CMR-316: An Investigational First-in-Class Regenerative Therapy for Pulmonary Disease

I. Executive Summary of CMR-316

A. Overview of CMR-316

CMR-316 is an innovative, first-in-class investigational small molecule drug candidate engineered for regenerative therapy of lung diseases.[1] Administered via inhalation, it is specifically designed to target and stimulate endogenous lung stem cells, particularly type 2 alveolar epithelial cells (AEC2s). The stimulation of these cells is intended to promote the regeneration of damaged lung tissue, offering a novel therapeutic paradigm.[1] The development of CMR-316 is being spearheaded by Calibr, the drug discovery and development division of Scripps Research, also known as the Calibr-Skaggs Institute for Innovative Medicines.[2]

The development trajectory of CMR-316, from initial screening of existing drug libraries to the creation of a highly specialized therapeutic agent, underscores a strategic shift in pharmaceutical research towards harnessing the body's intrinsic regenerative capabilities. This approach, centered on activating resident stem cell populations with small molecules, may offer advantages in scalability and cost-effectiveness compared to more complex cell-based therapies.[2] The progression from identifying a class of compounds through a repurposing library (ReFRAME) to engineering a novel, lung-targeted molecule like CMR-316 reflects an efficient and rational drug discovery process. This pathway strategically addressed the inherent limitations, such as high systemic exposure and potential for unsafe dosages, that would arise from attempting to directly repurpose existing Dipeptidyl Peptidase 4 (DPP4) inhibitors for lung regeneration.[5]

B. Lead Indication and Therapeutic Potential

The primary therapeutic target for CMR-316 is Idiopathic Pulmonary Fibrosis (IPF), a devastating and progressive lung disease of unknown cause, characterized by extensive lung scarring and a poor prognosis, with median survival rates of only 2-5 years post-diagnosis.[1] Crucially, current treatments for IPF, such as anti-fibrotic agents, primarily aim to slow disease progression but do not offer regenerative capabilities or a cure.[1]

Beyond IPF, the unique mechanism of CMR-316 holds promise for a wider range of pulmonary conditions characterized by AEC2 dysfunction or loss. These potentially include Chronic Obstructive Pulmonary Disease (COPD), emphysema, acute respiratory distress syndrome (ARDS), and lung damage resulting from infections such as influenza and COVID-19.[2]

C. Current Development Stage

CMR-316 is currently advancing through early-stage clinical development. It is the subject of a Phase 1/1b clinical trial, identified by the protocol code CBR-CMR316-3001, EU Clinical Trial (EUCT) number 2023-510456-23-00, and ClinicalTrials.gov identifier NCT06589219.[1] This first-in-human study is designed to meticulously evaluate the safety, tolerability, pharmacokinetics (PK), and pharmacodynamics (PD) of CMR-316. The trial is structured to include both healthy volunteers and patients diagnosed with IPF.[1] The clinical investigation is being conducted at the Fraunhofer Institute for Toxicology and Experimental Medicine (ITEM) in Hanover, Germany, a center specializing in inhalation therapies and early-phase clinical research.[1]

D. Key Differentiators

CMR-316 distinguishes itself from existing therapeutic approaches for lung diseases, particularly IPF, in several fundamental ways. Firstly, it embodies a paradigm shift from treatments that merely slow the inexorable progression of the disease to one that actively aims to promote the regeneration of damaged lung tissue.[1] Secondly, its formulation as an inhaled, lung-targeted medication is designed to deliver the therapeutic agent directly to the site of injury. This localized delivery strategy is anticipated to maximize efficacy within the pulmonary environment while minimizing systemic exposure, thereby potentially offering an improved safety profile compared to systemically administered drugs.[1]

II. Scientific Foundation: Mechanism of Action and Regenerative Potential

A. The Role of Alveolar Epithelial Type 2 (AEC2) Cells in Lung Health and Disease

Alveolar epithelial type 2 (AEC2) cells are indispensable components of the lung parenchyma, serving a dual role as surfactant producers and as crucial resident stem cells of the lower airway.[1] These cells are responsible for self-renewal and, critically, for differentiating into Type 1 Alveolar Epithelial Cells (AEC1s). AEC1s form the vast majority of the alveolar surface area and are the primary cells responsible for gas exchange, a fundamental process for life. They also play a vital role in maintaining the structural integrity and stability of the lung alveoli.[1]

In the context of progressive fibrotic lung diseases such as Idiopathic Pulmonary Fibrosis (IPF), a reduction in the number or functional impairment of AEC2s is a recognized hallmark of the pathology.[1] This deficiency in the AEC2 stem cell pool leads to an inadequate repair response following lung injury. Instead of proper re-epithelialization by new AEC1s, the damaged alveolar basement membranes become sites of aberrant wound healing, characterized by the proliferation of fibroblasts and excessive deposition of extracellular matrix, culminating in fibrosis and irreversible scarring. Consequently, strategies aimed at stimulating AEC2 proliferation and their subsequent differentiation into functional AEC1s represent a highly promising therapeutic avenue for lung regeneration and the potential reversal of fibrotic lung damage.[1]

B. CMR-316 as a Dipeptidyl Peptidase 4 (DPP4) Inhibitor: Elucidating the Regenerative Pathway

CMR-316 is characterized as a potent and selective inhibitor of the enzyme Dipeptidyl Peptidase 4 (DPP4).[5] The mechanism by which DPP4 inhibition leads to lung regeneration is a key aspect of CMR-316's scientific rationale. While DPP4 is widely known for its role in glucose metabolism through the processing of incretin hormones (the basis for its use in type 2 diabetes treatment), research underlying CMR-316 has unveiled a distinct, localized role for DPP4 within the pulmonary environment. Specifically, studies have indicated that DPP4 present in the luminal compartment of the lung actively degrades Insulin-like Growth Factor 1 (IGF-1) and Interleukin-6 (IL-6).[5] Both IGF-1 and IL-6 are recognized as essential signaling molecules that promote the expansion and proliferation of AEC2s.

Therefore, the proposed mechanism of action for CMR-316 involves the targeted inhibition of DPP4 activity directly within the lung. This inhibition is expected to prevent the degradation of local IGF-1 and IL-6, leading to an increase in their concentrations within the lung microenvironment. Elevated levels of these growth factors, in turn, are hypothesized to stimulate the proliferation of the resident AEC2 stem cell population. These expanded AEC2s can then differentiate into new AEC1s, thereby facilitating the repair of the damaged alveolar epithelium and promoting regenerative processes in the lower airways.[5] This mechanistic understanding was significantly informed by preclinical studies involving NZ-97, a prototype drug that is chemically analogous to CMR-316 and shares its DPP4 inhibitory activity and lung-targeting properties.[5] The discovery of this specific role of DPP4 in modulating local growth factors critical for AEC2 homeostasis represents a significant advancement, offering a novel therapeutic lever for lung-specific regeneration that is distinct from the enzyme's systemic metabolic functions.

The capacity to promote the proliferation of endogenous stem cells, as CMR-316 aims to do, suggests a pathway towards a more physiological and potentially sustainable repair process. Unlike therapies that introduce exogenous cells or solely focus on inhibiting fibrotic pathways, stimulating the lung's own regenerative machinery could lead to a more comprehensive and integrated restoration of tissue structure and function.

C. Advantages of Lung-Targeted Inhaled Delivery

A critical design feature of CMR-316 is its formulation for nebulization and direct administration to the lungs via inhalation.[1] This route of administration is pivotal for achieving the desired therapeutic effect while optimizing the drug's safety profile. By delivering CMR-316 directly to the pulmonary tissue, the therapy aims to achieve high local concentrations at the site of action—the alveolar epithelium—where AEC2 regeneration is needed. This localized approach is anticipated to maximize the drug's efficacy in stimulating stem cell proliferation.

Concurrently, direct inhalation is designed to minimize systemic exposure to the DPP4 inhibitor. This is a crucial distinction from orally administered DPP4 inhibitors used in diabetes management, which achieve systemic drug levels. High systemic levels of DPP4 inhibition, if required to achieve therapeutic concentrations in the lung with a non-targeted drug, could lead to undesirable side effects. Preclinical research indicated that achieving effective lung concentrations with systemic DPP4 inhibitors would necessitate doses 50 to 100 times higher than those used for diabetes, potentially leading to an unacceptable safety profile.[5]

To further enhance its lung-specific action, CMR-316 has been chemically modified to exhibit lung-retention properties.[5] This means the drug is designed to persist in the lung tissue for an extended period following inhalation. This sustained local presence not only contributes to maximizing the therapeutic effect on AEC2s but also enables a convenient once-weekly dosing regimen. This sophisticated drug design, combining targeted delivery with engineered lung retention, was a critical step in making the DPP4 inhibition strategy viable for lung regeneration, overcoming the pharmacokinetic and safety hurdles associated with attempting to repurpose systemic agents for this novel indication.

III. Preclinical Validation: From Discovery to Proof of Concept

A. Identification via the ReFRAME Drug Repurposing Library

The journey towards CMR-316 began with an innovative screening approach utilizing the ReFRAME (Repurposing, Focused Rescue, and Accelerated Medchem) drug repurposing library.[5] This comprehensive collection of previously FDA-approved compounds and other clinically investigated molecules was developed by Calibr-Skaggs to facilitate the rapid identification of existing drugs that might possess novel therapeutic activities against different diseases. Through high-content imaging screens focused on AEC2 biology, DPP4 inhibitors emerged as a class of compounds with the potential to modulate AEC2 proliferation.[5] This initial "hit" from a repurposing library provided a crucial starting point, leveraging known pharmacology to explore a new therapeutic application.

B. Key Preclinical Studies and Findings with NZ-97 (PNAS, April 10, 2024)

The scientific underpinnings and preclinical validation for CMR-316 are extensively detailed in a pivotal study published in the Proceedings of the National Academy of Sciences (PNAS) on April 10, 2024, titled "Pharmacological expansion of type 2 alveolar epithelial cells promotes regenerative lower airway repair" by Sida Shao, Michael J. Bollong, Peter G. Schultz, and colleagues (DOI: 10.1073/pnas.2400077121).[3] This publication provides the biological proof of concept for the therapeutic strategy.

The PNAS research describes the development and characterization of NZ-97, a prototype molecule that is chemically similar to CMR-316 and shares its DPP4 inhibitory mechanism.[5] NZ-97 was specifically engineered as a lung-targeted and lung-persistent DPP4 inhibitor to overcome the limitations of systemic DPP4 inhibitors, which would require excessively high and potentially unsafe doses to achieve therapeutic concentrations in the lung.[5]

NZ-97 demonstrated remarkable efficacy in promoting AEC2 expansion and facilitating regenerative lower airway repair across multiple murine models of lung damage.[5] These models encompassed pathologies relevant to IPF, as well as other significant lung conditions such as emphysema and COPD, indicating a broad potential for this therapeutic approach.[2] The consistent efficacy observed across these diverse lung injury models suggests that NZ-97, and by extension CMR-316, targets a fundamental and common mechanism of lung repair—the proliferation and differentiation of AEC2s—rather than a pathway specific to a single disease. This characteristic significantly enhances the potential therapeutic applicability of CMR-316.[11]

Mechanistic studies detailed in the PNAS paper confirmed that the regenerative effects of NZ-97 are mediated through the inhibition of DPP4. This inhibition leads to increased local concentrations of IGF-1 and IL-6 in the lung, factors identified as essential for driving AEC2 expansion.[5] Furthermore, due to its lung-retained properties, NZ-97 exhibited good tolerability in these preclinical models, with minimal peripheral (systemic) exposure, thereby mitigating concerns about off-target effects associated with systemic DPP4 inhibition.[5] The combination of initial screening using the ReFRAME library, followed by rational, targeted medicinal chemistry to create a lung-retained analogue like NZ-97, represents an efficient drug discovery strategy. This method effectively marries the expediency of repurposing with the precision of de novo drug design tailored for a specific therapeutic need and organ system.

C. Ex vivo Studies on IPF Patient-Derived Cells

A critical component of the preclinical validation, also reported in the PNAS study, involved ex vivo experiments using AEC2s derived from IPF patient donors.[5] These studies demonstrated that NZ-97 could successfully replenish the growth capacity of these diseased human stem cells. This finding is particularly significant as it provides a direct translational link between the observations in animal models and the potential for therapeutic efficacy in human IPF patients. By showing that the targeted mechanism is operational and responsive in cells from individuals with the target disease, these ex vivo data substantially de-risk the subsequent progression of CMR-316 into clinical trials and strengthen the rationale for its development as a regenerative therapy for IPF.

IV. Clinical Development: The Phase 1/1b Study (CBR-CMR316-3001 / EUCT 2023-510456-23-00 / NCT06589219)

The transition of CMR-316 from preclinical validation to human testing is marked by a comprehensive Phase 1/1b clinical trial. This study is crucial for establishing the initial safety, tolerability, and pharmacokinetic/pharmacodynamic profile of the drug in humans.

A. Trial Overview and Objectives

The ongoing first-in-human study is titled "A Phase 1/1b Study to Assess Safety, Tolerability, Pharmacokinetics and Pharmacodynamics of Nebulized CMR316 in Healthy Volunteers and Patients with Idiopathic Pulmonary Fibrosis".[3] The primary objectives are to evaluate the safety and tolerability of single and multiple inhaled doses of CMR-316.[1] Secondary objectives include the assessment of its pharmacokinetic (PK) and pharmacodynamic (PD) profiles.[1] While specific outcome measures are not exhaustively detailed in all provided sources, typical Phase 1 safety assessments include monitoring adverse events, laboratory parameters, vital signs, and electrocardiograms (ECGs).[31] PK parameters generally involve measuring drug concentrations over time (e.g., Cmax, Tmax, AUC, half-life), and PD markers would relate to the drug's biological effect, potentially including biomarkers of AEC2 activation or changes in lung function parameters in the IPF patient cohort.[33]

Table 1: Summary of Clinical Trial CBR-CMR316-3001 / EUCT 2023-510456-23-00 / NCT06589219

Parameter	Details	Citations
Trial Title	A Phase 1/1b Study to Assess Safety, Tolerability, Pharmacokinetics and Pharmacodynamics of Nebulized CMR316 in Healthy Volunteers and Patients with Idiopathic Pulmonary Fibrosis	3
EUCT Number	2023-510456-23-00	14
NCT Number	NCT06589219	16
Protocol Code	CBR-CMR316-3001	14
Phase	Phase 1 / Human Pharmacology (First administration to humans)	7
Sponsor	The Scripps Research Institute (Calibr as its drug discovery division)	14
Lead Indication	Idiopathic Pulmonary Fibrosis (IPF)	7
Participant Type	Healthy Volunteers (Parts 1 & 2), Patients with IPF (Part 3)	1
Intervention Arms	Part 1: Single Ascending Doses (SAD) of nebulized CMR316 or placebo (Healthy Volunteers) <br> Part 2: Multiple Ascending Doses (MAD) of nebulized CMR316 or placebo, once weekly for 4 weeks (Healthy Volunteers) <br> Part 3: Multiple doses of nebulized CMR316, once weekly for 4 weeks, open-label (IPF Patients)	1
Key Objectives	Primary: Safety and tolerability of CMR316 <br> Secondary: Pharmacokinetics (PK) and Pharmacodynamics (PD) of CMR316	1
Estimated Enrollment	106 participants	15
Key Location	Fraunhofer ITEM, Hanover, Germany	1
EU Trial Start Date	August 14, 2024	14
Estimated Recruitment Start (EU/EEA)	May 1, 2024	14
Estimated Primary Completion	March 1, 2026 (Ozmosi); April 23, 2025 (TrialScreen for NCT06589219)	7
Estimated Study Completion (EU/EEA)	October 31, 2025	14

B. Study Design and Methodology

The trial employs a robust three-part, single-center design.[1]

• Part 1 (SAD): Healthy volunteers receive single ascending doses of nebulized CMR316 or a matching placebo. This part aims to establish the safety and tolerability of single administrations across a range of doses.
• Part 2 (MAD): Healthy volunteers receive multiple ascending doses of nebulized CMR316 or placebo, administered once weekly for a duration of 4 weeks. This part assesses the safety and PK of repeated dosing.
• Part 3 (IPF Patients): Patients with IPF receive multiple doses of nebulized CMR316 in an open-label fashion, also once weekly for 4 weeks. This part provides initial safety, tolerability, PK, and potentially exploratory PD data in the target patient population.

A key methodological feature of this trial is the inclusion of bronchoscopies in subgroups of participants to directly evaluate lung pharmacokinetics.[1] This is particularly pertinent for an inhaled, lung-targeted therapy like CMR-316, as it allows for the direct measurement of drug concentrations at the intended site of action, providing more relevant data than systemic (plasma) concentrations alone. Such data are crucial for confirming the lung-retention characteristics observed preclinically and for informing dose selection in subsequent trial phases.

C. Participant Population

The study enrolls distinct populations for its different parts: healthy male and female volunteers for Parts 1 and 2, and patients diagnosed with IPF for Part 3.[1] The total estimated enrollment is 106 participants.[15]

Key eligibility criteria for healthy volunteers (Parts 1 & 2) generally include an age range of 18-60 years, a BMI between 18-33 kg/m², normal lung function (FVC and FEV1 > 80% predicted, SaO2 > 95% on room air), and good overall health. Exclusion criteria typically cover significant medical conditions, recent hospitalizations, smoking history (≥ 10 pack-years or current use of nicotine products), and substance or alcohol use disorders.[15]

For IPF patients (Part 3), eligibility typically includes an age of ≥ 40 years, a confirmed diagnosis of IPF according to established criteria (e.g., ATS/ERS/JRS/ALAT 2011) within five years, and evidence of mild to moderate disease severity (e.g., predicted FVC ≥ 55%, predicted DLCO > 40%). An important provision is that patients on stable, well-tolerated doses of existing oral anti-fibrotic treatments (pirfenidone or nintedanib) for at least 8 weeks prior to consent may participate, provided no changes to their therapy dose or schedule are anticipated during the study.[17] This pragmatic inclusion acknowledges the standard of care for IPF and allows for early assessment of CMR-316 in a more representative patient context, potentially as an add-on therapy. Exclusions for IPF patients include alternative causes of pulmonary fibrosis, other active significant lung diseases, life expectancy less than one year, or being listed for lung transplant.[17]

Notably, individuals with Type 1 or Type 2 diabetes are excluded from all parts of the trial.[17] Given that CMR-316 is a DPP4 inhibitor—a class of drugs also used in the management of Type 2 diabetes—this exclusion is likely a measure to avoid confounding variables related to glycemic control, potential interactions with concomitant diabetes medications, or the underlying disease's impact on DPP4 pathways. This ensures that the initial safety and efficacy signals of CMR-316 can be assessed more clearly in a non-diabetic population.

D. Trial Conduct and Status

The trial is sponsored by The Scripps Research Institute, with its drug discovery arm Calibr leading the development of CMR-316.[14] The clinical execution is taking place at the Fraunhofer ITEM in Hanover, Germany.[1] As of the latest available information, the trial is "Ongoing, Recruiting".[7] A significant milestone was reached with the announcement of the first dose administered on October 30, 2024.[3]

Timelines for the trial vary slightly across different registry databases, which is common for clinical trials due to the dynamic nature of recruitment and study conduct. The EU Clinical Trials Register indicates a trial start date of August 14, 2024, with an estimated end date in the EU/EEA of October 31, 2025.[14] Ozmosi lists an estimated primary completion date of March 1, 2026 [7], while TrialScreen for NCT06589219 suggests an estimated study completion of April 23, 2025.[15] These variations underscore the importance of consulting the most current official trial records for up-to-date timeline information.

V. Formulation, Administration, and Intellectual Property

A. Formulation and Administration

CMR-316 is specifically formulated as a solution intended for administration via nebulization, ensuring direct delivery to the lungs.[1] This inhaled route is integral to its lung-targeted therapeutic strategy. The dosing regimen under investigation and planned for clinical use is once-weekly.[1]

A notable aspect of CMR-316 is its projected low human dose, anticipated to be in the range of 1 mg to 2 mg per administration, inhaled over a period of a few minutes.[5] This low dosage is a direct consequence of its design for lung targeting and retention, which aims to concentrate the drug's effect locally within the pulmonary tissue and minimize systemic exposure. The once-weekly nebulized administration, if proven effective and safe, could offer a significant advantage in terms of patient convenience and adherence for chronic conditions like IPF, which necessitate long-term management. This regimen compares favorably to daily oral medications or more frequent administration schedules often associated with other chronic disease therapies. Furthermore, the low projected human dose supports the success of the lung-retention strategy and suggests the potential for a favorable therapeutic window, reducing the risk of systemic side effects that might be associated with DPP4 inhibition at higher systemic concentrations.

B. Intellectual Property

The innovative nature of CMR-316 and its underlying scientific discoveries are protected by intellectual property filings. Key patents concerning small molecule regulators of alveolar type 2 cell proliferation for the treatment of pulmonary diseases have been filed by The Scripps Research Institute and its drug discovery arm, Calibr. The listed inventors on these applications include prominent scientists involved in the drug's development, such as Michael J. Bollong, Peter G. Schultz, Sida Shao, Arnab K. Chatterjee, Jeffrey Jian Chen, and Nan Zhang.[13]

Specific international patent applications (PCT) identified include WO2022159955A1, filed on January 20, 2022, claiming priority from January 21, 2021, and WO2022155674A1, filed on January 14, 2022, with a priority date of January 15, 2021.[23] These patent applications generally cover the novel compounds, including those described by Formula I, II, and III in WO2022159955A1, their pharmaceutical compositions, and their methods of use.[38] The core claims revolve around the selective promotion of AEC2 proliferation, the inhibition of DPP4 for therapeutic benefit in the lungs, and the treatment of a range of pulmonary diseases, with a particular emphasis on IPF, ARDS, and Infant Respiratory Distress Syndromes (IRDS).[38]

The patent filings specifically addressing compounds for AEC2 proliferation and the treatment of pulmonary diseases via DPP4 inhibition underscore the novelty of this therapeutic application. While DPP4 inhibitors as a class are known, particularly for their use in diabetes [5], their targeted application for lung regeneration by stimulating AEC2 proliferation represents a distinct inventive step. This focus secures intellectual property rights around this new medical use and the specifically engineered lung-targeted compounds, thereby creating a unique IP position for CMR-316 and related molecules.

Table 2: Key Intellectual Property for CMR-316 and Related Compounds

Patent/Application Number	Title	Inventors (Selected)	Assignee	Filing Date	Priority Date	Key Claims Summary	Citations
WO2022159955A1	Small molecule regulators of alveolar type 2 cell proliferation for the treatment of pulmonary diseases	Bollong, M. J., Schultz, P. G., Shao, S., Chatterjee, A. K., Chen, J., Zhang, N.	The Scripps Research Institute	January 20, 2022	January 21, 2021	Compounds (Formula I, II, III), pharmaceutical compositions thereof, and methods for selectively increasing AEC2 proliferation, inhibiting DPP4, and treating pulmonary diseases (IPF, ARDS, IRDS).	23
WO2022155674A1	Small molecule regulators of alveolar type 2 cell proliferation for the treatment of pulmonary diseases	Bollong, M. J., Schultz, P. G., Shao, S., Chatterjee, A. K., Chen, J., Zhang, N.	The Scripps Research Institute	January 14, 2022	January 15, 2021	Similar scope to WO2022159955A1, covering compounds for AEC2 proliferation and treatment of pulmonary diseases. (Detailed claims not available in provided snippets beyond title and inventors).	23

VI. Therapeutic Outlook and Strategic Implications

A. Potential of CMR-316 to Transform IPF Management

Should CMR-316 prove successful in clinical trials, it stands to significantly alter the treatment landscape for Idiopathic Pulmonary Fibrosis (IPF).[1] Current therapies for IPF, such as pirfenidone and nintedanib, primarily function by slowing the rate of disease progression and fibrotic processes. In contrast, CMR-316 is designed to actively promote the regeneration of damaged lung tissue by stimulating endogenous AEC2 stem cells. This regenerative approach addresses a core pathological deficit in IPF—the depletion and dysfunction of AEC2s—and offers the prospect of not just halting, but potentially reversing, lung damage.

The distinct mechanism of action of CMR-316, focused on AEC2 stimulation, also suggests its potential utility in combination with existing anti-fibrotic drugs.[3] Anti-fibrotics target pathways involved in scar formation, while CMR-316 aims to rebuild functional lung tissue. A combination therapy approach, where CMR-316 works synergistically with drugs like pirfenidone or nintedanib, could offer a more comprehensive treatment for IPF. Such a regimen might simultaneously inhibit fibrosis and promote regeneration, potentially leading to substantially improved clinical outcomes compared to monotherapy with either class of agent. The design of the Phase 1b portion of the current clinical trial, which allows for the inclusion of IPF patients already on stable doses of these standard-of-care anti-fibrotics, provides an early opportunity to assess the safety and tolerability of such co-administration.[17]

B. Broader Applications in Other Pulmonary and Regenerative Medicine Contexts

The therapeutic principle underlying CMR-316—the targeted stimulation of AEC2 regeneration—may extend beyond IPF to a variety of other pulmonary diseases characterized by alveolar damage and impaired repair mechanisms. Conditions such as Chronic Obstructive Pulmonary Disease (COPD), emphysema, Acute Respiratory Distress Syndrome (ARDS), and lung injury resulting from severe infections like influenza or COVID-19 could potentially benefit from a therapy that enhances the lung's intrinsic regenerative capacity.[2] The broad efficacy of the prototype NZ-97 in diverse preclinical lung injury models supports this wider potential.[2]

Furthermore, the successful clinical development of CMR-316 as a lung-targeted, inhaled regenerative small molecule could have profound implications for the broader field of regenerative medicine. It would serve as a compelling validation of the strategy to use small molecules to activate endogenous stem cells for tissue repair. This approach, as envisioned by the Scripps Research and Calibr-Skaggs team, could be adapted to target resident stem cell populations in other organs, potentially leading to novel regenerative therapies for a range of conditions affecting the heart, cornea, kidney, and colon.[2] Such organ-specific regenerative therapies based on small molecules could offer advantages over more complex and costly cell-based therapies or systemic drugs that often come with broader side effect profiles.

C. Current Challenges and Future Directions in Development

Despite the promising preclinical data and innovative mechanism, the development of CMR-316 faces several challenges inherent in translating novel therapies from the laboratory to clinical practice. A primary hurdle is the successful demonstration of safety and efficacy in human subjects. While preclinical models provide valuable insights, the response in human IPF patients, particularly regarding true lung regeneration, remains to be established through rigorous clinical trials.

The long-term safety and efficacy of CMR-316 in IPF patients will need to be carefully evaluated in subsequent, larger, and longer-duration clinical studies beyond the current Phase 1/1b trial. Identifying appropriate patient populations who are most likely to benefit from this regenerative approach will also be critical. This may involve developing and validating pharmacodynamic biomarkers that can monitor treatment response and reflect AEC2 activation or regenerative activity in the lung.[19] Defining robust clinical endpoints that capture true tissue repair and meaningful functional improvement beyond what is achieved by current anti-fibrotic therapies will be a key challenge for later-phase trials. This may necessitate the exploration of novel imaging techniques or functional assessments capable of quantifying lung regeneration.

Finally, navigating the regulatory pathway for a first-in-class regenerative therapy like CMR-316 will require close interaction with regulatory agencies to establish appropriate development plans and approval criteria. The novelty of its approach means that precedents may be limited, requiring thorough justification and evidence generation at each step of development.

VII. Concluding Remarks

CMR-316 emerges from the provided research as a highly innovative, first-in-class investigational therapeutic agent with the potential to address a significant unmet medical need in the management of Idiopathic Pulmonary Fibrosis and potentially other debilitating lung diseases. Its development represents a departure from existing treatments that primarily focus on slowing disease progression, by instead aiming to stimulate the lung's own regenerative capacities.

The core of CMR-316's innovation lies in its unique lung-targeted mechanism of Dipeptidyl Peptidase 4 (DPP4) inhibition, which is designed to selectively promote the proliferation and differentiation of endogenous type 2 alveolar epithelial cells (AEC2s)—the resident stem cells of the lower airway. This approach, supported by compelling preclinical evidence from studies with the prototype molecule NZ-97, offers the prospect of repairing and regenerating damaged alveolar tissue.

The ongoing Phase 1/1b clinical trial (CBR-CMR316-3001 / EUCT 2023-510456-23-00 / NCT06589219) is a critical step in evaluating the safety, tolerability, and preliminary pharmacokinetic and pharmacodynamic profile of CMR-316 in humans. The results from this study will be paramount in determining the future clinical viability of this novel regenerative strategy. The foundation laid by meticulous preclinical research, from the initial discovery through drug repurposing libraries to the rational design of a lung-retained inhaled therapeutic, provides a strong rationale for its continued investigation. If successful, CMR-316 could not only revolutionize the treatment of IPF but also pave the way for a new class of small molecule regenerative medicines for a variety of currently intractable diseases.

Works cited

1. Innovative inhalation therapy for lung tissue regeneration ..., accessed May 27, 2025, https://www.item.fraunhofer.de/en/r-d-expertise/lung-research/inhalation-therapy.html
2. Scripps Research Advances Breakthrough Regenerative Medicines to Reverse Aging-Related Diseases - BioSpace, accessed May 27, 2025, https://www.biospace.com/press-releases/scripps-research-advances-breakthrough-regenerative-medicines-to-reverse-aging-related-diseases
3. Calibr-Skaggs announces initial dosing of a first-in-class regenerative lung medicine in a phase 1 trial for idiopathic pulmonary fibrosis | Scripps Research, accessed May 27, 2025, https://www.scripps.edu/news-and-events/press-room/2024/20241030-cmr316-clinical-trial.html
4. Pipeline - Calibr-Skaggs at Scripps Research, accessed May 27, 2025, https://calibr.scripps.edu/our-pipeline/
5. CMR-316 - Drug Targets, Indications, Patents - Synapse, accessed May 27, 2025, https://synapse.patsnap.com/drug/38472c38023d4f7b85c8e1124f1f2d8e
6. How a new drug prototype regenerates lung tissue - Scripps Research, accessed May 27, 2025, https://www.scripps.edu/news-and-events/press-room/2024/20240410-schultz-bollong-lung-regeneration.html
7. CMR-316 Drug Profile - Ozmosi, accessed May 27, 2025, https://pryzm.ozmosi.com/product/cmr-316
8. NZ-97 - Drug Targets, Indications, Patents - Patsnap Synapse, accessed May 27, 2025, https://synapse.patsnap.com/drug/7205e60cc2834cedac0b396772a9a078
9. One pursuit to regenerate lung tissue - Pulmonary, accessed May 27, 2025, https://www.ampulmonary.com/pulmonary/article/22893430/one-pursuit-to-regenerate-lung-tissue
10. Drug Prototype May Enhance Lung Regeneration - Technology Networks, accessed May 27, 2025, https://www.technologynetworks.com/drug-discovery/news/drug-prototype-may-enhance-lung-regeneration-385626
11. New Regenerative Lung Therapy Begins Phase 1 Trials | CMR316 & IPF Treatment, accessed May 27, 2025, https://www.youtube.com/watch?v=1cQzlhgi0w4&pp=0gcJCdgAo7VqN5tD
12. Pharmacological expansion of type 2 alveolar epithelial cells ..., accessed May 27, 2025, https://www.pnas.org/doi/abs/10.1073/pnas.2400077121
13. Pharmacological expansion of type 2 alveolar epithelial cells promotes regenerative lower airway repair - PubMed, accessed May 27, 2025, https://pubmed.ncbi.nlm.nih.gov/38598345/
14. Study to assess the safety and tolerability of CMR316 in healthy volunteers and patients with Idiopathic Pulmonary Fibrosis. - Clinical Trials in the European Union - EMA, accessed May 27, 2025, https://euclinicaltrials.eu/ctis-public/view/2023-510456-23-00?lang=en
15. Study to Assess CMR316 in Healthy Volunteers and Patients With Idiopathic Pulmonary Fibrosis | TrialScreen, accessed May 27, 2025, https://app.trialscreen.org/trials/phase-1-to-assess-cmr316-healthy-volunteers-patients-idiopathic-pulmonary-trial-nct06589219
16. California Institute for Biomedical Research - Drug pipelines, Patents, Clinical trials - Patsnap Synapse, accessed May 27, 2025, https://synapse.patsnap.com/organization/5f7d13e51d45fedb0b09be704a4155d1
17. Study to Assess CMR316 in Healthy Volunteers and Patients With Idiopathic Pulmonary Fibrosis - ClinicalTrials.Veeva, accessed May 27, 2025, https://ctv.veeva.com/study/study-to-assess-cmr316-in-healthy-volunteers-and-patients-with-idiopathic-pulmonary-fibrosis
18. Pharmacological inhaled agents with antifibrotic properties: in vitro and murine models. - ResearchGate, accessed May 27, 2025, https://www.researchgate.net/figure/Pharmacological-inhaled-agents-with-antifibrotic-properties-in-vitro-and-murine-models_tbl1_385372623
19. Idiopathic pulmonary fibrosis – Overview of Information and Clinical Research, accessed May 27, 2025, https://clinicaltrials.eu/disease/idiopathic-pulmonary-fibrosis/
20. Pharmacological Treatment of Interstitial Lung Diseases: A Novel Landscape for Inhaled Agents - ResearchGate, accessed May 27, 2025, https://www.researchgate.net/publication/385372623_Pharmacological_Treatment_of_Interstitial_Lung_Diseases_A_Novel_Landscape_for_Inhaled_Agents
21. Pharmacological Treatment of Interstitial Lung Diseases: A Novel Landscape for Inhaled Agents - MDPI, accessed May 27, 2025, https://www.mdpi.com/1999-4923/16/11/1391
22. Lung research - Fraunhofer ITEM, accessed May 27, 2025, https://www.item.fraunhofer.de/en/r-d-expertise/lung-research.html
23. Sida Shao, Ph.D. - Westlake University, accessed May 27, 2025, https://en.westlake.edu.cn/faculty/sida-shao.html
24. Galapagos FLORA trial targets IPF | Drug Discovery News, accessed May 27, 2025, https://www.drugdiscoverynews.com/galapagos-flora-trial-targets-ipf-11886
25. Biomarkers of Response to Nintedanib in IPF - Fortune Journals, accessed May 27, 2025, http://www.fortunejournals.com/articles/biomarkers-of-response-to-nintedanib-in-ipf.html
26. Effects of the angiotensin II type 2 receptor agonist buloxibutid on human lung myofibroblasts and IPF lung tissue - ERS Publications, accessed May 27, 2025, https://publications.ersnet.org/content/erj/64/suppl68/pa3380
27. Увредени белодробни тъкани могат да бъдат регенерирани - Puls.bg, accessed May 27, 2025, https://www.puls.bg/liubopitno-c-70/uvredeni-belodrobni-tkani-mogat-da-bdat-regenerirani-n-50776
28. Shaochen You (0009-0009-8849-7114) - ORCID, accessed May 27, 2025, https://orcid.org/0009-0009-8849-7114
29. Lung regeneration: mechanisms, applications and emerging stem cell populations - PMC, accessed May 27, 2025, https://pmc.ncbi.nlm.nih.gov/articles/PMC4229034/
30. Therapeutic Reprogramming toward Regenerative Medicine | Chemical Reviews, accessed May 27, 2025, https://pubs.acs.org/doi/10.1021/acs.chemrev.4c00332
31. How to Submit Your Results - ClinicalTrials.gov, accessed May 27, 2025, https://clinicaltrials.gov/submit-studies/prs-help/how-submit-results
32. Protocol Registration Data Element Definitions for Interventional and Observational Studies, accessed May 27, 2025, https://clinicaltrials.gov/policy/protocol-definitions
33. Results Data Element Definitions for Interventional and Observational Studies | ClinicalTrials.gov, accessed May 27, 2025, https://clinicaltrials.gov/policy/results-definitions
34. Secondary outcome measure - Toolkit, accessed May 27, 2025, https://toolkit.ncats.nih.gov/glossary/secondary-outcome-measure/
35. A Study to Assess the Safety, Tolerability, Pharmacokinetics, and Pharmacodynamics of AZD0780 in Healthy Subjects - AstraZeneca Clinical Trials, accessed May 27, 2025, https://www.astrazenecaclinicaltrials.com/study/D7960C00001/
36. Multiple-Dose Pharmacokinetics, Pharmacodynamics, Safety, and Tolerability of Subcutaneous Rusfertide, a Hepcidin Mimetic, in Healthy Subjects - PubMed, accessed May 27, 2025, https://pubmed.ncbi.nlm.nih.gov/39888264/
37. Pharmacological Treatment of Interstitial Lung Diseases: A Novel Landscape for Inhaled Agents - PMC - PubMed Central, accessed May 27, 2025, https://pmc.ncbi.nlm.nih.gov/articles/PMC11597590/
38. WO2022159955A1 - Small molecule regulators of alveolar type 2 ..., accessed May 27, 2025, https://patents.google.com/patent/WO2022159955A1/en
39. WO2000034241A1 - N-substituted 2-cyanopyrrolidines - Google Patents, accessed May 27, 2025, https://patents.google.com/patent/WO2000034241A1/en
40. Metabolomic Biomarkers Evaluation in Pulmonary Fibrosis | TrialScreen, accessed May 27, 2025, https://app.trialscreen.org/trials/metabolomic-biomarkers-evaluation-pulmonary-fibrosis-study-nct06974799