LYT-100

Our programs 1
Discovery
Preclinical
Phase 1
Phase 2
Phase 3
LYT-100
Deupirfenidone
IPF & potentially other PF-ILDs

2

IPF & potentially other progressive fibrosing ILDs

~200K U.S. (PF-ILDs, including IPF) 


Therapeutic candidate being advanced for the potential treatment of conditions involving inflammation and fibrosis, including lung disease (e.g., idiopathic pulmonary fibrosis (IPF) and potentially other progressive fibrosing interstitial lung diseases (PF-ILDs) and Long COVID respiratory complications and related sequelae), and disorders of lymphatic flow, such as lymphedema.

LYT-100
Deupirfenidone
Long COVID2 respiratory complications & related sequelae

2

Long COVID respiratory complications & related sequelae

>150M Worldwide

Therapeutic candidate being advanced for the potential treatment of conditions involving inflammation and fibrosis, including lung disease (e.g., idiopathic pulmonary fibrosis (IPF) and potentially other progressive fibrosing interstitial lung diseases (PF-ILDs) and Long COVID respiratory complications and related sequelae), and disorders of lymphatic flow, such as lymphedema.
LYT-100
Deupirfenidone
Lymphatic flow disorders, including lymphedema

2a

Lymphatic flow disorders, incl. lymphedema

~1M U.S.

Therapeutic candidate being advanced for the potential treatment of conditions involving inflammation and fibrosis, including lung disease (e.g., idiopathic pulmonary fibrosis (IPF) and potentially other progressive fibrosing interstitial lung diseases (PF-ILDs) and Long COVID respiratory complications and related sequelae), and disorders of lymphatic flow, such as lymphedema.
Phase completedPhase in progressRegistration-enabling studies planned

1 We have an active IND on file with the FDA for LYT-100. The FDA and corresponding regulatory authorities will ultimately review our clinical results and determine whether our wholly-owned therapeutic candidates are safe and effective. No regulatory agency has made any such determination that LYT-100 is safe or effective for use by the general public for any indication.
2 Long COVID is a term being used to describe the emerging and persistent complications following the resolution of COVID-19 infection, also known as post-acute COVID-19 syndrome (PACS).

Deuterated, oral small molecule for the potential treatment of conditions involving inflammation and fibrosis and disorders of lymphatic flow 

Our lead wholly-owned therapeutic candidate, LYT-100 (deupirfenidone), is being advanced for the potential treatment of conditions involving inflammation and fibrosis, including lung disease (e.g., idiopathic pulmonary fibrosis (IPF) and potentially other progressive fibrosing interstitial lung diseases (PF-ILDs) and Long COVID respiratory complications and related sequelae), and disorders of lymphatic flow, such as lymphedema. LYT-100 is a selectively deuterated form of pirfenidone and has demonstrated anti‑inflammatory and anti-fibrotic activity. LYT-100 retains the beneficial pharmacology of pirfenidone but is expected to be metabolized slower and with less variability between patients. Given these properties, we will be evaluating whether LYT-100 can offer tolerability and efficacy with less frequent dosing, and our goal is to mitigate some of the gastrointestinal (GI) -related tolerability issues that have historically been associated with pirfenidone and limited its usage.

  • Key Points of Differentiation
    • Pirfenidone (Esbriet®) slows the progression of IPF and has been approved for the treatment of IPF in the United States and other countries. Pirfenidone has been granted FDA Breakthrough Therapy designation in uILD. Pirfenidone has also shown activity in investigational clinical studies in patients with uILD, as well as other indications and has demonstrated activity in a preclinical model of lymphedema and radiation-induced fibrosis. There are serious limitations in the clinical use of pirfenidone, particularly GI-related tolerability issues, which have significantly limited its usage. For example, in a large post-marketing analysis of 10,996 patients diagnosed with IPF, only 13.2 percent received treatment with pirfenidone during a five-year follow-up period3. Additionally, real-world experience with pirfenidone in the IPF treatment setting highlights significant problems with treatment compliance, resulting in approximately half of the patients that start therapy either discontinuing therapy, dose-reducing or switching to other therapies, all of which lead to suboptimal disease management. Thus, despite a proven pharmacology, pirfenidone has severe shortcomings that limit its use. We are developing LYT-100 to offer a differentiated safety profile compared to current standard of care drugs, which may support improved patient compliance and may potentially lead to improved treatment compliance while retaining or exceeding its efficacy, and will potentially be an attractive therapeutic option for a range of lung fibrosis indications, such as IPF and potentially other PF-ILDs.

     

     

    • LYT-100 (deupirfenidone, a selectively deuterated form of pirfenidone or Esbriet®) has the potential to overcome the foregoing challenges of pirfenidone and improve the management of lung disease. Selective deuterium substitution of pirfenidone is expected to retain its pharmacology while improving the metabolic stability of LYT-100, resulting in attenuated formation of the predominant inactive metabolite of both LYT-100 and pirfenidone. This metabolite was found to be associated with GI tolerability issues in a pirfenidone clinical study7. We believe improved metabolic stability and attenuated formation of this major metabolite seen with LYT-100 could contribute to improved tolerability, less frequent dosing and better treatment compliance compared to pirfenidone, which should translate to an overall improvement in treatment outcomes.
    • Single-dose and multiple ascending dose clinical studies suggest that LYT-100 has highly differentiated metabolic stability and pharmacokinetic (PK) profiles, which support the potential for LYT-100 to offer improved safety and tolerability.
    • We believe LYT-100 has the potential to replace pirfenidone as standard of care in IPF and to become a backbone treatment for IPF and potentially other PF-ILDs.
  • Program Discovery Process by the PureTech Team
    • LYT-100 was originally developed by Auspex Pharmaceuticals, Inc. (Auspex) for the treatment of IPF. We selected and acquired LYT-100 in July 2019 based on insights into the lymphatic system gained internally and via unpublished findings through our network of collaborators, coupled with the relationships of our team members and their insights into the program previously developed at Auspex. These insights led us to an initial target indication of lymphedema, and we also believe that LYT-100 has the potential to be evaluated in multiple fibrotic and inflammatory indications beyond lymphedema, such as IPF and potentially other PF-ILDs, and Long COVID respiratory complications and related sequelae.
  • Patient Need & Market Potential

    Fibrosis and Inflammation-Related Lung Diseases

    • Fibrosis and inflammation are a common mechanism across several lung diseases. There are acute diseases with high mortality or that lead to long-term fibrosis; chronic diseases linked to a specific cause, like a virus or autoimmune disease; and diseases like IPF, where the causes are unclear but have been postulated to include viruses, genetic factors and a variety of environmental exposures. In a large percentage of these various lung conditions, there are few approved treatments that address inflammation and fibrosis of the lungs. Many of these diseases can increase the risk for worsening of lung fibrosis, and there is a clear unmet need to stop inflammation and fibrosis and to preserve lung function.
    • PF-ILDs
      • There are approximately 200,000 people living with PF-ILDs, including IPF, in the United States. IPF is a progressive condition characterized by irreversible scarring of the lungs, which worsens over time and makes it difficult to breathe. The prognosis of IPF is poor, with the median survival after diagnosis generally estimated at two to five years.
      • Even in IPF, for which pirfenidone is approved, high need exists for patients to have additional treatment options. Despite these unmet needs, pirfenidone sales peaked above $1 billion in 2018 and 2019.

     

     

    • In 2020, we engaged an independent third-party market research firm to conduct a survey of 100 pulmonologists who actively treat patients with IPF, to assess the potential commercial opportunity for LYT-100 in IPF. Certain results from this survey are depicted in the graphic above (right panel). Data from this survey are consistent with findings of independent publications that point to significant tolerability issues, particularly GI-based adverse events, as the greatest limitations of the current standard of care in IPF. In this survey, when physicians were asked on an unaided basis for the most significant improvements needed in new treatment options being developed for IPF, 48 percent highlighted the need for therapies with improved side effect profiles. Pulmonologists in this survey were also presented with a hypothetical profile of LYT-100, labelled “Product X”, that indicated an improved tolerability and dosing profile with comparable efficacy relative to standard of care in IPF. Based on this profile, physicians indicated they may prescribe Product X to approximately 30 percent of their IPF patients. Across the survey, pulmonologists highlighted an unmet need for treatments with improved tolerability profiles, especially related to GI-related AEs that often lead to dose reduction or discontinuation of treatment and poor disease management.
    • Long COVID (PACS) Respiratory Complications and Related Sequelae
      • The COVID-19 pandemic has affected over 150 million people around the world. There is increasing data around the longer-term complications of COVID-19, referred to as Long COVID (PACS) including data regarding respiratory issues that persist following recovery. Survivors of the virus can have lung fibrosis and shortness of breath and other problems that could potentially last for years.
      • Post-acute injuries are hypothesized to be due to a cascade of inflammation and fibrosis that begins during the acute phase of COVID-19 and continues after the infection resolves. A high proportion of mild, moderate and severe COVID-19 patients (up to 53 percent) already show signs of lung fibrosis at three weeks post symptom onset. Clinicians are also reporting lung fibrosis that persists beyond the acute infection, and of COVID-19 patients with pneumonia, 44 percent had fibrosis on CT imaging at nine days post‑discharge.
      • COVID-19 post-acute injuries appear to mimic respiratory complications of other viral pneumonias like Severe Acute Respiratory Syndrome (SARS) and Middle East Respiratory Syndrome (MERS). Up to one third of SARS and MERS survivors had abnormal pulmonary testing and lung imaging findings that persisted for years.
    • Lymphedema
      • Lymphedema is a chronic, disfiguring and painful condition that afflicts millions of people globally and is characterized by severe swelling in parts of the body, typically the arms or legs, due to the build-up of lymph fluid and inflammation, fibrosis and adipose deposition. By conservative estimates, lymphedema afflicts approximately one million people in the United States, including approximately 500,000 breast cancer survivors. Secondary lymphedema is the most prevalent form of lymphedema. Secondary lymphedema can develop after surgery, infection or trauma, and is frequently caused by cancer, cancer treatments such as radiation and chemotherapy, resulting in damage to or the removal of lymph nodes.
      • The current standard of care for lymphedema is symptom management, primarily with compression and physical therapy to control swelling. These approaches are cumbersome, uncomfortable and non-curative, and they do not address the underlying disease. Even with management, many patients will progress from mild-to-moderate lymphedema to more severe forms. No approved drugs therapies exist to treat the underlying causes of lymphedema. We believe the lack of treatments for lymphedema represents a major unmet medical need.
  • Milestones Achieved & Development Status
    • In November 2020, we announced the completion of a Phase 1 randomized, double-blind multiple ascending dose (MAD) and food effect study, which was designed to evaluate the safety, tolerability and PK profile of LYT-100 in healthy volunteers. The study demonstrated favorable proof-of-concept for the tolerability and PK profile of LYT-100.
      • All adverse events, or AEs, that were possibly or probably related to LYT-100 were mild and transient and there were no discontinuations. No serious AEs or dose-limiting toxicities were observed in the study. The maximum tolerated dose was not determined after dosing up to 1,000 mg twice per day.
      • The food effect portion of the study evaluated two common PK measures that are used to determine the optimal dose of a therapeutic candidate – area under the curve, or AUC, and Cmax. Under fed conditions, the AUC of LYT-100 was reduced by about 19 percent, which is comparable to the AUC reduction of 16 percent seen with pirfenidone as stated in the Esbriet® U.S. Prescribing Information. The Cmax reduction observed with LYT-100 was 23 percent, while the Cmax reduction seen with pirfenidone was 49 percent as stated in the Esbriet® (pirfenidone) U.S. Prescribing Information. Based on these findings, we are likely to evaluate LYT-100 in future clinical studies without regard to timing of food consumption of trial participants.
      • The therapeutic dose of pirfenidone approved by FDA for the treatment of IPF is 801 mg three times a day. LYT-100 is designed to potentially improve upon this regimen. In a previously conducted single-dose crossover study, an 801 mg dose of LYT-100 resulted in greater drug exposure than an 801 mg dose of pirfenidone. In the recently completed Phase 1 multiple ascending dose study, LYT-100 was well-tolerated at a dose above 801 mg. These data, together with our PK modelling of LYT-100 and pirfenidone exposures, indicate the potential for twice-a-day dosing with LYT-100.

     

     

    • Long COVID (PACS) respiratory complications and related sequelae
      • In December 2020, we announced the initiation of a global, randomized, double-blind, placebo-controlled Phase 2 trial to evaluate the efficacy, safety and tolerability of LYT-100 in adults with Long COVID respiratory complications and related sequelae.
      • In preclinical rodent studies, LYT-100 was observed to suppress levels of IL-6 and TNF-α induced by lipopolysaccharide administration, which we believe translates into the potential impact of LYT-100 on acute inflammation and cytokine release shown to be triggered by SARS-CoV-2 infection. LYT-100 anti-fibrotic activity was also observed in preclinical studies, which could be related to the lung fibrosis that develops in some patients following the acute phase of COVID-19. For more information on our clinical trial, please visit ClinicalTrials.gov.
    • Lymphedema
      • In December 2020, we announced the initiation of a Phase 2a proof-of-concept study of LYT-100 in patients with breast cancer related, upper limb secondary lymphedema. The primary endpoint of the study is safety and tolerability of LYT-100. Secondary endpoints include outcome measures of lymphedema, including relative limb volume, bioimpedance spectroscopy (a measure of extracellular fluid change), tonometry (a measure of fibrosis) and serum levels of inflammatory and fibrotic biomarkers. The study may also examine patient reported outcomes using validated self-report instruments specific to upper-arm lymphedema. The study is not powered to evaluate statistical significance of drug effect versus placebo, but we hope that results will be suitable to inform the design of future clinical protocols. For more information on our clinical trial, please visit ClinicalTrials.gov.
      • In preclinical studies, LYT-100 showed greater anti-fibrotic and anti-inflammatory activity when compared to pirfenidone. Additionally, LYT-100 was tested by one of our academic collaborators in a preclinical model of lymphedema which showed that LYT-100 halted progression of lymphedema and reduced overall volume. These results still need to be confirmed in clinical trials.
  • Expected Milestones
    • We expect to announce plans related to the design and initiation of registration-enabling studies of LYT-100 for the treatment of IPF and potentially other PF-ILDs later in 2021.
    • We expect topline results from the Phase 2 trial of LYT-100 in adults with Long COVID respiratory complications and related sequelae in the second half of 2021.
    • We expect topline results from the Phase 2a proof-of-concept study of LYT-100 in patients with breast cancer-related, upper limb secondary lymphedema in the first half of 2022.
    • We plan to initiate additional clinical trials of LYT-100 in 2021 to explore further the PK, dosing and tolerability in healthy volunteers. One of these trials is an extension of the previously completed MAD study, in which the maximum tolerated dose was not reached. Results from these trials are anticipated in 2021 and are expected to provide additional supportive data to help with the clinical development of LYT-100 across indications.
  • Intellectual Property
    • As of December 31, 2020, the LYT-100 patent portfolio includes 31 active patents acquired, and one patent application licensed from Auspex. These patents and application provide broad coverage of compositions of matter, formulations and methods of use for deuterated pirfenidone, including the LYT-100 deupirfenidone compound, comprising six issued U.S. patents, which are expected to expire in 2028, one U.S. patent application which if issued, is expected to expire in 2035, and 25 patents issued in 23 foreign jurisdictions, without taking into account any possible patent term extension or regulatory exclusivities. In addition, we have filed additional patent applications on deupirfenidone, including 29 pending U.S. patent applications and one international PCT application directed to the use of deuterated pirfenidone, including LYT-100, for the treatment of a range of conditions involving inflammation and fibrosis, including lung disease (e.g., IPF and potentially other PF-ILDs and Long COVID respiratory complications and related sequelae), and disorders of lymphatic flow, such as lymphedema. Any issued patents claiming priority to these applications are expected to expire in 2039 through 2041, exclusive of possible patent term adjustments or extensions or other exclusivities.

3 Rubino CM, Bhavnani SM, Ambrose PG, Forrest A, Loutit JS. Effect of food and antacids on the pharmacokinetics of pirfenidone in older healthy adults. Pulmonary Pharmacology & Therapeutics. 2009 Aug;22(4):279-285. DOI: 10.1016/j.pupt.2009.03.003.

4 InterMune, Inc., Esbriet (pirfenidone) [package insert]. U.S. Food and Drug Administration website.

5 Pan, L., Belloni, P., Ding, H.T. et al. A Pharmacokinetic Bioequivalence Study Comparing Pirfenidone Tablet and Capsule Dosage Forms in Healthy Adult Volunteers. Adv Ther 34, 2071–2082 (2017). https://doi.org/10.1007/s12325-017-0594-8.

6 Other most common AEs in pirfenidone vs. placebo include upper resp. infect (27% vs. 25%), fatigue (26% vs. 19%), GERD (11% vs. 7%), sinusitis (11% vs. 10%), insomnia (10% vs. 7%), weight decrease (10% vs. 5%), arthalgia (10% vs. 7%).

7 Dempsey TM, Payne S, Sangaralingham L, Yao X, Shah ND, Limper AH. Adoption of the Anti-Fibrotic Medications Pirfenidone and Nintedanib for Patients with Idiopathic Pulmonary Fibrosis. Ann Am Thorac Soc. 2021 Jan 19. doi: 10.1513/AnnalsATS.202007-901OC. Epub ahead of print. PMID: 33465323.

8 GlobalData Idiopathic Pulmonary Fibrosis: Opportunity Analysis and Forecasts to 2029; Wong, A., et al. Respiratory Research (2020) 21:32; Sauleda, J., et al. Medical Sciences (2018) 6:110; 16 major markets: U.S., EU5 (Germany, Spain, Italy, France, UK), Australia, Brazil, Canada, China, India, Japan, Mexico, Russia, South Africa, South Korea; CTD: Connective Tissue Disease; iNSIP: Idiopathic Non-specific Interstitial Pneumonia; HP: Hypersensitivity Pneumonitis.

9 100 pulmonologists were surveyed, no pricing information/assumptions was shared.

10 Based on 2019 Esbriet and OfevWW sales; in addition to IPF, Ofevis indicated for SSc-ILD and PF-ILD.

12 Protocol originally specified 750 mg BID as maximum dose. 750 mg BID was well tolerated and a 1000 mg BID cohort was added.

13 Adverse Events (AE) possibly or probably related to treatment; does not include AEs not related to treatment.

LYT-100 demonstrated favorable proof-of-concept for its tolerability and PK profile in a Phase 1 multiple ascending dose and food effect study. It is being advanced for the potential treatment of conditions involving inflammation and fibrosis and disorders of lymphatic flow. These include lung disease (e.g., IPF and potentially other PF-ILDs and Long COVID respiratory complications and related sequelae) and disorders of lymphatic flow, such as lymphedema.