nirsevimab cont.

Place In Therapy

RSV is a common contagious respiratory virus that usually causes mild, cold-like symptoms lasting 1 to 2 weeks. In the US each year, RSV infection leads to approximately 2.1 million outpatient visits, 58,000 to 80,000 hospitalizations, and 100 to 300 deaths in children < 5 years of age. Children who are at particular risk for serious RSV infections are premature infants, children < 2 years of age with CLD or CHD of prematurity, and children who are immunocompromised or have neuromuscular disorders.

Typically, the RSV season in the US occurs during approximately November through April but may vary by region. However, the regular RSV circulation pattern was disrupted by the COVID-19 pandemic, leading to interseasonal variability. There is no FDA-approved medication to treat RSV or vaccine to prevent RSV illness in the pediatric population. Treatment of mild cases consists of symptom management, including use of antipyretics and analgesics; however, palivizumab (Synagis®), an RSV F protein inhibitor monoclonal antibody, is the only agent FDA-approved for the prevention of RSV. It is indicated for use only in infants and young children who are at high risk for serious RSV LRTI (preterm infants < 6 month of age and children ≤ 24 months of age with CLD or CHD of prematurity). Palivizumab is typically administered once monthly per IM injection for 5 consecutive doses beginning just before the start of the RSV season, as based on the American Academy of Pediatrics guidelines. However, during the period of an unusual RSV circulating pattern observed during the COVID-19 pandemic, additional or off-season doses may have been warranted.

If approved, nirsevimab will be the first single-dose option to prevent RSV LRTI. It could also provide protection for a broader pediatric population, including healthy infants, whereas palivizumab requires monthly dosing for use only in high risk patients. Nirsevimab demonstrated comparable safety and tolerability as palivizumab and may provide enhanced viral efficacy against RSV-related hospitalization in at-risk children, as suggested in the MEDLEY trial and non-comparison study data.

Other products in the pipeline for RSV include Merck’s monoclonal antibody clesrovimab, which is in phase 3 trials for use in patients < 1 year of age who are at increased risk for severe RSV infection. Pfizer’s RSV vaccine candidate (PF-06928316) has been submitted to the FDA for maternal administration during pregnancy to protect the infant from RSV after birth and has the potential to be the first RSV vaccine approved to protect infants from RSV LRTI. Novavax’s RSV vaccine is also in phase 3 research for maternal administration.

RSV can also cause serious illness in older adults. Two RSV vaccines by GlaxoSmithKline (GSK3844766A) and Pfizer (PF-06928316) have been submitted to the FDA for prevention of RSV in older adults (≥ 60 years of age). The FDA decisions for these vaccines are anticipated in May 2023. FDA APPROVAL TIMELINE

July to September 2023

 Breakthrough Therapy  Fast Track

Infectious Disease

Proposed Indications

Invasive fungal infections in patients who have limited or no treatment options

Clinical Overview

Olorofim is an orotomide antifungal. It inhibits the dihydroorotate dehydrogenase (DHODH) enzyme in the fungal pyrimidine synthesis pathway resulting in cell death. It has shown in vitro activity against Aspergillus species (spp). (including azole-resistant and cryptic species), rare molds (e.g., Lomentospora prolificans, Scedosporium spp., Scopulariopsis spp.), and dimorphic fungi (e.g., Histioplasma spp., Blastomyces spp., Coccidioides spp.).

The ongoing, open-label, phase 2b FORMULA-OLS trial (NCT03583164) evaluated olorofim in adults with resistant invasive fungal disease due to Lomentospora prolificans, Scedosporium spp., Aspergillus spp., or other resistant fungi lacking appropriate treatment options. Patients 16 or 17 years of age weighing ≥ 40 kg were also allowed study entry. Patients received olorofim for up to 90 days (median, 84 days). Approximately 75% of the first 100 patients had moderate to high levels of immunosuppression. Data from the first 100 patients revealed that at day 42, the ORR was 69%, including stable response. A complete or partial response was observed in 44% of patients. At days 42 and 84, the rates for all-cause mortality were 15% and 20%, respectively. Olorofim was generally well tolerated. Nausea, vomiting, and diarrhea were reported. Eight patients (8%) experienced drug-induced liver injury, a serious adverse effect possibly related to olorofim; 2 (2%) patients were required to discontinue therapy.

Olorofim was administered orally as an initial loading dose of 150 mg twice daily on day 1, followed by 90 mg twice daily for up to 90 days.

Place In Therapy

Invasive fungal infections cause considerable morbidity and mortality, particularly among immunocompromised patients. Antifungal agents that have been approved in the past 20 years to fight invasive fungal infections include azoles (e.g., extended-spectrum triazoles, voriconazole, posaconazole, and isavuconazole); amphotericin B lipid formulations; and the echinocandins. However, current antifungals have limitations, including limited dosage forms, drug-drug interactions, and significant adverse reactions. The increase in fungal pathogens resistant to current antifungals adds to the increased need for new treatment options.

Olorofim is a first-in-class orotomide antifungal. Its ability to reversibly inhibit fungal DHODH, a key enzyme in the biosynthesis of pyrimidines, leads to impairment of nucleic acid production and fungal cell lysis. This mechanism of action allows for activity against isolates that are resistant to current treatment options. Olorofim is active against many molds and dimorphic fungi, including species that are resistant to azoles and amphotericin B. However, it lacks activity against yeasts, including Candida spp. and Cryptococcus spp., and the Mucorales group. Olorofirm exhibits time-dependent fungicidal activity and wide tissue distribution, including the CNS. Olorofim is metabolized by multiple CYP450 enzymes, including CYP3A4; however, based on current evidence, it does not appear to have any effect on CYP450 enzymes, and therefore, may have limited potential for drug-drug interactions.

If approved, olorofim may be an important oral option for patients with invasive fungal infections, including patients with immunocompromise, limited treatment options, or with difficult-to-treat organisms. Olorofim does not possess broad-spectrum antifungal activity, but it may play a key role in treating multi-drug resistant fungal infections and/or endemic mycoses. F2G has initiated the phase 3 OASIS trial comparing olorofim with liposomal amphotericin B injection (Ambisome®) followed by SOC to treat invasive aspergillosis of the lower respiratory tract.

FDA APPROVAL TIMELINE

June 17, 2023

 Breakthrough Therapy  LPAD  Orphan Drug  QIPD

FINANCIAL FORECAST (reported in millions)

The financial forecast for olorofim is not currently available.

Behavioral Health

Zuranolone Oral

Sage/Biogen

Proposed Indications

» Major depressive disorder (MDD)

» Postpartum depression (PPD)

Clinical Overview

Zuranolone is a neuroactive steroid that acts as a positive allosteric GABA-A receptor modulator. It is designed to rapidly rebalance dysregulated neuronal networks in the brain that affect mood, arousal, behavior, and cognition.

Zuranolone is being evaluated in adults with moderate or severe MDD across several randomized, doubleblind (unless otherwise noted), placebo-controlled, phase 3 clinical trials. Baseline HAMD-17 scores were ≥ 24 in WATERFALL and CORAL, ≥ 22 in MOUNTAIN, and ≥ 20 in SHORELINE.

» The 42-day WATERFALL trial (NCT04442490; n=543) demonstrated significant improvement from baseline with zuranolone 50 mg compared to placebo in depressive symptoms, based on HAMD-17 score at day 15 (primary endpoint; difference, −1.7; p=0.0141). A significant difference compared to placebo was seen as early as day 3 (difference, −3; p<0.0001). A significant improvement in anxiety based on HAM-A score was also reported at day 8 (difference, -1.7; p=0.0011) and day 15 (difference, -1.4; p=0.0199). Numerical improvements were maintained through day 42.

» The CORAL study (NCT04476030; n=440) evaluated zuranolone 50 mg co-initiated with a SOC antidepressant (SSRI, SNRI) in adults with MDD with elevated anxiety. The mean change in HAMD-17 score from baseline to day 3 (primary endpoint) was -8.9 with combination therapy, compared to -7 with SOC alone (p=0.0004). The mean changes over the 14-day treatment period were -11.7 and -10.1, respectively (the difference was not statistically significant).

» The MOUNTAIN study (NCT03672175) enrolled patients with an HDRS-17 (a.k.a. HAMD-17) total score ≥ 22. Based on a post hoc analysis, patients who received zuranolone 30 mg (n=194) experienced significant improvement in HDRS-17 total score compared to those who received placebo (n=193) at days 3, 8, 12, and 15 (p<0.05 at all time points). In a blinded follow-up, the response was maintained in 74.5% of responders to zuranolone 30 mg at day 182.

» The ongoing, open-label, 1-year longitudinal SHORELINE study (NCT03864614) assessed the need for retreatment after a 14-day course of zuranolone. Patients initiated therapy with zuranolone 30 mg (n=725) or 50 mg (n=52), which led to mean changes in their HAMD-17 scores from baseline to day 15 by -14.9 and -16, respectively. Among those who received zuranolone 30 mg, 71.6% achieved a response (HAMD-17 reduced by ≥ 50%) and 39.8% achieved remission (HAM-D ≤ 7). Likewise, initial doses of 50 mg resulted in a response rate of 74.9% and a remission rate of 40.2%. During the year-long study, retreatment was reported in 55.5% (mean, 1.9 treatments per year) of patients who responded to initial treatment with zuranolone 30 mg and 45.2% (range, 1 to 5 treatment courses) of those who responded to initial treatment with zuranolone 50 mg. Updated data revealed that the median times to first retreatment were 135 and 249 days with zuranolone 30 mg and 50 mg, respectively. No significant difference in response was observed between patients who were on pre-existing antidepressants and those who were not taking other antidepressant agents.

The randomized, double-blind, placebo-controlled ROBIN and SKYLARK trials evaluated zuranolone in adult women with PPD (HAMD-17 ≥ 26) that began no earlier than the third trimester and no later than the first 4 weeks following delivery. Additionally, patients were ≤ 6 months (ROBIN) or ≤ 12 months (SKYLARK) postpartum.

» In ROBIN (NCT02978326; n=153), a statistically significant improvement in depressive symptoms as based on the HAMD-17 score was observed at day 15 (primary endpoint) with zuranolone 30 mg compared to placebo (−17.8 versus −13.6, respectively; p=0.003). Significant differences in HAMD-17 between zuranolone 30 mg and placebo were reported as early as day 3 (difference, -2.7; p=0.03) and at day 45 (difference, -4.1; p=0.003).

CLINICAL OVERVIEW cont.

» In SKYLARK (NCT04442503; n=195), a statistically significant and clinically meaningful improvement in the HAMD-17 score was observed at day 15 (primary endpoint) with zuranolone 50 mg compared to placebo (−15.6 versus −11.6, respectively; p=0.0007). More patients in the zuranolone group achieved response (reported at days 3 through 28; p<0.05 at all time points) or remission (reported on day 3 and day 45; p<0.05 at day 45) than in the placebo group. Significant improvements in anxiety were also reported with zuranolone compared to placebo.

In the MDD and PPD studies, zuranolone was dosed orally once daily for 14 consecutive days. The drug was generally well tolerated. The most common TEAEs included somnolence, dizziness, headache, fatigue, diarrhea, nausea, and sedation. In the SHORELINE trial, more frequent TEAEs were reported with the 50 mg dose compared to 30 mg, but the severity of TEAEs was similar between the groups. Weight gain, sexual dysfunction, and sleep disruption were not observed with zuranolone. One patient in the ROBIN trial zuranolone group experienced a serious adverse event of confusion. Similar efficacy and safety were reported in patients ≥ 65 years of age and younger populations with MDD.

Place In Therapy

MDD is defined as a depressed mood or loss of interest in daily activity with a majority of certain symptoms (e.g., difficulty sleeping, impaired concentration, negative self-worth) lasting ≥ 2 weeks. It is one of the most common mental disorders in the US, with an estimated 21 million adults reporting at least 1 MDD episode in 2020 and 14.8 million reporting severe impairment. Prevalence is higher among females than males (10.5% and 6.2%, respectively) and is highest among those 18 to 25 years of age. First-line pharmacotherapy for MDD includes an SSRI, SNRI, bupropion, or mirtazapine. Select atypical anti-psychotics may be added when an adequate response is not achieved after multiple trials with an antidepressant alone.

The CDC reports that about 1 in 8 women with a recent live birth experience symptoms of PPD, including intense feelings of sadness, anxiety, or despair that interfere with activities of daily living. PPD symptoms may occur up to 1 year after delivery. Primary treatment includes cognitive behavioral therapy and interpersonal therapy, particularly in patients who are breastfeeding; however, antidepressant medication, notably SSRIs in breastfeeding women, may be considered. Sage Therapeutics’ IV-administered neuroactive steroid GABA-A receptor positive modulator brexanolone (Zulresso®) is FDA-approved for the treatment of PPD in females ≥ 15 years of age. Brexanolone (Zulresso) is a schedule IV controlled substance that may cause excessive sedation and sudden loss of consciousness; therefore, it must be administered in a certified healthcare facility to allow for continuous monitoring during the 60-hour single-dose infusion and the patient and facility must enroll in the REMS program.

If approved, oral zuranolone could fill an unmet need in patients experiencing moderate to severe MDD. Its unique dosing, rapid onset (as early as 3 days), short duration of therapy (14 days), and proven safety and efficacy with retreatment could change how patients are treated for depression, as well as how follow-up care is administered. In contrast, currently available antidepressants (e.g., SSRIs, SNRIs) require long-term continuous use and take 6 to 8 weeks to realize their full effect. An exception to this is intranasal esketamine (Spravato®), an N-methyl D-aspartate (NMDA) receptor antagonist indicated in conjunction with an oral antidepressant for resistant MDD or MDD associated with suicidal ideation or behavior. Esketamine has demonstrated an onset of effect for MDD as early as 24 hours. However, unlike zuranolone, the schedule III controlled substance esketamine carries risks of abuse and misuse and may cause sedation and dissociation after administration; therefore, patients must be monitored for at least 2 hours after each dose.

Zuranolone could also be an oral alternative to IV brexanolone (Zulresso) for PPD. Symptoms of excessive sedation and loss of consciousness that are seen with IV brexanolone have not been reported with oral zuranolone. It remains to be seen whether oral zuranolone’s labeling will carry boxed warnings regarding excessive sedation or loss of consciousness, similar to brexalonone, or warnings regarding suicidal thoughts and behaviors, like other oral antidepressants. In clinical trials, women receiving oral zuranolone were not permitted to breastfeed during treatment and for 7 days after the last dose.