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Item 1. Business

2024-02-27 compared with 2023-03-09 · 201 added, 153 removed, 430 unchanged (45% of the section changed)

We are a clinical stage biopharmaceutical company focused on discovering and developing novel therapies for the treatment of fibrosis and related diseases.

We are a late stage biopharmaceutical company focused on discovering and developing novel therapies for the treatment of fibrosis and related diseases.

Our initial focus is on treating fibrosis by inhibiting integrin-mediated activation of TGF-β.

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Our wholly-owned lead product candidate, bexotegrast (PLN-74809), is an oral, small molecule, dual selective inhibitor of αvß6 and αvß1 integrins that we are developing for the treatment of idiopathic pulmonary fibrosis, or IPF, and primary sclerosing cholangitis, or PSC.

We are currently conducting three Phase 2a trials in our lead indications:

two in IPF and one in PSC.

We announced positive interim data from our Phase 2a INTEGRIS-IPF trial in July 2022 and January 2023.

We expect to release final data from the INTEGRIS-IPF trial in the second quarter of 2023.

We expect to release interim data from our Phase 2a trial in PSC in the third quarter of 2023.

We have also developed a second clinical stage product candidate, PLN-1474, an oral, small molecule selective inhibitor of αvß1 for the treatment of liver fibrosis associated with nonalcoholic steatohepatitis, or NASH.

We are currently conducting a Phase 2b trial in IPF and a Phase 2a trial in PSC.

We announced positive data from our Phase 2a INTEGRIS-IPF trial in May 2023.

We are currently conducting BEACON-IPF, a 52-week, randomized, double-blind, placebo-controlled Phase 2b trial, in patients with IPF.

We announced positive interim data from our Phase 2a INTEGRIS-PSC trial in September 2023 and February 2024.

We expect to release final data from the INTEGRIS-PSC trial in mid-2024.

In January 2023, we received FDA clearance of investigational new drug application, or IND, for our third clinical program to date, PLN-101095, a dual inhibitor of integrins αvß8 and αvß1 for the treatment of solid tumors that are resistant to immune checkpoint inhibitors.

We are currently dosing the third of five planned dose cohorts in a Phase 1 open label dose-escalation trial of PLN-101095 as monotherapy and in combination with pembrolizumab in patients with solid tumors that are resistant to immune checkpoint inhibitors.

We expect to release preliminary data from the trial in late 2024.

Our fourth program to date, PLN-101325, in development for treatment of muscular dystrophies, including Duchenne muscular dystrophy.

PLN-101325 is a monoclonal antibody designed to act as an allosteric agonist of integrin α7ß1.

We expect to file with regulators for first-in-human studies in the first quarter of 2024.

We have developed PLN-1474, an oral, small molecule selective inhibitor of αvß1 for the treatment of liver fibrosis associated with nonalcoholic steatohepatitis, or NASH.

PLN-1474 is Phase 2-ready, having shown an excellent safety and pharmacokinetic profile in Phase 1 trials.

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In February 2023, Novartis returned global rights to PLN-1474 to Pliant.

In January 2023, we received FDA clearance of investigational new drug application, or IND, for our third clinical program, PLN-101095, a dual inhibitor of integrins αvß8 and αvß1 for the treatment of solid tumors that are resistant to immune checkpoint inhibitors.

We expect to initiate a Phase 1 trial of PLN-101095 in the second quarter of 2023.

In addition to our clinical programs, we are currently advancing a preclinical integrin-based program targeting muscular dystrophies.

Our Lead Candidate - Bexotegrast

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They both serve as activators of TGF-β, leading to increased collagen production and fibrosis in these tissues.

By blocking TGF-β activation by both αvß6 and αvß1, we believe bexotegrast may slow and potentially halt the progression of fibrosis in these patient populations.

Bexotegrast has been granted orphan drug designation by the United States Food and Drug Administration, or

FDA and the European Medicines Agency, or EMA, for both IPF and PSC.

By blocking TGF-β activation by both

αvß6 and αvß1, we believe bexotegrast may slow and potentially halt the progression of fibrosis in these patient populations.

Bexotegrast has been granted orphan drug designation by the United States Food and Drug Administration, or FDA and the European Medicines Agency, or EMA, for both IPF and PSC.

In addition, bexotegrast has been granted Fast Track designation by the FDA for IPF and PSC.

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Bexotegrast is an oral small molecule that selectively inhibits both αvß6 and αvß1 integrins that we are developing as a potential therapy for IPF and PSC.

We have determined that TGF-β activation in fibrosis associated with IPF and PSC involves both αvß6 and αvß1 integrins.

It has been shown that expression of both αvß6 on epithelial cells and αvß1 on fibroblasts can lead to excessive activation of TGF-β in fibrosis.

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Each of these tissues contains multiple cell types including epithelial cells and fibroblasts.

An important secondary effect of the TGF-β cascade is that it promotes upregulation of αvß1 on epithelial cells.

An important secondary effect of the TGF-β cascade is that it promotes upregulation of αvß6 on epithelial cells and αvß1 on fibroblasts.

The increased expression of these integrins on the cell surface contributes in turn to further TGF-β activation in a TGF-β-driven positive feed-forward loop.

In July 2022, we announced positive interim data from the 40 mg, 80 mg and 160 mg dose groups of INTEGRIS-IPF, a multinational, randomized, double-blind, placebo-controlled Phase 2a clinical trial of bexotegrast in patients with IPF.

In May 2023 we announced final data from INTEGRIS-IPF, a multinational, randomized, double-blind, placebo-controlled Phase 2a clinical trial of bexotegrast in patients with IPF.

The trial compared bexotegrast doses of 40 mg, 80 mg, 160 mg and 320 mg versus placebo over 12 weeks of treatment, with the 320 mg dose group allowed to treat for at least 24 weeks.

The trial met its primary and secondary endpoints demonstrating that bexotegrast was well tolerated over a 12-week treatment period and displayed a favorable pharmacokinetic profile.

The trial’s exploratory efficacy endpoints assessing changes in forced vital capacity, or FVC, and Quantitative Lung Fibrosis, or QLF, imaging, demonstrated a dose-dependent treatment effect on FVC and QLF versus placebo over 12 weeks in bexotegrast treated patients.

Bexotegrast was well tolerated over 12 weeks of treatment with no drug related serious adverse events, or SAEs, and no treatment discontinuations due to adverse events

In January 2023, we announced additional positive 12-week interim data from the 320 mg dose group of INTEGRIS-IPF.

The 320 mg group met its primary and secondary endpoints demonstrating that bexotegrast was well tolerated over a 12-week treatment period and displayed a favorable pharmacokinetic profile.

Bexotegrast at 320 mg demonstrated a statistically significant mean increase in FVC from baseline at all timepoints, surpassing all lower dose groups, and showed a strong treatment effect on FVC percent predicted, or FVCpp, QLF and profibrotic biomarkers versus placebo at 12 weeks.

Bexotegrast was well tolerated over 12 weeks of treatment at 320 mg with no drug-related severe or serious adverse events.

The trial’s exploratory efficacy endpoints assessing changes in forced vital capacity, or FVC, Quantitative Lung Fibrosis, or QLF, imaging, serum biomarkers and clinical symptoms.

Bexotegrast demonstrated a dose-dependent treatment effect on FVC, FVC percent predicted, or FVCpp, and QLF, as well as serum biomarkers and cough compared to placebo over 12 weeks in treated patients.

Bexotegrast was well tolerated over 12 weeks of treatment with no drug related serious adverse events, or SAEs.

Bexotegrast at 320 mg demonstrated a statistically significant mean increase in FVC from baseline at all timepoints up to 12 weeks, surpassing all lower dose groups, and showed a strong treatment effect on FVC, FVCpp, QLF, profibrotic biomarkers and cough versus placebo at 12 weeks.

Change in FVC from Baseline of Bexotegrast 320 mg Over 12 Weeks in INTEGRIS-IPF;

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Change from Baseline at 4- and 12-Weeks vs Placebo

The bexotegrast 320 mg group at 24 weeks met its primary and secondary endpoints demonstrating that bexotegrast was well tolerated over the 24-week treatment period and displayed a favorable pharmacokinetic profile.

At Week 24, bexotegrast at 320 mg, in combination with standard of care, reduced FVC decline by 80% relative to standard of care alone.

Eighty-nine percent of bexotegrast-treated patients who experienced an increase in FVC from baseline at Week 12 maintained an increase at Week 24.

Bexotegrast at 320 mg showed a strong treatment effect with stabilization of fibrosis as measured by QLF imaging at Week 24.

Bexotegrast was well tolerated up to 40 weeks of treatment at 320 mg with no drug-related serious adverse events.

Change in FVC from Baseline of Bexotegrast 320 mg Over 24 Weeks

Proportion of Patients with FVC Change from Baseline of Bexotegrast 320 mg

Over 12 and 24 Weeks versus Placebo - Intent to Treat Population

QLF Mean Percent Change from Baseline at Weeks 12 and 24 versus Placebo – Per CT Protocol Population

In August 2023, we initiated BEACON-IPF, a 52-week, multinational, randomized, dose-ranging, double-blind, placebo-controlled Phase 2b trial evaluating bexotegrast at doses of 160 mg or 320 mg.

BEACON-IPF is a multinational trial enrolling approximately 270 patients with IPF.

The primary endpoint is an assessment of the change from baseline in absolute mL of forced vital capacity (FVC) at Week 52.

Key secondary endpoints include the measurement of time to disease progression (defined as either a ≥10% decline from baseline in FVC precent predicted (FVCpp), respiratory-related hospitalization, or all-cause mortality), change from baseline of absolute FVC (mL) with or without background therapies, change from baseline in patient reported measurements of symptoms, well-being at Week 52 and safety and tolerability.

Bexotegrast for Treatment of Primary Sclerosing Cholangitis

PSC is a progressive liver disorder affecting approximately 30,000 to 45,000 patients in the United States.

The disease is characterized by fibrosis originating in the bile ducts that ultimately results in bile flow obstruction or cholestasis, causing liver damage and progressive fibrosis of the liver.

The disease is characterized by fibrosis originating in the bile ducts that ultimately results in bile flow obstruction or cholestasis, causing liver inflammation and progressive fibrosis of the liver.

Patients have a median survival of 10 to 12 years without intervention and carry high lifetime risk of developing gastrointestinal malignancies.

There are currently no FDA-approved therapies for PSC.

We are currently conducting a Phase 2a trial of bexotegrast in PSC.

The trial is a 12-week randomized, double-blind, placebo-controlled trial enrolling approximately 84 PSC patients across four treatment groups consisting of three bexotegrast doses (40 mg, 80 mg and 160 mg) and one placebo group that will evaluate safety, tolerability and PK.

We also plan to evaluate exploratory efficacy endpoints including fibrosis biomarkers such as Pro-C3 and ELF, as well as ALP and liver imaging.

We expect to announce data from this trial in the third quarter of 2023.

We are currently conducting INTEGRIS-PSC, a Phase 2a trial of bexotegrast in PSC.

The trial is a 12-week multinational, randomized, double-blind, placebo-controlled trial enrolling approximately 112 PSC patients across bexotegrast doses of 40 mg, 80 mg, 160 mg and 320 mg versus placebo that will evaluate safety, tolerability and PK.

We also plan to evaluate exploratory efficacy endpoints including fibrosis biomarkers such as Pro-C3 and enhanced liver fibrosis (ELF) score, as well as alkaline phosphatase ( ALP) and liver imaging.

While the lower doses end the treatment period at 12 weeks, the 320 mg dose cohort will be allowed to continue treatment to at least 24 weeks.

In January 2024, we released 12-week data from all four dose cohorts of the INTEGRIS-PSC data.

The trial met its primary and secondary endpoints demonstrating that bexotegrast was well tolerated over a 12-week treatment period with no drug-related severe or serious adverse events (SAEs).

Notably, PSC related AEs of cholangitis and pruritis occurred at lower rates in the treated groups compared to placebo.

Bexotegrast displayed a favorable pharmacokinetic profile with exposures increasing with dose.

All bexotegrast doses reduced the fibrotic biomarkers ELF (Enhanced Liver Fibrosis score) and PRO-C3 relative to placebo at week 12 with PRO-C3 achieving statistical significance at the 40 mg and 160 mg doses.

All doses also showed improvement in liver function and bile flow as measured by MRI imaging at week 12.

In patients with elevated baseline alkaline phosphatase (ALP) levels, all bexotegrast doses showed improvement of ALP relative to placebo at week 12.

Lastly, all bexotegrast doses displayed improvement in itch relative to placebo as measured by the itch numerical rating scale, with statistical significance achieved at the 160 mg and 320 mg doses.

Change in ELF Score at 12 Weeks in INTEGRIS-PSC - Single Doses, Pooled Doses and Pooled Placebo

We are planning to share data from the INTEGRIS-PSC trial with regulatory authorities to discuss the path to registration.

Twenty-four week data from the 320 mg dose group of the INTEGRIS-PSC trial is expected in mid-2024.

PLN-101095 for Treatment of Solid Tumors That are Resistant to Immune Checkpoint Inhibitors

Our third clinical program to date, PLN-101095, is an oral, dual inhibitor of αvß8 and αvß1 integrins for the treatment of solid tumors with a suboptimal response to immune checkpoint inhibitors, or ICIs.

As TGF-β biology has been elucidated, it has become increasingly understood in the scientific literature that TGF-β plays an important anti-inflammatory role in the tumor micro-environment, preventing T-cell infiltration and inhibiting release of various cytokines.

This mechanism is becoming increasingly recognized as a potential cause of the resistance to checkpoint inhibitors such as anti-PD-1 therapies seen in many tumors.

We are targeting the TGF-β activating integrins αvβ8 and αvβ1, which are upregulated in certain tumors, with the goal of sensitizing tumors to checkpoint inhibitors.

We are currently dosing the third of five planned dose cohorts in a Phase 1 open label dose-escalation trial of PLN-101095 as monotherapy for 14 days, followed by combination therapy with pembrolizumab in patients with solid tumors that are resistant to immune checkpoint inhibitors.

We expect to release preliminary data from the trial in late 2024.

PLN-101325 for Treatment of Muscular Dystrophies

We are developing PLN-101325, a monoclonal antibody targeting α7β1 for treatment of muscular dystrophies, including Duchenne Muscular Dystrophy, or DMD.

The α7β1 integrin is upregulated on muscle cells in several muscular dystrophy indications.

It partially compensates for the lack of dystrophin by helping to anchor muscle cells to the extracellular matrix.

PLN-101325 binds and allosterically activates α7β1 in order to augment this naturally occurring compensatory mechanism.

Because the antibody is not mutation specific, it could potentially be effective as a single therapy or in combination with other treatment modalities across multiple muscular dystrophy indications.

We expect to file with regulators for first-in-human studies in the first quarter of 2024 .

PLN-1474 for Treatment of Liver Fibrosis Associated with NASH

NASH is highly prevalent, affecting approximately 16.5 million adults in the United States, including approximately 3.3 million with stage F3/F4 fibrosis.

The stage of fibrosis is the strongest predictor of liver-related morbidity and all-cause mortality in NASH.

Patients with F3 and F4 fibrosis carry liver-related mortality risk that is 17 times and 42 times greater, respectively, than NASH patients without fibrosis.

Therefore, we believe that treating F3/F4

liver fibrosis will have an impact on liver-related morbidity and all-cause mortality in NASH.

There are currently no approved therapies for NASH and the candidates in development to date have shown only modest antifibrotic effects in published clinical trials.

We have developed a second clinical stage product candidate, PLN-1474, which is an oral, small molecule, selective inhibitor of TGF-β activation by the integrin αvß1 in development for treatment of advanced liver fibrosis associated with NASH.

We have developed a clinical stage product candidate, PLN-1474, which is an oral, small molecule, selective inhibitor of TGF-β activation by the integrin αvß1 in development for treatment of advanced liver fibrosis associated with NASH.

αvß1 serves as an activator of TGF-β and its expression has been shown to be upregulated in hepatic stellate cells in late-stage NASH-associated liver fibrosis.

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Please refer to Note 8 to our financial statements appearing elsewhere in this Annual Report for further information about the license and collaboration.

PLN-101095 for Treatment of Solid Tumors That are Resistant to Immune Checkpoint Inhibitors

In December 2022, we filed an IND for our third clinical program, PLN-101095 an oral, dual inhibitor of αvß8 and αvß1 integrins for the treatment of solid tumors with a suboptimal response to immune checkpoint inhibitors, or ICIs.

In January 2023 we received clearance from the FDA to begin clinical trials.

This mechanism is becoming increasingly recognized as a potential cause of the resistance to checkpoint inhibitors such as anti-PD-1 therapies seen in many tumors.

We are targeting the TGF-β activating integrins αvβ8 and αvβ1, which are upregulated in certain tumors, with the goal of sensitizing tumors to checkpoint inhibitors.

We plan to initiate Phase 1 first-in-human study evaluating PLN-101095 in patients with solid tumors with a suboptimal response to immune checkpoint inhibitors, or ICIs, in the second quarter of 2023.

PLN-101325 for Treatment of Muscular Dystrophies

In addition to our clinical programs, we are developing a preclinical allosteric agonistic monoclonal antibody against α7β1 for treatment of muscular dystrophies, including Duchenne Muscular Dystrophy, or DMD.

The α7β1 integrin is upregulated on muscle cells in several muscular dystrophy indications, partially compensating for the lack of dystrophin and helping to anchor muscle cells to the extracellular matrix.

The program utilizes an allosteric agonistic antibody to activate the target in order to augment the naturally occurring compensatory mechanism.

Because the antibody is not mutation specific, it could potentially be effective as a single therapy or in combination with other treatment modalities across multiple muscular dystrophy indications.

Our muscular dystrophy candidate is currently undergoing IND enabling studies with submission of an IND expected in 2023.

We have assembled an executive team with highly relevant experience in fibrosis, small molecule drug discovery and clinical development.

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There are a number of biopharmaceutical and biotechnology companies that are currently pursuing the development of products for the treatment of fibrosis.

Companies that we are aware of that are targeting the treatment of various fibrosis indications through inhibiting various parts of the TGF-β pathway include companies with significant financial resources such as AbbVie Inc., AstraZeneca plc, Bristol Myers Squibb Co., Corbus Pharmaceutical, DiCE Therapeutics, Inc., FibroGen, Inc., Merck & Co., Inc., Morphic Therapeutics, Inc., Novartis AG, Scholar Rock and Takeda Pharmaceutical Company.

Boehringer Ingelheim's PDE4B inhibitor (BI 1015550), FibroGen Inc.'s monoclonal antibody against connective tissue growth factor (pamrevlumab) and United Therapeutics' prostacyclin vasodilator (treprostinil) are the most advanced development candidates for the treatment of IPF.

Roche Holding AG recently discontinued its Phase 3 trial of recombinant human pentraxin-2 monoclonal antibody.

Although our novel approach is unique from most other existing or investigational therapies across the disease areas where we are focusing our development, we will need to compete with currently approved therapies, and potentially those in currently in development if they are approved.

Companies that we are aware of that are targeting the treatment of various fibrosis indications through inhibiting various parts of the TGF-β pathway include companies with significant financial resources such as AbbVie Inc., AstraZeneca plc, Bristol Myers Squibb Co., Corbus Pharmaceutical, Merck & Co., Inc., Morphic Therapeutics, Inc., Novartis AG, Scholar Rock, Inc.

and Takeda Pharmaceutical Company.

Boehringer Ingelheim's PDE4B inhibitor (BI 1015550), Bristol Myers Squibb Co.’s LPAR1 inhibitor (BMS-986278) and United Therapeutics Corporation prostacyclin vasodilator (treprostinil) are the most advanced development candidates for the treatment of IPF.

We are aware of several marketed and investigational products in our leading disease areas, including but not limited to:

There are currently two approved products for the treatment of IPF;

Esbriet, marketed by Roche Holding AG, and Ofev, marketed by Boehringer Ingelheim GmbH.

Companies currently developing product candidates in IPF include Boehringer Ingelheim Pharmaceuticals, Inc., FibroGen Inc., Galecto Biotech, Inc., Amgen Inc., Bristol Myers Squibb Co., United Therapeutics Corporation, Vicore Pharma Holding, CSL Behring, and Endeavor BioMedicines, Inc.

pirfenidone – brand name Esbriet ® , marketed by Roche Holding AG, with generics marketed by Sandoz Group AG, Teva Pharmaceutical Industries Ltd., and others, and nintedanib – brand name Ofev ® , marketed by Boehringer Ingelheim GmbH.

Companies currently developing product candidates in IPF include Boehringer Ingelheim Pharmaceuticals, Inc., Bristol Myers Squibb Co., United Therapeutics Corporation, Amgen, Roche Holding AG, Vicore Pharma Holding, CSL Behring, PureTech Health PLC, BridgeBio Pharma Inc, Syndax Pharmaceuticals Inc., Endeavor BioMedicines, Inc., and Avalyn Pharma Inc..

There are currently no approved therapies for the treatment of PSC.

Companies currently developing product candidates in PSC include Dr.

Falk Pharma GmbH, Mirum Pharmaceuticals, Inc., Chemomab Therapeutics Ltd., HighTide Therapeutics Inc., and Escient Pharmaceuticals, Inc.

Falk Pharma GmbH, Mirum Pharmaceuticals, Inc., Chemomab Therapeutics Ltd., Ipsen Biopharmaceuticals Inc., Curome Biosciences, NGM Biopharmaceuticals, Inc.

and Escient Pharmaceuticals, Inc.

There are currently no FDA-approved therapies for the treatment of NASH.

There are a number of companies developing product candidates for the treatment of NASH including 89bio, Inc., AbbVie Inc., Akero Therapeutics, Inc., Amgen Inc., AstraZeneca plc, Boehringer Ingelheim, Bristol Myers Squibb Co., Cascade Pharmaceuticals, Inc., Cirius Therapeutics, Inc., Dr.

Falk Pharma GmbH, Eli Lilly & Company, Enanta Pharmaceuticals, Inc., Gannex Pharma Co., Ltd., Galectin Therapeutics Inc., Gilead Sciences, Inc., Genfit SA, Genentech, Inc., GlaxoSmithKline plc, Intercept Pharmaceuticals, Inc., Inventiva Pharma, Ionis Pharmaceuticals, Inc., Johnson & Johnson, Madrigal Pharmaceuticals, Inc., Merck & Co., Inc., Metacrine, Inc., NGM Biopharmaceuticals, Inc., NorthSea Therapeutics B.V., Novo Nordisk, Pfizer Inc., Roche Holding AG, Regeneron Pharmaceuticals, Inc., Sanofi S.A., Takeda Pharmaceutical Company, Terns Pharmaceuticals, Inc., Viking Therapeutics, Inc.

Falk Pharma GmbH, Eli Lilly & Company, Enanta Pharmaceuticals, Inc., Gannex Pharma Co., Ltd., Galectin Therapeutics Inc., Gilead Sciences, Inc., Genfit SA, GlaxoSmithKline plc, Inventiva Pharma, Ionis Pharmaceuticals, Inc., Johnson & Johnson, Madrigal Pharmaceuticals, Inc., Merck & Co., Inc., Metacrine, Inc., NGM Biopharmaceuticals, Inc., NorthSea Therapeutics B.V., Novo Nordisk, Pfizer Inc.,Roche Holding AG, Regeneron Pharmaceuticals, Inc., Sanofi S.A., Takeda Pharmaceutical Company, Terns Pharmaceuticals, Inc., Viking Therapeutics, Inc.

and Zydus Therapeutics Inc.

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With respect to both licensed and company-owned intellectual property, we cannot be sure that patents will be granted with respect to any of our pending patent applications or with respect to any patent applications filed by us in the future, nor can we be sure that any of our existing patents or any patents that may be granted to us in the future will be commercially useful in protecting our commercial products and methods of manufacturing the same.

As of March 5, 2023, we own, co-own or license over 250 pending patent applications worldwide in over 26 patent families, including United States and corresponding foreign patent applications.

As of March 5, 2023, nine U.S.

patents and four foreign patents have been issued or allowed.

As of February 13, 2024, we own or co-own over 300 pending patent applications worldwide in over 30 patent families, including United States and corresponding foreign patent applications.

As of February 13, 2024, twelve U.S.

patents and seventeen foreign patents have been issued, granted or allowed.

Our patents and any patents that may issue from our pending patent applications are generally expected to expire between the years 2037 to 2044, subject to possible patent term adjustment and/or extension.

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Certain applications in these families relate to our bexotegrast and PLN-1474 small molecule product candidates, backup compounds and structural analogs, various unit dosages, dosing regimens, and routes of administration.

We are also pursuing innovative ways to modulate integrin function using antibodies and have 36 pending patent applications to that technology in the United States and foreign jurisdictions.

We are also pursuing innovative ways to modulate integrin function using antibodies and have 36 pending patent applications to that technology in the United States and foreign jurisdictions, and one issued foreign patent.

Patents that may issue from these company owned applications are generally expected to expire between the years 2040 to 2044, subject to possible patent term adjustment and/or extension.

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Manufacturing

Our product candidates, bexotegrast and PLN-1474, are small molecule inhibitors amenable to standard formulation technologies.

Our lead product candidate, bexotegrast, is a small molecule inhibitor amenable to standard formulation technologies.

We have confirmed the utility of the synthetic process and manufactured multi-kilogram quantities sufficient to provide drug product for our clinical trials.

The manufacturing process of the drug substance for such product candidates is robust and accessed from readily available starting materials.

The manufacturing process of the drug substance for such product candidate is robust and accessed from readily available starting materials.

The synthetic route is amenable to large-scale production and does not require unusual equipment or handling during the manufacturing process.

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We also rely on internal personnel with extensive cGMP manufacturing experience in order to ensure effective technology transfer and to manage the manufacturing and development processes conducted by third-party manufacturers.

We have established an adequate supply of the drug substance for bexotegrast from our Asian contract manufacturing organizations, or CMOs, to satisfy both our clinical and preclinical requirements and have evaluated additional suppliers in North America and Europe to mitigate supply chain risk and maximize flexibility.

We have established an adequate supply of the drug substance for bexotegrast from our Asian contract manufacturing organizations, or CMOs, to satisfy both our clinical and preclinical requirements.

As our development programs expand and we build new process efficiencies, we expect to continually evaluate this strategy with the objective of satisfying demand for our clinical trials and, if approved, the manufacture, sale, and distribution of commercial products.

Government Regulation

The FDA and comparable regulatory authorities in state and local jurisdictions and in other countries impose substantial and burdensome requirements upon companies involved in the clinical development, manufacture, marketing, and distribution of drugs, such as those we are developing.

These agencies and other federal, state, and local entities regulate, among other things, the research and development, testing, manufacture, quality control, safety, effectiveness, labeling, storage, record keeping, approval, advertising and promotion, distribution, post-approval monitoring and reporting, sampling and export and import of our product candidates.

The FDA, CMS,HHS-OIG and comparable regulatory authorities in state and local jurisdictions and in other countries impose substantial and burdensome requirements upon companies involved in the clinical development, manufacture, marketing, and distribution of drugs, such as those we are developing.

government regulation of drug products

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Failure to comply with the applicable U.S.

requirements at any time during the product development process, approval process or after approval, may subject an applicant to a variety of administrative or judicial sanctions, such as the FDA’s refusal to approve pending New Drug Applications, or NDAs, withdrawal of an approval, imposition of a clinical hold, issuance of warning letters, product recalls, product seizures, total or partial suspension of production or distribution, injunctions, fines, refusals of government contracts, restitution, disgorgement or civil or criminal penalties.

requirements at any

time during the product development process, approval process or after approval, may subject an applicant to a variety of administrative or judicial sanctions, such as the FDA’s refusal to approve pending New Drug Applications, or NDAs, withdrawal of an approval, imposition of a clinical hold, issuance of warning letters, product recalls, product seizures, total or partial suspension of production or distribution, injunctions, fines, refusals of government contracts, restitution, disgorgement or civil or criminal penalties.

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

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

The drug is administered to an expanded patient population, generally at geographically dispersed clinical trial sites, in well-controlled clinical trials to generate enough data to statistically

evaluate the efficacy and safety of the product for approval, to establish the overall risk-benefit profile of the product, and to provide adequate information for the labeling of the product.

The drug is administered to an expanded patient population, generally at geographically dispersed clinical trial sites, in well-controlled clinical trials to generate enough data to statistically evaluate the efficacy and safety of the product for approval, to establish the overall risk-benefit profile of the product, and to provide adequate information for the labeling of the product.

Progress reports detailing the results of the clinical trials must be submitted at least annually to the FDA and more frequently if serious adverse events occur.

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Before approving an NDA, the FDA typically will inspect the facility or facilities where the product is manufactured.

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

specifications.

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

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Even with submission of this additional information, the FDA ultimately may decide that the application does not satisfy the regulatory criteria for approval.

If and when those conditions

have been met to the FDA’s satisfaction, the FDA will typically issue an approval letter.

If and when those conditions have been met to the FDA’s satisfaction, the FDA will typically issue an approval letter.

An approval letter authorizes commercial marketing of the drug with specific prescribing information for specific indications.

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Orphan exclusivity will not bar approval of another product under certain circumstances, including if a subsequent product with the same active ingredient for the same indication is shown to be clinically superior to the approved product on the basis of greater efficacy or safety, or providing a major contribution to patient care, or if the company with orphan drug exclusivity is not able to meet market demand.

Further, the FDA may approve more than one product for the same orphan indication or disease as long as the products contain different active ingredients.

Further, the FDA may approve more than one

product for the same orphan indication or disease as long as the products contain different active ingredients.

Moreover, competitors may receive approval of different products for the indication for which the orphan product has exclusivity or obtain approval for the same product but for a different indication for which the orphan product has exclusivity.

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Later discovery of previously unknown problems with a product, including adverse events of unanticipated severity or frequency, or with manufacturing processes, or failure to comply with regulatory requirements, may result in mandatory revisions to the approved labeling to add new safety information;

imposition of post-market studies or clinical trials to assess new safety risks;

imposition of post-market studies or clinical trials to assess new safety

or imposition of distribution or other restrictions under a REMS program.

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Arrangements with third party payors, healthcare providers and physicians, in connection with the clinical research, sales, marketing and promotion of products, once approved, and related activities, may expose a pharmaceutical manufacturer to broadly applicable fraud and abuse and other healthcare laws and regulations.

In the United States, these laws include, without limitation, state and federal anti- kickback, false claims, physician transparency, and patient data privacy and security laws and regulations, including but not limited to those described below:

In the United States, these laws include, without limitation, state and federal anti- kickback, false claims, physician payment transparency, price transparency, and patient data privacy and security laws and regulations, including but not limited to those described below:

• the federal Anti-Kickback Statute, or AKS, which makes it illegal for any person, including a prescription drug manufacturer (or a party acting on its behalf) to knowingly and willfully solicit, receive, offer or pay any remuneration (including any kickback, bribe, or rebate), directly or indirectly, overtly or covertly, in cash or in kind, that is intended to induce or reward, referrals including the purchase recommendation, order or prescription of a particular drug for which payment may be made under a federal healthcare program, such as the Medicare and Medicaid programs.

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or knowingly concealing or knowingly and improperly avoiding or decreasing such an obligation.

Similar to the federal Anti-Kickback Statute, a person or entity does not need to have actual knowledge of these statutes or specific intent to violate them in order to have committed a violation.

Violations of the False Claims Act can result in civil penalties of up to more than $25,000 per false claim or statement (an amount adjusted annually for inflation) plus three times the amount of damages sustained by the government;

pretenses, representations, or promises, any of the money or property owned by, or under the custody or control of, any healthcare benefit program, regardless of the payor (e.g., public or private) and knowingly and willfully falsifying, concealing or covering up by any trick or device a material fact or making any materially false statements in connection with the delivery of, or payment for, healthcare benefits, items or services relating to healthcare matters;

A person or entity does not need to have actual knowledge of these statutes or specific intent to violate them in order to have committed a violation.

Violations of the False Claims Act can result in civil penalties of up

to more than $25,000 per false claim or statement (an amount adjusted annually for inflation) plus three times the amount of damages sustained by the government;

• the federal Health Insurance Portability and Accountability Act of 1996, or HIPAA, which created additional federal criminal statutes that prohibit knowingly and willfully executing, or attempting to execute, a scheme to defraud any healthcare benefit program or obtain, by means of false or fraudulent pretenses, representations, or promises, any of the money or property owned by, or under the custody or control of, any healthcare benefit program, regardless of the payor (e.g., public or private) and knowingly and willfully falsifying, concealing or covering up by any trick or device a material fact or making any materially false statements in connection with the delivery of, or payment for, healthcare benefits, items or services relating to healthcare matters;

• HIPAA, as amended by the Health Information Technology for Economic and Clinical Health Act of 2009, or HITECH, and their respective implementing regulations, which impose requirements on certain covered healthcare providers, health plans, and healthcare clearinghouses as well as their respective business associates that perform services for them that involve the creation, use, receipt, maintenance or disclosure of individually identifiable health information, relating to the privacy, security and transmission of individually identifiable health information;

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For example, in June 2018, the State of California enacted the California Consumer Privacy Act of 2018, or the CCPA, which came into effect on January 1, 2020 and provides new data privacy rights for consumers and new operational requirements for companies, which may increase our compliance costs and potential liability.

The CCPA gives California residents expanded rights to access and delete their personal

information, opt out of certain personal information sharing, and receive detailed information about how their personal information is used.

The CCPA gives California residents expanded rights to access and delete their personal information, opt out of certain personal information sharing, and receive detailed information about how their personal information is used.

The CCPA provides for civil penalties for violations, as well as a private right of action for data breaches that is expected to increase data breach litigation.

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In the event we decide to conduct clinical trials or continue to enroll subjects in our ongoing or future clinical trials, we may be subject to additional privacy restrictions.

The collection, use, storage, disclosure, transfer, or other processing of personal data regarding individuals in the European Economic Area, or EEA, including personal health data, is subject to the EU General Data Protection Regulation, or EU GDPR, which became effective on May 25, 2018.

The EU GDPR is wide-ranging in scope and imposes numerous requirements on companies that process personal data (i.e., data relating to identified or identifiable individuals), including requirements relating to having legal bases for processing personal data, transferring such personal data outside the EEA, including to the United States, processing health and other sensitive data, obtaining consent of the individuals to whom the personal data relates, providing information to individuals regarding data processing activities, responding to individuals’ requests to exercise their rights in respect of their personal data, implementing safeguards to protect the security and confidentiality of personal data, having data processing agreements with third parties who process personal data on our behalf, providing notification of data breaches, and taking certain measures when engaging third-party processors, conducting data protection impact assessments, and record-keeping.

The EU GDPR increases substantially the penalties to which we could be subject in the event of any non-compliance and permits data protection authorities to impose large penalties for violations of the EU GDPR, including potential fines of up to €20 million or 4% of annual global revenues, whichever is greater.

The EU GDPR also confers a private right of action on data subjects and consumer associations to lodge complaints with supervisory authorities, seek judicial remedies, and obtain compensation for damages resulting from violations of the EU GDPR.

The EU GDPR may increase our responsibility and liability in relation to personal data that we process where such processing is subject to the EU GDPR, and we may be required to put in place additional mechanisms to ensure compliance with the EU GDPR, including as implemented by individual countries.

Compliance with the EU GDPR is a rigorous and time-intensive process that may increase our cost of doing business or require us to change our business practices, and despite those efforts, there is a risk that we may be subject to fines and penalties, litigation, and reputational harm in connection with our European activities.

The EU GDPR also prohibits the transfer of personal data from the EEA to the United States and other countries that are not recognized as having “adequate” data protection laws by the European Commission unless the parties to the transfer have implemented specific safeguards to protect the transferred personal data.

In the European Union, the collection, use, storage, disclosure, transfer, or other processing of personal data including special categories of personal data such as health data, is subject to the EU General Data Protection Regulation, or EU GDPR.

has implemented the EU GDPR as the U.K.

GDPR which sits alongside the U.K.

Data Protection Act 2018, or the U.K.

GDPR, and together with the EU GDPR, the GDPR.

The GDPR is wide-ranging in scope and imposes numerous requirements on controllers that process personal data (i.e., data relating to identified or identifiable individuals), including requirements around (among others):

accountability and transparency, relating to having legal bases for processing personal data, including specific requirements for obtaining valid consent where consent is the legal basis for processing, responding to individuals’ requests to exercise their rights in respect of their personal data, implementing safeguards to protect the security and confidentiality of personal data to provide notification of personal data breaches to data protection authorities and affected individuals in certain circumstances, having data processing agreements with third parties who process personal data on our behalf, and to undertake due diligence in relation to such third-party processors, considering data protection when any new products or services are developed and designed, as well as obligations for data protection impact assessments, record-keeping and accountability.

The EU GDPR also prohibits the international transfer of personal data from the EEA to the United States and other countries that are not recognized as having “adequate” data protection laws by the European Commission unless the parties to the transfer have implemented specific safeguards to protect the transferred personal data or a derogation under the EU GDPR can be relied upon.

One of the primary safeguards allowing U.S.

companies to import personal data from the EEA had been certification to the EU-U.S.

companies to import personal data from the EEA had historically been certification to the EU-U.S.

Privacy Shield framework administered by the U.S.

Department of Commerce.

However, the European Court of Justice issued a decision in July 2020 which invalidated the EU-U.S.

Privacy Shield framework for international transfers (Schrems II) and imposed further restrictions on using the specific safeguard standard contractual clauses (SCCs) including, a requirement for companies to carry out a transfer privacy impact assessment, which among other things, assesses laws governing access to personal data in the recipient country and considers whether supplementary measures that provide privacy protections additional to those provided under the SCCs will need to be implemented to ensure an essentially equivalent level of data protection to that afforded in the EU.

However, the European Court of Justice, or the CJEU, issued a decision in July 2020 which invalidated the EU-U.S.

Privacy Shield framework for purposes of international transfers (Schrems II) and imposed further restrictions on using the specific safeguard standard contractual clauses (EU SCCs) including, a requirement for companies to carry out a transfer privacy impact assessment, or a TIA.

A TIA, among other things, assesses laws governing access to personal data in the recipient country and considers whether supplementary measures that provide privacy protections additional to those provided under the EU SCCs will need to be implemented to ensure an “essentially equivalent” level of data protection to that afforded in the EEA.

Following that decision, the Swiss Federal Data Protection and Information Commissioner took a similar view and considered that data transfers based on the Swiss-U.S.

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Privacy Shield has not been officially invalidated).

Further to Schrems II, the European Commission published new EU SCCs in June 2021, which place onerous obligations on the contracting parties.

Therefore, until recently, there were few, if any, viable alternatives to the SCCs.

However, on 7 October 2022, President Biden introduced an Executive Order to facilitate a new Trans-Atlantic Data Privacy Framework which will act as a successor to the invalidated EU-U.S.

Privacy Shield.

If approved by the European Commission and implemented, the agreement will facilitate the transatlantic flow of personal data and provide additional safeguards to any existing data transfer mechanisms (including SCCs) for companies transferring personal data from the EU to the U.S.

However, before entities rely on the new EU-U.S.

Privacy Shield, there are still legislative and regulatory steps that must be undertaken both in the U.S.

and in the EU.

Therefore, at present the new EU SCCs are still the primary safeguard available for personal data transfers from the EU to the U.S.

As such, the current legal position may have implications for our cross-border data flows and may result in compliance costs.

In addition, further to the UK’s exit from the EU on January 31, 2020, the EU GDPR ceased to apply in the UK at the end of the transition period on December 31, 2020.

However, as of January 1, 2021, the UK’s European Union (Withdrawal) Act 2018 incorporated the EU GDPR (as it existed on December 31, 2020 but subject to certain UK specific amendments) into UK law (referred to as the 'UK GDPR').

The UK GDPR and the UK Data Protection Act 2018 set out

the UK’s data protection regime, which is independent from but aligned to the EU’s data protection regime.

Non-compliance with the UK GDPR may result in monetary penalties of up to £17.5 million or 4% of worldwide revenue, whichever is higher.

As a result, we are potentially exposed to two parallel data protection regimes, each of which authorizes fines and the potential for divergent enforcement actions.

The European Commission adopted the adequacy decision for the UK in June 2021, allowing a free flow of personal data from the EU to the UK where it benefits from an essentially equivalent level of protection to that guaranteed under EU data protection law.

It should be noted that the UK GDPR also prohibits the transfer of personal data from the UK to other countries that are not recognized as having “adequate” data protection laws, including the U.S., in a similar manner to the EU.

In addition, the UK Government has published its own form of SCCs, known as the International Data Transfer Agreement and International Data Transfer Addendum to the new EU SCCs.

The UK Information Commissioner’s Office has also published its version of the transfer impact assessment and revised guidance on international transfers, although companies may choose to either use the EU style or UK style transfer impact assessment.

In terms of international data transfers between the UK and US, it is understood that the UK and the US are negotiating an adequacy agreement.

On October 7, 2022, U.S.

President Biden introduced an Executive Order to facilitate a new Trans-Atlantic Data Privacy Framework, or the DPF, and on July10, 2023, the European Commission adopted its Final Implementing Decision granting the U.S.

adequacy, or the Adequacy Decision, for EU-U.S.

transfers of personal data for entities self-certified to the DPF.

Entities relying on EU SCCs for transfers to the U.S.

are also able to rely on the analysis in the Adequacy Decision as support for their TIA regarding the equivalence of U.S.

national security safeguards and redress.

GDPR also prohibits the transfer of personal data from the U.K.

to countries that the U.K.

Government does not recognize as having “adequate” data protection laws, including the U.S., in a similar manner to the EU.

In addition, the U.K.

Government has published its own form of EU SCCs, known as the International Data Transfer Agreement and an International Data Transfer Addendum to the new EU SCCs.

Information Commissioner’s Office, or the ICO, has also published its own version of the TIA and revised guidance on international transfers, although companies may choose to either use the EU-style or U.K.-style TIA.

Further, on September 21, 2023, the U.K.

Secretary of State for Science, Innovation and Technology established a U.K.-U.S.

data bridge (i.e., a U.K.

equivalent of the Adequacy Decision) and adopted U.K.

regulations to implement the U.K.-U.S.

Personal data may now be transferred

from the U.K.

under the U.K.-U.S.

data bridge through the U.K.

extension to the DPF to organizations self-certified under the U.K.

extension to DPF.

The GDPR permits data protection authorities to impose large penalties for violations of the GDPR, including potential fines of up to €20 million (£17.5 million under the U.K.

GDPR) or 4% of annual global revenues, whichever is greater.

The GDPR also confers a private right of action on data subjects and consumer associations to lodge complaints with supervisory authorities, seek judicial remedies, and obtain compensation for damages resulting from violations of the EU GDPR.

The GDPR may increase our responsibility and liability in relation to personal data that we process where such processing is subject to the GDPR, and we may be required to put in place additional mechanisms to ensure compliance with the GDPR, including as implemented by individual countries in the EEA or required in connection with our clinical trials.

Compliance with the GDPR is a rigorous and time-intensive process that increases our cost of doing business and increases risk that we may be subject to fines and penalties, litigation, and reputational harm in connection with our European activities.

Current and future healthcare reform legislation

In both the United States and certain foreign jurisdictions, there have been a number of legislative and regulatory changes to the health care system.

In the United States, in March 2010, the Patient Protection and Affordable Care Act, as amended by the Health Care and Education Reconciliation Act, collectively known as the ACA, was enacted, which substantially changed the way healthcare is financed by both governmental and private payors, and significantly affected the pharmaceutical industry.

The ACA, among other things, addressed a new methodology by which rebates owed by manufacturers under the Medicaid Drug Rebate Program are calculated for drugs that are inhaled, infused, instilled, implanted or injected, increased the minimum Medicaid rebates owed by manufacturers under the Medicaid Drug Rebate Program and extended the rebate program to individuals enrolled in Medicaid managed care organizations, established annual fees and taxes on manufacturers of certain branded prescription drugs, and created a new Medicare Part D coverage gap discount program, in which manufacturers must agree to offer 50% (increased to 70% pursuant to the Bipartisan Budget Act of 2018, effective as of 2019) point-of-sale discounts off negotiated prices of applicable brand drugs to eligible beneficiaries during their coverage gap period, as a condition for the manufacturer’s outpatient drugs to be covered under Medicare Part D.

Under the Inflation Reduction Act of 2022, or the IRA, this coverage gap discount program will be eliminated beginning January 1, 2025.

Manufacturers will then be required to pay 10% of the negotiated price of brands, biologics and biosimilar products when Medicare Part D beneficiaries are in the initial coverage phase, and 20% of the negotiated price during the catastrophic phase of Medicare Part D coverage.

There have been numerous historic judicial, administrative, executive, and legislative challenges and amendments (including recent amendments that expand access to care) to certain aspects of the ACA.

For example, in the United States, in March 2010, the Patient Protection and Affordable Care Act, as amended by the Health Care and Education Reconciliation Act, collectively known as the ACA, was enacted, which substantially changed the way healthcare is financed by both governmental and private payors, and significantly affected the pharmaceutical industry.

The ACA, among other things, addressed a new methodology by which rebates owed by manufacturers under the Medicaid Drug Rebate Program are calculated for drugs that are inhaled, infused, instilled, implanted or injected, increased the minimum Medicaid rebates owed by manufacturers under the Medicaid Drug Rebate Program and extended the rebate program to individuals enrolled in Medicaid managed care organizations, established annual fees and taxes on manufacturers of certain branded prescription drugs, and created a new Medicare Part D coverage gap discount program (which has been subsequently eliminated by the Inflation Reduction Act of 2022, or the IRA), in which manufacturers were required to provide certain point-of-sale discounts off negotiated prices of applicable brand drugs to eligible beneficiaries during their coverage gap period, as a condition for the manufacturer’s outpatient drugs to be covered under Medicare Part D.

There have been numerous historic judicial, administrative, executive, and legislative challenges and amendments (including recent amendments that aimed at expanding access to care and reforming prescription drug pricing) to certain aspects of the ACA and other healthcare laws.

In June 2021, the Supreme Court dismissed a lawsuit challenging the constitutionality of certain aspects of the ACA, without ruling on the meris of the constitutionality arguments.

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For example, in August 2022, President Biden signed into law the IRA, which implements substantial changes to the Medicare program, including drug pricing reforms and changes to the Medicare Part D benefit design.

Among other reforms, the Inflation Reduction Act of 2022 imposes inflation rebates on drug manufacturers for products reimbursed under Medicare Parts B and D if the prices of those products increase faster than inflation;

Among other reforms, the IRA imposes inflation rebates on drug manufacturers for products reimbursed under Medicare Parts B and D if the prices of those products increase faster than inflation;

implements changes to the Medicare Part D benefit that, beginning in 2025, will cap benefit annual out-of-pocket spending at $2,000, while imposing new discount obligations for pharmaceutical manufacturers (requiring manufacturers to pay 10% of the negotiated price of brands, biologics and biosimilar products when Medicare Part D beneficiaries are in the initial coverage phase, and 20% of the negotiated price during the catastrophic phase of Medicare Part D coverage);

and, beginning in 2026, establishes a “maximum fair price” for a fixed number of high spend pharmaceutical and biological products covered under Medicare Parts B and D following a price negotiation process with the Centers for Medicare and Medicaid Services.

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However, those drugs with multiple orphan designations are not explicitly excluded from drug price negotiation.

It remains to be seen how the maximum fair prices or other drug pricing provisions imposed by the IRA will affect orphan drug development or the broader pharmaceutical industry.

Since its enactment, the CMS has taken steps to implement various drug pricing provisions of the IRA.

This includes, without limitation, issuing new guidance on June 30, 2023 detailing the requirements and parameters of the first round of price negotiations, to take place during 2023 and 2024, for products subject to the “maximum fair price” provision that would become effective in 2026 and, on August 29, 2023, releasing the initial list of 10 drugs subject to price negotiations.

It remains to be seen how the maximum fair prices or other drug pricing provisions imposed by the IRA will affect orphan drug and small molecule development or the broader pharmaceutical industry.

Several pharmaceutical manufacturers and other industry stakeholders have challenged the law, including through lawsuits brought against the HHS, the Secretary of HHS, CMS, and the CMS Administrator challenging the constitutionality and

administrative implementation of the IRA’s drug price negotiation provisions.

We cannot predict whether the IRA, or any of its component parts, will be overturned, repealed, replaced, or amended nor can we predict the likelihood, nature, or extent of other health reform initiatives that may arise from future legislation, administrative, or other action.

However, we expect these initiatives to increase pressure on drug pricing.

The increasing efforts by governmental and third-party payors in the United States and abroad to cap or reduce healthcare costs may cause such organizations to limit both coverage and the level of reimbursement for newly approved products and, as a result, they may not cover or provide adequate payment for our product candidates.

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Congressional inquiries and proposed and enacted federal and state legislation designed to, among other things, bring more transparency to drug pricing, reduce the cost of prescription drugs under Medicare, review the relationship between pricing and manufacturer patient programs, and reform government program reimbursement methodologies for drugs.

At the state level, legislatures are increasingly passing legislation and implementing regulations designed to control biopharmaceutical and biologic product pricing, including price or patient reimbursement constraints, discounts, restrictions on certain product access and marketing cost disclosure and transparency measures, and, in some cases, designed to encourage importation from other countries and bulk purchasing.

These laws, regulations, and actions, and any state or federal healthcare reform measures that may be adopted in the future, could reduce coverage or reimbursement Medicare and other government programs, may result in a similar reduction in coverage or payment from private payers, and may otherwise affect the prices we may obtain for any of our product candidates for which we may obtain regulatory approval or the frequency with which any such product candidate is prescribed or used.

Additionally, we expect to experience pricing pressures in connection with the sale of any future approved product candidates due to the trend toward managed healthcare, the increasing influence of health maintenance organizations, cost containment initiatives and additional legislative changes.

At the state level, legislatures are increasingly passing legislation and implementing regulations designed to control biopharmaceutical and biologic product pricing, including price or patient reimbursement constraints, discounts, restrictions on certain product access, marketing cost disclosure and other transparency measures, and, in some cases, legislation, regulation or other guidance designed to encourage or facilitate importation from other countries and bulk purchasing.

Some states have also established prescription drug affordability boards tasked with identifying certain high-cost prescription products that may pose affordability challenges for consumers and payers, conducting cost reviews on such products, and, in some circumstances, imposing upper payment limits on such products.

These laws, regulations, and actions, and any state or federal healthcare reform measures that may be adopted in the future, could reduce coverage or reimbursement from Medicare and other government programs, may result in a similar reduction in coverage or payment from private payers, and may otherwise affect the prices we may obtain for any of our product candidates for which we may obtain regulatory approval or the frequency with which any such product candidate is prescribed or used.

Legislative and regulatory proposals, and enactment of laws, at the foreign, federal, and state levels, directed at containing or lowering the cost of healthcare, will likely continue into the future.

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In addition to data privacy requirements, many jurisdictions have mandatory clinical trial information obligations on sponsors.

In the EU this is under the Transparency Regulation No 1049/ 2001, EMA Policy 0043, EMA Policy 0070, as well as the Clinical Trials Regulation No 536/2014, all of which impose on sponsors the obligation to make publicly available certain information stemming from clinical studies, either proactively or in response to third party requests.

available certain information stemming from clinical studies, either proactively or in response to third party requests.

In the EU, the transparency framework provides for a wide right for (EU-based at the moment) interested parties to submit an access to documents request to the EMA for information included in the marketing authorization application dossier for approved medicinal products.

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European drug review and approval

To obtain a marketing authorization in the EEA (comprising the EU Member States, plus Norway, Iceland, and Liechtenstein), a company may submit marketing authorization applications either under a centralized procedure administered by the European Medicines Agency, or EMA, or one of the procedures administered by competent authorities in the EEA Member States (decentralized procedure, national procedure, or mutual recognition procedure).

To obtain a marketing authorization in the EEA (comprising the EU Member States, plus Norway, Iceland, and Liechtenstein), a company may submit marketing authorization applications either under a centralized procedure administered by the EMA or one of the procedures administered by competent authorities in the EEA Member States (decentralized procedure, national procedure, or mutual recognition procedure).

The centralized procedure is compulsory for certain medicines, including those produced by biotechnology, products designated as orphan medicinal products, advanced therapy medicinal products (gene therapy, somatic cell therapy and tissue-engineered products) and those with a new active substance indicated for the treatment of HIV, AIDS, cancer, neurodegenerative disorders, autoimmune and other immune dysfunctions, viral diseases, or diabetes.

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Where the CHMP gives a positive opinion, it provides the opinion together with supporting documentation to the European Commission, who make the final decision to grant a marketing authorization, which is issued within 67 days of receipt of the EMA’s positive opinion.

On April 26, 2023, the European Commission adopted a proposal for a new Regulation set to replace Regulation (EC) No 726/2004 and a new Directive replacing Directive 2001/83 on the Community Code relating to medicinal products for human use.

If made into law, this proposal will revise the existing general pharmaceutical legislation.

This reform would provide for a simplified regulatory framework with faster authorizations of new medicines.

For instance, for its assessment, EMA will have 180 days instead of 210 days.

For the authorization, the Commission will have 46 days instead of 67 days.

Furthermore, the scope of the centralized procedure, would be extended to include priority antimicrobial medicinal products and products seeking a pediatric use marketing authorization.

Accelerated assessment might be granted by the CHMP in exceptional cases, when a medicinal product is expected to be of major public health interest, particularly from the point of view of therapeutic innovation.

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According to Swissmedic's practice, this includes the authorization procedures of the following countries:

Australia, the member states of the EU, the EFTA states in the EEA (Liechtenstein, Norway and Iceland), Japan, Canada, New Zealand, Singapore and the United States.

Now that the UK (which comprises Great Britain and Northern Ireland) has left the EU, Great Britain will no longer be covered by centralized marketing authorizations (under the Northern Irish Protocol, centralized marketing authorizations will continue to be recognized in Northern Ireland).

Australia, the member states of the EU, the EFTA states in the EEA (Liechtenstein, Norway and Iceland), Japan, Canada, New Zealand, Singapore, the United Kingdom and the United States.

Now that the U.K.

(which comprises Great Britain and Northern Ireland) has left the EU, Great Britain will no longer be covered by centralized marketing authorizations (under the Northern Irish Protocol, centralized marketing authorizations will continue to be recognized in Northern Ireland).

All medicinal products with an existing centralized marketing authorization were automatically converted to Great Britain marketing authorizations on January 1, 2021.

For a period of two years from January 1, 2021, the Medicines and Healthcare Products Regulatory Agency, or MHRA, the UK medicines regulator, may rely on a decision taken by the European Commission on the approval of a new marketing authorization in the centralized procedure.

A separate application will, however, still be required.

The MHRA has ceased to participate in the assessment of any centralized procedures since January 1, 2021.

Since then, the MHRA has launched the Innovative Licensing and Access Pathway, or ILAP, a new accelerated assessment procedure for marketing authorization applications facilitating the interaction with pricing authorities and HTA bodies and aiming to enable companies to enter the UK market faster.

market faster.

On January 1, 2024, the MHRA launched a new International Recognition Procedure for Great Britain (England, Scotland and Wales) marketing authorization applications whereby the MHRA will, when considering such applications, recognize the approval of medicines by Australia, Canada, Switzerland, Singapore, Japan, United States and the EU following its own abbreviated assessment.

European orphan drug designation and exclusivity

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The general pharmaceutical legislative framework, as well as the framework applicable to orphan and pediatric medicinal products in the EU, is under review.

The European Commission expects to publish its position on this in March 2023.

However, draft proposals by the European Commission for a new Regulation set to replace Regulation (EC) No 726/2004 and a new Directive replacing Directive 2001/83 on the Community Code relating to medicinal products for human use were recently leaked to the press on January 31, 2023.

Although the final proposals are not yet known, it is expected that there will be a reduction in applicable regulatory exclusivities which will significantly affect all medicinal products that will be authorized after the legislative changes have taken effect.

If made into law, this proposal will revise the existing general pharmaceutical legislation and may reduce applicable regulatory exclusivities which will significantly affect all medicinal products that will be authorized after the legislative changes have taken effect.

Brexit and the Regulatory Framework in the United Kingdom

The UK officially left the EU on January 31, 2020.

A transition period began on February 1, 2020, during which EU pharmaceutical law remained applicable to the UK.

officially left the EU on January 31, 2020.

A transition period began on February 1, 2020, during which EU pharmaceutical law remained applicable to the U.K.

This transition period ended on December 31, 2020.

Since the regulatory framework in the UK covering the quality, safety and efficacy of pharmaceutical products, clinical trials, marketing authorization, commercial sales and distribution of pharmaceutical products is derived from EU Directives and Regulations, it continues to apply presently as “retained EU law”.

However, as UK legislation now has the potential to diverge from EU legislation, the future regulatory regime which applies to products and the approval of product candidates in the UK may change.

It remains to be seen how Brexit will impact regulatory requirements for product candidates and products in the UK in the long-term.

The MHRA published detailed guidance for industry and organizations to follow which will be updated as the UK’s regulatory position on medicinal products evolves over time.

Since the regulatory framework in the U.K.

covering the quality, safety and efficacy of pharmaceutical products, clinical trials, marketing authorization, commercial sales and distribution of pharmaceutical products is derived from EU Directives and Regulations, it continues to apply presently as “retained EU law”.

However, as U.K.

legislation now has the potential to

diverge from EU legislation, the future regulatory regime which applies to products and the approval of product candidates in the U.K.

It remains to be seen how Brexit will impact regulatory requirements for product candidates and products in the U.K.

in the long-term.

The MHRA published detailed guidance for industry and organizations to follow which will be updated as the U.K.’s regulatory position on medicinal products evolves over time.

‘Retained EU law,’ which has prevented substantial divergence to the regulation of medicines.

However, some changes to the UK legislation have been necessary, including the implementation of the Northern Ireland Protocol (NIP), pursuant to which the EU pharmaceutical legal framework continues to apply in Northern Ireland (subject to periodic consent of the Northern Ireland Legislative Assembly), and only products compliant with EU law can be placed in the Northern Ireland market.

This dynamic adds an extra layer of regulatory complexity for companies withing to commercialize medicinal products in Great Britain (namely, England, Wales and Scotland, as EU law continues to apply in Northern Ireland), as such companies now need to comply with separate UK regulatory legal framework.

The UK government is currently trying to renegotiate certain aspects of the Northern Ireland Protocol so this is an unpredictable area for companies in the near future.

The Trade and Cooperation Agreement signed between the UK and the EU allows for future deviation from the current regulatory framework and it is not known if and/or when any deviations may occur, which may have an impact on development, manufacture, marketing authorization, commercial sales and distribution of pharmaceutical products.

However, some changes to the U.K.

legislation have been necessary, including the implementation of the Northern Ireland Protocol (NIP), pursuant to which the EU pharmaceutical legal framework continues to apply in Northern Ireland (subject to periodic consent of the Northern Ireland Legislative Assembly), and only products compliant with EU law can be placed in the Northern Ireland market.

regulatory legal framework.

Government and the European Union recently adopted a new agreement, the “Windsor Framework,” which will replace the Northern Ireland Protocol.

According to the Windsor Framework, medicinal products intended for the U.K.

market, including Northern Ireland, will be authorized by the MHRA and will bear a “U.K.

These new measures will be implemented from January 1, 2025.

The Trade and Cooperation Agreement signed between the U.K.

and the EU allows for future deviation from the current regulatory framework and it is not known if and/or when any deviations may occur, which may have an impact on development, manufacture, marketing authorization, commercial sales and distribution of pharmaceutical products.

Coverage and reimbursement

Successful commercialization of new drug products depends in part on the extent to which coverage and reimbursement, as applicable, for those drug products will be available from government health administration authorities, private health insurers, and other organizations.

Government authorities and third-party payors, such as private health insurers and health maintenance organizations, decide which drug products they will cover and pay for and establish

reimbursement levels.

Government authorities and third-party payors, such as private health insurers and health maintenance organizations, decide which drug products they will cover and pay for and establish reimbursement levels.

The availability and extent of coverage and reimbursement by governmental and private payors is essential for most patients to be able to afford a drug product.

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Additionally, beginning in 2025, manufacturers must pay additional discounts for products covered under Medicare Part D.

Moreover, while the MMA Part D plan policies applies only to drug benefits for Medicare beneficiaries, private payors often follow Medicare coverage policies and payment limitations in setting their own payment rates coverage guidelines.

Any reduction in payment restrictions in Part D coverage that results from the MMA may result in a similar reduction in payment restrictions from non-governmental payors.

Any reduction in payment restrictions in Part D

coverage that results from the MMA may result in a similar reduction in payment restrictions from non-governmental payors.

For a drug product to receive federal reimbursement under the Medicaid or Medicare Part B programs or to be sold directly to U.S.

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As 340B drug pricing is determined based on AMP and Medicaid rebate data, the revisions to the Medicaid rebate formula and AMP definition described above could cause the required 340B discount to increase.

The 340B drug pricing program may be subject to future changes in light of ongoing litigation and attempts to reform the program.

The 340B drug pricing program may be subject to future changes in light of ongoing litigation and attempts to reform the program, including legislative proposals to reform the 340B program.

It is unclear how any such changes could affect our obligation to offer 340B pricing to certain entities.

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We focus on recruiting, retaining, and developing employees from a diverse range of backgrounds to conduct our research, development, and clinical activities.

As part of our measures to attract and retain a highly skilled workforce, we offer a number of benefits to our full-time employees to help support their health and financial well-being, including medical, dental and vision insurance, life insurance, 401k retirement program with a company match, flexible spending accounts, and paid holiday and vacation time.

As part of our measures to attract and retain a highly skilled workforce, we offer a competitive suite of benefits to our full-time employees to help support their health and financial well-being, including medical, dental and vision insurance, life insurance, 401k retirement program with a company match, flexible spending accounts, paid holiday and vacation time, and flexible work arrangements.

We provide our employees with competitive salaries and bonuses, opportunities for equity ownership, development opportunities that enable continued learning and growth and a robust recognition program that recognizes and celebrates their accomplishments.

In addition, we regularly conduct an employee survey to gauge employee engagement and identify areas of focus.

The health and safety of our employees is a priority.

In 2022, we maintained the employee benefits enhancements that were implemented in response to the COVID-19 pandemic.

For example, we increased company-wide flexible work arrangements, provided weekly onsite COVID-19 testing for all employees routinely working onsite through the Omicron surge and provided at-home COVID-19 test kits to any employee who may have been exposed to COVID-19 at work.

Our management has continued to assess and respond to the evolving needs of our workforce throughout the pandemic.

Corporate and Available Information

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Our website address is https://pliantrx.com.

We file or furnish electronically with the U.S.

Securities and Exchange Commission (the “SEC”) annual reports on Form 10-K, quarterly reports on Form 10-Q, current reports on Form 8-K and amendments to those reports filed or furnished pursuant to Section 13(a) or 15(d) of the Exchange Act.

We file or furnish electronically with the SEC annual reports on Form 10-K, quarterly reports on Form 10-Q, current reports on Form 8-K and amendments to those reports filed or furnished pursuant to Section 13(a) or 15(d) of the Exchange Act.

We make copies of these reports available free of charge through our investor relations website as soon as reasonably practicable after we file or furnish them with the SEC.

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

What changed 10-K

Item 1. Business