Pliant Therapeutics Stock

Pliant Therapeutics, Inc. (Pliant) operates as a late stage biopharmaceutical company focused on discovering and developing novel therapies for the treatment of fibrosis and related diseases.

The company’s initial focus is on treating fibrosis by inhibiting integrin-mediated activation of TGF-ß. The company has applied its deep understanding of fibrosis biology, along with the company’s medicinal chemistry and translational medicine expertise to develop a set of proprietary tools designed to discover and de-risk product candidates quickly and efficiently. The company’s wholly-owned lead product candidate, bexotegrast (PLN-74809), is an oral, small molecule, dual selective inhibitor of avß6 and avß1 integrins that the company is developing for the treatment of idiopathic pulmonary fibrosis, or IPF, and primary sclerosing cholangitis, or PSC. The company is conducting a Phase 2b trial in IPF and a Phase 2a trial in PSC. The company announced positive data from its Phase 2a INTEGRIS-IPF trial in May 2023. The company is conducting BEACON-IPF, a 52-week, randomized, double-blind, placebo-controlled Phase 2b trial, in patients with IPF. The company announced positive interim data from its Phase 2a INTEGRIS-PSC trial in September 2023 and February 2024. The company expects to release final data from the INTEGRIS-PSC trial in mid-2024.

In January 2023, the company received FDA clearance of investigational new drug application, or IND, for the company’s third clinical program to date, PLN-101095, a dual inhibitor of integrins avß8 and avß1 for the treatment of solid tumors that are resistant to immune checkpoint inhibitors. The company is 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. The company expects to release preliminary data from the trial in late 2024.

The company’s fourth program to date, PLN-101325, in development for the treatment of muscular dystrophies, including Duchenne muscular dystrophy. PLN-101325 is a monoclonal antibody designed to act as an allosteric agonist of integrin a7ß1. The company expects to file with regulators for first-in-human studies in the first quarter of 2024.

The company has developed PLN-1474, an oral, small molecule selective inhibitor of avß1 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. PLN-1474 was licensed to Novartis in 2019. As part of a broad strategic realignment, Novartis has discontinued clinical development in NASH and, as a result, discontinued development of PLN-1474. In February 2023, Novartis returned global rights to PLN-1474 to Pliant.

Lead Candidate – Bexotegrast

The company’s lead wholly-owned product candidate, bexotegrast, is an oral, small molecule, dual-selective inhibitor of avß6 and avß1 that the company is advancing in IPF and PSC. While expressed at very low levels in normal tissues, avß6 and avß1 are upregulated in the pulmonary tissues of IPF patients, and in the liver tissues of PSC patients. They both serve as activators of TGF-ß, leading to increased collagen production and fibrosis in these tissues. By blocking TGF-ß activation by both avß6 and avß1, 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.

Bexotegrast for the Treatment of IPF

Bexotegrast is an oral small molecule that selectively inhibits both avß6 and avß1 integrins that the company is developing as a potential therapy for IPF and PSC. It has been shown that expression of both avß6 on epithelial cells and avß1 on fibroblasts can lead to excessive activation of TGF-ß in fibrosis. Epithelial tissue includes any tissue that lines the surfaces of the body, such as alveoli, bile ducts, urinary tract, skin, and gastrointestinal tract. Each of these tissues contains multiple cell types, including epithelial cells and fibroblasts. An important secondary effect of the TGF-ß cascade is that it promotes upregulation of avß6 on epithelial cells and avß1 on fibroblasts. The increased expression of these integrins on the cell surface contributes in turn to further TGF-ß activation in a TGF-ß-driven positive feed-forward loop.

In May 2023, the company 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, 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.

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.

In August 2023, the company 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 the Treatment of Primary Sclerosing Cholangitis

The company is 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. The company also plans 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, the company 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.

The company is 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 the Treatment of Solid Tumors That are Resistant to Immune Checkpoint Inhibitors

The company’s third clinical program to date, PLN-101095, is an oral, dual inhibitor of avß8 and avß1 integrins for the treatment of solid tumors with a suboptimal response to immune checkpoint inhibitors, or ICIs. As TGF-ß biology has been elucidated, it has become increasingly understood in the scientific literature that TGF-ß 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. The company is targeting the TGF-ß activating integrins avß8 and avß1, which are upregulated in certain tumors, with the goal of sensitizing tumors to checkpoint inhibitors. The company is 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. The company expects to release preliminary data from the trial in late 2024.

PLN-101325 for the Treatment of Muscular Dystrophies

The company is developing PLN-101325, a monoclonal antibody targeting a7ß1 for the treatment of muscular dystrophies, including Duchenne Muscular Dystrophy, or DMD. The a7ß1 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 a7ß1 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. The company expects to file with regulators for first-in-human studies in the first quarter of 2024.

PLN-1474 for the Treatment of Liver Fibrosis Associated with NASH

The company has developed a clinical stage product candidate, PLN-1474, which is an oral, small molecule, selective inhibitor of TGF-ß activation by the integrin avß1 in development for the treatment of advanced liver fibrosis associated with NASH. avß1 serves as an activator of TGF-ß and its expression has been shown to be upregulated in hepatic stellate cells in late-stage NASH-associated liver fibrosis.

PLN-1474 has completed a first-in-human, randomized, double-blind, placebo-controlled Phase 1 dose escalation trial that enrolled 84 healthy volunteers across single ascending dose and multiple ascending dose groups. Results showed that PLN-1474 was rapidly absorbed and well tolerated with no dose- or treatment-limiting toxicities observed with adverse events that were mostly mild with no severe or serious adverse events observed.

In October 2019, the company entered into a collaboration and license agreement with Novartis in which Novartis licensed global rights to PLN-1474. As part of a broad strategic realignment, Novartis has discontinued clinical development in NASH and, as a result, discontinued development of PLN-1474. In February 2023, Novartis returned global rights to PLN-1474 to Pliant.

Strategy

The company’s key strategies are to rapidly advance bexotegrast through clinical development and commercialization in IPF and PSC; selectively evaluate additional partnerships in indications and geographies where partners can add significant commercial and/or development capabilities; explore opportunities for the company’s pipeline assets in additional fibrotic indications; and leverage the company’s industry leading tools and capabilities to advance the company’s intention of becoming a leading fibrosis company.

Intellectual Property

As of February 13, 2024, the company owned or co-owned over 300 pending patent applications worldwide in over 30 patent families, including the United States and corresponding foreign patent applications. As of February 13, 2024, twelve U.S. patents and seventeen foreign patents had been issued, granted or allowed. The company’s patents and any patents that may issue from the company’s pending patent applications are generally expected to expire between the years 2037 to 2044, subject to possible patent term adjustment and/or extension.

Company Owned IP

The company owns multiple families of patent applications that are directed to small molecule compositions capable of modulating integrins and methods for treating or preventing diseases associated with integrins. Certain applications in these families relate to the company’s bexotegrast and PLN-1474 small molecule product candidates, backup compounds and structural analogs, various unit dosages, dosing regimens, and routes of administration. The company is 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.

Trademark Protection

The company has two registered U.S. trademarks for use in connection with the company’s products.

License Agreements

Novartis Collaboration and License Agreement

In October 2019, the company entered into a collaboration and license agreement, or the Novartis Agreement, with Novartis Institutes for Biomedical Research, Inc., or Novartis, for the research, development, and commercialization of PLN-1474. Pursuant to the terms of the Novartis Agreement, the PLN-1474 IND was transferred to Novartis in the first quarter of 2021 following completion of the company’s first-in-human Phase 1 clinical trial. Upon transfer of the IND, Novartis assumed responsibility for all future development, manufacturing, and commercialization and the company earned research and development services revenues in performing certain activities outlined in the Novartis Agreement. All such services were substantially complete as of December 31, 2022.

In addition, the Novartis Agreement provided for an early research program for up to three additional integrin targets, or the Research Targets. The research term, as amended in 2022, concludes in the first quarter of 2023. During the research term, the company collaborates with Novartis to biologically validate certain potential Research Targets and identify and synthesize potential research compounds for each Research Target in accordance with the applicable research plan. In the second quarter of 2022, the company validated one of the Research Targets and began synthesizing potential research compounds.

As part of a broad strategic realignment, Novartis has discontinued clinical development in NASH, and as a result, discontinued development of PLN-1474. In February 2023, Novartis issued a termination notice for the collaboration and license agreement, and returned global rights to Pliant for PLN-1474, as well as the early research targets and associated compounds.

Government Regulation

The United States Food and Drug Administration, the Centers for Medicare and Medicaid Services, the Department of Health and Human Services Office of the Inspector General, 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 the company is 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, coverage, reimbursement, pricing, and export and import of the company’s product candidates.

While there is an exception for protected health information that is subject to the federal Health Insurance Portability and Accountability Act of 1996 (HIPAA) and clinical trial regulations, as written, the California Consumer Privacy Act of 2018 impacts certain of the company’s business activities.

History

Pliant Therapeutics, Inc. was founded in 2015. The company was incorporated under the laws of the state of Delaware in 2015.