Special Note Regarding Forward-Looking Statements The report contains forward-looking statements subject to risks and uncertainties that could cause actual results to differ materially from expectations - The report contains forward-looking statements under the Private Securities Litigation Reform Act of 1995, which are subject to various risks and uncertainties that could cause actual results to differ materially from expectations911 - Key areas of forward-looking statements include regulatory approval, commercialization, sales and marketing, clinical trial timing, market size, intellectual property, regulatory developments, supplier performance, competition, personnel, COVID-19 impact, and financing10 Summary of Risks Associated with Our Business Investing in the company's common stock involves a high degree of risk, including a limited operating history, significant losses, and dependence on product candidate success - Investing in the company's common stock involves a high degree of risk, including a limited operating history, significant losses, dependence on product candidate success, potential clinical trial delays, extensive regulatory hurdles, and intense competition1516 - Other significant risks include the need for substantial additional financing, reliance on third-party intellectual property, and challenges in obtaining and maintaining intellectual property protection16 PART I Item 1. Business Mirum Pharmaceuticals develops and commercializes novel therapies for orphan cholestatic liver diseases with maralixibat and volixibat Overview Mirum Pharmaceuticals is a biopharmaceutical company focused on developing and commercializing late-stage novel therapies for debilitating orphan cholestatic liver diseases - Mirum Pharmaceuticals is a biopharmaceutical company focused on developing and commercializing late-stage novel therapies for debilitating liver diseases, specifically orphan cholestatic liver diseases17 - The company's pipeline includes two clinical-stage product candidates, maralixibat and volixibat, targeting conditions like Alagille syndrome (ALGS), progressive familial intrahepatic cholestasis (PFIC), biliary atresia (BA), primary sclerosing cholangitis (PSC), intrahepatic cholestasis of pregnancy (ICP), and primary biliary cholangitis (PBC)171819 - Maralixibat's NDA for ALGS cholestatic pruritus was completed in January 2021, with a potential launch in H2 2021. An MAA for PFIC2 has been submitted to the EMA. Volixibat's Phase 2b trials for PSC and ICP have initiated, with a PBC trial planned for H2 20211819 Our Product Pipeline Mirum's pipeline features maralixibat and volixibat, novel ASBT inhibitors reducing toxic bile acid accumulation - Mirum owns exclusive worldwide rights to its product candidates, maralixibat and volixibat, which are novel, oral, minimally-absorbed ASBT inhibitors designed to reduce systemic bile acid levels2021 - ASBT inhibition works by increasing bile acid excretion in feces, thereby lowering toxic bile acid accumulation in the liver and systemically, aiming to improve long-term outcomes and symptoms21 Maralixibat Maralixibat, a lead oral ASBT inhibitor, has an extensive safety profile and holds Breakthrough Therapy and Orphan Drug Designations - Maralixibat is a lead product candidate, an oral ASBT inhibitor, with an extensive safety dataset from over 1,600 human subjects and over 120 children treated in ALGS and PFIC studies21 - It has received Breakthrough Therapy Designation for pruritus associated with ALGS and for PFIC2, as well as Orphan Drug Designation for ALGS, PFIC, and BA21232728 Maralixibat in ALGS Maralixibat for Alagille syndrome (ALGS) shows significant pruritus and sBA reductions, with an NDA submitted for approval - ALGS affects 1 in 30,000 births in the US and Europe, with an estimated 2,000-2,500 eligible children in the US. There are no approved therapies, and liver transplant is often the only definitive treatment22 - The Phase 2b ICONIC trial showed statistically significant reductions in pruritus (ItchRO(Obs) score, p<0.0001), serum bile acids (sBA, 36% reduction, p<0.01), and xanthomas (44% reduction, p<0.01) at week 48, with improved quality of life23 - An NDA for cholestatic pruritus in ALGS patients was completed in January 2021, with a potential FDA review decision and commercial launch in H2 202125 Maralixibat in PFIC Maralixibat for Progressive Familial Intrahepatic Cholestasis (PFIC) has an MAA submitted to EMA, with a Phase 3 trial ongoing - PFIC affects 1 in 50,000 to 100,000 births in the US and Europe, with no approved therapies. Surgical options like PEBD and liver transplantation are available but have significant complications26 - An MAA for maralixibat in PFIC2 has been submitted to the EMA, based on five-year results from the Phase 2 INDIGO trial, showing improved transplant-free survival, pruritus, and growth in responders27 - The Phase 3 MARCH clinical trial is ongoing, evaluating higher doses of maralixibat in a broader PFIC population, with enrollment expected to complete in Q2 2021 and topline data in early 202227 Maralixibat in BA Maralixibat is being evaluated in a Phase 2b trial for Biliary Atresia (BA), a rare infant liver disorder - BA is a rare liver disorder in infants, affecting 1 in 10,000 to 15,000 live births in the US, and is the most common reason for liver transplantation in children28 - The standard Kasai procedure has a success rate of 30-40%, with remaining patients at risk of progressive liver disease requiring transplant. ASBT inhibition is believed to have therapeutic potential by reducing sBA28 - Recruitment for the EMBARK Phase 2b clinical trial of maralixibat in BA began in Q1 2021, and maralixibat has Orphan Drug Designation for BA28 Volixibat Volixibat, an oral ASBT inhibitor, is being developed for adult cholestatic liver diseases, with Phase 2b trials initiated - Volixibat is a novel, oral, minimally-absorbed ASBT inhibitor being developed for adult cholestatic liver diseases, including ICP, PSC, and PBC29 - Clinical trials in over 400 adults have shown significant activity on ASBT and bile acid markers, demonstrating potent biological activity29 - The OHANA Phase 2b trial for ICP and VISTAS Phase 2b trial for PSC initiated in Q1 2021, with a PBC trial planned for H2 2021. There are no approved therapies for PSC or ICP in the US19313234 Our History Mirum Pharmaceuticals was incorporated in May 2018, began operations in November 2018, and completed its IPO in July 2019 - Mirum Pharmaceuticals was incorporated in Delaware in May 2018 and began operations in November 2018, completing its IPO in July 201935 - The management team has significant experience in developing and commercializing liver and orphan disease therapies35 Our Strategy Mirum's strategy focuses on leading liver disease treatment by advancing maralixibat and volixibat, and expanding its pipeline - Mirum's strategy is to be a leader in liver disease treatment by advancing maralixibat for ALGS, PFIC, and BA, and volixibat for PSC, ICP, and PBC36 - The company plans to commercialize approved products in North America and Europe with a targeted specialty sales force, and seek strategic collaborations for other territories3640 - Mirum also aims to actively manage its product portfolio and expand its pipeline by identifying, acquiring, in-licensing, and advancing additional product candidates for liver diseases40 Overview of Cholestatic Liver Diseases Cholestatic liver diseases involve impaired bile flow, leading to toxic bile acid accumulation, severe pruritus, and liver injury - Cholestatic liver diseases involve impaired bile flow, leading to accumulation of toxic bile acids in the liver and systemically, causing severe pruritus, liver injury, and potentially liver failure38 - ASBT is responsible for recycling 95% of bile acids from the intestine to the liver; inhibiting it leads to increased fecal excretion and lower systemic bile acid levels37 - Symptoms include jaundice, pruritus, progressive liver disease, and growth delay, significantly impacting patient quality of life and caregiver well-being38 Alagille Syndrome Alagille Syndrome (ALGS) is a rare genetic disorder causing malformed bile ducts, severe pruritus, and progressive liver disease - ALGS is a rare genetic disorder (1 in 30,000 births in US/Europe) characterized by malformed bile ducts, leading to bile accumulation and progressive liver disease39 - The addressable patient population in the US is estimated at 2,000-2,500 pediatric ALGS patients, with severe pruritus being a major symptom and driver for liver transplantation3940 - Current options, PEBD and liver transplantation, are invasive and have significant complications, highlighting a substantial unmet medical need41 Progressive Familial Intrahepatic Cholestasis Progressive Familial Intrahepatic Cholestasis (PFIC) is a rare genetic disorder causing cholestasis and progressive liver disease - PFIC is a rare genetic disorder (1 in 50,000 to 100,000 births in US/Europe) causing cholestasis and progressive liver disease, often leading to liver failure in infancy4244 - Mirum's initial focus is on nt-PFIC2 patients (50% of PFIC population) who have residual BSEP function, making them potential responders to ASBT inhibition4345 - Severe pruritus is a prominent symptom, and current treatments (PEBD, liver transplant) are often the only options, indicating a high unmet medical need4445 Biliary Atresia Biliary Atresia (BA) is a rare infant liver disorder, the most common reason for pediatric liver transplantation - BA is a rare infant liver disorder (1 in 10,000 to 15,000 live births in the US) involving blocked or absent bile ducts, leading to bile accumulation and liver damage, and is the most common reason for pediatric liver transplantation47 - The Kasai procedure is the standard surgical treatment, but its success rate is only 30-40%, with many patients still requiring liver transplantation, often before two years of age49 - Elevated serum bile acids (sBA) and bilirubin levels post-Kasai procedure are associated with a higher risk of progression to transplant, supporting the potential of ASBT inhibition49 Intrahepatic Cholestasis of Pregnancy Intrahepatic Cholestasis of Pregnancy (ICP) increases perinatal risks and causes severe pruritus, with no FDA-approved therapy - ICP is a liver disorder in pregnant women (estimated 40,000 cases in US, 100,000 in Europe annually) that increases risks of stillbirth, preterm labor, and neonatal complications, and is associated with severe pruritus5051 - Elevated sBA levels in ICP correlate with worsened perinatal risks. There is no FDA-approved therapy in the US, and off-label UDCA offers minimal improvement5152 - ASBT inhibition is believed to offer therapeutic potential for ICP patients due to its impact on sBA levels52 Primary Sclerosing Cholangitis Primary Sclerosing Cholangitis (PSC) is a rare, chronic cholestatic liver disease leading to liver failure and debilitating pruritus - PSC is a rare, chronic cholestatic liver disease (estimated 29,000 in US, 50,000 in Europe) characterized by progressive inflammation and destruction of bile ducts, leading to liver failure53 - Up to 70% of PSC patients suffer from debilitating pruritus. Liver transplantation is the only treatment shown to improve clinical outcomes, but recurrence rates post-transplant can be as high as 25%555657 - There is an acute need for novel therapies, as off-label UDCA does not improve pruritus. ASBT inhibition is believed to address symptoms and potentially delay liver transplantation5657 Primary Biliary Cholangitis Primary Biliary Cholangitis (PBC) is a chronic, immune-mediated cholestatic liver disease causing severe pruritus and liver damage - PBC is a chronic, rare cholestatic liver disease caused by immune-mediated destruction of intrahepatic bile ducts, leading to increased hepatic bile acid concentrations and progressive liver damage58 - PBC disproportionately affects women (10:1 ratio) and is typically diagnosed between 40-60 years of age. Up to 70% of patients experience severe pruritus, significantly impacting quality of life5960 - Existing therapies for PBC-associated pruritus are temporary or suboptimal, highlighting an unmet need for effective treatments61 Our Solutions Mirum's solutions for cholestatic liver diseases focus on ASBT inhibition to increase bile acid excretion and relieve symptoms - Mirum's solutions for cholestatic liver diseases focus on inhibiting ASBT, which increases bile acid excretion and reduces systemic bile acid levels, leading to improved liver function and symptom relief62 Overview of Maralixibat Maralixibat, an oral ASBT inhibitor, shows significant efficacy in ALGS and PFIC, with NDA/MAA submissions underway - Maralixibat is a lead product candidate, an oral, minimally-absorbed ASBT inhibitor with an extensive safety dataset from over 1,600 human subjects63 - In ALGS, Phase 2b ICONIC trial showed statistically significant reductions in pruritus and sBA, leading to an NDA submission for cholestatic pruritus in ALGS patients64 - In PFIC, Phase 2 INDIGO trial showed multi-parameter response in nt-PFIC2 patients, forming the basis for EMA MAA submission. Phase 3 MARCH trial is ongoing for broader PFIC subtypes65 Historical Clinical Development of Maralixibat This section details maralixibat's clinical development, including ALGS, PFIC, and BA trials, highlighting efficacy and safety data Our Clinical Trials of Maralixibat in ALGS Maralixibat's Phase 2b ICONIC trial in ALGS demonstrated statistically significant reductions in pruritus and sBA - The Phase 2b ICONIC trial in ALGS patients met its primary endpoint, showing a statistically significant difference in sBA reduction between treatment and placebo groups (p<0.05) during randomized withdrawal6768 - Patients treated with maralixibat in ICONIC showed approximately 60% mean reduction in pruritus (ItchRO(Obs) score, p<0.0001) and 31% mean reduction in sBA levels at week 18, with sustained improvements through week 204717374 - ICONIC trial also demonstrated significant improvements in xanthomas (44% reduction at week 48, p<0.01) and a clinically meaningful acceleration in height growth (p≤0.01) with long-term treatment7980 Additional Phase 2 Trials in ALGS Additional Phase 2 trials (ITCH and IMAGO) in ALGS evaluated lower maralixibat doses, showing less pronounced pruritus reduction - Two additional Phase 2 trials (ITCH and IMAGO) in ALGS evaluated lower doses of maralixibat, which showed less pronounced pruritus reduction compared to the ICONIC trial's higher dose83 Pruritus Results from Phase 2 ITCH and IMAGO Clinical Trials in ALGS (Week 13) | | ITCH MRX | ITCH PBO | IMAGO MRX | IMAGO PBO | | :--- | :--- | :--- | :--- | :--- | | Change from Baseline ItchRO(Obs) | -1.19 | -0.58 | -0.61 | -0.59 | | % Change from Baseline ItchRO(Obs) | -39% | -21% | -22% | -19% | - Long-term open-label extensions of ITCH (IMAGINE II) and IMAGO (IMAGINE I) showed sustained pruritus relief despite initial non-significant differences from placebo at week 1384 Registrational Path for Maralixibat in ALGS Mirum completed its NDA submission for maralixibat in ALGS, benefiting from Breakthrough Therapy and Rare Pediatric Disease Designations - Mirum completed its NDA submission for maralixibat for cholestatic pruritus in ALGS patients in January 2021, following Breakthrough Therapy Designation and Rare Pediatric Disease Designation85 - The Rare Pediatric Disease Designation may qualify the company for a priority review voucher if the NDA is approved85 - Discussions with the EMA regarding submission plans for ALGS are pending further analysis of long-term extension treatment data compared to natural history data86 Our Clinical Trials of Maralixibat in PFIC The Phase 2 INDIGO trial in PFIC2 patients showed profound sBA reductions and pruritus improvements, leading to Breakthrough Therapy Designation - The Phase 2 INDIGO trial in PFIC2 patients showed profound and durable reductions in sBA and significant improvements in pruritus, particularly in nt-PFIC2 patients with residual BSEP function8791 - INDIGO data indicated that 100% of maralixibat patients who achieved the NAPPED sBA response threshold remained transplant-free, demonstrating a clear pattern of response leading to long-term transplant-free survival95 - The observed responses in PFIC2 patients led to Breakthrough Therapy Designation for maralixibat in this indication91 Registrational Program for Maralixibat in PFIC Mirum submitted an MAA to the EMA for maralixibat in PFIC2, with the Phase 3 MARCH trial ongoing to support a future FDA NDA - Mirum submitted an MAA to the EMA for maralixibat for PFIC2 treatment in Q4 2020, based on INDIGO trial results and natural history comparisons, which is currently under review96 - The Phase 3 MARCH clinical trial is a randomized, placebo-controlled study evaluating higher doses of maralixibat (up to 570 µg/kg BID) in up to 30 nt-PFIC2 patients (aged 1-17 years), with a primary endpoint of pruritus reduction9798 - Topline data from the Phase 3 MARCH trial is expected in early 2022, and if positive, will support a planned NDA submission to the FDA for maralixibat in PFIC98 Safety and Tolerability Data for Maralixibat Maralixibat's clinical development program showed mild to moderate GI adverse reactions, with no serious drug-induced liver injury - In the ALGS clinical development program (86 patients, up to 760 µg/kg/day), the most common adverse reactions were mild to moderate diarrhea and abdominal pain, which resolved with continued treatment99 - Independent safety reviews concluded no serious concern for drug-induced liver injury, though isolated, asymptomatic, and reversible ALT elevations were observed in some ALGS participants, likely disease-related101 - No cases of drug-induced liver injury or liver-related morbidity/mortality have been reported in over 1600 adult and pediatric study participants101 Maralixibat in BA Maralixibat is being evaluated in the Phase 2 EMBARK trial for Biliary Atresia (BA) infants, supported by preclinical data - Preclinical data in bile duct ligated rats showed maralixibat treatment significantly reduced sBA and liver transaminases, supporting its therapeutic potential in BA102103 - Clinical observations indicate that lower bilirubin and sBA levels post-Kasai procedure predict improved transplant-free survival in BA patients104105107109 - The Phase 2 EMBARK trial in BA infants (approx. 72 patients post-Kasai) will evaluate maralixibat's safety and efficacy, with primary endpoint of change in total serum bilirubin and secondary endpoints including sBA reduction and transplant-free survival110 Overview of Volixibat Volixibat is a novel, oral ASBT inhibitor for adult cholestatic diseases, demonstrating potent biological activity - Volixibat is a novel, oral, minimally-absorbed ASBT inhibitor aimed at treating adult cholestatic diseases by blocking bile acid recycling, thereby reducing systemic and liver bile acid levels111 - Phase 1 and Phase 2 clinical trials demonstrated volixibat's potent biological activity through decreases in LDL cholesterol and increases in 7αC4 and fecal bile acid content111 Development of Volixibat Volixibat has been evaluated in over 400 adults, showing general tolerability and dose-dependent ASBT inhibition - Volixibat has been evaluated in over 400 adults, showing general tolerability with common mild to moderate GI events in Phase 1 trials112 - A Phase 1 dose-ranging study in healthy adults confirmed dose-dependent increases in fecal bile acid excretion and bile acid synthesis (7αC4), with 20 mg and 80 mg BID doses selected for registrational programs114 - Previous development for NASH was discontinued by Shire plc, but results indicated ASBT inhibition, leading Mirum to pursue development for adult cholestatic liver diseases113 On-going and Future Clinical Development of Volixibat This section outlines the ongoing and planned clinical development of volixibat for ICP, PSC, and PBC, including Phase 2a/2b trials Phase 2a/2b OHANA Trial in ICP The OHANA Phase 2a/2b trial is evaluating volixibat in ICP patients, assessing sBA reduction and pruritus improvements - The OHANA Phase 2a/2b clinical trial is evaluating two doses of volixibat (80 mg BID or 20 mg BID) versus placebo in approximately 260 ICP patients with elevated sBA levels117118 - The primary endpoint is the mean change from baseline in total sBA concentration, with secondary endpoints assessing pruritus improvements, perinatal outcomes, safety, and tolerability119 Phase 2b VISTAS Trial in PSC The VISTAS Phase 2b trial is evaluating volixibat in PSC patients with pruritus, including an adaptive interim analysis - The VISTAS Phase 2b clinical trial is evaluating volixibat in approximately 120 PSC patients with pruritus, including an adaptive interim analysis120 - The confirmatory phase will compare a single dose of volixibat to placebo, with patients eligible for an open-label extension to assess durability of response and changes in fibrosis markers120 Phase 2b Clinical Trial in PBC Mirum plans to initiate a Phase 2b clinical trial of volixibat in PBC in H2 2021, focusing on treating cholestatic pruritus - Mirum plans to initiate a Phase 2b clinical trial of volixibat in PBC in the second half of 2021, focusing on treating cholestatic pruritus with elevated or normal alkaline phosphatase122 License, Finance and Royalty Agreements This section details Mirum's key license, finance, and royalty agreements with various partners, outlining payment obligations Assignment and License Agreement with Shire International GmbH (Takeda) Mirum acquired exclusive worldwide rights to maralixibat and volixibat from Shire (Takeda), involving upfront payments, milestones, and royalties - In November 2018, Mirum acquired exclusive worldwide rights to maralixibat and volixibat from Shire (now Takeda) through an assignment and license agreement, including rights to underlying Pfizer, Satiogen, and Sanofi agreements123124 - Mirum made an upfront payment of $7.5 million and issued 1,859,151 shares of common stock to Shire. Milestone payments include $2.5 million for Phase 3 MARCH trial initiation (July 2019), $10.0 million for PFIC2 MAA acceptance (Dec 2020), and $2.0 million for volixibat development milestone (Jan 2021)125127 - Future obligations include up to $107.0 million for maralixibat clinical/regulatory milestones (ALGS, PFIC, BA), $25.0 million for each other maralixibat indication, $30.0 million for volixibat's first indication, tiered sales milestones up to $30.0 million, and tiered royalties (low double-digits to mid-teens) on worldwide net sales, reducible by Sanofi/Satiogen royalties126128129 License Agreement with Pfizer Inc. Mirum obtained an exclusive worldwide license to Pfizer's know-how for maralixibat, with obligations for low single-digit royalties - Through the Shire License Agreement, Mirum obtained an exclusive, worldwide license to Pfizer's know-how related to maralixibat for development, manufacture, and commercialization132 - Mirum is obligated to pay Pfizer a low single-digit royalty on net sales of products utilizing the Pfizer Know-How, continuing until the eighth anniversary of the first commercial sale135 - Mirum has the right to unilaterally terminate the agreement with 90 days' notice. Pfizer retains rights for internal research133137 License Agreement with Sanofi-Aventis Deutschland GmbH Mirum obtained an exclusive worldwide license from Sanofi for volixibat patents and know-how, with milestone and tiered royalty payments - Mirum obtained an exclusive, worldwide license from Sanofi for patents and know-how related to volixibat, with rights to develop, commercialize, and manufacture138 - Mirum exercised an option in May 2020 to manufacture volixibat and is transferring manufacturing to a third-party contract manufacturer138 - Payment obligations include up to $36.0 million in regulatory, commercialization, and sales milestones, tiered royalties (mid to high single-digit) on net sales, and a percentage of sublicense fees (mid-teens to low-thirties)141 License Agreement with Satiogen Pharmaceuticals, Inc. Mirum obtained an exclusive worldwide license from Satiogen for ASBTi and TGR5 Technology, with milestone and low single-digit royalties - Mirum obtained an exclusive, worldwide license from Satiogen for ASBTi Technology and TGR5 Technology for human diseases (excluding diabetes/obesity), with sublicensing rights145 - Payment obligations include up to $10.5 million in milestones ($0.5 million development, $5.0 million regulatory, $5.0 million commercialization) and a low single-digit royalty on net sales, creditable against Shire royalties148 - Mirum paid a $0.5 million development milestone in July 2019 for the initiation of the Phase 3 MARCH clinical trial148 Revenue Interest Purchase Agreement with Oberland Mirum entered a RIPA with Oberland Capital, receiving $50.0 million upfront with potential for $150.0 million more, for tiered revenue interest - In December 2020, Mirum entered a Revenue Interest Purchase Agreement (RIPA) with Oberland Capital, receiving $50.0 million upfront (less costs)152 - Mirum may receive up to an additional $150.0 million in installments: $65.0 million upon FDA acceptance of ALGS NDA, $35.0 million upon FDA approval of ALGS, and up to $50.0 million at Purchasers' option for in-licenses/acquisitions152 - In return, Purchasers receive tiered Revenue Interest Payments (initially 9.75% at Tier 1, 2.00% at Tier 2/3) on annual net sales of maralixibat, terminating when payments reach 195.0% of Cumulative Purchaser Payments153 Intellectual Property Mirum's success relies on proprietary protection for its product candidates through patents, trade secrets, and exclusivity - Mirum's success depends on obtaining and maintaining proprietary protection for its product candidates, including patents, trade secrets, and know-how154 - The company holds rights to pending and issued patents in various jurisdictions covering methods of treating cholestasis using ASBTis with limited systemic exposure, expiring in October 2032154155 - Maralixibat lacks composition-of-matter patents, relying primarily on method-of-use and dosage form patents. Both maralixibat and volixibat may be eligible for 5 years of new chemical entity exclusivity and 7 years of orphan drug exclusivity in the US upon approval156158159 Sales and Marketing Mirum is building a commercial organization and medical affairs team to support maralixibat and volixibat in North America and Europe - Mirum is building a commercial organization to support maralixibat and volixibat in North America and Europe, targeting a small number of specialists who treat pediatric cholestasis163164 - The company is also developing a medical affairs organization to provide scientific and medical education to healthcare providers and patients in the rare liver disease community165 - In October 2020, Mirum partnered with Eversana for integrated distribution, specialty pharmacy, medical information, and patient services for maralixibat in the US, if approved166 Manufacturing Mirum relies entirely on third-party contract manufacturers for raw materials, API, and finished products, lacking its own facilities - Mirum does not own manufacturing facilities and relies entirely on third-party contract manufacturers for raw materials, active pharmaceutical ingredients (API), and finished products for its product candidates167 - The company currently lacks contractual arrangements for commercial supplies and plans to enter into such agreements with third-party suppliers prior to any FDA approval167 Competition The biopharmaceutical industry is highly competitive, with Mirum facing rivals developing ASBT inhibitors and existing off-label treatments - The biopharmaceutical industry is highly competitive, with Mirum facing competition from major pharmaceutical companies, biotechnology firms, academic institutions, and research institutions, many with greater resources168169 - There are no FDA-approved therapies for ALGS, PFIC, BA, PSC, or ICP in the US, but symptomatic treatments like cholestyramine and UDCA are used off-label171172173 - Competitors like Albireo Pharma, Inc. and GlaxoSmithKline plc are developing ASBT inhibitors for cholestatic liver diseases, with Albireo's odevixibat having an NDA accepted for PFIC173 Government Regulation and Product Approval This section outlines extensive US and international government regulations governing drug development, approval, and commercialization U.S. Drug Development Process The US drug development process is extensively regulated by the FDA, requiring substantial time and resources for preclinical and clinical trials - The US drug development process is extensively regulated by the FDA under the FDCA, requiring substantial time and financial resources for preclinical testing, IND submission, and multi-phase clinical trials (Phase 1, 2, 3)176177178183 - Clinical trials must comply with Good Laboratory Practice (GLP) and Good Clinical Practice (GCP) regulations, and require IRB approval and ongoing monitoring177178179 - Successful completion of clinical trials is necessary to establish safety and efficacy, followed by NDA submission and FDA review for commercial marketing approval178 U.S. Review and Approval Processes The FDA reviews NDAs for safety, effectiveness, and manufacturing compliance, potentially requiring advisory committee review or post-market studies - The FDA reviews NDAs for safety and effectiveness, manufacturing compliance (cGMP), and may require advisory committee review or additional post-market studies (Phase 4)184187188190 - The Pediatric Research Equity Act (PREA) generally requires pediatric clinical trials for new drugs, unless a deferral or waiver is granted, or the drug has orphan designation for that indication185 - FDA approval may be limited to specific indications or dosages, or require a Risk Evaluation and Mitigation Strategy (REMS) to ensure safe use190 Orphan Drug Designation Orphan Drug Designation provides 7 years of market exclusivity for drugs treating rare diseases, along with financial incentives - Orphan Drug Designation is granted by the FDA for drugs treating rare diseases (fewer than 200,000 individuals in the US) and, if first approved, provides 7 years of market exclusivity191192 - Exclusivity can be lost under certain circumstances, such as a showing of clinical superiority by a competitor or if the designation criteria are no longer met192 - Orphan designation does not expedite the regulatory review process but offers financial incentives like grant funding, tax advantages, and user-fee waivers191192 Rare Pediatric Disease Priority Review Voucher Program The FDA awards priority review vouchers for drugs approved for rare pediatric diseases, which are transferable and can expedite subsequent applications - The FDA awards priority review vouchers for drugs approved for 'rare pediatric diseases' (serious/life-threatening conditions primarily affecting individuals aged 0-18 years and meeting Orphan Drug Act criteria)193195 - Vouchers can be redeemed for priority review of a subsequent marketing application for a different product and are transferable193 - The program is authorized until September 30, 2024, with eligibility for vouchers if designation is received before this date and approval before September 30, 2026195 Expedited Development and Review Programs The FDA offers Fast Track, Priority Review, Accelerated Approval, and Breakthrough Therapy programs to expedite development - The FDA offers Fast Track, Priority Review, and Accelerated Approval programs to expedite development and review for drugs treating serious/life-threatening conditions with unmet medical needs or potential for substantial improvement196197198 - Breakthrough Therapy designation, granted to maralixibat, provides intensive FDA interaction and guidance, and includes Fast Track features199 - These designations do not change approval standards and do not guarantee faster development, review, or approval, nor do they assure a material commercial advantage198200 Post-Approval Requirements Approved drug products are subject to ongoing FDA regulation, including record-keeping, adverse event reporting, and strict promotion rules - Approved drug products are subject to ongoing FDA regulation, including record-keeping, adverse event reporting, product sampling, distribution, and strict promotion/advertising requirements (e.g., no off-label promotion)202 - Manufacturing processes must continuously conform to cGMP requirements, and facilities are subject to periodic FDA inspections203 - Discovery of post-approval problems or non-compliance can lead to product restrictions, recalls, withdrawal of approval, fines, and other penalties203204 U.S. Patent Term Restoration and Marketing Exclusivity The Hatch-Waxman Amendments allow for patent term restoration and marketing exclusivity for new chemical entities and clinical investigations - The Hatch-Waxman Amendments allow for up to 5 years of patent term restoration to compensate for regulatory review time, but cannot extend a patent beyond 14 years from approval205 - New chemical entities receive 5 years of non-patent marketing exclusivity, preventing FDA approval of generic or 505(b)(2) applications for the same active moiety206 - Three years of marketing exclusivity is granted for new clinical investigations essential to approval (e.g., new indications), and pediatric exclusivity can add 6 months to existing exclusivity periods206207 Other U.S. Healthcare Laws and Compliance Requirements The company is subject to federal and state anti-kickback, fraud and abuse, false claims, privacy, and transparency laws - The company is subject to federal and state anti-kickback, fraud and abuse, false claims, privacy and security (HIPAA, HITECH), and Physician Payments Sunshine Act laws208209213214215216 - Violations can lead to significant civil, criminal, and administrative penalties, including fines, exclusion from government programs, and reputational harm176221 - The California Consumer Privacy Act (CCPA) and GDPR impose stringent requirements on personal data processing, with significant fines for non-compliance and challenges for cross-border data transfers217218219 Pharmaceutical Coverage, Pricing and Reimbursement Sales of approved products depend on coverage and adequate reimbursement from third-party payors, a costly and time-consuming process - Sales of approved products depend on coverage and adequate reimbursement from third-party payors (federal, state, private insurers), who increasingly challenge prices and medical necessity224 - Obtaining coverage and reimbursement is a costly and time-consuming process, requiring scientific, clinical, and cost-effectiveness data, with no assurance of adequate rates224227 - Participation in government programs (Medicaid, VHCA) may require significant discounts and rebates, potentially lowering product prices225 Healthcare Reform Healthcare reform initiatives, including the ACA and drug pricing regulations, create uncertainty and potential downward pressure on prices - The Affordable Care Act (ACA) and subsequent legislative changes have introduced cost-containment measures, including fees on drug manufacturers, increased Medicaid rebates, and Medicare payment reductions228230231232 - Ongoing challenges to the ACA and new executive orders/regulations related to drug pricing (e.g., Most Favored Nation rule) create uncertainty and potential downward pressure on drug prices230234 - State-level legislation also aims to control pharmaceutical pricing through price/reimbursement constraints, discounts, and transparency measures, which could harm business and profitability235236 The U.S. Foreign Corrupt Practices Act The FCPA prohibits offering or paying anything of value to foreign officials to influence business decisions, requiring accurate accounting - The U.S. Foreign Corrupt Practices Act (FCPA) prohibits offering or paying anything of value to foreign officials to influence business decisions and requires accurate accounting records237238 - Violations can lead to criminal liability and serious consequences, including fines, imprisonment, and reputational harm, impacting the ability to compete internationally108519 Europe / Rest of World Government Regulation Foreign operations are subject to diverse regulations for clinical trials, product licensing, pricing, and reimbursement, with penalties for non-compliance - Operations in foreign countries are subject to diverse regulations for clinical trials, product licensing, pricing, and reimbursement, similar to but with important differences from US regulations239240 - The European Union offers centralized and national authorization procedures for marketing approval, with orphan drug designation providing 10 years of market exclusivity (extendable to 12 years)241242243244245 - Failure to comply with foreign regulatory requirements can result in fines, withdrawal of approvals, product recalls, and criminal prosecution247 Human Capital Management Mirum employs 68 full-time staff, prioritizing talent attraction, development, and retention through training and diversity initiatives - As of December 31, 2020, Mirum employed 68 full-time employees (61 in US, 7 in Switzerland), with 17 holding Ph.D. or M.D. degrees, and expects to add more in 2021248249 - The company prioritizes attracting, developing, and retaining key personnel through training, performance management, and engagement surveys, and is committed to diversity and inclusion250251253 - In response to COVID-19, Mirum implemented work-from-home policies, enhanced safety measures for in-office work (health attestations, PPE, increased cleaning), and prohibited non-essential travel250251 Corporate Information Mirum Pharmaceuticals, Inc. was incorporated in Delaware in May 2018, with principal executive offices located in Foster City, California - Mirum Pharmaceuticals, Inc. was incorporated in Delaware in May 2018, with principal executive offices in Foster City, California254 Emerging Growth Company Mirum is an 'emerging growth company' under the JOBS Act, benefiting from reduced reporting requirements, but opted out of extended accounting transition - Mirum is an 'emerging growth company' under the JOBS Act, allowing it to take advantage of reduced public company reporting requirements until December 31, 2024, or earlier if certain conditions are met255 - The company has irrevocably elected not to use the extended transition period for complying with new or revised financial accounting standards, adhering to the same standards as other public companies256 - Mirum also qualifies as a 'smaller reporting company,' enabling it to use scaled disclosures as long as its non-affiliate common stock market value is below $250 million or annual revenue is below $100 million and market value below $700 million256 Item 1A. Risk Factors This section details significant risks to Mirum's business, including operational, financial, intellectual property, and stock ownership challenges Risks Related to Our Business and Industry Mirum faces risks from its limited operating history, significant losses, COVID-19 impacts, dependence on product candidates, and intense competition - Mirum has a very limited operating history since its inception in May 2018 and has incurred significant net losses, totaling $173.2 million accumulated deficit as of December 31, 2020, with expectations of continued losses259260261 - The COVID-19 pandemic has adversely affected operations, including patient enrollment in clinical trials (e.g., Phase 3 MARCH), potential delays in regulatory approvals, and disruptions to supply chains and financial markets263265268270271 - The business is highly dependent on the successful clinical testing, regulatory approval, and commercialization of maralixibat and volixibat, which is a lengthy, expensive, and uncertain process, with potential for delays or failure to demonstrate safety and efficacy274276284289 - Market opportunities for rare cholestatic liver diseases may be smaller than anticipated, and competition from other biotechnology and pharmaceutical companies, including those developing ASBT inhibitors, is significant302349351 - Even with Breakthrough Therapy and Orphan Drug Designations, there is no guarantee of faster approval or market exclusivity, and product candidates may cause undesirable side effects or fail to gain market acceptance306322352356360 Risks Related to Our Reliance on Third Parties Mirum is highly dependent on third-party licensed IP, CROs for clinical trials, and contract manufacturers for drug supplies, posing significant risks - Mirum is highly dependent on intellectual property licensed from third parties (Shire, Pfizer, Satiogen, Sanofi), and termination of these licenses due to non-compliance or disputes could severely harm its business397398448449 - The company relies on third-party CROs for clinical trials and contract manufacturers for drug supplies, and their failure to perform, comply with regulations (GCPs, cGMPs), or meet deadlines could delay or terminate development and commercialization399400404405407 - Reliance on single-source suppliers and manufacturers, and potential disruptions from events like COVID-19, could jeopardize the supply of product candidates and increase costs405407408 Risks Related to Our Financial Position and Capital Requirements Mirum requires substantial additional financing, with potential for stockholder dilution or restrictive debt covenants, and NOL carryforward limitations - Mirum will require substantial additional financing to fund clinical development, commercialization, and operations, and may need to raise funds sooner than anticipated due to unforeseen expenses or market volatility410411414 - Raising additional capital through equity or convertible debt will dilute existing stockholders, while debt financing may impose restrictive covenants. Strategic partnerships could require relinquishing valuable rights416417 - The company's ability to utilize its federal and state net operating loss (NOL) carryforwards (approx. $123.5 million federal, $2.6 million state as of Dec 31, 2020) and tax credits may be limited by ownership changes (Section 382) or state-level suspensions418419421 Risks Related to Our Intellectual Property Mirum's success depends on obtaining and maintaining intellectual property protection, facing challenges with method-of-use patents and infringement claims - Mirum's commercial success depends on obtaining and maintaining sufficient intellectual property protection, including patents, trade secrets, and confidentiality agreements, which is complex and uncertain422423424426427428 - Maralixibat relies on method-of-use and formulation patents, which are generally weaker than composition-of-matter patents and do not prevent competitors from marketing identical products for unpatented uses ('off-label')438439 - The company faces risks of third-party claims alleging patent infringement, which could lead to costly litigation, development delays, substantial damages, or the need to obtain licenses on unfavorable terms458460462463 - Protecting trade secrets is difficult, and unauthorized disclosure or independent development by competitors could harm Mirum's competitive position. Trademark protection is also crucial for brand recognition481482484485487 Risks Related to Ownership of Our Common Stock The common stock price is highly volatile, stockholder returns depend on appreciation, and anti-takeover provisions could limit market price - The trading price of Mirum's common stock is highly volatile, influenced by clinical trial results, regulatory decisions, competition, financing, and general market conditions, potentially leading to significant fluctuations489491 - The company does not intend to pay dividends, so stockholder returns depend solely on stock appreciation. Principal stockholders and management own a significant percentage, allowing them to exert substantial control493494 - Payment obligations under the Revenue Interest Purchase Agreement (RIPA) could adversely affect financial position, increase vulnerability to downturns, and restrict cash flow for future operations499 - Anti-takeover provisions in charter documents and Delaware law could delay or prevent a change of control, potentially limiting the market price of common stock507508509 General Risk Factors Mirum faces risks from cybersecurity incidents, compliance with U.S. and foreign laws, and its status as an emerging growth company - Mirum's computer systems and those of its third-party partners are vulnerable to cybersecurity incidents, which could disrupt development programs, compromise intellectual property, and lead to significant liabilities513516 - The company is subject to U.S. and foreign export/import controls, sanctions, anti-corruption laws (FCPA), and anti-money laundering laws, with violations potentially leading to criminal liability and business harm519 - As an emerging growth company and smaller reporting company, Mirum benefits from reduced reporting requirements, but this status may make its stock less attractive to some investors and could lead to increased volatility521522 Item 1B. Unresolved Staff Comments This item states that there are no unresolved staff comments from the SEC - Not applicable533 Item 2. Properties Mirum Pharmaceuticals leases its headquarters in Foster City, California and an office in Basel, Switzerland, deeming current facilities adequate - Mirum leases 11,200 square feet for its headquarters in Foster City, California, with the agreement expiring in March 2025534 - The company also leases approximately 1,400 square feet for an office in Basel, Switzerland, under an agreement expiring in May 2024534 - Existing facilities are considered adequate for current needs, and additional alternative spaces are expected to be available on commercially reasonable terms534 Item 3. Legal Proceedings Mirum Pharmaceuticals may be involved in ordinary course legal proceedings, but management believes no pending claims will have a material adverse effect - The company may become involved in legal proceedings from the ordinary course of business535 - Management believes there are currently no claims or actions pending that could materially adversely affect results of operations, financial condition, or cash flows535 Item 4. Mine Safety Disclosures This item is not applicable to Mirum Pharmaceuticals - None536 PART II Item 5. Market for Registrant's Common Equity, Related Stockholder Matters and Issuer Purchases of Equity Securities This section covers Mirum's common stock market, stockholder matters, dividend policy, and the use of proceeds from its initial public offering Market Information Mirum Pharmaceuticals' common stock has been listed on the Nasdaq Global Market under 'MIRM' since July 18, 2019 - Mirum Pharmaceuticals' common stock has been listed on the Nasdaq Global Market under the symbol 'MIRM' since July 18, 2019539 Holders of Common Stock As of March 5, 2021, there were 30,419,707 shares of common stock outstanding, held by approximately 15 record holders - As of March 5, 2021, there were 30,419,707 shares of common stock outstanding, held by approximately 15 record holders540 Dividend Policy Mirum has never paid cash dividends and intends to retain future earnings for business development and operations - Mirum has never declared or paid any cash dividends on its common stock and intends to retain future earnings for business development and operations541 - Future dividend policy will be determined by the board of directors based on financial condition, operating results, and other relevant factors541 Securities Authorized for Issuance Under Equity Compensation Plans Information regarding equity compensation plans is incorporated by reference from Item 12 of Part III of this Annual Report - Information regarding equity compensation plans is incorporated by reference from Item 12 of Part III of this Annual Report542 Stock Performance Graph This item is not applicable - Not applicable543 Use of Proceeds Mirum completed its IPO in July 2019, generating $67.2 million net proceeds, with management retaining broad discretion over their application - Mirum completed its IPO in July 2019, selling 5,000,000 shares at $15.00/share, generating net proceeds of $67.2 million after deducting $7.8 million in underwriting discounts and offering expenses544545 - As of December 31, 2020, approximately $19.0 million of the IPO net proceeds have been used, with funds invested in short- and intermediate-term, interest-bearing obligations546 - Management retains broad discretion over the application of net proceeds, which will vary based on factors like additional financing, clinical trial success, and costs548 Item 6. Selected Financial Data This item states that selected financial data is not applicable - Not applicable549 Item 7. Management's Discussion and Analysis of Financial Condition and Results of Operations This section discusses Mirum's financial condition, operations, and liquidity, highlighting its limited history, losses, financing, and R&D focus Overview Mirum Pharmaceuticals is a biopharmaceutical company focused on developing and commercializing late-stage novel therapies for orphan cholestatic liver diseases - Mirum Pharmaceuticals is a biopharmaceutical company focused on developing and commercializing late-stage novel therapies for debilitating orphan cholestatic liver diseases551 - The company's pipeline includes maralixibat (for ALGS, PFIC, BA) and volixibat (for PSC, ICP, PBC), with regulatory submissions and clinical trials ongoing551 - Mirum has a limited operating history since November 2018, has incurred significant operating losses, and has not generated product sales revenue to date, funding operations primarily through debt and equity financings552553 Financing Transactions Mirum completed its IPO and subsequent public offerings, generating significant net proceeds, and entered a Revenue Interest Purchase Agreement - Mirum completed its IPO in July 2019, selling 5,000,000 shares at $15.00/share, yielding $67.2 million net proceeds554 - In January 2020, a follow-on public offering of 2,400,000 shares at **$20.00/sh
Mirum(MIRM) - 2020 Q4 - Annual Report