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Item 7. Management’s Discussion and Analysis

2024-02-20 compared with 2023-02-23 · 229 added, 189 removed, 274 unchanged (60% of the section changed)

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For a discussion of our financial condition and results of operations for 2022 as compared to 2021, except as set forth below, please refer to Item 7, “Management’s Discussion and Analysis of Financial Condition and Results of Operations” in our 202 2 Annual Report on Form 10-K , which discussion is incorporated by reference herein.

We are a biopharmaceutical company headquartered in San Diego, California, focused on identifying, developing and delivering life-changing therapies to people living with rare kidney, liver, and metabolic diseases.

Our approach centers on advancing our innovative pipeline with multiple late-stage clinical programs targeting rare diseases with significant unmet medical needs.

Upon approval of any of our late-stage programs, we intend to leverage the skills of our talented commercial organization which has successfully identified, supported and treated patients prescribed our approved products over the last nine years.

FILSPARI® (sparsentan)

On February 17, 2023, the FDA granted accelerated approval of FILSPARI™ (sparsentan) to reduce proteinuria in adults with primary IgAN at risk of rapid disease progression, generally at UPCR ≥1.5 gram/gram.

We expect FILSPARI to be available beginning the week of February 27, 2023, and will be providing a comprehensive patient support program throughout the patient’s treatment journey.

This indication is granted under accelerated approval based on reduction in proteinuria.

It has not been established whether FILSPARI slows kidney function decline in patients with IgAN.

The continued approval of FILSPARI may be contingent upon confirmation of a clinical benefit in the ongoing Phase 3 PROTECT Study, which is designed to demonstrate whether FILSPARI slows kidney function decline.

Topline results from the two-year confirmatory endpoints in the PROTECT Study are expected in the fourth quarter of 2023 and are intended to support traditional approval of FILSPARI.

On February 17, 2023, the FDA granted accelerated approval of FILSPARI® (sparsentan) to reduce proteinuria in adults with primary IgAN at risk of rapid disease progression, generally a UPCR ≥1.5 gram/gram.

FILSPARI became commercially available in the U.S.

beginning the week of February 27, 2023, and we are providing a comprehensive patient support program throughout the patient’s treatment journey.

This indication was granted under accelerated approval based on reduction in proteinuria.

The continued approval of FILSPARI may be contingent upon confirmation of a clinical benefit in the Phase 3 PROTECT Study.

As described in more detail below, in September 2023, we announced topline two-year confirmatory secondary endpoint results from the PROTECT Study, and in December 2023, we announced the completion of a successful pre-NDA meeting with the FDA for FILSPARI in IgAN.

Following our regulatory engagement, we plan to submit a supplemental New Drug Application (sNDA) in the first quarter 2024 for conversion of the existing U.S.

accelerated approval of FILSPARI to full approval.

FILSPARI, a once-daily, oral medication is designed to selectively target two critical pathways in the disease progression of IgAN (endothelin 1 and angiotensin-II) and is the first and only non-immunosuppressive therapy approved for the treatment of this condition.

FILSPARI (sparsentan) is a dual endothelin angiotensin receptor antagonist (DEARA).

FILSPARI is a dual endothelin angiotensin receptor antagonist (DEARA).

Pre-clinical data have shown that blockade of both endothelin type A and angiotensin II type 1 pathways in forms of rare chronic kidney disease, reduces proteinuria, protects podocytes and prevents glomerulosclerosis and mesangial cell proliferation.

Sparsentan has been granted Orphan Drug Designation for the treatment of IgAN in the U.S.

We expect that FILSPARI will be granted seven years of Orphan Drug Exclusivity for proteinuria in adults with primary IgAN at risk of rapid disease progression.

and the EEA and FILSPARI has been granted seven years of Orphan Drug Exclusivity in the U.S.

for the reduction of proteinuria in adults with primary IgAN at risk of rapid disease progression.

IgAN is characterized by hematuria, proteinuria, and variable rates of progressive renal failure.

With an estimated prevalence of up to 150,000 people in the United States and greater numbers in Europe and Asia, IgAN is the most common primary glomerular disease.

Most patients are diagnosed between the ages of 16 and 35, with up to 40% progressing to end stage kidney disease within 15 years.

Most patients are diagnosed between the ages of 16 and 35, with up to 40% progressing to kidney failure within 15 years.

FILSPARI is the first and only non-immunosuppressive therapy approved for this condition.

At launch, we expect approximately 30,000 to 50,000 patients in the United States to be addressable under FILSPARI's accelerated approval indication statement.

The approval of FILSPARI, granted under the FDA’s accelerated approval pathway, is based on clinically meaningful and statistically significant improvements in proteinuria compared to an active comparator in the pivotal and ongoing Phase 3 PROTECT Study, the largest head-to-head interventional study to date in IgAN.

It is a global, randomized, multicenter, double-blind, parallel-arm, active-controlled clinical trial evaluating the

safety and efficacy of 400mg of sparsentan, compared to 300mg of irbesartan, in 404 patients ages 18 years and up with IgAN and persistent proteinuria despite available ACE or ARB therapy.

We estimate approximately 30,000 to 50,000 patients in the United States to be addressable under FILSPARI's accelerated approval indication statement.

Data to support the accelerated approval of FILSPARI was generated from the Phase 3 PROTECT Study, the largest head-to-head interventional study to date in IgAN.

It is a global, randomized, multicenter, double-blind, parallel-arm, active-controlled clinical trial that evaluated the safety and efficacy of 400mg of sparsentan, compared to 300mg of irbesartan, in 404 patients ages 18 years and up with IgAN and persistent proteinuria despite available ACE or ARB therapy, and is currently ongoing in the open label extension phase of the study.

The PROTECT Study protocol provided for an unblinded analysis of at least 280 patients to be performed after 36 weeks of treatment to evaluate the primary efficacy endpoint - the change in proteinuria (UPCR) at week 36 from baseline.

Secondary efficacy endpoints include the rate of change in eGFR following the initiation of randomized treatment over 58-week and 110-week periods, as well as the rate of change in eGFR over 52-week and 104-week periods following the first six weeks of randomized treatment in approximately 380 patients.

Secondary efficacy endpoints include the rate of change in estimated glomerular filtration rate (eGFR) following the initiation of randomized treatment over 58-week and 110-week periods, as well as the rate of change in eGFR over 52-week and 104-week periods following the first six weeks of randomized treatment in approximately 380 patients.

In August 2021, we announced positive topline interim results from the ongoing Phase 3 PROTECT Study.

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After 36 weeks of treatment, patients receiving FILSPARI achieved a mean reduction in proteinuria from baseline of 49.8 percent, compared to a mean reduction in proteinuria from baseline of 15.1 percent for irbesartan-treated patients (p<0.0001).

We believe that preliminary eGFR data available at the time of the interim analysis are indicative of a potential clinically meaningful treatment effect after two years of treatment.

Results from the interim assessment in the PROTECT Study showed that FILSPARI was well tolerated with a clearly defined safety profile that has been consistent across all clinical trials conducted to date.

In PROTECT, the most common adverse reactions (≥ 5%) are peripheral edema, hypotension (including orthostatic hypotension), dizziness, hyperkalemia, and anemia.

Because of the risks of liver injury and birth defects, FILSPARI is available only through a REMS approved by the FDA.

Per request from the FDA, the efficacy data contained in the FDA-approved label is a post-hoc sensitivity analysis that evaluates the first 281 randomized patients, a subset of the full trial population.

In PROTECT, at the interim assessment, the most common adverse reactions (≥ 5%) were peripheral edema, hypotension (including orthostatic hypotension), dizziness, hyperkalemia, and anemia.

FILSPARI is available only through a risk evaluation and mitigation strategy (REMS) approved by the FDA.

Per request from the FDA, the efficacy data contained in the FDA-approved label under accelerated approval is a post-hoc sensitivity analysis that evaluates the first 281 randomized patients, a subset of the full trial population.

The mean reduction in proteinuria from baseline in the post-hoc sensitivity analysis is 45% for FILSPARI versus 15% for the active control, irbesartan.

Both the pre-specified and post-hoc sensitivity analyses have demonstrated that FILSPARI achieves a rapid and sustained reduction in proteinuria, with statistically significant and clinically meaningful improvement compared to the active comparator irbesartan.

The PROTECT Study is fully enrolled and is scheduled to continue as planned on a blinded basis to assess the treatment effect on eGFR slope over 110 weeks in the confirmatory endpoint analysis.

Beginning in 2023, we plan to expand data generation through a sub study in the open-label extension of the ongoing PROTECT Study, as well as an open-label clinical study to investigate the safety and efficacy of sparsentan in combination with sodium glucose cotransporter-2 inhibitors (SGLT2i) for the treatment of IgAN.

In September 2023, we announced topline two-year confirmatory secondary endpoint results from the PROTECT Study;

eGFR total and chronic slope are the secondary confirmatory endpoints for the U.S.

and the EU, respectively.

FILSPARI demonstrated long-term kidney function preservation and achieved a clinically meaningful difference in eGFR total and chronic slope versus irbesartan, narrowly missing statistical significance in eGFR total slope while achieving statistical significance in eGFR chronic slope for purposes of regulatory review in the EU.

All topline efficacy endpoints favored FILSPARI as compared to irbesartan.

A preliminary review of the safety results through 110 weeks of treatment indicates FILSPARI was generally well-tolerated and the overall safety profile in the study has been consistent between treatment groups.

In December 2023, we announced the completion of a successful pre-NDA meeting with the FDA for FILSPARI in IgAN.

Following our regulatory engagement, we plan to submit a supplemental New Drug Application (sNDA) in the first quarter of 2024 for conversion of the existing U.S.

accelerated approval of FILSPARI to full approval.

In August 2022, we and Vifor (International) Ltd.

("CSL Vifor"), with whom we entered into a license and collaboration agreement ("License Agreement") in September 2021, announced that the European Medicines Agency ("EMA") had accepted for review the conditional marketing authorization application of sparsentan for the treatment of IgAN in Europe.

A review decision is expected in the second half of 2023.

("CSL Vifor"), with whom we entered into a license and collaboration agreement ("License Agreement") in September 2021, announced that the EMA had accepted for review the conditional marketing authorization ("CMA") application of sparsentan for the treatment of IgAN in the EU.

We anticipate an opinion by the Committee for Medicinal Products for Human Use (the "CHMP") in the first quarter of 2024.

In January 2024, we announced our entry into an exclusive licensing agreement with Renalys Pharma, Inc.

("Renalys"), to bring sparsentan to patients in Japan and other countries in Asia, for the treatment of IgAN.

Renalys will hold regional rights to sparsentan for Japan, South Korea, Taiwan, Brunei, Cambodia, Indonesia, Laos, Malaysia, Myanmar, the Philippines, Singapore, Thailand, and Vietnam.

Following successful meetings with the Pharmaceuticals and Medical Devices Agency (PMDA) in 2023, Renalys plans to initiate an open label registrational study of sparsentan in Japan in the second quarter of 2024 to support potential approval of sparsentan in Japan.

Results from the urine protein/creatinine ratio (UP/C) endpoint in the study are expected in the second half of 2025 to support a submission for approval to PMDA.

Under the terms of the licensing agreement, Renalys will be responsible for development, regulatory matters, and commercialization in the licensed territories.

Clinical-Stage Programs:

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Sparsentan has been granted Orphan Drug Designation for the treatment of FSGS in the U.S.

FSGS is a leading cause of end-stage kidney disease (ESKD) and nephrotic syndrome.

FSGS is a leading cause of kidney failure and nephrotic syndrome.

There are currently no FDA-approved pharmacologic treatments for FSGS and there remains a high unmet need for patients living with FSGS as off-label treatments such as ACE/ARBs, steroids, and immunosuppressant agents are effective in only a subset of patients and use of some of these off-label treatments may be further inhibited by their safety profiles.

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In 2016, we generated positive data from our Phase 2 DUET study in FSGS.

In 2018, we announced the initiation of the Phase 3 DUPLEX study of sparsentan in FSGS.

In 2018, we announced the initiation of the Phase 3 clinical trial designed to serve as the basis for an NDA and MAA filing for sparsentan for the treatment of FSGS (the "DUPLEX Study").

The DUPLEX Study is a global, randomized, multicenter, double-blind, parallel-arm, active-controlled clinical trial evaluating the safety and efficacy of sparsentan in 371 patients.

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In February 2021, we announced that the ongoing Phase 3 DUPLEX Study achieved its pre-specified interim FSGS partial remission of proteinuria endpoint following the 36-week interim period.

After 36 weeks of treatment, 42.0 percent of patients receiving sparsentan achieved FPRE, compared to 26.0 percent of irbesartan-treated patients (p=0.0094).

A preliminary review of the results from the interim analysis suggests that, as of the data cut-off, sparsentan has been generally well-tolerated and the overall safety results have been generally comparable between treatment groups.

The confirmatory primary endpoint of the DUPLEX Study to support traditional regulatory approval is the rate of change in eGFR over 108 weeks of treatment.

As of the time of the interim analyses, available long-term eGFR data for the confirmatory endpoint were limited.

Consistent with the DUPLEX Study protocol, patients will continue in a blinded manner to assess the treatment effect on eGFR slope over 108 weeks in the confirmatory endpoint analysis.

The DUPLEX Study is fully enrolled and topline results from the confirmatory endpoint are expected in the second quarter of 2023.

In May 2021, we provided a regulatory update regarding the sparsentan FSGS program, including feedback from the FDA that additional data would be needed to potentially support a submission for accelerated approval under subpart H.

We and the FDA subsequently aligned on a plan for us to provide the FDA with additional eGFR data from a 2022 data-cut to potentially support a submission for accelerated approval for FSGS.

We provided the FDA with such additional eGFR data from the ongoing DUPLEX Study in the first half of 2022 and held a subsequent Type A meeting with the FDA to discuss the data and the potential for a submission for accelerated approval.

Following review of the data, the FDA has communicated that it does not deem such data sufficiently supportive for an accelerated approval submission, but indicated that the DUPLEX Study as designed maintains the potential for traditional approval pending completion of the study.

We are planning to continue the study to completion which is expected to occur in the second quarter of 2023, and if the data are supportive, file for traditional approval in the second half of 2023.

Pending completion of the DUPLEX Study and data supportive of approval, we and CSL Vifor are targeting to submit by the end of 2023 a subsequent variation of sparsentan for the treatment of FSGS in Europe.

If sparsentan receives marketing authorization in any of the licensed territories, CSL Vifor will be responsible for all commercialization activities in such licensed territories.

We remain responsible for the clinical development of sparsentan and will retain all rights to sparsentan in the United States and rest of world outside of the licensed territories, provided that CSL Vifor has a right of negotiation to expand the licensed territories into Canada, China, Brazil and/or Mexico.

Pegtibatinase (TVT-058)

Pegtibatinase (TVT-058) is a novel investigational human enzyme replacement candidate being evaluated for the treatment of classical homocystinuria (HCU).

After 36 weeks of treatment, 42.0 percent of patients receiving sparsentan achieved FPRE, compared to 26.0 percent of irbesartan-treated

patients (p=0.0094).

Following engagement with the FDA on the interim proteinuria analysis and a subsequent eGFR data-cut, we elected to forego the previously planned submission for accelerated approval and pursue a potential traditional approval upon completion of the DUPLEX Study.

In May 2023, we announced topline primary efficacy results from the pivotal Phase 3 DUPLEX Study of sparsentan in FSGS.

The confirmatory primary endpoint of the DUPLEX Study designed to support traditional regulatory approval was the rate of change in eGFR over 108 weeks of treatment.

At the end of the 108-week double-blind period, sparsentan was observed to have a 0.3 mL/min/1.73m 2 per year (95% CI:

-1.74, 2.41) favorable difference on eGFR total slope and a 0.9 mL/min/1.73m 2 per year (95% CI:

-1.27, 3.04) favorable difference on eGFR chronic slope compared to the active control irbesartan, which was not statistically significant.

After 108 weeks of treatment, sparsentan achieved a mean reduction in proteinuria from baseline of 50%, compared to 32% for irbesartan.

Although the DUPLEX Study did not achieve its two-year primary endpoint with statistical significance over the active control irbesartan, we are encouraged by the results, including the secondary endpoints on proteinuria and topline exploratory endpoints, including renal outcomes, which trended favorably for sparsentan.

In addition, a review of the safety results through 108 weeks of treatment indicate sparsentan was generally well-tolerated and the overall safety profile in the study to date was generally consistent between treatment groups.

In December 2023, we announced that we completed our planned Type C meeting with the FDA to discuss previously reported results from the Phase 3 DUPLEX Study of sparsentan in FSGS.

The FDA acknowledged the high unmet need for approved therapies as well as the challenges in studying FSGS but indicated that the two-year results from the Phase 3 DUPLEX Study alone are not sufficient to support an sNDA submission.

The FDA acknowledged the work being done by the larger nephrology community to better understand proteinuria and eGFR as endpoints in clinical trials of FSGS and indicated a willingness to continue to engage with us on a potential path forward for sparsentan in FSGS following our consideration of additional evidence.

Together with CSL Vifor, we also plan to engage with the EMA to determine the potential for a subsequent variation to the Conditional Marketing Authorization (CMA) of sparsentan for the treatment of FSGS, if the MAA of sparsentan in IgA nephropathy is approved.

Given the high unmet need of FSGS patients, with no medicines currently approved for the condition, and the challenges associated with studying FSGS due to its heterogeneity and other attributes, we are conducting additional analyses of FSGS data and intend to engage with regulators to evaluate potential regulatory pathways for a sparsentan FSGS indication.

If sparsentan receives marketing authorization in any of the licensed territories covered by the exclusive license to CSL Vifor, CSL Vifor will be responsible for all commercialization activities in such licensed territories.

If sparsentan receives marketing authorization in any of the territories covered by the exclusive license to Renalys, Renalys will be responsible for all development, regulatory matters, and commercialization activities in such licensed territories.

We remain responsible for the clinical development of sparsentan in the applicable territories and we will retain all rights to sparsentan in the United States and rest of world outside of the territories licensed to CSL Vifor and Renalys, provided that CSL Vifor has a right of negotiation to expand the licensed territories into Canada, China, Brazil and/or Mexico.

Pegtibatinase

Pegtibatinase is a novel investigational human enzyme replacement candidate being evaluated for the treatment of classical homocystinuria (HCU).

Classical HCU is a rare metabolic disorder characterized by elevated levels of plasma homocysteine that can lead to vision, skeletal, circulatory and central nervous system complications.

It is estimated that there are at least 3,500 people living with HCU in the United States with similar numbers in Europe.

It is estimated that there are approximately 7,000 to 10,000 people living with HCU globally.

Pegtibatinase has been granted Rare Pediatric Disease, Fast Track and Breakthrough Therapy designations by the FDA, as well as orphan drug designation in the United States and European Union.

Pegtibatinase is currently being evaluated in the Phase 1/2 COMPOSE Study, a double blind, randomized, placebo-controlled dose escalation study to assess its safety, tolerability, pharmacokinetics, pharmacodynamics and clinical effects in patients with classical HCU.

In December 2021, we announced positive topline results from the Phase 1/2 COMPOSE Study.

In December 2021, we announced positive topline results from the Phase 1/2 COMPOSE Study, a double blind, randomized, placebo-controlled dose escalation study to assess its safety, tolerability, pharmacokinetics, pharmacodynamics and clinical effects in patients with classical HCU.

Pegtibatinase demonstrated dose-dependent reductions in total homocysteine (tHcy) during the 12 weeks of treatment, and in the highest dose cohort to date evaluating 1.5mg/kg of pegtibatinase twice weekly (BIW), treatment with pegtibatinase resulted in rapid and sustained reductions in total homocysteine (tHcy) through 12 weeks of treatment, including a 55.1% mean relative reduction in tHcy from baseline as well as maintenance of tHcy below a clinically meaningful threshold of 100 μmol.

Additionally, in a dose-dependent manner in the study to date, methionine levels were substantially reduced and cystathionine levels were substantially elevated following treatment with pegtibatinase, suggesting that pegtibatinase acts in a manner similar to the native CBS enzyme.

To date in the study, pegtibatinase has been generally well-tolerated , with no discontinuations due to treatment-related adverse events.

Following positive results from the first five cohorts of the ongoing Phase 1/2 COMPOSE Study, we are evaluating pegtibatinase in a final cohort in the COMPOSE Study to further inform our pivotal development program to ultimately support potential approval of pegtibatinase for the treatment of HCU.

The additional cohort was initiated to inform and refine formulation work for future development and commercial purposes and to further evaluate the dose response curve for pegtibatinase.

In the fourth quarter of 2022, enrollment completed in the sixth and final cohort of the ongoing Phase 1/2 COMPOSE Study.

We anticipate reporting additional data from COMPOSE in mid-2023.

In parallel with completing the final cohort in the COMPOSE Study, we are preparing for the potential initiation of a pivotal Phase 3 clinical trial of pegtibatinase in patients with HCU in the second half of 2023, subject to communications and feedback from the FDA and associated program assessments.

In May 2023, we announced positive topline results from the sixth cohort of the Phase 1/2 COMPOSE Study, which was initiated to inform and refine formulation work for future development and commercial purposes and to further evaluate the dose response curve for pegtibatinase, and to further inform our pivotal development program to ultimately support potential approval of pegtibatinase for the treatment of HCU.

In this cohort, five patients were randomized in a blinded fashion to receive 2.5 mg/kg of lyophilized pegtibatinase or placebo twice weekly (BIW), with four patients assigned to the treatment group.

In this highest dose cohort to date, treatment with pegtibatinase resulted in rapid and sustained reductions in total homocysteine (tHcy), with a 67.1% mean relative reduction in tHcy from baseline, as well as maintenance of mean tHcy below the clinically meaningful threshold of 100 μmol, over weeks 6 to 12.

In the double-blind period, pegtibatinase was generally well-tolerated , with no discontinuations due to treatment-related adverse events.

In December 2023, we initiated the pivotal Phase 3 HARMONY Study to support the potential approval of pegtibatinase for the treatment of classical HCU.

The HARMONY Study is a global, randomized, multi-center, double-blind, placebo-controlled Phase 3 clinical trial designed to evaluate the

efficacy and safety of pegtibatinase as a novel treatment to reduce total homocysteine (tHcy) levels.

Topline results from the HARMONY Study are expected in 2026.

We acquired pegtibatinase as part of the November 2020 acquisition of Orphan Technologies Limited.

Chenodal (chenodeoxycholic acid or CDCA) is a naturally occurring bile acid that is approved for the treatment of people with radiolucent stones in the gallbladder.

While indicated for radiolucent stones in the gallbladder, Chenodal has been recognized as the standard of care for cerebrotendinous xanthomatosis (CTX) for more than three decades, although it is not currently labeled for this indication.

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

In September 2022, we were granted Fast Track designation by the FDA for the investigation of Chenodal for CTX.

In January 2020, we randomized the first patients in our Phase 3 RESTORE Study to evaluate the effects of Chenodal in adult and pediatric patients with CTX, and the study enrollment remains open.

The pivotal study is intended to support an NDA submission for marketing authorization of Chenodal for CTX in the United States.

During 2023, we expect to complete the ongoing Phase 3 RESTORE Study in CTX.

Pending supportive data, we anticipate being in position to subsequently submit an NDA for a CTX indication.

Preclinical Programs:

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In May 2021, a generic option for the 100 mg version of the original formulation of Thiola (tiopronin tablets) became available and in June 2022, a second option for the 100 mg version of the original formulation of Thiola (tiopronin tablets) was approved.

These generic versions of the original formulation of Thiola have impacted sales, and these or additional generic versions of either formulation could have a material adverse impact on sales.

Cholbam (cholic acid)

The FDA approved Cholbam (cholic acid capsules) in March 2015, the first FDA-approved treatment for pediatric and adult patients with bile acid synthesis disorders due to single enzyme defects, and for adjunctive treatment of patients with peroxisome biogenesis disorder-Zellweger spectrum disorder.

The effectiveness of Cholbam has been demonstrated in clinical trials for bile acid synthesis disorders and the adjunctive treatment of peroxisomal disorders.

An estimated 200 to 300 patients are current candidates for therapy.

Chenodal (chenodiol)

Chenodal is a synthetic oral form of chenodeoxycholic acid ("CDCA"), a naturally occurring primary bile acid synthesized from cholesterol in the liver.

The FDA approved Chenodal for the treatment of people with radiolucent stones in the gallbladder.

In 2010, Chenodal was granted orphan drug designation for the treatment of cerebrotendinous xanthomatosis ("CTX"), a rare autosomal recessive lipid storage disease.

We acquired Chenodal in March 2014.

While Chenodal is not labeled for CTX, it received a medical necessity determination in the US by the FDA and has been used as the standard of care for more than three decades.

We are working to obtain FDA approval of Chenodal for the treatment of CTX and initiated a Phase 3 clinical trial for this indication in January 2020.

The prevalence of CTX is estimated in the literature to be as high as 1 in 70,000 in the overall population.

Pathogenesis of CTX involves deficiency of the enzyme 27-hydroxylase (encoded by the gene CYP27A1), a rate-limiting enzyme in the synthesis of primary bile acids, including CDCA, from cholesterol.

The disruption of primary bile acid synthesis in CTX leads to toxic accumulation of cholesterol and cholestanol in most tissues.

Patients may present with intractable diarrhea, premature cataracts, tendon xanthomas, atherosclerosis, and cardiovascular disease in childhood and adolescence.

Neurological manifestations of the disease, including dementia and cognitive and cerebellar deficiencies, emerge during late adolescence and adulthood.

The types, combinations and severity of symptoms can be different from person to person, and making diagnosis challenging and often delayed.

Oral administration of CDCA has been shown to normalize primary bile acid synthesis in patients with CTX.

These generic versions of the original formulation of Thiola have impacted our sales, and these or additional generic versions of either formulation could have a material adverse impact on sales.

During 2023, two generic versions of Thiola EC (100 mg and 300 mg) were approved by the FDA.

Following receipt of paragraph IV certification notices from these manufacturers, we and our licensor Mission Pharmacal entered into agreements with these manufacturers in order to settle disputes around patent validity and infringement, providing for a license entry date of April 1, 2026 of these generic versions of Thiola EC (100mg and 300mg), or earlier under certain circumstances.

On January 30, 2024, the FDA approved an additional generic version of Thiola EC (100mg and 300mg).

Accordingly, Thiola EC is subject to immediate generic competitio n, which could impact our sales of Thiola EC.

Sale of Bile Acid Product Portfolio

On July 16, 2023, we entered into an Asset Purchase Agreement (the “Purchase Agreement”) with Mirum Pharmaceuticals, Inc.

("Mirum Pharmaceuticals" or “Mirum”), pursuant to which Mirum agreed to purchase substantially all of the assets primarily related to our business of development, manufacture (including synthesis, formulation, finishing or packaging) and commercialization of Chenodal and Cholbam (also known as Kolbam, and together with Chenodal, the “Products”), collectively, the "bile acid business".

On August 31, 2023, we consummated the transactions contemplated by the Purchase Agreement (the "Closing").

In connection with the Closing, we received an upfront cash payment of $210.0 million.

Pursuant to the Purchase Agreement, after the Closing, we are eligible to receive up to $235.0 million upon the achievement of certain milestones based on specified amounts of annual net sales (tiered from $125.0 million to $500.0 million) of the Products.

A $226.0 million gain, net of tax, was recognized on the transaction as a component of net income from discontinued operations in the Consolidated Statements of Operations.

The bile acid business has been classified as a discontinued operation for all periods presented and is excluded from the following discussion of the results of our continuing operations in the results of operations.

Refer to Note 19 of our Consolidation Financial Statements for additional information.

Strategic Reorganization

In December 2023, we implemented an approximate 20% workforce reduction focused on non-field-based employees in an effort to align our resources on the ongoing FILSPARI launch and the pivotal Phase 3 HARMONY Study to support the potential approval of pegtibatinase as the first potential disease-modifying treatment for HCU.

These restructuring adjustments are expected to result in an estimated annualized savings of approximately $25.0 million beginning in 2024, and an estimated non-recurring charge of approximately $12.0 million to $14.0 million, of which $11.4 million was recognized in the fourth quarter 2023.

We expect that we will incur the remaining estimated restructuring costs during 2024.

Critical Accounting Estimates

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For the years ended December 31, 2023, 2022 and 2021, the Company recorded a net product revenue increase of $0.4 million, $0.2 million, and $0.2 million, respectively, related to performance obligations satisfied in previous periods.

Government Rebates:

We calculate the rebates that we will be obligated to provide to government programs and deduct these estimated amounts from our gross product sales at the time the revenues are recognized.

Allowances for government rebates and discounts are established based on an estimated allocation of payers and the government-mandated discounts applicable to government-funded programs.

Rebate discounts are included in accrued expenses in the accompanying consolidated balance sheets.

Commercial Rebates:

We calculate the rebates we incur according to any contracts with certain commercial payers and deduct these amounts from our gross product sales at the time the revenues are recognized.

Allowances for commercial rebates are established based on actual payer information, which is reasonably estimated at the time of delivery for applicable products.

Rebate discounts are included in accrued expenses in the accompanying consolidated balance sheets.

Prompt Pay Discounts:

We offer discounts to certain customers for prompt payments.

We accrue for the calculated prompt pay discount based on the gross amount of each invoice for those customers at the time of sale.

Product Returns:

Consistent with industry practice, we offer our customers a limited right to return product purchased directly from us, which is principally based upon the product’s expiration date.

Historically, returns have been immaterial.

Co-pay Assistance:

We offer a co-pay assistance program, which is intended to provide financial assistance to qualified commercially insured patients with prescription drug co-payments required by payers.

The calculation of the accrual for co-pay assistance is based on an estimate of claims and the estimated cost per claim associated with product that has been recognized as revenue.

Payments received under collaboration and licensing agreements may include non-refundable fees at the inception of the arrangements, milestone payments for specific achievements and royalties on the sale of products.

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If the licenses to intellectual property are determined to be distinct from the other performance obligations identified in the arrangement, we recognize revenues from non-refundable, upfront fees allocated to the license when the license is transferred to the licensee and the licensee is able to benefit from the license.

appropriate method of measuring progress for purposes of recognizing revenue from non-refundable, upfront fees.

For licenses that are not distinct from other promises, we apply judgment to assess the nature of the combined performance obligation to determine whether the combined performance obligation is satisfied over time or a point in time and, if over time, the appropriate method of measuring progress for purposes of recognizing revenue from non-refundable, upfront fees.

We evaluate the measure of progress each reporting period and, if necessary, adjust the related revenue recognition accordingly.

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Expenses related to clinical trials are accrued based on our estimates of the progress of services performed, including actual level of patient enrollment, completion of patient studies and progress of the clinical trials or the delivery of goods.

We currently have three Phase 3 clinical trials in process that are in varying stages of activity, with ongoing non-clinical support trials that are significant and changes in estimates could have a material impact on expenses we recognize.

We currently have one Phase 1/2 clinical trial and three Phase 3 clinical trials in process that are in varying stages of activity, with ongoing non-clinical support trials that are significant and changes in estimates could have a material impact on expenses we recognize.

Stock-Based Compensation

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We use the Black-Scholes option valuation model to estimate the fair value of our stock options at the date of grant.

The Black-Scholes option valuation model requires the input of subjective assumptions to calculate the value of stock options.

The Black-Scholes option valuation model

requires the input of subjective assumptions to calculate the value of stock options.

For restricted stock units, the value of the award is based on our stock price at the grant date.

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Expected dividend yield — — —

Total non-cash stock-based compensation expense consisted of the following for the years ended December 31, 2022, 2021 and 2020:

$39.2 million, $30.8 million and $23.6 million, respectively.

Contingent Consideration

We record contingent consideration resulting from a business combination at its fair value on the acquisition date.

On a quarterly basis, we revalue these obligations and record increases or decreases from their fair value as an adjustment to the Consolidated Statements of Operations and Comprehensive Loss.

In estimating the fair value of our contingent consideration, we use a Monte Carlo Simulation.

Changes to contingent

consideration obligations can result from changes to discount rates, accretion of the liability due to the passage of time, changes in revenue forecasts and long-term growth rates.

The determination of the contingent consideration liabilities requires significant judgments including the reasonableness of estimates and assumptions included in the forecasts of future net sales and the discount rates applied to such forecasts.

Changes in these estimates and assumptions could have a significant impact on the fair value of the contingent consideration liabilities.

We acquired two businesses, related to the Cholbam and Chenodal products, whose purchase price included potential future payments that are contingent on the achievement of certain milestones and percentages of future net sales derived from the products acquired.

Discount rates used to determine the fair value at December 31, 2022 and 2021 are as follows:

Revenue Discount Payment Discount

Cholbam Chenodal

December 31, 2022 7.75% 8.00% 8.10%

December 31, 2021 6.25% 7.25% 6.48%

For the years ended December 31, 2022, 2021 and 2020 we recognized a change in the fair value of contingent consideration of $15.0 million, $22.3 million, and $3.7 million, respectively.

For the years ended December 31, 2023, 2022 and 2021, non-cash stock-based compensation expense totaled $44.2 million, $38.1 million and $29.6 million, respectively.

We capitalize inventory costs associated with our products after regulatory approval, when, based on management’s judgment, future commercialization is considered probable and the future economic benefit is expected to be realized.

Until the date at which regulatory approval has been received, costs related to the production of inventory are recorded as research and development expenses as incurred.

We periodically analyze our inventory levels to identify inventory that may expire prior to expected sale or has a cost basis in excess of its estimated realizable value, and write down such inventory as appropriate.

In addition, our products are subject to strict quality control and monitoring which our suppliers and manufacturers perform throughout their manufacturing process.

If certain batches or units of product no longer meet quality specifications or become obsolete due to expiration, we record a charge to write down such inventory to its estimated realizable value.

Impairment of Intangible Assets subject to amortization

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Intangible assets subject to amortization are reviewed for impairment whenever events or circumstances indicate that the carrying amount of these assets may not be recoverable and are also reviewed annually to determine whether any impairment is necessary.

We are subject to generic competition, and if additional generic versions of Thiola, any generic versions of Thiola EC, any generic versions of FILSPARI following the expiration of patent or regulatory exclusivity for the product, or generic versions of Cholbam or Chenodal or any of our current or future products, are approved, sales of that product likely would be negatively impacted, which could have a material adverse impact on the recoverability of certain related intangible assets.

Generic versions of the original formulation of Thiola have been approved and have impacted sales, and these or additional generic versions of either formulation could have a material adverse impact on sales.

We are subject to generic competition, and if additional generic versions of Thiola and Thiola EC, any generic versions of FILSPARI following the expiration of patent or regulatory exclusivity for the product, or any of our current or future products, are approved, sales of that product likely would be negatively impacted, which could have a material adverse impact on the recoverability of certain related intangible assets.

Generic versions of Thiola and Thiola EC have been approved and have impacted sales, and these or additional generic versions of either formulation could have a material adverse impact on sales and the recoverability of the intangible assets depending on the timing of the market entry and the related impact on net sales.

Recently Issued Accounting Pronouncements

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Results of Operations

Unless noted otherwise, the discussion below, and the revenue and expense amounts discussed below, are based on and relate to our continuing operations.

For further background on our net product sales and license and collaboration revenue, see Revenue Recognition under our Critical Accounting Estimates.

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2023 2022 Change 2022 2021 Change

Bile acid products $ 102,558 $ 95,654 $ 6,904 $ 95,654 $ 89,438 $ 6,216

Tiopronin products $ 98,329 $ 97,970 $ 359 $ 97,970 $ 115,122 $ (17,152)

FILSPARI 29,208 — 29,208 — — —

Total net product sales 127,537 97,970 29,567 97,970 115,122 (17,152)

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Net product sales

Net product sales for the years ended December 31, 2022, 2021 and 2020 were $200.5 million, $210.8 million and $198.3 million, respectively, and consisted of sales of Chenodal and Cholbam ("Bile acid products") and Thiola ("Tiopronin products").

The decrease in net product sales for the year ended December 31, 2022 as compared to the same period in 2021 was primarily due to a decrease in Thiola net sales, partially offset by an increase in net sales of our bile acid products.

The increase in sales of our bile acid products was driven organically, whereas the decrease in Thiola net sales was a result of generic competition.

The $29.6 million increase in total net product revenues for the year ended December 31, 2023 compared to the year ended December 31, 2022 was primarily due the launch of FILSPARI in February 2023 and subsequent sales throughout the year.

The $17.2 million decrease in total net product revenues for the year ended December 31, 2022 as compared to the year ended December 31, 2021, which consisted of Thiola net sales, was a result of generic competition.

License and collaboration revenue

The decrease in license and collaboration revenue for the year ended December 31, 2022 as compared to the same period in 2021 was primarily due to the recognition of $12.0 million in license revenue upon entering into the CSL Vifor License Agreement in September 2021, offset by an increase in collaboration revenue associated with the CSL Vifor License Agreement.

The increase in license and collaboration revenue for the year ended December 31, 2023 compared to the year ended December 31, 2022 was due to a $3.3 million sale of active pharmaceutical ingredients to CSL Vifor in March 2023 in preparation for a potential European Union approval and subsequent commercial launch, along with a $2.9 million increase in amortization of deferred revenue under the cost-to-cost model, which saw total costs for clinical development activities decrease as a result of the restructuring announced in December 2023.

We recognize costs for clinical development activities in research and development;

costs related to sale of active pharmaceutical ingredients are recognized in cost of goods sold.

The decrease in license and collaboration revenue for the year ended December 31, 2022 as compared to the year ended December 31, 2021 was primarily due to the recognition of $12.0 million in license revenue upon entering into the CSL Vifor License Agreement in September 2021, offset by an increase in collaboration revenue associated with the CSL Vifor License Agreement.

Collaboration revenue, derived from the performance of clinical development activities and based upon the ratio of costs incurred to total estimated costs, increased by $6.8 million from $4.7 million in 2021 to $11.5 million in 2022, primarily due to a full year of performance in 2022 as compared to a partial year of performance in 2021.

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2023 2022 Change 2022 2021 Change

Cost of goods sold $ 7,592 $ 6,784 $ 808 $ 6,784 $ 6,126 $ 658

Cost of goods sold - product sales $ 8,406 $ 4,420 $ 3,986 $ 4,420 $ 3,818 $ 602

Cost of goods sold - license and collaboration 3,044 — 3,044 — — —

Total cost of goods sold 11,450 4,420 7,030 4,420 3,818 602

Research and development 244,990 227,333 17,657 227,333 201,159 26,174

Selling, general and administrative 265,542 197,520 68,022 197,520 126,284 71,236

Change in fair value of contingent consideration 15,006 22,260 (7,254) 22,260 3,655 18,605

Acquired IPR&D expense — — — — 97,131 (97,131)

Restructuring 11,394 — 11,394 — — —

Total operating expenses $ 533,376 $ 429,273 $ 104,103 $ 429,273 $ 331,261 $ 98,012

Operating expenses for the year ended December 31, 2022, were $478.6 million compared to $389.3 million for the year ended December 31, 2021, an increase of $89.3 million.

Cost of goods sold

Cost of goods sold includes the cost of inventory sold, third party manufacturing and supply chain costs, product shipping and handling costs, and provisions for excess and obsolete inventory.

Cost of goods sold increased by $0.8 million due to increased sales quantities.

Cost of goods sold includes the cost of inventory sold, third party manufacturing and supply chain costs, product shipping, tracking and handling costs, and provisions for excess and obsolete inventory.

Prior to the February 2023 FDA accelerated approval of FILSPARI (sparsentan), we recognized approximately $7.5 million in research and development expenses related to the production of active pharmaceutical ingredients to support the commercial launch of FILSPARI.

For the year ended December 31, 2023, sales of FILSPARI primarily consisted of zero-cost inventories.

As of December 31, 2023, we had $7.2 million of zero-cost inventory remaining.

We expect to continue to benefit from the sale of previously expensed inventories through at least 2025.

We began capitalizing inventory costs associated with FILSPARI (sparsentan) following the February 2023 approval for treatment in IgAN.

At December 31, 2023, our evaluation of excess inventory and obsolescence considered certain minimum purchase obligations, which in combination with lower forecasted sales of FILSPARI resulted in a $3.2 million charge to cost of goods sold.

The charge to cost of goods sold included a $2.1 million write-down of inventory balances and $1.1 million accrued for firm purchase commitments.

For the year ended December 31, 2023 compared to the year ended December 31, 2022, our cost of goods sold - license and collaboration increased by $3.0 million due to the sale of active pharmaceutical ingredients to CSL Vifor in March 2023.

Research and development expenses

Research and development costs include expenses related to sparsentan, pegtibatinase (TVT-058) and our other pipeline programs.

Research and development costs include expenses related to sparsentan, pegtibatinase and our other pipeline programs.

We expense all research and development costs as they are incurred.

Our research and development costs are comprised of salaries and bonuses, benefits, non-cash share-based compensation, license fees, milestones under license agreements, costs paid to third-party contractors to perform research, conduct clinical trials, and develop drug materials and delivery methods, and associated overhead expenses and facilities costs.

Our research and development costs are comprised of salaries and bonuses, benefits, non-cash share-based compensation, license fees, milestones under license agreements, costs paid to third-party contractors to perform research, conduct clinical trials, and develop drug materials and delivery methods, manufacture drug product supplies to support clinical development, and associated overhead expenses and facilities costs.

We charge direct internal and external program costs to the respective development programs.

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These consist of internal shared resources related to the development and maintenance of systems and processes applicable to all of our programs.

We currently have one Phase 1/2 clinical trial and three Phase 3 clinical trials in process that are in varying stages of activity, with ongoing non-clinical support studies.

As such, clinical trial expenses will vary depending on the all the factors set forth above and may fluctuate significantly from quarter to quarter.

We currently have one Phase 1/2 clinical trial and three Phase 3 clinical trials in process that are in various stages of activity, with ongoing non-clinical support trials.

As such, clinical trial expenses will vary depending on the all the factors set forth above and may fluctuate significantly from quarter to quarter and year to year.

We routinely engage vendors and service providers for scientific research, clinical trial, regulatory compliance, manufacturing and other consulting services.

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Such grants may be funded in lump sums or installments.

The following table summarizes our research and development expenses during the years ended December 31, 2022, 2021 and 2020.

The internal costs include personnel, facility costs, and discovery and research related activities associated with our pipeline.

The external program costs reflect external costs attributable to our clinical development candidates and preclinical candidates selected for further development.

Such expenses primarily include third-party contract costs relating to clinical trial activities, nonclinical studies and manufacturing.

The following table provides information regarding research and development expenses ( in thousands ):

For the Year Ended December 31,

(in thousands)

2023 2022 2021

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Pegtibatinase 50,780 42,100 27,823

General 30,465 18,786 15,433

Fosmetpantotenate (discontinued) (56) 1 (124) 1 (2,295) 1

General and other product candidates 17,850 21,971 9,493

Total external service provider costs 160,332 151,669 140,666

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Total research and development $ 244,990 $ 227,333 $ 201,159

1 Credit received in 2022, 2021 and 2020.

Research and development costs increased by $25.5 million due to increases in clinical trial expenses, chemistry manufacturing and control costs, and related expenses associated with the advancement of our programs in development.

For the year ended December 31, 2023 compared to the year ended December 31, 2022, our research and development expenses increased by $17.7 million.

Internal personnel costs to support all programs increased by $9.0 million, reflecting increased headcount along with rising labor costs driven in part by inflation.

External service provider costs increased by $8.7 million, which was largely driven by increases in investment toward the December 2023 initiation of the Phase 3 HARMONY Study for pegtibatinase.

While costs associated with the development of sparsentan have been decreasing throughout the year as our Phase 3 programs advance towards completion, we observed a year over year increase as a result of increased investment in Medical Affairs initiatives supporting the IgAN program.

For the year ended December 31, 2022 compared to the year ended December 31, 2021, our research and development costs increased by $26.2 million due to increases in clinical trial expenses, chemistry manufacturing and control costs, and related expenses associated with the advancement of our programs in development.

Internal personnel costs to support all programs increased by $15.2 million, reflecting increased headcount along with rising labor costs.

External service provider costs increased by $11.0 million, which included a $14.3 million increase in such costs for the development of pegtibatinase along with a $12.5 million increase in other general research and development costs, offset by a $15.8 million decrease in external service provider costs associated with the development of sparsentan as the program progresses through the development cycle.

Certain costs associated with the production of inventory that could potentially be available to support the commercial launch of FILSPARI (sparsentan) have been recognized as research and development expense prior to regulatory approval.

As of December 31, 2022, we have recognized approximately $7.5 million in research and development expenses related to the production of active pharmaceutical ingredient that could potentially support the commercial launch of FILSPARI.

Selling, general and administrative expenses

Selling, general and administrative expenses consist of salaries and bonuses, benefits, non-cash share-based compensation, legal and other professional fees, rent, depreciation and amortization, travel, insurance, business development, sales and marketing programs, and other operating expenses.

Selling, general and administrative expenses increased by $70.3 million due to increased headcount as a result of operational growth, including rising labor costs, and commercial launch preparations in anticipation of the U.S.

For the year ended December 31, 2023 compared to the year ended December 31, 2022, our selling, general and administrative expenses increased by $68.0 million due to the onboarding of the dedicated sales force and other related commercial preparations and activity to support the U.S.

launch of FILSPARI.

Increases include an increase in combined employee compensation and stock compensation costs of $22.0 million, an increase in commercial support expenses of $19.1 million, an increase in various professional services expenses of $2.0 million, and an increase in various legal expenses of $5.0 million, along with incremental increases in information technology expense, legal fees, travel expense, and depreciation and amortization.

A change in the estimated useful life of the Thiola intangible asset and the accelerated amortization recognized in connection with the change also contributed to the increase in expense.

For the year ended December 31, 2022 compared to the year ended December 31, 2021 our selling, general and administrative expenses increased by $71.2 million due to increased headcount as a result of operational growth, including rising labor costs, and commercial launch preparations in anticipation of the U.S.

launch of FILSPARI.

Increases include combined employee compensation and stock compensation costs of $31.9 million, increases in commercial support expenses of $15.6 million and increases in various professional services expenses of $12.0 million.

A combined increase in selling, general and administrative expenses of $7.2 million was primarily attributable to incremental increases in information technology expense, legal fees, travel expense, and depreciation and amortization.

Change in the valuation of contingent consideration

Fair value of contingent consideration decreased by $7.3 million due to increases in market driven discount rates, including increases in treasury rates and credit spreads.

Incremental increases in information technology expense, legal fees, travel expense, and depreciation and amortization also contributed to the increase in selling, general and administrative expenses.

Restructuring expenses

In December 2023, we initiated a restructuring plan that resulted in a reduction of our workforce by approximately 20%, primarily impacting non-field-based employees.

Restructuring adjustments are expected to result in an estimated annualized savings of approximately $25.0 million beginning in 2024, and a total estimated non-recurring charge of approximately $12.0 million to $14.0 million.

For the year ended December 31, 2023, we recognized restructuring costs of $11.4 million, comprised of one-time termination benefits, including severance, continuation of health insurance coverage, and other benefits for a specified period of time.

Other Income/Expenses

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Loss on extinguishment of debt — (7,578) 7,578 (7,578) — (7,578)

Total other expense, net $ (11,603) $ (17,917) $ 6,314 $ (17,917) $ (12,627) $ (5,290)

Total other expense, net for the year ended December 31, 2022 was $11.6 million compared to total other expense, net of $17.9 million for the year ended December 31, 2021, which represents a change of $6.3 million.

The change was primarily due to loss on extinguishment of debt in connection with the partial repurchase in 2022 of the Convertible Senior Notes due 2025, offset by reduced interest expense due to adoption of ASU 2020-06, Accounting for Convertible Instruments and Contracts in an Entity's Own Equity ("ASU 2020-06") as debt discount is no longer amortized.

Total other income (expense), net $ 12,028 $ (11,342) $ 23,370 $ (11,342) $ (17,458) $ 6,116

The $23.4 million change in our total other income (expense), net for the year ended December 31, 2023 compared to the year ended December 31, 2022, is primarily attributable to a $15.5 million increase in interest income in 2023, which was due to increases in short-term interest rates and higher average balances on our interest-bearing security investments, and the $7.6 million loss on extinguishment of debt that was recognized in 2022 in connection with the partial repurchase of the Convertible Senior Notes due 2025.

For the year ended December 31, 2023, we also recognized other income of $1.0 million in connection with the transition services agreement entered into with Mirum as part of our sale of the bile acid business.

The $6.1 million change in our total other income (expense), net for the year ended December 31, 2022 compared to the year ended December 31, 2021 was primarily due to loss on extinguishment of debt in connection with the partial repurchase in 2022 of the Convertible Senior Notes due 2025, offset by reduced interest expense due to adoption of ASU 2020-06, Accounting for Convertible Instruments and Contracts in an Entity's Own Equity ("ASU 2020-06") as debt discount is no longer amortized.

In 2021, we recognized $10.3 million in interest expense for the amortization of the debt discount in accordance with the previous accounting guidance.

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Income Tax Benefit (Provision)

The tax provision was $0.3 million for fiscal 2022 as compared to $0.4 million for fiscal 2021, a decrease of $0.1 million.

Inflation generally affects us by increasing our salaries and fees paid to third-party contract service providers.

Recent inflationary pressures have primarily impacted our operations through increased labor costs.

While we continue to monitor the effects of macroeconomic factors, inflationary pressures have not affected our current outlook or business objectives.

The tax provision was $0.2 million for fiscal 2023 compared to $0.3 million for fiscal 2022, a decrease of $0.1 million.

The tax provision was $0.4 million for fiscal 2021.

Discontinued Operations

Results of discontinued operations are as follows ( in thousands ):

Year Ended December 31, Year Ended December 31,

2023 2022 Change 2022 2021 Change

Income from discontinued operations, net of tax $ 264,934 $ 52,986 $ 211,948 $ 52,986 $ 37,201 $ 15,785

The $211.9 million increase in income from discontinued operations, net of tax for the year ended December 31, 2023 compared to the year ended December 31, 2022 is primarily due to the August 31, 2023 sale of our bile acid business, which resulted in a gain, net of tax, of $226.0 million.

The gain consists of net consideration, including the upfront payment and the deduction of investment banker fees owed upon the Closing, plus the derecognition of the carrying value of the net liabilities included in the transaction and the immaterial tax due on the sale.

The increase arising from the gain was offset by four months less of bile acid business operations as a result of the divestiture on August 31, 2023.

The $15.8 million increase in income from discontinued operations, net of tax for the year ended December 31, 2022 compared to the year ended December 31, 2021 was due in part to a $6.9 million increase in net sales of our bile acid products.

The remainder of the increase in income from discontinued operations, net of tax, was primarily due to changes in the fair value of contingent consideration arising from updated revenue projections and changes in market driven discount rates.

See Note 19 to our Consolidated Financial Statements for further discussion.

Liquidity and Capital Resources

We have financed our operations through a combination of borrowings, sales of our equity securities, and revenues generated from our commercialized products, including Chenodal, Cholbam, Thiola and Thiola EC, along with proceeds from license and collaboration agreements.

We have experienced significant growth in recent years in the number of our employees and the scope of our operations.

We have expanded our sales and marketing, compliance and legal functions in addition to expansion of all functions to support a commercial organization, including by adding additional members to our sales force in anticipation of the commercialization of FILSPARI in the United States for the treatment of IgAN.

We anticipate that our expenses will continue to increase as we expand our sales and marketing infrastructure to commercialize FILSPARI and our other current approved products and any other new products for which we may obtain regulatory approval, advance the research and development of sparsentan for the treatment of IgAN and FSGS, along with the research and development for additional product candidates including pegtibatinase (TVT-058), and expand operational, financial, and management information systems and personnel, including personnel to support product development efforts and our obligations as a public company.

We have financed our operations through a combination of borrowings, sales of our equity securities, and revenues generated from our commercialized products, along with proceeds from license and collaboration agreements and the divestiture of our bile acid business.

We experienced significant growth in recent years in the number of our employees and the scope of our operations.

We also expanded our sales and marketing, compliance and legal functions in addition to expansion of all functions to support a commercial organization, including by adding additional members to our sales force in connection with the recent commercial launch of FILSPARI in the United States for IgAN.

These restructuring adjustments are expected to result in an estimated annualized savings of approximately $25.0 million beginning in 2024.

We believe that our available cash and short-term investments as of the date of this filing, together with anticipated cash generated from operations, will be sufficient to fund our anticipated level of operations beyond the next 12 months.

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December 31, 2023 December 31, 2022

Revenue $ 212,018 $ 227,490

Net loss $ (278,482) $ (180,091)

Cash and cash equivalents $ 58,176 $ 61,688

Marketable debt securities, at fair value $ 508,675 $ 388,557

Convertible debt $ 377,263 $ 375,545

Accumulated deficit $ (1,125,622) $ (1,014,223)

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As of December 31, 2023, we had cash and cash equivalents of $58.2 million and available-for-sale marketable debt securities of $508.7 million.

Substantial sources of funds over the past two fiscal years, as summarized further below, have included an upfront payment of $55.0 million in connection with a license agreement, net proceeds of $189.3 million from an underwritten public offering of our common stock, net proceeds of $55.2

million from the sale of our shares of common stock under an ATM facility, and net proceeds of $95.0 million from the issuance of debt after giving effect to the partial repurchase of our previously outstanding debt, along with collections from sales of our commercialized products.

Over the next 12 months, our expected financial obligations include, but are not limited to, funding our operations, operating lease payments, interest payments on our outstanding debt, royalties on sales of our existing commercialized products, research and development expenses pertaining to clinical and preclinical development activities across our pipeline, expenses associated with the potential launch of FILSPARI, including purchase commitments for manufactured product, and, if approved, related milestone payments.

Additional sources of cash over this period include net revenues from sales of our products, the sale or maturity of investments in our portfolio of marketable debt securities, and certain earned and potential milestone payments associated with sparsentan in connection with our license and collaboration arrangement with CSL Vifor.

Beyond the next 12 months and over the foreseeable future, our known commitments and potential financial obligations will likely include ongoing operations funding, operating lease payments, interest payments on our outstanding debt, royalties on sales of our existing commercialized products, research and development expenses pertaining to clinical and preclinical development activities across our pipeline, milestone and royalty payments associated with FILSPARI, pegtibatinase (TVT-058), and other developmental programs based upon the achievement of certain agreement-specific criteria, along with sales-based royalties and the repayment of principal on the outstanding 2025 Notes and 2029 Notes upon their respective maturities.

Substantial sources of funds since the start of 2023, as summarized further below, include an upfront cash payment of $210.0 million in connection with the sale of our bile acid product portfolio, and net proceeds of $215.8 million from an underwritten public offering of our common stock and pre-funded warrants to purchase shares of our common stock.

Over the next 12 months, our expected financial obligations include, but are not limited to, funding our operations, operating lease payments, interest payments on our outstanding debt, anticipated milestone payments, royalties on sales of our existing commercialized products, research and development expenses pertaining to clinical and preclinical development activities across our pipeline, expenses associated with the launch of FILSPARI.

Sources of cash over this period include net revenues from sales of our products, the sale or maturity of investments in our portfolio of marketable debt securities, and certain earned and potential milestone payments.

We anticipate achieving milestones with both FILSPARI and pegtibatinase that will result in us making net payments of approximately $50.0 million during the next 12 months.

Beyond the next 12 months and over the foreseeable future, our known commitments and potential financial obligations will likely include ongoing operations funding, operating lease payments, interest payments on our outstanding debt, royalties on sales of our existing commercialized products, research and development expenses pertaining to clinical and preclinical development activities across our pipeline, milestone and royalty payments associated with FILSPARI, pegtibatinase, and other developmental programs based upon the achievement of certain agreement-specific criteria, along with sales-based royalties and the repayment of principal on the outstanding 2025 Notes and 2029 Notes upon their respective maturities.

Potential sources of cash over this time horizon may include net revenues from sales of our existing products and, if commercialized, our pipeline products, licensing revenue, the sale or maturity of marketable debt securities in our investment portfolio, the refinancing of all or a portion of our debt, including the 2025 Notes and 2029 Notes, on or before maturity, or the issuance of additional debt or equity.

In addition, depending on prevailing market conditions, our liquidity requirements, contractual restrictions, and other factors, we may also from time to time seek to retire or purchase our outstanding debt, including the 2025 Notes or 2029 Notes, through cash purchases and/or exchanges for equity securities, in open market purchases, privately negotiated transactions or otherwise.

In light of global and macroeconomic conditions, including rising interest rates and volatility in the capital markets, we may not be able to successfully conduct financing or refinancing activity on favorable terms or at all.

In light of global and macroeconomic conditions, including rising interest rates, liquidity concerns at, and failures of, banks and other financial institutions, and volatility in the capital markets, we may not be able to successfully conduct financing or refinancing activity on favorable terms or at all.

Purchase Agreement Proceeds

Sale of Bile Acid Product Portfolio

On July 16, 2023, we entered into the Purchase Agreement with Mirum, pursuant to which Mirum agreed to purchase substantially all of the assets primarily related to our business of development, manufacture and commercialization of the Products, which comprised our bile acid business.

Upon the Closing of the transaction on August 31, 2023, we received an upfront cash payment of $210.0 million.

Pursuant to the Purchase Agreement, we are eligible to receive up to $235.0 million upon the achievement of certain milestones based on specified amounts of annual net sales (tiered from $125.0 million to $500.0 million) of the Products.

Collaboration and License Proceeds

License and Collaboration Agreement with CSL Vifor

On September 15, 2021, we entered into a License Agreement with CSL Vifor, pursuant to which we granted an exclusive license to CSL Vifor for the commercialization of sparsentan in the Licensed Territories.

In September, 2021, we entered into a License Agreement with CSL Vifor, pursuant to which we granted an exclusive license to CSL Vifor for the commercialization of sparsentan in the Licensed Territories.

Under the terms of the License Agreement, we received an upfront payment of $55.0 million in September 2021, and will be eligible for up to $135.0 million in aggregate regulatory and market access related milestone payments and up to $655.0 million in aggregate sales-based milestone payments for a total potential value of up to $845.0 million.

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2023 Underwritten Public Offering of Common Stock

In February 2021, we sold an aggregate of 7.5 million shares of our common stock in an underwritten public offering, at a price of $26.75 per share.

The net proceeds to us from the offering, after deducting the underwriting discounts and offering expenses, were $189.3 million.

In February 2023, we sold an aggregate of approximately 9.7 million shares of our common stock and pre-funded warrants to purchase 1.25 million shares of our common stock in an underwritten public offering, at a price to the public of $21.00 per share of common stock and $20.9999 per pre-funded warrant.

The pre-funded warrants are exercisable immediately, subject to certain beneficial ownership limitations which can be modified by the respective holders with at least 61 days' notice, and are exercisable for one share of our common stock.

The exercise price of each pre-funded warrant is $0.0001 per share of common stock.

The net proceeds to us from the offering, after deducting the underwriting discounts and offering expenses, were approximately $215.8 million.

At-the-Market Equity Offering

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An additional $51.9 million were sold under our effective registration statement on Form S-3 (Registration Statement No.

333-259311), which included $20.1 million from the settlement of 701,600 shares under the ATM Agreement in the year ended December 31, 2022.

333-259311), which included $20.1 million in the year ended December 31, 2022.

We did not sell any shares under the ATM Agreement during the year ended December 31, 2023.

As of December 31, 2023, an aggregate amount of $19.5 million remained eligible for sale under the ATM Agreement.

Authorized Shares of Common Stock

On May 14, 2021, in connection with our 2021 Annual Meeting of Stockholders, the Company’s stockholders approved, among other matters, a Certificate of Amendment (“Certificate of Amendment”) to our Certificate of Incorporation to increase the number of shares of common stock authorized for issuance thereunder from 100,000,000 to 200,000,000.

Effective May 18, 2021, the Certificate of Amendment was filed with the Secretary of State of the State of Delaware.

Operating Leases

Future Minimum Rental Commitments

We have future minimum rental commitments totaling $38.2 million arising from our operating leases.

As of December 31, 2023, we have future minimum rental commitments totaling $31.9 million arising from our operating leases.

These commitments represent the aggregate base rent through August 2028.

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Manufactured Product

Certain of the Company's contractual arrangements with contract manufacturing organizations ("CMOs") require binding forecasts or commitments to purchase minimum amounts for the manufacture of drug product supply, which may be material to the Company's financial statements.

As of December 31, 2022, we have a commitment to purchase $36.3 million in active pharmaceutical ingredient to be delivered in 2023.

Certain of our contractual arrangements with contract manufacturing organizations ("CMOs") require binding forecasts or commitments to purchase minimum amounts for the manufacture of drug product supply, which may be material to our financial statements.

Royalties and Contingent Cash Payments

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("Ligand") for a worldwide sublicense to develop, manufacture and commercialize sparsentan (the “Ligand License Agreement”).

As consideration for the license, we are required to make substantial payments upon the achievement of certain milestones, totaling up to $114.1 million, including a $23.0 million milestone payment to Ligand (and Bristol-Myers Squibb Company ("BMS")) that we plan to make in the first quarter of 2023, which was triggered upon the accelerated approval of FILSPARI in February 2023.

Through December 31, 2022, we have made payments under this arrangement totaling $18.4 million.

In addition, we are obligated to pay to Ligand (and BMS) an escalating annual royalty between 15% and 17% of net sales of FILSPARI and any other products containing sparsentan or related compounds.

The license agreement will continue until neither party has any further payment obligations under the agreement and is expected to continue for approximately 10 to 20 years from the effective date.

As consideration for the license, the Company is required to make substantial payments upon the achievement of certain milestones, totaling up to $114.1 million.

Through December 31, 2023, we have paid $41.4 million for contractual milestone payments under the Ligand License Agreement, which includes a $23.0 million milestone payment to Ligand (and Bristol-Myers Squibb Company ("BMS")) in March 2023 that was triggered upon the accelerated approval of FILSPARI in February 2023.

Following commercialization of sparsentan or any products containing related compounds, we are obligated to pay to Ligand an escalating royalty between 15% and 17% of net sales of all such products, with payments due quarterly.

We began incurring costs associated with such royalties following the February 2023 approval of FILSPARI (sparsentan).

For the year ended December 31, 2023, we capitalized $4.4 million to intangible assets for royalties owed on net sales of FILSPARI.

The license agreement will continue until neither party has any further payment obligations under the agreement and is expected to continue for up to 20 years from the effective date.

Ligand may terminate the license agreement due to (i) our insolvency, (ii) our material uncured breach of the agreement, (iii) our failure to use commercially reasonable efforts to develop and commercialize sparsentan as described above or (iv) certain other conditions.

We may terminate the license agreement due to a material uncured breach of the agreement by Ligand.

See Note 9 to Consolidated Financial Statements for further discussion.

See Note 9 to our unaudited Consolidated Financial Statements for further discussion.

Thiola License Agreement

In 2014, we entered into a license agreement with Mission Pharmacal ("Mission"), pursuant to which we obtained an exclusive, royalty-bearing license to market, sell and commercialize Thiola (tiopronin) in the United States and Canada, and a non-exclusive license to use know-how relating to Thiola to the extent necessary to market Thiola.

We paid Mission an up-front license fee of $3.0 million and during the term of the agreement will pay guaranteed minimum royalties during each calendar year the greater of $2.0 million or 20% of our net sales of Thiola in the United States and Canada.

In November 2017, we amended the license agreement to extend the term through May 2029.

In November 2018, the license agreement was amended to remove all territorial restrictions on our license rights.

As consideration for the expanded territory we paid an up-front fee of $0.3 million and will pay guaranteed minimum royalties equaling the greater of $0.1 million or 20% of our Thiola net sales generated outside of the United States during each calendar year.

Under the terms of the license agreement, as subsequently amended, which runs through May 2029, we are obligated to pay to Mission the greater of $2.1 million, representing the guaranteed minimum royalty, or 20% of our Thiola net sales generated globally during each calendar year.

See Note 9 to Consolidated Financial Statements for further discussion.

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We acquired Orphan by purchasing all of its outstanding shares.

In exchange for the shares, we made an upfront cash payment at closing of $90.0 million plus closing adjustments, net liabilities assumed, and transaction expenses of $1.2 million, $1.8 million, and $4.2 million, respectively.

Under the Agreement, we also agreed to make contingent cash payments up to an aggregate of $427.0 million based on the achievement of certain development, regulatory and commercialization events as set forth in the Agreement, as well as additional tiered mid-single digit royalty payments based upon future net sales of any pegtibatinase products in the US and Europe, subject to certain reductions as set forth in the Agreement, and a contingent payment in the event a pediatric rare disease voucher for any pegtibatinase product is granted.

See Note 5 to Consolidated Financial Statements for further discussion.

Under the Stock Purchase Agreement ("the Agreement"), we agreed to make contingent cash payments up to an aggregate of $427.0 million based on the achievement of certain development, regulatory and commercialization events as set forth in the Agreement, as well as additional tiered mid-single digit royalty payments based upon future net sales of any pegtibatinase products in the US and Europe, subject to certain reductions as set forth in the Agreement, and a contingent payment in the event a pediatric rare disease voucher for any pegtibatinase product is granted.

Stock Purchase and Collaboration Agreement with PharmaKrysto

On March 8, 2022, the Company entered into a Collaboration Agreement with PharmaKrysto Limited (“PharmaKrysto”), a privately held pre-clinical stage company related to PharmaKrysto's early-stage cystinuria discovery program, and concurrently therewith entered into a Stock Purchase Agreement with PharmaKrysto (together, the "Agreements").

Pursuant to the terms of the Agreements, the Company paid PharmaKrysto's shareholders $0.6 million in cash to purchase 5% of the outstanding common shares of PharmaKrysto and $0.4 million to PharmaKrysto as a one-time signing fee.

Under the Collaboration Agreement, the Company will fund all research and development expenses for the pre-clinical activities associated with the cystinuria program, which are estimated to be approximately $5.0 million.

The Agreements require the Company to purchase an additional 5% of the outstanding common shares for $1.0 million upon the occurrence of a specified pre-clinical milestone, and grant an option to the Company to purchase the remaining outstanding shares of PharmaKrysto for $5.0 million upon the occurrence of a subsequent pre-clinical milestone prior to expiration of the option on March 8, 2025.

If the Company elects to exercise the option, it would be required to perform commercially reasonable clinical diligence obligations.

In addition, it would be required to make cash milestone payments totaling up to an aggregate $16.0 million upon the achievement of certain development and regulatory milestones, plus tiered royalty payments of less than 4% on future net sales of a product, if approved.

The Company has the right to terminate the Agreements and return the shares for a nominal price at any time upon 60 days' notice, subject to survival of contingent obligations, if any.

On March 8, 2022, we entered into a Collaboration Agreement with PharmaKrysto Limited (“PharmaKrysto”), a privately held pre-clinical stage company related to PharmaKrysto's early-stage cystinuria discovery program, and concurrently therewith entered into a Stock Purchase Agreement with PharmaKrysto (together, the "Agreements").

Pursuant to the terms of the Agreements, we acquired 5% of the outstanding common shares and are required to purchase an additional 5% of the outstanding common shares for $1.0 million upon the occurrence of a specified pre-clinical milestone.

The Agreements also require us to fund all research and development expenses for the pre-clinical activities associated with the cystinuria program, which are expected to be approximately $5.0 million.

In addition, the Agreements grant us an option to purchase the remaining outstanding shares of PharmaKrysto for $5.0 million upon the occurrence of a subsequent pre-clinical milestone prior to expiration of the option on March 8, 2025.

If we elect to exercise the option, we would be required to perform commercially reasonable clinical diligence obligations.

In addition, we would be required to make cash milestone payments totaling up to an aggregate $16.0 million upon the achievement of certain development and regulatory milestones, plus tiered royalty payments of less than 4% on future net sales of a product, if approved.

We have the right to terminate the Agreements and return the shares for a nominal price at any time upon 60 days' notice, subject to survival of contingent obligations, if any.

See Note 5 to Consolidated Financial Statements for further discussion.

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We believe that our available cash and short-term investments as of the date of this filing will be sufficient to fund our anticipated level of operations beyond the next 12 months.

We expect to use cash flows from operations and outside financings to meet our current and future financial obligations, including funding our operations, debt service and capital expenditures.

We expect to use cash flows from operations and, when necessary, outside financings, to meet our current and future financial obligations, including funding our operations, debt service and capital expenditures.

Our ability to make these payments depends on our future performance, which will be affected by financial, business, economic, regulatory and other factors, many of which we cannot control.

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• the timing of, and costs involved in, commercial activities, including product marketing, sales and distribution;

• our ability to successfully commercialize FILSPARI for IgAN and to obtain regulatory approval for, and successfully commercialize, sparsentan for FSGS and our other or future product candidates;

• increases or decreases in revenue from our marketed products, including decreases in revenue resulting from generic entrants or health epidemics or pandemics such as COVID-19;

• our ability to successfully commercialize FILSPARI for IgAN, to obtain full regulatory approval for, and successfully commercialize, FILSPARI for the treatment of IgAN, and to obtain regulatory approval for, and successfully commercialize, sparsentan for FSGS and our other or future product candidates;

• increases or decreases in revenue from our marketed products, including decreases in revenue resulting from generic entrants or health epidemics or pandemics;

• debt service obligations on the 2025 Notes and 2029 Notes;

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Net cash used in operating activities $ (280,021) $ (186,291) $ (14,792)

Net cash used in investing activities (32,553) (137,623) (61,327)

Net cash provided by (used in) investing activities 55,776 (32,553) (137,623)

Net cash provided by financing activities 218,752 117,573 231,683

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Cash and cash equivalents, end of year 58,176 61,688 165,753

Marketable debt securities, at fair value 508,675 388,557 387,129

Total cash and cash equivalents and marketable debt securities $ 566,851 $ 450,245 $ 552,882

Management considers marketable debt securities to be available to fund current operations, and they are classified as available for sale and included within current assets in our Consolidated Balance Sheets.

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Operating activities used $280.0 million of cash during the year ended December 31, 2023 compared to $186.3 million of cash used for the year ended December 31, 2022.

The increase in cash used was primarily attributable to increased research and development and sales, general and administrative expenses, driven largely by the advancement of our programs in development and operational growth, including increases in clinical trial expenses, chemistry and manufacturing control costs, employee-related costs, commercial support expenses, and various professional expenses.

The receipt of the $55.0 million upfront payment in September 2021 in connection with the CSL Vifor License Agreement also contributed to the change.

The increase in cash used was primarily attributable to increased research and development and sales, general and administrative expenses.

Cash Flows from Investing Activities

Cash used in investing activities for the year ended December 31, 2022 was $32.6 million compared to cash used of $137.6 million for the year ended December 31, 2021.

The decrease in cash used was due to the decrease in net purchases of marketable debt securities attributable to the investment in such securities of funds received in the February 2021 underwritten public offering of common stock.

Cash provided by investing activities for the year ended December 31, 2023 was $55.8 million compared to cash used of $32.6 million for the year ended December 31, 2022.

The change was due to $207.4 million in net proceeds from the sale of our bile acid business in the third quarter 2023, offset by an increase in net purchases of marketable debt securities and the $23.0 million milestone payment to Ligand (and BMS) in March 2023 that was triggered upon the accelerated approval of FILSPARI in February 2023.

Cash Flows from Financing Activities

For the year ended December 31, 2023, cash provided by financing activities was $218.8 million compared to cash provided of $117.6 million for the year ended December 31, 2022.

The decrease in cash provided was primarily due to the February 2021 issuance of stock through an underwritten public offering that provided $189.3 million, offset by net proceeds of $95.0 million from the March 2022 issuance of the 2029 Notes and repurchase of the 2025 Notes.

Net proceeds from the issuance of common stock under the ATM Agreement also decreased by $16.1 million.

The increase in cash provided was due to the March 2023 issuance of common stock and pre-funded warrants through an underwritten public offering that provided $215.8 million in net proceeds, compared with net proceeds of $95.0 million from the March 2022 issuance of the 2029 Notes and repurchase of the 2025 Notes and $19.5 million in net proceeds from sales under the ATM Agreement in 2022.

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 7. Management’s Discussion and Analysis