FiberNeer Jascade Rheumatology Phase One Clinical Data Notes

Phase 2 Training Schedule and Overview

• Current Status: Today marks the conclusion of Phase 1 training. Phase 2 is scheduled to take place from July 6th through July 10th.

• Phase 2 Schedule Specifics:

  • Monday, July 6th: Focuses on the Viva call and training on both branded and unbranded resources.

  • Tuesday, July 7th: Disease state teach-backs are presented; these are prepared in partnerships. This day also includes branded component practice and role-playing.

  • Wednesday, July 8th: Includes a baseline verbal assessment with the Area Director and a mandatory compliance call.

  • Thursday, July 9th – Friday, July 10th: Includes various specific calls such as Care Connect for me and omnichannel training sessions.

• Training Theme: Phase 2 utilizes a "CAMP" theme.

• Calendar Aside: A specific song was played to celebrate July 4th falling on a Saturday, a phenomenon that reportedly has not happened in several years and will not recur for another $11$ years.

Jascade Mechanism of Action (MOA) and Differentiation

• Core Classification: Jascade (neridromalast) is a novel, preferential $PDE4B$ inhibitor.

• Differentiation from Competitors:

  • Otezla (apremilast): Rheumatologists are familiar with $PDE4$ inhibitors via Otezla. Jascade is differentiated by the "B" component.

  • Localization: $PDE4B$ is heavily expressed in the lungs and the immune system, but less so in the gastrointestinal (GI) tract. This localization suggests a cleaner safety profile regarding GI issues compared to non-selective inhibitors.

• Triple Threat Pathogenesis: Jascade targets the three key prongs of Interstitial Lung Disease (ILD):

  • Anti-fibrotic effects: Directly impacts the fibrotic process.

  • Vascular properties: Technically defined as reducing microvascular permeability. In simpler terms, it reduces "blood vessel leakiness." This is significant because leakiness increases inflammation.

  • Immunomodulatory effects: Specifically reduces the expression of pro-inflammatory cytokines. This is an important talking point for rheumatologists.

• Preferential Inhibition: Jascade increases $cAMP$ levels ($\text{High cAMP = Good; Low cAMP = Bad}$).

FiberNeer Phase 3 Trial Design

• Trial Name: FiberNeer ILD.

• Structure: Phase 3, randomized, double-blind, placebo-controlled trial.

• Enrollment: approximately $1200$ patients.

• Randomization Arms: Patients were randomized $1:1:1$ into:

  • Jascade $18\,mg$ BID (twice daily).

  • Jascade $9\,mg$ BID.

  • Placebo.

• Stratification Factors:

  • Background Antifibrotic Use: Patients used nintedanib ($OFEV$). Pirfenidone was not included because it lacks the Progressive Pulmonary Fibrosis (PPF) indication.

  • HRCT Pattern: Patients were stratified by Usual Interstitial Pneumonia (UIP) or UIP-like fibrotic patterns versus other fibrotic patterns (e.g., $NSIP$ or Non-Specific Interstitial Pneumonitis).

Trial Inclusion and Progression Definitions

• Age Requirement: Patients aged $18$ years or older.

• Lung Function Thresholds:

  • Forced Vital Capacity (FVC) $\geq 45\%$.

  • Diffusing Capacity for Carbon Monoxide (DLCO) $\geq 25\%$.

  • Inclusion required meeting one of these two criteria.

• Defining Progression (PPF): Selection required relevant fibrosis (defined as $10\%$ fibrotic features on HRCT) and meeting at least two of the following three criteria:

  • Worsening Symptoms: Self-reported or clinician-observed decline.

  • FVC Decline: Objective measurement of lung function worsening.

  • Imaging Decline: Increased fibrosis visible on HRCT.

• Background Medication Considerations:

  • Nintedanib: Patients had to be on a stable dose for at least $12$ weeks. Study results showed that Jascade can be used concomitantly with nintedanib safeley.

  • Washout: There is no hard washout period required for switching from nintedanib to Jascade in clinical practice, though the trial used an $8$-week discontinuation for purity in monotherapy assessment.

  • Exclusions: Initial exclusion included prednisone > 15\,mg/day, cyclophosphamide, Actemra, mycophenolate, pirfenidone (within $8$ weeks), or Rituximab (within $6$ months). These were excluded to assess Jascade as a standalone molecule, though they could be layered back in after $6$ months.

Baseline Demographics and Autoimmune Subgroup Characteristics

• General Trial Demographics:

  • Mean Age: $66$ years (range $26$ to $88$).

  • Gender: $56\%$ male, $44\%$ female.

  • Baseline FVC: $70\%$.

  • Mean Time Since Diagnosis: $4.2$ years.

  • Supplemental Oxygen Use: $28\%$ at baseline.

• Autoimmune ILD Subgroup (The Rheumatology Focal Point):

  • This population represented $28\% - 30\%$ of the total trial.

  • Mean Age: $63$ years.

  • Baseline FVC: $72\%$.

  • HRCT Pattern: $80\%$ had UIP; $21\%$ had other patterns.

  • Background Immunosuppressant Use: $55\%$ in the autoimmune subgroup compared to $25\%$ for the total trial population.

  • Specific Immunosuppressants: After $6$ months, common medications like methotrexate, azathioprine, and hydroxychloroquine were layered in, though the number of patients requiring reintroduction was low (often < 1\% for certain drugs like mycophenolate).

Primary Efficacy: Lung Function and FVC Data

• Primary Endpoint: Absolute change from baseline in FVC ($mL$) over a $52$-week period compared to placebo.

• Outcome Gold Standard: FVC is utilized because it is the strongest predictor of mortality in ILD.

• Statistical Significance: Both the $18\,mg$ and $9\,mg$ doses met the primary endpoint with statistical significance.

• Recommended Dose: Jascade $18\,mg$ BID is the recommended therapeutic dose.

• Subgroup Reductions (FVC Decline):

  • Total Autoimmune ILD Population: $39\%$ relative reduction.

  • UIP Pattern: $27\%$ relative reduction.

  • Other Fibrotic Patterns (NSIP, etc.): $72\%$ relative reduction.

  • Monotherapy (No background antifibrotic): $39\%$ relative reduction.

  • Combination (With background nintedanib): $47\%$ relative reduction. This is considered an "additive benefit" on top of the benefit already received from $OFEV$.

• Onset of Action: Separation from placebo was observed as early as Week 2. There was a slight uptick in FVC early on, followed by a consistent treatment effect over $52$ weeks.

Secondary Endpoints: Composite and Individual Signals

• Key Secondary Endpoint: A composite endpoint including:

  1. Time to first acute ILD exacerbation.

  2. Hospitalization for respiratory cause.

  3. Death.

• Statistical Result: As a composite, the result was neutral (did not meet statistical significance). However, the individual signals within the composite were clinically meaningful.

• Death Analysis:

  • $24$ patients died in the Jascade $18\,mg$ group vs. $50$ patients in the placebo group.

  • This represents a $52\%$ relative risk reduction in death (Hazard Ratio = $0.48$). All data points favored Jascade over placebo.

Numbers Needed to Treat (NNT) and Exploratory Data

• Definition: NNT is the number of patients that need to be treated for one additional patient to see a specific benefit. It is calculated by $\frac{1}{\text{Absolute Risk Reduction}}$.

• Acute ILD Exacerbation or Death (All group): Relative risk reduction of $41\%$; NNT = $12$.

• Death (All group): NNT = $18$.

• Autoimmune Subgroup Death (Exploratory): NNT = $11$.

• Contextual Comparison: For reference, the NNT for medications like Jardiance in heart failure is approximately $38$. The low NNT with Jascade (ranging $11 - 18$) highlights high clinical relevance.

Survival Data and Clinical Significance

• First for Antifibrotics: Jascade is the first antifibrotic on the market to show survival data in the autoimmune ILD population.

• Autoimmune ILD Survival Sub-analysis:

  • $72\%$ relative risk reduction in death for the autoimmune subgroup.

  • Absolute Risk Reduction: $9.8\%$.

  • NNT: $11$.

• Communication Strategy: This is described as a "mic drop" slide. Reps are encouraged to ask providers: "How could data like this change the conversation you have with your patients?"

Safety Profile and Clinical Tolerability

• Labels: No warnings or precautions; no contraindications. It is described as a "peaceful" drug.

• Adverse Events (AEs):

  • Diarrhea: The most common AE ($49\%$ in the total group; $27\%$ in monotherapy users). Diarrhea was typically mild to moderate and transient, usually occurring within the first $3$ months.

  • Discontinuation: Only $1\%$ of monotherapy patients discontinued due to diarrhea.

  • Other common AEs: Cough, upper respiratory tract infections (URTI), and weight decrease.

  • Infections: Significant or serious infections were lower in the Jascade group ($14\%$) than the placebo group ($17\%$).

• Malignancies: No signals warranted label changes; numbers were extremely small.

Dosing, Administration, and Lab Monitoring

• Standard Dose: $18\,mg$ BID.

• Dose Adjustment: If the patient cannot tolerate $18\,mg$, they can be titrated down to $9\,mg$ BID.

• Flexibility: Can be taken with or without food.

• Lab Requirements: No lab monitoring required. Unlike nintedanib, which requires liver function tests (LFTs) every $30$ days for the first $90$ days, Jascade requires no blood work.

• Dysphagia: Tablets can be dispersed in water for patients who have difficulty swallowing.

Practical Sales Resources and Administrative Procedures

• Summary Page: A high-level view containing the six high-level points (MOA, Primary Endpoint, NNT, Survival, Safety, Dosing/No Labs). This is recommended for "elevator pitches."

• Patient Profiles: Profiles exist for RA, Scleroderma, and Mixed Connective Tissue disease patients to help clinicians identify appropriate candidates.

• Prescription/Administrative Info:

  • ICD-10 Codes: Pulmonary fibrosis unspecified ($J84.10$) or Progressive fibrosing interstitial lung disease ($J84.170$). Patients should not be coded with IPF unless applicable.

  • Hub Services: Shared via "Care Connect for me." Third-party servicing is moving away from CoverMyMeds.

  • Reference Materials: Literature can be ordered via Hibbert.

Questions & Discussion

• Question: "How do you handle the vascular property explanation in simple terms?"

• Answer: It means Jascade reduces blood vessel leakiness, which in turn reduces inflammation.

• Question: "What is the separation from placebo for other antifibrotics compared to Week 2?"

• Answer: OFEV had good separation but did not show the slight FVC uptick seen with Jascade. The Week 2 separation is a major point of interest for academic centers.

• Question: "Is there a specific ICD-10 code for PPF?"

• Answer: Not a single specific one; clinicians use $J84.170$ (used for OFEV) or $J84.10$. Avoid the IPF code for autoimmune patients.

• Question: "What do you say when a rheumatologist won't write the script because they don't want to step on the Pulmonologist's toes?"

• Answer: Explore that relationship. Not all pulmonologists are ILD experts. If the wait time is long, suggest the rheumatologist initiate therapy while the referral is pending. Stress that many pulmonologists are burnt out and may appreciate the rheumatologist handling the initial paperwork and prior authorization.

Phase 2 Training Schedule and Overview - Current Status: Today marks the conclusion of Phase 1 training. Phase 2 is scheduled to take place from July 6th through July 10th. - Phase 2 Schedule Specifics:- Monday, July 6th: Focuses on the Viva call and training on both branded and unbranded resources. - Tuesday, July 7th: Disease state teach-backs are presented; these are prepared in partnerships. This day also includes branded component practice and role-playing. - Wednesday, July 8th: Includes a baseline verbal assessment with the Area Director and a mandatory compliance call. - Thursday, July 9th – Friday, July 10th: Includes various specific calls such as Care Connect for me and omnichannel training sessions. - Training Theme: Phase 2 utilizes a "CAMP" theme. - Calendar Aside: A specific song was played to celebrate July 4th falling on a Saturday, a phenomenon that reportedly has not happened in several years and will not recur for another $11$ years.

Elevator Pitch:

Representatives are encouraged to ask providers: "How could data like this change the conversation you have with your patients?"

Jascade Mechanism of Action (MOA) and Differentiation - Core Classification: Jascade (neridromalast) is a novel, preferential $PDE4B$ inhibitor. - Differentiation from Competitors:- Otezla (apremilast): Rheumatologists are familiar with $PDE4$ inhibitors via Otezla. Jascade is differentiated by the "B" component. - Localization: $PDE4B$ is heavily expressed in the lungs and the immune system, but less so in the gastrointestinal (GI) tract. This localization suggests a cleaner safety profile regarding GI issues compared to non-selective inhibitors. - Triple Threat Pathogenesis: Jascade targets the three key prongs of Interstitial Lung Disease (ILD):- Anti-fibrotic effects: Directly impacts the fibrotic process. - Vascular properties: Technically defined as reducing microvascular permeability. In simpler terms, it reduces "blood vessel leakiness." This is significant because leakiness increases inflammation. - Immunomodulatory effects: Specifically reduces the expression of pro-inflammatory cytokines. This is an important talking point for rheumatologists. - Preferential Inhibition: Jascade increases $cAMP$ levels ($ext{High cAMP = Good; Low cAMP = Bad}$).

FiberNeer Phase 3 Trial Design - Trial Name: FiberNeer ILD. - Structure: Phase 3, randomized, double-blind, placebo-controlled trial. - Enrollment: approximately $1200$ patients. - Randomization Arms: Patients were randomized $1:1:1$ into:- Jascade $18\,mg$ BID (twice daily). - Jascade $9\,mg$ BID. - Placebo. - Stratification Factors:- Background Antifibrotic Use: Patients used nintedanib ($OFEV$). Pirfenidone was not included because it lacks the Progressive Pulmonary Fibrosis (PPF) indication. - HRCT Pattern: Patients were stratified by Usual Interstitial Pneumonia (UIP) or UIP-like fibrotic patterns versus other fibrotic patterns (e.g., $NSIP$ or Non-Specific Interstitial Pneumonitis).

Trial Inclusion and Progression Definitions - Age Requirement: Patients aged $18$ years or older. - Lung Function Thresholds:- Forced Vital Capacity (FVC) $\geq 45\%$. - Diffusing Capacity for Carbon Monoxide (DLCO) $\geq 25\%$. - Inclusion required meeting one of these two criteria. - Defining Progression (PPF): Selection required relevant fibrosis (defined as $10\%$ fibrotic features on HRCT) and meeting at least two of the following three criteria:- Worsening Symptoms: Self-reported or clinician-observed decline. - FVC Decline: Objective measurement of lung function worsening. - Imaging Decline: Increased fibrosis visible on HRCT. - Background Medication Considerations:- Nintedanib: Patients had to be on a stable dose for at least $12$ weeks. Study results showed that Jascade can be used concomitantly with nintedanib safeley. - Washout: There is no hard washout period required for switching from nintedanib to Jascade in clinical practice, though the trial used an $8$-week discontinuation for purity in monotherapy assessment. - Exclusions: Initial exclusion included prednisone > 15\,mg/day, cyclophosphamide, Actemra, mycophenolate, pirfenidone (within $8$ weeks), or Rituximab (within $6$ months). These were excluded to assess Jascade as a standalone molecule, though they could be layered back in after $6$ months.

Baseline Demographics and Autoimmune Subgroup Characteristics - General Trial Demographics:- Mean Age: $66$ years (range $26$ to $88$). - Gender: $56\%$ male, $44\%$ female. - Baseline FVC: $70\%$. - Mean Time Since Diagnosis: $4.2$ years. - Supplemental Oxygen Use: $28\%$ at baseline. - Autoimmune ILD Subgroup (The Rheumatology Focal Point):- This population represented $28\% - 30\%$ of the total trial. - Mean Age: $63$ years. - Baseline FVC: $72\%$. - HRCT Pattern: $80\%$ had UIP; $21\%$ had other patterns. - Background Immunosuppressant Use: $55\%$ in the autoimmune subgroup compared to $25\%$ for the total trial population. - Specific Immunosuppressants: After $6$ months, common medications like methotrexate, azathioprine, and hydroxychloroquine were layered in, though the number of patients requiring reintroduction was low (often ## Primary Efficacy: Lung Function and FVC Data - Primary Endpoint: Absolute change from baseline in FVC (mL$) over a$52$-week period compared to placebo. - <strong>Outcome Gold Standard:</strong> FVC is utilized because it is the strongest predictor of mortality in ILD. - <strong>Statistical Significance:</strong> Both the$18\,mg$and$9\,mg$doses met the primary endpoint with statistical significance. - <strong>Recommended Dose:</strong> Jascade$18\,mg$BID is the recommended therapeutic dose. - <strong>Subgroup Reductions (FVC Decline):</strong>- <strong>Total Autoimmune ILD Population:</strong>$39\%$relative reduction. - <strong>UIP Pattern:</strong>$27\%$relative reduction. - <strong>Other Fibrotic Patterns (NSIP, etc.):</strong>$72\%$relative reduction. - <strong>Monotherapy (No background antifibrotic):</strong>$39\%$relative reduction. - <strong>Combination (With background nintedanib):</strong>$47\%$relative reduction. This is considered an "additive benefit" on top of the benefit already received from$OFEV$. - <strong>Onset of Action:</strong> Separation from placebo was observed as early as <strong>Week 2</strong>. There was a slight uptick in FVC early on, followed by a consistent treatment effect over$52$weeks.</h4><h4 id="d874402d-04f0-43a2-8046-495d1b36e13d" data-toc-id="d874402d-04f0-43a2-8046-495d1b36e13d" collapsed="false" seolevelmigrated="true">Secondary Endpoints: Composite and Individual Signals - <strong>Key Secondary Endpoint:</strong> A composite endpoint including:1. Time to first acute ILD exacerbation. 2. Hospitalization for respiratory cause. 3. Death. - <strong>Statistical Result:</strong> As a composite, the result was neutral (did not meet statistical significance). However, the individual signals within the composite were clinically meaningful. - <strong>Death Analysis:</strong>-$24$patients died in the Jascade$18\,mg$group vs.$50$patients in the placebo group. - This represents a <strong>$52\%$relative risk reduction</strong> in death (Hazard Ratio =$0.48$). All data points favored Jascade over placebo.</h4><h4 id="f1f77a57-da13-4c23-9656-97b306ef19be" data-toc-id="f1f77a57-da13-4c23-9656-97b306ef19be" collapsed="false" seolevelmigrated="true">Numbers Needed to Treat (NNT) and Exploratory Data - <strong>Definition:</strong> NNT is the number of patients that need to be treated for one additional patient to see a specific benefit. It is calculated by$\frac{1}{\text{Absolute Risk Reduction}}$. - <strong>Acute ILD Exacerbation or Death (All group):</strong> Relative risk reduction of$41\%$; NNT =$12$. - <strong>Death (All group):</strong> NNT =$18$. - <strong>Autoimmune Subgroup Death (Exploratory):</strong> NNT =$11$. - <strong>Contextual Comparison:</strong> For reference, the NNT for medications like Jardiance in heart failure is approximately$38$. The low NNT with Jascade (ranging$11 - 18$) highlights high clinical relevance.</h4><h4 id="dcfd88b0-f1ab-44ae-8b6b-93c21127348a" data-toc-id="dcfd88b0-f1ab-44ae-8b6b-93c21127348a" collapsed="false" seolevelmigrated="true">Survival Data and Clinical Significance - <strong>First for Antifibrotics:</strong> Jascade is the first antifibrotic on the market to show survival data in the autoimmune ILD population. - <strong>Autoimmune ILD Survival Sub-analysis:</strong>- <strong>$72\%$relative risk reduction</strong> in death for the autoimmune subgroup. - <strong>Absolute Risk Reduction:</strong>$9.8\%$. - <strong>NNT:</strong>$11$. - <strong>Communication Strategy:</strong> This is described as a "mic drop" slide. Reps are encouraged to ask providers: "How could data like this change the conversation you have with your patients?"</h4><h4 id="fbb0110e-cf53-4815-b30c-9f330bb67611" data-toc-id="fbb0110e-cf53-4815-b30c-9f330bb67611" collapsed="false" seolevelmigrated="true">Safety Profile and Clinical Tolerability - <strong>Labels:</strong> No warnings or precautions; no contraindications. It is described as a "peaceful" drug. - <strong>Adverse Events (AEs):</strong>- <strong>Diarrhea:</strong> The most common AE ($49\%$in the total group;$27\%$in monotherapy users). Diarrhea was typically mild to moderate and transient, usually occurring within the first$3$months. - <strong>Discontinuation:</strong> Only$1\%$of monotherapy patients discontinued due to diarrhea. - <strong>Other common AEs:</strong> Cough, upper respiratory tract infections (URTI), and weight decrease. - <strong>Infections:</strong> Significant or serious infections were lower in the Jascade group ($14\%$) than the placebo group ($17\%$). - <strong>Malignancies:</strong> No signals warranted label changes; numbers were extremely small.</h4><h4 id="4981d4c5-5a2a-4e97-adbc-b711066f0534" data-toc-id="4981d4c5-5a2a-4e97-adbc-b711066f0534" collapsed="false" seolevelmigrated="true">Dosing, Administration, and Lab Monitoring - <strong>Standard Dose:</strong>$18\,mg$BID. - <strong>Dose Adjustment:</strong> If the patient cannot tolerate$18\,mg$, they can be titrated down to$9\,mg$BID. - <strong>Flexibility:</strong> Can be taken with or without food. - <strong>Lab Requirements:</strong> <strong>No lab monitoring required.</strong> Unlike nintedanib, which requires liver function tests (LFTs) every$30$days for the first$90$days, Jascade requires no blood work. - <strong>Dysphagia:</strong> Tablets can be dispersed in water for patients who have difficulty swallowing.</h4><h4 id="042eea00-7930-4121-8f3d-a06a1db279c4" data-toc-id="042eea00-7930-4121-8f3d-a06a1db279c4" collapsed="false" seolevelmigrated="true">Practical Sales Resources and Administrative Procedures - <strong>Summary Page:</strong> A high-level view containing the six high-level points (MOA, Primary Endpoint, NNT, Survival, Safety, Dosing/No Labs). This is recommended for "elevator pitches." - <strong>Patient Profiles:</strong> Profiles exist for RA, Scleroderma, and Mixed Connective Tissue disease patients to help clinicians identify appropriate candidates. - <strong>Prescription/Administrative Info:</strong>- <strong>ICD-10 Codes:</strong> Pulmonary fibrosis unspecified ($J84.10$) or Progressive fibrosing interstitial lung disease ($J84.170). Patients should not be coded with IPF unless applicable. - Hub Services: Shared via "Care Connect for me." Third-party servicing is moving away from CoverMyMeds. - Reference Materials: Literature can be ordered via Hibbert.

Questions & Discussion - Question: "How do you handle the vascular property explanation in simple terms?" - Answer: It means Jascade reduces blood vessel leakiness, which in turn reduces inflammation. - Question: "What is the separation from placebo for other antifibrotics compared to Week 2?" - Answer: OFEV had good separation but did not show the slight FVC uptick seen with Jascade. The Week 2 separation is a major point of interest for academic centers. - Question: "Is there a specific ICD-10 code for PPF?" - Answer: Not a single specific one; clinicians use J84.170$(used for OFEV) or$J84.10$$. Avoid the IPF code for autoimmune patients. - Question: "What do you say when a rheumatologist won't write the script because they don't want to step on the Pulmonologist's toes?" - Answer: Explore that relationship. Not all pulmonologists are ILD experts. If the wait time is long, suggest the rheumatologist initiate therapy while the referral is pending. Stress that many pulmonologists are burnt out and may appreciate the rheumatologist handling the initial paperwork and prior authorization.