What changed in this filing

/stocks — the workspaceLOADING

Item 1. Business

2026-03-05 compared with 2025-03-06 · 335 added, 426 removed, 661 unchanged (54% of the section changed)

1 unchanged sentence

We target biological pathways associated with specific clinical impairments that we believe, once modulated, will demonstrably alter the course of disease.

We have focused our efforts on developing selective compounds targeting challenging molecular pathways and have built a portfolio of small molecule drug candidates.

We focus on developing selective compounds targeting challenging molecular pathways and have built a portfolio of small molecule drug candidates.

We believe our two clinical-stage, internally-discovered drug candidates, PIPE-791 and PIPE-307, will have broad applicability across multiple NI&I indications.

We are developing PIPE-307 in collaboration with J&J.

Our wholly-owned lead asset, PIPE-791, is a novel, brain penetrant, small molecule inhibitor of the lysophosphatidic acid 1 receptor (“LPA1R”) in development for idiopathic pulmonary fibrosis (“IPF”), progressive multiple sclerosis (“PrMS”), and chronic pain.

LPA1R antagonism is a clinically validated mechanism in IPF, and we believe that our preclinical studies and Phase 1 healthy volunteer data support the development of PIPE-791 for IPF, as well as PrMS and chronic pain.

Specifically, based on its high bioavailability, low plasma protein binding, and long receptor residence time in our preclinical studies compared to the preclinical data of other LPA1R antagonists, we believe PIPE-791 has the potential to be a differentiated LPA1R therapy.

We have completed a Phase 1 clinical trial of PIPE-791 in healthy volunteers in support of clinical development in IPF, PrMS and chronic pain.

In December 2024, we commenced a Phase 1b open-label trial to measure the relationship of pharmacokinetics (“PK”) to lung and brain receptor occupancy by positron emission tomography (“PET”) imaging.

We expect the top-line data from this trial will be available in the second quarter of 2025.

This Phase 1b PET trial will inform dose selection for our planned Phase 2 trials of PIPE-791 in IPF and PrMS.

In November 2024, the FDA authorized our Investigational New Drug application (“IND”) for the treatment of chronic pain associated with two separate indications, osteoarthritis (“OA”) and low back pain (“LBP”).

On March 4, 2025, we announced the initiation of patient dosing in an exploratory PIPE-791 Phase 1b, randomized, double-blind, placebo-controlled, crossover, chronic pain trial.

We expect to enroll approximately 40 patients at up to five sites in the U.S., and a treatment duration of 28 days.

We anticipate top-line data from this trial in early 2026.

Our second drug candidate, PIPE-307, is a novel, small molecule selective inhibitor of the muscarinic type 1 receptor (“M1R”), in development for depression and relapse-remitting multiple sclerosis (“RRMS”).

LPA1R antagonism is a clinically validated mechanism in IPF, and we believe that our preclinical studies, Phase 1 healthy volunteer data, and Phase 1 positron emission tomography (“PET”) data support the development of PIPE-791 for IPF and chronic pain.

Specifically, based on its high bioavailability, high selectivity, low plasma protein binding, and long receptor residence time, we believe PIPE-791 has the potential to be a differentiated LPA1R therapy.

In September 2025, we reported positive top-line data from our completed Phase 1b PET trial which measured the relationship of pharmacokinetics (“PK”) to receptor occupancy (“RO”) by PET imaging.

The data from the Phase 1b PET trial further affirmed the planned dose selection for our Phase 2 trial of PIPE-791 in IPF, which was initiated in December 2025.

In the fourth quarter of 2025, we completed enrollment for a phase 1b, randomized, double-blind, placebo-controlled, crossover study which was designed to explore the safety and efficacy of oral PIPE-791 in subjects with chronic osteoarthritic pain (“COAP”) or chronic low back pain (“CLBP”).

We anticipate top-line data from this trial in the second quarter of 2026.

Our second novel drug candidate, PIPE-307, is a selective, small-molecule inhibitor of the muscarinic type 1 receptor (“M1R”), in development for depression and relapse-remitting multiple sclerosis (“RRMS”).

We have completed two Phase 1 trials of PIPE-307 in healthy volunteers.

In 2023, we initiated a Phase 2 VISTA trial of PIPE-307 for the potential treatment of RRMS.

In January 2025, we announced that we have fully enrolled our Phase 2 VISTA trial.

We expect the top-line data from this trial will be available in the second half of 2025.

In December 2024, J&J began recruiting participants for a Phase 2 trial of PIPE-307 (also referred to as JNJ-5120) for the potential treatment of major depressive disorder (“MDD”).

In December 2024, J&J began recruiting an estimated 124 adult participants for the Phase 2 Moonlight-1 trial of PIPE-307, renamed by J&J to JNJ-89495120.

This trial is a randomized, double-blind, multicenter, placebo-controlled, proof-of-concept study to evaluate the efficacy, safety, and tolerability of PIPE-307/JNJ-89495120 as a monotherapy in adult participants with major depressive disorder (“MDD”).

In November 2025, we reported top-line data from our Phase 2 VISTA trial of PIPE-307 for the treatment of patients with RRMS.

The trial demonstrated acceptable safety and tolerability at both doses that were investigated in the trial.

The trial did not meet its prespecified primary and secondary efficacy endpoints.

J&J has sole discretion whether or not to further develop PIPE-307 for RRMS, MDD, or any other indication.

We believe PIPE-307 is the most advanced selective M1R antagonist in clinical development.

In addition, we are leveraging our drug discovery capabilities to expand our clinical portfolio.

In January 2024, we nominated and commenced preclinical studies for CTX-343, a peripherally-restricted (unable to access the central nervous system (“CNS”)) LPA1R antagonist.

In parallel, we are actively conducting preclinical and discovery-phase experiments targeting other NI&I indications where our internally-discovered molecules may have therapeutic potential.

Our Clinical Pipeline

1 unchanged sentence

We retain worldwide rights to our LPA1R programs and discovery portfolio, and we have partnered with J&J for the development and potential commercialization efforts of PIPE-307.

(1) We made a strategic decision to defer further clinical development of our PIPE-791 progressive multiple sclerosis (“PrMS”) program and to defer the initiation of clinical development for our CTX-343 program until funding is obtained to specifically move these programs forward.

(2) J&J has sole discretion whether or not to further develop PIPE-307 for RRMS and MDD.

We are also actively conducting preclinical and discovery-phase experiments targeting other NI&I indications where our internally-discovered molecules may have therapeutic potential.

Our Competitive Strengths

We have a strong, complementary relationship between our medicinal chemistry and biology teams, which allows us to develop drug candidates for historically difficult targets.

We have a strong, complementary relationship between our medicinal chemistry, biology, drug metabolism and pharmacokinetics, and clinical teams, which fosters the development of differentiated drug candidates to treat diseases of high unmet need.

We believe that our competitive strengths include:

Our broad expertise with NI&I indications allows us to maximize the value of our drug candidates by developing them across multiple therapeutic areas.

Our lead drug candidate, PIPE-791, targets the LPA1R, a clinically validated target for IPF, and, we believe, pending further clinical development and FDA approval, has the potential to treat IPF with once-daily dosing.

We are advancing a new treatment paradigm in multiple sclerosis (“MS”), by leveraging novel pathways that have the potential to support remyelination and reduce neuroinflammation.

We are leveraging our drug discovery capabilities to develop additional drug candidates that are synergistic with our existing portfolio, including our peripherally-restricted LPA1R antagonist, CTX-343.

• Our broad expertise with NI&I indications allows us to maximize the value of our novel drug candidates by developing them across multiple therapeutic areas.

• Our lead drug candidate, PIPE-791, targets the LPA1R, a clinically validated target for IPF, and, we believe, pending further clinical development and FDA approval, has the potential to treat IPF with once-daily oral dosing and improved efficacy, tolerability and patient compliance over the currently approved IPF therapies.

• We harness our drug discovery capabilities to build a franchise with a deliberate focus on developing therapeutics that are synergistic with our existing portfolio.

• We have assembled a distinguished team with decades of expertise in drug discovery and development.

3 unchanged sentences

We have built our current pipeline with the goal of minimizing clinical risk.

We leverage external validation for our wholly-owned programs such as PIPE-791 for IPF, PrMS and chronic pain and our partnered program PIPE-307 for both depression and RRMS.

Based on scientific rationale, we are also progressing programs in additional disease areas, where we believe there is potential to create significant clinical benefit and address unmet need.

Pursue clinical development of PIPE-791, an LPA1R antagonist, for the treatment of IPF, a sizeable patient population market with significant unmet need.

There are approximately 130,000 patients in the United States with IPF, of which the average life span after diagnosis is three to five years.

Currently, there are only two FDA-approved treatments in IPF, nintedanib and pirfenidone, which are limited by issues associated with safety, tolerability and compliance.

LPA1R antagonism is a clinically validated mechanism, and we believe that our preclinical studies and Phase 1 healthy volunteer data support the continued development of PIPE-791 for IPF.

Pursue clinical development of PIPE-791 in PrMS to address the significant unmet need for a therapy that has the potential to reduce neuroinflammation and support remyelination.

We believe PIPE-791 has strong biological rationale to be a potentially novel treatment for PrMS.

Seek to maximize the value of PIPE-791 by investigating its applicability in a broad range of NI&I disorders beyond IPF, PrMS, and chronic pain.

We believe PIPE-791 has the potential for broad indication expansion due to the central role of LPA1 in multiple NI&I diseases and we are actively conducting preclinical experiments across those areas.

Our future development strategy will be guided by data from our ongoing preclinical studies, observed external validation, and our focus on therapeutic potential in areas of high unmet need.

We leverage external validation for our wholly-owned programs such as PIPE-791 for IPF and chronic pain and our partnered

program PIPE-307 for both MDD and RRMS.

Based on scientific rationale, we are also advancing programs in other disease areas where we believe there is potential to create significant clinical benefit.

Pursue clinical development of PIPE-791, an LPA1R antagonist, for the treatment of IPF, a sizeable patient population with significant unmet need.

The overall incidence of IPF is increasing worldwide.

In the United States alone, there are approximately 130,000 patients with IPF, with a reported median survival after diagnosis ranging between two to five years.

Currently, there are three FDA-approved treatments in IPF, which have historically been limited by issues related to tolerability and compliance.

LPA1R antagonism is a clinically validated mechanism, and we believe that our preclinical studies and the data from our completed Phase 1 trials support the continued development of PIPE-791 for IPF.

Seek to maximize the value of PIPE-791 by investigating its applicability in a broad range of NI&I disorders beyond IPF and chronic pain.

We believe PIPE-791 has the potential for broad indication expansion due to the central role of LPA1 in multiple NI&I diseases.

Our future development strategy will be guided by data from our completed and ongoing preclinical studies, observed external validation, and our focus on therapeutic potential in areas of high unmet need.

Support the advancement of PIPE-307 through a broad clinical development strategy in partnership with J&J.

J&J is an experienced innovator with a strong commitment to neuroscience, reporting $7.1 billion of neuroscience sales in 2024.

J&J is an experienced innovator with a strong commitment to neuroscience, reporting $7.8 billion of neuroscience-focused drug sales in 2025.

Our collaboration provides a foundation for the development of PIPE-307 with access to J&J's robust R&D and commercialization capabilities, which we believe will allow us to achieve the full potential of PIPE-307.

Leverage our drug discovery capabilities to build out a franchise with deliberate focus on developing therapeutics that are synergistic with our existing portfolio, including our peripherally-restricted LPA1R antagonist, CTX-343.

We believe that the development of a peripherally-restricted LPA1R antagonist drug candidate will provide us with critical optionality for our portfolio.

Harness our drug discovery capabilities to build a franchise with a deliberate focus on developing therapeutics that are synergistic with our existing portfolio.

We will continue to leverage the capabilities and expertise of our team to identify and develop drug candidates with the highest likelihood of clinical and commercial success in NI&I.

2 unchanged sentences

Our collective expertise and strategic approach will guide us in selecting not only drug candidates with therapeutic potential, but also ideal partners that can meaningfully contribute to the development and commercialization of our therapeutic portfolio.

LPA1 Franchise

Our lead asset, PIPE-791, is a novel, high affinity, brain penetrant, small molecule LPA1R antagonist.

We are initially developing PIPE-791 for the treatment of IPF, PrMS and chronic pain.

We are also exploring in preclinical studies the potential utility of PIPE-791 in additional disorders where the LPA1R pathway has been implicated.

We completed a Phase 1 trial to evaluate the safety, tolerability, and PK of single and multiple doses of PIPE-791 in healthy volunteers.

In 2024, we commenced a Phase 1b open-label trial to measure the relationship of PK to lung and brain receptor occupancy by PET imaging.

We expect the top-line data from this trial will be available in the second quarter of 2025.

This Phase 1b trial will inform dose selection for planned future Phase 2 trials of PIPE-791.

In addition, we are advancing CTX-343, a peripherally-restricted LPA1R antagonist.

In November 2024, the FDA authorized our IND for the treatment of chronic pain associated with two separate indications, OA and LBP.

On March 4, 2025, we announced the initiation of patient dosing in an exploratory PIPE-791 Phase 1b, randomized, double-blind, placebo-controlled, crossover, chronic pain trial.

We expect to enroll approximately 40 patients at up to five sites in the U.S., and a treatment duration of 28 days.

We anticipate top-line data from this trial in early 2026.

We are initially prioritizing the development of PIPE-791 for the treatment of IPF, with an additional exploratory Phase 1b study in chronic pain.

We are also exploring the potential utility of PIPE-791 in additional disorders where the LPA1R pathway has been implicated.

We have previously completed a Phase 1 trial to evaluate the safety, tolerability, and PK of single and multiple doses of PIPE-791 in healthy volunteers.

In September 2025, we completed a Phase 1b open-label trial that measured the relationship of PK to LPA1 RO by PET imaging.

This Phase 1b trial further affirmed the planned dose selection for our recently initiated Phase 2 trial of PIPE-791 in IPF.

This trial (PROPEL-IPF) is a 26-week randomized, double-blinded, placebo-controlled, global clinical trial evaluating the efficacy, safety, tolerability, and pharmacokinetics of PIPE-791 in patients with IPF.

We expect to enroll approximately 324 subjects globally in this trial, which is designed to assess safety and tolerability, as well as efficacy measured by the absolute change from baseline in forced vital capacity (“FVC”) through week 26.

We anticipate top-line data from this trial in the second quarter of 2026.

In 2025, we made a strategic decision to defer further clinical development of our PIPE-791 PrMS program and to defer the initiation of clinical development for our CTX-343 program until funding is obtained to specifically move these programs forward.

PIPE-791 for the Potential Treatment of IPF

5 unchanged sentences

Inhibition of LPA1 can reduce these detrimental processes and may be a beneficial treatment for IPF.

We have demonstrated this by our evaluation of PIPE-791 to reduce fibrosis in response to injury in a key in vivo rodent model for IPF.

We have demonstrated this by our evaluation of PIPE-791 to reduce fibrosis in response to injury in a

key in vivo rodent model for IPF.

In addition, this rationale is supported by third-party LPA1R antagonist programs, which have demonstrated clinical proof-of-concept in multiple Phase 2 clinical trials in IPF patients.

Based on the dosing profile from our preclinical studies and the PK data from our Phase 1 healthy volunteer trial, we believe PIPE-791, pending further clinical development and FDA approval, has the potential to treat IPF with once-daily dosing.

In contrast, currently approved IPF therapies require multiple-daily dosing regimens.

Based on the dosing profile from our preclinical studies and the PK data from our completed Phase 1 trials, we believe PIPE-791, pending further clinical development and FDA approval, has the potential to treat IPF with once-daily dosing, in contrast to the currently approved IPF therapies which require multiple-daily dosing regimens, as well as to improve tolerability and patient compliance compared to currently approved IPF therapies.

Disease Background

3 unchanged sentences

IPF is a rare disease with approximately 130,000 patients in the United States and, as of 2017, 30,000 to 40,000 new cases diagnosed annually.

As of 2023, worldwide prevalence is estimated to be three million cases.

As of 2023, worldwide prevalence is estimated to be three million cases, with an overall incidence that is increasing worldwide.

Although the mechanisms of fibrosis in IPF remain poorly understood, generally accepted concepts of disease pathogenesis involve recurrent subclinical injuries to alveoli (lung tissue) and failure of normal lung tissue repair.

7 unchanged sentences

Current Approved Therapies

While there is no pharmacological cure for IPF, there are two FDA-approved therapies to treat the disease:

pirfenidone (Esbriet, marketed by Genentech/Roche) and nintedanib (Ofev, marketed by Boehringer Ingelheim).

Both drugs were approved in 2014 and are recommended by the most recent treatment guidelines from 2015.

While there is no pharmacological cure for IPF, there are three FDA-approved therapies to treat the disease:

pirfenidone (Esbriet, marketed by Genentech/Roche), nintedanib (Ofev, marketed by Boehringer Ingelheim), and nerandomilast (JASCAYD marketed by Boehringer Ingelheim.

Both pirfenidone and nintedanib were approved in 2014 and are recommended by the most recent treatment guidelines from 2015.

Neither drug stops the progression of IPF and both are limited by issues associated with safety, tolerability and compliance with multi-daily dosing regimens.

Lung transplant is currently the only cure for patients with IPF, but, due to age and comorbidities, this is a limited treatment option for most patients.

We believe that PIPE-791 has the potential to address the limitations of current therapies and serve a large unmet need for IPF patients.

Pirfenidone is an orally available, synthetic compound that exerts anti-fibrotic, anti-inflammatory and antioxidant properties through down-regulation of key pro-fibrotic growth factors including TGF-b, inhibition of inflammatory cytokines (e.g., tumor necrosis factor-a) production and release, and reduction of lipid peroxidation and oxidative stress.

Four registrational trials have evaluated the efficacy of pirfenidone in patients with IPF, with three showing that pirfenidone slows down disease progression as measured by rate of deterioration in forced vital capacity (“FVC”).

Pirfenidone is prescribed in a dose-escalating pattern three times daily (“TID”) over a 14-day period to a target dose of 801 mg TID (total daily dose of 2,403 mg administered by nine 267 mg capsules).

Common side effects of pirfenidone include gastrointestinal intolerance characterized by nausea, vomiting, dyspepsia, and diarrhea.

Dose modification or discontinuation may be necessary in the case of severe side effects, with 19% of patients requiring dose reductions or interruptions due to gastrointestinal events in the clinical trials.

Pirfenidone also carries the risk of skin reactions involving photosensitivity and rashes, with patients instructed to take sun exposure precautions.

Nintedanib is an intracellular inhibitor of vascular endothelial growth factor receptor 1–3, fibroblast growth factor receptor 1–3, and platelet-derived growth factor receptor a and b.

By inhibiting these tyrosine kinase receptors, nintedanib interferes with a number of processes that have been implicated in the pathogenesis of IPF.

Treatment with nintedanib in multiple clinical trials demonstrated a reduction in the one-year rate of decline in FVC by approximately 50%.

The recommended dosage of nintedanib is 150 mg twice daily (“BID”) approximately 12 hours apart.

The most frequent side effects associated with nintedanib are diarrhea (reported by approximately 60% of patients within the first 3 months of treatment, with over 10% of patients requiring permanent dose reduction), nausea, and vomiting.

In addition to these gastrointestinal side effects, data from clinical trials with nintedanib noted a risk of arterial thromboembolic events, bleeding disorders, and gastrointestinal perforation.

In addition to the side effects noted above, which are associated with discontinuation of therapy, both pirfenidone and nintedanib have demonstrated risk for transaminitis, or elevation in liver enzymes.

Both drugs require routine monitoring of liver function that can prompt dose reductions or treatment discontinuations, and each drug’s label includes a warning relating to elevated liver enzymes and gastrointestinal disorders.

Specifically, both pirfenidone and nintedanib have the additional warning of drug-induced liver injury and severe liver injury with fatal outcomes.

Due to these issues associated with safety and tolerability, it has been estimated that approximately 40% to 50% of patients discontinued treatment on either drug within one year of initiation.

Despite the limitations highlighted above, pirfenidone and nintedanib generated more than $4 billion in combined total sales globally in 2022.

Nerandomilast was approved for marketing in the United States in 2025 and, like nintedanib and pirfenidone, only attenuates disease progression with tolerability issues that are further complicated when combined with an existing therapy.

Pirfenidone and nintedanib generated approximately $4 billion in combined total sales globally in 2022.

Patent expiration for pirfenidone is 2022 (U.S.) and 2026 (EU and Japan), and the patent covering the active pharmaceutical ingredients (“APIs”) for nintedanib is 2025 (U.S., EU, Japan), respectively.

1 unchanged sentence

Scientific Rationale for LPA1R Antagonism in IPF

LPA is a bioactive lysophospholipid that regulates numerous aspects of cellular function, such as proliferation, migration and cytoskeletal reorganization, and has been recognized as a novel mediator of wound healing and tissue fibrosis.

LPA mediates its effects by signaling through a family of six G protein-coupled receptors, LPA1 to LPA6.

9 unchanged sentences

However, dose-related hepatobiliary toxicity led to early termination of the trial.

After conducting additional toxicology investigations, BMS reported that hepatobiliary toxicity was likely caused by off-target inhibition of bile acids efflux transporters such as bile salt export pump (“BSEP”).

BMS-986278 is a second generation LPA1R antagonist that is biased away from BSEP, and the results of a Phase 2 trial in 276 IPF patients with this compound were recently released at the 2023 American Thoracic Society annual meeting.

After conducting additional toxicology investigations, Bristol Myers Squibb reported that hepatobiliary toxicity was likely caused by off-target inhibition of bile acids efflux transporters such as bile salt export pump (“BSEP”).

BMS-986278 is a second generation LPA1R antagonist that is biased away from BSEP, and the results of a Phase 2 trial in 276 IPF patients with this compound were released at the 2023 American Thoracic Society annual meeting.

The outcome of the Phase 2 trial showed a statistically significant reduction in the decline in FVC following a 26-week administration of 60mg BID dose of BMS-986278 versus placebo with or without the use of background antifibrotic therapy.

A global Phase 3 trial of BMS-986278 for IPF is currently enrolling.

A global Phase 3 trial of BMS-986278 for IPF has completed enrollment and is currently ongoing.

With regard to its high bioavailability, low plasma protein binding, and long receptor residence time in our preclinical studies, compared to the preclinical data of other LPA1R antagonists that we know are currently in development, we believe PIPE-791 has the potential to be a differentiated LPA1R therapy.

We are developing PIPE-791 as a once daily (“QD”) therapy at low doses (≤ 10 mg), compared to other LPA1R antagonists, including BMS-986278, which are being studied at significantly higher dose ranges (60-120 mg) all with BID administration.

PIPE-791 for the Potential Treatment of Progressive MS

MS is a chronic, immune-mediated disease of the CNS characterized by neuroinflammation and demyelination.

The three main clinical categories of MS include RRMS, Secondary Progressive MS (“SPMS”), and Primary Progressive MS (“PPMS”).

We are developing PIPE-791 for the potential treatment of SPMS and PPMS, which are collectively referred to as PrMS.

We believe that PIPE-791 has the potential to be a disease-modifying treatment (“DMT”) by impacting the neurodegeneration secondary to chronic demyelination and neuroinflammation, the two leading pathological contributors to clinical disability in PrMS.

The development of a brain penetrant small molecule therapy that prevents worsening, reverses damage, and restores function would potentially address the major therapeutic unmet need in PrMS.

The three main clinical forms of MS have differences in prevalence and presentation.

RRMS comprises 85% of newly diagnosed MS patients, and the clinical course is marked by relapses and remissions, defined as disease flare-ups followed by periods of partial recovery.

Many RRMS patients eventually progress to worsening disease, and it is estimated that roughly 50% to 70% of diagnosed RRMS patients progress to SPMS within 10 to 15 years.

PPMS is estimated to include approximately 10% to 15% of newly diagnosed MS patients, which is marked by a steady course of clinical progression from the time of presentation.

In 2020, the global prevalence of MS was estimated to be 2.8 million patients, and we believe that more than 750,000 of this global population have PrMS (i.e., the collective population of SPMS and PPMS patients).

Although substantial progress has been made in the development of effective immune-modulating treatments for RRMS, many of these approved drugs have been tested in PrMS with limited results.

The relative lack of effective therapies for PrMS has further justified the exploration of novel treatment approaches.

The LPA/LPA1R axis has been proposed as a potential active pathway contributing to the pathophysiology of MS.

Specifically, LPA is a pro-inflammatory lipid that has been shown to be elevated in the plasma and cerebrospinal fluid (“CSF”) of MS patients and that may promote neuroinflammation and limit remyelination through the activation of the LPA1R.

We have demonstrated in our preclinical studies that blocking LPA1R with PIPE-791 reduces neuroinflammation and promotes remyelination.

We further demonstrated that the biological mechanism leading to remyelination involves PIPE-791-induced oligodendrocyte formation and survival.

We confirmed this remyelination was functional via observed improvements in visual evoked potential (“VEP”) latency, a clinically translatable functional biomarker of remyelination.

We believe that PIPE-791 can be the first potential therapeutic to demonstrate the role of LPA1R antagonism in addressing the chronic neuroinflammation and demyelination associated with PrMS.

We believe that PIPE-791 is the only brain penetrant LPA1R antagonist in clinical development for PrMS.

Disease Background

MS is a chronic, immune-mediated disease of the CNS characterized by demyelination and neuroinflammation which ultimately results in axonal loss and clinical disability.

The destruction of myelin in the CNS is associated with activation of the adaptive immune system, represented by peripheral circulating T and B cells, and the innate immune system of the CNS, represented by microglia and macrophages.

While demyelination, and subsequent failure of remyelination, is a core pathological feature across all forms and stages of MS, the adaptive immune system appears more active in the early (i.e., RRMS) stages of MS, and the innate immune system is more active in the later stages of MS (i.e., PrMS).

The prominent pathological features of demyelination and neuroinflammation in PrMS, combined with insufficient endogenous remyelination, ultimately results in axonal loss and clinical disability.

Demyelinated axons are susceptible to chronic injury and degeneration, as well as to reduced conduction capacity.

In addition to demyelination, the chronically activated microglia of the innate immune system are implicated to play a central role in the neurodegeneration in PrMS.

In post-mortem examinations of PrMS patients, activated microglia have been observed in chronically active lesions as well as normal-appearing white matter.

Excessive activation of microglia is hypothesized to drive both acute and chronic axonal loss, as well as compounding further inflammation through the release of cytokines and inflammatory mediators that may attract additional immune cells.

The chronic activation of microglia characteristic of PrMS is considered a major component of the emerging pathological construct referred to as “smoldering inflammation.”

The chronic neuroinflammation in PrMS is also associated with a relatively impermeable blood brain barrier (“BBB”) in PrMS as compared to the more open BBB in RRMS.

It has been hypothesized that in the setting of PrMS, the innate immune system drives neuroinflammation by activating local cellular responses behind a BBB that is less penetrable to peripheral T and B cells of the adaptive immune system.

Because many DMTs that act on peripheral T and B cells depend on a disrupted BBB for access to the CNS targets, this hypothesis may also explain the relative efficacy of DMTs in RRMS as compared to PrMS.

The clinical courses of SPMS and PPMS, while distinct from RRMS, are considered generally similar.

PrMS is generally characterized by accrual of neurological disability independent of clinical relapses.

The most common clinical manifestation in PrMS is myelopathy, or weakness of the legs and difficulty walking, followed by difficulty with balance and visual impairment.

Patients with PrMS typically score more poorly than RRMS patients on the Expanded Disability Status Scale (“EDSS”), a common measure of neurological disability in MS.

Current Approved Therapies

In RRMS, the adaptive immune system drives neuroinflammation and demyelination that results in clinical relapses associated with new lesions observed by magnetic resonance imaging (MRI).

In contrast, PrMS is marked by the accrual of clinical disability that is generally independent of relapses and new focal lesion formation.

The majority of DMTs that dampen the inflammatory activity of adaptive immune cells associated with early disease course typified by RRMS have generally not been effective in PrMS.

With the exception of mitoxantrone for the specific diagnosis of secondary (chronic) SPMS (which is rarely used in the United States due to safety and tolerability issues), and ocrelizumab for PPMS, none of the MS medications approved by the FDA carry a specific indication for PrMS.

Although many DMTs approved for RRMS also carry the indication for SPMS with clinical evidence of active inflammation, the EXPAND Phase 3 trial for siponimod was the only study in the last 20 years to meet the primary efficacy endpoint of slowing disability accumulation compared to placebo in active SPMS.

The active form of SPMS is defined as including the presence of clinical relapses or new lesions by MRI examination.

In contrast, natalizumab, one of the most effective DMTs in suppressing peripherally mediated inflammation in RRMS, did not reduce the proportion of SPMS patients with confirmed disability progression (“CDP”) in the ASCEND two-year Phase 3 trial.

The outcomes of the ASCEND and EXPAND trials are consistent with the concept that increasing clinical disability in PrMS is being driven by immune processes compartmentalized to the CNS and that the adaptive immune system plays a less prominent role.

The treatment options for patients with PPMS are even more limited.

Ocrelizumab, a monoclonal antibody against the CD20 antigen on B cells, is the only FDA-approved treatment option for PPMS.

Ocrelizumab was studied in an event-driven trial, with CDP as the primary endpoint.

The key inclusion criteria were patients aged younger than 55, evidence of specific clinical disability by EDSS score, and the presence of CSF-specific oligoclonal bands or evidence of CNS inflammation through the presence of immunoglobulins.

The primary outcome of the trial showed a 24% reduction in CDP (p=0.03).

This reduction in CDP is considered moderate, and there was no significant between-group difference in the physical component of the quality-of-life measure.

Safety risks related to ocrelizumab, while infrequent, can be severe and include infusion reactions, increased risk of infection, and reactivation of hepatitis B and herpes.

In summary, patients with PrMS have very few treatment options based on approved effective therapies.

Scientific Rationale for LPA1R Antagonism in PrMS

LPA is a pro-inflammatory lipid that is elevated in the plasma and CSF of MS patients and may promote neuroinflammation and limit remyelination through the activation of specific receptors such as the LPA1R.

LPA activates the G-protein coupled receptor LPA1, resulting in increased cytokine and chemokine levels in the CNS, infiltration of peripheral immune cells, and microglial and astrocyte activation, which is part of the neuroinflammatory response that leads to demyelination.

LPA may also suppress remyelination by directly activating LPA1R located on oligodendrocyte precursor cells (“OPCs”).

Blocking the LPA/LPA1R pathway with PIPE-791 has the potential to be disease-modifying by reducing neuroinflammation and promoting remyelination through inducing OPC differentiation into oligodendrocytes capable of remyelination.

Additionally, PIPE-791 enhances survival of oligodendrocytes within an inflammatory environment.

The following figures show LPA1 is a key regulator of remyelination and neuroinflammation.

The following figure shows mature oligodendrocytes derived from differentiation of OPCs wrap the axons of neurons to protect and facilitate nerve conduction.

The inability to restore myelin after a demyelinating injury to the axon results in long-term degeneration of the neuron.

Based on the potential for PIPE-791 to support remyelination and mitigate neuroinflammation, the leading causes of neurodegeneration and accrual of disability, we believe that there is strong biological rationale for LPA1R antagonism to have a clinical benefit in PrMS patients.

PIPE-791 for the Potential Treatment of Chronic Pain

We are developing PIPE-791 for the potential treatment of chronic pain, initially associated with OA and LBP.

Based on the results of external and internal preclinical studies and extensive scientific literature, we believe that PIPE-791, due to its ability to penetrate the CNS, could be the first LPA1 antagonist to comprehensively test the hypothesis that mitigation of the LPA1 pathway can improve chronic pain associated with OA and LBP.

Disease Background

Chronic pain is a condition often resulting from damage or dysfunction in the nervous system which can be associated with neuropathic symptoms of heightened pain sensitivity and persistent discomfort.

Current treatments often provide inadequate relief and are associated with significant side effects, underscoring the need for novel therapeutic approaches.

The LPA1 receptor has emerged as a promising target in the context of neuropathic pain due to its involvement in pain signaling pathways.

LPA1 activation may contribute to hypersensitivity and the persistence of pain by promoting the demyelination of nerve fibers, increasing neuronal excitability, and enhancing neuroinflammatory responses in the CNS.

By selectively blocking LPA1 receptor activity, a LPA1 antagonist may prevent or reverse the maladaptive changes in the nervous system that lead to chronic pain, offering a targeted and potentially effective non-opioid treatment option for patients.

The development of an LPA1 receptor antagonist could thus represent a novel, mechanism-based approach to addressing a significant unmet medical need in pain management.

Specifically, pain syndromes associated with OA and the form of LBP associated with lumbar spinal stenosis (“LSS”) have been linked to the lysophosphatidic acid (“LPA”) signaling pathway by evidence from relevant nonclinical models, as well as elevated levels of LPA in the synovial fluid of patients with knee OA and elevated levels of LPA in the CSF of patients with LSS.

These findings indicate that antagonists of the LPA signaling pathway may have promise as analgesics for the treatment of chronic pain.

Osteoarthritis

Chronic OA is the most common joint disease characterized by chronic pain and decreased mobility.

There are approximately 33 million people in the United States with OA and 595 million people globally.

Current pharmacological treatments for pain associated with OA consist of non-steroidal anti-inflammatory drugs (“NSAIDS”), topical agents, antidepressants and steroid injections.

These drugs do not address the neuropathic component of OA and thus are ineffective in subpopulations of OA.

Low Back Pain

Chronic LPB is a common condition that affects the lumbar region and lasts longer than 3 months.

The majority of LBP is considered mechanical and/or musculoskeletal in etiology which may also be complicated by spinal nerve compression and inflammation.

Low back pain affects approximately 619 million people globally and 45 million people in the United States.

Pharmacologic options focus on pain relief and reducing inflammation.

Over the counter or prescription NSAIDS, antidepressants, steroid injections, muscle relaxants and opioids are commonly used for pain, inflammation reduction and/or overcoming stiffness.

Most of these drugs are ineffective for neuropathic pain or have poor tolerability and/or addiction potential.

Current Approved Therapies

Standard-of-care medications for pain include NSAIDS such as ibuprofen, naproxen, COX-2 inhibitors, topical agents, anticonvulsants, antidepressants, muscle relaxants and opioids.

Many of these approved therapies are offered as over-the-counter or prescription generics.

Our competition may also include other programs in clinical development for the treatment of OA and/or LBP being developed by Eli Lilly and Company, GSK plc, Novartis AG and AstraZeneca PLC.

Scientific Rationale for LPA1R Antagonism in Neuropathic Pain

LPA activates LPA1, a G-protein-coupled receptor, implicated in various physiological and pathological processes, including inflammation, fibrosis and pain modulation.

In neuropathic pain models, LPA1 activation has been shown to contribute to hypersensitivity and the persistence of pain by promoting the demyelination of nerve fibers, increasing neuronal excitability and enhancing neuroinflammatory responses along the ascending pain pathways.

Specifically, LPA1 signaling has been associated with the upregulation of pro-inflammatory cytokines and chemokines, which exacerbate nerve injury and prolong pain sensations.

Preclinical studies using LPA1 gene knockout animals and receptor antagonists have demonstrated significant reductions in pain behavior in animal models of neuropathic pain.

Importantly, both peripheral as well as centrally located receptors are involved in this process.

Consistent with the observations from animal models, LPA has been shown to be associated with neuropathic pain intensity and symptoms in patients.

The following figures show LPA1 is a key regulator of the ascending pain pathway.

Our PIPE-791 Phase 1 Healthy Volunteer Trial

We completed a Phase 1 single ascending dose (“SAD”)/multiple ascending dose (“MAD”) and food effect (“FED”) clinical trial of PIPE-791 in healthy volunteers in January 2024.

This trial was a single-center, double-blind, placebo-controlled safety, tolerability, and PK trial of oral administration of PIPE-791 in healthy male and female volunteers aged 18 to 55 years.

The primary objective of the trial was to assess the safety and tolerability of single and repeat oral doses of PIPE-791 in healthy volunteer subjects.

The secondary objective of the trial was to assess the single and repeat dose PK profile of PIPE-791.

The trial met the primary and secondary objectives.

In the SAD component of the trial, we administered single doses of PIPE-791 to 24 participants across four dose cohorts of 1, 5, 10 and 20 mg, with six participants at each dose cohort (SAD1, SAD2, SAD3, and SAD4, respectively).

Eight additional participants in the SAD component of the Phase 1 trial received placebo doses.

We tested the subjects in the 10 mg SAD cohort after a single dose of PIPE-791 in both the fasted and FED state.

In the MAD component of the trial, we administered PIPE-791 to 18 participants over 1, 3 and 10 mg dose cohorts, with six participants at each dose cohort (MAD1, MAD2, and MAD3, respectively).

Six additional participants in the MAD component of the Phase 1 trial received placebo doses.

The 1 and 3 mg MAD dose cohort participants received once-daily dosing over 7 days, and the 10 mg MAD dose cohort participants received once-daily dosing over 14 days.

In this Phase 1 trial, PIPE-791 was shown to be well-tolerated across all four SAD and three MAD dose cohorts in healthy volunteers.

Excluding adverse events (“AEs”) related to soreness secondary to venipuncture and contact dermatitis related to electrocardiogram (“EKG”) electrode pads, only three treatment emergent adverse events (“TEAEs”) were considered Grade 1.

The two Grade 2 TEAEs under active drug assignment included a Grade 2 AE of back pain (SAD4) and a Grade 2 AE of constipation (MAD3).

A Grade 2 AE of headache was reported in a single placebo subject.

There were no Grade 3 or Grade 4 AEs reported during the trial.

All reported AEs recovered and resolved, and there were no dose-limiting AEs nor was a relationship or pattern to AEs and dose detected.

There were no notable abnormal clinical laboratory values, EKG, or vital signs observed.

The following table provides the TEAEs that were reported in two or more trial participants.

PIPE-791 displayed a SAD half-life dependent on dose that ranged from 55 to 31 hours for the 1 mg and 20 mg dose cohorts, respectively.

Co-administration of PIPE-791 with food slightly delayed Tmax and reduced Cmax relative to the fasted state, but with no overall impact on exposure.

The figures below provide the SAD PK for all four dose cohorts to Day 14 (left figure) and the 24-hour MAD PK for all three dose cohorts for Day 1 and Day 7 (MAD1 and MAD2) and Day 1 and Day 14 (MAD3) (right figure).

Our PIPE-791 Preclinical Toxicity Studies

We evaluated the toxicity profile of PIPE-791 in comprehensive animal studies.

The toxicology studies consisted of oral dosing in rodents and minipigs for up to 28 days, with four-week recovery periods.

Furthermore, we completed a battery of in vitro and in vivo genotoxicity studies to assess the genotoxic potential of PIPE-791.

Based on these data, we initiated six-month rodent and nine-month minipig chronic toxicity studies in January 2024.

We expect to have the final reports from these toxicology studies in the second quarter of 2025.

Our PIPE-791 Development in IPF

Overview of PIPE-791 Preclinical Proof-of-Concept Studies

7 unchanged sentences

The slow on-rate kinetics of PIPE-791 likely contribute to the shift in potency observed going from the 30 minutes to the 24 hour Ca2+ mobilization assay.

PIPE-791 also showed selectivity against the two most homologous LPA receptor isoforms, LPA2 and LPA3, with >30 fold selectivity.

PIPE-791 also showed selectivity against the two most homologous LPA

receptor isoforms, LPA2 and LPA3, with >30 fold selectivity.

PIPE-791 was screened against 78 targets (Eurofin SAFETYscan) at a concentration of 30 µM with no appreciable activity.

1 unchanged sentence

We assessed selectivity using a three hour incubation of PIPE-791.

Properties In vitro Profile

Radioligand binding Ki (nM) 0.752 (IC 50 :

K off (min -1 )

Functional LPA1 Ca 2+ mobilization (nM, 30 minutes)

Functional LPA1 Ca 2+ mobilization (nM, 24 hours)

PIPE-791 In Vivo Lung LPA1R Occupancy

12 unchanged sentences

Preclinical Data Comparison Between PIPE-791 and Other LPA1R Antagonists

We believe that our preclinical studies and Phase 1 healthy volunteer data support the continued development of PIPE-791 for both IPF and PrMS.

We believe that our preclinical studies and Phase 1 data support the continued development of PIPE-791 for multiple disease areas, including IPF.

Specifically, with regard to its high bioavailability, low plasma protein binding, and long receptor residence time in our preclinical studies compared to the preclinical data of other LPA1R antagonists, we also believe PIPE-791 has the potential to be a differentiated LPA1R therapy.

18 unchanged sentences

The free acid form was used for each compound.

Assays PIPE-791 BMS-986278 BMS-986020 AMG-670

hLPA (Ca 2+ flux) IC 50

9.9 nM 80 nM 2.0 nM 9.2 nM

Plasma protein binding, % Free (Rodent) 5.7 15 0.2 0.07

Oral bioavailability, *F (%) 78 138 64 4.7

* Fraction absorbed

Our PIPE-791 Preclinical Toxicity Studies

We evaluated the toxicity profile of PIPE-791 in comprehensive animal studies.

The toxicology studies consisted of oral dosing in rodents and minipigs for up to 28 days, with four-week recovery periods.

Furthermore, we completed a battery of in vitro and in vivo genotoxicity studies to assess the genotoxic potential of PIPE-791.

In 2025, we completed six-month rodent and nine-month minipig chronic toxicity studies, which were required to support Phase 2 clinical trials.

Clinical Development of PIPE-791