Isaiah

Idiopathic Intracranial Hypertension (IIH) is defined as a condition characterized by elevated intracranial pressure (ICP) without a detectable cause. The diagnosis of IIH is based on the modified Dandy criteria, which include:

1. Increased intracranial pressure, as documented by lumbar puncture, with an opening pressure of 25 cm H2O or higher in a non-obese patient and 28 cm H2O or higher in an obese patient.

2. Presence of symptoms such as headache, vision changes, or tinnitus.

3. Normal cerebrospinal fluid (CSF) composition.

4. No evidence of hydrocephalus, mass lesion, or structural lesion on imaging studies such as MRI or CT scans.

5. No other identifiable cause of increased ICP, such as a medical condition or medication.

6. Awake and alert patient, with no evidence of coma or altered mental status.

The diagnosis of IIH requires a thorough evaluation to rule out other potential causes of increased ICP. Patients with IIH often experience symptoms such as headache, vision changes, including double vision or transient vision obscurations, and tinnitus. The condition is more common in women, particularly those of childbearing age, and is often associated with obesity.

Table 1: Modified Dandy Criteria for IIH Diagnosis

Note: The above information is based on the available data and is intended to provide a general understanding of IIH. For a specific diagnosis and treatment plan, it's essential to consult a qualified medical professional.

The prevalence of Idiopathic Intracranial Hypertension (IIH) in the Western world is estimated to be around 1-2 per 100,000 people per year. However, the exact number of IIH patients in the Western world is difficult to determine due to variations in diagnosis, reporting, and population demographics.

A study published in the journal Neurology found that the annual incidence of IIH in the United Kingdom was approximately 1.6 per 100,000 people. Another study in the United States reported an annual incidence of 2.5 per 100,000 people.

Table 2: Estimated Prevalence of IIH in Western Countries

Assuming an average prevalence of 1.8 per 100,000 people per year, we can estimate the number of IIH patients in Western countries with a total population of around 500 million people.

Estimated number of IIH patients: 500,000,000 (total population) x 1.8 (prevalence per 100,000 people per year) / 100,000 = 9,000 new cases per year

Using this estimate, the total number of IIH patients in the Western world can be roughly estimated to be around 90,000, assuming an average disease duration of 10 years. However, please note that this is a rough estimate and the actual number of IIH patients may be higher or lower due to various factors such as underdiagnosis, misdiagnosis, and variations in population demographics.

Figure 1: Estimated Number of IIH Patients in Western Countries

Note: The above estimates are based on available data and should be used as a rough guide only. For accurate and up-to-date information, it's essential to consult a qualified medical professional or recent research studies.

The risk factors for Idiopathic Intracranial Hypertension (IIH) include both genetic and environmental factors.

Genetic factors: The involvement of genetic elements in IIH development is indicated by familial occurrences of the condition and the identification of candidate regions on chromosomes 5, 13, and 14 in a genome-wide association study. However, a definitive Mendelian inheritance pattern has not been established, suggesting that multiple genes, each with a modest effect, likely contribute to IIH development.

Environmental factors: Notably, obesity and weight gain significantly influence IIH risk. Obesity, particularly prevalent among women of childbearing age, stands as a well-established risk factor for IIH.

Risk Factors for Idiopathic Intracranial Hypertension can be categorized into highly likely, probable, and possible:

Highly likely risk factors female gender obesity/weight gain endocrine disorders Addison's disease hypoparathyroidism steroid withdrawal growth hormone use in children nutritional disorders hypervitaminosis A (vitamin, liver or isotretinoin intake and all-trans retinoic acid for acute pro-myelocytic leukemia) hyperalimentation in deprivation dwarfism

Probable risk factors chlordecone (kepone) ketoprofen or indomethacin in Bartter's syndrome thyroid replacement therapy in hypothyroid children tetracycline and its derivatives Uremia

Possible risk factors sleep apnea systemic lupus erythematous amiodarone hypovitaminosis A iron deficiency anemia lithium carbonate nalidixic acid sarcoidosis sulfa antibiotics Hypophosphatasia

Women with IIH are at twice the risk of heart conditions, suggesting that cardiovascular risk factors may also play a role in IIH. Early assessment and management of modifiable cardiovascular risk factors may help minimize long-term complications from cardiovascular disease in IIH patients.

It is essential to consult a physician for personalized evaluation and discussion of risk factors, as they can provide the most accurate and up-to-date information based on individual circumstances.

The diagnostic criteria for Idiopathic Intracranial Hypertension (IIH) are as follows:

1. Papilledema

2. Normal neurological examination except for cranial nerve abnormalities

3. Neuroimaging: Normal brain parenchyma without hydrocephalus, mass or structural lesion and no abnormal meningeal enhancement or venous sinus thrombosis on MRI and MR venography; if MRI is unavailable or contraindicated, contrast-enhanced CT may be used

4. Normal CSF composition

5. Elevated CSF opening pressure (≥ 25 cmH2O in adults and ≥ 28 cmH2O in children) in a properly performed lumbar puncture

A diagnosis of IIH is considered definite in patients who fulfill all of these criteria. If criteria 1-4 are met but the CSF pressure is lower than specified, the diagnosis is considered probable.

It's also worth noting that there are specific criteria for IIH without papilledema (IIHWOP), which include:

• Presence of criteria for IIH plus normal neurological examination (except for sixth cranial nerve palsy)

• Neuroimaging findings suggestive of raised intracranial pressure, such as empty sella, elevated lumbar puncture pressure, flattening of the posterior aspect of the globe, distention of the perioptic subarachnoid space, tortuous optic nerve, and transverse venous sinus stenosis.

These criteria are based on the revised diagnostic criteria for IIH, which were adapted from the 2013 revised diagnostic criteria.

The symptoms and signs of Idiopathic Intracranial Hypertension (IIH) include:

1. Headaches

2. Feeling Sleepy

3. Tinnitus (ringing in the ears)

4. Feeling and Being Sick

5. Temporary Blindness

6. Feeling Irritable

7. Double Vision

8. Photophobia (Difficulty with Bright Lights)

9. Blind Spots

10. Pulsatile tinnitus (hearing a pulsing rhythmic noise in the ears)

11. Neck and Shoulder Pain

12. Problems with Coordination and Balance

13. Peripheral (side) Vision Loss

14. Mental Confusion

These symptoms can mimic those of a brain tumor and are often related to increased pressure around the brain. It's essential to consult a healthcare professional for proper diagnosis and treatment.

Idiopathic intracranial hypertension (IIH) is a seriously debilitating disease characterized by severe headache and impaired vision, with a significant impact on quality of life. It is a neurological disorder that manifests with recurrent and persistent headaches, nausea, vomiting, progressive and transient obstruction of the visual field, and papilledema. Visual loss can be irreversible. The condition is characterized by isolated increased intracranial pressure, which can lead to severe and debilitating symptoms.

Yes, the incidence of Idiopathic Intracranial Hypertension (IIH) is increasing. This increase is largely attributed to the rising rates of obesity. Research suggests that the incidence of IIH is increasing in line with the global epidemic of obesity. Studies have shown that the incidence of IIH is higher in obese women of childbearing age, with a significant increase in incidence among females aged 20 to 44 years who are more than 20% above their ideal body weight.

For example, a study by Kilgore et al. (2017) found that the incidence of IIH is increasing, particularly among obese women. Another study by Friesner et al. (2011) also documented the increasing incidence of IIH in the USA, which is largely attributed to the rapid increase in obesity.

The incidence rates vary, but according to the data, the incidence of IIH is approximately 0.9 to 1.0 per 100,000 in the general population, with a higher incidence of 3.5 per 100,000 among females, and a significantly higher incidence of 19-20 per 100,000 among obese women of childbearing age.

The current guidelines for managing IIH involve a combination of medical and surgical interventions, as well as diet and lifestyle modifications. According to the 2018 Consensus Guidelines on Management of Idiopathic Intracranial Hypertension, the goals of treatment are to alleviate symptoms, prevent vision loss, and improve quality of life.

The guidelines recommend the following:

1. Weight loss: Weight loss is recommended for all patients with IIH who are overweight or obese, as it has been shown to reduce intracranial pressure and alleviate symptoms.

2. Medications: Medications such as acetazolamide, a carbonic anhydrase inhibitor, may be prescribed to reduce intracranial pressure and alleviate symptoms such as headache and vision loss. However, it should be noted that while some physicians may propose acetazolamide as a treatment, it is not indicated for IIH and has some dose-limiting side effects.

3. Surgical interventions: Surgical procedures such as optic nerve sheath fenestration or lumboperitoneal shunting may be considered for patients who do not respond to medical therapy or who have severe vision loss.

4. Regular monitoring: Regular monitoring of vision, including visual field testing and optical coherence tomography, is recommended to detect any changes in vision and to adjust treatment as needed.

5. Lifestyle modifications: Patients with IIH are advised to avoid activities that may exacerbate symptoms, such as heavy lifting or bending, and to get regular exercise and maintain a healthy diet.

It is essential to note that these guidelines are based on the available evidence and may be updated as new research emerges. Patients with IIH should work closely with their healthcare provider to develop an individualized treatment plan that takes into account their specific needs and circumstances.

The level of cerebral spinal pressure measured by a spinal tap that determines whether a patient has IIH is 250 mm H₂O (25 cm H₂O) or higher in adults. This is the standard cerebrospinal fluid (CSF) opening pressure that confirms a diagnosis of IIH.

Medical experts classify spinal tap pressure readings for adults into three distinct categories:

1. Normal: Below 200 mm H₂O.

2. Borderline (Gray Zone): 200 to 250 mm H₂O.

3. Elevated (Definite IIH): 250 mm H₂O or higher.

It's worth noting that for children, the diagnostic threshold is slightly higher, with an opening pressure of 280 mm H₂O (28 cm H₂O) or higher generally required to diagnose IIH.

The primary importance of reducing intracranial pressure (ICP) in patients with IIH is to prevent permanent vision loss and alleviate severe neurological symptoms. Lowering the pressure stabilizes the central nervous system and directly prevents irreversible damage through several critical mechanisms, including preserving vision and optic nerve function.

Specifically, reducing intracranial pressure helps to reverse papilledema, which is the swelling of the optic disc caused by high ICP forcing cerebrospinal fluid (CSF) into the optic nerve sheath. This mechanical compression can lead to microstructural damage and potentially cause permanent vision loss if left untreated. By reducing the pressure, the mechanical compression on the optic nerve is stopped, helping to preserve vision and prevent further damage.

In addition to preserving vision, reducing intracranial pressure can also help alleviate other severe neurological symptoms associated with IIH, such as headache, pulsatile tinnitus, and generalized weakness. Overall, reducing intracranial pressure is a critical aspect of managing IIH and preventing long-term complications, particularly those related to vision loss.

The management of IIH involves multiple specialties due to its multidisciplinary manifestations. Patients with IIH frequently consult primary care physicians upon the onset of headache and/or visual disturbances. Referrals are common to neurologists, ophthalmologists, and neuro-ophthalmologists. In addition, upon the onset of severe symptoms, patients may opt for the services of a hospital emergency department or ambulatory day care units. Neurosurgeons manage surgical interventions such as shunting procedures (lumbar or ventricular shunts for Cerebral Spinal Fluid [CSF] diversion) and optic nerve sheath decompression (ONSD).

The IIH consensus guidelines emphasize the need for clear communication between clinicians for seamless joint care between various specialties.

For a comprehensive understanding of the specific specialties treating IIH, it is recommended to speak with a qualified medical professional.

Several drugs are used off-label to treat IIH; specifically, the following off-label uses are noted:

1. Migraine preventative drugs: The IIH consensus guidelines on management state that “many of these drugs are used off-label in IIH” for headache treatment, similar to their use in migraine treatment.

2. Acetazolamide: This is the drug predominantly used off-label for IIH. The most commonly reported complaints include:

• Paresthesia (tingling sensations in the hands and feet)
• Taste alternations (particularly with carbonated beverages)
• Metabolic issues (mild metabolic acidosis and electrolyte changes [e.g., low potassium])
• Other (fatigue, nausea, and an increased risk of kidney stones)

3. Topiramate: This drug is used off-label for IIH. Topiramate is a potent medication and can cause a range of notable side effects. It is typically introduced slowly (a process called titration) to minimize these issues. The most commonly reported complaints include:

• Paresthesia (tingling sensations in the hands and feet)
• Cognitive complaints (often referred to as “brain fog,” memory issues, or word-finding difficulties)
• Fatigue or drowsiness
• Taste alternations (particularly with carbonated beverages)
• Kidney stones or metabolic acidosis

While studies have shown modest benefits for acetazolamide for some outcomes, there is insufficient evidence to recommend or reject the efficacy of this intervention, or any other treatments currently available, for treating people with IIH.

Additionally, simple analgesics, opiates, and non-steroidal anti-inflammatory drugs are commonly used but may lead to medication-overuse headache.

If you're looking for more detailed information on off-label treatments for IIH or specific guidance on treatment options, it is recommended to speak with a qualified medical professional.

GLP-1 receptor agonists (GLP-1 RAs) may be used to supplement therapy for IIH for several reasons based on the available data.

First, GLP-1 RAs have been shown to reduce CSF secretion and intracranial pressure (ICP) in an in vivo rodent model with elevated ICP. The reduction in ICP was of a greater magnitude than that observed with commonly used drugs in IIH. This suggests that GLP-1 RAs could potentially be more effective in managing IIH.

Second, GLP-1 RAs are known to reduce sodium reabsorption and promote diuresis through actions in the renal proximal tubule, which could contribute to reducing ICP.

Third, GLP-1 receptors are expressed in the choroid plexus, the predominant CSF-secreting structure in the brain, indicating a potential mechanism by which GLP-1 RAs could influence CSF secretion.

Additionally, a cohort study involving 1110 propensity score-matched patients with IIH found that GLP-1 RA therapy was associated with significantly lower medication use, fewer symptoms and signs, and reduced need for procedural interventions over a 1-year follow-up period compared to conventional therapies.

Furthermore, GLP-1 agonists have been shown to effectively reduce BMI, a major risk factor for IIH. In some cases, the use of GLP-1 agonists allowed for a reduction in acetazolamide dosage without changing the clinical outcome, suggesting that they could be used to supplement or potentially reduce the need for other IIH treatments.

Overall, the available data suggest that GLP-1 RAs may offer an alternative or supplementary management strategy for IIH by reducing ICP, CSF secretion, and BMI, and by potentially decreasing the need for other medications and interventions.

Invex Therapeutics was developing a subcutaneous injection of the GLP-1 compound Exenatide for IIH patients. A Phase 2 trial of Exenatide delivered by subcutaneous injection reported only a 4.7 mm decrease in intracranial pressure and there was no impact on reported monthly headache days at 12 weeks of therapy. In June 2023 the Company reported lower-than-expected enrollment in a Phase 3 trial. In August 2023, Invex closed the trial.

NBO Pharma Inc. is repurposing the compound octreotide (a somatostatin analog) for the treatment of IIH delivered by an intranasal spray.

Octreotide is a Somatostatin compound; it activates somatostatin receptors.

Octreotide inhibits peptides known to cause IIH. Octreotide can reduce intracranial pressure by regulating cerebral spinal fluid flow. Octreotide can reduce visual obscurations by regulating ion/water transport systems in the retina.

Several small-scale clinical studies and case reports have explored the safety and efficacy of octreotide delivered by subcutaneous injection for IIH patients who failed to respond to or tolerate standard medical therapies (like weight loss or carbonic anhydrase inhibitors). In these studies, an injectable form of octreotide lowered cerebrospinal fluid (CSF) pressure and relieved symptoms like headaches and papilledema by inhibiting growth hormone and reducing CSF production.

Growth hormone (GH) and insulin-like growth factor-1 (IGF-1) play a role in regulating CSF secretion. Because octreotide is a synthetic somatostatin analog, it acts as a potent inhibitor of GH and IGF-1. It suppresses the hypersecretion of CSF in the choroid plexus and may also promote CSF absorption. Somatostatin receptors are highly concentrated in the brain's choroid plexus and arachnoid granulations, making octreotide a targeted intervention.

NBO's intranasal spray has been tested in two animal species with positive results. A phase 1 clinical trial in healthy volunteers using the intranasal spray also demonstrated positive results.

Octreotide has been shown to reduce intracranial pressure (ICP) more effectively than exenatide. Data from three studies on injectable octreotide demonstrated significant reductions in ICP: 48% (from 58cm to 33cm), 57% (from 34.4cm to 14.7cm), and 65% (from 26cm to 9cm).

In contrast, despite rodent model work suggesting that exenatide reduces CSF production, a Phase 2 study in IIH patients showed minimal reduction in ICP (4.7 mm) following 12 weeks of treatment with exenatide, which was a reduction of 18-21%.

Additionally, it is noted that weight loss alone, which is a potential effect of GLP-1RA drugs like exenatide, may be insufficient to reduce ICP and alleviate symptoms, as it takes time and the required amount of weight loss is unclear.

Intranasal administration is considered a potential method to deliver drugs to the CNS because it allows bypassing the blood-brain barrier, a significant obstacle to drug transport from the blood to the brain. The blood-brain barrier consists of a tight layer of endothelial cells surrounded by astrocyte foot processes, making it challenging for many drug molecules to reach the brain in therapeutic quantities.

By depositing drugs at the olfactory region of the nares via the nasal route, they can travel to the brain via mechanisms that are still not fully understood, including travel across nerve fibers and via a perivascular pathway. This route has been hypothesized as a potential way to treat diseases of the brain.

However, it's essential to note that intranasal administration comes with its own set of challenges, such as limited dose volume (100-150 μL per nostril), permeability across the nasal epithelia, and drug removal via mucociliary clearance and local cellular mechanisms. Additionally, nasal irritation, congestion, or lesions may reduce absorption.

To effectively deliver drugs via the nose-to-brain route, a specifically designed nasal delivery device is required. Traditional nasal droppers and other methods, such as using a mucosal atomization device (MAD) attached to a syringe, have limitations and may not be optimal for intranasal administration.

The suitability of this method depends on various factors, including the specific drug, its formulation, and the delivery device used.

Shunts and stents are surgical interventions used to lower dangerously high cerebrospinal fluid (CSF) pressure in Idiopathic Intracranial Hypertension (IIH) when medical treatments like weight loss and medications have failed or when vision is rapidly deteriorating. They work through different mechanical approaches.

Shunts divert excess CSF away from the brain, providing immediate, high-volume pressure relief. They are traditionally used for patients experiencing severe, persistent headaches or acute, severe vision loss (fulminant IIH) that needs to be halted instantly.

On the other hand, stents are used to widen narrowed veins, specifically the transverse venous sinuses, to improve natural fluid drainage. A stent is a tiny, self-expanding metal mesh tube that props open the structural bottleneck in the brain's venous sinuses, restoring normal blood outflow and lowering venous pressure. This allows the body to reabsorb CSF properly again.

The choice between shunts and stents depends on the patient's condition and the underlying cause of their IIH. Shunts are more commonly used for immediate pressure relief, while stents are used to address the underlying venous sinus stenosis that may be contributing to the IIH.

Shunting procedures are more common.

Stenting, on the other hand, is typically performed unilaterally, even in cases of bilateral stenosis, with the stent usually placed on the side with the greater degree of stenosis or in the dominant transverse/sigmoid sinus. A meta-analysis of 143 IIH patients undergoing venous sinus stenting (VSS) found that 96% received unilateral stents, and 69% of the stents were placed in the right transverse/sigmoid sinus.

It's worth noting that both shunts and stents carry risks and potential complications. Shunts, for example, are associated with risks of shunt failure, intracranial hypotension, and infection, requiring revision, explantation, and potentially multiple procedures. In one study, fewer than half of patients had only a single shunt procedure, with 9 months as the average time before shunt replacement and 64% lasting <6 months.

If you're considering shunts or stents as a treatment option for IIH, it's essential to discuss the potential benefits and risks with your physician to determine the best course of treatment for your specific condition.

Both shunts and stents have been used as surgical interventions for Idiopathic Intracranial Hypertension (IIH). Shunts have been highly effective at immediately lowering global intracranial pressure and providing rapid relief of headaches and papilledema. However, they are notorious for high failure rates, often up to 30-40% within a year, due to complications such as catheter migration, valve malfunction, or infection. This frequently necessitates "revision" surgeries, making it a higher-maintenance long-term option. In one study, fewer than half of patients had only a single shunt procedure, with 9 months as the average time before shunt replacement and 64% lasting <6 months.

On the other hand, stents, specifically Venous Sinus Stenting (VSS), have been used to widen narrowed veins to improve natural fluid drainage. VSS is a minimally invasive endovascular procedure where a mesh tube is placed in the narrowed transverse venous sinus to restore proper blood outflow. Large-scale, multi-institutional database studies report that stents have significantly lower treatment failure rates (under 10%) compared to shunts. Stents are only an option for patients whose imaging shows significant venous stenosis.

In a meta-analysis of 143 IIH patients undergoing VSS, 96% received unilateral stents, and 69% of the stents were placed in the right transverse/sigmoid sinus. Unilateral VSS was performed more often even if the patient had evidence of bilateral stenosis, commonly on the side with the greater degree of stenosis or in the dominant transverse/sigmoid sinus.

While both procedures have their place in treating IIH, the choice between them may depend on individual patient factors, including the presence of significant venous stenosis and the risk of complications.

Injectable octreotide has shown consistent, rapid, and sustained efficacy in all measures of idiopathic intracranial hypertension (IIH). The safety and efficacy results of injectable octreotide in IIH patients have been promising, with octreotide providing consistent rapid and sustained efficacy in all measures of IIH.

Octreotide, a somatostatin analogue, has been shown to reduce intracranial pressure (ICP) and improve headache in IIH patients. In a small case series of individuals who had tried and failed multiple other treatments, octreotide demonstrated its potential as a therapeutic option for IIH. For example, in one study, 24 out of 26 patients had improvement in headache, visual symptoms, and significant reduction in intracranial pressure. Patients were treated for a mean of 42 weeks with an average dose of 380µg per day, divided into three doses (TID). Octreotide was well tolerated, and follow-up for 3 years showed no recurrence of symptoms.

In another instance, a study reported on the successful treatment of 3 patients with IIH using a 100µg subcutaneous (SC) dose of octreotide administered three times a day. This treatment resulted in improved clinical symptoms of headache and visual changes, as well as a significant reduction in CSF pressure.

In an other study, treatment with subcutaneous octreotide resulted in significant improvement of headaches,and normalization of visual fields and papilledema. The patient tolerated the treatment well, except for formation of gallstones, for which treatment was stopped at around 9 months. However the patient continued to have persistent normalization of the vision and normal computerized perimetry after one and half years in follow up.

A 13-week twice-daily intranasal GLP toxicity study of Octreotide Acetate in Beagle dogs evaluated the potential toxicity and toxicokinetics (TK) of Octreotide Acetate for potential treatment of Idiopathic Intracranial Hypertension. The study administered Octreotide Acetate to Beagle dogs as twice-daily intranasal doses for 13 weeks, followed by a 4-week recovery period to assess the potential for latent toxicity, reversibility of toxicity, or progression of toxicity. The study also evaluated systemic exposure.

There were no Octreotide-related changes in postdose cageside and clinical observations, body weights, body weight changes, qualitative food consumption values, ophthalmic observations, hematology, coagulation, clinical chemistry, and urinalysis parameters, electrocardiogram measurements, macroscopic findings, or organ weight changes in any dose group on study.

Octreotide Acetate-related microscopic changes at the terminal necropsy on Study Day 92 were minimally decreased cellularity of Goblet cells and minimal atrophy of cilia in the ventral respiratory epithelium of the nasal turbinates in all males and all females at 10,000 μg/day. These changes completely recovered during the 4-week recovery period. In conclusion, groups of male and female Beagle dogs were administered Octreotide Acetate at 2,500, 5,000, or 10,000 μg/day for 13 weeks followed by a recovery period of 4 weeks. Octreotide Acetate related findings were limited to decreased cellularity of Goblet cells and minimal atrophy of cilia in the ventral respiratory epithelium of the nasal turbinates in all males and all females at 10,000 μg/day. None of these were considered adverse since the changes were minimal and completely recovered after 4 weeks. Therefore, the No-Observed-Adverse-Effect-Level (NOAEL) was considered to be 10,000 μg/day when administered twice daily. At this dosage, the Cmax and AUClast were 34.9 ng/. None of these were considered adverse since the changes were minimal and completely recovered after 4 weeks. Therefore, the No-Observed-Adverse-Effect-Level (NOAEL) was considered to be 10,000 μg/day when administered twice daily. At this dosage, the Cmax and AUClast were 34.9 ng/mL and 28.0 hr*ng/mL for males and 98.8 ng/mL and 89.9 hr*ng/mL in females, respectively.

Following intranasal dosing of Octreotide in rats, there were no apparent Octreotide-related effects among hematology, clinical chemistry, or urinalysis endpoints. There were no macroscopic findings considered test article-related in male and female rats across the study groups. Twice daily administration of Octreotide intranasally at 1500 and 1000 μg/dose resulted in test article-related microscopic findings in the nasal cavity, nasopharynx (i.e., nasopharyngeal duct) and the trachea of male and female Sprague Dawley rats in the Main study cohort and the trachea of male and female rats in the Recovery cohort. There was complete recovery of the test article-related microscopic findings in the nasal cavity and nasopharynx and partial recovery of the test article-related finding in the trachea of male and female rats in the Recovery cohort. Test article-related findings were not observed in the nasal cavity, nasopharynx or trachea of Main study cohort rats treated with 500 μg/dose or the trachea of Recovery cohort rats treated with 500 μg/dose.

The results of the exposure and brain distribution of the intranasal formulation of octreotide in rats are as follows:

In the study, male Sprague Dawley rats were administered 50, 100, 400, or 1200 μg of octreotide intranasally in 10 μL increments, 50 μL per nostril for a total volume of 100 μL. Plasma and whole brain (without olfactory bulbs) were collected from n=3 per group at 30, 60, and 90 minutes postdose.

The study found that CNS exposure is achieved at all three doses (100 μg, 400 μg, and 1200 μg) and persists beyond the plasma half-life, suggesting receptor binding. The brain sample includes choroid plexus, dura and arachnoid membranes, and olfactory bulb, which are the targets of interest.

The whole brain octreotide concentrations were measured, and the results are as follows:

• Group 5 (100 μg): The brain concentration of octreotide was measured at 0.5, 1, 1.5, and 2 hours after administration.

• Group 6 (400 μg): The brain concentration of octreotide was measured at 0.5, 1, 1.5, and 2 hours after administration.

• Group 7 (1200 μg): The brain concentration of octreotide was measured at 0.5, 1, 1.5, and 2 hours after administration.

The exact brain concentration values are not provided in the available data. However, the study suggests that the intranasal formulation of octreotide achieves CNS exposure and persists beyond the plasma half-life, indicating potential therapeutic effects.

It's worth noting that the dose was not normalized to body weight, which may have contributed to the absence of measurable brain exposure in some cases. The animals in Phase 1 were heavier than those in Phase 2, with weights ranging from 338.3 ± 48.4 g compared to 287.7-324.1 g.

The study (NBO-001) was a Phase 1, randomized, open-label, single-dose, active-controlled, five-way crossover trial that evaluated the safety, tolerability, and pharmacokinetics (PK) of intranasal (IN) octreotide (NBO-001) compared to subcutaneous (SC) octreotide in 20 healthy volunteers.

The primary objective was to assess the safety and tolerability of single IN doses of octreotide (NBO-001), with endpoints including the incidence of adverse events (AEs) and serious AEs (SAEs), as well as changes from baseline in clinical laboratory parameters and electrocardiograms (ECGs).

The secondary objective was to assess the PK parameters of single doses of 75µg, 150µg, 300µg, or 450µg IN octreotide (NBO-001) compared to a single dose of 100µg SC octreotide. The PK parameters evaluated included Cmax (ng/ml), Tmax (h), AUC0-t (h x ng/ml), AUC0-inf (h x ng/ml), λz (1/h), t1/2 (h), and relative bioavailability (F) for the IN treatments.

In this randomized open-label, single-dose, active-controlled five-way crossover study, NBO-001 was generally well tolerated and appeared safe. The adverse event profile was comparable to that of SC octreotide. Adverse events occurred across all IN doses but were mostly mild, all resolved without treatment and none were definitely related to study treatment. While more adverse events occurred following the 100μg SC dose than following the IN doses, they were also mostly mild and resolved without treatment. All laboratory values and vital signs were within normal limits or showed no clinically significant deviations.

All doses of NBO-001 resulted in measureable systemic exposure to octreotide, with a dose-related increase in exposure. However Cmax and AUC(inf) were 1-2 orders of magnitude lower than following SC octreotide administration. As anticipated, the PK data demonstrated that systemic exposure was lower following IN administration compared to SC doses of octreotide. A prior preclinical study in rats demonstrated that IN delivery of this formulation results in central nervous system (CNS) exposure within 30 min, with persistence of the octreotide as long as 90 min after delivery of drug, the last time point measured. Octreotide has a high affinity for somatostatin receptors located in the choroid plexus, the site of cerebral fluid formation, and in the subarachnoid membranes, the site of CSF reabsorption. Thus, although the systemic exposure is lower than observed in the SC administration, there is likely to be CNS exposure following IN delivery, the target of interest in the treatment of IIH. The occurrence of adverse events across all doses of NBO-001 also suggests physiologic effects of the exposure to octreotide.

This is an open-label study of octreotide nasal spray (NBO-001) for the treatment of IIH. Up to 20 participants with IIH who fulfill the Friedman criteria (i.e., the Modified Dandy Criteria) for IIH, meet all other inclusion criteria, and have no exclusionary criteria will be treated with NBO-001 150 µg TID for 35 days.

Before a participant is eligible for participation, the sponsor will review clinical and lab data used to diagnose IIH during the screening period.

Data to be reviewed to confirm the diagnosis of IIH based on the Friedman criteria includes: results of the neurologic exam, confirmation of papilledema on ophthalmologic exam, neuroimaging findings, and results of the lumbar puncture (LP), including opening pressure and CSF laboratory findings (glucose, protein, and cell count).

In addition, results of automated visual field test, assessment of visual acuity using the ETDRS chart, and optical coherence tomography should be provided.

Primary endpoint: Change from baseline in opening cerebrospinal fluid (CSF) pressure at Day 28.

Secondary endpoints:

Change from baseline in papilledema grade based on the Frisén scale.

Change from baseline in perimetric mean deviation (PMD) in the eye with the most severe visual loss.

Change from baseline in PMD in the fellow eye.

Change from baseline in visual acuity using the Early Treatment Diabetic Retinopathy Study (ETDRS) chart.

Change from baseline (Day 1 pre-treatment) in the Headache Impact Test (HIT-6) score

Headache responder analysis: the percentage of participants with a ≥50% reduction in the incidence of severe headache based on the headache event tracker.

Safety:

Safety will be assessed using the incidence of adverse events (AEs) and serious adverse events (SAEs), as well as changes from baseline in clinical laboratory parameters and electrocardiograms (ECGs).