Business description of Mirum-Pharmaceuticals-Inc from last 10-k form

The cautionary statements made in this Annual Report are intended to be applicable to all related forward-looking statements wherever they may appear in this Annual Report. We urge you not to place undue reliance on these forward-looking statements, which speak only as of the date of this Annual Report. Except as required by law, we assume no obligation to update our forward-looking statements publicly, or to update the reasons actual results could differ materially from those anticipated in any forward-looking statements, whether as a result of new information, future events or otherwise.

2

PART I

Item 1. Business.

Overview

We are a biopharmaceutical company focused on the development and commercialization of a late-stage pipeline of novel therapies for debilitating liver diseases. We focus on diseases for which the unmet medical need is high and the biology for treatment is clear. Our pipeline consists of two clinical-stage product candidates with mechanisms of action that have potential utility across a wide range of orphan cholestatic liver diseases. We are initially developing maralixibat for the treatment of pediatric patients with Alagille syndrome (“ALGS”) and progressive familial intrahepatic cholestasis (“PFIC”). Based on improvements in pruritus, or itching, and other outcomes and disease markers observed in Phase 2 clinical trials, we are planning to initiate a rolling submission of a New Drug Application (“NDA”), for the treatment of cholestatic pruritus associated with ALGS in the third quarter of 2020. We expect to complete the rolling submission of our NDA in the first quarter of 2021, and pending a successful submission, we will plan for a potential launch in ALGS in the second half of 2021. We are also conducting the Phase 3 MARCH clinical trial in PFIC, from which we expect to complete enrollment in the second quarter of 2020 and announce topline Phase 3 data in late-2020. Further, we are also conducting an analysis of our long-term treatment data in PFIC against a natural history control group in conjunction with the NAtural course and Prognosis of PFIC and Effect of biliary Diversion (“NAPPED”) Consortium and plan to share these results with regulators in 2020. We are developing volixibat for the treatment of adult patients with cholestatic liver diseases and expect to initiate our first clinical trial in these indications in late 2020.

Our initial focus is on rare cholestatic liver diseases, including ALGS, PFIC, biliary atresia (“BA”), primary sclerosing cholangitis (“PSC”), and intrahepatic cholestasis of pregnancy (“ICP”). Cholestasis is characterized by impaired flow of bile resulting in accumulation of toxic bile acids in the liver. This leads to liver injury, progressive liver disease and, if left untreated, can result in fibrosis, cirrhosis, liver failure and death. The expected transplant-free survival rate in ALGS at age 18 is approximately 25% and approximately half of PFIC patients will need a transplant by the age of ten. Patients with cholestatic liver disease typically experience debilitating pruritus, which dramatically impacts quality of life and can lead to scarring, sleep deprivation, significant fatigue and psycho-social effects. In some patients, intractable pruritus alone can justify liver transplantation. In ALGS, it has been reported that the majority of transplants are due to cholestatic symptoms. Other general manifestations of cholestatic liver diseases include jaundice, progressive liver disease and growth delay. Cholestatic liver diseases represent a significant unmet medical need, with no therapies approved by the U.S. Food and Drug Administration (“FDA”), for treatment of the indications we are currently pursuing.

Our Product Pipeline

Our team has strategically assembled a pipeline of novel product candidates that target a specific biological mechanism implicated in cholestatic liver diseases. We own exclusive worldwide rights to each of our product candidates. Maralixibat and volixibat are investigational, novel, oral, minimally-absorbed agents designed to inhibit the apical sodium-dependent bile acid transporter (“ASBT”), which is primarily responsible for recycling bile acids from the intestine to the liver. The following graphic depicts each of our product candidates, the respective indications we are pursuing, the expected next milestones and regulatory designations:

Abbreviations: LPI, Last Patient In; FPI, First Patient In; BTD, Breakthrough Therapy Designation; FDA, Food and Drug Administration; EMA, European Medicines Agency

Our lead product candidate, maralixibat, is a novel, oral, minimally-absorbed agent designed to selectively inhibit ASBT, also known as ileal bile acid transporter. ASBT is primarily responsible for recycling bile acids from the intestine back to the liver. ASBT inhibition results in more bile acids being excreted in the feces, leading to lower levels of bile acids systemically, thereby reducing bile acid mediated effects and liver damage. We believe that by targeting bile acids in these settings, maralixibat has the potential to improve long-term outcomes and symptoms in our targeted settings and provide an alternative treatment to liver transplant. Maralixibat possesses an extensive safety dataset, having been evaluated in more than 1,500 human subjects. Maralixibat has been studied in a number of completed and ongoing clinical trials in ALGS and PFIC with over 100 children treated and some on study for up to six years. Based on the results of our Phase 2 programs, we received breakthrough therapy designation for maralixibat for the treatment of pruritus associated with ALGS in patients one year of age and older and for the treatment of PFIC2. We also have orphan designation granted for ALGS and PFIC and rare pediatric disease designation for ALGS. Although maralixibat may be eligible as a breakthrough therapy for priority review and accelerated approval by the FDA, breakthrough therapy designation may not lead to a faster development, regulatory review or approval process, and it does not increase the likelihood that maralixibat will receive marketing approval.

Maralixibat in ALGS

ALGS is a multi-organ disease that affects approximately 23,000 people in the United States and Europe, and patients are typically diagnosed in infancy. There are no approved therapies for the treatment of ALGS. Partial External Biliary Diversion (“PEBD”) surgery is associated with significant complications, and liver transplantation is the only definitive treatment for cholestasis due to ALGS, but is expensive, requires long-term administration of immuno-suppressants, and only a portion of the patients who require a liver transplant are able to match with a suitable donor organ or can tolerate the surgery.

4

In the Phase 2b ICONIC clinical trial with a placebo-controlled drug withdrawal period, there was a statistically significant difference in pruritus between the treatment group and placebo group as measured by ItchRO(Obs) score (p<0.0001). The ItchRO(Obs) score is a caregiver-reported outcome assessment developed for use in cholestatic liver diseases, which measures severity of itch on a 0-4 scale. Additionally, at week 48 as compared to baseline, 72% of patients had a clinically meaningful reduction in the ItchRO(Obs) score (p<0.0001); mean serum bile acids (“sBA”) were reduced by 36% (p<0.01); xanthomas, which are deposits of cholesterol under the skin, were decreased by 44% (p<0.01), as measured by the Clinician Xanthoma Scale; and quality of life scores improved by a mean of 9.5 points. Maralixibat has been granted orphan drug designation for ALGS by the FDA and European Medicines Agency (“EMA”) and breakthrough designation for the treatment of pruritus associated with ALGS in patients one year of age and older by the FDA.

Further, long-term analysis of the ICONIC clinical trial has shown durable response. In November 2019 at the American Association for the Study of Liver Disease annual Liver Meeting, four-year data from the ICONIC clinical trial were presented. This analysis showed persistent significant improvements from baseline in sBA, pruritus, xanthomas and growth in patients remaining on study at week 191.

Over the course of 2019 we had a number of interactions with the FDA to discuss the adequacy of the ICONIC data set to support an NDA submission. These interactions culminated in a pre-NDA meeting in November 2019 and the receipt of breakthrough therapy designation for maralixibat for the treatment of pruritus associated with ALGS in patients one year of age and older. During this meeting, we and the FDA reached consensus on the components required and the timeline for initiating a rolling submission of an NDA in the third quarter of 2020. Pending a successful submission, we are preparing to commercialize maralixibat for ALGS in the second half of 2021.

In addition, in November 2019, we were granted Rare Pediatric Disease Designation for maralixibat for ALGS, and as a result, we may qualify for the receipt of a priority review voucher if our NDA is approved before October 1, 2022.

Maralixibat in PFIC

We are advancing maralixibat for the treatment of PFIC in the Phase 3 MARCH trial. PFIC affects approximately 8,000 people in the United States and Europe and is typically diagnosed within the first three to six months of life. Currently, there are no approved therapeutics for the treatment of PFIC. PEBD is associated with significant complications, and liver transplantation is the only definitive treatment but is expensive, requires life-long administration of immuno-suppressants and has potential for significant comorbidities. Only a portion of the patients who require a liver transplant are able to match with a suitable donor organ, and there can be serious complications, for example, rapid re-occurrence of disease and steatosis.

In the Phase 2 INDIGO clinical trial, a multi-parameter response on pruritus, sBA, and growth was observed in patients with nt-PFIC2, a genetically distinct subtype of PFIC that accounts for approximately 50% of the PFIC patient population. At week 48, 55% of the PFIC2 patients treated with maralixibat experienced a clinically meaningful reduction in pruritus, defined as a reduction of at least 1.0 point in the ItchRO(Obs) score. In addition, patients treated with maralixibat experienced normalization or significant reductions in sBA levels from baseline, increases in quality of life and, in those patients with elevated baseline values, a normalization of alanine aminotransferase (“ALT”), and bilirubin levels. This multi-parameter response supported maralixibat’s breakthrough therapy designation from the FDA for the treatment of PFIC2. The disease-modifying potential of maralixibat is further supported by data from a long-term analysis of the INDIGO clinical trial, which showed an improvement in growth for those patients who experienced significant improvements in sBA levels and pruritus. Maralixibat has been granted orphan drug designation for PFIC by the FDA and the EMA. We commenced enrollment in the Phase 3 MARCH trial in the second quarter of 2019 with a primary endpoint focused on pruritus in patients with nt-PFIC2, and we expect to complete enrollment in the second quarter of 2020 and report topline Phase 3 data in late-2020. In addition to the MARCH clinical trial, we are conducting comparisons on long-term outcomes from our ongoing Phase 2 program with natural history datasets.

Maralixibat in BA

We also plan to advance maralixibat for the treatment of BA in a clinical program based on its mechanism, the high unmet medical need, maralixibat clinical experience in other cholestatic liver disease settings and results from a non-clinical efficacy model.

BA is a rare liver disorder in which there is a blockage or absence of large bile ducts that leads to bile accumulation in the liver and ultimately results in progressive cholestasis and liver damage. BA occurs in infants and is estimated to affect one in every 10,000 to 15,000 live births in the United States. BA is the most common reason for liver transplantation in children. There remains a substantial unmet medical need for therapeutic interventions as invasive surgery is often unsuccessful. The standard of care for BA is the Kasai procedure, a surgery in which a segment of the small intestine is used to attach the small intestine directly to the liver where bile is expected to drain and is most successful if conducted in the first eight weeks of life. The success rate for the Kasai procedure is approximately 30% to 40%, while the remaining patients are at risk of progressive liver disease requiring liver transplantation. We believe ASBT inhibition has therapeutic potential in this patient population, and our clinical development pathway will be informed by further discussions with the FDA regarding our clinical trial design for BA.

Volixibat

We are advancing our second product candidate, volixibat, a novel, oral, minimally-absorbed agent designed to inhibit ASBT, for the treatment of adult patients with cholestatic liver diseases. We intend to initially develop volixibat for the treatment of PSC and ICP. PSC is a serious, idiopathic chronic cholestatic liver disease characterized by the progressive inflammation and destruction of bile ducts, which can lead to life-threatening complications. It is estimated that approximately 29,000 people in the United States and approximately 50,000 people in Europe suffer from PSC. Up to 70% of PSC patients suffer from pruritus during the course of the disease. Liver transplantation is the only treatment shown to improve clinical outcomes in PSC but is expensive, requires long-term administration of immuno-suppressants and only a portion of the patients who require a liver transplant are able to match with a suitable donor organ. Ursodeoxycholic acid (“UDCA”), is used off-label in PSC but has been shown to be minimally effective. ICP is typically diagnosed in pregnant women during the second or third trimester and increases the risk of stillbirth and preterm labor. Additionally, ICP is associated with severe pruritus. We estimate that each year there are approximately 40,000 cases of ICP in the United States and approximately 100,000 cases of ICP in Europe. There are no approved therapies for PSC or ICP in the United States.

Volixibat has been extensively studied in adults, with data from several clinical trials showing target engagement. Previously conducted clinical trials have shown that volixibat increased bile acid excretion and positively affected related bile acid measures. In a Phase 2 clinical trial in non-alcoholic steatohepatitis (“NASH”), volixibat-treated patients showed reductions in cholesterol levels and increases in 7αC4 levels, a marker of bile synthesis, which are indicative of ASBT inhibition. Proof-of-concept data from a Phase 2 clinical trial of maralixibat in PSC provides evidence of the benefits of ASBT inhibition. In the Phase 2 CAMEO trial in PSC patients, treatment with maralixibat resulted in a statistically significant reduction from baseline in ItchRO score and sBA levels. We are conducting a Phase 1 dose ranging bile acid excretion clinical trial to determine dose levels for our planned efficacy studies. We expect to initiate clinical trials of volixibat in PSC and ICP in 2020 and early 2021, respectively.

Our History and Team

Our mission is to develop life-changing therapies for patients suffering from debilitating liver diseases. Our management team has significant experience in progressing liver and orphan diseases therapies from early stage research to clinical trials and ultimately to regulatory approval and commercialization. Michael Grey, our co-founder and Chairman of our board of directors, was the Chief Executive Officer of Lumena Pharmaceuticals, Inc. (“Lumena”), where he led the development of maralixibat and volixibat prior to Lumena’s acquisition by Shire plc in June 2014. Christopher Peetz, our President, Chief Executive Officer and co-founder, as well as several other members of our management team, previously held leadership positions at Tobira Therapeutics, Inc., a liver disease company, prior to its acquisition by Allergan plc in November 2016. As part of our strategy to acquire and advance therapeutic candidates for debilitating liver diseases, we acquired maralixibat and volixibat in November 2018 from Shire plc and are continuing to advance these product candidates for rare cholestatic liver diseases with the assistance of key program leaders from Shire plc who joined us following the acquisition.

Our Strategy

Our goal is to be a leader in the treatment of liver diseases for which the unmet medical need is high. The key components of our strategy include: