ALAS2 (+++) X Heme PPOX CPOX UROD UROS HMBS ALAD ↓ Glycine
Bitopertin Reduced PPIX in Models of EPP / XLP Effects on PPIX have the potential to be disease-modifying EC50 3.8 nM Free PPIX (pmol / 1x106 cells) Bitopertin log[M] Data presented at the 63rd ASH Annual Meeting (December 2021); Studies performed in collaboration with Boston Children’s Hospital (PI: Paul Schmidt, Advisor: Mark Fleming) Sources: † Heerfordt et al. (2016) Br J. Dermatol.; Wulf et al. (2019) Photodiagn and Photodyn Ther; Poh-Fitzpatrick (1997) J Am Acad Derm ↓ PPIX Levels by up to ~90% Bitopertin reduced PPIX, the driver of disease pathophysiology, and, based on the data, is expected to be disease-modifying Reductions in PPIX levels of >30% reported in literature to have a major impact on photosensitivity in patients†; Bitopertin has been shown in an animal model of EPP (data presented at ASH 2022) to reduce liver fibrosis In vivo - EPP Model (Mouse) FECHm1pas Missense Mutation In vivo - XLP Model (Mouse) ALAS2Q548X Gain-of-Function Mutation In vitro – EPP Model (K562 Cell) FECHIVS3-48C/KO Mutation ↓ PPIX Levels by 45% ↓ PPIX Levels by 73%
Bitopertin Robust Data Package Extensive non-clinical, CMC and clinical development has already been completed Non-Clinical CMC Clinical Genetic toxicity and Safety pharmacology Long-term GLP toxicology Juvenile GLP toxicology studies supporting patients ≥2 y/o Carcinogenicity studies Full reproductive GLP toxicology Metabolites fully qualified Commercial-scale production Optimized oral formulation (tablet and capsule) Highly stable molecule (at least 5 years) Healthy volunteer studies Drug-drug interaction studies Hepatic impairment Renal impairment TQT (heart rhythm) study Pharmacokinetics in patients of Asian descent 30+ Other clinical trials Note: Total clinical experience of bitopertin is extensive and includes 700+ HV and 4,000 patients in over 30 clinical trials; all trials referenced conducted by Roche
BEACON Trial: Open-Label Ph 2 Trial in EPP / XLP Open-label, parallel-dose trial to establish POC and assess efficacy, safety in patients (N~22) Trial Design Trial endpoints: Changes in blood PPIX levels, light tolerance, time to prodromal symptom (TTPS), QOL, safety, tolerability, and PK Data availability: Initial, open-label, data presented at EHA; data on all patients to be presented by year-end 60 mg QD Bitopertin 20 mg QD Bitopertin Open-label, randomized EPP and XLP; 18 years + Two dose levels, parallel Not receiving afamelanotide Australia Tx Duration: 24 weeks Treatment Arms Time to prodromal symptom = the time until a patient experiences an early warning signal of a phototoxic attack, measured through a weekly sunlight challenge; QD = daily, Tx = treatment; POC = proof of concept; QOL = quality of life
Initial BEACON Data: % Change in Whole-Blood PPIX PPIX data as of 7 April 2023 PPIX Changes Over Time Individual PPIX Data Whole-blood (WB) metal-free PPIX reduction was observed in trial participants Dose-dependent reductions were observed across broad range of baseline WB PPIX levels (140-3,410 µg/dL) Overall N 15 9 6 5 2 1 2 1 20mg 8 5 3 2 1 0 1 0 60mg 7 4 3 3 1 1 1 1 20 mg 8 5 3 2 1 0 1 0 60 mg 7 4 3 3 1 1 1 1 % Change in WB PPIX Study Day 0 -80 -20 0 15 29 43 71 113 169 -40 -60 Study Day 0 -80 -20 20 15 29 43 71 113 169 -40 -60 0 Overall 20 mg 60 mg 20 mg 60 mg 155 155 >40%
Light Tolerance: Time to First Prodromal Symptom Individual Patient Sunlight Challenges (20 mg QD) Additional data not visible due to y-axis scale include prodrome (*) after 2 minutes of sunlight and prodrome-free (*) challenge with 4 minutes of sunlight Sunlight challenge time for individual participant while receiving 20 mg of bitopertin. Participants could complete more than 1 sunlight exposure challenge per week and if a patient was unable to elicit a prodrome during a sunlight challenge (blue bars), the patient would record the amount of time that the patient chose to remain in sunlight >80x increase in sunlight challenge time Patient did not report a prodrome with sunlight challenge after Day 20 Sunlight Challenge Time (min) Study Day BL 0 100 200 300 400 20 27 41 47 63 82 88 96 125 147 154 4.5 min * 390 min >80x Prodrome-Free Prodrome Dose: 20 mg Baseline PPIX 2,740 µg/dL Day 71 Change in PPIX: -30% Day 155 Change in PPIX: -38% *
Light Tolerance: Time to First Prodromal Symptom Individual Patient Sunlight Challenges (60 mg QD) Sunlight challenge time for individual participant while receiving 60 mg of bitopertin. Participants could complete more than 1 sunlight exposure challenge per week and if a patient was unable to elicit a prodrome during a sunlight challenge (blue bars), the patient would record the amount of time that the patient chose to remain in sunlight Prodrome-Free Prodrome Dose: 60 mg Baseline PPIX 1,100 µg/dL Day 71 Change in PPIX: -59% Day 169 Change in PPIX: -72% Sunlight Challenge Time (min) Study Day BL 0 100 200 300 9 15 23 29 30 33 35 36 44 50 57 64 65 72 74 75 77 106 113 114 115 116 120 121 122 123 124 125 126 141 145 153 159 EOS >200x 1.25 min 255 min >200x increase in sunlight challenge time Patient did not report a prodrome with most sunlight challenges after Day 57
Initial BEACON Data: Light Tolerance Days without Symptoms or Prodromes *as assessed with a daily diary; **as assessed with a weekly sunlight challenge; ***summed across all patients Percentages calculated relative to total number of days with sunlight exposure (left) or total number of weekly sunlight exposure challenges (right) from all study participants (n=15) during screening or while receiving bitopertin (20 mg and 60 mg dose groups combined). Days w/ Sun Exposure Sunlight Challenges Screening 163 42 On-Treatment 679 135 96% reduction in patient-reported full phototoxic reactions* An increase in the proportion of total symptom-free days (no prodrome / early warning symptoms or full phototoxic reactions) with sun exposure was observed*** Relative Proportion
Initial BEACON Data: Aggregated Light Tolerance Data Time to Prodrome and Weekly Total Time in Sunlight Time to prodrome during weekly sun exposure challenges averaged over a two-week period, including cumulative time in sunlight challenges where the patient did not report a prodrome (left); if a patient was unable to elicit a prodrome during a sunlight challenge, the patient would record the amount of time that the patient chose to remain in light. Data are averaged for 20 mg and 60 mg bitopertin dose groups combined. Average total time in sun recorded in daily sun exposure diaries over a one-week period for 20 mg and 60 mg bitopertin dose groups combined. Incomplete diary entries counted as zero minutes; The data for weeks 23 and 24 represents the available diary data for completed weeks at the time of the data cut-off and represents 1 subject Time to Prodrome Weekly Total Time in Sunlight No. of Subjects 15 13 14 11 8 4 5 1 1 2 2 1 No. of Challenges 42 27 30 25 13 8 10 2 1 12 5 2 No. of Subjects 15 14 13 11 8 5 4 3 2 2 2 2 1 No. of Diary Entries 163 55 64 39 28 20 21 13 12 13 11 11 7 Mean Time to Prodrome (min) Week 0 4 8 12 16 20 24 0 100 200 300 400 500 Mean Weekly Total Time in Sunlight (min) Week 0 4 8 12 16 20 24 0 600 900 1200 300 Patients reported an increase in average time to prodrome, and average total time patients were able to spend in the sun over a one-week period, for both 20 mg and 60 mg groups
Initial BEACON Data: Measures of Quality of Life QOL data may be entered at Day 43 ± 3 days and includes data from 1 participant who had not completed Day 43 visit; Responses at baseline or most recent visit while receiving bitopertin (combined 20/60 mg doses, n=10), subjects with data beyond Day 43 shown in blue; for subjects at Day 43, relative improvements noted in green and no change in grey; Responses based on replies to EPP Questionnaire Patient Global Impression of Change at Day 43 10/10 participants reported their EPP was much better (n=8) or a little better (n=2) Patient Global Impression of Severity at Day 43 9/10 participants reported their EPP was mild (n=3) or not at all severe (n=6) EPP Questionnaire “In the past 7 days, how much did having EPP impact your overall quality of life?” Not at all A little bit Somewhat Quite a bit Very much Subjects at Day 43 w/ improvement Subjects at Day 43 w/o improvement Subjects > Day 43
Initial BEACON Data: Safety and Tolerability Data as of 8 May 2023. Summaries include uncoded TEAEs categorized by verbatim terms; hgb = hemoglobin. Bitopertin 20 mg (n=8) Bitopertin 60 mg (n=7) Total (n=15) Total Number of TEAEs (all Grade 1) 8 8 16 Subjects with any TEAE (all Grade 1) 6 (75%) 6 (86%) 12 (80%) TEAEs reported in >1 subject Dizziness 4 (50%) 5 (71%) 9 (60%) Headache 2 (25%) 1 (14%) 3 (20%) No reported serious adverse events No observed meaningful changes in mean hgb levels No reported discontinuations or dose reductions All reported TEAEs were Grade 1 in severity and transient (median / mean time to resolution, 0.5 / 2 days)
AURORA Trial: Ph 2 Trial in EPP Randomized, Double-Blind, Placebo Controlled trial to assess efficacy, safety in patients (N~75) Trial Design Trial endpoints: Changes in blood PPIX levels, time in daylight without pain, light tolerance, time to prodromal symptom (TTPS), QOL, safety / tolerability Data availability: Data expected by year-end 2023, to be presented early 2024 Double-blind, placebo-controlled (1:1:1) EPP; 18 years + Stratified by light tolerance Not receiving afamelanotide US Tx Duration: 17 weeks Treatment Arms 60 mg QD Bitopertin Placebo 20 mg QD Bitopertin Time to prodromal symptom = the time until a patient experiences an early warning signal of a phototoxic attack, measured through a weekly sunlight challenge; QD = daily, Tx = treatment; POC = proof of concept; QOL = quality of life
Glycine Hemoglobin Heme Porphyrins + Globin + Iron + Succinyl CoA Porphyrin Toxicity Erythropoietic Protoporphyria X-Linked Protoporphyria Congenital Erythropoietic Porphyria Hepatic Porphyrias Heme Toxicity Diamond-Blackfan Anemia Myelodysplastic Syndromes Globin Toxicity Beta-Thalassemia Sickle Cell Disease Mature red blood cells (RBCs) Excess RBCs Polycythemia Vera Multiple Additional Potential Applications of Bitopertin Inhibiting heme synthesis with bitopertin has potential to address a wide range of hematologic diseases bold (trial ongoing) / bold (trial planned)
Hepcidin Modulation Iron Homeostasis
Iron is Fundamental to RBC Biology Hepcidin is a regulatory hormone that plays a central role in iron metabolism and homeostasis GI Tract Iron Intake Spleen Iron Storage Hepcidin Gatekeeper Function: Blocks iron absorption and recycling RBC Production in Bone Marrow Induced by Inflammation
Hepcidin is a Therapeutic Target for Diseases Dysregulated hepcidin drives a wide range of hematologic diseases Anemias of Inflammatory Disease Myelofibrosis Chronic Kidney Disease Autoimmune / Inflammatory Disorders Iron Overload and Excess Red Blood Cell Disorders Polycythemia Vera Hereditary Hemochromatosis Myelodysplastic Syndromes High Hepcidin Low Hepcidin Regulated erythropoiesis Regulated iron Restricted Iron Iron Overload DISC-0974 MWTX-003
DISC-0974: Novel Anti-HJV mAb to Suppress Hepcidin Designed to enhance iron availability to address a wide range of hematologic disorders Releases iron stores Enables GI absorption Increases Iron Reduces Hepcidin Inhibits endogenous production of hepcidin Potential to treat wide range of anemias Enables RBC Production
Anemia of Inflammation or Chronic Disease Inflammation caused by a wide range of conditions results in anemia due to elevated hepcidin Anemia of inflammation (also called Anemia of Chronic Disease or ACD) is the 2nd most common form of anemia Estimated 40% of all anemias are driven by or have an inflammatory component Hepcidin is up-regulated and correlates with anemia, driven by inflammation Anemia Types US Prev. Est. % Anemic Myelofibrosis (MF) 16-18.5K 87% Chronic Kidney Disease (CKD) 37 MM 17-50% Inflammatory Bowel Disease 1.6 MM 25-35% Anemia of Cancer 17 MM 35-80% Systemic Lupus Erythematosus 210K 50% Sources: Weiss (2019); Maccio (2014); Tefferi (2012); Lupus Foundation; Stauffer (2014); Filmann (2014); Koutroubakis (2015); Crohn’s and Colitis Foundation
Genetic validation in patients with Juvenile Hemochromatosis (lower hepcidin and elevated iron levels) Loss-of-function mutations in HJV are phenotypically indistinguishable from mutations in HAMP (hepcidin) gene Functionally specific to hepcidin / iron Tissue specific expression primarily in the liver Inhibiting Hemojuvelin (HJV) Prevents Hepcidin Expression and Increases Iron Sources: Finberg et al, (2010) Blood; Zhang et al, (2010) J Biol Chem Targeting Hemojuvelin (HJV) to Suppress Hepcidin Critical and specific target for hepcidin expression
DISC-0974 Mechanism of Action Designed to reduce hepcidin and increase serum iron levels Potent and rapid effects on hepcidin and iron with single 5 mg / kg dose (NHP) Days DISC-0974 mAb binds to and prevents signaling through hemojuvelin (HJV) co-receptor x
Phase 1 SAD Trial in Healthy Volunteers Established proof-of-mechanism based on hepcidin and iron parameters Dose Level 7 mg IV 6 Treated / 2 Placebo Dose Level 14 mg SC 6 Treated / 2 Placebo Dose Level 28 mg SC 6 Treated / 2 Placebo Assessment of safety, PK, hepcidin and iron after each dose level Single-ascending dose in ≥32 healthy volunteers Key outcome measures: Safety and PK Hepcidin level, serum iron level, % TSAT Dose escalation until TSAT > 40% for at least 2 weeks Dose levels: 7 mg dose (IV); 14, 28 and 56 mg doses (SC) Trial Design Dose Level 56 mg SC 6 Treated / 2 Placebo Final Escalation Cohort - Dosing Complete TSAT = transferrin saturation; IV = intravenous; SC = subcutaneous
DISC-0974 Phase 1 SAD Data Dosing of DISC-0974 demonstrated a reduction of hepcidin and iron mobilization DISC-0974 Increased TSAT DISC-0974 Reduced Hepcidin Production TSAT = transferrin saturation; SAD = single ascending dose
DISC-0974 Phase 1 SAD Data (cont.) Top dose (56 mg) pharmacodynamic activity improved key clinical parameters (> 1g/dL Hgb) 56 mg SC Placebo Hgb = hemoglobin; SAD = single ascending dose
DISC-0974 Phase 1 SAD Safety Safety profile was consistent with selective target biology and preclinical studies; no serious or AEs > Grade 1 Total n=42 Pooled Placebo n=10 7 mg IV n=8 14 mg SC n=6 28 mg SC n=6 28 mg IV n=6 56 mg SC n=6 Diarrhea 1 (2.4) 1 (10.0) 0 0 0 0 0 Dizziness 2 (4.8) 0 0 0 0 1 (16.7) 1 (16.7) Dyspepsia 1 (2.4) 0 0 0 0 0 1 (16.7) Eye pruritis 1 (2.4) 0 0 0 1 (16.7) 0 0 Peripheral swelling 1 (2.4) 0 0 0 0 1 (16.7) 0 Headache 1 (2.4) 0 0 0 1 (16.7) 0 0 Myalgia 1 (2.4) 0 0 0 0 0 1 (16.7) Nasal congestion 1 (2.4) 0 0 0 0 0 1 (16.7) Pain in extremity 1 (2.4) 1 (10.0) 0 0 0 0 0 Seasonal allergy 1 (2.4) 0 0 0 1 (16.7) 0 0 Vessel puncture site bruise 1 (2.4) 1 (10.0) 0 0 0 0 0 Vomiting 1 (2.4) 1 (10.0) 0 0 0 0 0
DISC-0974 Development Strategy Aim to demonstrate POC in anemia of MF and CKD Establish POM in Healthy Volunteers Ph 1b / 2a in MF Patients with Transfusion-Dependent Anemia – Ongoing Ph 1b / 2a in CKD Patients with Anemia (Non-Dialysis Dependent) – Ongoing Expansion in Other Forms of Anemia of Inflammation Initiate studies to demonstrate POC Plan to assess safety, PK, hepcidin, iron, hemoglobin and transfusion burden (MF) and others
DISC-0974: Anemia of Inflammation Initiate development in parallel in anemias of MF and NDD-CKD Anemia of Myelofibrosis (MF) Anemia of CKD (NDD and DD) Est. # Patients 16,000 to 18,500 patients (US alone) 5 to 6 million patients (US alone) Etiology of Anemia High hepcidin from inflammation JAKi’s worsen anemia; Loss of marrow function High hepcidin from inflammation & poor renal clearance Compromised erythropoietin production Unmet Medical Needs Severe and difficult to treat; high transfusion burden No approved or effective anemia therapy Anemia limits optimal JAKi treatment Majority patients untreated or under-treated ESAs restricted due to safety and black box Mean Hb 9.3 g/dL in patients initiating dialysis NDD: Non-Dialysis Dependent; DD: Dialysis Dependent
Hepcidin is a Key Driver of MF Anemia Clinical POC* that inhibiting hepcidin axis can impact Hb Levels Source: Pardanani et al (2013) Am. J. Hematol; Oh et al., (2020) Blood Adv: TI-R: Transfusion-Independent for > 12 weeks by week 24; TI-NR: Transfusion Independent Non-Response; *from third party Hepcidin Levels are Elevated in MF ~ 12x higher than control and associated with severity of anemia and transfusion burden Median % change in Hb from baseline Clinical Proof-of-Principle Hepcidin suppression increased Hb and reduced transfusion burden (41% TI and 85% transfusion reduction) Week 2 Week 4 Week 8 Week 12 Week 16 Week 20 Week 24 Baseline or Pre-TI-R Median % change in hemoglobin (Q1, Q3) 35 30 25 20 15 10 5 0 -5 -10 -15 TI-NR TI-R 6.5 6 5.5 5 4.5 4 3.5 High Intermediate-2 Intermediate-1 Low Hepcidin logscale Myelofibrosis Risk Score MF Patients Median 156,279 pg/mL Control Group Median 13,449 pg/mL Hepcidin levels are 12x higher in MF patients (p<0.0001)
DISC-0974 Lowered Hepcidin in Inflammation Model NHP: IL6-induced hepcidin and hypoferremia Similar effects in animal models of infection-induced hypoferremia, IRIDA and anemia of inflammation D-0 D-1 D-10 D-1 D-10 D-1 D-10 IL-6 Vehicle IL-6+‘974 0.6mpk IL-6+’974 6mpk D-0 D-1 D-10 D-1 D-10 D-1 D-10 IL-6 Vehicle IL-6+‘974 0.6mpk IL-6+’974 6mpk DISC-0974 Increased Serum Iron Levels DISC-0974 Reduced Hepcidin Production
Phase 1b / 2 Trial in MF Anemia Aim to evaluate efficacy and safety and position program for pivotal trial; Ph 1b data expected by year-end 2023 N ~ 26 Severity: DIPSS INT-2/High Transfusion Dependent +/- JAK inhibitor permitted DISC-0974 in TD MF Patient Population Design Study Arms Open-label Flexibility to add additional exploratory cohorts Key endpoints: Transfusion-independence (TI) Hb, Iron, Hepcidin, hematologic parameters Treatment Duration: 6 months (q28d) N =1-9 per cohort†, initial dose: 14 mg SC Open-label, adaptive design (BOIN), accelerated titration Receiving transfusions or Hb < 10 g/dL Key endpoints: Hemoglobin, Iron, Hepcidin Design Treatment Duration: 6 cycles (q28d) Phase 1b Dose Escalation in Pts Phase 2 Trial Focused on Transfusion-Dependent (TD) Patients †Note: In Part 1, expect one patient per cohort until iron mechanism is engaged; TD MF = transfusion-dependent myelofibrosis
Hepcidin is a Key Driver of CKD Anemia Clinical POC* that inhibiting hepcidin axis can impact Hb levels Sources: Troutt et al. (2013), J Clin Lab Analy; Sheetz et al. (2019) Br J Clin Pharmacol. (2019); *from third party Clinical Proof-of-Principle* Hepcidin inhibition via single dose of mechanistically similar BMP-6 mAb increases Hb in dialysis patients Hepcidin Levels Elevated in CKD Patients ~20x higher than healthy subjects and increases with disease severity Healthy Subjects 0.001 0.1 10 1000 CKD Patients Hepcidin-25 (µg/L) 3.0 ± 0.5 60.4 ± 6.1* *P < 0.001 vs. healthy 3 2 1 0 -1 -2 Hb – Absolute change relative to baseline (g/dL) 0 7 14 21 28 35 42 49 56 63 70 77 84 91 Time (day)
DISC-0974 Improved Anemia in Model of CKD Rat Model of Adenine Diet-Induced CKD 1.7 g/dL vs. Vehicle DISC-0974 Reduced Hepcidin Expression DISC-0974 Increased Serum Iron DISC-0974 Increased Hemoglobin Levels Red:0.75% Adenine + DISC-0974 (20 mg/kg) Blue:0.75% Adenine + Vehicle Red:0.75% Adenine + DISC-0974 (20 mg/kg) Blue:0.75% Adenine + Vehicle 0.75% Adenine + DISC-0974 0.75% Adenine + Vehicle Fold Expression (normalized to vehicle control) 80 60 40 20 0 umol/L 14 13 12 11 10 9 8 g/dL 0 10 20 30 40 Days 0 10 20 30 40 Days 2.0 1.5 1.0 0.5 0.0
Phase 1b / 2a POC Trial in NDD-CKD Anemia Aim to evaluate efficacy and safety in non-dialysis dependent patients 28 mg 40 mg 60 mg Dose TBD x 3 (Once-monthly) Phase 1b Single-Ascending Dose Treatment Duration: 3 months (q28d) Stage II-V CKD; Adult Not receiving dialysis Hb (g/dL) < 10.5 (F), 11 (M) Exclude iron-deficient anemia by ferritin and TSAT Key Endpoints / Measures: Change in hemoglobin; iron, hepcidin, and other hematologic parameters, safety / tolerability Trial Population Phase 2a Open-Label, Multiple-Dose N=8 per Cohort (6 Active, 2 Placebo) Assessment of safety, PK, hepcidin and iron after each dose level DISC-0974 (n=12); Placebo (n=4) Data availability: Initial data expected by year-end 2023 90 mg
Anti-TMPRSS6 mAb Induces Hepcidin Designed to limit iron levels with potential to address a wide range of hematologic disorders Promotes Iron Restriction Decreases GI Absorption Limits Iron Availability Increases Hepcidin Enables Endogenous Production of Hepcidin Erythrocytosis (PV) Ineffective Erythropoiesis Iron Overload Modulates RBC Production
Genetic validation in patients with IRIDA (Iron-Refractory Iron Deficiency Anemia) LOF TMPRSS6 mutation increases hepcidin and reduces iron availability Functionally specific to hepcidin / iron Tissue specific expression primarily in the liver Targeting TMPRSS6 to Increase Hepcidin Potent, specific target controls endogenous hepcidin production Inhibiting TMPRSS6 with an Antibody Enables Hepcidin Production to Suppress Iron TMPRSS6 selectively degrades HJV TMPRSS6
Potent PD effects observed across multiple preclinical studies consistent with TMPRSS6 inhibition Hepcidin: 3-4 fold induction Serum iron: ~ 60-70% suppression MWTX-003 demonstrated excellent safety profile in non-clinical GLP safety studies MWTX-003 Effects in Non-Human Primates Resulted in deep and sustained suppression of serum iron levels Single dose of MWTX-003 resulted in ~ 70% suppression of serum iron lasting 3 weeks Chen B. et al Blood (2021) 138 (Supplement 1): 941, ASH 2021 Annual Meeting
Effects in HbbTh3/+ Model of Beta-Thalassemia Significant effects on hallmarks of disease including iron overload, ineffective erythropoiesis and splenomegaly were observed HbbTh3/+ mice were treated with the lead anti-TMPRSS6 antibody at 10 mg/kg IP for 4 weeks ↓ Serum and Liver Iron 60-65% Reduction ↑ Hepcidin Production Up to 4-fold (mRNA) ↑ RBC Production ↓ Spleen Weight Chen B. et al Blood (2021) 138 (Supplement 1): 941, ASH 2021 Annual Meeting
MTWX-003 Development Plans Aim to establish phase 1 proof-of-mechanism and advance program into POC studies with focus on Polycythemia Vera Phase 1 SAD / MAD in HV Plan to Initiate 2H’23 Phase 2 Proof-of-Concept Trial in Polycythemia Vera Additional POC Studies in a Range of Indications Demonstrate proof-of-mechanism (hepcidin, iron, hematologic parameters) Strong proof of therapeutic hypothesis; clarity on regulatory development path Assess safety, PK, hepcidin, iron, hematologic parameters; %Hct and requirement for phlebotomy Hereditary Hemochromatosis Beta-thalassemia Myelodysplastic Syndromes Hct = hematocrit; HV = healthy volunteers
Disc is Building a Leading Company Dedicated to Treating Hematologic Diseases Focused on fundamental and well-validated pathways that affect heme biosynthesis and iron homeostasis Initial data DISC-0974 Phase 1b/2 trials in anemias of NDD-CKD and MF; data from bitopertin Phase 2 trials in EPP / XLP Bitopertin (Phase 2): Potential 1st disease-modifying treatment for debilitating, orphan diseases EPP / XLP DISC-0974 (Phase 1b/2): Targeting anemia of inflammation opportunity with non-ESA mechanism MWTX-003 (IND accepted): Targeting polycythemia vera and disease of iron overload Leadership with deep experience developing and commercializing therapies; strong balance sheet with support from top-tier healthcare investors Clinical-stage biopharmaceutical company developing therapies for hematologic diseases Portfolio of 3 distinct “pipeline-in-a-product” programs with broad applications and opportunity for growth Entering catalyst-rich period with multiple data read-outs anticipated across portfolio in next 6-12 months Strong foundation positions us to build Disc into a leading hematology company
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