CN117396133A

CN117396133A - Implantable corticosteroid matrices for sinus conditions

Info

Publication number: CN117396133A
Application number: CN202280019715.4A
Authority: CN
Inventors: A·瑟文; J·里默; A·沃贝尔; Y·阿比拉克; L·布拉通; Y·匡
Original assignee: Laila Pharmaceutical Co
Current assignee: Laila Pharmaceutical Co
Priority date: 2021-03-08
Filing date: 2022-03-08
Publication date: 2024-01-12

Abstract

The present invention relates to materials, devices, kits and methods for treating patients with sinus conditions, including patients with (or at risk of) severe chronic nasal and sinus inflammatory (CRS) symptoms. More specifically, in certain embodiments, one device is a long-acting corticosteroid matrix.

Description

Implantable corticosteroid matrices for sinus conditions

Technical Field

Background

Topical steroids are first-line treatment of chronic nasal and nasal sinusitis (CRS), but do not provide adequate symptomatic control for many patients. However, current clinical practice guidelines generally recommend topical corticosteroids as a first line treatment for CRS patients ^2,3 . Corticosteroids reduce inflammation associated with known CRS isoforms and are particularly effective in inhibiting T2 (T cell type II) inflammation.

However, intranasal corticosteroids (INCS) do not provide adequate symptomatic control for patients because of one or more of their limited ability to reach deep inflammation within the sinus passages, rapid clearance, and poor patient compliance ^7,8 . About 40-60% of CRS patients fail to receive medication administration ⁹ And are candidates for Functional Endoscopic Sinus Surgery (FESS). Many of these patients who have failed medication choose not to undergo surgery becauseIt does not address the underlying inflammation of CRS nor does it eliminate the need for continued drug therapy. In addition, approximately 65% of patients develop recurrent symptoms within the first year after FESS. ¹⁰

Thus, for CRS patients with current medication failure, a new treatment modality is needed, whether or not accompanied by nasal polyps.

Summary of The Invention

The present invention relates to materials, devices, kits and methods for treating patients with sinus conditions, including patients with (or at risk of) severe chronic nasal and sinus inflammatory (CRS) symptoms. In one embodiment, the invention contemplates a method of treating a sinus condition in a patient or group of patients. In one embodiment, the implant may be used to improve sinus patency, for example in a surgically modified sinus space or in a space such as the middle nasal meatus that has not been previously surgically modified. Furthermore, these stents may be used to deliver local therapeutic agents such as Mometasone Furoate (MF) to the nasal cavity, including, for example, as part of a treatment plan for sinus surgery (e.g., an alternative to FESS), or in some embodiments in other cases as part of post-operative care for FESS. In one embodiment, implantable sinus treatment achieves 24 weeks (or longer) benefit by single bilateral administration of MF eluting implants in the first and second middle nasal passages of an unskilled CRS patient with or without nasal polyps. In one embodiment, the subject continues to improve, exhibiting a sustained response, even after removal of the implant. Importantly, removal does not result in any immediate increase in adverse symptoms.

In one embodiment, the patient is a candidate for a sinus surgery, such as a Functional Endoscopic Sinus Surgery (FESS), based on the first trial score. In one embodiment, the first trial score is a 22-sinus result trial (SNOT-22) severity score of greater than or equal to 20 prior to implantation of the first implant. In one embodiment, after implantation of both sides of the MF eluting implant, the patient is no longer a candidate for sinus surgery, such as Functional Endoscopic Sinus Surgery (FESS), based on the second trial score. In one embodiment, the second trial score is a 22-sinus result trial (SNOT-22) severity score of less than 20 after implantation of the first implant. In one embodiment, the patient is no longer a candidate for Functional Endoscopic Sinus Surgery (FESS) based on the second trial score 1 month after implantation of the first implant. In one embodiment, the patient is no longer a candidate for Functional Endoscopic Sinus Surgery (FESS) based on the second trial score 3 months after implantation of the first implant. In one embodiment, the patient is no longer a candidate for Functional Endoscopic Sinus Surgery (FESS) based on the second trial score 6 months after implantation of the first implant. Avoiding surgical intervention in CRS treatment is preferred for patients because these procedures present surgical related risks, cause post-operative pain and discomfort, and require cumbersome and expensive post-operative cleaning.

In certain embodiments, the stent or implant can be easily placed in the first and second middle nasal passages on both sides of the subject (and they can be easily removed later) in an office environment. In certain embodiments, patients with drug eluting stents or implants experience significant symptom relief within 7 days, lasting effects lasting for at least 12 weeks, up to 16 weeks, up to 3 months, up to 4 months, up to 5 months, up to 6 months and above. In certain embodiments, a patient with a stent or implant is a CRS surgical candidate patient prior to implantation of an implant or stent comprising Mometasone Furoate (MF), and is transitioned to a patient that no longer requires surgery (i.e., the patient's symptoms are alleviated such that the patient no longer meets the criteria for designating the patient as a surgical candidate). In certain embodiments, the stent results in rapid symptomatic improvement as early as 1 week. In certain embodiments, a significant effect is observed within 3 months, with most patients transitioning from surgical candidates to no longer meeting the criteria of the surgical candidates.

In one embodiment, the method comprises: a) Providing first and second implants each comprising about 7500 micrograms of mometasone furoate; b) Implanting the first implant into a first middle nasal meatus of a first patient (or first patient population) having a sinus condition; c) Implanting the second implant into a second middle nasal meatus of the first patient (or first patient population); d) Monitoring the first patient (or first patient population) for a period of at least 12 weeks for a sinus condition, wherein the first patient (or first patient population) implanted with first and second implants each comprising about 7500 micrograms of mometasone furoate exhibits a reduced need for rescue therapy as compared to a second patient (or second patient population) with a sinus condition implanted with first and second implants each comprising about 2500 micrograms of mometasone furoate. Monitoring may be performed intermittently, for example once a week, once every two weeks, once every four weeks; it need not be continuous. The monitoring may be accomplished by a physician, nurse, technician, or other medical personnel. The monitoring may be performed in person, for example in a medical office, or remotely, for example by telephone. Monitoring may be as simple as obtaining subjective reports from the patient regarding their status (e.g., level and number of symptoms, if any).

The present invention is not intended to limit patients (or patient populations) with respect to previous treatments. Nonetheless, in a preferred embodiment, the first patient has failed drug management (e.g., using a local steroid) and becomes a candidate for Functional Endoscopic Sinus Surgery (FESS). In a preferred embodiment, the patient (or patient population) is not surgical, i.e., they have not received any prior sinus/nasal surgery. In one embodiment, the patient has or does not have nasal polyps.

The present invention is not intended to limit the nature of rescue treatments. In one embodiment, the rescue therapy is a drug. Such rescue drugs may include intranasal corticosteroids (INCS), oral corticosteroids, antibiotics, antihistamines, oral decongestants, and monoclonal antibodies.

The present invention is not intended to limit the nature of the drug release kinetics of the implant. Nevertheless, in a preferred embodiment, the drug is released in a substantially linear manner over at least 12 weeks of implantation, e.g. from week two to week 13. In a more preferred embodiment, the implant exhibits zero order release for at least 12 weeks of implantation, e.g., from week two to week 13. In one embodiment, the first and second implants are configured to release 20 to 80% of the mometasone furoate during the first 12 cycles. In one embodiment, wherein 80% of the mometasone furoate is released within 24 weeks.

The response to about 7500 micrograms of drug (in each implant) is not meant to be shown only in terms of reduced rescue treatments. In one embodiment, the sinus condition of the first patient (or first patient population) is improved more rapidly than a second patient (or second patient population) implanted with a first and second implant comprising 2500 micrograms of mometasone furoate. In one embodiment, a first patient (or first patient population) receiving LYR-210 (7500 μg) experiences generally less headache as compared to LYR-210 (2500 μg) and saline. In one embodiment, a first patient (or first patient population) receiving LYR-210 (7500 μg) has fewer treatment-related adverse events than LYR-210 (2500 μg). In one embodiment, a first patient (or first patient population) receiving LYR-210 (7500 μg) exhibits improved symptoms of nasal congestion, facial pain/compression, and/or runny nose as compared to LYR-210 (2500 μg) and nasal saline. In one embodiment, a first patient (or first patient population) receiving LYR-210 (7500 μg) exhibits an improvement in symptoms of olfactory loss compared to LYR-210 (2500 μg) and a control treated with saline alone. In one embodiment, a first patient (or first patient population) receiving LYR-210 (7500 μg) exhibits an improvement in symptoms as measured by SNOT-22 score as compared to LYR-210 (2500 μg). In one embodiment, a first patient (or first patient population) receiving LYR-210 (7500 μg) exhibits a greater early SNOT-22 improvement in patients with polyps than LYR-210 (2500 μg). In one embodiment, a first patient (or first patient population) receiving LYR-210 (7500 μg) exhibits a greater reduction in ethmoid sinus inflammation compared to LYR-210 (2500 μg) and a control treated with saline alone.

In one embodiment, the sinus condition is a chronic sinus condition. In one embodiment, the sinus condition is characterized by at least two symptoms selected from the group consisting of: nasal congestion, dyspnea through the nasal passages, nasal polyps, runny nose, loss of smell and facial pain. In one embodiment, the CRS is characterized by 2 or more of the following symptoms (for at least 12 weeks): runny nose (rhinorrhea or posterior rhinorrhea), nasal obstruction or congestion, hyposmia and facial pressure or pain.

The present invention is not intended to be limited to the specific configuration of the implant. In a preferred embodiment, however, at least one of the first or second implants is a braided structure. In a preferred embodiment, at least one of the first or second implants is a tubular structure. In a preferred embodiment, at least one of the first or second implants is self-expanding. In another embodiment, the implant comprises a helical wire. An exemplary implant is shown in fig. 9C. In another embodiment, the implant is a sheet. The permeable or semi-permeable sheet material may be implanted flat or in a rolled state. In a crimping embodiment, the crimped sheet comprises an internal cavity. In this exemplary embodiment, the drug delivery device is comprised of a semipermeable polymeric hollow sheet filled with a drug or Active Pharmaceutical Ingredient (API) in the absence or presence of a zymogen (osmogen). Examples are shown in fig. 11-12.

The monitoring is not intended to be limited to just 12 weeks. In another embodiment, monitoring of the first patient for a sinus condition is performed for a period of at least 16 weeks. In yet another embodiment, monitoring of the first patient for a sinus condition is performed for a period of at least 20 weeks. In yet another embodiment, the monitoring is performed for a period of 24 weeks or more. Monitoring may be performed intermittently, for example once a week, once every two weeks, once every four weeks; it need not be continuous. The monitoring may be accomplished by a physician, nurse, technician, or other medical personnel. The monitoring may be performed in person, for example in a medical office, or remotely, for example by telephone. Monitoring may be as simple as obtaining subjective reports from the patient regarding their status (e.g., level and number of symptoms, if any).

The present invention is not intended to limit how the implant is loaded with a drug. However, in a preferred embodiment, the first and second implants each comprise at least one coating containing about 7500 micrograms of mometasone furoate, which means 7000 micrograms to 8000 micrograms, and more typically 7500 micrograms ± 10%. In a preferred embodiment, the coating is a polymeric coating. In another embodiment, the drug containing coating is covered (at least in part) with another drug free polymeric coating or "top coating". In one embodiment, the thickness of the topcoat controls the amount and/or timing of drug release.

In one embodiment, the invention contemplates a method of treating a sinus condition, the method comprising: a) Providing first and second implants each comprising about 7500 micrograms of mometasone furoate; b) Implanting the first implant into a first middle nasal meatus of a first patient (or first patient population) having a sinus condition; c) Implanting the second implant into a second middle nasal meatus of the first patient (or first patient population); d) Monitoring the first patient (or first patient population) for a period of at least 12 weeks of a sinus condition, wherein the first patient (or first patient population) implanted with first and second implants each comprising about 7500 micrograms of mometasone furoate exhibits a reduced need for rescue therapy as compared to a second patient (or second patient population) having a sinus condition administered only a saline flush therapy and no mometasone furoate. Monitoring may be performed intermittently, for example once a week, once every two weeks, once every four weeks; it need not be continuous. The monitoring may be accomplished by a physician, nurse, technician, or other medical personnel. The monitoring may be performed in person, for example in a medical office, or remotely, for example by telephone. Monitoring may be as simple as obtaining subjective reports from the patient regarding their status (e.g., level and number of symptoms, if any).

The present invention is not intended to limit patients (or patient populations) with respect to previous treatments. Nonetheless, in a preferred embodiment, the first patient has failed drug management (e.g., using a local steroid) and becomes a candidate for Functional Endoscopic Sinus Surgery (FESS). In a preferred embodiment, the patient (or patient population) is not surgical, i.e., they have not received any prior sinus/nasal surgery. In one embodiment, the patient has or does not have nasal polyps. In one embodiment, the CRS is characterized by 2 or more of the following symptoms (for at least 12 weeks): runny nose (rhinorrhea or posterior rhinorrhea), nasal obstruction or congestion, hyposmia and facial pressure or pain.

The present invention is not intended to limit the nature of the drug release kinetics of the implant. Nevertheless, in a preferred embodiment, the drug is released in a substantially linear manner over at least 12 weeks of implantation, e.g. from week two to week 13. In a more preferred embodiment, the implant exhibits zero order release for at least 12 weeks of implantation, e.g., from week two to week 13. In one embodiment, the first and second implants are configured to release 20 to 80% of the mometasone furoate during the first 12 cycles.

In one embodiment, the sinus condition of the first patient (or first patient population) is improved compared to the second patient. The present invention is not intended to limit how such improvements may be embodied. In one embodiment, a first patient (or first patient population) receiving LYR-210 (7500 μg) experiences generally fewer headaches than a patient receiving saline alone. In one embodiment, a first patient (or first patient population) receiving LYR-210 (7500 μg) exhibits improved symptoms of nasal obstruction, facial pain/compression, and/or runny nose as compared to a patient receiving saline alone. In one embodiment, a first patient (or first patient population) receiving LYR-210 (7500 μg) exhibits an improvement in symptoms of olfactory loss as compared to a control treated with saline alone. In one embodiment, a first patient (or first patient population) receiving LYR-210 (7500 μg) exhibits a greater reduction in ethmoid sinus inflammation than a control treated with saline alone.

The present invention is not intended to be limited to the specific configuration of the implant. In a preferred embodiment, however, at least one of the first or second implants is a braided structure. In a preferred embodiment, at least one of the first or second implants is a tubular structure. In a preferred embodiment, at least one of the first or second implants is self-expanding. In another embodiment, the implant comprises a helical wire. An exemplary implant is shown in fig. 9C. In another embodiment, the implant is a sheet. The permeable or semi-permeable sheet material may be implanted flat or in a rolled state. In a crimping embodiment, the crimped sheet comprises an internal cavity. In this exemplary embodiment, the drug delivery device is comprised of a semipermeable polymeric hollow sheet filled with a drug or Active Pharmaceutical Ingredient (API) in the absence or presence of a zymogen (osmogen).

The present invention is not intended to limit how the implant is loaded with a drug. However, in a preferred embodiment, the first and second implants each comprise at least one coating containing about 7500 micrograms of Mometasone Furoate (MF), which refers to 7000 micrograms to 8000 micrograms, and more typically 7500 micrograms ± 10%. In a preferred embodiment, the coating is a polymeric coating. In another embodiment, the drug containing coating is (at least partially) covered with another drug free polymeric coating or "top coating". In one embodiment, the thickness of the topcoat controls the amount and/or timing of drug release. Sustained delivery of MF to the sinus mucosa and sustained symptom relief is achieved by a single administration of the implant (rather than repeated re-administration of the drug). In a preferred embodiment, the implants are delivered for treatment of CRS in non-surgical adult patients with or without nasal polyps, including those with failed drug management.

In one embodiment, the invention contemplates a method of treating a sinus condition, the method comprising: a) Providing first and second implants each comprising about 7500 micrograms of mometasone furoate; b) Implanting the first implant into a first middle nasal meatus of a first patient (or first patient population) having a sinus condition; c) Implanting the second implant into a second middle nasal meatus of the first patient (or first patient population); d) Monitoring the first patient (or first patient population) for a period of at least 8 weeks for a sinus condition, wherein the first patient (or first patient population) implanted with first and second implants each comprising about 7500 micrograms of mometasone furoate improves more rapidly than the second patient (or second patient population) with a sinus condition implanted with first and second implants each comprising about 2500 micrograms of mometasone furoate. Monitoring may be performed intermittently, for example once a week, once every two weeks, once every four weeks; it need not be continuous. The monitoring may be accomplished by a physician, nurse, technician, or other medical personnel. The monitoring may be performed in person, for example in a medical office, or remotely, for example by telephone. Monitoring may be as simple as obtaining subjective reports from the patient regarding their status (e.g., level and number of symptoms, if any).

The present invention is not intended to limit when an improvement is detected. However, in one embodiment, improvement in a first patient (or first patient population) implanted with first and second implants each comprising about 7500 micrograms of mometasone furoate is observed at least as early as 8 weeks (or as early as 10, 12, 14, or 16 weeks) after implantation of the implant, as compared to a second patient (or second patient population) implanted with first and second implants each comprising about 2500 micrograms of mometasone furoate. Furthermore, in one embodiment, improvement in a first patient (or first patient population) implanted with first and second implants each comprising about 7500 micrograms of mometasone furoate is observed as early as 4 weeks after implantation of the implant, but more typically at or after 8 weeks, as compared to a second patient (or second patient population) implanted with first and second implants each comprising about 2500 micrograms of mometasone furoate. Acute exacerbations of chronic sinusitis occur less frequently in LYR-210 (7500 μg) treated groups during the 24 week treatment period.

The present invention is not intended to be limited to the specific configuration of the implant. In a preferred embodiment, however, at least one of the first or second implants is a braided structure. In a preferred embodiment, at least one of the first or second implants is a tubular structure. In a preferred embodiment, at least one of the first or second implants is self-expanding. In another embodiment, the implant comprises a helical wire. In another embodiment, the implant comprises a sheet. In another embodiment, the implant comprises a folded sheet. An exemplary implant is shown in fig. 9C. In another embodiment, the implant is a sheet. The permeable or semi-permeable sheet material may be implanted flat or in a rolled state. In a crimping embodiment, the crimped sheet comprises an internal cavity. In this exemplary embodiment, the drug delivery device is comprised of a semipermeable polymeric hollow sheet filled with a drug or Active Pharmaceutical Ingredient (API) in the absence or presence of a zymogen.

The monitoring is not intended to be limited to just 8 weeks. In another embodiment, the monitoring of the first patient for sinus conditions is performed for a period of at least 12 weeks. In yet another embodiment, monitoring of the first patient for a sinus condition is performed for a period of at least 16 weeks. In yet another embodiment, the monitoring is performed for a period of 20 weeks or more. Monitoring may be performed intermittently, for example once a week, once every two weeks, once every four weeks; it need not be continuous. The monitoring may be accomplished by a physician, nurse, technician, or other medical personnel. The monitoring may be performed in person, for example in a medical office, or remotely, for example by telephone.

The present invention is not intended to limit how the implant is loaded with a drug. However, in a preferred embodiment, the first and second implants each comprise at least one coating containing about 7500 micrograms of mometasone furoate, which means 7000 micrograms to 8000 micrograms, and more typically 7500 micrograms ± 10%. In a preferred embodiment, the coating is a polymeric coating. In another embodiment, the drug containing coating is covered (at least in part) with another drug free polymeric coating or "top coating". In one embodiment, the thickness of the topcoat controls the amount and/or timing of drug release. In one embodiment, the first and second implants are configured to release 20 to 80% of the mometasone furoate during the first 12 cycles.

In one embodiment, the present invention contemplates a self-expanding implantable device comprising about 7500 micrograms of mometasone furoate. The present invention is not intended to limit the amount of self-expansion. Nonetheless, in one embodiment, the devices of the present disclosure preferably expand to 70 to 100% of their as-manufactured configuration after crimping (e.g., to a smaller shape to facilitate delivery).

The present invention is not intended to be limited to the specific structure of the device. In a preferred embodiment, however, the device is a braided structure. In a preferred embodiment, the device is a tubular structure. In a preferred embodiment, the device comprises a spiral. In a preferred embodiment, the device is configured to conform to the middle nasal meatus space. In certain embodiments, the device is configured to have a relatively high RRF to be able to maintain open nasal features, such as the middle nasal meatus, but a relatively low COF to avoid applying potentially harmful forces to the walls of the middle nasal meatus. An exemplary device is shown in fig. 9C. In one embodiment, the device is part of a kit comprising a delivery device.

The present invention is not intended to limit how the device is loaded with medicament. However, in a preferred embodiment, the device comprises at least one coating containing about 7500 micrograms of mometasone furoate, which means 7000 micrograms to 8000 micrograms, and more typically 7500 micrograms ± 10%. In a preferred embodiment, the coating is a polymeric coating. In another embodiment, the drug containing coating is covered (at least in part) with another drug free polymeric coating or "top coating". In one embodiment, the thickness of the topcoat controls the amount and/or timing of drug release.

The present invention is not intended to limit the nature of the drug release kinetics of the implant. Nevertheless, in a preferred embodiment, the drug is released in a substantially linear manner over at least 12 weeks of implantation, e.g. from week two to week 13. In a more preferred embodiment, the implant exhibits zero order release for at least 12 weeks of implantation, e.g., from week two to week 13. In one embodiment, the device is configured to release 20 to 80% of the mometasone furoate during the first 12 cycles.

In one embodiment, the present invention contemplates a stent conforming to the shape of the middle nasal meatus space comprising: a) A stent comprising a plurality of polymeric wires, the polymeric wires comprising a first polymeric material; b) A coating on the stent comprising a crosslinked elastomer; and c) a layer comprising about 7500 micrograms of mometasone furoate. In one embodiment, the device further comprises d) a top coat over the layer comprising mometasone furoate, wherein the thickness of the top coat is configured such that the mometasone furoate is released substantially linearly over 6 weeks after placement of the stent into the middle nasal meatus. In one embodiment, the topcoat does not contain a drug. In one embodiment, the substantially linear release is after the first week. In one embodiment, the polymeric material comprises poly (lactide-co-glycolide). In one embodiment, the elastomeric material comprises poly (lactide-co-caprolactone). In one embodiment, the elastomeric material comprises poly (lactide-co-caprolactone) having a lactide mole percentage in the range of 30 to 50% and a caprolactone mole percentage in the range of 50 to 70%. In one embodiment, the invention contemplates delivering the stent to the middle nasal meatus space of a person. In one embodiment, the human has a sinus condition. In one embodiment, the sinus condition is chronic. In one embodiment, the present invention contemplates delivering first and second stents, each comprising about 7500 micrograms of mometasone furoate, to first and second middle nasal passages of a human on both sides. In one embodiment, the human has a sinus condition. In one embodiment, the sinus condition is chronic.

In one embodiment, the invention contemplates a combination therapy for use in a method of treating a sinus condition comprising first and second implants, each comprising at least one coating comprising about 7500 micrograms of mometasone furoate, wherein the first implant is configured to fit within a first middle nasal tract of a patient, the mometasone furoate is configured to be released in the first nasal cavity for more than 12 weeks; and wherein the second implant is configured to fit inside a second middle nasal meatus of the patient, the mometasone furoate is configured to be released in the second nasal passages for more than 12 weeks.

In one embodiment, the invention contemplates an implant configured to fit inside the middle nasal meatus, said implant comprising a coating comprising about 7500 micrograms of mometasone furoate, said implant configured to exhibit zero order release of at least 60% of said mometasone furoate. In one embodiment, the implant is configured to exhibit zero order release between 1 and 12 weeks. In one embodiment, the implant is configured to exhibit zero order release between day 20 and day 55 after implantation. In one embodiment, the present invention contemplates delivering the implant to the middle nasal meatus space of a person. In one embodiment, the human has a sinus condition. In one embodiment, the sinus condition is chronic. In one embodiment, the present invention contemplates delivering first and second implants each comprising about 7500 micrograms of mometasone furoate to first and second middle nasal passages of a human on both sides. In one embodiment, the human has a sinus condition. In one embodiment, the sinus condition is chronic.

In one embodiment, the invention contemplates an implant configured to fit inside the middle nasal meatus, the implant comprising a coating containing about 7500 micrograms of mometasone furoate, the implant configured to produce an approximately constant mometasone furoate plasma concentration of less than 100 picograms/ml. In one embodiment, the approximately constant mometasone furoate plasma concentration is 60 picograms/ml or less after week 1 and typically about 50 picograms/ml or less after week 1 (as shown in fig. 10). In one embodiment, the present invention contemplates delivering the implant to the middle nasal meatus space of a person. In one embodiment, the human has a sinus condition. In one embodiment, the sinus condition is chronic. In one embodiment, the present invention contemplates that the first and second stents, each comprising about 7500 micrograms of mometasone furoate, are delivered to the first and second middle nasal passages of a human on both sides. In one embodiment, the human has a sinus condition. In one embodiment, the sinus condition is chronic.

In one embodiment, the present invention contemplates that the patient will continue to improve in their sinus condition for a period of time even after removal of the implant (e.g., 2-4 weeks, 4-8 weeks, and even 16 weeks after removal). Thus, in one embodiment, the invention contemplates a method of treating a sinus condition, the method comprising: a) Providing first and second implants, each comprising mometasone furoate; b) Implanting the first implant inside a first middle nasal passage of a patient having a sinus condition; c) Implanting the second implant inside a second middle nasal meatus of the patient; d) Removing the first and second implants from the patient; and e) detecting an improvement in the patient's sinus condition for a period of at least 4 weeks after removal of the implant. In one embodiment, the patient is implanted with first and second implants each comprising about 7500 micrograms of mometasone furoate. In one embodiment, the patient is implanted with first and second implants each comprising about 2500 micrograms of mometasone furoate. In one embodiment, the improvement detected in the patient's sinus condition is reduced nasal obstruction, facial pain, runny nose (anterior/posterior), and/or loss of sense of smell. The improvement may be one or all of these symptoms. In one embodiment, the patient's condition continues to improve for a period of at least 8 weeks after removal of the implant. In one embodiment, the patient's condition continues to improve for a period of at least 12 weeks after removal of the implant. In one embodiment, the patient's condition continues to improve for a period of at least 16 weeks after removal of the implant. The present invention is not intended to limit any precise point in time when the implant is removed. However, in a preferred embodiment, the implant is removed after 12 weeks, 16 weeks, 20 weeks, 24 weeks or longer.

In one embodiment, the present invention contemplates that the patient's symptoms will remain at the level of the last week of treatment (e.g., based on the SNOT score) for a period of time after removal of the implant (e.g., 2-4 weeks, 4-8 weeks, and even 16 weeks after removal). This durable response suggests that this approach has benefits even after removal of the implant. Thus, in one embodiment, the invention contemplates a method of treating a sinus condition, the method comprising: a) Providing first and second implants, each comprising mometasone furoate; b) Implanting the first implant inside a first middle nasal passage of a patient having a sinus condition; c) Implanting the second implant inside a second middle nasal meatus of the patient; d) Removing the first and second implants from the patient; and e) measuring symptoms in the patient after removal of the implant, wherein the symptoms maintain the same level (e.g., based on a SNOT score) for a period of at least 4 weeks after removal. In one embodiment, the patient is implanted with first and second implants each comprising about 7500 micrograms of mometasone furoate. In one embodiment, the patient is implanted with first and second implants each comprising about 2500 micrograms of mometasone furoate. In one embodiment, the measured symptom comprises nasal obstruction, facial pain, runny nose (anterior/posterior), and/or loss of smell. The maintained level may be one or all of these symptoms. In one embodiment, the patient's symptom level is maintained for a period of at least 8 weeks after removal of the implant. In one embodiment, the patient's symptom level is maintained for a period of at least 12 weeks after removal of the implant. In one embodiment, the patient's symptom level is maintained for a period of at least 16 weeks after removal of the implant.

In one embodiment, the invention contemplates an implant configured to fit within the middle nasal meatus for preventing a need for surgery in a subject as a candidate for sinus surgery, the implant comprising a coating comprising about 7500 micrograms of mometasone furoate, the implant configured to exhibit zero order release of at least 60% of the mometasone furoate, characterized in that the implant is delivered to the subject prior to surgery. In one embodiment, the implant is configured for treatment for at least 4 months. In one embodiment, the sinus surgery is a Functional Endoscopic Sinus Surgery (FESS). In one embodiment, the implant is configured to release 20 to 80% of the mometasone furoate during the first 12 cycles. In one embodiment, the implant is configured to exhibit zero order release between 1 and 12 weeks. In one embodiment, the zero order release is in vitro at 37 ℃ in pH 7.4PBS buffer containing 2% SDS. In one embodiment, the implant is used in a method of improving sinus patency. In one embodiment, the implant is used in a method of treating a chronic sinus condition. In one embodiment, the chronic sinus condition is characterized by at least two symptoms selected from the group consisting of: nasal congestion, dyspnea through the nasal passages, nasal polyps, runny nose, and facial pain. In one embodiment, the implant is a braided structure. In one embodiment, the implant is a tubular structure. In one embodiment, the implant comprises a helical wire. In one embodiment, the implant is self-expanding. In one embodiment, the implant has a diameter of at least 13 mm. In one embodiment, the implant has a length of at least 10 mm. In one embodiment, the subject has a 22-sinus outcome test (SNOT-22) severity score of greater than or equal to 20.

In yet another embodiment, the invention contemplates an implant configured to fit inside a middle nasal meatus for preventing a need for surgery in a subject that is a candidate for Functional Endoscopic Sinus Surgery (FESS), the implant comprising a coating comprising about 7500 micrograms of mometasone furoate, the implant configured to exhibit zero order release of at least 60% of the mometasone furoate, characterized in that the implant is delivered to the subject prior to surgery, wherein the subject is treated for at least 4 months. In one embodiment, the implant is configured to release 20 to 80% of the mometasone furoate during the first 12 cycles. In one embodiment, the implant is configured to exhibit zero order release between 1 and 12 weeks. In one embodiment, the zero order release is in vitro at 37 ℃ in pH 7.4PBS buffer containing 2% SDS. In one embodiment, the implant is used in a method of improving sinus patency. In one embodiment, the implant is used in a method of treating a chronic sinus condition. In one embodiment, the chronic sinus condition is characterized by at least two symptoms selected from the group consisting of: nasal congestion, dyspnea through the nasal passages, nasal polyps, runny nose, and facial pain. In one embodiment, the implant is a braided structure. In one embodiment, the implant is a tubular structure. In one embodiment, the implant comprises a helical wire. In one embodiment, the implant is self-expanding. In one embodiment, the implant has a diameter of at least 13 mm. In one embodiment, the implant has a length of at least 10 mm. In one embodiment, the subject has a 22-sinus outcome test (SNOT-22) severity score of greater than or equal to 20.

In one embodiment, the invention contemplates a method of treating a sinus condition, the method comprising: a) Providing first and second implants, each comprising at least one coating comprising about 7500 micrograms of mometasone furoate, and wherein the first implant is configured to fit within a first middle nasal meatus of a patient, and wherein the second implant is configured to fit within a second middle nasal meatus of the patient; b) Implanting the first and second implants into the first and second middle nasal passages of a patient having symptoms of a sinus condition, and c) detecting a reduction in one or more symptoms, thereby treating the sinus condition. In one embodiment, the mometasone furoate configured in each implant exhibits zero order release over 12 weeks or more of the planned implantation phase. In one embodiment, the reduction in one or more symptoms is reflected in the SNOT score. In one embodiment, the sinus condition is a chronic sinus condition. In one embodiment, the sinus condition is characterized by at least two symptoms selected from the group consisting of: nasal congestion, dyspnea through the nasal passages, nasal polyps, runny nose, loss of smell and facial pain. In one embodiment, the implant comprises a further coating at least partially covering the drug-containing coating. In one embodiment, the additional coating lacks a drug. In one embodiment, at least one of the first or second implants is a braided structure. In one embodiment, at least one of the first or second implants is a tubular structure. In one embodiment, at least one of the first or second implants is self-expanding. In one embodiment, at least one of the first or second implants is configured as a sheet. In one embodiment, at least one of the first or second implants is configured as a curled sheet. In one embodiment, the decrease comprises a 50% improvement in the SNOT-22 score at week 24 of the implantation phase (relative to baseline, i.e., the value measured prior to implantation or just at the beginning of the implantation phase). In one embodiment, the alleviation comprises no symptoms (or only mild symptoms) at week 24 of the implantation phase.

In yet another embodiment, the invention contemplates a method of reducing sleep dysfunction, the method comprising a) providing first and second implants, each comprising at least one coating comprising about 7500 micrograms of mometasone furoate, and wherein the first implant is configured to fit inside a first middle nasal meatus of a patient, and wherein the second implant is configured to fit inside a second middle nasal meatus of the patient; b) Implanting the first and second implants into first and second middle nasal passages of a patient having symptoms of sleep dysfunction, and c) detecting a reduction in one or more symptoms, thereby treating the sleep dysfunction. In one embodiment, the sleep dysfunction symptoms include difficulty falling asleep, waking at night, lack of good night sleep, tiredness on waking, and fatigue. In one embodiment, the reduction in one or more symptoms is reflected in the SNOT score. In one embodiment, the subject with sleep dysfunction has a sinus condition. In one embodiment, the sinus condition is a chronic sinus condition. In one embodiment, the sinus condition is characterized by at least two symptoms selected from the group consisting of: nasal congestion, dyspnea through the nasal passages, nasal polyps, runny nose, loss of smell and facial pain. In one embodiment, the implant comprises a further coating at least partially covering the drug-containing coating. In one embodiment, the additional coating lacks a drug. In one embodiment, at least one of the first or second implants is a braided structure. In one embodiment, at least one of the first or second implants is a tubular structure. In one embodiment, at least one of the first or second implants is self-expanding. In one embodiment, at least one of the first or second implants is configured as a sheet. In one embodiment, at least one of the first or second implants is configured as a curled sheet. In one embodiment, the reduction comprises a 50% improvement in the SNOT-22 score at week 24 of the implantation phase (relative to baseline, i.e., the value measured prior to implantation or just at the beginning of the implantation phase).

In one embodiment, the invention contemplates a method of treating a sinus condition comprising a) providing first and second implants, each comprising at least one coating comprising about 7500 micrograms of mometasone furoate, and wherein the first implant is configured to fit within a first middle nasal passage of a patient, the mometasone furoate being configured to have zero order release over 12 weeks or more of a planned implantation phase; and wherein the second implant is configured to fit inside the second middle nasal passage of the patient, the mometasone furoate is configured to have zero order release over 12 weeks or more of the planned implantation phase, b) implanting the first and second implants into the first and second middle nasal passages of a patient having symptoms of a sinus condition, and c) detecting and/or measuring the alleviation of one or more symptoms, thereby treating the sinus condition.

In another embodiment, the invention contemplates a method of treating a sinus condition comprising a) implanting first and second implants into first and second middle nasal passages of a patient having a sinus condition, wherein the patient is a sinus surgical candidate, each implant comprising at least one coating comprising about 7500 micrograms of mometasone furoate, and b) detecting and/or measuring a reduction in one or more symptoms, wherein after 20-24 weeks (and more preferably just after 8 weeks, 10 weeks, 12 weeks, or 16 weeks), the patient is no longer a sinus surgical candidate, thereby treating the sinus condition. In one embodiment, the patient is a sinus surgical candidate based on the symptoms' SNOT score. In one embodiment, the patient (after step b) is no longer a sinus surgical candidate based on the SNOT score. In one embodiment, the patient is no longer a sinus surgical candidate based on a 4-principal symptom complex score (4 CS) that includes nasal obstruction, runny nose, facial pain/pressure, and loss of sense of smell. In one embodiment, the patient is no longer a sinus surgical candidate based on a 3-major symptom complex score (3 CS) that includes nasal obstruction, facial pain/pressure, and runny nose. In one embodiment, with 3 CS.ltoreq.4, the patient is no longer a sinus surgical candidate.

In one embodiment, the invention contemplates a combination for preventing a need for surgery in a subject as a candidate for sinus surgery [ such as Functional Endoscopic Sinus Surgery (FESS) ] comprising first and second implants, each comprising at least one coating comprising about 7500 micrograms of mometasone furoate, wherein the first implant is configured to fit within a first middle nasal meatus of the subject, the mometasone furoate being configured to have zero order release for more than 12 weeks; and wherein the second implant is configured to fit inside a second middle nasal meatus of the subject, the mometasone furoate is configured to have zero order release for more than 12 weeks, characterized in that the combination is delivered to the subject prior to surgery, wherein the subject is treated for at least 4 months. In one embodiment, the first and second implants are configured to release 20 to 80% of the mometasone furoate during the first 12 cycles. In one embodiment, each of the first and second implants is configured to exhibit zero order release between 1 and 12 weeks. In one embodiment, the zero order release is exhibited in vitro at 37 ℃ in pH 7.4PBS buffer containing 2% sds. In one embodiment, the combination is for use in a method of treating a chronic sinus condition. In one embodiment, the chronic sinus condition is characterized by at least two symptoms selected from the group consisting of: nasal congestion, dyspnea through the nasal passages, nasal polyps, runny nose, and facial pain.

In one embodiment, at least one of the first or second implants is a braided structure. In one embodiment, at least one of the first or second implants is a tubular structure. In one embodiment, at least one of the first or second implants comprises a helical wire. In one embodiment, at least one of the first or second implants is self-expanding.

Brief Description of Drawings

The document of this patent contains at least one color drawing. The patent and trademark office will provide a copy of this patent with colored drawings, after requesting and paying the necessary fee.

Exemplary embodiments are illustrated in referenced figures. It is intended that the embodiments and figures disclosed herein are to be considered illustrative rather than limiting.

FIG. 1 shows a schematic diagram of the LANTERN 2 phase study design; including LYR-210 implants in the range of 2500 μg-7500 μg.

Fig. 2.lantern phase 2 study patient treatment (CONSORT) schematic ITT = intent to treat.

Figures 3A-C. Patient symptoms improved in terms of nasal obstruction, facial pain/compression and runny nose the average Change (CFBL) in 7 balance scores from baseline in terms of nasal obstruction (figure 3A), facial pain/compression (figure 3B) and runny nose (anterior/posterior) in (figure 3C). Data represent LSM. P <0.05 was considered statistically significant relative to the control.

Figures 4A-c. Symptom improvement of patient olfactory loss in patients with moderate to severe baseline disease for patients with moderate to severe baseline olfactory loss (baseline score of > 2 of olfactory loss), average Change From Baseline (CFBL) in 7 balance average score of olfactory loss. Fig. 4a.4cs scored CFBL. Fig. 4b.3cs scored CFBL. Fig. 4C CFBL with olfactory loss. LYR-210 (7500 μg) (n=15 patients), LYR-210 (2500 μg) (n=20 patients), control (n=20 patients). Data represent LSM. P <0.05 was considered statistically significant relative to the control.

Figures 5A-B patient symptoms improved as measured by a composite score of 4 principal symptoms (4 CS) (top of figure 5A) and 3 principal symptoms (3 CS) (figure 5B). Average Changes From Baseline (CFBL) in the 7 balance average score for 4CS included nasal obstruction, facial pain, runny nose (anterior/posterior), and loss of smell. 3CS includes nasal obstruction, facial pain, and runny nose (anterior/posterior). Data represent LSM. P <0.05 was considered statistically significant relative to the control. The bottom of FIG. 5A shows the average trend of the long lasting therapeutic effect of LYR-210 after removal. There was approximately 73% average compliance with daily nasal saline washout throughout the post-treatment period.

* Excluded from post-treatment analysis: patients who received rescue treatment prior to completion of 80% of post-treatment follow-up; and patients who have lost data in the post-treatment stage.

Fig. 6A-c. patient symptom improvement measured by SNOT-22 (fig. 6A) average Change From Baseline (CFBL) of SNOT-22 total score. Data represent LSM. P <0.05 was considered statistically significant relative to the control. FIG. 6B percentage of patients on either side of LYR-210 (2500 μg), on either side of LYR-210 (7500 μg), or in control that achieved minimal clinically significant differences (MCID) in SNOT-22 overall scores at week 24. FIG. 6C shows a comparison of the percentage of patients with and without nasal polyps on either side LYR-210 (2500 μg), on either side LYR-210 (7500 μg), or in control for MCID administration achieved at week 24 with respect to the overall score of SNOT-22.

Figure 7 ethmoid sinus inflammation reduction as measured by the two sided Zinreich MRI score. Average Change From Baseline (CFBL) at 24 weeks in both ethmoid sinuses Zinreich scores (composite score of anterior and posterior ethmoid sinuses Zinreich scores). Data represent mean values. P <0.05 was considered statistically significant relative to the control.

Fig. 8. Time to first rescue treatment use in 24 weeks. Event is the time of first rescue treatment use. Patients who did not send events were examined at the end of the treatment date or at the early expiration date. LYR-210 (7500 μg) (n=1 patients), LYR-210 (2500 μg) (n=2 patients), saline flush control (n=7 patients) used rescue treatment during the 24 week treatment period.

Fig. 9A is a diagram showing anatomical landmarks as a color schematic of a coronal MRI image.

Fig. 9B shows an enlarged endoscopic view of the left (relative to the patient) nostril as a reference, showing the septum (S), the Middle Turbinate (MT) and the Middle Meatus (MM).

Fig. 9C shows the stent deployed from the portion of the end of the applicator sheath outside the nose for illustrative purposes only. When deployed from an applicator, the LYR-210 matrix self-swells from a constrained state.

Fig. 10 is a graph showing the time-varying mometasone furoate plasma concentrations obtained after implantation of the following implants on both sides in the middle nasal passages of subjects with sinus conditions (e.g., CRS patients): 1) First and second implants each comprising about 7500 micrograms of mometasone furoate, or 2) first and second implants each comprising about 2500 micrograms of mometasone furoate. The plasma concentration achieved remained relatively constant between days 5 and 55, indicating that the release of drug from the implant was substantially linear and even zero-order (e.g., for days 5-55, and particularly days 25-55). Plasma MF-concentration-time profile of LYR-210 (2500. Mu.g) and LYR-210 (7500. Mu.g) over 56 days. Data are expressed as mean and standard deviation. C (C) _ss =steady state concentration.

Fig. 11 shows a schematic of a crimped osmotic drug delivery sheet embodiment that comprises one or more delivery apertures (500), a semipermeable polymer membrane (501), an API (502), and a zymogen (503).

Fig. 12 shows a schematic view of an embodiment of a self-expandable implant comprising an osmotic drug delivery fiber (600) having an orifice (601).

Definition of the definition

The terms "sinus" and "sinus cavity" as used herein refer to cavities that include the maxillary sinus, frontal sinus, ethmoid funnel, and sphenoid sinus. The middle nasal meatus represents the nasal cavity other than the sinus cavity. The osteomeatal complex is a channel connecting the frontal sinus, anterior ethmoid sinus air chamber, and maxillary sinus to the middle meatus, allowing airflow and mucociliary drainage.

As used herein, "disorder" refers to a particular state of presence. An example is a "medical condition" which refers to the degree of well being of a person's physical state. "medical condition" is also a broad term and includes disorders, diseases, lesions and symptoms thereof. Medical conditions may also include specific types of body areas, such as when the term "sinus condition" is used to mean any symptom or symptoms including "primary" or "defining symptoms.

"chronic sinus condition" or "CRS" means inflammation of the nose and paranasal sinuses characterized by the presence of two or more of the following symptoms for more than 12 weeks: 1) Nasal obstruction/blockage/congestion; 2) Nasal discharge; 3) Facial pain/compression; 4) Reduced or lost smell (ref-1). Objective confirmation of diagnosis by sinus CT scan or nasal endoscopy, which will also determine phenotype: CRSsNP or CRSwNP. Based on the presence of nasal polyps, CRS is divided into two subtypes: CRS with nasal polyps (CRSwNP) and CRS without nasal polyps (CRSsNP). In adults, nasal polyps may be seen in both nasal passages, and any unilateral polyp should take into account other etiologies, such as malignancy.

"chronic sinusitis" refers to a sinus condition having at least two symptoms including, but not limited to: damaged nasal obstruction, congestion, nasal discharge when blowing, spontaneous nasal discharge from one or both nostrils, nasal discharge to throat area, facial pain, facial compression, facial distention, headache, loss of sense of smell, etc. In some cases, the CRS may be heavy CRS.

Chronic nasal and nasal sinusitis with nasal polyps (CRSwNP) represent a clinical diagnosis of the presence of subjective and/or objective evidence of chronic nasal sinus inflammation.

"nasal polyp" means an inflammatory lesion that protrudes into the nasal airway (lumen). Polyps are typically bilateral, but polyps may also appear in one nasal airway, rather than on both sides. Polyps may be soft, painless, non-cancerous growths on the inner walls of the nasal passages or sinuses. CRSwNP is often associated with asthma and allergic rhinitis.

"principal symptoms" means symptoms (having signs or symptoms) that may be diagnostic and/or characteristic signs, which specifically characterize or indicate a particular disease or disorder. For example only, CRS may be one or more of nasal obstruction, facial pain, runny nose (anterior/posterior), and loss of sense of smell, including symptoms such as anterior or posterior rhinorrhea, nasal congestion, hyposmia, and/or facial compression or pain lasting more than 12 weeks. The 4 principal symptom complex scores included nasal obstruction, runny nose, facial pain/pressure and loss of sense of smell. The 3CS composite score included nasal obstruction, facial pain/pressure, and runny nose. In a preferred embodiment, 3CS = 7-balance all combined score for 3 principal symptoms of nasal obstruction/blockage/congestion, anterior/posterior runny nose, and facial pain/compression.

As used herein, "generally tubular" includes hollow shapes of circular cross-section or non-circular cross-section (e.g., oval, etc.) as well as hollow shapes of constant diameter or variable diameter (e.g., tapered diameter, such as in a hollow frustum).

Implantable medical devices of certain embodiments of the present disclosure are generally self-expanding devices. In certain embodiments, they are generally tubular devices, although it is contemplated that certain embodiments are configured as sheets or folded sheets. In a preferred embodiment, the device comprises a "wire" and a "filament". As used herein, "device," "stent," "scaffold," "carrier," and "implant" may be used synonymously.

Stents according to certain embodiments of the present disclosure have expansion and mechanical properties suitable for the stent to effectively achieve its intended purpose. Two measures of such mechanical properties used herein are "radial resistance" ("RRF") and "chronic outward force" ("COF"). RRF is the force applied by the stent against the crimping force and COF is the force applied by the stent against the static abutment surface. In certain embodiments, the stent is configured to have a relatively high RRF to be able to maintain open body cavities, cavity and nasal features, etc., but a relatively low COF to avoid applying potentially harmful forces to the walls of the body cavities, optic nerves, brain, etc. For example, the stents of the present disclosure preferably expand to 70 to 100% of their as-manufactured configuration after crimping, have RRF in the range of 50 to 300mmHg, and/or have acute COF (at the time of delivery) in the range of 10 to 100 mmHg. Stents according to certain embodiments of the present disclosure are generally tubular devices that can be of various sizes, including various diameters and lengths, and which can be used in a variety of sinus applications. For an object of non-circular cross-section, "diameter" means width.

As used herein, "strength" and "stiffness" may be used synonymously, meaning the resistance of the medical stent of the present disclosure to deformation caused by radial forces or forces exerted by the stent against a static abutting object. Examples of strength and stiffness measurements used to characterize the medical stents of the present disclosure include radial resistance and chronic outward forces, as further described herein.

Implantable medical devices of certain embodiments of the present disclosure are generally self-expanding devices. As used herein, "self-expanding" is intended to include such devices: which is crimped into a reduced delivery configuration for delivery into the body and thereafter tends to expand to a larger, suitable configuration once released from the delivery configuration, without the aid of any additional inflation means or with the aid of balloon-assisted or similarly-assisted inflation portions. Many stent embodiments of the present disclosure are self-expanding in that they are manufactured in a first diameter, then reduced or "crimped" to a second reduced diameter for placement within a delivery catheter, and self-expand to the first diameter upon extrusion from the delivery catheter at an implantation site. In certain embodiments, the first diameter may be at least 10% greater than the diameter of the body cavity in which it is implanted. In certain embodiments, the scaffold may be designed to recover at least about 70%, at least about 80%, at least about 90%, up to about 100% of the first diameter it is manufactured from.

As used herein, "thread" and "filament" are used interchangeably and include single fiber threads and filaments (also referred to as monofilaments) as well as multi-fiber threads and filaments. And (5) a spiral line. In certain embodiments, which may be used in combination with any of the embodiments, the braided structure may comprise opposing sets of spirals. For example, each set of spirals may contain 2 to 64 members, more generally 8 to 32 members.

In certain preferred embodiments, the implant is a "long term" implant such that the implant can be in contact with sinus tissue for up to 20 weeks, and more preferably 24 weeks or more. In certain preferred embodiments, the implant is a "long acting" implant such that a patient having an implant in contact with sinus tissue may exhibit a sinus tissue effect for up to 4 weeks, up to 8 weeks, up to 12 weeks, up to 16 weeks, up to 20 weeks, up to 24 weeks, or more.

"encoding" as used herein means the use of standardized (or selected) terms to convert symptoms that are "adverse events" or "AEs" into terms for consistent analysis of clinical data. AE may also be described as a "serious adverse event" or "SAE". More specifically, the MedDRA code represents an eight-digit number assigned to each term and is not confused with the text string of the term itself. Each term in MedDRA has a unique non-expressive 8-bit code for data analysis.

As an example, a code was selected for use as described in the regulatory active medical dictionary (Medical Dictionary for Regulatory Activities, med dra) version 23.0. MedDRA provides a versatile coding method suitable for use at any stage of biopharmaceutical and medical product development, as briefly described herein. https:// www.meddra.org/how-to-use/case-s tunes/yield-case-student https:// www.meddra.org/glassary. One advantage of the MedDRA is that it supports simple and complex analysis. MedDRA may be used to analyze individual medical events (e.g., "chronic sinusitis") or problems related to systems, organs, or etiologies (e.g., infections) using its hierarchical structure. AE was encoded using MedDRA version 23.0.

"monitoring" may be performed intermittently, e.g., weekly, biweekly, weekly; it need not be continuous. The monitoring may be accomplished by a physician, nurse, technician, or other medical personnel. The monitoring may be performed in person, for example in a medical office, or remotely, for example by telephone. Monitoring may be as simple as obtaining subjective reports from the patient regarding their status (e.g., level and number of symptoms, if any).

When used with numbers, terms such as "about" and "approximately" are intended to indicate a range of + -10%.

Description of the invention

The present invention relates to materials, devices, kits and methods for treating patients with sinus conditions, including patients with severe chronic nasal and sinus inflammatory (CRS) symptoms (or at risk thereof). In one embodiment, the present invention contemplates an implant designed for use in patients with sinus conditions who fail after standard drug treatment. In one embodiment, the present invention contemplates an implantable matrix (LYR-210) (7500 μg MF) that locally elutes mometasone furoate (e.g., from the nasal passages to inflamed sinus tissue) in non-surgically CRS patients with and without nasal polyps for 8-12 weeks, and more preferably for 24 weeks or more. LYR-210 showed clinically relevant improvement in 22-sinus outcome test (SNOT-22) in an open label phase 1 study. LYR-210 (7500 μg) was further evaluated for safety and efficacy in CRS in LANTERN 2 phase studies.

The method comprises the following steps: 67 adult CRS patients who did not undergo surgery, failed past drug management, and were seeking further treatment were enrolled into a multi-center, blind, control, dose-range LANTERN study. Patients had moderate to severe disease based on a comprehensive 7 balance average score of SNOT-22 and 4 major CRS symptoms (4 CS) and were confirmed by nasal endoscopy and MRI. Patients were randomized (1:1:1) to saline only rinse controls or to both diagnostic rooms for LYR-210-2500. Mu.g or LYR-210-7500. Mu.g. Safety and efficacy were assessed over 24 weeks.

LYR-210 (7500 μg) is based on XTreo ^TM Drug delivery technology platform ¹¹ Designed to continuously elute Mometasone Furoate (MF), for up to 24 weeks, for example from the middle nasal meatus (implantation site) to the local sinus mucosa. LYR-210 is designed to fit within and dynamically conform to the middle nasal meatus. The middle nasal meatus allows drainage of the paranasal sinuses and accommodates the sinus oronasal meatus complex, a site of origin of mechanical obstruction leading to secondary infection in CRS ¹² . The active ingredient MF is embedded in an inactive ingredient composed of biocompatible and bioabsorbable polymers, which aids in the controlled and sustained delivery of MF to the sinus mucosa through a single bilateral application. LYR-210 (7500 μg) is being developed for treating CRS in non-surgical adult patients with failed drug management. LYR-210 was well tolerated in the open label phase 1 study (ClinicalTrials. Gov Identifier: NCT 02967731) and showed clinically relevant improvement in the 22-sinus outcome trial (SNOT-22) for 24 weeks in 20 non-surgical CRS patients ¹³ . To further evaluate the safety and efficacy of LYR-210, we performed a multicenter, randomized, blind, control, dose-range LANTERN 2 phase study (ClinicalTrials. Gov Identifier: NCT 04041609).

Results: both LYR-210 doses were safe and well tolerated during the 24 week treatment period. LYR-210 showed rapid and long lasting dose-dependent symptomatic improvement based on 4CS and SNOT-22, and LYR-210-7500 μg reached statistical significance as early as 8 weeks and up to 24 weeks compared to the control. LYR-210 (7500 μg) reduced rescue therapy use and radiographic screening Dou Hunzhuo at week 24 compared to the control.

In one embodiment, the implant is removed and the patient continues to improve and/or maintain improvement in the reduced symptoms of the sinus condition. In one embodiment, the patient continues to improve for at least 2 weeks and even 4 weeks. Importantly, removal does not result in any immediate increase in adverse symptoms. In practice, symptom levels are maintained, for example as measured by SNOT and/or 4CS scores.

Experimental results

Patient characteristics

The LANTERN 2 phase study program recruits up to 150 adult CRS patients who have failed medication management and have not received sinus surgery. Patient recruitment was curtailed in advance due to the global pandemic of covd-19. During the period 5 in 2019 to 3 in 2020, 71 patients were randomized, 70 patients received trial study treatment procedures, and 67 patients were successfully enrolled. Of these, 23 patients were administered LYR-210 (2500. Mu.g) on both sides, 21 patients were administered LYR-210 (7500. Mu.g) on both sides, and 23 patients received both-sided sham surgery (saline only rinse control). The 6 patients in each study group discontinued treatment before 24 weeks of completion of the plan. At week 22, 80% of the administered LYR-210 drug matrix was retained. Patient treatment is shown in figure 2.

Of 67 successfully enrolled patients, 35 (52.2%) were male and 37 (55.2%) were diagnosed endoscopically with bilateral nasal polyps, each accounting for about half of the patients in each study group. Nasal polyps are large, extending mostly outside the middle nasal meatus. Patients reported moderate to severe CRS symptoms at baseline ¹⁶ The average SNOT-22 score was 68.2±18.4 (range 25 to 107) and the average 4CS score was 9.7±1.59 (range 7.0 to 12.0). Furthermore, based on their baseline Zinreich scores (average 20.3±12.33 (median 17, range 1-53)), patients exhibited sinus inflammation. Patients underwent at least 1 INCS test prior to screening, while 19.4%, 49.2% and 73.1% of patients were previously treated with oral corticosteroid, antibiotic and saline washes, respectively. Table 1 summarizes patient demographics, CRS medical history, and baseline clinical disease severity metrics.

Table 1 patient demographics, medical history, and baseline characteristics.

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COPD = chronic obstructive pulmonary disease; NSAID = non-steroidal anti-inflammatory drug; a 7 balance-averaged score for 4CS = chronic rhinosinusitis; SD = standard deviation; SNOT-22 = 22-sinus outcome trial.

Analysis of variance (ANOVA) was used to compare the average of the continuous variables between groups. Fisher's exact test was used to compare the classification variables between groups.

Safety of

Table 2 summarizes AEs appearing in treatment reported for more than 1 patient in any study group. The most common AEs reported in the LYR-210 (2500 μg) group were chronic sinusitis, epistaxis, and rhinorrhea (n=4 each); the most common AEs reported in the LYR-210 (7500 μg) group were chronic sinusitis and rhinitis (n=4 each); and the most common AE reported in the control group was chronic sinusitis (n=7). Other less common AEs include upper respiratory tract infections, oropharyngeal pain, nasal congestion, facial pain, dizziness and hyperkalemia. Only one Serious Adverse Event (SAE) was reported in this study, in which one patient in the LYR-210 (2500 μg) group had acarodermatitis, which was determined by the treating physician to be independent of the study treatment.

The mean CFBL of IOP at week 24 was decreased in LYR-210 (7500 μg) group (-0.5+ -2.8, range-5.5 to 7.5) and LYR-210 (2500 μg) group (-0.1+ -2.5, range-6.3 to 4.0) and increased in control group (0.9+ -2.7, range-4.0 to 9.5). No patient in this study showed clinically significant increases in IOP. One patient in the control group developed clinically significant nuclear cataracts in this study. At weeks 4, 12 or 24, there was no significant decrease in serum cortisol levels in the morning. No AE indicating adrenal insufficiency was reported.

Table 2. Summary of adverse events and serious adverse events occurring in the treatment.

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AE = adverse event; medDRA = supervisory active medical dictionary, SAE = serious adverse event.

Preferred terms are summarized for AEs reported for more than 1 patient in any study group.

If a patient reports an AE more than once within the system organ type/preferred terminology, the patient counts only once within the system organ type/preferred terminology.

The correlation of AE with study treatment or procedure is determined by the treating physician.

AE was encoded using MedDRA version 23.0.

* MedDRA, a preferred term for exacerbation/exacerbation of chronic sinusitis

Efficacy of

The therapeutic effect of LYR-210 was evaluated in 24 weeks based on improvement of patient symptoms, reduction of sinus inflammation, and reduction of the need for rescue treatment. LYR-210 showed dose-dependent improvement in patients with CRS for the entire 24-week treatment period with nasal obstruction, facial pain/compression, and runny nose (FIGS. 3A-C). Specifically, LYR-210 (7500 μg) achieved statistically significant improvement in nasal congestion (weeks 16, 20, and 24) (FIG. 3A), facial pain/pressure (weeks 12, 16, 20, and 24) (FIG. 3B), and runny nose (weeks 16, 20, and 24) (FIG. 3C) compared to the control. Analysis of enrolled patients exhibiting moderate to severe olfactory loss at baseline (as defined by a baseline score of > 2 for olfactory loss) showed that LYR-210 (7500 μg) improved the patient's smell (FIG. 4C).

The 4 principal symptoms were analyzed as a composite score (4 CS) throughout the 24 week treatment period, which is the primary efficacy endpoint. The 4 principal symptom complex scores included nasal obstruction, runny nose, facial pain/pressure and loss of sense of smell. LYR-210 showed a dose-dependent improvement in the 4CS score, which became more pronounced over 24 weeks (upper panel of FIG. 5A). LYR-210 (7500 μg) showed statistically significant improvement over baseline at weeks 16, 20 and 24 compared to control. At week 24, patients had different health phases, LYR-210 (7500 μg) was significantly improved over the control group.

To determine how LYR-210 treated patients responded after matrix removal, their 24-week score was set to the new baseline (FIG. 5A lower panel). For this analysis, patients requiring rescue treatment prior to completion of 80% of post-treatment follow-up and patients lacking data in the post-treatment stage were excluded. Although the number was small, the average trend indicated a durable therapeutic effect after LYR-210 removal, while the control showed a deterioration relative to week 24 baseline. Throughout the post-treatment period, the patient received nasal saline washout and had compliance with daily use for approximately 73% of the time during these 24 weeks. No significant rebound effects were seen in the post-treatment stage. Thus, the implant may be removed and the patient may experience a durable therapeutic effect and even continue to improve.

Since only a fraction of patients showed moderate to severe loss of smell at baseline, we also analyzed a composite score of 7 balance-averaged scores for nasal congestion, facial pain/pressure, and runny nose (3 major symptoms (3 CS)), which was not the endpoint pre-specified in this study. LYR-210 showed a dose-dependent therapeutic effect, and LYR-210 (7500 μg) achieved a significant improvement in 3CS score from week 12 to week 24 compared to the control (FIG. 5B).

The SNOT-22 questionnaire is a clinical gold standard for measuring the burden and quality of life of patients with CRS ¹⁴ . As shown in FIG. 6A, a dose response between LYR-210 (7500 μg), LYR-210 (2500 μg) and the control was observed during the 24 week treatment period. LYR-210 showed a rapid, long lasting and clinically significant improvement over baseline in SNOT-22 scores. Patients administered bilateral LYR-210 (7500 μg) showed statistically significant improvement over the control at 8, 16, 20, and 24 peripheral surfaces. Notably, LYR-210 (7500 μg) achieved 19-point improvement of SNOT-22 compared to control at week 24; this is more than 2 times the minimum clinically significant difference (MCID) at 8.9 points ¹⁴ 。

SNOT-22 responder analysis showed that LYR-210 (7500 μg) was excellent in terms of percentage of subjects who achieved MCID at week 24 [ odds ratio >999.999 (< 0.001, > 999.999) relative to LYR-210 (2500 μg) and control ],100% of patients administered LYR-210 (7500 μg) achieved ≡MCID in terms of total score of SNOT-22 at week 24, as compared to 70% in LYR-210 (2500 μg) and 65% in control group (FIG. 6B-C).

After further evaluation of LYR-210 (7500 μg) administered patients, 70% of patients achieved ≡MCID in SNOT-22 overall scores as early as week 4 (Table 3A). Importantly, this early onset is observed in patients with substantial nasal polyps and in patients without nasal polyps. 80% of CRSsNP patients and 60% of CRSwNP patients in LYR-210 (7500. Mu.g) achieved. This powerful therapeutic effect persisted throughout the study, and increased to 100% of patients in the LYR-210 (7500 μg) group before week 24 achieved MCID in terms of SNOT-22 overall scores (tables 3A-3B).

Table 3A. Percent of subjects achieving MCID in terms of SNOT-22 overall score (%). LYR-210 7500 μg.

Time point	N	RSP	PCT
				Week 2	19	9	47.4％
Week 4	20	14	70.0％
				Week 8	20	16	80.0％
Week 12	20	17	85.0％
				Week 16	20	18	90.0％
Week 20	20	19	95.0％
				Week 24	20	20	100.0％

Table 3B percentage of subjects achieving MCID in terms of SNOT-22 overall score (%). LYR-210 7500 μg-polyp versus non-polyp.

Sleep dysfunction or poor sleep is associated with reduced quality of life and is a common complaint for about 60% -75% of individuals with CRS, compared to 8% -18% of the general population ¹⁷ . To evaluate the therapeutic effect of LYR-210 on sleep, a score was made The area of sleep dysfunction derived from SNOT-22 was analyzed. The measure of sleep dysfunction includes difficulty falling asleep, night awakening, lack of good night sleep, tiredness and fatigue upon awakening ¹⁸ . LYR-210 (7500 μg) improved sleep dysfunction symptoms throughout the 24 week treatment period, with 90% of patients achieving MCID at 2.9 points in the SNOT-22 sleep dysfunction area at week 24, as defined by Chordhury et al ¹⁹ (Table 3C).

Table 3℃ Percent of subjects achieving MCID in the SNOT-22 sleep dysfunction field (%). LYR-210 7500 μg.

Time point	N	RSP	PCT
				Week 2	19	10	52.6％
Week 4	20	11	55.0％
				Week 8	20	14	70.0％
Week 12	20	13	65.0％
				Week 16	20	16	80.0％
Week 20	20	15	75.0％
				Week 24	20	18	90.0％

Based on previous studies by others, this finding was surprising in the field of SNOT-22 sleep dysfunction at week 24, indicating the lack of such improvement with non-surgical drug treatment. As an example, deConde, et al Int Forum Allergy rhinol.4 (12): 972-979,2014 indicated that non-surgical drug treatment did not significantly improve 2 general health related QOL (quality of life) areas, namely sleep dysfunction and mental dysfunction, whereas surgical treatment and sustained drug management were possible. Indeed, in addition to higher psychological dysfunction prior to surgery, patients who choose surgical treatment rather than non-surgical medication often report significantly higher pre-treatment sleep dysfunction. Examples of drug therapies include oral, broad-spectrum or culture-directed antibiotics; topical nasal corticosteroid sprays or systemic steroid treatment trials for 5 days.

Furthermore, deConde et al report that there is a direct relationship between a poor baseline SNOT-22 score and a higher likelihood of patient selection for surgery. The baseline symptom severity indicator appears to be more effective in predicting patient selection of treatment regimens than a variety of other indicators, including personality traits, risk avoidance, degree of social support, economic factors, and patient-physician relationships. DeConde, et al Int Forum Allergy Rhinol.4 (12): 972-979,2014.

Indeed, endoscopic Sinus Surgery (ESS) has proven to be a more effective interventional therapy than continuous medication in all SNOT-22 categories, but has also been found to exhibit different effects in certain areas. DeConde, et al Int Forum Allergy Rhinol.4 (12): 972-979,2014. Factor analysis of the SNOT-22 survey identified 5 different areas that were variously affected by Endoscopic Sinus Surgery (ESS) relative to drug treatment. The first two areas described above are improved by surgery, but the drug treatment is not improved (i.e. sleep dysfunction and psychological dysfunction). In contrast, the 3 sinus-specific symptomatic areas (i.e., nasal, extra-nasal, and ear/face symptoms) are ameliorated by any of these treatments, but with caution (caveat). Although a significant average improvement in the difference between all domain scores within ESS and non-LYR-210 medication was reported, the greatest improvement was in the group selected and subjected to sinus surgery.

While both surgical and pharmaceutical treatment modalities have resulted in improvements in all areas, subjects selecting surgical interventions have experienced greater relative improvements. That is, although subjects receiving ESS achieved greater gains than medication management in all areas, these gains are minimal in the areas of sleep dysfunction and mental dysfunction. DeConde, et al, int Forum Allergy rhinol.4 (12): 972-979, 2014. Thus, surgical intervention can improve patient disease-specific quality of life (QOL) scores to a greater extent than drug management.

As shown herein, sleep dysfunction showed a statistically significant improvement in the SNOT-22 score of patients receiving non-surgical LYR-210 drug treatment, inspired by this surprising finding, the following study was conducted to see which additional areas of non-surgical drug treatment with LYR-210 (7500 μg) could be improved compared to the untreated control patient group.

Furthermore, using Patient Reported Outcome Measures (PROMs) (e.g., SNOT-22) to track clinical improvement can lead to the problem of how to analyze these more abstract values of patient self-reporting in a clinically relevant context, i.e., as a guideline for one or more of the following approaches: measuring the effect of LYR-210 drug therapy over time; measuring whether the therapeutic outcome of LYR-210 is similar to the outcome of the surgical intervention; etc. In certain embodiments, the method for measuring the therapeutic outcome is comparative LYR-210 drug therapy, i.e., 2500 μg versus 7500 μg. In certain embodiments, the method for measuring the outcome of a treatment is a comparative LYR-210 drug treatment of a control or sham operated (sham) patient. In certain embodiments, methods for measuring the therapeutic outcome of LYR-210 are used to suggest a type of treatment or alter therapy (treatment).

Thus, while assays like SNOT-22 are validated in many publications as reliable measures of disease at specific time points, the validation process provides little guidance on how to interpret the change in score over time. Thus, another object herein is to use a previously established threshold by which a change in score (e.g., CFBL) reflects a true change in health; and used in results studies. This threshold is commonly referred to as the minimum clinically significant change score (MCID), see, e.g., cook, "Clinimetrics corner: the minimal clinically important change score (MCID): a nearest prestreense," Journal of Manual & Manipulative Therapy 16, no.4:82E-83E (2008).

The MCID of the SNOT-22 sum SNOT-22 (sub) domain was calculated as the average MCID value of the SNOT-22 sum SNOT-22 domain scores before and after ESS, see Chordhury, et al, int Forum Allergy Rhinol.7 (12): 1149-1155,2017. As one example, chogdhury et al suggested that 8.9 is generally considered a post-sinus surgery improved MCID threshold for CRS treatment outcome studies, but further suggested that 9.0 be used alternatively for ESS treated CRS patients.

Thus, as demonstrated herein, patients with chronic nasal and nasal sinusitis were also evaluated using a predetermined MCID (see bar charts and tables), as provided for by patients with CRS surgery in Hopkins et al, clinical Otolaryngology,34,447-454,2009 and CRS patients with ESS surgery in chordhury et al, int Forum Allergy rhinol.7 (12): 1149-1155, 2017. One MCID change unit for the distribution-based approach is the average MCID of the SNOT-22 total score or SNOT-22 domain score. The average MCID of the SNOT-22 total score used herein was about 9.0. The average MCIDs used for nasal, ear/face, psychological and sleep domain scores were 3.8, 2.4, 3.2, 3.9 and 2.9, respectively. Although calculated for surgical results, these thresholds are used to measure the outcome of LYR-210 drug treatment, see A below.

Furthermore, as used herein, the minimum clinically significant difference (MCID) means that a threshold is defined by which statistically significant results can also be considered to provide clinically significant results. As an example, the SNOT-22 results of LYR-210 7500 μg psychological dysfunction at week 24 showed significant statistical differences from baseline, and the MCID appeared to have at least one 3.9 unit of change from control. In addition, 90% of patients achieved at least MCID at week 24, see tables 9A and 9B.

Although MCID was observed in table 9B at weeks 4 and 8 as though it was near 3.9, there was no significant statistical difference compared to the control. The percentage of patients who achieved at least one MCID increased from about 65% to 75% over this same period of time, as shown in table 9B. Patients with nasal polyps showed 80-90% response to LY-210 7500 μg and patients without nasal polyps showed 70-90% response at weeks 12-24 as an improvement in MCID for sleep dysfunction when patients were divided into polyp groups and non-polyp groups. See table 9C.

Thus, in general, the results at weeks 12-24 are considered clinically significant, while the values at weeks 4-8 show that improvement in clinical MCID is achieved around week 12.

In another embodiment, LYR-210 7500 μg SNOT-22 results of sleep dysfunction at weeks 8-24 show improved statistical differences, while at least about 65-90% of patients have an MCID of at least 2.9 relative to the control. See table 9A. Patients with nasal polyps also showed 80-100% response to LYR-210 7500 μg at weeks 12-24 as an improvement in MCID of sleep dysfunction when the patients were divided into polyp and non-polyp groups. See table 9B.

Taken together, this analysis supports the surprising results of LYR-210 7500 μg treatment for improving sleep dysfunction and extends these findings to the surprising results of non-surgical drug treatment for improving mental dysfunction.

A. Effects of long-acting implantable corticosteroid matrix on the SNOT-22 (sub) area in patients with chronic nasal and sinusitis: results from the LANTERN study.

LYR-210 is an implantable matrix designed to release mometasone furoate to inflamed nasal mucosa for 24 weeks in chronic nasal and sinus (CRS) patients. In the LANTERN study, LYR-210 showed a dose-dependent and significant improvement in 22-sinus outcome test (SNOT-22) overall score compared to the control, and all LYR-210 (7500 μg) treated patients achieved 8.9-point minimal clinical significant differences (MCID) at week 24. The change from baseline in each SNOT-22 (sub) field in the lanter study and the proportion of patients who achieved MCID at week 24 were evaluated. Lower (more negative) CFBL scores in the SNOT-22 survey project indicate better patient function and improved symptoms. SNOT-22 represents a patient reported outcome measure that is used to provide a group average that in turn can be used to determine if there is a minimum clinically significant change score (MCID). MCID represents a change in score, e.g., a predetermined CFBL score, which may indicate a change in the management of patients in the group. Cook. "Clinimetrics corner: the minimal clinically important change score (MCID): a nearest preamble." Journal of Manual & Manipulative Therapy 16, no.4:82E-83E (2008).

The method comprises the following steps: non-surgical adults with moderate to severe CRS and prior drug management failures were recruited into a multicentric, randomized, control, dose range (LANTERN) study. 23 patients received sham surgery (control); and 21 or 23 patients received bilateral administration of LYR-210 (7500 μg) or LYR-210 (2500 μg), respectively. MCID values for nasal, nasal-nasal, ear/face, psychological and sleep (dysfunction) areas scores were 3.8, 2.4, 3.2, 3.9 and 2.9, respectively (chogdhury et al 2017). The mean CFBL and the percentage of patients achieving MCID in each SNOT-22 sub-domain were analyzed using the ANCOVA model and logistic regression model, respectively.

As a result, LYR-210 showed a dose-dependent symptomatic improvement compared to the control at week 24, with LYR-210 (7500 μg) reaching statistical significance (p < 0.05) in each SNOT-22 (sub) field. On week 24, more LYR-210 (7500 μg) treated patients achieved MCID in the nasal (90% versus 65%), nasal-nasal (71% versus 52%), ear/face (80% versus 48%), psychological (90% versus 78%) and sleep (90% versus 61%) areas than the control. See tables 4A-B through 9A-C.

Tables 4A-B through 9A-C show that LYR-210 showed a dose-dependent symptomatic improvement over the control at week 24, with LYR-210 (7500 μg) reaching statistical significance (p < 0.05) in each SNOT-22 field.

The table shows the percentage of subjects who achieved MCID (minimal clinically significant difference) in SNOT-22 total or sub-domain scores. Data were analyzed for ITT (intent to treat) populations, including all subjects who underwent successful treatment surgery and were evaluated for efficacy after at least one randomization, as well as LOCF (last observation of a corotation).

Tables 4A and 4B show exemplary MCID responses in the total score of SNOT-22. The data represent the percentage of subjects achieving at least 8.9-point reduced MCID in terms of the SNOT-22 overall score. As defined in Hopkins et al, clinical otolyngology 34,447-454,2009.

Table 4A. Percent (%) subjects who achieved MCID in terms of SNOT-22 overall score.

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Table 4B. Percent subjects achieving MCID in SNOT-22 overall score (%) -polyp versus non-polyp.

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Table 5A shows exemplary CFBL in terms of SNOT-22 rhinology field scores.

Table 5a. Change in snot-22 nasal symptoms from baseline.

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Tables 5B and 5C show exemplary MCID responses in terms of SNOT-22 nasal domain scores. The data represent the percentage of subjects achieving an MCID of at least 3.8-point reduction in SNOT-22 nasal domain score as defined in chordhury et al, int Forum allergyrhinol.7 (12): 1149-1155, 2017.

Table 5B. Percent (%) subjects achieving MCID in the SNOT-22 nasal domain.

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Table 5℃ Subject percentage (%) -polyp versus non-polyp achieving MCID in the SNOT-22 nasal field.

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Table 6A shows exemplary CBFLs in terms of SNOT-22 nasal surgical field scores.

Table 6a. Change from baseline in snot-22 nasal surgical symptoms.

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Tables 6B and 6C show exemplary MCID responses in terms of SNOT-22 nasal surgical field scores. The data represent the percentage of subjects achieving an MCID of at least 2.4-point reduction in SNOT-22 nasal surgical field score as defined in chogdhury, et al, int Forum Allergy rhinol.7 (12): 1149-1155, 2017.

Table 6B. Percent (%) subjects achieving MCID in the SNOT-22 nasal surgery field.

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Table 6C-percentage of subjects achieving MCID (%) -polyp versus non-polyp in SNOT-22 nasal surgery field.

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Table 7A shows exemplary CFBL in terms of SNOT-22 ear/face domain scores.

Table 7a. Change in snot-22 ear/face symptoms from baseline.

Tables 7B and 7C show exemplary MCID responses in terms of SNOT-22 ear/face area scores. The data represent the percentage of subjects achieving an MCID of at least 3.2-point reduction in the SNOT-22 ear-face area score as defined in chordhury et al Int Forum Allergy rhinol.7 (12): 1149-1155, 2017.

Table 7B. Percent (%) subjects achieving MCID in the SNOT-22 ear/face area.

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Table 7℃ Subject percentage (%) -polyp versus non-polyp achieving MCID in the SNOT-22 ear/face field.

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Table 8A shows exemplary CFBL in terms of SNOT-22 mental dysfunction domain scores.

Table 8a. Change in snot-22 psychological dysfunction from baseline.

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Tables 8B and 8C show exemplary MCID responses in terms of SNOT-22 mental dysfunction area scores. The data represent the percentage of subjects achieving an MCID of at least 3.9-point reduction in the SNOT-22 psychology domain score, as defined in chordhury et al Int Forum Allergy rhinol.7 (12): 1149-1155, 2017.

Table 8B. Percent (%) subjects achieving MCID in SNOT-22 psychology.

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Table 8C-percentage of subjects achieving MCID in SNOT-22 psychology (%) -polyp versus non-polyp.

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Table 9A shows exemplary CFBL in terms of SNOT-22 sleep dysfunction domain scores.

Table 9a. Change from baseline in snot-22 sleep dysfunction.

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Tables 9B and 9C show exemplary MCID responses in terms of SNOT-22 sleep dysfunction area scores. The data represent the percentage of subjects achieving an MCID of at least 2.9-point reduction in the SNOT-22 sleep dysfunction area score, as defined in chordhury et al, int Forum Allergy rhinol.7 (12): 1149-1155, 2017.

Table 9B. Percentage (%) of subjects achieving MCID in the field of SNOT-22 sleep dysfunction.

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Table 9C-percentage of subjects achieving MCID (%) -polyp versus non-polyp in the SNOT-22 sleep dysfunction field.

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Conclusion: LYR-210 shows improvement in all SNOT-22 (sub) fields and may be a promising long-acting sinus treatment for non-surgical CRS patients.

In addition, when patients are surgical candidates, these improvements indicate that when such patients receive LYR-2107500 μg treatment, they may no longer be considered ESS candidates. Determining the least significant differences would provide a way to interpret scores in a clinical setting and may help improve patient treatment options or guide a treatment professional or patient to choose to receive surgery or choose medication, such as 2500 μg or 7500 μg of LYR-210. In other words, if a patient is primarily intended to improve sleep dysfunction, the patient may be treated with LYR-2107500 μg.

In part because the surprising discovery that non-surgical drug management using LYR-210 (2500 μg) and/or LYR-210 (7500 μg) improves quality of life similar to ESS treated patients as part of the 22-sinus result test (SNOT-22), further studies were conducted to support this surprising discovery, which was used in accordance with the MCID value.

B. Quality of life evaluation using 36-short term health surveys in chronic nasal and sinusitis patients treated with a long-acting implantable corticosteroid matrix.

The quality of life of the LANTERN study patients was evaluated using 36-item short term health survey version 2 (SF-36 v 2). LYR-210 is an implantable matrix designed to release mometasone furoate to the inflamed sinus mucosa in patients with chronic nasal and sinus inflammation (CRS) for 24 weeks. LYR-210 (7500 μg) showed clinically relevant symptomatic improvement on 24 th peripheral surface, as well as reduced screen Dou Hunzhuo and need for rescue medication in randomized control LANTERN studies.

The method comprises the following steps: non-surgical adults with moderate to severe CRS and prior drug management failure were recruited into a multicentric, randomized, control, dose-range study. Patients were randomized (1:1:1) to either side of LYR-210 (2500 μg) (n=23) or LYR-210 (7500 μg) (n=21) or sham-operated controls (n=23). SF-36v2 was completed by ePRO at baseline and week 24. Psychological health component summaries (MCSs) and (sub) areas thereof (vitality, social function, emotional role, mental health) and physical health component summaries (PCS) and (sub) areas thereof (physical function, physical role, physical pain, general health) were analyzed as changes from baseline. LYR-210 was compared to a control using the ANCOVA model. P <0.05 is statistically significant.

Results: at week 24, both LYR-210 doses significantly improved the MCS score by >8 points compared to the control. LYR-210 (7500 μg) reached statistical significance in each of the 4 MCS fields (vitality, social function, emotional role, and mental health). LYR-210 (2500. Mu.g) and (7500. Mu.g) increased in value the PCS score compared to the control at week 24, while LYR-210 (7500. Mu.g) reached statistical significance in 3 PCS fields (body function, body role and body pain). The orientation of the score for each domain is such that a higher score represents a better health. See tables 10-11.

Tables 10-11 show quality of life evaluations using SF-36v2 health surveys. Data from ITT populations were analyzed using ANCOVA model. Missing data is not estimated. The data provided is a least squares mean. LYR-210 (2500. Mu.g) and LYR-210 (7500. Mu.g) both significantly improved the mean psychological component summary (MCS) score at week 24. LYR-210 (7500 μg) achieved statistical significance in each of the 4 psychological component (MCS) areas (vitality, social function, emotional role, and mental health). LYR-210 (2500. Mu.g) and (7500. Mu.g) increased the body composition (PCS) score numerically at week 24 compared to the control, with LYR-210 (7500. Mu.g) reaching statistical significance in 3 PCS fields (body function, body role, and body pain). Each (sub) domain score is directional, so a higher score represents a better health. * Statistical significance was indicated (single sided p <0.05 compared to control).

Tables 10A-10E show exemplary CFBL's in SF-36v2 scores for mental health component summaries (MCSs) along with vitality, social function, emotional role, and mental health scores.

Table 10a. Change in sf-36 psychological component score from baseline.

Table 10B. Changes in SF-36 activity from baseline.

Table 10c. Changes in sf-36 social function from baseline.

Table 10d. Changes in sf-36 emotional roles from baseline.

Table 10 e.changes in sf-36 mental health from baseline.

Tables 11A-11E show exemplary CFBL for SF-36v2 scores for body health component summaries (PCS) along with body function, body role, body pain and general health scores.

Table 11a. Change in sf-36 body part scores from baseline.

Table 11b. Changes in sf-36 body function from baseline.

Table 11 c.changes in sf-36 body role from baseline.

Table 11d. Changes in sf-36 body pain from baseline.

Table 11E. Changes in SF-36 general health from baseline.

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Conclusion: LYR-210 may improve the quality of life of patients with non-surgical CRS who failed prior drug management. In addition, the results of the SF-36v2 score indicate a statistically significant higher quality of life, e.g., improvement in psychological components, vitality, social function, mood, and overall psychological health, during and/or after LYR-210 7500ug treatment as compared to the pre-treatment score. The results of the SF-36v2 score indicate a statistically significant higher quality of life, e.g., improvement in psychological components, social functions, mood, and overall psychological health, during and/or after LYR-210 2500ug treatment as compared to the pre-treatment score. The results of the SF-36v2 score indicate a statistically significant higher quality of life, e.g., improvement in body composition, body function, body role, and body pain, during and/or after the LYR-210 7500ug treatment as compared to the pre-treatment score. The results of the SF-36v2 score indicate a statistically significant higher quality of life, e.g., improvement in body pain, during and/or after LYR-210 2500ug treatment as compared to the pre-treatment score.

Thus, using a preset MCID value in a particular treatment as part of measuring improvements in the field of SNOT-22 allows for a better assessment of how a particular treatment affects the quality of life of CRS patients. To illustrate this, consider a hypothetical scenario in which two competing interventions for CRS have similar overall SNOT-22 improvements, e.g., surgery or LY10, both of which achieve MCID improvement in the area of sleep dysfunction, while the other non-surgical treatments do not. When providing clinical options for CRS patients desiring to significantly improve sleep dysfunction, clinicians may be more inclined to promote treatment that would achieve MCID in the sleep area, even though such treatment may not improve as much in at least one other symptom area.

To evaluate the therapeutic effect of LYR-210 on sinus mucosal inflammation, patients received paranasal sinus MRI at baseline and at the end of treatment (week 24). Since LYR-210 was placed in the middle nasal meatus and designed to deliver MF locally to surrounding nasal tissue, the effect of LYR-210 on inflammation in the ethmoid sinus (the paranasal sinus nearest the middle nasal meatus) was examined. LYR-210 showed improvement in the bilateral ethmoid sinus Zinreich MRI score in a dose-dependent manner at week 24, with LYR-210 (7500 μg) showing significant improvement over the control (FIG. 7).

The time to first rescue treatment is also assessed and a physician decides whether rescue treatment is needed. In other words, as determined by the inventors and at least partially described herein (see table 2), patients at risk for sinus "events" were divided into at least 3 trial groups: no treatment, LYR-210 (2500. Mu.g) and LYR-210 (7500. Mu.g). Thus, as the patient at risk first experiences an adverse event, they are administered rescue medication.

As another example, the number of patients without such health events is listed below the chart in fig. 8.

LYR-210 showed a dose-dependent decrease in the need for rescue treatment, and LYR-210 (7500 μg) group required significantly less rescue treatment than control (risk ratio=0.1, P < 0.05). During the 24-week treatment period, only 1 patient administered LYR-210 (7500. Mu.g) and 2 patients administered LYR-210 (2500. Mu.g) were in need of rescue treatment, while 7 patients in the control group were in need of rescue treatment (FIG. 8). In addition, the first occurrence of rescue treatment in the control group was at week 2, whereas the only patient receiving rescue treatment in LYR-210 (7500 μg) did not require treatment until after 18 weeks of treatment.

Discussion of experimental results

Both doses of LYR-210 were safe and well tolerated by the patient throughout the 24 week treatment period. Treatment-related SAE are not reported, and all treatment-related AEs that occur are consistent with known MF safety ²⁰ . In this study, 80% of the administered LYR-210 drug matrix was retained at week 22. This indicates that the elastomeric properties of LYR-210 allow prolonged contact with the sinus mucosa and thus achieve therapeutically effective local MF delivery throughout the 24-week treatment period.

The composite score and SNOT-22, which focus on the primary symptoms of CRS, both provide information about the effect of CRS on patients and the effectiveness of treatment. In this study, LYR-210 (7500 μg) showed significant improvement in nasal obstruction, facial pain/compression and runny nose at 16, 20 and 24 weeks compared to saline flush controls. In addition, LYR-210 (7500 μg) improves the smell of patients exhibiting moderate to severe loss of smell at baseline (baseline score of > 2 for loss of smell). Since only a fraction of the enrolled patients had a compromised smell in the present study, the 3CS composite score for nasal congestion, facial pain/pressure, and runny nose might be a more suitable endpoint for measuring symptom improvement in non-surgical CRS patients with or without nasal polyps, as they are more reliably present in the present study population. LYR-210 (7500 μg) showed a symptomatic improvement of the 3CS composite score at 12, 16, 20 and 24 weeks, which was statistically significant compared to the saline flush control. LYR-210 (7500 μg) also achieved a statistically significant improvement in SNOT-22 at weeks 8, 16, 20 and 24 compared to saline flush controls. LYR-210 (7500 μg) significantly reduced screen Dou Hunzhuo and the need for rescue treatment compared to the control.

In addition, patients administered LYR-210 (7500 μg) on both sides showed reduced mucosal inflammation as assessed by MRI. LYR-210 (7500 μg) significantly reduced the need for and time to first rescue treatment compared to the control, with only one patient in the LYR-210 (7500 μg) group requiring rescue treatment after 18 weeks.

Despite the reduced recruitment of 67 patients, LYR-210 exhibited rapid and long lasting dose-dependent symptomatic improvement throughout 24 weeks. The primary efficacy endpoint for the LANTERN 2 study was the average CFBL scored at 4CS at week 4, which was-2.2 for LYR-210 (2500 μg) and-2.5 for LYR-210 (7500 μg) (FIG. 5A). The reason for choosing week 4 as the primary efficacy endpoint was based on regulatory precedents in the LANTERN study design, i.e., week 4 for FDA approved steroid eluting sinus implants ^21,22 . Although neither dose reached statistical significance at week 4 compared to saline flush controls, clinically significant therapeutic effects were observed at week 4 for both doses of LYR-210, showing an improvement of more than half the standard deviation of the baseline value (CFBL at-0.8 point in 4CS score), which is a widely accepted statistical rule for QOL evaluation [ Norman et al 2003; soler et al 2010; philips et al 2018; levi et al 2017 ]. LYR-210 (7500 μg) showed a significant improvement in 4CS scores at 16, 20 and 24 weeks compared to saline flush control, indicating a long-lasting and sustained therapeutic effect. In the SNOT-22 evaluation, 70% of patients administered LYR-210 (7500 μg) achieved MCID of SNOT-22 at week 4, which persisted and became more pronounced, with 100% of patients achieving MCID before week 24 (Table 3A). A larger scale multicentric, randomized, blind, control clinical study was planned to further evaluate the efficacy of LYR-210 (7500 μg) in CRS patients.

The control group in this study reported symptom improvement based on 4CS and SNOT-22 evaluations, especially over the first 4 weeks. This response can be attributed to the procedure in which the patient receives the decongestant and cleans his sinuses, and the patient is subjected to a daily nasal saline flush. Nasal saline washout is the primary guideline driving standard for care treatment of CRS ^2,3 And has been demonstrated to be useful as monotherapyWill increase the SNOT-22 score by about 20 points relative to baseline ²³ . Importantly, the patients in this study showed high compliance (average 82.6% ± 26.7%, median 94.6%) with nasal saline washout regimen throughout the 24 week treatment period, well above real life use ⁸ 。

The LANTERN 2 phase study was the first clinical trial showing the dose response of implantable sinus treatment in CRS patients, which provided sustained corticosteroid treatment within 24 weeks after a single administration. LYR-210 showed reproducible therapeutic effects in non-surgically CRS patients regardless of polyp status in 2 different clinical studies. CFBL in SNOT-22 during the 24-week treatment period observed for LYR-210 (2500 μg) in the LANTERN 2 phase study was consistent with the same dose of LYR-210 in the 1-phase study ¹³ This further verifies that in this clinical study and XTreo ^TM Discovery in drug delivery platforms, whereby sustained drug delivery for months can be achieved.

Current FDA approved steroid eluting sinus implants provide treatment for up to 90 days for the sinuses of CRSwNP patients with FESS ^21,22 This ignores the vast majority of patients suffering from CRS, i.e. patients before surgery and without nasal polyps. Sustained high dose drug delivery to inflamed sinus mucosa over long periods of time without patient-dependent actuation has been identified as one factor in achieving adequate symptomatic control in CRS ^24,25 . LYR-210 (7500 μg) improved over current FDA approved steroid eluting sinus implants, with about 5.5 times higher total steroid dose, and demonstrated up to 24 weeks clinical benefit in CRS patients after a single administration, independent of polyp status. In addition, LYR-210 placement in the middle nasal meatus may provide a direct long-lasting treatment of sites of CRS inflammation, which may address the INCS limitations. Since LYR-210 is early in the CRS treatment paradigm, it may provide a promising new therapy for optimizing drug management to control CRS (i.e., patient symptoms).

Conclusion and gist

LYR-210 is the first anti-inflammatory implantable drug treatment, showing up to 24 weeks of benefit in non-surgical CRS patients, independent of polyp status. LYR-210 is the first implantable sinus treatment, and may achieve up to 24 weeks of benefit after a single administration for non-surgical CRS patients with or without nasal polyps. LYR-210 may be a promising treatment option as an alternative to invasive sinus surgery or systemic treatment for patients with failed drug management. The therapeutic effect may continue even after the implant is removed. Importantly, removal does not result in any immediate increase in adverse symptoms.

Chronic nasal and nasal sinusitis (CRS) is described in the literature as an "unrecognized epidemic" because of its high prevalence, its significant impact on the quality of life of patients, and significant limitations in treatment options " ¹ . CRS is characterized by sinus inflammation, and patients exhibit at least 2 of 4 major symptoms (nasal obstruction, facial pain/pressure, runny nose and loss of sense of smell) for a duration of more than 12 weeks ^2,3 . Historically, CRS was divided into 2 phenotypes (CRSwNP and CRSsNP, respectively) based on the presence or absence of nasal polyps. Recently, CRS has been classified as an endotype defined by a molecular mechanism that supports tissue inflammatory patterns ^4,5 . From this point of view, 85% of western CRSwNP patients exhibit type 2 (T2) inflammation with significant eosinophilia ⁶ . Western CRSsNP is more heterogeneous, with approximately 50% of patients exhibiting T2 inflammation ⁶ . Importantly, T2 CRS isotype is associated with severe symptoms and high treatment failure rate ³ . Since CRS is incurable, current pharmaceutical and surgical interventions aim to manage the symptoms of CRS by reducing inflammation and eradicating any existing infection. Furthermore, there is currently no FDA approved drug therapy for the treatment of CRSsNP, although some drugs approved for nasal polyps are used outside of the label in this population.

Reference to the literature

Norman et al 2003; soler et al 2010; philips et al 2018; levi et al 2017.

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10.Schaitkin B,May M,Shapiro A,Fucci M,Mester SJ.Endoscopic sinus surgery:4-year meal-up on the first 100 components.Laryngoscillope.1993, 10; 103 (10) 1117-20.Doi:10.1288/00005537-199310000-00007

11.Sharma U,Concagh D,Core L, et al The development of bioresorbable composite polymeric implants with high mechanical strength. Nat Mater.2018, month 1; 17 (1) 96-103. Doi:10.1038/mat 5016

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13.Douglas RG,Psaltis AJ,Rimmer J,Kuruvilla T,Cervin A,Kuang Y.Phase 1clinical study to assess the safety of a novel drug delivery system providing long-term topical steroid therapy for chronic rhinostinuser.int Forum allegy rhinol.2019, month 4; 9 (4) 378-387.Doi:10.1002/alr.22288

14.Hopkins C,Gillett S,Slack R,Lund VJ,Browne JP.Psychometric validity of the 22-item Sinonasal Outcome test.Clin Otolaryngol.2009 month 10; 34 447-54.Doi:10.1111/j.1749-4486.2009.01995.X

15.Zinreich SJ.Imaging for staging of rhinosinusitis.Ann Otol Rhinol Laryngol journal 5 of 2004; 193:19-23.Doi:10.1177/00034894041130s506

16.Toma S,Hopkins C.Stratification of SNOT-22scores into mild,moderate or severe and relationship with other subjective instruments.Rhinology.2016 years 6 month; 54 (2) 129-33.Doi:10.4193/rhin15.072

17.Mahdavinia M,Schleimer RP,Keshavarzian A.Sleep disruption in chronic rhinosinusitis.Expert Rev Anti Infect Ther.2017 years and 5 months; 15 (5) 457-465.Doi:10.1080/14787210.2017.1294063

18.DeConde AS,Mace JC,Bodner T, et al, SNOT-22quality of life domains differentially predict treatment modality selection in chronic rhinosinusitis.Int Forum Allergy Rhinol.2014, month 12; 4 (12): 972-9.Doi:10.1002/alr.21408

19.Chowdhury NI,Mace JC,Bodner TE, et al Investigating the minimal clinically important difference for SNOT-22symptom domains in surgically managed chronic rhinosinusitis.Int Forum Allergy Rhinol.2017, month 12; 7 (12): 1149-1155.Doi:10.1002/alr.22028

20.Zitt M,Kosoglou T,Hubbell J.Mometasone furoate nasal spray:a review of safety and systemic effects.Drug Saf.2007；30(4):317-26.doi:10.2165/00002018-200730040-00004

21.Marple BF,Smith TL,Han JK, et al, advanced II: adaptive, randomized study assessing safety and efficacy of bioabsorbable steroid-releasable singus displacement, otolaryngol Head Neck surg, 2012, month 6; 146 (6) 1004-11.Doi:10.1177/0194599811435968

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LYR-210 pharmacokinetics and drug release

The plasma MF concentrations of patients administered LYR-210 (2500. Mu.g) or LYR-210 (7500. Mu.g) on both sides were evaluated 1 hour after placement (day 1) and on days 2, 3, 7, 14, 21, 28, 42 and 56. Figure 10 shows MF plasma concentrations that were constant and dose dependent throughout the 56 day study period. For LYR-210 (2500. Mu.g) and LYR-210 (7500. Mu.g) groups,plasma MF concentrations were each at day 2 (C _max =21.5 pg/mL) and day 3 (C _max =58.9 pg/mL) reached a peak. Plasma MF concentration decreased slightly and tended to stabilize after day 7. In this 56 day study, LYR-210 delivered consistent daily doses of MF, LYR-210 (2500. Mu.g) and LYR-210 (7500. Mu.g) achieved steady state concentrations of 12.2pg/mL and 41.2pg/mL (C _ss )。

The percentage of total MF remaining on LYR-210 matrix removed from the patient was determined by HPLC-UV at day 56. After 56 days of treatment, approximately 80% of total MF loaded onto LYR-210 matrix remained, indicating that 18.3.+ -. 5.2% and 19.1.+ -. 4.7% of total MF doses were released from LYR-210 (2500. Mu.g) and LYR-210 (7500. Mu.g) matrices, respectively.

Table 12 arithmetic mean plasma MF concentration (pg/mL).

Table 12 demonstrates the ability of an implant comprising 7500 micrograms of Mometasone Furoate (MF) to deliver a drug for up to 12 weeks.

Additional therapeutic benefits.

Additional therapeutic benefits are described below, with each matrix containing a dose of mometasone furoate of 7500 μg (i.e., 7500 μg per side nose, 15000 μg total per patient).

Dose response was observed in patients with two mometasone furoate implants (i.e., 7500 μg each) which resulted in greater improvement than patients with two 2500 μg implants, e.g., 7500 μg improved chronic nasal and sinusitis (CRS) symptoms in patients with moderate/severe conditions, as measured by one or more types of CRS symptoms at week 24. The categories of improved CRS symptoms include, but are not limited to: 3CS, 4CS, nasal obstruction, runny nose, facial pain, and SNOT-22 scores.

LYR-210 (7500 μg) treatment did not worsen the patient's CRS symptoms from baseline to a more severe category at week 24 in terms of 3CS, 4CS, nasal obstruction, runny nose, facial pain, or SNOT-22.

LYR-210 (7500 μg) may cause mild or no CRS symptoms at week 24 based on 3 CS. LYR-210 (7500 μg) showed a 50% improvement in SNOT-22 scores for some patients over baseline at week 24.

LYR-210 (7500 μg) converts the surgical candidates to non-surgical candidates before the end of the treatment (week 24). The transition is determined at least in part when a change to a non-surgical candidate is defined by 3 CS.ltoreq.4 at week 24.

In certain preferred embodiments, when 3CS of the patient is less than or equal to 4 at week 24, the surgical candidate patient being treated is no longer a surgical candidate.

LYR-210 (7500 μg) may reduce the incidence of acute exacerbations of chronic sinusitis during the treatment phase.

Mometasone furoate released from LYR-210 (7500 μg) was detectable in plasma at least at week 24.

Additional data analysis

The following data support several benefits of patient treatment comprising 7500 μg of mometasone furoate implant, including but not limited to comparison with patients treated with implants comprising 2500 μg of mometasone furoate.

Lanterenn: LYR-210 (7500 μg) improved CRS symptom severity (based on 3CS scores) at week 24 in patients with moderate/severe disease (at baseline).

Analysis of the data showed that some patients with severe disease at baseline had at least one 3CS symptom classification improved, either to moderate disease at week 24 or to mild disease from moderate disease. Analysis of the data shows that at week 24 at least two categories of 3CS symptoms in some patients with severe disease improve to mild disease or from moderate disease to no/no disease. See table 13 below.

Patients treated with LYR-210 (7500 μg) did not worsen to a more severe category (based on 3CS scores) at week 24.

In particular, patients with severe disease at baseline treated with 7500 μg mometasone furoate implant improved at least one 3CS severity category prior to week 24. More specifically, 5/7 patients (71.4%) improved from severe to moderate disease; 1 patient (14.3%) improved from severe to mild disease; and 1 patient (14.3%) improved from severe disease to no disease symptoms. See table 13 below.

Dose responses were observed for certain disease categories and time points. In particular, dose responses were observed for patients with severe disease at baseline, such that LYR-210 (2500 μg) was less effective at week 24 than LYR-210 (7500 μg), with 21.4% of patients with severe disease continuing to have severe symptoms. In contrast, 4/12 (33.3%) of sham/control patients with severe disease at baseline continued to have severe disease at week 24.

Furthermore, unlike 2500 μg of treated patients, 12/13 (92.3%) of LYR-210 (7500 μg) treated patients had moderate disease at baseline and showed improvement to mild or no (zero) disease at week 24. In contrast, 8/11 (72.7%) of sham surgery/control patients with moderate disease at baseline did not improve (i.e., remained moderate) or worsen (to severe) at week 24. See table 13 below.

Lanterr: 3CS transfer from baseline to week 24 (last observed with forward (LOCF)).

None= [0, 1.5); mild= [1.5,4.5); intermediate= [4.5,7.5); severe= [7.5,9]

Lanterenn: LYR-210 (7500 μg) improved nasal obstruction severity at week 24.

Analysis of the data showed that some patients with severe disease at baseline had improved severity of nasal congestion at week 24, to moderate disease, or to mild disease at week 24. Analysis of the data showed that some patients with severe disease had improved at least two symptom categories, improving to mild disease at week 24. Analysis of the data showed that some patients with severe disease improved in at least three symptom categories, improving to no/no disease at week 24.

Patients treated with LYR-210 (7500 μg) did not worsen to a more severe category at week 24.

More specifically, 100% of patients with severe disease at baseline who were treated with LYR-210 7500 μg mometasone furoate implant were improved in at least one severity category prior to week 24. Specifically, 7/12 (58.3%) patients improved from severe to moderate disease before week 24, while 4/12 (33.3%) patients improved from severe to mild disease before week 24. Still further, 1/12 (8.3%) of patients improved from severe disease to no/no disease by week 24. In contrast, 4/14 (28.6%) of sham/control patients with severe disease at baseline still had severe disease at week 24. See table 14 below.

Table 14. Lanterenn: transition from baseline to 24 th week nasal obstruction (LOCF).

None= [0, 0.5); mild= [0.5, 1.5); middle= [1.5, 2.5); severe= [2.5,3]

Lanterenn: LYR-210 (7500 μg) improved the runny nose severity at week 24.

Analysis of the data shows that at week 24, at least one symptom category of some patients with severe disease at baseline improves to moderate disease, or patients with moderate disease at baseline improves to mild disease. Analysis of the data showed that at week 24, at least two symptom categories for some patients with severe disease at baseline improved to mild disease. See table 15.

Patients treated with LYR-210 (7500 μg) did not worsen to a more severe category of runny nose at week 24.

More specifically, 100% of patients with severe disease at baseline treated with 7500 μg mometasone furoate implant were improved in at least one severity category prior to week 24. Specifically, 5/8 (62.5%) of patients with severe disease were improved to have moderate disease, while 3/8 (37.5%) of patients with severe disease were improved to have mild disease. 11/12 (91.6%) of LYR-210 (7500 μg) treated patients that were moderate at baseline improved to have mild or no/no disease at week 24. In contrast, 4/13 (30.8%) of sham/control patients with severe disease at baseline continued to have severe disease at week 24. See table 15.

Lanterrn: transition from baseline to 24 th week runny nose (LOCF).

None= [0, 0.5); mild= [0.5, 1.5); middle= [1.5, 2.5); severe= [2.5,3]

Lanterenn: transition from baseline to 24 th peripheral surface pain improvement.

LYR-210 (7500 μg) reduced the severity of facial pain in the patient at week 24. At week 24, data analysis showed that some patients with severe disease at baseline had at least one symptom classification improved to moderate disease, or patients with moderate disease at baseline improved to patients with mild disease at week 24. Analysis of the data showed that some patients with moderate disease at baseline had improved at least two symptom categories, and improved to no/no disease at week 24. Analysis of the data showed that some patients with severe disease at baseline had improved at least three symptom categories, improving to no/no disease at week 24. See table 16 below.

Patients treated with LYR-210 (7500 μg) did not have pain worsening to a more severe category at week 24, shi Mianbu.

More specifically, 100% of patients with severe disease at baseline who were treated with 7500 μg mometasone furoate implant were improved in at least one severity category prior to week 24. Specifically, 3/4 (75%) of patients with severe disease were improved to have moderate disease, while 1/4 (25%) of patients with severe disease were improved to be disease-free/non-disease. In addition, 12/15 (80%) of patients treated with LYR-210 (7500 μg) with moderate disease at baseline improved to have mild or no/no disease at week 24. In contrast, 3/12 (25%) of sham surgery/control patients with severe disease at baseline still had severe disease at week 24. See table 16 below.

Lanterr: transition from baseline to 24 th peripheral surface pain improvement (LOCF).

None= [0, 0.5); mild= [0.5, 1.5); middle= [1.5, 2.5); severe= [2.5,3]

Lanterenn: patients treated with two 7500 μg implants showed an improvement in the 3CS symptom response at week 24.

One hundred percent (100%) of patients treated with two LYR-210 7500 μg mometasone furoate implants reported at least a 1-point relief of 3CS severity symptoms at week 24. This improvement represents a statistically significant improvement over the 65.2% improvement for control/sham operated patients.

In addition, 90.5% of LYR-210 (7500 μg) treated patients reported at least a 2-point reduction in 3CS severity symptoms at week 24. This improvement was statistically significant compared to the 43.5% improvement for the control patient.

Furthermore, a dose response was also demonstrated in which patients with 7500 μg implant showed a greater response than patients with 2500 μg implant. See table 17 below.

Lanterrn: 3CS response (LOCF) at week 24.

Lanterenn: patients with two 7500 μg implants showed an improvement in 4CS dose response compared to patients with two 2500 μg implants observed at week 24.

One hundred percent (100%) of patients treated with two LYR-210 7500 μg mometasone furoate implants reported at least a 1-point relief of 4CS severity symptoms at week 24. This improvement was a statistically significant improvement over the 65.2% improvement in the control patient. 7500 μg of the treated patient showed a dose response relative to 2500 μg of the treated patient.

In addition, 90.5% of LYR-210 (7500 μg) treated patients reported at least a 2-point reduction in 4CS severity symptoms at week 24. This improvement was statistically significant relative to the 52.2% improvement in the control patients.

Still further, 76.2% of LYR-210 (7500 μg) treated patients reported at least a 3-point reduction in 3CS at week 24. This improvement was statistically significant over the 43.5% improvement in the control patients. See table 18 below.

Lanterr: 4CS response (LOCF) at week 24.

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Lanterenn: SNOT-22MCID response at week 24 (improvement. Gtoreq.8.9).

100% of patients treated with 7500 μg mometasone furoate implant improved at least 8.9 points in SNOT-22 score at week 24, which is the smallest clinically significant score difference. The results were statistically significant compared to the improvement of patients in the sham (control) group. The SNOT-22 improvement was statistically significant relative to the control (p=0.0034). See table 19 below.

Table 19.lanterenn: SNOT-22 response (improvement. Gtoreq.8.9) at week 24 (LOCF).

TRT01P	N	RSP	PCT	XPL_FISH
					LYR-210 7500μg	20	20	100.0％	0.0034
LYR-210 2500μg	23	16	69.6％	0.5000
					False operation	23	15	65.2％	.

Lanterenn: patient as surgical candidate transition to non-surgical candidate at 24 th week.

Surprisingly, at this 24-week observation time point, for patients implanted with two LYR-210 (7500 ug per implant), 71.4% of surgical candidates were reclassified (changed) as non-surgical candidates when their symptoms became to have a value of 3 CS.ltoreq.4. In contrast, 26.1% of control patients were reclassified based on the same criteria. Although having the ethmoid sinreich score=0 was determined as a reclassification criterion, none of the patients evaluated here had the ethmoid sinreich score=0. See table 20 below.

In addition, dose responses were observed in reclassification between patients with high dose (7500 ug) versus low dose (2500 ug) implants.

Table 20. Lanterenn: transition of non-surgical candidates at 24 weeks (LOCF). 3cs.ltoreq.4 or ethmoid sinearrich score=0.

TRT01P	N	NONSURG	PCT	XPL_FISH
					LYR-210 7500μg	21	15	71.4％	0.0031
LYR-210 2500μg	23	9	39.1％	0.2651
					False operation	23	6	26.1％	.

Lanterenn: acute exacerbation of CS during the treatment phase.

Less acute exacerbations of chronic sinusitis occurred in LYR-210 (7500 μg) in the treatment group during the 24 week treatment period. See table 21 below.

Lanterrn: acute exacerbation of CS during the treatment phase.

TRT01P	N	ACU_EXAC	PCT	XPR_FISH
					LYR-210 7500μg	21	2	9.5％	0.0883
LYR-210 2500μg	23	6	26.1％	0.5000
					False operation	23	7	30.4％	.

Lanterenn: correlation between changes in 3CS and SNOT-22 at week 24.

At this 24-week observation time point, SNOT-22 and 3CS correlated strongly with each other and indicated a statistically significant improvement over baseline disease.

In addition, 3CS also provided a clinically relevant assessment of the effect of treatment on CRS symptoms at week 24. See table 22 below.

Lanterr: correlation between changes in 3CS and SNOT-22 at week 24.

Lanterenn: at least one positive response to MF implant at week 24.

The patient group with two LYR-210 (7500 μg) implants per person showed a significantly higher proportion of responders at week 24 than untreated controls (i.e., no implant or no MF prosthetic implant). The observations are based on the parameters listed in table 23.

In other words, a patient is considered a responder if the patient experiences at least 1 positive response and no negative response in the parameters listed in table 23.

Lanterr: at week 24, at least 1 positive and no negative for any response (LOCF).

Lanterenn: LYR-210 (7500 μg) treatment at week 24 resulted in mild or no CRS symptoms (3 CS based).

70% of patients treated with LYR-210 (7500 μg) showed improvement to mild or no (no) CRS symptoms at week 24. This was statistically significant compared to the sham surgery/control. Furthermore, in this analysis, a dose-dependent effect was observed between LYR-210 2500 μg patient and LYR-210 7500 μg treated patient.

Patients with mild disease were removed from the analysis, which corresponds to removal of 1 patient from the LYR-210 (7500 μg) group and 0 patient from the sham group. See table 24 below.

Table 24. Lanterenn: no/mild 3CS severity (LOCF) at week 24.

None= [0, 1.5); mild= [1.5,4.5); intermediate= [4.5,7.5); severe= [7.5,9]

XPL_FISH single-sided p-value obtained from Fisher's exact test.

Lanterenn: LYR-210 (7500 μg) improves CRS symptoms by at least 1 severity category based on 3 CS.

At 24 weeks after implantation of the implant, a dose-dependent effect of improved disease severity was observed in at least one 3CS disease category of the patient.

More specifically, 90.5% of patients treated with LYR-210 (7500 μg) improved at least one 3CS severity category at week 24. This was statistically significant compared to the sham surgery/control. See table 25 below.

Lan terenn: 3CS severity improvement (LOCF) at 24 weeks of ≡1 category.

TRT01P	N	RSP	PCT	XPL_FISH
					LYR-210 7500μg	21	19	90.5％	0.0027
LYR-210 2500μg	23	16	69.6％	0.1154
					False operation	23	11	47.8％	.

None= [0, 1.5); mild= [1.5,4.5); intermediate= [4.5,7.5); severe= [7.5,9]

XPL_FISH Single-sided p-value obtained from Fisher's exact test

Lanterenn: no/mild 3CS severity and ≡1 class improvement (LOCF) at week 24.

At 24 weeks after implantation of the implant, in patients showing no (no) or mild symptoms, a dose-dependent effect of an improved severity of the disease of at least one 3CS disease category was observed.

More specifically, 66.7% of patients treated with LYR-210 (7500 μg) had no or mild CRS symptoms at week 24 and improved in at least one severity category of 3CS at week 24. The results were statistically significant compared to sham surgery/controls. See table 26 below.

Lanterr: no/mild 3CS severity and ≡1 class improvement (LOCF) at week 24.

TRT01P	N	RSP	PCT	XPL_FISH
					LYR-210 7500μg	21	14	66.7％	0.0078
LYR-210 2500μg	23	8	34.8％	0.3747
					False operation	23	6	26.1％	.

None= [0, 1.5); mild= [1.5,4.5); intermediate= [4.5,7.5); severe= [7.5,9]

XPL_FISH single-sided p-value obtained from Fisher's exact test.

Materials and methods

Research product

LYR-210 is a research product designed and manufactured by Lyra Therapeutics, inc. (Watertown, mass., U.S.). LYR-210 has a tubular mesh structure with a repeating diamond pattern throughout the structure, composed of biocompatible and bioabsorbable polymers, formulated for precise control of the gradual release of MF up to 2500 μg (LYR-210 (2500 μg)) or 7500 μg (LYR-210 (7500 μg)) over 24 weeks, and gradual softening over time. The engineered elastomeric properties enable dynamic expansion of LYR-210 to the target anatomy, thereby facilitating continuous apposition to the surrounding mucosa to achieve effective and consistent local MF delivery over a 24 week period. LYR-210 is placed within the middle nasal meatus on both sides of a CRS patient, which is not deformed by prior surgical intervention, with a disposable applicator used in office-based surgery after local anesthesia in endoscopic visualization. FIG. 9C shows LYR-210 self-expanding from a constrained state after deployment from an applicator. It is intended that LYR-210 be removed 24 weeks or earlier (at the discretion of the physician) using standard equipment.

Study design

CRS patients with prior drug management failure were recruited into the multicenter, randomized, blind, control, dose-range lanterrn 2 phase trial to evaluate efficacy, safety, and tolerability of LYR-210 (2500 μg) and LYR-210 (7500 μg). 14 otorhinolaryngological clinics in Poland, the Czech republic, australia and New Zealand recruited and recruited patients. The study was conducted according to the declaration of helsinki and the guidelines of good clinical trial specifications. Both study protocols and patient informed consent were reviewed and approved by the ethics committee of each study center according to regulatory requirements of each country. Patients signed informed consent prior to participation in the study.

Inclusion criteria included patients aged 18 years or older, at least 2 of 4 principal symptoms (4 CS) with CRS for at least 12 weeks ^2,3 And the baseline average 4CS score at the previous 7 days was 7 or higher on a 0-12 scale. Patients show suppuration, inflammation and/or nasal polyps in rhinoendoscopy and show radiological evidence of sinusitis in paranasal CT or MRI. The recruited patients were previously subjected to at least 2 drug treatment trials for CRS, independent of the lanter study, for at least 4 weeks including at least one course of intranasal corticosteroid spray (INCS); the duration is based on ICAR-2016 guidelines for the "length of time for appropriate drug treatment prior to ESS" (Orlandi RR, kingdom TT, hwang PH. International Consensus Statement on Allergy and Rhinology: rhinosinusitis Executive Summary. Int Forum Allergy Rhinol.2016, month 2; 6 supplement 1:S3-21.). Patients enrolled in this trial were reported to use an average of 1.9 courses of INCS (median: 2, max: 5) just prior to screening for the past year. LYR-210 (7500 μg) achieved clinically significant improvement over the control over up to 24 weeks without INCS, supporting its potential use as monotherapy. Thus, one potential advantage of LYR-210 is the opportunity to eliminate the problem of patient compliance with INCS in real life and to alleviate the treatment burden. 100% of patients administered LYR-210 (7500 μg) achieved MCID of SNOT-22 at week 24, which is superior to LYR-210 (2500 μg) and control. Although the data reported in this study were analyzed using 8.9 points as the MCID of SNOT-22 ¹⁴ But it has also been reported that MCID is 12 points in drug-managed CRS patients ²⁶ . Using this 12-point alternative MCID,90% of patients administered LYR-210 (7500 μg) achieved this MCID at week 24, as compared to 65% of patients in the control group in this study.

Patient exclusion criteria included past history of FESS, evidence of significant mucosal damage under nasal endoscopes (e.g., ulcers or erosion), perforation of the nasal septum, severe nasal obstruction by nasal polyps (which prevents entry into or observation of the middle nasal tract), concurrent seasonal allergic rhinitis (if symptom onset within 4 weeks of random groupings is expected), perennial allergic rhinitis (if well controlled by regular use of INCS), or severe asthma. In addition, patients were excluded if they exhibited a bilateral Zinreich score of less than 4 in 3 pairs of posterior, frontal and sphenoid sinuses (0-5 scale per sinus) at the time of screening MRI. Patients who were not resistant to local anesthesia or corticosteroids, who received Systemic Corticosteroids (SCS) within 1 month prior to screening or had history or evidence of immunodeficiency, intracranial or orbital complications, evidence of podophyllosis/mycoball, sinus mucus cysts or invasive fungal nasal and nasal sinusitis were also excluded.

From the screening visit until the end of the study, certain drugs that might interfere with study evaluation are not allowed to be used unless they are used as rescue treatments. Such rescue drugs may include intranasal corticosteroids (INCS), oral/intramuscular corticosteroids (except for a stabilization regimen of inhaled corticosteroids for asthma that has been administered for at least 3 months prior to screening and maintained throughout the study), oral decongestants, and monoclonal antibodies. Such drugs are only allowed to be used when patients continue to administer antiallergic drugs at consistent doses from screening visit to study period.

Following the screening evaluation, the patient underwent a washout period of at least 14 days. From the beginning of the washout period to the end of the 24-week treatment period, the patient was provided and instructed to use nasal saline washout daily. During the washout period, the patient received no other positive treatment for CRS. After the washout period, on the day of surgery (day 1), patients were randomized (1:1:1) to one of three study groups: LYR-210 (7500 μg) was administered into the middle nasal meatus on both sides, LYR-210 (2500 μg) was administered into the middle nasal meatus on both sides, or saline rinse control only daily. To ensure that the patients were blinded to the study treatment assignment, patients randomly assigned to the control group were also subjected to a sham operation in which the applicator was inserted into and removed from the middle nasal passage. The patient received a local anesthetic and decongestant prior to surgery and was wearing an eye mask to ensure that the treatment was dispensed blindly. Clinical researchers and clinical staff were not blinded to LYR-210 relative to the control, but they were blinded to the administered LYR-210 dose. The sponsor was blinded to the study.

Patients returned to the clinic for follow-up assessment at weeks 4, 12 and 24 and for telephone follow-up at weeks 8, 16 and 20 to record any Adverse Events (AEs) and concomitant medications/procedures. Patients wear eye shields during endoscopy only at all post-screening visits to maintain unknowns about study treatment assignment. At visit 24 weeks (end of treatment), LYR-210 (2500. Mu.g) or LYR-210 (7500. Mu.g) was removed using standard equipment, and control patients received sham removal surgery. After the end of treatment visit, the patient underwent a post-treatment follow-up period lasting about 24 weeks. The LANTERN 2 phase study design is summarized in fig. 1.

Security assessment

Safety was assessed by changes in the incidence of AE, laboratory checks, vital signs, morning serum cortisol levels, nasal endoscopy assessment, intraocular pressure (IOP) and slit lamp checks. AE was encoded using the medicated active medical dictionary (MedDRA) version 23.0 dictionary. AE were recorded throughout the study and reported for severity and association with study treatment or procedure. Researchers classify the severity of AE as mild, moderate or severe.

Ocular safety was assessed by measuring IOP at baseline and weeks 4, 12 and 24, and mydriatic slit lamp examination of the lens for the presence of lens cloudiness at baseline and week 24. The lens haze was graded using a WHO/PBD simplified cataract grading system. Ophthalmic assessment was performed by an ophthalmologist blinded to the study treatment received by the patient.

Efficacy assessment

The patient reported symptoms and daily use of saline washout were recorded using an electronic patient reporting results (ePRO) system. The patient reported a score for each of 4CS of CRS on ePRO each morning, starting at least 7 days prior to visit on day 1 and lasting for the entire 24 week treatment period. Each of the four symptoms (nasal obstruction, facial pain/pressure, runny nose, and loss of sense of smell) was rated on a 0-3 scale (0 = none, 1 = mild, 2 = moderate, and 3 = severe). Patients also passed SNOT-22 at baseline and at weeks 2, 4, 8, 12, 16, 20 and 24 ¹⁴ The severity of its symptoms and social/emotional outcome of CRS were recorded. To evaluate the effect of LYR-210 on reducing sinus inflammation, patients received baseline and treatment at the end (week 24)Sinus MRI was performed. Sinus turbidity levels for each of the anterior and posterior sinuses were scored by an independent imaging core laboratory using a Zinreich (modified Lund-Mackay) scoring system that classifies the turbidity percentages on a scale of 0 to 5 (0=0%, 1=1-25%, 2=26-50%, 3=51-75%, 4=76-99%, and 5=100% or total occlusion ¹⁵ . The time to first rescue treatment use was also assessed and defined as worsening or acute exacerbation of CRS in the enrolled subjects, resulting in researchers recommending INCS, SCS, decongestants, and/or FESS.

Data analysis

Patients receiving trial or successful study treatment procedures were included in the safety analysis (safety population). Efficacy analysis was performed on the intent-to-treat (ITT) population, which included patients who received a successful study treatment program and were subjected to at least one randomized efficacy assessment. Patient demographics, medical history, and baseline disease characteristics are reported as the frequency or percentage of patients in the ITT patient population. AEs occurring in treatment were reported as counts of patients experiencing the event. For primary and secondary endpoints of Change From Baseline (CFBL), an analysis of covariance (ANCOVA) model was used, which adjusts the treatment group, baseline scores and grading variables (nasal allergies, nasal polyps) and experiments were performed at a unilateral significance level of 0.05.

No adjustment is made for multiplicity. Unless otherwise indicated, CFBL averages are reported as least squares averages (LSMs) and Standard Error (SE) from the ANCOVA model. The time to first rescue treatment use was analyzed using the Kaplan-Meier method and the risk ratio. Subjects who did not realize the event were examined at the end of the treatment date or at the early expiration date. Risk ratio, 90% CI on both sides and p-value tested at single-sided significance level of 0.05 were applied to Cox proportional risk models. For symptom-based endpoints, if the patient exits the trial or otherwise does not report data at a particular point in time during the treatment phase, a last observed with forward (LOCF) protocol is used to estimate the deficit value. Furthermore, for a patient requiring rescue treatment in the treatment phase, post-rescue data is set to be absent, and the value of the post-rescue time point is estimated using the LOCF. Statistical analysis was performed using SAS version 9.4 or higher.

While various embodiments are specifically illustrated and described herein, it will be appreciated that modifications and variations of the present disclosure are covered by the above teachings and within the purview of the appended claims without departing from the spirit and intended scope of the disclosure.

Alternative embodiments

In one exemplary embodiment of the implantable device of the present invention, the device comprises a permeable, impermeable or semi-permeable sheet containing the active ingredient. The sheet may be considered a permeable, impermeable or semi-permeable membrane. Embodiments of the device comprising the sheet material may contain an osmotic drug delivery component, as seen in fig. 11. The permeable or semi-permeable sheet material may be implanted flat or in a rolled state. In a crimping embodiment, the crimped sheet comprises an internal cavity. In this exemplary embodiment, the drug delivery component is comprised of a semipermeable polymeric hollow sheet containing a drug (e.g., MF) or other Active Pharmaceutical Ingredient (API) in the absence or presence of a zymogen.

The implantable device may comprise a permeable, impermeable or semi-permeable membrane, such as one or more fibers or sheets. In one embodiment, the permeability to the fluid is achieved by using a permeable material. In another embodiment, permeability is achieved by one or more delivery apertures in the hollow fiber or sheet wall. Any number of orifices is contemplated, including but not limited to one, two, three, four, five, six, seven, eight, nine, ten, twenty-five, fifty, one hundred, two hundred, one thousand, and the like. Consider an impermeable embodiment, for example, a metal tube having a bore, where the bore may be a drilled hole.

In one embodiment, the devices herein may be coated or covered. The invention is not intended to be limited by the type (such as elastomer), thickness, or degree of coverage (e.g., partial or complete) of the coating. The device may be fully or partially coated. In one embodiment, an elastomeric coating may be present on top of the permeable or semi-permeable membrane, such as on the hollow fiber or sheet, to cover or uncover any delivery orifice. The elastomer may be coated onto the implant to render it self-expanding. One or more apertures may be formed in the semipermeable membrane either before or after the elastomer is coated. The coating may have a thickness, among other possibilities, ranging from, for example, about 1 μm to about 25 μm (e.g., from about 1 to 2 to 5 to 20 to 25 μm). The coating thickness may also be less than 1 μm or greater than 25 μm.

In one embodiment, the devices herein may be coated or covered. The present invention is not intended to be limited by the type, thickness or coverage of the coating, such as an elastomer. The device may be fully or partially coated. In one embodiment, an elastomeric coating, such as a hollow fiber or sheet, may be present on top of the permeable or semi-permeable membrane, covering or not covering any delivery orifice, as seen in fig. 11. The elastomer may be coated onto the implant to render it self-expanding. One or more apertures may be formed in the semipermeable membrane either before or after the elastomer is coated.

Claims

1. A method of treating a sinus condition, the method comprising: a) Providing first and second implants, each comprising at least one coating comprising about 7500 micrograms of mometasone furoate, and wherein the first implant is configured to fit within a first middle nasal meatus of a patient, and wherein the second implant is configured to fit within a second middle nasal meatus of the patient; b) Implanting the first and second implants into the first and second middle nasal passages of a patient having symptoms of a sinus condition, and c) detecting a reduction in one or more symptoms, thereby treating the sinus condition.

2. The method of claim 1, wherein mometasone furoate deployed in each implant exhibits zero order release over 12 weeks or more of the planned implantation phase.

3. The method of claim 1, wherein the reduction in one or more symptoms is reflected in a SNOT score.

4. The method of claim 1, wherein the sinus condition is a chronic sinus condition.

5. The method of claim 1, wherein the sinus condition is characterized by at least two symptoms selected from the group consisting of: nasal congestion, dyspnea through the nasal passages, nasal polyps, runny nose, loss of smell and facial pain.

6. The method of claim 1, wherein the sinus condition is characterized by two or more symptoms selected from the group consisting of: runny nose, nasal congestion or congestion, hyposmia and facial compression or pain.

7. The method of claim 1, wherein at least one of the first or second implants is a braided structure.

8. The method of claim 1, wherein at least one of the first or second implants is a tubular structure.

9. The method of claim 1, wherein at least one of the first or second implants is self-expanding.

10. The method of claim 1, wherein at least one of the first or second implants is configured as a sheet.

11. The method of claim 9, wherein at least one of the first or second implants is configured as a curled sheet.

12. The method of claim 3, wherein the reduction comprises a 50% improvement in SNOT-22 score at week 24 of the implantation phase.

13. The method of claim 1, wherein the alleviating comprises no symptoms at week 24 of the implantation phase.

14. An implant configured to fit within the middle nasal meatus for preventing a need for surgery in a subject that is a candidate for sinus surgery, the implant comprising a coating comprising about 7500 micrograms of mometasone furoate, the implant configured to exhibit zero order release of at least 60% of the mometasone furoate, characterized in that the implant is delivered to the subject prior to surgery.

15. The implant of claim 12, wherein the subject is treated for at least 4 months.

16. The implant of claim 12, wherein the implant is configured to release 20 to 80% of the mometasone furoate during the first 12 cycles.

17. The implant of claim 12, wherein the zero order release is exhibited in vitro at 37 ℃ in pH 7.4PBS buffer containing 2% sds.

18. The implant of claim 12, wherein the implant is for use in a method of treating a chronic sinus condition.

19. The implant of claim 16, wherein the chronic sinus condition is characterized by at least two symptoms selected from the group consisting of: nasal congestion, dyspnea through the nasal passages, nasal polyps, runny nose, and facial pain.

20. The implant of claim 12, wherein the implant is a braided structure.

21. The implant of claim 12, wherein the implant is a tubular structure.

22. The implant of claim 12, wherein the implant is self-expanding.

23. The implant of claim 12, wherein the implant has a diameter of at least 13 mm.

24. The implant of claim 12, wherein the implant has a length of at least 10 mm.

25. A method of treating a sinus condition comprising a) implanting first and second implants into first and second middle nasal passages of a patient having a sinus condition, wherein the patient is a sinus surgical candidate, each implant comprising at least one coating comprising about 7500 micrograms of mometasone furoate, and b) detecting a reduction in one or more symptoms, wherein after 20 weeks the patient is no longer a sinus surgical candidate, thereby treating the sinus condition.

26. The method of claim 24, wherein the patient is a sinus surgical candidate based on the symptoms' SNOT score.

27. The method of claim 24, wherein the patient is no longer a sinus surgical candidate based on the SNOT score.

28. The method of claim 24, wherein the patient is no longer a sinus surgical candidate based on a 3-principal symptom complex score (3 CS) comprising nasal obstruction, facial pain/pressure, and runny nose.

29. The method of claim 24, wherein the patient is no longer a sinus surgical candidate at 3CS +.4.

30. A combination for preventing a need for surgery in a subject as a sinus surgical candidate, the combination comprising first and second implants, each comprising at least one coating comprising about 7500 micrograms of mometasone furoate, wherein the first implant is configured to fit inside a first middle nasal tract of the subject, the mometasone furoate being configured to have zero order release for more than 12 weeks; and wherein the second implant is configured to fit inside a second middle nasal meatus of the subject, the mometasone furoate is configured to have zero order release for more than 12 weeks, characterized in that the combination is delivered to the subject prior to surgery, wherein the subject is treated for at least 4 months.

31. The combination of claim 30, wherein the subject is a candidate for Functional Endoscopic Sinus Surgery (FESS).

32. The combination of claim 30, wherein the first and second implants are configured to release 20 to 80% of the mometasone furoate during the first 12 cycles.

33. The combination of claim 30, wherein each of the first and second implants is configured to exhibit zero order release after week 1.

34. The combination of claim 30, wherein the zero order release is exhibited in vitro at 37 ℃ in pH 7.4PBS buffer containing 2% sds.

35. The combination of claim 30, wherein the combination is for use in a method of treating a chronic sinus condition.

36. The combination of claim 35, wherein the chronic sinus condition is characterized by at least two symptoms selected from the group consisting of: nasal congestion, dyspnea through the nasal passages, nasal polyps, runny nose, and facial pain.

37. The combination of claim 30, wherein at least one of the first or second implants is a braided structure.

38. The combination of claim 30, wherein at least one of the first or second implants is a tubular structure.

39. The combination of claim 15, wherein at least one of the first or second implants comprises a spiral.

40. The combination of claim 15, wherein at least one of the first or second implants is self-expanding.

41. A method of treating a sinus condition, the method comprising:

a) Providing first and second implants each comprising about 7500 micrograms of mometasone furoate;

b) Implanting the first implant inside a first middle nasal passage of a first patient having a sinus condition;

c) Implanting the second implant inside a second middle nasal meatus of the first patient; and

d) Monitoring the first patient for a sinus condition for a period of at least 12 weeks, wherein the first patient implanted with first and second implants each comprising about 7500 micrograms of mometasone furoate exhibits a reduced need for rescue therapy when compared to a second patient with a sinus condition implanted with first and second implants each comprising about 2500 micrograms of mometasone furoate.

42. The method of claim 41, wherein the first and second implants are configured to release 20 to 80% of the mometasone furoate during the first 12 cycles.

43. The method of claim 41, wherein the sinus condition of the first patient is improved more rapidly than a second patient implanted with first and second implants comprising 2500 micrograms of mometasone furoate.

44. The method of claim 41, wherein the sinus condition is a chronic sinus condition.

45. The method of claim 41, wherein the sinus condition is characterized by at least two symptoms selected from the group consisting of: nasal congestion, dyspnea through the nasal passages, nasal polyps, runny nose, loss of smell and facial pain.

46. The method of claim 41, wherein at least one of the first or second implants is a braided structure.

47. The method of claim 41, wherein at least one of the first or second implants is a tubular structure.

48. The method of claim 41, wherein at least one of the first or second implants is self-expanding.

49. The method of claim 41, wherein the implant comprises a spiral.

50. The method of claim 41, wherein monitoring of the first patient for sinus conditions is performed for a period of at least 16 weeks.

51. The method of claim 41, wherein monitoring of the first patient for a sinus condition is performed for a period of at least 20 weeks.

52. The method of claim 41, wherein each of the first and second implants comprises at least one coating comprising about 7500 micrograms of mometasone furoate.

53. A method of treating a sinus condition, the method comprising:

d) Monitoring the first patient for a period of at least 12 weeks of a sinus condition, wherein the first patient implanted with first and second implants each comprising about 7500 micrograms of mometasone furoate exhibits a reduced need for rescue therapy when compared to a second patient with a sinus condition administered only a saline flush therapy and no mometasone furoate.

54. The method of claim 53, wherein the first and second implants are configured to release 20 to 80% of the mometasone furoate during the first 12 cycles.

55. The method of claim 53, wherein the sinus condition of the first patient is improved when compared to the second patient.

56. The method of claim 53, wherein the sinus condition is a chronic sinus condition.

57. The method of claim 53, wherein the sinus condition is characterized by at least two symptoms selected from the group consisting of: nasal congestion, dyspnea through the nasal passages, nasal polyps, runny nose, loss of smell and facial pain.

58. The method of claim 53, wherein at least one of the first or second implants is a braided structure.

59. The method of claim 53, wherein at least one of the first or second implants is a tubular structure.

60. The method of claim 53, wherein at least one of the first or second implants is self-expanding.

61. The method of claim 53, wherein the implant comprises a spiral.

62. The method of claim 53, wherein monitoring of the first patient for a sinus condition is performed for a period of at least 16 weeks.

63. The method of claim 53, wherein monitoring of the first patient for a sinus condition is performed for a period of at least 20 weeks.

64. The method of claim 53, wherein each of the first and second implants comprises at least one coating comprising about 7500 micrograms of mometasone furoate.

65. A method of treating a sinus condition, the method comprising:

d) Monitoring the first patient for a period of at least 8 weeks of sinus condition, wherein the first patient implanted with first and second implants each comprising about 7500 micrograms of mometasone furoate improves more rapidly than a second patient with sinus condition implanted with first and second implants each comprising about 2500 micrograms of mometasone furoate.

66. The method of claim 65, wherein the improvement in a first patient implanted with first and second implants each comprising about 7500 micrograms of mometasone furoate is observed at least as early as 8 weeks after implantation of the implant as compared to a second patient implanted with first and second implants each comprising about 2500 micrograms of mometasone furoate.

67. The method of claim 65, wherein the first and second implants are configured to release 20 to 80% of the mometasone furoate during the first 12 cycles.

68. The method of claim 65, wherein the sinus condition is a chronic sinus condition.

69. The method of claim 65, wherein the sinus condition is characterized by at least two symptoms selected from the group consisting of: nasal congestion, dyspnea through the nasal passages, nasal polyps, runny nose, loss of smell and facial pain.

70. The method of claim 65, wherein at least one of the first or second implants is a braided structure.

71. The method of claim 65, wherein at least one of the first or second implants is a tubular structure.

72. The therapy of claim 65, wherein at least one of the first or second implants is self-expanding.

73. The method of claim 65, wherein monitoring of the first patient for sinus conditions is performed for a period of at least 16 weeks.

74. The method of claim 65, wherein monitoring of the first patient for a sinus condition is performed for a period of at least 20 weeks.

75. The method of claim 65, wherein each of the first and second implants comprises at least one coating comprising about 7500 micrograms of mometasone furoate.

76. The method of claim 65, wherein the implant comprises a spiral.

77. The method of claim 65, wherein the first patient is a patient with nasal polyps.

78. The method of claim 65, wherein the 7500 μg implant reduces rescue therapy use by the first patient.

79. The method of claim 65, wherein the 7500 μg implant reduces a radiographic screen Dou Hunzhuo of the first patient at week 24.

80. The method of claim 65, further comprising e) measuring the plasma concentration of mometasone furoate in the first patient.

81. The method of claim 80, wherein the patient exhibits a dose-dependent plasma concentration.

82. The method of claim 81, wherein the patient shows the dose-dependent plasma concentration for 56 days.

83. A self-expanding implantable device comprising about 7500 micrograms of mometasone furoate.

84. The device of claim 83, wherein the device is a braided structure.

85. The device of claim 83, wherein the device is a tubular structure.

86. The device of claim 83, wherein the device comprises a spiral.

87. The device of claim 83, wherein the device comprises at least one coating comprising about 7500 micrograms of mometasone furoate.

88. The device of claim 83, wherein the device is configured to conform to the middle nasal meatus space.

89. A method of treating a sinus condition, the method comprising:

a) Providing first and second implants, each comprising mometasone furoate;

b) Implanting the first implant inside a first middle nasal passage of a patient having a sinus condition;

c) Implanting the second implant inside a second middle nasal meatus of the patient;

d) Removing the first and second implants from the patient; and

e) After removal of the implant, the patient is tested for improvement in sinus conditions for a period of at least 4 weeks.

90. The method of claim 89, wherein the patient is implanted with first and second implants each comprising about 7500 micrograms of mometasone furoate.

91. The method of claim 89, wherein the patient is implanted with first and second implants each comprising about 2500 micrograms of mometasone furoate.

92. The method of claim 89, wherein the improvement detected in the patient's sinus condition is reduced nasal obstruction, facial pain, runny nose (anterior/posterior), and/or loss of sense of smell.

93. The method of claim 89, wherein the patient's condition continues to improve for a period of at least 8 weeks after removal of the implant.

94. The method of claim 89, wherein the patient's condition continues to improve for a period of at least 12 weeks after removal of the implant.

95. The method of claim 89, wherein the patient's condition continues to improve for a period of at least 16 weeks after removal of the implant.

96. The method of claim 89, wherein the implant is removed after 24 weeks.