• Pirfenidone (Esbriet^®2) slows the progression of IPF and has been approved for the treatment of IPF in the U.S. and other countries. IPF is a chronic orphan condition that causes progressive scarring of the lungs and affects about three million people worldwide. Median overall survival of IPF patients is 3-5 years. In a real-world study, pirfenidone has been shown to improve survival by approximately 3 years compared to supportive care alone.³ Pirfenidone is one of the two standard of care treatments for IPF, with nintedanib (OFEV®²) being the other drug. Despite its proven efficacy, there are serious limitations to pirfenidone’s clinical use primarily due to severe GI-related tolerability issues, which have significantly curtailed its effectiveness in patients with IPF.^4,5 The other standard of care treatment for IPF, nintedanib, has similar GI-related tolerability issues and limitations that have limited its broad usage. Although the combined sales of these two standard of care IPF drugs are over $3B, only about 25% of IPF patients are currently being treated with either of these drugs.⁶ The vast majority of IPF patients are not currently on any approved therapies, primarily due to tolerability issues associated with these drugs. In a large post-marketing analysis of 10,996 patients diagnosed with IPF, only 13.2% received treatment with pirfenidone during a five-year follow-up period.⁷ 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. We are developing LYT-100 to offer an improved tolerability profile compared to current standard of care drugs, which may enable better patient compliance and potentially lead to improved disease outcomes. Pirfenidone has also shown activity in investigational clinical studies in patients with unclassifiable interstitial lung disease (uILD), radiation induced fibrosis, myocardial fibrosis and other organ system fibrosis and has demonstrated activity in a preclinical model of lymphedema and radiation-induced fibrosis.

• LYT-100 is a selectively deuterated form of pirfenidone that is designed to retain the potent and clinically-validated anti-fibrotic and anti-inflammatory activity of pirfenidone with a highly differentiated PK profile that has translated into improved tolerability, as demonstrated by data from multiple human clinical studies.
• As recently demonstrated in a crossover trial comparing LYT-100 to pirfenidone in healthy older adults, lower maximal LYT-100 drug concentration (Cmax) with exposure that is bioequivalent to pirfenidone was achieved. This is supportive of the observed improved tolerability.
• A PK profile of LYT-100 that is substantially better tolerated than pirfenidone while maintaining comparable efficacy has the potential to allow patients to stay on the drug longer. As a result, we believe LYT-100 has the potential to replace pirfenidone as standard of care and to become a backbone therapy in the treatment for IPF.

• LYT-100 (deupirfenidone) was originally developed by Auspex Pharmaceuticals, Inc. (Auspex, now a wholly owned subsidiary of Teva Pharmaceuticals), a company that pioneered the deuteration technology and successfully developed deutetrabenazine (Austedo®), becoming the first and only deuterated drug that has received FDA approval.² We selected and acquired LYT-100 (from Teva Pharmaceuticals) 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 while in development at Auspex. We believe that the commercial success of the first and only deuterated drug, Austedo, based on a comparable efficacy to tetrabenazine but a highly differentiated, favorable safety and tolerability profile, could potentially serve as a good precedent for LYT-100.

Fibrosis and Inflammation-Related Lung Diseases

• Fibrosis and inflammation are a common mechanism across several lung diseases. These 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. For the majority of these lung conditions, there are few approved treatments that address the underlying inflammation and fibrosis affecting the lungs. Many of these diseases are progressive, and there is a clear unmet need to halt the inflammation and progressive fibrosis in order to preserve lung function.
• IPF
  • There are approximately 3 million people living with IPF globally. IPF is a progressive condition characterized by irreversible scarring of the lungs that worsens over time, making 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, there remains a need for more tolerable treatment options. Despite the limitations of this therapy, pirfenidone sales peaked above $1 billion each year from 2018 to 2021.

• In 2022, 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. In this survey, pulmonologists highlighted an unmet need for treatments with improved tolerability profiles. 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 AEs, as the greatest limitations of the current standard of care in IPF. When physicians were asked the primary reasons patients discontinue or dose reduce current standard of care for IPF, 80-90% highlighted GI AEs as a main cause. Pulmonologists in this survey were also presented with a hypothetical profile¹⁸ of LYT-100, labeled “Product X”, that indicated an improved tolerability profile with comparable efficacy relative to standard of care in IPF. Based on this profile, physicians indicated they would prescribe Product X to nearly 44% of their new IPF patients. Furthermore, nearly 80% of physicians indicated they would prescribe Product X more than pirfenidone. Based on this survey, LYT-100 is expected to have a significant impact on the IPF market based on its improved tolerability profile and similar efficacy compared to standard of care, which is consistent with findings from the prior market research.

IPF

• In June 2022, we announced the initiation of a clinical trial of LYT-100 for the potential treatment of IPF to support our registration-enabling package.
  • The global, randomized, placebo-controlled registration-enabling trial is designed to evaluate the efficacy, tolerability, safety and dosing regimen of LYT-100 to help inform the trial design for a potential pivotal trial and to assess the relative efficacy of LYT-100 compared to pirfenidone. A total of approximately 240 patients will be randomized 1:1:1:1 to receive either one of two dose levels of LYT-100, the FDA-approved dose of pirfenidone, or a placebo. One of the LYT-100 arms will evaluate 550 mg three times a day (TID) of LYT-100, which has previously demonstrated the comparable exposure as the currently approved dose of pirfenidone (801 mg TID), and the other arm will evaluate an 825 mg TID dose of LYT-100, which has demonstrated higher exposure than the currently approved dose of pirfenidone with the potential for improved efficacy. The primary objective of the trial is to demonstrate a statistically significant and clinically meaningful difference in the slope of decline in a measure of lung function, Forced Vital Capacity (FVC), in the LYT-100 treatment arms compared to placebo over 6 months. The trial will also evaluate safety, tolerability and the slope of FVC decline in the LYT-100 treatment arms compared to pirfenidone, though this analysis is not powered to demonstrate strict non-inferiority.
• In January 2022, we announced results from a randomized, double-blind crossover trial in healthy older adults demonstrating that approximately 50% fewer subjects treated with LYT-100 (deupirfenidone) experienced gastrointestinal (GI)-related adverse events (AE) compared to subjects treated with pirfenidone (17.4% vs. 34.0%). In an additional clinical trial, LYT-100 also demonstrated that it can be safely dosed with a higher total drug exposure than the currently approved dose of pirfenidone, which could translate into improved efficacy over pirfenidone. These results, along with the additional data generated from our robust LYT-100 clinical program and regulatory feedback, further guided the advancement of LYT-100 into late-stage clinical development for the treatment of IPF.
  
  • The double-blind, randomized, crossover trial evaluated the tolerability of LYT-100 550 mg three times daily (TID) versus pirfenidone 801 mg TID in 49 older healthy adults aged 60-79, an age group that is representative of the IPF patient population. The dose of LYT-100 used in this study was selected based on PK and modeling data from prior studies, which together suggest that 550 mg TID results in similar drug exposure levels achieved with 801 mg TID of pirfenidone. The trial results demonstrated that 38% fewer subjects treated with LYT-100 experienced any AE compared with those treated with pirfenidone (30.4% vs. 48.9%). Additionally, approximately 50% fewer subjects experienced GI-related AEs with LYT-100 compared with pirfenidone (17.4% vs. 34.0%), most notably nausea (15.2% with LYT-100 vs. 29.8% with pirfenidone), which is the most common AE associated with pirfenidone. No serious AEs were reported in the trial, and there was one AE-related discontinuation in each arm. Though not powered to show statistical significance, this trial provides evidence that LYT-100 has the potential to offer an important tolerability advantage over pirfenidone and will help to inform our development plans with this therapeutic candidate in IPF.

• In May 2022, we announced the presentation of additional data for LYT-100 at the American Thoracic Society 2022 International Conference. The data were shared in a scientific poster session and detailed the outcomes of a study in healthy older adults showing that LYT-100 demonstrated a lower incidence of AEs compared to pirfenidone at comparable exposure levels. Notably, LYT-100 at 550 mg TID (fed state) met the criteria for bioequivalence for exposure compared to the FDA-approved dosage of pirfenidone – 801 mg TID – but with a lower Cmax. Higher dosages of LYT-100 may provide enhanced antifibrotic and anti-inflammatory activity. The data support the upcoming registration-enabling studies in which PureTech plans to investigate LYT-100 in patients with IPF at the planned 550 mg TID dose as well as a dose with a higher total drug exposure than the currently approved dose of pirfenidone to evaluate if higher exposure could translate into improved efficacy.
• In November 2020, we announced the completion of a Phase 1 randomized, double-blind multiple ascending dose (MAD) and food effect trial, which was designed to evaluate the safety, tolerability and PK profile of LYT-100 in healthy volunteers. The trial demonstrated favorable proof-of-concept for the tolerability and PK profile of LYT-100. In August 2021, we presented the results of the trial at the virtual European Respiratory Society (ERS) International Congress. In November 2021, the full study was published in Clinical Pharmacology in Drug Development.
  
  • All 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 trial. The maximum tolerated dose was not determined after dosing up to 1,000 mg twice per day.
  • The food effect portion of the trial evaluated two common PK measures that are used to determine the optimal dose of a therapeutic candidate – area under the curve (AUC) and Cmax. Under fed conditions, the AUC of LYT-100 was reduced by about 19%, which is comparable to the AUC reduction of 16% seen with pirfenidone as stated in the Esbriet^® U.S. Prescribing Information. The Cmax reduction observed with LYT-100 was 23%, while the Cmax reduction seen with pirfenidone was 49% as stated in the Esbriet^® (pirfenidone) U.S. Prescribing Information.

• In 2021, we initiated additional Phase 1 clinical trials to further evaluate the PK, dosing and tolerability of LYT-100 in healthy volunteers and healthy older adults to inform the clinical development of LYT-100 across multiple indications. Results from these trials demonstrated that LYT-100 was well-tolerated at 824mg TID dosing with low rates of GI AEs that were comparable to placebo. These results will further inform our dose-ranging trial design in treatment-naïve IPF patients.
• In April 2021, we announced the formation of a Clinical Advisory Board for IPF and other PF-ILDs. These physicians and researchers with deep expertise in the clinical development of novel therapies in PF-ILDs include Bill Bradford, M.D., Ph.D., biopharma advisor with broad expertise in drug development; Vincent Cottin, M.D., Professor of Respiratory Medicine at Université Claude Bernard Lyon and Coordinator of the National Coordinating Reference Center for Rare Pulmonary Diseases at Louis Pradel Hospital, Hospices Civils de Lyon, Lyon, France; Kevin Flaherty, M.D., Professor at the University of Michigan specializing in IPF and other ILDs; Toby Maher, M.D., Ph.D., Professor of Clinical Medicine and Director of Interstitial Lung Disease at Keck School of Medicine of the University of Southern California; Paul Noble, M.D., Chair of the Department of Medicine at Cedars-Sinai Medical Center and a noted researcher in lung inflammation and fibrosis; and Marlies Wijsenbeek, M.D., Ph.D., pulmonary physician at the Erasmus Medical Center.

Radiation Induced Fibrosis

• In 2022, we initiated a pre-clinical study of LYT-100 for the prevention and treatment of radiation induced fibrosis, an indication for which the United States Government stockpiles medical countermeasures. This program is subject to the Animal Rule, which allows for the approval of drugs based on validated animal models when human efficacy studies are not ethical or feasible. The use of the Animal Rule is intended for drugs and biological products developed to reduce or prevent serious or life-threatening conditions caused by exposure to lethal or permanently disabling toxic chemical, biological, radiological or nuclear substances.

• Topline results from the Phase 2 dose-ranging trial of LYT-100 in patients with IPF are expected in 2024. We also plan to pursue a streamlined development program for LYT-100 in IPF, capitalizing on efficiencies of the 505(b)(2) pathway. Pending positive clinical and regulatory feedback, the program will advance into a Phase 3 study. We believe the results of the Phase 2 study, together with a Phase 3 study, could serve as the basis for registration in the U.S.

• As of December 31, 2021, the LYT-100 patent portfolio includes 31 active patents acquired, and one issued patent 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 which 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. We have also filed additional patent applications on deupirfenidone, including 13 pending U.S. patent applications, three international PCT applications and 13 foreign applications directed to the use of deuterated pirfenidone, including LYT-100, for the treatment of a range of conditions involving inflammation and fibrosis, including idiopathic pulmonary fibrosis. We expect that any issued patents claiming priority to these applications will expire in 2039 through 2042, exclusive of possible patent term adjustments or extensions or other exclusivities.