Chenodiol

iStockphoto/ Olivier Le Moal ITF, IntraBio and Orchard are among the companies that have won FDA nods in the past year for Duchenne muscular dystrophy, Niemann-Pick disease type C, metachromatic leukodystrophy and more. Rare Disease Day, which falls at the end of February each year, is an opportunity to take stock of advances in this space, as well as the many remaining gaps in care and treatment. Defined as diseases that affect fewer than 200,000 people in the U.S., rare diseases collectively afflict about 350 million people worldwide, according to the National Organization for Rare Disorders . An estimated 7,000 of these conditions have been identified, and more than 90% of them have no FDA-approved treatment. Yet progress toward developing such treatments continues, particularly among smaller companies. Here are five rare diseases that have seen drug approvals since last year’s Rare Disease Day. Duchenne Muscular Dystrophy Duchenne muscular dystrophy (DMD) is a relatively common rare disease, affecting about one out of every 3,600 baby boys. This X-linked genetic disease affects the dystrophin protein, a component of muscle, and causes progressive weakening of skeletal and heart muscle. Families affected by DMD saw a spate of treatment approvals in 2023 and 2024, including Sarepta Therapeutics’ Elevidys and Catalyst Pharmaceuticals’ Agamree. The most recent was Duvyzat (givinostat), a small molecule therapy marketed by ITF Therapeutics. It targets histone deacetylases, enzymes that modulate gene and protein expression in the muscle. “Deregulation of HDACs is a major consequence of the lack of dystrophin associated with DMD,” Matt Trudeau, head of ITF, told BioSpace in an email ahead of the FDA decision in March 2024. “We believe givinostat’s mode of action has the potential to inhibit HDAC pathological overactivity and thereby impact the cascade of events leading to muscle damage which, in turn, may counteract disease pathology and slow muscle deterioration.” In the Phase III Epidys trial , givinostat met the primary endpoint of a change in the four-stair climb assessment from baseline to 72 weeks. Italfarmaco, the parent company of ITF which developed the drug, also reported that it showed “favorable outcomes” in key secondary measures, including on the North Star Ambulatory Assessment (NSAA), a scale that measures motor function skills. On the NSAA, patients treated with the new drug saw less worsening compared to placebo after 18 months. Givinostat was generally well tolerated, with no treatment-related severe or serious adverse events. Metachromatic Leukodystrophy Metachromatic leukodystrophy (MLD) is a metabolic disease that affects one in every 100,000 live births. It is caused by a mutation in the arylsulfatase-A ( ARSA ) gene, which codes for an enzyme that breaks down sulfatides, and is characterized by a pathological build-up of sulfatides in the brain, liver, kidneys, spleen and other body parts. Over time this buildup can lead to organ damage and neurological issues, and patients often experience motor, behavioral and cognitive problems, as well as seizures. Most patients die within five years of disease onset. The FDA approved the first therapy for early juvenile or early symptomatic forms of the disease, Lenmeldy (atidarsagene autotemcel), in March 2024. The gene therapy, marketed by Orchard Therapeutics, uses a patient’s own stem cells to deliver a functioning copy of the ARSA gene. Lenmeldy was also approved by the European Union in December 2020 , where it is marketed as Libmeldy. The FDA’s approval of Lenmeldy is backed by data from two single-arm, open-label trials enrolling a total of 37 pediatric MLD patients. Over a median follow-up of 6.76 years, Lenmeldy led to significantly better overall survival compared with natural history data. The gene therapy also preserved motor and cognitive function in late-infantile MLD patients. Lenmeldy’s most common adverse events were febrile neutropenia, stomatitis, respiratory tract infections and rashes. WHIM Syndrome Fewer than 1,000 people in the U.S. have been diagnosed with WHIM syndrome, according to the NIH. The condition’s name is an acronym of the four characteristics of the disease: warts, hypogammaglobulinemia (low antibody levels), infections and myelokathexis (a white blood cell disorder). The syndrome is caused by mutations in the chemokine receptor ( CXCR4 ) gene that increase the activity level of the resulting protein. In April 2024, the FDA approved X4 Pharmaceuticals’ Xolremdi (mavorixafor) as the first targeted treatment for WHIM. Xolremdi is an oral CXCR4 antagonist that draws white blood cells from the bone marrow into the blood to improve immune deficiencies. It is approved for patients 12 and older. Phase III results from the 4WHIM trial of Xolremdi showed a 60% reduction in annualized infection rate compared to placebo; trial participants had less than one infection per year compared with 4.5 for the placebo group. Teresa Tarrant, an associate professor at Duke University’s School of Medicine and lead investigator of the 4WHIM trial, told BioSpace last year that previous treatments for the disease were only supportive. “I think that for a lot of patients, the idea that there is a targeted therapy . . . something that is directly correcting the underlying problem for the individual, I think that gives them a lot of hope, a lot of optimism,” Tarrant said. “I think WHIM is going to be a poster child for rare diseases and the ability where we’re at now in modern medicine to design therapies to treat underlying genetic disorders.” Niemann-Pick Disease Type C Afflicting approximately one in every 150,000 people , Niemann-Pick disease type C (NPC) is an ultrarare lysosomal storage disease that progressively impairs patients’ physical and cognitive function. It is caused by mutations in the NPC1 and NPC2 genes that hinder the body’s ability to clear cholesterol and other lipids from inside cells, leading to their pathologic build-up in the brain and other crucial organs. NPC affects patients’ speech, motor and swallowing functions. According to the FDA , patients with NPC typically live only up to around 13 years of age. September 2024 saw not one, but two approvals of therapies for NPC. The first, Zevra Therapeutics’ Miplyffa (arimoclomol), is an oral drug approved for patients 2 years and older that is intended to be used alongside miglustat , a small molecule approved to treat the neurological manifestations of NPC. According to the company , Miplyffa activates transcriptional factors, resulting in the upregulation of coordinated lysosomal expression and regulation (CLEAR) genes. In a clinical trial, Zevra found that Miplyffa plus miglustat stopped disease progression during 12 months of treatment, decreasing patients’ scores on an assessment of NPC symptom severity. Meanwhile, patients treated with miglustat alone experienced a progression in symptoms. The second approval was for IntraBio’s Aqneursa (levacetylleucine) in adults and children weighing at least 15 kg. According to the company, it is not clear what Aqneursa’s target is, but it may activate cerebral glucose metabolism in the cerebellum and thus boost cerebellar activity. A randomized, double-blinded and placebo-controlled crossover study found that during the 12-week period that patients were treated with Aqneursa, they showed better functional performance as measured by a score that assesses their gait, sitting, stance and speech. The drug was well-tolerated, with common side effects including vomiting, abdominal pain, difficulty swallowing and upper respiratory tract infections. The drug’s label includes a warning for embryo-fetal harm if used during pregnancy. The back-to-back NPC approvals highlighted the FDA’s commitment to supporting the development of innovative therapies for rare diseases, Janet Maynard, director of the agency’s Office of Rare Diseases, Pediatrics, Urologic and Reproductive Medicine, said in a statement . Cerebrotendinous Xanthomatosis Cerebrotendinous xanthomatosis (CTX) is a very rare metabolic disease, affecting just one in a million people globally . It is characterized by the inability to break down certain types of cholesterol and other lipids, leading to their toxic accumulation throughout the body, particularly in the brain and connective tissues. Patients with CTX suffer from neurological abnormalities in early adulthood, including seizures and problems with movement and speech. Just last week, CTX got its first approved drug with the FDA’s greenlight of Mirum Pharmaceuticals’ oral therapy Ctexli (chenodiol). CTX is caused by mutations in the CYP27A1 gene, which codes for an enzyme that breaks down cholesterol into bile acids, and Ctexli replenishes the body’s levels of bile acids. This reduces the build-up of the toxic metabolites that cause the disease. Mirum’s application for approval of the drug included data from the Phase III RESTORE study, a June 2024 readout of which showed the drug could lower bile alcohols “with high statistical significance,” the biotech said at the time. Ctexli’s benefit was 20-fold greater in magnitude than that of placebo. The most common adverse events associated with Ctexli include hypertension, muscle weakness and diarrhea, and its label includes precautions about potential liver toxicity.

- 2024 net product sales of $336.4 million - 2025 expected global net product sales of $420 million to $435 million - VISTAS study of volixibat in PSC expected to complete enrollment in second half 2025; topline data expected 2026 - CTEXLI (chenodiol) approved in the US for cerebrotendinous xanthomatosis - Conference call to provide business updates today, February 26 at 1:30 p.m. PT/4:30 p.m. ET FOSTER CITY, Calif.--(BUSINESS WIRE)-- Mirum Pharmaceuticals, Inc. (Nasdaq: MIRM) today reported financial results for the fourth quarter and year-end 2024 and provided a business update. “2024 was another year of significant growth and accomplishments for Mirum and in 2025 we expect this momentum to continue,” said Chris Peetz, chief executive officer of Mirum. “We continue to expand the reach of our three commercial medicines within our patient communities and look forward to another year of strong financial performance. On top of this, we are looking forward to multiple upcoming clinical and regulatory milestones, such as PSC where we’re expecting full enrollment of our VISTAS trial in the second half of the year.” Future Expectations and Milestones 2025 Guidance: expect continued revenue growth with global net product sales of approximately $420 million to $435 million and positive cash flow. Volixibat VISTAS study in primary sclerosing cholangitis (PSC) expected to complete enrollment in second half 2025; topline data expected in 2026. Volixibat VANTAGE study in primary biliary cholangitis (PBC) expected to complete enrollment in 2026. LIVMARLI EXPAND Phase 3 study for pruritus in rare cholestatic conditions expected to complete enrollment in 2026. Expect to initiate Phase 2 study for MRM-3379 in Fragile X Syndrome (FXS) in 2025. 2024 Highlights Commercial: Strong growth across all three approved medicines Total net product sales of $336.4 million in 2024. 2024 LIVMARLI net product sales totaled $213.3 million. 2024 Bile Acid Medicines net product sales totaled $123.1 million. Global LIVMARLI business grew to 30 countries with commercial access, including successful reimbursement negotiation and launch in the four major European markets. Regulatory and Pipeline: Achieved multiple significant milestones and expanded pipeline Positive interim results for volixibat in VISTAS PSC and VANTAGE PBC studies. Volixibat granted breakthrough therapy designation for treatment of cholestatic pruritus in PBC by the U.S. Food and Drug Administration (FDA). LIVMARLI approved by the FDA for cholestatic pruritus in progressive familial intrahepatic cholestasis (PFIC) patients 12 months and older and in Europe for treatment of PFIC in patients three months and older. Initiated the LIVMARLI EXPAND Phase 3 study for pruritus in rare cholestatic conditions. In-licensed global rights to PDE4D inhibitor MRM-3379 for FXS. Corporate and Financial: Strong financial performance Total net product sales for the full year ended December 31, 2024, was $336.4 million compared to $178.9 million for the full year ended December 31, 2023. Total operating expenses were $424.5 million for the full year ended December 31, 2024 compared to $295.5 million for the full year ended December 31, 2023. Total operating expenses for the full year ended December 31, 2024 included $79.4 million of non-cash stock-based compensation, intangible amortization, and other non-cash expenses compared to $48.8 million for the full year ended December 31, 2023. Cash, cash equivalents and investments of $292.8 million as of December 31, 2024 compared to $286.3 million as of December 31, 2023. Business Update Conference Call Mirum will host a conference call today, February 26 at 1:30 p.m. PT/4:30 p.m. ET, to provide business updates. Join the call using the following details: Conference Call Details: U.S./Toll-Free: +1 833 470 1428 International: +1 404 975 4839 Passcode: 126145 You may also access the call via webcast by visiting the Events & Presentations section on Mirum’s website. A replay of this webcast will be available for 30 days. About LIVMARLI® (maralixibat) oral solution LIVMARLI® (maralixibat) oral solution is an orally administered, ileal bile acid transporter (IBAT) inhibitor approved by the U.S. Food and Drug Administration for two pediatric cholestatic liver diseases. It is approved for the treatment of cholestatic pruritus in patients with Alagille syndrome (ALGS) in the U.S. three months of age and older and in Europe for patients two months of age and older. It is also approved in the U.S. for the treatment of cholestatic pruritus in patients with progressive familial intrahepatic cholestasis (PFIC) 12 months of age and older and in Europe for the treatment of PFIC in patients three months of age and older. For more information for U.S. residents, please visit LIVMARLI.com. LIVMARLI has received orphan designation for ALGS and PFIC. LIVMARLI is currently being evaluated in the Phase 3 EXPAND study in additional settings of cholestatic pruritus. To learn more about ongoing clinical trials with LIVMARLI, please visit Mirum’s clinical trials section on the company’s website. IMPORTANT SAFETY INFORMATION Limitation of Use: LIVMARLI is not for use in PFIC type 2 patients who have a severe defect in the bile salt export pump (BSEP) protein. LIVMARLI can cause side effects, including Liver injury. Changes in certain liver tests are common in patients with ALGS and PFIC but can worsen during treatment. These changes may be a sign of liver injury. In PFIC, this can be serious or may lead to liver transplant or death. Your healthcare provider should do blood tests and physical exams before starting and during treatment to check your liver function. Tell your healthcare provider right away if you get any signs or symptoms of liver problems, including nausea or vomiting, skin or the white part of the eye turns yellow, dark or brown urine, pain on the right side of the stomach (abdomen), bloating in your stomach area, loss of appetite or bleeding or bruising more easily than normal. Stomach and intestinal (gastrointestinal) problems. LIVMARLI can cause stomach and intestinal problems, including diarrhea and stomach pain. Your healthcare provider may advise you to monitor for new or worsening stomach problems including stomach pain, diarrhea, blood in your stool or vomiting. Tell your healthcare provider right away if you have any of these symptoms more often or more severely than normal for you. A condition called Fat Soluble Vitamin (FSV) Deficiency caused by low levels of certain vitamins (vitamin A, D, E, and K) stored in body fat is common in patients with Alagille syndrome and PFIC but may worsen during treatment. Your healthcare provider should do blood tests before starting and during treatment and may monitor for bone fractures and bleeding which have been reported as common side effects. US Prescribing Information EU SmPC Canadian Product Monograph About Volixibat Volixibat is an oral, minimally absorbed agent designed to selectively inhibit the ileal bile acid transporter (IBAT). Volixibat may offer a novel approach in the treatment of adult cholestatic diseases by blocking the recycling of bile acids, through inhibition of IBAT, thereby reducing bile acids systemically and in the liver. Volixibat is currently being evaluated in Phase 2b studies for primary sclerosing cholangitis (PSC) (VISTAS study), and primary biliary cholangitis (PBC) (VANTAGE study). In June, Mirum announced positive interim results from the Phase 2b VANTAGE study showing statistically significant improvement in pruritus as well as meaningful reductions in serum bile acids and improvements in fatigue for patients treated with volixibat. No new safety signals were observed, and the most common adverse event was diarrhea with all cases mild to moderate. Volixibat has been granted breakthrough therapy designation for the treatment of PBC. About CHOLBAM® (cholic acid) capsules The FDA approved CHOLBAM (cholic acid) capsules in March 2015, the first FDA-approved treatment for pediatric and adult patients with bile acid synthesis disorders due to single enzyme defects, and for adjunctive treatment of patients with peroxisome biogenesis disorder-Zellweger spectrum disorder. The effectiveness of CHOLBAM has been demonstrated in clinical trials for bile acid synthesis disorders and the adjunctive treatment of peroxisomal disorders. An estimated 200 to 300 patients are current candidates for therapy. CHOLBAM® (cholic acid) Indication CHOLBAM is a bile acid indicated for Treatment of bile acid synthesis disorders due to single enzyme defects. Adjunctive treatment of peroxisomal disorders, including Zellweger spectrum disorders, in patients who exhibit manifestations of liver disease, steatorrhea, or complications from decreased fat-soluble vitamin absorption. LIMITATIONS OF USE The safety and effectiveness of CHOLBAM on extrahepatic manifestations of bile acid synthesis disorders due to single enzyme defects or peroxisomal disorders, including Zellweger spectrum disorders, have not been established. IMPORTANT SAFETY INFORMATION WARNINGS AND PRECAUTIONS – Exacerbation of liver impairment Monitor liver function and discontinue CHOLBAM in patients who develop worsening of liver function while on treatment. Concurrent elevations of serum gamma glutamyltransferase (GGT) and alanine aminotransferase (ALT) may indicate CHOLBAM overdose. Discontinue treatment with CHOLBAM at any time if there are clinical or laboratory indicators of worsening liver function or cholestasis. ADVERSE REACTIONS The most common adverse reactions (≥1%) are diarrhea, reflux esophagitis, malaise, jaundice, skin lesion, nausea, abdominal pain, intestinal polyp, urinary tract infection, and peripheral neuropathy. Please see full Prescribing Information for additional Important Safety Information. About CTEXLI™ (chenodiol) tablets CTEXLI™ (chenodiol) tablets is FDA-approved for the treatment of adults with cerebrotendinous xanthomatosis (CTX). Chenodiol is another name for chenodeoxycholic acid (CDCA). CDCA is a naturally occurring bile acid that was originally approved for the treatment of people with radiolucent stones in the gallbladder. CTEXLI was evaluated as part of the Phase 3 RESTORE study, the first and only clinical trial for CTX. CTX is a rare progressive disease that can affect the brain, spinal cord, tendons, eyes and arteries. IMPORTANT SAFETY INFORMATION CTEXLI can cause side effects, including : Liver Injury : You will need to undergo laboratory testing before starting and while taking CTEXLI to check your liver function. Changes in certain liver tests may occur during treatment and may be a sign of liver injury. This can be serious. Stop taking CTEXLI immediately and tell your healthcare provider right away if you get any signs or symptoms of liver problems, including, stomach (abdomen) pain, bruising, dark-colored urine, feeling tired (fatigue), bleeding, yellowing of the skin and eyes, nausea, and itching. Most Common Side Effects : Diarrhea, headache, stomach pain, constipation, high blood pressure, muscular weakness, and upper respiratory tract infection. Tell your healthcare provider about all the medications that you take, as CTEXLI may interact with other medicines. US Prescribing Information About Mirum Pharmaceuticals Mirum Pharmaceuticals, Inc. is a biopharmaceutical company dedicated to transforming the treatment of rare diseases affecting children and adults. Mirum has three approved medications: LIVMARLI® (maralixibat) oral solution, CHOLBAM® (cholic acid) capsules, and CTEXLI™ (chenodiol) tablets. LIVMARLI, an IBAT inhibitor, is approved for the treatment of two rare liver diseases affecting children and adults. It is approved for the treatment of cholestatic pruritus in patients with Alagille syndrome in the U.S. (three months and older), in Europe (two months and older), and in other regions globally. It is also approved in the U.S. in cholestatic pruritus in PFIC patients 12 months of age and older; in Europe, it is approved for patients with PFIC three months of age and older. Mirum is also initiating the Phase 3 EXPAND study, a label expansion opportunity for LIVMARLI in additional settings of cholestatic pruritus. CHOLBAM is FDA-approved for the treatment of bile acid synthesis disorders due to single enzyme deficiencies and adjunctive treatment of peroxisomal disorders in patients who show signs or symptoms of liver disease. CTEXLI is FDA-approved for the treatment of cerebrotendinous xanthomatosis (CTX) in adults. Mirum's late-stage pipeline includes two investigational treatments for several rare diseases. Volixibat, an IBAT inhibitor, is being evaluated in two potentially registrational studies including the Phase 2 VISTAS study for primary sclerosing cholangitis (PSC) and Phase 2b VANTAGE study for primary biliary cholangitis. Volixibat has been granted Breakthrough Therapy Designation for the treatment of cholestatic pruritus in patients with PBC. Mirum is also planning for a Phase 2 study evaluating MRM-3379, a PDE4D inhibitor for the treatment of Fragile X syndrome, a rare genetic neurocognitive disorder. To learn more about Mirum, visit mirumpharma.com and follow Mirum on Facebook, LinkedIn, Instagram and Twitter (X). Forward-Looking Statements Statements contained in this press release regarding matters that are not historical facts are “forward-looking statements” within the meaning of the Private Securities Litigation Reform Act of 1995. Such forward-looking statements include statements regarding, among other things, significant increase or continued commercial results for our approved products, including continued financial growth, being on track to achieve our yearly financial guidance, delivering life changing medicines for patients suffering from rare diseases, the results, enrollment, conduct and progress of Mirum’s ongoing and planned studies for its product candidates, including newly in-licensed product candidates, the timing and results of interim analyses of our ongoing studies and the regulatory approval path for our product candidates in any indication or any specific territory. Because such statements are subject to risks and uncertainties, actual results may differ materially from those expressed or implied by such forward-looking statements. Words such as “expected,” “will,” “could,” “would,” “guidance,” “potential” and similar expressions are intended to identify forward-looking statements. These forward-looking statements are based upon Mirum’s current expectations and involve assumptions that may never materialize or may prove to be incorrect. Actual results could differ materially from those anticipated in such forward-looking statements as a result of various risks and uncertainties, which include, without limitation, risks and uncertainties associated with Mirum’s business in general, the impact of geopolitical and macroeconomic events, and the other risks described in Mirum’s Report for the quarter ended December 31, 2024 and subsequent filings with the Securities and Exchange Commission. All forward-looking statements contained in this press release speak only as of the date on which they were made and are based on management’s assumptions and estimates as of such date. Mirum undertakes no obligation to update such statements to reflect events that occur or circumstances that exist after the date on which they were made, except as required by law. Mirum Pharmaceuticals, Inc. Condensed Consolidated Statement of Operations Data (in thousands, except share and per share amounts) (Unaudited) Three Months Ended December 31, Year Ended December 31, 2024 2023 2024 2023 Revenue: Product sales, net $ 99,430 $ 69,554 $ 336,409 $ 178,874 License and other revenue (16 ) — 479 7,500 Total revenue 99,414 69,554 336,888 186,374 Operating expenses: Cost of sales (1) 22,780 25,020 81,643 47,039 Research and development 44,026 30,935 140,630 102,609 Selling, general and administrative 56,830 46,184 202,221 145,880 Total operating expenses (2) 123,636 102,139 424,494 295,528 Loss from operations (24,222 ) (32,585 ) (87,606 ) (109,154 ) Other income (expense): Interest income 3,204 3,775 13,792 13,735 Interest expense (3,579 ) (3,563 ) (14,311 ) (15,105 ) Loss from termination of revenue interest purchase agreement — — — (49,076 ) Other income (expense), net 231 (3,061 ) 1,213 (2,824 ) Net loss before provision for income taxes (24,366 ) (35,434 ) (86,912 ) (162,424 ) (Benefit from) provision for income taxes (576 ) 225 1,030 991 Net loss (23,790 ) (35,659 ) (87,942 ) (163,415 ) Net loss per share, basic and diluted $ (1.85 ) $ (4.00 ) Weighted-average shares of common stock outstanding, basic and diluted 47,522,594 40,885,124 (1) Amounts include intangible amortization expense as follows: Intangible amortization $ 5,894 $ 5,305 $ 22,783 $ 10,404 (2) Amounts include stock-based compensation expense as follows: Cost of sales $ 311 $ — $ 948 $ — Research and development 4,210 2,879 15,188 10,892 Selling, general and administrative 8,730 6,841 32,308 24,131 Total stock-based compensation $ 13,251 $ 9,720 $ 48,444 $ 35,023 Mirum Pharmaceuticals, Inc. Condensed Consolidated Balance Sheet Data (in thousands) (Unaudited) December 31, 2024 2023 Assets Current assets: Cash and cash equivalents $ 222,503 $ 286,326 Short-term investments 57,812 — Accounts receivable 78,286 67,968 Inventory 22,403 22,312 Prepaid expenses and other current assets 11,784 10,935 Total current assets 392,788 387,541 Restricted cash 425 — Long-term investments 12,526 — Intangible assets, net 249,819 252,925 Other noncurrent assets 15,196 6,155 Total assets $ 670,754 $ 646,621 Liabilities and Stockholders’ Equity Current liabilities: Accounts payable $ 14,618 $ 7,416 Accrued expenses 110,224 78,544 Operating lease liabilities, current 1,709 1,104 Total current liabilities 126,551 87,064 Operating lease liabilities, noncurrent 7,972 617 Convertible notes payable, net, noncurrent 308,082 306,421 Other liabilities 2,509 3,849 Total liabilities 445,114 397,951 Commitments and contingencies Stockholders’ equity: Preferred stock — — Common stock 5 5 Additional paid-in capital 870,189 803,260 Accumulated deficit (644,181 ) (556,239 ) Accumulated other comprehensive (loss) income (373 ) 1,644 Total stockholders’ equity 225,640 248,670 Total liabilities and stockholders’ equity $ 670,754 $ 646,621 Investor Contacts: Andrew McKibben ir@mirumpharma.com Media Contact: Erin Murphy media@mirumpharma.com