What changed in this filing

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Item 1. Business

2026-02-25 compared with 2025-02-26 · 260 added, 227 removed, 642 unchanged (43% of the section changed)

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We have three approved medicines:

LIVMARLI® (maralixibat) oral solution (“Livmarli”), CHOLBAM® (cholic acid) capsules (“Cholbam”), and CHENODAL® or CTEXLI® (chenodiol) tablets (“Chenodal” or “Ctexli”).

Livmarli is a novel, orally administered, minimally-absorbed ileal bile acid transporter (“IBAT”) inhibitor (“IBATi”) that is approved for the treatment of cholestatic pruritus in patients with Alagille syndrome (“ALGS”) in the United States (“U.S.”) and various other countries around the world and for cholestatic pruritus in patients with progressive familial intrahepatic cholestasis (“PFIC”) in the U.S and for the treatment of PFIC in the European Union (“EU”).

We market and commercialize Livmarli in the United States, Canada and certain countries in Europe through our specialized and focused commercial team.

LIVMARLI® (maralixibat) (“Livmarli”), CHOLBAM® (cholic acid) capsules (“Cholbam”), and CTEXLI® (chenodiol) tablets (“Ctexli”).

Livmarli is a novel, orally administered, minimally-absorbed ileal bile acid transporter (“IBAT”) inhibitor (“IBATi”) that is approved for the treatment of cholestatic pruritus in patients with Alagille syndrome (“ALGS”) in the United States (“U.S.”), the European Union (“EU”) and various other countries around the world and for cholestatic pruritus in patients with progressive familial intrahepatic cholestasis (“PFIC”) in the U.S., Canada and Japan and for the treatment of PFIC in the EU.

We market and commercialize Livmarli in the U.S., Canada and certain countries in Europe through our specialized and focused commercial team.

We have also entered into license and distribution agreements with several rare disease companies for the commercialization of Livmarli in additional countries.

On August 31, 2023, we completed the acquisition of assets of Travere Therapeutics, Inc.

We are also seeking to add to the approved indications for Livmarli by conducting the EXPAND study in settings of cholestatic pruritus due to other rare conditions.

In August 2023, we completed the acquisition of assets of Travere Therapeutics, Inc.

(“Travere”) that are primarily related to the development, manufacture (including synthesis, formulation, finishing or packaging) and commercialization of chenodiol and Cholbam (also known as Kolbam) (and together with chenodiol, the “Bile Acid Medicines”) pursuant to an asset purchase agreement dated July 16, 2023 (such acquisition, the “Bile Acid Portfolio Acquisition”).

Food and Drug Administration (“FDA”) approved Cholbam in March 2015 as 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 peroxisomal disorders, including peroxisome biogenesis disorder-Zellweger spectrum disorder (“PBD-ZSD”).

Chenodiol is standard of care for the treatment of cerebrotendinous xanthomatosis (“CTX”) in the United Sates with a medical necessity recognition by the FDA.

Chenodiol is currently commercialized under the brand name Chenodal.

We submitted an NDA for chenodiol for the treatment of CTX in 2024 and received FDA approval for the treatment of adults with CTX in February 2025, which will be commercialized under the brand name Ctexli.

We currently commercialize Chenodal and Cholbam, and plan to commercialize Ctexli, in the United States through our specialized and focused commercial team.

Chenodiol is standard of care for the treatment of cerebrotendinous xanthomatosis (“CTX”) in the U.S.

with a medical necessity recognition by the FDA and was commercialized under the brand name Chenodal.

We submitted a New Drug Application (“NDA”) for chenodiol for the treatment of CTX in 2024 and received FDA approval for the treatment of adults with CTX in February 2025.

Chenodiol is commercialized under the brand name Ctexli.

We currently market and commercialize Cholbam and Ctexli in the U.S.

through our specialized and focused commercial team.

We have also assumed license and distribution agreements with several rare disease companies for the commercialization of Cholbam and chenodiol in additional countries.

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We are developing volixibat in the setting of primary sclerosing cholangitis (“PSC”) and primary biliary cholangitis (“PBC”).

Volixibat has received breakthrough therapy and orphan drug designation from the FDA for cholestatic pruritus in PBC patients based on the positive interim analysis of the VANTAGE Phase 2b study.

Volixibat has received FDA breakthrough therapy and orphan drug designation for cholestatic pruritus in PBC patients based on the positive interim analysis of the VANTAGE Phase 2b study.

Volixibat has also completed a successful interim analysis of the VISTAS Phase 2b study in PSC patients.

We expect to complete enrollment of our VISTAS Phase 2b clinical trial in PSC in the second half of 2025 and of our VANTAGE Phase 2b clinical trial in PBC in 2026.

Enrollment of our VISTAS Phase 2b clinical trial in PSC was completed in the third quarter of 2025 and we expect to announce top-line results from this trial in the second quarter of 2026.

Enrollment of our VANTAGE Phase 2b clinical trial in PBC is expected to be completed in the second half of 2026.

On January 23, 2026, we completed the acquisition of Bluejay Therapeutics, Inc.

(“Bluejay” and such acquisition, the “Bluejay Acquisition”) and its lead product candidate brelovitug (BJT-778).

We are advancing brelovitug for the treatment of chronic hepatitis D virus (“HDV”) infection.

Brelovitug is a fully human IgG1 monoclonal antibody that binds the hepatitis B surface antigen, thereby clearing virions and subviral particles and preventing HDV infection and replication.

Brelovitug has been granted FDA Breakthrough Therapy designation and European Medicines Agency (“EMA”) Priority Medicines (“PRIME”) scheme designation and European Commission orphan medicinal product designation.

Brelovitug is currently being evaluated in the global AZURE clinical program with topline results from the AZURE-1 and AZURE-4 registration-enabling clinical trials expected in the second half of 2026.

We are also advancing our product candidate MRM-3379, a novel, oral, CNS-penetrant PDE4D inhibitor for the treatment of fragile X syndrome (“FXS”).

We are planning to initiate a dose ranging Phase 2 study of MRM-3379 in 2025.

We are currently enrolling patients in the BLOOM Phase 2 clinical study of MRM-3379 in FXS and expect topline data in 2027.

Our goal is to strengthen our leadership position in rare and orphan diseases for which the unmet medical need is high.

The key components of our strategy include:

• Commercialize and develop Livmarli for the treatment of ALGS, PFIC and other rare cholestatic conditions.

Livmarli is approved by the FDA and the European Commission for the treatment of cholestatic pruritus in patients with ALGS, approved by the FDA for treatment of cholestatic pruritus in patients with PFIC and approved by European Medicines Agency (“EMA”) for the treatment of PFIC.

• Commercialize medicines for rare diseases.

We are commercializing Livmarli in the United States, Canada, and certain countries in Europe through direct sales.

Additionally, we have entered into several distributor and licensing agreements to advance Livmarli in numerous territories outside of the markets where we commercialize Livmarli directly.

We are also seeking to add to the approved indications for Livmarli by conducting the EXPAND study in settings of cholestatic pruritus due to other rare conditions.

• Commercialize and further develop Ctexli and Cholbam.

Chenodiol is standard of care in the U.S.

for the treatment of CTX under a medical necessity recognition from the FDA.

We submitted an NDA for chenodiol tablets for the treatment of adults with CTX and this NDA was approved by the FDA in February 2025.

for the treatment of CTX and is being commercialized under the brand name Ctexli.

Cholbam is approved for the treatment of bile acid synthesis disorders and adjunctive treatment of patients with peroxisomal disorders, including PBD-ZSD and we expect to continue to commercialize the medicine for these indications.

We are commercializing Chenodal and Cholbam, and plan to commercialize Ctexli, in the United States through one specialty pharmacy.

• Develop and commercialize volixibat for the treatment of adults with PSC and PBC.

We are commercializing Ctexli and Cholbam in the United States through one specialty pharmacy.

• Advance our current pipeline of clinical programs to regulatory approval.

We are seeking to add to the approved indications for Livmarli by conducting the EXPAND study in settings of cholestatic pruritus due to other rare conditions.

We plan to further leverage our understanding of cholestatic liver disease with volixibat in adult settings.

We are conducting adaptive, potentially registrational, Phase 2b clinical trials of volixibat in PSC and PBC.

• Develop and commercialize MRM-3379 for the treatment of FXS.

We acquired Bluejay in January 2026 and plan to continue to develop brelovitug for the treatment of chronic HDV infection.

We are conducting the global AZURE program to enable registration in the U.S., Europe and other geographies.

MRM-3379 is a novel PDE4D inhibitor, which we expect to develop for FXS, a rare genetic neurocognitive disorder.

We plan to initiate a dose ranging phase 2 trial in 2025.

• Actively manage our product portfolio and expand our pipeline of novel product candidates.

We initiated a dose ranging Phase 2 trial in 2025 with data expected in 2027.

• Continue to acquire additional pipeline or commercial rare disease products or companies.

We have assembled a team of scientific, clinical and business leaders with highly relevant experience to enable the advancement of therapeutics for rare and orphan diseases.

We intend to leverage our collective expertise to identify, acquire, in-license and advance additional product candidates for the treatment of rare and orphan diseases.

• Deploy our resources efficiently to maximize value creation and long term financial performance.

Our financial objective is value creation through long-term cash-flow generating revenue growth.

We aim to accomplish this by successfully commercializing current approved medicines and successfully developing and commercializing current and future clinical-stage product candidates.

Our Product Pipeline

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FDA & EMA Approved

Cholestatic Pruritus (Additional Settings) EXPAND Phase 3, expect enrollment completion 2026

Cholestatic Pruritus (Additional Settings) EXPAND Phase 3, topline data expected in Q4 2026

Ctexli (Chenodiol)

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Bile acid synthesis disorders and PBD-ZSD 4

Primary Sclerosing Cholangitis VISTAS positive interim analysis, expect enrollment completion H2 2025

Primary Biliary Cholangitis VANTAGE positive interim analysis, expect enrollment completion 2026

Fragile X Syndrome (FXS) Phase 2, initiating 2025

Primary Sclerosing Cholangitis VISTAS positive interim analysis, confirmatory topline data expected Q2 2026

Primary Biliary Cholangitis VANTAGE positive interim analysis, expect enrollment completion H2 2026

Hepatitis Delta Virus (HDV)

AZURE 1 and 4, Phase 3 topline data expected H2 2026 (US registrational program)

AZURE 2 and 3, Phase 3 topline data expected H1 2028 (EU registrational program)

Fragile X Syndrome (FXS) BLOOM Phase 2, topline data expected in 2027

1 Received FDA approval for cholestatic pruritus in patients with ALGS three months of age and older.

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European Commission has granted marketing authorization for Livmarli oral solution for the treatment of PFIC in patients 3 months of age and older.

3 Received FDA approval for the treatment of adults with CTX in February 2025.

3 Received FDA approval for the treatment of adults with CTX.

4 Bile acid synthesis disorders include PBD-ZSD.

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Livmarli for cholestatic pruritus in patients with ALGS

Livmarli is a novel, orally administered, minimally-absorbed solution approved by the FDA and EMA for cholestatic pruritus in patients with ALGS.

Livmarli is a novel, orally administered, minimally-absorbed medicine approved by the FDA and EMA for cholestatic pruritus in patients with ALGS.

Livmarli is an IBATi that prevents absorption of bile acids in the ileum, thereby lowering serum bile acid (“sBA”) levels in settings of cholestasis where excess bile acids cause symptomatic and progressive disease burden.

ALGS is a rare genetic disorder of severe cholestasis in which bile ducts are abnormally narrow, malformed and reduced in number, which leads to bile accumulation in the liver and ultimately progressive liver disease.

In patients with ALGS, multiple organ systems may be affected by the mutation, including the liver, heart, kidneys and central nervous system.

The accumulation of bile acids prevents the liver from working properly to eliminate waste from the bloodstream and leads to progressive liver disease.

Signs and symptoms arising from cholestasis in ALGS may include jaundice, pruritus, xanthomas and growth deficit.

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In children with cholestasis due to ALGS, it is estimated that six in 10 of children progress to transplant or death by adulthood.

Furthermore, it is reported that the majority of liver transplants in ALGS are due to cholestatic symptoms rather than progressive liver damage.

In patients who have not received a liver transplant, 75% have active scratching, with 32% having destruction of skin, bleeding or scarring.

Children with ALGS experience a markedly impaired quality of life largely due to the intense pruritus and associated skin lesions and disruptions in sleep and mood.

A study to assess the health-related quality of life in ALGS patients indicated a significant burden in physical, psychological and social health accompanies the disease.

We believe the prevalent patient population in the United States and Europe is approximately 4,000 - 5,500 pediatric ALGS patients, which, based on our current expectations and beliefs, represents a greater than $500.0 million market opportunity.

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Livmarli for cholestatic pruritus in patients with PFIC

Livmarli is a novel, orally administered, minimally-absorbed solution approved by the FDA for cholestatic pruritus in patients with PFIC and by the EMA for treatment of patients with PFIC.

Livmarli is a novel, orally administered, minimally-absorbed medicine approved by the FDA for cholestatic pruritus in patients with PFIC and by the EMA for treatment of patients with PFIC.

PFIC is a group of rare autosomal recessive liver diseases characterized by canalicular bile transport defects, resulting in disrupted bile formation, progressive cholestasis with elevation of sBA, and pruritus.

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In addition, a minority of patients with PFIC phenotype elude genetic diagnosis using current methods, and are diagnosed clinically.

Recent broadening of use of genetic testing in adult hepatology practices has resulted in an increased diagnosis of late-onset PFIC patients.

Severe pruritus is a common feature of PFIC, greatly affecting quality of life, and leading to liver transplant when symptoms are refractory.

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Chenodeoxycholic acid, chenodiol or CDCA is a naturally occurring bile acid that was until recently approved only for the treatment of people with radiolucent stones in the gallbladder.

While indicated for radiolucent stones in the gallbladder, chenodiol has received medical necessity recognition by the FDA for the treatment of CTX, and is the standard of care for CTX.

We submitted a new drug application to the FDA for the approval of chenodiol in CTX in 2024 and received FDA approval to treat CTX in adults in February 2025, which will be commercialized under the brand name Ctexli.

CDCA received FDA approval to treat CTX in February 2025, which is commercialized under the brand name Ctexli.

CTX is a rare, progressive and under diagnosed bile acid synthesis disorder affecting many parts of the body.

We estimate there are 1,000 - 2,000 prevalent CTX patients in the United States, however only 10% are currently diagnosed.

In September 2022, chenodiol was granted Fast Track designation by the FDA for the treatment of CTX.

In CTX, a deficiency of the bile acid CDCA leads to a buildup of bile alcohols which precedes a toxic accumulation of cholestanol.

Cholestanol is the key driver of symptomatic burden and disease progression, including irreversible neurologic dysfunction.

Results from the RESTORE study demonstrated that treatment with chenodiol not only improved urine bile alcohols but also serum cholestanol.

Additionally, a greater proportion of patients receiving placebo required blinded rescue therapy, demonstrating the robustness of the effect.

The most commonly reported adverse events while on chenodiol were diarrhea and headache.

The majority of adverse events reported were mild or moderate in severity and not considered to be treatment-related.

Cholbam for the treatment of bile acid synthesis disorders and peroxisomal disorders, including PBD-ZSD

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Through the EXPAND phase 3 study we are exploring the treatment of pruritus in rare cholestatic settings other than ALGS, PFIC, PSC, intrahepatic cholestasis of pregnancy and PBC.

We believe that the prevalent patient population in the United States and Europe in these additional rare cholestatic settings to be approximately 1,000 patients.

We expect to complete enrollment of this trial in 2026.

We believe that the prevalent pediatric patient population in the United States and Europe in these additional rare cholestatic settings is approximately 1,000 patients.

We expect topline results from the EXPAND study in the fourth quarter of 2026.

We are advancing our product candidate, volixibat, a novel, oral, minimally-absorbed agent designed to inhibit IBAT, for the treatment of adult patients with cholestatic liver diseases.

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Volixibat has been studied in over 400 adults for up to 48 weeks.

Clinical trials of volixibat have shown significant activity on IBAT and bile acid markers such as 7αC4, fecal bile acids and cholesterol, demonstrating potent biological activity.

Clinical trials of volixibat have shown

significant activity on IBAT and bile acid markers such as 7αC4, fecal bile acids and cholesterol, demonstrating potent biological activity.

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.

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VISTAS is an adaptive, randomized Phase 2b clinical trial evaluating the effect of volixibat on pruritus, sBA and fibrosis markers in patients with PSC and pruritus.

We expect to complete enrollment in the first half of 2025.

We expect to announce topline results from the VISTAS study in the second quarter of 2026.

PBC is a chronic, rare, cholestatic liver disease characterized by progressive liver bile flow impairment caused by immune-mediated destruction of intrahepatic bile ducts.

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We estimate a worldwide total addressable market for volixibat in PSC and PBC to be more than $1 billion.

We are advancing brelovitug for the treatment of chronic HDV infection.

Brelovitug is a novel fully human IgG1 monoclonal antibody that binds the hepatitis B surface antigen, thereby clearing virions and subviral particles and preventing HDV infection and replication.

The results of the brelovitug Phase 2 study show the potential for this treatment to substantially decrease viral load and improve liver function.

The Phase 2 study in 47 adults with chronic HDV infection demonstrated 100% virologic response, defined as a 2 log or greater reduction or target not detected (“TND”) for HDV RNA.

This was observed across all dose groups at 48 weeks, with nearly all patients achieving this response by 24 weeks.

Additionally, 65-82% of subjects achieved the composite endpoint of virologic response and Alanine Aminotransferase (“ALT”) normalization.

The safety profile was favorable with no grade 3 or higher adverse events, no serious adverse events, a low rate of flu-like symptoms and no ALT elevation or neutropenia.

Based on this data, brelovitug was granted FDA breakthrough designation and EMA PRIME designation.

Brelovitug is currently being evaluated in the global AZURE Phase 3 program which is designed to meet expected registrational requirements in both the U.S.

and EU with a primary combined endpoint of virologic response and ALT normalization.

Registration in the U.S.

will be supported by the AZURE-1 and AZURE-4 studies with the primary composite endpoint of virologic response and ALT normalization.

Virologic response is defined as 2 log or greater decline or undetectable HDV RNA.

Studies AZURE-1 and -4 are evaluating two doses of brelovitug, a once weekly 300 mg subcutaneous dose and a once monthly 900 mg subcutaneous dose with a primary analysis after 24 weeks.

Each study also includes an extension period to support long term safety and efficacy.

We expect to complete the 24-week trial period of both AZURE-1 and -4 and announce topline results in the second half of 2026.

AZURE-2 and AZURE-3 will compare brelovitug to an active control, bulevirtide, which is approved in the EU.

AZURE-2 and -3 are 48-week and 24-week studies, respectively.

These studies are intended to support EMA registration as well as long-term efficacy and safety, with final data expected in the first half of 2028.

We are advancing MRM-3379 for the treatment of FXS.

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While both males and females may be affected, males typically experience more severe symptoms due to the presence of only one X chromosome, with the majority of males meeting the criteria for severe intellectual disability.

Patients can also present with severe behavioral alterations, including hyperactivity, impulsivity and anxiety in addition to poor language development and seizures.

Patients can also present with severe behavioral alterations, including hyperactivity, impulsivity and anxiety in addition to poor language development

and seizures.

It is estimated that there are approximately 50,000 males in the U.S.

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Inhibition of PDE4D increases signaling by cAMP, which is impaired in FXS patients, and may support the improved function of the biochemical cascades believed to regulate memory, learning, and cognitive processes.

We expect to initiate a phase 2 clinical study of MRM-3379 in male FXS patients in 2025.

MRM-3379 has been granted FDA Fast Track designation for the treatment of FXS.

We are currently enrolling patients in the BLOOM Phase 2 clinical study of MRM-3379 in FXS and expect topline data in 2027.

License, Finance, Royalty Agreements and Asset Purchases

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In November 2018, we entered into an assignment and license agreement (“Shire License Agreement”) with Shire International GmbH (“Shire”), which was subsequently acquired by Takeda Pharmaceutical Company Limited.

Pursuant to the Shire License Agreement, Shire assigned, transferred and conveyed all of its right, title and interest in and to the Pfizer Agreement, Satiogen Agreement and Sanofi Agreement, (collectively, the “Assigned License Agreements”), each of which is defined below.

Pursuant to the Shire License Agreement, Shire assigned, transferred and conveyed all of its right, title and interest in and to the license agreement, as amended (“Satiogen Agreement”), with Satiogen Pharmaceuticals, Inc.

(“Satiogen”), now a wholly owned Mirum entity, under which we obtained an exclusive, worldwide license to certain patents and know-how controlled by Satiogen related to ASBTis (“ASBTi Technology”) and TGR5 agonists (“TGR5 Technology”), the Pfizer Agreement and the Sanofi Agreement, both as defined below (collectively with the Satiogen Agreement, the “Assigned License Agreements”).

In addition, Shire granted us an exclusive, royalty bearing, sublicensable, worldwide license under certain regulatory materials as well as patents and know-how, which we refer to collectively as the Shire IP, relating to the Livmarli compound and the volixibat compound in development by Shire as of that date, which we collectively refer to as the Shire Licensed Products, to develop, have developed, make, have made, use, sell, have sold, offer for sale or import the Shire Licensed Products worldwide for the therapeutic or prophylactic application in human health.

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Lastly, upon certain annual worldwide net sales of all Shire Licensed Products, we are required to pay Shire, on a non-refundable and non-creditable basis, tiered royalties with rates ranging from low double-digits to mid-teens (“Shire royalties”).

As we make royalty payments to Satiogen, which is defined below, under the Satiogen Agreement, the Shire royalties will be reduced by a low single digit percentage of net sales.

As we make royalty payments to Satiogen under the Satiogen Agreement, the Shire royalties will be reduced by a low single digit percentage of net sales.

Similarly, if we actually make royalty payments to Sanofi, which is defined below, under the Sanofi Agreement, the Shire royalties will be reduced by low to high single digit percentages of certain net sales thresholds.

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Absent early termination, the Sanofi Agreement will remain in effect on a country-by-country and licensed product-by-licensed product basis until the expiration of our royalty payment obligations for such licensed product in such country.

License Agreement with Satiogen Pharmaceuticals, Inc.

Through the Shire License Agreement, we were assigned the rights to the license agreement, as amended (“Satiogen Agreement”), with Satiogen Pharmaceuticals, Inc.

(“Satiogen”), now a wholly-owned Mirum entity, under which we obtained an exclusive, worldwide license to certain patents and know-how controlled by Satiogen related to ASBTis (“ASBTi Technology”), and TGR5 agonists (“TGR5 Technology”).

Under the Satiogen Agreement, we are permitted to develop, manufacture and commercialize products utilizing the ASBTi Technology or TGR5 Technology for the diagnosis, treatment, prevention, mitigation and cure of human diseases and disorders, other than diabetes, obesity or a combination thereof, and to sublicense such rights.

In March 2017, the Satiogen Agreement was amended to terminate the license of certain patents related to the ASBTi Technology and TGR5 Technology as each relates to diabetes and obesity.

In May 2022, we completed the merger and acquisition of Satiogen in which Satiogen became our wholly-owned subsidiary.

We have sole responsibility and control over development and commercialization activities for products utilizing the ASBTi Technology or TGR5 Technology under the Satiogen Agreement and we are required to use commercially reasonable efforts to develop and commercialize such licensed products.

We are required to pay to Satiogen a low single-digit royalty on net sales of products utilizing the ASBTi Technology or TGR5 Technology sold by us and our affiliates.

Our royalty obligations continue on a licensed product-by-licensed product and country-by-country basis until the expiration of the last valid claim in a licensed patent or patent application covering the applicable licensed product in such country.

The term of the last patent or patent application licensed under the Satiogen Agreement ends on August 30, 2031, absent patent term adjustment or extension.

In the event we sublicense any of our rights under the ASBTi Technology or TGR5 Technology to a third party, we are obligated under the Satiogen Agreement to pay to Satiogen a fee based on a percentage of sublicense revenue received by us, which percentage ranges from the mid-teens to mid-twenties, depending on whether the right granted is in connection with the ASBTi Technology or TGR5 Technology, and the stage of development of such sublicensed technology.

In addition, we are obligated under the Satiogen Agreement to pay to Satiogen a percentage of royalties we receive in consideration for the grant of such sublicense based on a percentage of revenue generated by such sublicensee for sales of products utilizing the ASBTi Technology or TGR5 Technology, which percentage is in the low-fifties and is subject to adjustment in certain circumstances.

This payment will not exceed an amount that is one-half of our low single-digit royalty obligation to Satiogen.

We may unilaterally terminate the Satiogen Agreement for any reason or no reason upon 90 days’ written notice to Satiogen.

If we cease all research, development and commercialization efforts with respect to all licensed products related to the ASBTi Technology or the TGR5 Technology for over one year, or we determine to cease all such efforts, Satiogen may elect to terminate the Satiogen Agreement with respect to the license under the ASBTi Technology or the TGR5 Technology, respectively.

Either party may terminate the Satiogen Agreement for the other party’s material breach of the Satiogen Agreement which remains uncured after 90 days of receiving written notice of such breach.

Absent early termination, the Satiogen Agreement will automatically terminate upon the expiration of our royalty obligations.

License agreement with Novartis Pharma AG

Bluejay obtained a worldwide license to develop and commercialize brelovitug from Novartis in June 2021.

Under the terms of the license agreement, Novartis is entitled to receive up to $8.0 million in development milestones and up to $27.0 million in commercial milestones.

Novartis is also entitled to receive commercial royalties of mid-single digit percent of sales.

In addition, Bluejay agreed to pay Novartis a milestone payment of $4.0 million upon a change of control, which was earned upon closing of the acquisition of Bluejay in January 2026.

Manufacturing and License Agreement with Lonza Ltd.

In conjunction with the manufacture and commercialization of brelovitug, Bluejay entered into a master services agreement with Lonza Ltd.

(“Lonza”) in October 2021 and a license agreement with Lonza Sales AG in December 2022 (the “Lonza License Agreement”).

Lonza is manufacturing brelovitug using its proprietary cell line technology and related

intellectual property.

Under the Lonza License Agreement, Bluejay obtained a non-exclusive, sublicensable license under Lonza’s cell line technology and related know-how and patents for the manufacture and commercialization of brelovitug.

License Agreement with Enthorin Therapeutics, LLC and Dart Neuroscience LLC

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Pursuant to the Asklepion APA, we are required to pay Asklepion high single-digit to low double-digit tiered royalties on worldwide net revenues of Cholic Acid Products.

Master Services Agreement with The Aliceanna Group LLC

Through the Bile Acid Portfolio Acquisition, we were assigned Travere’s rights and obligations under the Master Services Agreement (“Aliceanna MSA”), dated January 10, 2015, between Travere and The Aliceanna Group LLC (“Aliceanna”) related to the performance of certain development services by Aliceanna related to Cholic Acid Products.

Pursuant to the Aliceanna MSA, we are obligated to pay Aliceanna a low single-digit royalty on net revenues of Cholic Acid Products.

Commercial Agreements related to chenodiol

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(“LGM”), and Manchester Pharmaceuticals, Inc.

(together with its affiliates, “Manchester”) related to the manufacture of chenodiol, pursuant to which

we obtained an exclusive, perpetual license to market chenodiol in the U.S.

related to the manufacture of chenodiol, pursuant to which we obtained an exclusive, perpetual license to market chenodiol in the U.S.

under the terms of an abbreviated new drug application approved by the FDA and owned by LGM, which grants to LGM the authority to manufacture and sell chenodiol in the U.S.

International Rights Purchase Agreement with Manchester Pharmaceuticals LLC

Through the Bile Acid Portfolio Acquisition, we were assigned the rights to the International Rights Purchase Agreement (“Manchester IRPA”), dated March 26, 2014, between Travere and Manchester, pursuant to which we acquired all right, title and interest to certain products of Manchester related to chenodiol (“Chenodiol Products”).

Pursuant to the Manchester IRPA, we are obligated to pay Manchester a mid-single-digit to low double-digit royalty on net sales of certain Chenodiol Products outside of the U.S.

Membership Interest Purchase Agreement with Loring Creek Holdings LLC et al.

Through the Bile Acid Portfolio Acquisition, we were assigned Travere’s rights and obligations under the Membership Interest Purchase Agreement (“Manchester MIPA”), dated March 26, 2014, among, on the one hand, Travere, and on the other, Loring Creek Holdings LLC and certain individuals (collectively, the “MIPA Sellers”), pursuant to which Travere had acquired from the MIPA Sellers all issued and outstanding membership interests in Manchester Pharmaceuticals LLC.

Pursuant to the Manchester MIPA, we are obligated to pay the MIPA Sellers a mid-single-digit to low double-digit royalty on net sales of certain Chenodiol Products in the U.S.

Asklepion APA

Pursuant to the Asklepion APA, we are required to pay Asklepion a low single-digit royalty on net sales of chenodiol in the U.S.

Revenue Interest Purchase Agreement with Oberland

In December 2020, we entered into a Revenue Interest Purchase Agreement (“RIPA”) with Mulholland SA LLC, an affiliate of Oberland Capital LLC, as agent for the purchasers party thereto (the “Purchasers”), and the Purchasers.

Pursuant to the RIPA, the Purchasers paid us $50.0 million on closing and $65.0 million in April 2021, less certain transaction expenses.

In April 2023, we exercised our option to terminate the RIPA and repurchase all future revenue interests from the Purchasers in exchange for a payment of $192.7 million.

Upon repurchase of the revenue interests from the Purchasers, the RIPA, in accordance with its terms, was terminated with no further payments due to the Purchasers and the $100.0 million of previously restricted cash equivalents was no longer restricted from use.

Convertible Notes

In April 2023, we completed an offering of $316.3 million aggregate principal of 4.00% Convertible Senior Notes due 2029 (the “Notes”), which includes the exercise of the initial purchasers’ option in full.

The offering resulted in net proceeds of $305.3 million after deducting the initial purchasers’ discounts and commissions and offering expenses.

We used a portion of the net proceeds to repurchase the revenue interests pursuant to the RIPA, entered into in December 2020, as amended in September 2021.

Asset Purchase Agreement with Travere Therapeutics, Inc.

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We paid $210.4 million upon closing of the transaction, and up to an additional $235.0 million is payable upon the achievement of certain milestones based on specified amounts of annual net sales of the Bile Acid Medicines.

We concurrently entered into a transitional services agreement with Travere, pursuant to which Travere was obligated to perform certain services for a period of time, not anticipated to last beyond 12 months post-close, with respect to our use and operation of the assets purchased.

The transitional services agreement has since terminated according to its terms.

As of December 31, 2025, the Company accrued $25.0 million for the achievement of a commercial milestone associated with achievement of certain net product sales, which is expected to be paid in the first quarter of 2026.

In connection with and immediately prior to the closing of the Bile Acid Portfolio Acquisition, we completed the private placement of 8,000,000 shares of our common stock at a price per share of $26.25, resulting in net proceeds of approximately $202.2 million.

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Our success depends in part on our ability to obtain and maintain proprietary protection for our product candidates and other discoveries, inventions, trade secrets and know-how that are critical to our business operations.

Our success also depends in part on our ability to operate without infringing the proprietary rights of others, and in part, on our

ability to prevent others from infringing our proprietary rights.

Our success also depends in part on our ability to operate without infringing the proprietary rights of others, and in part, on our ability to prevent others from infringing our proprietary rights.

A comprehensive discussion on risks relating to intellectual property is provided under “Risk Factors” under the subsection “Risks Related to Our Intellectual Property.”

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11,376,251, which is directed to methods of treating ALGS in a pediatric subject with maralixibat, expiring in October 2032.

We also have rights to U.S.

12,350,267, which is directed to methods of

treating PFIC in a pediatric subject with maralixibat, expiring in October 2032.

We also have rights to U.S Patent Nos.

10,512,657 and 11,229,661, which are directed to methods of treating or ameliorating PFIC2 and methods of treating or ameliorating a pediatric disorder characterized by having a non-truncating BSEP mutation selected from PFIC2, BRIC2, and drug induced cholestasis in a pediatric subject comprising administering maralixibat, respectively, both of which expire in October 2032.

These three U.S.

These four U.S.

patents are listed in the FDA’s Orange Book:

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We have rights to granted patents in Australia, Brazil, Canada, China, Israel, Japan, Mexico, South Korea, Armenia, Azerbaijan, Belarus, Kazakhstan, Kyrgyzstan, Russia, Tajikistan, Turkmenistan, South Africa and Macau covering the methods of treating cholestasis using IBATis that have limited systemic exposure, which expire in October 2032.

We also have rights to pending patent applications in United States, Europe, Eurasia, Hong Kong and Singapore, covering methods of treating pediatric cholestatic liver diseases using IBATis that have limited systemic exposure, which, if issued, would expire in October 2032, absent any patent term adjustments or extensions.

We also have rights to pending patent applications in United States, Europe, Hong Kong and Singapore, covering methods of treating pediatric cholestatic liver diseases using IBATis that have limited systemic exposure, which, if issued, would expire in October 2032, absent any patent term adjustments or extensions.

We have rights to granted patents in Australia, Brazil, Canada, China, Israel, Japan, Mexico, South Korea, South Africa, Singapore, Austria, Belgium, Czech Republic, Denmark, Estonia, Finland, France, Germany, Ireland, Italy, Netherlands, Norway, Poland, Portugal, Slovak Republic, Spain, Sweden, Switzerland, United Kingdom, Armenia, Azerbaijan, Belarus, Kazakhstan, Kyrgyzstan, Russia, Tajikistan, Macau and Turkmenistan covering methods of treating pediatric cholestatic liver diseases using IBATis that have limited systemic exposure, which expire in October 2032.

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patents are listed in the Orange Book for Livmarli.

We have rights to granted patents in Austria, Belgium, Bulgaria, Croatia, Denmark, Finland, France, Germany, United Kingdom, Ireland, Italy, the Netherlands, Norway, Poland, Portugal, Romania, Sweden, Switzerland, Turkey, United Kingdom, Spain, and Mexico, which are directed to maralixibat or volixibat for use in treating cholestatic liver disease in a subject having BSEP deficiency but without total loss of BSEP activity, which expire in February 2040.

We have rights to granted patents in Austria, Belgium, Bulgaria, Croatia, Denmark, Finland, France, Germany, United Kingdom, Ireland, Italy, the Netherlands, Norway, Poland, Portugal, Romania, Sweden, Switzerland, Turkey, United Kingdom, Spain, Mexico, Japan and Russia, which are directed to maralixibat or volixibat for use in treating cholestatic liver disease in a subject having BSEP deficiency but without total loss of BSEP activity, which expire in February 2040.

We have rights to pending patent applications in the United States, Europe, Canada, China, Japan, South Korea, Israel, Brazil, Russia, Mexico, Australia, New Zealand, UAE, and Saudi Arabia directed to methods for treating cholestatic liver disease and to methods for using patient genotype to predict response to IBATi administration in patients with BSEP deficiency.

Any patents issuing from these applications would expire in February 2040, absent any patent term adjustments or extensions.

We have rights to a granted patent in Russia directed to methods for treating ALGS comprising administering higher dosages of maralixibat.

We have rights to pending applications in the United States, Europe, Canada, China, Japan, South Korea, Israel, Brazil, Russia, Mexico, Australia, New Zealand, UAE, and Saudi Arabia directed to methods for treating cholestatic liver disease comprising administering higher dosages of IBATis.

We have rights to granted patents in Japan, Russia, Hong Kong, Croatia, Czech Republic, Ireland, Norway, Poland, Romania, Slovak Republic, Spain, Switzerland, and United Kingdom directed to methods of increasing growth in pediatric subjects having cholestatic liver disease by administering IBATis, which expire in February 2040.

We have rights to pending applications in the United States, Europe, Canada, China, Japan, South Korea, Israel, Brazil, Russia, Mexico, Australia, New Zealand, UAE, and Saudi Arabia directed to methods of increasing growth in pediatric subjects having cholestatic liver disease by administering IBATis.

We have rights to pending applications in the United States, Europe, Canada, South Korea, Israel, Brazil, Russia, Mexico, Australia, New Zealand, UAE, and Saudi Arabia directed to methods of increasing growth in pediatric subjects having cholestatic liver disease by administering IBATis.

Any patents issuing from these applications would expire in February 2040, absent any patent term adjustments or extensions.

We have rights to pending applications in the United States, Argentina, Taiwan, Europe, Canada, China, Japan, Korea, Australia, India, Israel, Singapore, Brazil, Mexico, Eurasia, New Zealand, United Arab Emirates, Saudi Arabia, Algeria, Morocco, Tunisia, Egypt, Chile, Colombia, Indonesia, Malaysia, Philippines, Thailand, Vietnam, South Africa and Hong Kong directed to formulations of maralixibat which, if issued, would expire in October 2042, absent any patent term adjustments or extensions.

We have rights to pending applications in the United States, Argentina, Taiwan, Europe, Canada, China, Japan, South Korea, Australia, India, Israel, Singapore, Brazil, Mexico, Eurasia, New Zealand, United Arab Emirates, Saudi Arabia, Morocco, Tunisia, Egypt, Chile, Colombia, Malaysia, Philippines, Thailand, Vietnam, South Africa and Hong Kong directed to formulations of maralixibat which, if issued, would expire in October 2042, absent any patent term adjustments or extensions.

We have rights to a granted patent in Luxemburg directed to increased event-free survival of long-term maralixibat patients which expires in October 2042.

We have rights to pending applications in the United States, Taiwan, Europe, Canada, China, Japan, South Korea, Israel, Singapore, Brazil, Mexico, Eurasia, South Africa, and Hong Kong directed to methods of treatment with IBATis in the fasted state which, if issued, would expire in October 2042, absent any patent term adjustments or extensions.

We have rights to pending applications in the United States, Taiwan,

Europe, Canada, China, Japan, South Korea, Australia, Israel, Singapore, Brazil, Mexico, South Africa, New Zealand, Chile, Malaysia, United Arab Emirates, Morocco, Tunisia, Lybia, Iraq, Algeria, and Hong Kong directed to increased event-free survival of long-term maralixibat patients which, if issued, would expire in November 2042, absent any patent term adjustments or extensions.

We have rights to pending applications in the United States, Argentina, Taiwan, Uruguay, Paraguay and Patent Cooperation Treaty (“PCT”) directed to highly pure maralixibat forms and intermediates which, if issued, would expire in September 2043, absent any patent term adjustments or extensions.

We have rights to pending applications in the United States, PCT, and Taiwan directed to maralixibat compositions and solid dosage forms which, if issued, would expire in October 2043, absent any patent term adjustments or extensions.

We have rights to pending applications in the United States, Taiwan, and PCT directed to methods of treating PFIC with maralixibat which, if issued, would expire in October 2043, absent any patent term adjustments or extensions.

We have rights to pending applications in the United States, Europe, Canada, China, Japan, Australia, Israel, Singapore, Mexico, Eurasia, South Africa, and Hong Kong directed to methods of treatment with IBATis in the fasted state which, if issued, would expire in October 2042, absent any patent term adjustments or extensions.

We have rights to pending applications in the United States, Europe, Canada, China, Japan, Australia, Israel, Singapore, Mexico, Eurasia, South Africa, New Zealand, Malaysia, Saudi Arabia, United Arab Emirates, Morocco, Tunisia, Lybia, Iraq, and Hong Kong directed to increased event-free survival of long-term maralixibat patients which, if issued, would expire in November 2042, absent any patent term adjustments or extensions.

We have rights to pending applications in the United States, Argentina, Taiwan, Uruguay, Paraguay, Europe, Canada, China, Hong Kong, Japan, South Korea, Australia, India, Israel, Singapore, Brazil, Mexico, Eurasia, South Africa,

New Zealand, Chile, and United Arab Emirates directed to highly pure maralixibat forms and intermediates which, if issued, would expire in September 2043, absent any patent term adjustments or extensions.

We have rights to U.S.

12,296,050 directed to maralixibat compositions and solid dosage forms expiring in October 2043.

This patent is listed in the Orange Book for Livmarli.

We have rights to pending applications in the United States, Patent Cooperation Treaty (“PCT”), and Taiwan directed to maralixibat compositions and solid dosage forms which, if issued, would expire in October 2043, absent any patent term adjustments or extensions.

We have rights to pending applications in the United States, Taiwan, Australia, Brazil, Canada, China, Eurasia, Europe, Hong Kong, Israel, Japan, South Korea, Mexico, New Zealand, Singapore and South Africa directed to methods of treating PFIC with maralixibat which, if issued, would expire in October 2043, absent any patent term adjustments or extensions.

We have rights to pending applications in the United States, Brazil, Canada, China, Eurasia, Europe, Israel, Japan, South Korea, Mexico, New Zealand and Singapore directed to pharmaceutical compositions comprising volixibat which, if issued, would expire in May 2044, absent any patent term adjustments or extensions.

We have rights to pending applications in the United States and PCT directed to methods of treating cholestatic pruritus in rare diseases which, if issued, would expire in May 2045, absent any patent term adjustments or extensions.

We have licensed patent applications in the United States, Hong Kong, and Europe from Satiogen covering therapeutic uses of IBATis that have limited systemic exposure for treating inflammatory intestinal conditions, which, if issued, would expire in May 2031, absent any patent term adjustments or extensions.

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patents covering MRM-3379 as a composition-of-matter, as well as a pending counterpart in the United States and issued foreign counterparts in Belgium, France, Germany, Norway, the Netherlands, Sweden, Switzerland, United Kingdom, Denmark, Italy, Ireland, Spain, United Kingdom, Australia, Canada, China, Japan, South Korea, Brazil, India, Israel, Mexico, New Zealand, Russia, Singapore, Hong Kong, and Taiwan, which are set to expire in March 2034, absent any patent term extensions.

We have rights to pending PCT and Taiwan applications covering methods of treating Fragile X syndrome using MRM-3379.

Patents related to MRM-3379 may be eligible for patent term extensions in certain jurisdictions, including the United States, upon approval of a commercial use of the corresponding product by a regulatory agency in the jurisdiction where the patent was granted.

Upon approval in the United States, as MRM-3379 has not previously been approved in the United States for any indication, it may be eligible for five years of NCE exclusivity, which would run concurrently with its seven years of orphan drug exclusivity if we obtain orphan drug exclusivity for FXS or another approved orphan indication.

We have rights to a patent portfolio and will continue to develop a patent portfolio around our product candidate brelovitug.

We have rights to two issued U.S.

patents, U.S.

11,932,681 and 12,331,104, covering brelovitug as a composition-of-matter and methods of treating hepatitis B, as well as a pending counterpart in the United States and issued foreign counterparts in China and Japan, as well as pending foreign counterparts in China, Europe, Hong Kong, and Japan, which are set to expire in 2039-2041 absent any patent term extensions.

We have rights to pending United States, Australia, Canada, Europe, Israel, India, Japan, Korea, Mongolia, New Zealand, Singapore, United Arab Emirates, and Taiwan applications covering methods of treating hepatitis D using brelovitug, which are set to expire in 2044, absent any patent term adjustment or extensions.

We have rights to a pending United States provisional application covering the pharmaceutical compositions of brelovitug, and any patent issued claiming priority to the provisional will expire in 2046 absent any patent term adjustments or extensions.

Patents related to brelovitug may be eligible for patent term extensions in certain jurisdictions, including the United States, upon approval of a commercial use of the corresponding product by a regulatory agency in the jurisdiction where the patent was granted.

Upon approval in the United States, as brelovitug has not previously been approved in the United States for any indication, it may be eligible for a 12-year biologics exclusivity which would run concurrently with its seven years of orphan drug exclusivity if we obtain orphan drug exclusivity for chronic HDV treatment or another approved orphan indication.

In addition to patent protection, we rely on trade secret protection, trademark protection and know-how to expand our proprietary position around our chemistry, technology and other discoveries and inventions that we consider important to our business.

We are a party to a number of license agreements under which we are granted intellectual property rights to know-how that are important to our business.

We have licensed know-how related to Livmarli in the United States, Europe and other countries from Pfizer.

We have access to, or have licensed, know-how related to Livmarli in the United States, Europe and other countries from Pfizer and Shire.

We have licensed know-how related to ASBTi Technology and TGR5 Technology from Satiogen.

We have licensed know-how related to volixibat from Sanofi.

We have access to, or have licensed, know-how related to volixibat from Sanofi and Shire.

We have licensed know-how related to brelovitug from Novartis.

We have licensed know-how related to MRM-3379 from Enthorin.

Our existing license agreements as related to Livmarli, volixibat, and MRM-3379 impose various development, regulatory and/ commercial diligence obligations, payment of milestones and/or royalties and other obligations.

Our existing license agreements as related to Livmarli, volixibat, brelovitug and MRM-3379 impose various development, regulatory and/ commercial diligence obligations, payment of milestones and/or royalties and other obligations.

In addition, we currently have orphan drug exclusivity for Livmarli for the treatment of ALGS and PFIC in the United States and the EU, providing seven years of market exclusivity in the United States, which can be extended to seven and a half years if trials are conducted in accordance with an agreed-upon pediatric investigational plan, and ten years of market exclusivity in the EU, which has been extended to 12 years in the EU for the treatment of ALGS in view of a pediatric award and may be extended to 12 years in the EU for PFIC.

In addition, we currently have orphan drug designation for volixibat for the treatment of PBC in the United States and in the EU, providing the opportunity to receive

seven years of market exclusivity in the United States, which can be extended to seven and a half years if trials are conducted in accordance with an agreed-upon pediatric investigational plan, and ten years of market exclusivity in the EU, which can be extended to 12 years in the EU if trials are conducted in accordance with an agreed-upon pediatric investigational plan.

In addition, we currently have orphan drug designation for volixibat for the treatment of PBC in the United States and in the EU, providing the opportunity to receive seven years of market exclusivity in the United States, which can be extended to seven and a half years if trials are conducted in accordance with an agreed-upon pediatric investigational plan, and ten years of market exclusivity in the EU, which can be extended to 12 years in the EU if trials are conducted in accordance with an agreed-upon pediatric investigational plan.

In the United States, maralixibat has been granted new chemical entity (“NCE”) exclusivity until September 29, 2026.

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To maintain and further develop the appropriate commercial infrastructure, we have invested and expect to continue to invest significant amounts of financial and management resources in our commercial organization.

In addition, we have built a medical affairs organization and multiple capabilities across North America and Europe to meet the scientific and medical educational needs of the healthcare providers and patients in the rare disease community that are focused on providing accurate disease state and balanced product information for appropriate management of patients with rare disorders.

management of patients with rare disorders.

Medical affairs is comprised of medical information, patient advocacy, patient diagnosis, medical science liaisons, research and educational grants.

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We do not have any current contractual arrangements for the manufacture of commercial supplies of volixibat.

We have entered into an agreement with Lonza for the manufacture of brelovitug.

We currently employ internal resources and third-party consultants to manage our manufacturing contractors.

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Such developments by competitors could reduce or eliminate the use of our products or may limit the utility and application of ongoing clinical trials for our product candidates.

We are aware of two other companies pursuing clinical development of therapies that reduce sBA levels via the IBAT pathway.

GlaxoSmithKline plc and Ipsen Pharma (“Ipsen”) have IBATis in clinical development for cholestatic liver diseases.

We are aware Ipsen has received approval for odevixibat (Bylvay) for the treatment of pruritus in patients with PFIC 3 months of age and older, and cholestatic pruritus in patients with ALGS 12 months of age and older, in the U.S., and for the treatment of PFIC in patients 6 months of age and older in the EU and for odevixibat (Kayfanda) for the treatment of cholestatic pruritus in ALGS in patients 6 months of age and older.

We are aware of two other companies pursuing clinical development and commercialization of therapies that reduce sBA levels via the IBAT pathway.

GlaxoSmithKline plc (“GSK”) and Ipsen Pharma (“Ipsen”) have IBATs in clinical development for cholestatic liver diseases.

We are aware Ipsen has received approval for odevixibat (Bylvay) for the treatment of pruritus in patients with PFIC and cholestatic pruritus in patients with ALGS in the U.S., and for the treatment of PFIC in the EU and for odevixibat (Kayfanda) for the treatment of cholestatic pruritus in ALGS.

In the EU, Bylvay and Kayfanda are authorized under exceptional circumstances.

Ipsen has opened enrollment in their ALGS open-label extension study to infants 11 months or younger and is also conducting a study of odevixibat in BA and plans to pursue other cholestatic liver diseases.

GSK announced in November 2024 that the Phase 3 GLISTEN trial with linerixibat in PBC met its primary pruritus endpoint and that GSK intends to submit marketing applications to the U.S., EU and other health authorities in first half of 2025 with potential approvals expected in the second half of 2025.

Ipsen has opened enrollment in their ALGS open-label extension study to infants 11 months or younger and is also conducting a study of odevixibat in biliary atresia and plans to pursue other cholestatic liver diseases.

GSK announced in November 2024 that the Phase 3 GLISTEN trial with linerixibat in PBC met its primary pruritus endpoint and that GSK has submitted marketing applications to the U.S., EU and other health authorities with potential approvals expected in 2026.

Other off-label medications are also used in ALGS, PFIC, PSC and PBC for cholestatic pruritus such as Ursodeoxycholic acid (“UDCA”), cholestyramine and other bile salt resins, rifampin, naltrexone and other agents, such as selective serotonin reuptake inhibitors.

Despite the lack of FDA approval, these older, generic agents are perceived as part of the standard of care for treating ALGS, PFIC, PSC and PBC patients suffering from cholestatic pruritus.

Further, we may compete with companies that are developing gene therapy for the treatment of PFIC.

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We are aware that Alfasigma S.p.’s (formerly Intercept Pharmaceuticals, Inc.) Ocaliva, Gilead Science’s Livdelzi, and Ipsen’s Iqirvo are approved as a second-line treatment for PBC in patients with inadequate response to ursodeoxycholic acid.

We are aware of several agents in clinical development for the treatment of PBC including Alfasigma’s Ocaliva and bezafibrate, Zydus Therapeutics Inc.’s saroglitazar magnesium, NGM Biopharmaceuticals, Inc.’s NGM282, Calliditas Therapeutics AB’s setanaxib, COUR Pharmaceuticals’ CNP-104, Ascletis Pharma’s ASC42, Umecrine Cognition’s golexanolone, Kowa Company Ltd’s K-808, HighTide Therapeutics Inc.’s HTD-1801, Hepagene Therapeutics Inc.’s HPG-1860, Tharimmune Inc.’s TH-104, Cascade Pharmaceuticals Inc.’s CS-0159, Rectify Pharmaceuticals, Inc.’s RTY-694, and GlaxoSmithKline’s linerixibat, another IBATi.

We are aware of several agents in clinical development for the treatment of PBC including Alfasigma’s Ocaliva and bezafibrate, Zydus Therapeutics Inc.’s saroglitazar magnesium, Calliditas Therapeutics AB’s setanaxib, COUR Pharmaceuticals’ CNP-104, Umecrine Cognition’s golexanolone, Kowa Company Ltd’s K-808, HighTide Therapeutics Inc.’s HTD-1801, Hepagene Therapeutics Inc.’s HPG-1860, Tharimmune Inc.’s TH-104, Cascade Pharmaceuticals Inc.’s CS-0159, and GSK’s linerixibat, another IBATi.

We are not aware of FDA or European Commission approved therapeutics for the treatment of PSC.

We are aware of several agents in clinical development for the treatment of PSC, including Dr.

Falk Pharma’s Norucholic acid, HighTide Therapeutics Inc.’s HTD-1801, Alfasigma’s Ocaliva, or obeticholic acid, Ipsen’s elafibranor and ritivixibat, NGM Biopharmaceuticals Inc.’s NGM282, Chemomab Therapeutics Ltd.’s CM-101, Cascade Pharmaceuticals Inc.’s CS-0159, LISCure Biosciences Inc.’s LB-P8, and Pliant Therapeutics’ bexotegrast.

Symptomatic treatment with antipruritics, such as cholestyramine, typically provides only modest relief.

Bristol Myers Squibb Company has discontinued its brand name cholestyramine, but generic versions of the drug are marketed by Upsher-Smith Laboratories, Inc., Par Pharmaceutical Companies, Inc., Sandoz Inc., the generic pharmaceuticals division of Novartis AG and others.

UDCA, also known as ursodiol, is marketed by a number of generic pharmaceutical companies such as Mylan Inc., Actavis Inc., Lannett Company, Inc.

and Par Pharmaceutical Companies, Inc.

There are other approved chenodeoxycholic acid products available outside of the U.S.

Falk Pharma GmbH and Leadiant Biosciences, Inc.

have FDA Orphan Drug Designations granted for the treatment of CTX (granted in 2004 and 2007, respectively);

and we believe that Leadiant Biosciences, based on publicly available information, may be conducting a clinical study in CTX.

have FDA Orphan Drug Designations granted for the treatment of CTX (granted in 2004 and 2007, respectively), and we believe that Leadiant Biosciences, based on publicly available information, may be conducting a clinical study in CTX.

There are currently no FDA-approved treatments in the U.S.

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and Laboratoires CTRS has received approval from the EMA for a version of cholic acid.

Under the Hatch-Waxman Amendments of the Federal Food, Drug, and Cosmetic Act, a pharmaceutical manufacturer may file an abbreviated new drug application (“ANDA”) seeking approval of a generic copy of an approved innovator product or an NDA under Section 505(b)(2) that relies on the FDA’s prior findings of safety and effectiveness in approving the innovator product.

There are currently no approved products available in the U.S.

for the treatment of chronic HDV infection.

Bulevirtide, which is commercialized by Gilead Sciences, is approved for commercial sale in the EU and Gilead is seeking approval from the FDA to commercialize bulevirtide in the U.S.

In addition, we are aware that Vir Biotechnology is developing tobevibart in combination with elebsiran for the treatment of chronic HDV.

We are aware of several other agents in clinical development for the treatment of chronic HDV including Gilead Science’s GS-4321, Shanghai HEP Pharmaceutical Co., Ltd.’s Hepalatide, Suzhou Ribo Life Science Co., Ltd.’s RBD1016, Assembly Biosciences’s ABI-6250, Huahui Health Ltd.’s Libevitug and HH-1270, Replicor Inc.’s REP 2139-Mg and REP 2139-Ca, and EIT Pharma’s Jitixib® (Lonafarnib).

Under the Hatch-Waxman Amendments of the Federal Food, Drug, and Cosmetic Act (the “Hatch-Waxman Act”), a pharmaceutical manufacturer may file an abbreviated new drug application (“ANDA”) seeking approval of a generic copy of an approved innovator product or an NDA under Section 505(b)(2) that relies on the FDA’s prior findings of safety and effectiveness in approving the innovator product.

A Section 505(b)(2) NDA may be for a new or improved version of the original innovator product.

Certain of our approved medicines, including Chenodal, Ctexli and Cholbam, are or may be subject to immediate competition from compounded and generic entrants, as the ANDA and NDA for these drug products have no remaining or current patent or non-patent exclusivity although Ctexli does have orphan designation for the CTX indication.

Certain of our approved medicines, including Ctexli and Cholbam, are or may be subject to immediate competition from compounded and generic entrants, as the ANDA and NDA for these drug products have no remaining or current patent or non-patent exclusivity although Ctexli does have orphan designation for the CTX indication.

Further, as described in more detail in Part I, Item 1A, “Risk Factors” and Note 15 in the notes to our consolidated financial statements appearing elsewhere in this Annual Report, we have initiated litigation against certain parties alleging infringement of certain “Orange Book” listed patents covering LIVMARLI in accordance with the procedures set out in the Hatch-Waxman Act following the submission by such parties of ANDAs directed to generic versions of LIVMARLI.

We cannot make any predictions about the final outcome of these matters or the timing thereof.

In December 2019, the Creating and Restoring Equal Access to Equivalent Samples Act of 2019 (the “CREATES Act”) was enacted, which provides a legislatively defined private right of action under which generic companies can bring suit against companies who refuse access to product for the bioequivalence testing needed to support approval of a generic product.

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Government Regulation and Product Approval

As a pharmaceutical company that operates globally, we are subject to extensive regulation.

As a biopharmaceutical company that operates globally, we are subject to extensive regulation.

Government authorities in the United States (at the federal, state and local level) and in other countries extensively regulate, among other things, the research, development, testing, manufacturing, quality control, approval, labeling, packaging, storage, record-keeping, promotion, advertising, distribution, post-approval monitoring and reporting, marketing and export and import of drug products such as those we are developing.

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Additionally, some significant aspects of regulation in the EU are addressed in a centralized way, but country-specific regulation remains essential in many respects.

Drug Development Process

In the United States, the FDA regulates drugs under the Federal Food, Drug and Cosmetic Act (“FDCA”), and implementing regulations.

Drugs are also subject to other federal, state and local statutes and regulations.

Biopharmaceutical Development Process

In the United States, the FDA regulates drugs under the Federal Food, Drug and Cosmetic Act (“FDCA”), and biologics additionally under the Public Health Service Act, and their implementing regulations.

Biopharmaceuticals are also subject to other federal, state and local statutes and regulations.

The process of obtaining regulatory approvals and the subsequent compliance with appropriate federal, state, local and foreign statutes and regulations require the expenditure of substantial time and financial resources.

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Any agency or judicial enforcement action could have a material adverse effect on us.

The process required by the FDA before a drug may be marketed in the United States generally involves the following:

The process required by the FDA before a drug or biologic may be marketed in the United States generally involves the following:

• completion of extensive preclinical laboratory tests, preclinical animal studies and formulation studies in accordance with applicable regulations, including the FDA’s Good Laboratory Practice (“GLP”), regulations and other applicable regulations;

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• performance of adequate and well-controlled human clinical trials in accordance with applicable regulations, including the FDA’s good clinical practice (“GCP”), regulations to establish the safety and efficacy of the proposed drug for its proposed indication;

• submission to the FDA of an NDA for a new drug;

• submission to the FDA of an NDA for a new drug or Biologics License Application (“BLA”) for a biologic;

• satisfactory completion of an FDA advisory committee review, if applicable;

• a determination by the FDA within 60 days of its receipt of an NDA to file the NDA for review;

• a determination by the FDA within 60 days of its receipt of an NDA or BLA to file the application for review;

• satisfactory completion of an FDA pre-approval inspection of the manufacturing facility or facilities where the drug is produced to assess compliance with the FDA’s current good manufacturing practice (“cGMP”), requirements to assure that the facilities, methods and controls are adequate to preserve the drug’s identity, strength, quality and purity;

• potential FDA inspection of the preclinical and/or clinical trial sites that generated the data in support of the NDA;

• FDA review and approval of the NDA prior to any commercial marketing or sale of the drug in the United States.

Before testing any compounds with potential therapeutic value in humans, the drug candidate enters the preclinical testing stage.

Preclinical tests include laboratory evaluations of product chemistry, toxicity and formulation, as well as animal studies, to assess the potential safety and activity of the drug candidate.

• potential FDA inspection of the preclinical and/or clinical trial sites that generated the data in support of the NDA or BLA;

• FDA review and approval of the NDA or BLA prior to any commercial marketing or sale of the drug or biologic in the United States.

Before testing any compounds with potential therapeutic value in humans, the candidate enters the preclinical testing stage.

Preclinical tests include laboratory evaluations of product chemistry, toxicity and formulation, as well as animal studies, to assess the potential safety and activity of the candidate.

The conduct of the preclinical tests must comply with federal regulations and requirements including GLPs.

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In such a case, the IND sponsor and the FDA must resolve any outstanding concerns before the clinical trial can begin.

The FDA may also impose clinical holds on a drug candidate at any time before or during clinical trials due to safety concerns or non-compliance.

Clinical trials involve the administration of the drug candidate to healthy volunteers or patients under the supervision of qualified investigators, generally physicians not employed by or under the trial sponsor’s control, in accordance with GCPs, which include the requirement that all research subjects provide their informed consent for their participation in any clinical trial.

Clinical trials are conducted under protocols detailing, among other things, the objectives of the clinical trial, dosing procedures, subject selection and exclusion criteria and the parameters to be used to monitor subject safety and assess efficacy.

The FDA may also impose clinical holds at any time before or during clinical trials due to safety concerns or non-compliance.

Clinical trials involve the administration of the investigational candidate to healthy volunteers or patients under the supervision of qualified investigators, generally physicians not employed by or under the trial sponsor’s control, in accordance with GCPs, which include the requirement that all research subjects provide their informed consent for their participation in any clinical trial.

Clinical trials are conducted under protocols detailing, among other things, the objectives

of the clinical trial, dosing procedures, subject selection and exclusion criteria and the parameters to be used to monitor subject safety and assess efficacy.

Each protocol, and any subsequent amendments to the protocol, must be submitted to the FDA as part of the IND.

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Human clinical trials are typically conducted in three sequential phases that may overlap or be combined:

The drug is initially introduced into healthy human subjects and tested for safety, dosage tolerance, absorption, metabolism, distribution and excretion, the side effects associated with increasing doses and if possible, to gain early evidence of effectiveness.

The candidate is initially introduced into healthy human subjects and tested for safety, dosage tolerance, absorption, metabolism, distribution and excretion, the side effects associated with increasing doses and if possible, to gain early evidence of effectiveness.

In the case of some products for severe or life-threatening diseases, especially when the product may be too inherently toxic to ethically administer to healthy volunteers, the initial human testing is often conducted in patients.

The drug is evaluated in a limited patient population to identify possible adverse effects and safety risks, to preliminarily evaluate the efficacy of the product for specific targeted diseases or conditions and to determine dosage tolerance, optimal dosage and dosing schedule.

The candidate is evaluated in a limited patient population to identify possible adverse effects and safety risks, to preliminarily evaluate the efficacy of the product for specific targeted diseases or conditions and to determine dosage tolerance, optimal dosage and dosing schedule.

Clinical trials are undertaken to further evaluate dosage, clinical efficacy and safety in an expanded patient population at geographically dispersed clinical trial sites.

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In certain instances, FDA may mandate the performance of Phase 4 trials.

In certain instances, the FDA may mandate the performance of Phase 4 clinical trials as a condition of approval of an NDA.

In certain instances, the FDA may mandate the performance of Phase 4 clinical trials as a condition of approval of an NDA or BLA.

Progress reports detailing the results of the clinical trials must be submitted at least annually to the FDA and written IND safety reports must be submitted to the FDA and the investigators for serious and unexpected adverse events or any finding from tests in laboratory animals that suggests a significant risk for human subjects.

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The FDA, the IRB, or the sponsor may suspend or terminate a clinical trial at any time on various grounds, including a finding that the research subjects or patients are being exposed to an unacceptable health risk.

Similarly, an IRB can suspend or terminate approval of a clinical trial at its institution if the clinical trial is not being conducted in accordance with the IRB’s requirements or if the drug has been associated with unexpected serious harm to patients.

Similarly, an IRB can suspend or terminate approval of a clinical trial at its institution if the clinical trial is not being conducted in accordance with the IRB’s requirements or if the candidate has been associated with unexpected serious harm to patients.

Additionally, some clinical trials are overseen by an independent group of qualified experts organized by the clinical trial sponsor, known as a data safety monitoring board or committee.

This group provides authorization for whether or not a trial may move forward at designated check points based on access to certain data from the trial.

Concurrent with clinical trials, companies usually complete additional animal studies and must also develop additional information about the chemistry and physical characteristics of the drug as well as finalize a process for manufacturing the product in commercial quantities in accordance with cGMP requirements.

The manufacturing process must be capable of consistently producing quality batches of the drug candidate and, among other things, must develop methods for testing the identity, strength, quality and purity of the final drug.

Additionally, appropriate packaging must be selected and tested and stability studies must be conducted to demonstrate that the drug candidate does not undergo unacceptable deterioration over its shelf life.

Concurrent with clinical trials, companies usually complete additional animal studies and must also develop additional information about the chemistry and physical characteristics of the candidate as well as finalize a process for manufacturing the product in commercial quantities in accordance with cGMP requirements.

The manufacturing process must be capable of consistently producing quality batches of the product and, among other things, must develop methods for testing the identity, strength, quality and purity of the final product.

Additionally, appropriate packaging must be selected and tested and stability studies must be conducted to demonstrate that the product does not undergo unacceptable deterioration over its shelf life.

Review and Approval Processes

The results of product development, preclinical studies and clinical trials, along with descriptions of the manufacturing process, analytical tests conducted on the chemistry of the drug, proposed labeling and other relevant information are submitted to the FDA as part of an NDA requesting approval to market the product.

Data may come from company-sponsored clinical trials intended to test the safety and effectiveness of a use of a product, or from a number of alternative sources, including studies initiated by investigators.

To support marketing approval, the data submitted must be sufficient in quality and quantity to establish the safety and effectiveness of the investigational drug product to the satisfaction of the FDA.

The submission of an NDA is subject to the payment of substantial user fees;

To support marketing approval, the data submitted must be sufficient in quality and quantity to establish the safety and effectiveness of the investigational product

to the satisfaction of the FDA.

The submission of an NDA or BLA is subject to the payment of substantial user fees;

a waiver of such fees may be obtained under certain limited circumstances.

In addition, the Pediatric Research Equity Act (“PREA”), requires a sponsor to conduct pediatric clinical trials for most drugs, for a new active ingredient, new indication, new dosage form, new dosing regimen or new route of administration.

Under PREA, original NDAs and supplements must contain a pediatric assessment unless the sponsor has received a deferral or waiver.

Under PREA, original applications and supplements must contain a pediatric assessment unless the sponsor has received a deferral or waiver.

The required assessment must evaluate the safety and effectiveness of the product for the claimed indications in all relevant pediatric subpopulations and support dosing and administration for each pediatric subpopulation for which the product is safe and effective.

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The FDA must send a non-compliance letter to any sponsor that fails to submit the required assessment, keep a deferral current or fails to submit a request for approval of a pediatric formulation.

Unless otherwise required by regulation, the Pediatric Research Equity Act does not apply to any drug for an indication for which orphan designation has been granted.

Unless otherwise required by regulation, the Pediatric Research Equity Act does not apply to any product for an indication for which orphan designation has been granted.

However, if only one indication for a product has orphan designation, a pediatric assessment may still be required for any applications to market that same product for the non-orphan indication(s).

The FDA reviews all NDAs submitted before it accepts them for filing and may request additional information rather than accepting an NDA for filing.

The FDA must make a decision on accepting an NDA for filing within 60 days of receipt.

Once the submission is accepted for filing, the FDA begins an in-depth review of the NDA.

Under the PDUFA, guidelines that are currently in effect, the FDA has a goal of ten months from the date of “filing” of a standard NDA for a new molecular entity to review and act on the submission.

This review typically takes twelve months from the date the NDA is submitted to FDA because the FDA has approximately two months to make a “filing” decision after it the

application is submitted.

The FDA reviews all NDAs and BLAs submitted before it accepts them for filing and may request additional information rather than accepting the application for filing.

The FDA must make a decision on accepting an application for filing within 60 days of receipt.

Once the submission is accepted for filing, the FDA begins an in-depth review.

Under the PDUFA, guidelines that are currently in effect, the FDA has a goal of ten months from the date of “filing” of a standard application to review and act on the submission.

This review typically takes twelve months from the date the application is submitted to FDA because the FDA has approximately two months to make a “filing” decision after it the application is submitted.

The FDA does not always meet its PDUFA goal dates for standard and priority NDAs, and the review process is often significantly extended by FDA requests for additional information or clarification.

After the NDA submission is accepted for filing, the FDA reviews the NDA to determine, among other things, whether the proposed product is safe and effective for its intended use and whether the product is being manufactured in accordance with cGMP to assure and preserve the product’s identity, strength, quality and purity.

The FDA may refer applications for novel drug products or drug products which present difficult questions of safety or efficacy to an advisory committee, typically a panel that includes clinicians and other experts, for review, evaluation and a recommendation as to whether the application should be approved and under what conditions.

After the NDA submission is accepted for filing, the FDA reviews the application to determine, among other things, whether the proposed product is safe and effective for its intended use (safe, pure and potent for a biologic) and whether the product is being manufactured in accordance with cGMP to assure and preserve the product’s identity, strength, quality and purity.

The FDA may refer applications for novel products or products which present difficult questions of safety or efficacy to an advisory committee, typically a panel that includes clinicians and other experts, for review, evaluation and a recommendation as to whether the application should be approved and under what conditions.

The FDA is not bound by the recommendations of an advisory committee, but it considers such recommendations carefully when making decisions and typically follows the advisory committee’s recommendations.

Before approving an NDA, the FDA will inspect the facilities at which the product is manufactured.

Before approving an NDA or BLA, the FDA will inspect the facilities at which the product is manufactured.

The FDA will not approve the product unless it determines that the manufacturing processes and facilities are in compliance with cGMP requirements and adequate to assure consistent production of the product within required specifications.

Additionally, before approving an NDA, the FDA may inspect one or more clinical sites to assure compliance with GCP requirements.

Additionally, before approving an NDA or BLA, the FDA may inspect one or more clinical sites to assure compliance with GCP requirements.

After the FDA evaluates the application, manufacturing process and manufacturing facilities, it may issue an approval letter or a Complete Response Letter.

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A Complete Response Letter indicates that the review cycle of the application is complete and the application will not be approved in its present form.

A Complete Response Letter usually describes all of the specific deficiencies in the NDA identified by the FDA.

A Complete Response Letter usually describes all of the specific deficiencies in the application identified by the FDA.

The Complete Response Letter may require additional clinical data and/or (an) additional pivotal Phase 3 clinical trial(s), and/or other significant and time-consuming requirements related to clinical trials, preclinical studies or manufacturing.

If a Complete Response Letter is issued, the applicant may either resubmit the NDA, addressing all of the deficiencies identified in the letter, or withdraw the application.

Even if such data and information is submitted, the FDA may ultimately decide that the NDA does not satisfy the criteria for approval.

If a Complete Response Letter is issued, the applicant may either resubmit the application, addressing all of the deficiencies identified in the letter, or withdraw the application.

Even if such data and information is submitted, the FDA may ultimately decide that the application does not satisfy the criteria for approval.

If a product receives regulatory approval, the approval may be significantly limited to specific diseases and dosages or the indications for use may otherwise be limited, which could restrict the commercial value of the product.

A product may also receive accelerated approval requiring confirmatory studies for full approval.

Further, the FDA may require that certain contraindications, warnings or precautions be included in the product labeling or may condition the approval of the NDA on other changes to the proposed labeling, development of adequate controls and specifications, or a commitment to conduct one or more post-market studies or clinical trials.

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If the FDA concludes a REMS is needed, the sponsor of the NDA must submit a proposed REMS;

the FDA will not approve the NDA without an approved REMS, if required.

the FDA will not approve the

NDA without an approved REMS, if required.

A REMS could include medication guides, physician communication plans, or elements to assure safe use, such as restricted distribution methods, patient registries and other risk minimization tools.

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Under the Orphan Drug Act, the FDA may grant orphan designation to a drug intended to treat a rare disease or condition, which is a disease or condition that affects fewer than 200,000 individuals in the United States or, if it affects more than 200,000 individuals in the United States, there is no reasonable expectation that the cost of developing and making a drug product available in the United States for this type of disease or condition will be recovered from sales of the product.

Orphan designation must be requested before submitting an NDA.

Orphan designation must be requested before submitting an NDA or BLA.

After the FDA grants orphan designation, the identity of the therapeutic agent and its potential orphan use are disclosed publicly by the FDA.

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Orphan exclusivity also could block the approval of one of our products for seven years if a competitor obtains approval of the same drug as defined by the FDA or if our product candidate is determined to be contained within the competitor’s product for the same indication or disease.

If an orphan designated product receives marketing approval for an

indication broader than what is designated, it may not be entitled to orphan exclusivity.

If an orphan designated product receives marketing approval for an indication broader than what is designated, it may not be entitled to orphan exclusivity.

Orphan drug status in the EU has similar but not identical benefits in that jurisdiction.

Expedited Development and Review Programs

The FDA has a Fast Track designation program that is intended to expedite or facilitate the process for reviewing new drug products that meet certain criteria.

Specifically, new drugs are eligible for Fast Track designation if they are intended to treat a serious or life-threatening disease or condition and demonstrate the potential to address unmet medical needs for the disease or condition.

Unique to a Fast Track product, the FDA may consider for review sections of the NDA on a rolling basis before the complete application is submitted, if the sponsor provides a schedule for the submission of the sections of the NDA, the FDA agrees to accept sections of the NDA and determines that the schedule is acceptable, and the sponsor pays any required user fees upon submission of the first section of the NDA.

The FDA has a Fast Track designation program that is intended to expedite or facilitate the process for reviewing new drug and biologic products that are intended to treat a serious or life-threatening disease or condition and demonstrate the potential to address unmet medical needs for the disease or condition.

Unique to a Fast Track product, the FDA may consider for review sections of the NDA or BLA on a rolling basis before the complete application is submitted, if the sponsor provides a schedule for the submission of the sections of the application, the FDA agrees to accept sections and determines that the schedule is acceptable, and the sponsor pays any required user fees upon submission of the first section of the application.

Any product submitted to the FDA for approval, including a product with a Fast Track designation, may also be eligible for other types of FDA programs intended to expedite development and review, such as priority review and accelerated approval.

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Breakthrough therapy designation includes all of the Fast Track program features, as well as more intensive FDA interaction and guidance.

The breakthrough therapy designation is a distinct status from both accelerated approval and priority review, which can also be granted to the same drug if relevant criteria are met.

The breakthrough therapy designation is a

distinct status from both accelerated approval and priority review, which can also be granted to the same drug if relevant criteria are met.

If a product is designated as breakthrough therapy, the FDA will work to expedite the development and review of such drug.

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Post-Approval Requirements

Any drug products for which we receive FDA approvals are subject to continuing regulation by the FDA, including, among other things, record-keeping requirements, reporting of adverse experiences with the product, providing the FDA with updated safety and efficacy information, product sampling and distribution requirements, and complying with FDA promotion and advertising requirements, which include, among others, standards for direct-to-consumer advertising, restrictions on promoting drugs for uses or in patient populations that are not described in the drug’s approved labeling (known as “off-label use”), limitations on industry-sponsored scientific and educational activities, and requirements for promotional activities involving the internet.

Although physicians may prescribe legally available drugs for off-label uses, manufacturers may not market or promote such off-label uses.

Any drug products for which we receive FDA approvals are subject to continuing regulation by the FDA, including, among other things, record-keeping requirements, reporting of adverse experiences with the product, providing the FDA with updated safety and efficacy information, product sampling and distribution requirements, and complying with FDA promotion and advertising requirements, which include, among others, standards for direct-to-consumer advertising, restrictions on promoting drugs for uses or in patient populations that are not described in the products’s approved labeling (known as “off-label use”), limitations on industry-sponsored scientific and educational activities, and requirements for promotional activities involving the internet.

Although physicians may prescribe legally available products for off-label uses, manufacturers may not market or promote such off-label uses.

In addition, quality control and manufacturing procedures must continue to conform to applicable manufacturing requirements after approval to ensure the long-term stability of the drug product.

We rely, and expect to continue to rely, on third parties for the production of clinical and commercial quantities of our products in accordance with cGMP regulations.

cGMP regulations require among other things, quality control and quality assurance as well as the corresponding maintenance of records and documentation and the obligation to investigate and correct any deviations from

Drug manufacturers and other entities involved in the manufacture and distribution of approved drugs are required to register their establishments with the FDA and certain state agencies, and are subject to periodic unannounced inspections by the FDA and certain state agencies for compliance with cGMP and other laws.

Manufacturers and other entities involved in the manufacture and distribution of approved biopharmaceuticals are required to register their establishments with the FDA and certain state agencies, and are subject to periodic unannounced inspections by the FDA and certain state agencies for compliance with cGMP and other laws.

Accordingly, manufacturers must continue to expend time, money, and effort in the area of production and quality control to maintain cGMP compliance.

Discovery of problems with a product after approval may result in restrictions on a product, manufacturer, or holder of an approved NDA, including, among other things, recall or withdrawal of the product from the market.

Discovery of problems with a product after approval may result in restrictions on a product, manufacturer, or holder of an approved NDA or BLA, including, among other things, recall or withdrawal of the product from the market.

In addition, changes to the manufacturing process are strictly regulated, and depending on the significance of the change, may require prior FDA approval before being implemented.

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However, patent term restoration cannot extend the remaining term of a patent beyond a total of 14 years from the product’s approval date.

The patent term restoration period is generally one-half the time during the patent’s term between the effective date of an IND and the submission date of an NDA plus the time during the patent’s term between the submission date of an NDA and the approval of that application.

The patent term restoration period is generally one-half the time during the patent’s term between the effective date of an IND and the submission date of an NDA or BLA plus the time during the patent’s term between the submission date of an NDA or BLA and the approval of that application.

Only one patent applicable to an approved drug is eligible for the extension and the application for the extension must be submitted prior to the expiration of the patent.

Patent and Trademark Office, in consultation with the FDA, reviews and approves the application for any patent term extension or restoration.

In the future, we may intend to apply for restoration of patent term for one of our currently owned or licensed patents to add patent life beyond its current expiration date, depending on the expected length of the clinical trials and other factors involved in the filing of the relevant NDA.

Market exclusivity provisions under the FDCA can also delay the submission or the approval of certain marketing applications.

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However, an applicant submitting a full NDA would be required to conduct, or obtain a right of reference to, all of the preclinical studies and adequate and well-controlled clinical trials necessary to demonstrate safety and effectiveness.

Reference biological products are granted 12 years of data exclusivity from the time of first licensure of the product.

The FDA will not accept an application for a biosimilar or interchangeable product based on the reference biological product until four years after the date of first licensure of the reference product.

Orphan drug exclusivity, as described above, may offer a seven-year period of marketing exclusivity for the approved indication, except in certain circumstances.

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Pediatric exclusivity, if granted, adds six months to existing exclusivity periods and patent terms.

six-month exclusivity, which runs from the end of other exclusivity protection or patent term, may be granted based on the voluntary completion of a pediatric trial in accordance with an FDA-issued “Written Request” for such a trial.

This six-month exclusivity, which runs from the end of other exclusivity protection or patent term, may be granted based on the voluntary completion of a pediatric trial in accordance with an FDA-issued “Written Request” for such a trial.

Healthcare Laws and Compliance Requirements

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We may also be subject to data privacy and security regulations by both the federal government and the states in which we conduct our business.

HIPAA, as amended by the Health Information Technology for Economic and Clinical

Health Act (“HITECH”), and its implementing regulations, impose requirements relating to the privacy, security and transmission of individually identifiable health information.

HIPAA, as amended by the Health Information Technology for Economic and Clinical Health Act (“HITECH”), and its implementing regulations, impose requirements relating to the privacy, security and transmission of individually identifiable health information.

Among other things, HITECH makes HIPAA’s privacy and security standards directly applicable to business associates, independent contractors or agents of covered entities that receive or obtain protected health information in connection with providing a service on behalf of a covered entity.

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up to the greater of €20 million or 4% of total global annual turnover.

In addition to the foregoing, a breach of the GDPR or other applicable privacy and data protection laws and regulations could result in regulatory investigations, reputational damage, orders to cease/change our use of data, enforcement notices, or potential civil claims including class action type litigation.

In addition, California recently enacted the California Consumer Privacy Act (“CCPA”), which requires covered companies to provide new disclosures to California residents and honor their requests to access, delete and opt-out of certain sharing of their personal data.

The CCPA, which took effect on January 1, 2020, provides for civil penalties for violations and private right of action for certain data breaches.

The CCPA has expanded substantially as a result of the California Privacy Rights Act of 2020, which, among other things, creates a new administrative agency to implement and enforce California’s privacy laws effective January 1, 2023.

While certain clinical trial activities are exempt from the CCPA’s requirements, other personal data that we handle may be subject to the CCPA, which may increase our compliance costs, exposure to regulatory enforcement action and other liabilities.

In addition to the foregoing, a breach of the GDPR or other

applicable privacy and data protection laws and regulations could result in regulatory investigations, reputational damage, orders to cease/change our use of data, enforcement notices, or potential civil claims including class action type litigation.

In addition, numerous U.S.

states have enacted comprehensive privacy laws that impose certain obligations on covered businesses, including providing specific disclosures in privacy notices and affording residents with certain rights concerning their personal data.

As applicable, such rights may include the right to access, correct, or delete certain personal data, and to opt-out of certain data processing activities, such as targeted advertising, profiling, and automated decision-making.

The exercise of these rights may impact our business and ability to provide our products and services.

Certain states also impose stricter requirements for processing certain personal data, including sensitive information, such as conducting data privacy impact assessments.

These state laws allow for statutory fines for noncompliance.

For example, California enacted the California Consumer Privacy Act (“CCPA”), which applies to personal data of consumers, business representatives, and employees who are California residents, and requires businesses to provide specific disclosures to California residents and honor individuals’ requests to exercise certain privacy rights.

The CCPA provides for civil penalties for violations and private right of action for certain data breaches.

While certain clinical trial activities are exempt from the CCPA and other U.S.

consumer privacy laws’ requirements, these developments may increase our compliance costs, exposure to regulatory enforcement action and other liabilities.

In order to distribute products commercially, we must comply with state laws that require the registration of manufacturers and wholesale distributors of pharmaceutical products in a state, including, in certain states, manufacturers and distributors who ship products into the state even if such manufacturers or distributors have no place of business within the state.

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All of our activities are potentially subject to federal and state consumer protection and unfair competition laws.

contractual damages, reputational harm, administrative burdens, diminished profits and future earnings, and the curtailment or restructuring of our operations, any of which could adversely affect our ability to operate our business and our results of operations.

If our operations are found to be in violation of any of the federal and state healthcare laws described above or any other governmental regulations that apply to us, we may be subject to penalties, including without limitation, significant civil, criminal and/or administrative penalties, damages, fines, disgorgement, exclusion from participation in government programs, such as Medicare and Medicaid, injunctions, imprisonment, private “qui tam” actions brought by individual whistleblowers in the name of the government, or refusal to allow us to enter into government contracts, contractual damages, reputational harm, administrative burdens, diminished profits and future earnings, and the curtailment or restructuring of our operations, any of which could adversely affect our ability to operate our business and our results of operations.

Pharmaceutical Coverage, Pricing and Reimbursement

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Third-party payors are increasingly challenging the price, examining the medical necessity and reviewing the cost-effectiveness of medical drug products and medical services, in addition to questioning their safety and efficacy.

Such payors may limit coverage to specific drug products on an approved list, also known as a formulary, which might not include all of the FDA-approved drugs for a particular indication.

For example, the Inflation Reduction Act (“IRA”) among other things, requires the U.S.

Department of Health and Human Services (“HHS”) to negotiate the price of certain single-source drugs that have been on the market for at least seven (7) years covered under Medicare as part of the Medicare Drug Price Negotiation Program.

Each year up to twenty (20) products will be selected by HHS for the Medicare Drug Price Negotiation Program.

Products subject to the Medicare Drug Price Negotiation Program are expected to experience a significant reduction in reimbursement from the Medicare program on a per unit basis.

In addition, the IRA imposes rebates on many Medicare Part B and Medicare Part D products to penalize price increases that outpace inflation on an annual basis.

Additionally, such payors may limit coverage to specific drug products on an approved list, also known as a formulary, which might not include all of the FDA-approved drugs for a particular indication.

Third party payors may require pharmaceutical companies to conduct expensive pharmaco-economic studies in order to demonstrate the medical necessity and cost-effectiveness of their products, in addition to the costs required to obtain the FDA approvals.

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For example, in March 2010, the Affordable Care Act was enacted, which affected existing government healthcare programs and resulted in the development of new programs.

Among other things, the Affordable Care Act established an annual, nondeductible fee on any entity that manufactures or imports specified branded prescription drugs and biologic agents;

expanded eligibility criteria for Medicaid programs;

increased the statutory minimum rebates a manufacturer must pay under the Medicaid Drug Rebate Program;

created a Medicare Part D coverage gap discount program;

established a Patient-Centered Outcomes Research Institute to oversee, identify priorities in and conduct comparative clinical effectiveness research, along with funding for such research;

and established a Center for Medicare & Medicaid Innovation at the Centers for Medicare & Medicaid Services to test innovative payment and service delivery models to lower Medicare and Medicaid spending.

There have been amendments and executive, judicial and Congressional challenges to certain aspects of the Affordable Care Act.

For example, on August 16, 2022, the Inflation Reduction Act of 2022 (“IRA”) was signed into law, which among other things, extends enhanced subsidies for individuals purchasing health insurance coverage in Affordable Care Act marketplaces through plan year 2025.

The IRA also eliminates the “donut hole” under the Medicare Part D program beginning in 2025 by significantly lowering the beneficiary maximum out-of-pocket cost and creating a new manufacturer discount program.

It is possible that the Affordable Care Act will be subject to judicial or Congressional challenges in the future.

For example, on July 4, 2025, the One Big Beautiful Bill Act (“OBBBA”) was signed into law, which narrowed access to Affordable Care Act marketplace exchange enrollment and declined to extend the Affordable Care Act enhanced advanced premium tax credits that expired at the end of 2025, which, among other provisions in the law, are anticipated to reduce the number of Americans with health insurance.

The OBBBA also is expected to reduce Medicaid spending and enrollment by implementing work requirements for some beneficiaries, capping state-directed payments, reducing federal funding, and limiting provider taxes used to fund the program.

Congress is considering proposed legislation intended to further reduce healthcare costs with alternatives to replace the expired Affordable Care Act subsidies.

It is unclear how such challenges and the healthcare reform measures of the current presidential administration will impact the Affordable Care Act and our business.

Other legislative changes have also been proposed and adopted in the United States since the Affordable Care Act was enacted.

On August 2, 2011, the Budget Control Act of 2011, among other things, included aggregate reductions to Medicare payments to providers of 2% per fiscal year, which went into effect on April 1, 2013 and, due to subsequent legislative amendments to the statute, will remain in effect until 2032, unless additional Congressional action is taken.

Additionally, on March 11, 2021, the American Rescue Plan Act of 2021 was signed into law, which eliminates the statutory Medicaid drug rebate cap, currently set at 100% of a drug’s average manufacturer price, for single source and innovator multiple source drugs, effective January 1, 2024.

There has been heightened governmental scrutiny recently over the manner in which pharmaceutical companies set prices for their marketed products, which has resulted in several Congressional inquiries and proposed federal legislation, as well as state efforts, designed to, among other things, bring more transparency to product pricing, reduce the cost of prescription drugs under Medicare, review the relationship between pricing and manufacturer patient programs, and reform government program reimbursement methodologies for drug products

At the federal level, several means have been used to propose or implement drug pricing reform, including through federal budget proposals, executive orders and policy initiatives.

Further, the IRA, among other things (i) directs the U.S.

Department of Health and Human Services (“HHS”) to negotiate the price of certain high-expenditure, single-source drugs and biologics that have been on the market for at least 7 years covered under Medicare (the “Medicare Drug Price Negotiation Program”) and (ii) imposes rebates under Medicare Part B and Medicare Part D to penalize price increases that outpace inflation.

These provisions took effect progressively starting in fiscal year 2023.

On August 15, 2024, HHS announced the agreed-upon prices of the first ten drugs that were subject to price negotiations, which take effect in January 2026.

HHS will select up to fifteen additional products covered under Part D for negotiation in 2025, although the Medicare Drug Price Negotiation Program is currently subject to legal challenges.

Each year thereafter more Part B and Part D products will become subject to the Medicare Drug Price Negotiation Program.

In addition, in response to an October 2022 executive order, on February 14, 2023, HHS released a report outlining three new models for testing by the Center for Medicare and Medicaid Innovation which will be evaluated on their ability to lower the cost of drugs, promote accessibility, and improve quality of care.

It is unclear whether the models will be utilized in any health reform measures in the future.

Further, on December 7, 2023, an initiative to control the price of prescription drugs through the use of march-in rights under the Bayh-Dole Act was announced.

On December 8, 2023, the National Institute of Standards and Technology published for comment a Draft Interagency Guidance Framework for Considering the Exercise of March-In Rights which for the first time includes the price of a product as one factor an agency can use when deciding to exercise march-in rights.

While march-in rights have not previously been exercised, it is uncertain if that will continue under the new framework.

At the state level, individual states in the United States have also increasingly passed legislation and implemented regulations designed to control pharmaceutical and biological product pricing, including price or patient reimbursement constraints, discounts, restrictions on certain product access and marketing cost disclosure and transparency

measures, and, in some cases, designed to encourage importation from other countries and bulk purchasing.

The current administration is pursuing policies to reduce regulations and expenditures across government agencies including at HHS, the FDA, Centers for Medicare & Medicaid Services (“CMS”), and related agencies.

These actions, presently directed by executive orders or memoranda from the Office of Management and Budget, may propose policy changes that create additional uncertainty for our business.

For example, the current administration has announced agreements with pharmaceutical companies that require the drug manufacturers to offer, through a direct-to-consumer platform, U.S.

patients and Medicaid programs prescription drug Most-Favored Nation pricing equal to or lower than those paid in other developed nations, with additional mandates for direct-to-patient discounts and repatriation of foreign revenues.

Other recent actions, for example, include (1) directing agencies to reduce agency workforce and cut programs;

(2) directing HHS and other agencies to lower prescription drug costs through a variety of initiatives, including by improving upon the Medicare Drug Price Negotiation Program and establishing Most-Favored-Nation pricing for pharmaceutical products;

(3) imposing tariffs on imported pharmaceutical products;

and (4) as part of the Make America Healthy Again Commission’s Strategy Report released in September 2025, working across government agencies to increase enforcement on direct-to-consumer pharmaceutical advertising.

Additionally, the current administration recently called on Congress to enact “The Great Healthcare Plan,” to codify and expand Most-Favored Nation pricing, lower government subsidies to private insurance companies, increase healthcare price transparency, expand pharmaceutical drugs available for over-the-counter purchase, and enact restrictions on pharmacy benefit manager (PBM) payment methodologies, among other things.

These actions and policies may significantly reduce U.S.

drug prices, potentially impacting manufacturers’ global pricing strategies and profitability, while increasing their operational costs and compliance risks.

Additionally, in its June 2024 decision in Loper Bright Enterprises v.

Raimondo (“Loper Bright”), the U.S.

Supreme Court greatly reduced greatly reduced judicial deference to regulatory agencies, which could increase successful legal challenges to federal regulations affecting our operations.

Congress may introduce and ultimately pass health care related legislation that could impact the drug approval process and make changes to the Medicare Drug Price Negotiation Program created under the IRA.

For example, on January 5, 2024, the FDA approved Florida’s proposal to import certain drugs from Canada for specific state healthcare programs.

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This application is identical to the application that would be submitted to the EMA for authorization through the centralized procedure.

The reference EU Member State prepares a draft assessment and drafts of the related materials within 120 days after receipt of a valid application.

The reference EU Member State prepares a draft assessment and drafts of

the related materials within 120 days after receipt of a valid application.

The resulting assessment report is submitted to the concerned EU Member States who, within 90 days of receipt, must decide whether to approve the assessment report and related materials.

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However, unlike the conditional marketing authorization, an applicant for authorization in exceptional circumstances is not subsequently required to provide the missing data.

Although the marketing authorization “under exceptional circumstances” is granted definitively, the risk-benefit balance of the medicinal product is reviewed annually, and the marketing authorization will be withdrawn if the risk-benefit ratio is no longer favorable.

Although the marketing authorization “under exceptional circumstances” is granted

definitively, the risk-benefit balance of the medicinal product is reviewed annually, and the marketing authorization will be withdrawn if the risk-benefit ratio is no longer favorable.

Pediatric Development in the EU

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Data exclusivity, if granted, prevents regulatory authorities in the EU from referencing the innovator’s data to assess a generic application or biosimilar application for eight years from the date of authorization of the innovative product, after which a generic or biosimilar MAA can be submitted, and the innovator’s data may be referenced.

The market exclusivity period prevents a successful generic or biosimilar applicant from commercializing its product in the EU until 10 years have elapsed from the initial marketing authorization of the reference

product in the EU.

The overall ten-year period may, occasionally, be extended for a further year to a maximum of 11 years if, during the first eight years of those ten years, the marketing authorization holder obtains an authorization for one or more new therapeutic indications which, during the scientific evaluation prior to their authorization, are held to bring a significant clinical benefit in comparison with existing therapies.

15 unchanged sentences

Orphan medicinal product designation entitles an applicant to incentives such fee reductions or fee waivers, protocol assistance, and access to the centralized marketing authorization procedure.

Upon grant of a marketing authorization, orphan medicinal products are entitled to a ten-year period of market exclusivity for the approved therapeutic indication, which means that the EMA cannot accept another marketing authorization application or accept an application to extend for a similar product and the European Commission cannot grant a marketing authorization for the same indication for a period of ten years.

to extend for a similar product and the European Commission cannot grant a marketing authorization for the same indication for a period of ten years.

The period of market exclusivity is extended by two years for orphan medicinal products that have also complied with an agreed PIP.

27 unchanged sentences

The outcome of HTA regarding specific medicinal products will often influence the pricing and reimbursement status granted to these medicinal products by the competent authorities of individual EU Member States.

In December 2021, Regulation No 2021/2282 on Health Technology Assessment (“HTA Regulation”) was adopted.

The HTA Regulation is intended to boost cooperation among EU Member States in assessing health technologies, including new medicinal products, and providing the basis for cooperation at EU level for joint clinical assessments in these areas.

The HTA Regulation began to apply on January 12, 2025 through a phased implementation.

It is intended to harmonize the clinical benefit assessment of HTA across the EU.

On January 12, 2025, Regulation No 2021/2282 on Health Technology Assessment (“HTA Regulation”) entered into application through a phased implementation.

The HTA Regulation initially applies to new active substances for oncology and advanced therapy medicinal products.

It will be expanded to orphan medicinal products in January 2028, and to all centrally authorized medicinal products as of 2030.

Select high-risk medical devices also came into scope in 2026.

The HTA Regulation is intended to boost cooperation among EU Member States in assessing health technologies, including

new medicinal products.

The HTA Regulation establishes a framework for EU‑level joint clinical assessments, increasing cooperation among Member States on clinical aspects of health technology evaluation.

Individual EU Member States will continue to be responsible for assessing non-clinical (e.g., economic, social, ethical) aspects of health technologies, and making decisions on pricing and reimbursement.

For other countries outside of the EU, such as countries in Eastern Europe, Latin America or Asia, the requirements governing the conduct of clinical trials, product licensing, pricing and reimbursement vary from country to country.

1 unchanged sentence

Human Capital Management

As of December 31, 2024, we employed 322 employees, all of whom are full time, consisting of clinical, research, operations, finance and business development personnel.

Forty-eight of our employees hold Ph.D.

As of December 31, 2025, we employed 372 employees, of whom 369 are full time, consisting of clinical, research, operations, finance and business development personnel.

Fifty-five of our employees hold Ph.D.

Further, 289 of our employees are located in the United States, and 76 in Europe and seven in Canada.

26 unchanged sentences

Compared sentence by sentence after normalising whitespace, quotation marks, case and digits, so re-formatting and restated figures do not read as changed language. Wording changes appear as one removal and one addition. The current filing and the prior one are authoritative.

What changed 10-K

Item 1. Business