elafibranor oral

Manufacturer: Genfit / Ipsen

PROPOSED INDICATIONS

Primary biliary cholangitis (PBC)

CLINICAL OVERVIEW

Mechanism of action

Elafibranor is a dual peroxisome proliferator-activated receptor alpha and delta (PPAR-α/δ) agonist

Clinical trials

The randomized (2:1), double-blind, placebo-controlled phase 3 ELATIVE trial (NCT04526665) evaluated the efficacy and safety of elafibranor in 161 patients with PBC who had an inadequate response to ursodeoxycholic acid (UDCA). The primary endpoint was a biochemical response (defined as an alkaline phosphatase [ALP] level of < 1.67 × ULN, with a reduction of ≥ 15% from baseline, and normal total bilirubin levels) at week 52. This was achieved in 51% of patients who received elafibranor compared to 4% who received placebo (difference, 47%; p<0.001). There was no significant difference in resolution of moderate to severe pruritus between the groups. The most common TEAEs (≥ 10%) were abdominal pain, diarrhea, nausea and vomiting.

Dosage and administration

In the clinical trial, elafibranor 80 mg was administered orally once daily.

FDA APPROVAL TIMELINE

June 10, 2024

FDA designations: Breakthrough Therapy, Orphan Drug, Priority Review

FINANCIAL FORECAST (reported in millions)

seladelpar oral

Manufacturer: Cymabay

PROPOSED INDICATIONS

Primary biliary cholangitis (PBC), including pruritus, in adults without cirrhosis or with compensated cirrhosis (Child Pugh A) who are inadequate responders or intolerant to UDCA

CLINICAL OVERVIEW

Mechanism of action

Seladelpar is a selective peroxisome proliferator-activated receptor-delta (PPAR-δ) agonist

Clinical trials

The randomized, double-blind, placebo-controlled phase 3 ENHANCE trial (NCT03602560) evaluated the efficacy and safety of seladelpar in 265 patients with PBC who had an inadequate response or intolerance to UDCA. Patients were randomized 1:1:1 to seladelpar 5 mg, seladelpar 10 mg, or placebo. The original primary endpoint was a composite biochemical response (defined as ALP < 1.67 × ULN, ≥ 15% ALP decrease from baseline, and total bilirubin ≤ ULN) at month 12. However, due to an erroneous safety signal (fully reversible and asymptomatic grade 3 aminotransferase increase) in a concurrent NASH trial, the ENHANCE trial was stopped early. At month 3, the mean duration of exposure was 17.7 weeks. At this timepoint a biochemical response was achieved in 57.1% and 78.2% of patients who received seladelpar 5 mg and 10 mg, respectively, compared to 12.5% who were given placebo (p<0.0001 for both doses). In addition, significantly more patients treated with seladelpar 10 mg had a significant reduction in pruritus compared to the placebo group (p=0.02). The most common TEAEs (≥ 5%), reported more often with seladelpar than placebo were upper abdominal pain and nausea.

Interim data from the similarly designed phase 3 RESPONSE trial (NCT04620733; n=193) reported at month 12, 61.7% of patients treated with seladelpar 10 mg achieved the primary composite response endpoint compared to 20% who received placebo (p<0.0001). In addition, a significant improvement in pruritus with seladelpar 10 mg compared to placebo was reported at month 6 and maintained through month 12.

The open-label ASSURE trial (NCT03301506) reported long-term safety and efficacy of seladelpar 5 mg and 10 mg for up to 2 years; the study was terminated early due to erroneous safety signals in a concurrent NASH trial. No serious TEAEs were reported among the 106 patients treated with seladelpar for 2 years. Response rates increased from years 1 to 2 for the composite endpoint (ALP <1.67 × ULN, ≥ 15% decrease in ALP, and total bilirubin ≤ ULN) from 66% to 79%.

Dosage and administration

In the clinical trials, seladelpar 5 mg and/or 10 mg were administered orally once daily.

PLACE IN THERAPY

PBC is a rare, progressive, autoimmune liver disease in which bile ducts are gradually destroyed. In PBC, bile acids accumulate causing damage to hepatocytes, and if left untreated, can lead to liver failure and death. Common symptoms of PBC include fatigue and pruritus, which can be debilitating. The majority of PBC cases occur in women 30 to 60 years of age. In the U.S., the prevalence is 654 per 1 million persons for women and 121 per 1 million persons for men. Genetic predisposition and environmental triggers have been associated with PBC and highly specific autoantibodies (antimitochondrial antibodies) are detected in most cases. Notably, elevated serum ALP and total bilirubin levels are biomarkers associated with poor clinical outcomes in PBC.

UDCA (Urso Forte), a bile salt, is approved for the treatment of PBC. It protects the liver against toxic bile salts and inhibits apoptosis and fibrosis. If started early in the disease process, UDCA may delay disease progression. The oral farnesoid X receptor agonist, obeticholic acid (Ocaliva^®), is approved as add-on therapy for patients with an inadequate response to UDCA, which accounts for up to 40% of patients treated with UDCA. While obeticholic acid may improve laboratory measures (ALP, GGT, transaminase levels), it does not improve survival or PBC symptoms. Off-label use of oral fibrates can also be considered as an alternative for patients without decompensated liver disease who do not adequately respond to UDCA. Methotrexate, cyclosporine, colchicine and corticosteroids have also been used.

The peroxisome proliferator activator receptor (PPAR) is a nuclear receptor involved in a variety of metabolic processes, including bile acid homeostasis. It has three isoforms: α, δ and γ. PPAR-α is primarily expressed in the liver and regulates bile acid synthesis and detoxification, phospholipid secretion, and inflammatory pathways. PPAR-δ and PPAR -γ are more universally found in metabolic active tissues and when activated, they affect lipid and glucose metabolism, and exhibit anti-inflammatory and anti-fibrotic properties. While seladelpar stimulates PPAR- δ, elafibranor acts on both PPAR- α and PPAR-δ. In clinical trials, elafibranor and seladelpar were well tolerated and demonstrated a significant biochemical response. However, while seladelpar led to a marked improvement in pruritus, the characteristic symptom of PBC, the same was not true for elafibranor. If approved, these agents will be the first PPAR agonists available to treat PBC in patients with an inadequate response to UDCA and will be additional therapeutic options to Ocaliva.

FDA APPROVAL TIMELINE

August 14, 2024

FDA designations: Breakthrough Therapy, Orphan Drug, Priority Review

FINANCIAL FORECAST (reported in millions)

imetelstat IV

Manufacturer: Geron

PROPOSED INDICATIONS

Transfusion-dependent anemia in patients with lower-risk myelodysplastic syndromes (MDS) who have failed to respond to, have lost response to, or are ineligible for erythropoiesis-stimulating agents (ESAs)

CLINICAL OVERVIEW

Mechanism of action

Imetelstat is a telomerase inhibitor. It selectively targets malignant hematopoietic stem and progenitor cells with high telomerase activity by direct binding to the RNA template, resulting in malignant cell apoptosis and potential disease-modifying activity.

Clinical trials

The randomized, double-blind, placebo-controlled, phase 3 IMerge trial (NCT02598661) evaluated imetelstat in 178 adults with RBC transfusion-dependent, low- or intermediate-risk MDS that was relapsed, refractory to, or ineligible for ESA therapy. Patients had not received prior treatment with azacitidine, decitabine, or lenalidomide. The median follow-up was 19.5 months in the imetelstat group and 17.5 months in the placebo group. The study demonstrated that significantly more patients treated with imetelstat achieved the primary endpoint of RBC transfusion independence in ≥ 8 weeks compared to those who were given placebo (40% versus 15%, respectively; p=0.0008). In addition, 28% and 13.6% of patients treated with imetelstat remained RBC transfusion-independent at ≥ 24 weeks and ≥ 1 year, respectively, compared to 3.3% and 1.7%, respectively, in those who received placebo. Grade 3 to 4 TEAEs occurred in 91% of patients in the imetelstat group compared to 47% in the placebo group. Of these, neutropenia and thrombocytopenia were the most common, and occurred most often during the first three treatment cycles. Cytopenia was managed with treatment delays and dose adjustments in accordance with the study protocol.

Dosage and administration

In the clinical trial, imetelstat 7.5 mg/kg was administered IV over 2 hours every four weeks until disease progression or unacceptable toxicity occurred.

PLACE IN THERAPY

In MDS, the bone marrow fails to produce healthy blood cells, leading to cytopenia. The incidence rate of MDS is approximately 4.5 per 100,000 people per year in the general population; however, individuals over 60 years of age are most commonly affected. About 90% of cases are primary or idiopathic in nature, resulting from age-related injury to stem cells. The remaining cases are the result of cytotoxic chemotherapy or radiation therapy. The majority of patients (85%) with MDS experience fatigue or shortness of breath due to underlying anemia. Neutropenia and thrombocytopenia usually occur during advanced stages of the disease. Once termed preleukemia, MDS evolves into acute myeloid leukemia (AML) in about 30% of patients.

HSCT is the only available curative treatment for MDS. Allogeneic HSCT is considered in transplant candidates with intermediate or greater risk disease. When HSCT is not appropriate, an alternative therapy is RBC transfusions. Pharmacologic agents include ESAs (e.g., epoetin alfa, darbepoetin) and the erythroid maturation agent luspatercept-aamt (Reblozyl®; for sideroblastic MDS). Agents used to slow progression of the disease include hypomethylating agents (e.g., azacytidine, decitabine) and immune therapy (e.g., lenalidomide). In addition, use of investigational drugs in clinical trials remains an important aspect of MDS management.

Imetelstat is a first-in-class telomerase inhibitor. If approved, imetelstat would provide a new mechanism of action leading to durable transfusion independence when treating MDS-related anemia after treatment with ESAs has failed or in patients who are ESA ineligible. This agent could compete with Reblozyl in patients with ring sideroblastic MDS. On March 14, 2024, the FDA’s Oncologic Drugs Advisory Committee (ODAC) voted in favor (12:2) of imetelstat for the treatment of anemia for low-risk MDS patients who are refractory or intolerant to ESAs.

Imetelstat is also in phase 3 trials for myelofibrosis and phase 2 trials for AML.

FDA APPROVAL TIMELINE

June 14, 2024

FDA designations: Fast Track, Orphan Drug

FINANCIAL FORECAST (reported in millions)

midomafetamine oral

Manufacturer: Lykos

PROPOSED INDICATIONS

Post-traumatic stress disorder (PTSD)

CLINICAL OVERVIEW

Mechanism of action

Midomafetamine (MDMA) is a psychoactive entactogen. It promotes the release of monoamines and hormones in the brain, including serotonin, norepinephrine, dopamine, oxytocin and cortisol that modulate emotional memory circuitry.

Clinical trials

Two multi-site, double-blind, phase 3 trials, MAPP1 (NCT03537014; n=90) and MAPP2 (NCT04077437; n=104), evaluated MDMA in patients with severe or moderate to severe PTSD, respectively. Patients were randomized 1:1 to MDMA or placebo, each used in combination with psychotherapy. The primary endpoint in both trials was change from baseline in the Clinician-Administered PTSD Scale for DSM-5 (CAPS-5) total severity score at week 18; a ≥ 10-point reduction in CAPS-5 total severity score was considered clinically meaningful. The mean baseline CAPS-5 total severity score was 39 points  in MAPP1 and 44.1 points in MAPP2. Both trials met the primary endpoint, demonstrating a significant improvement in the CAPS-5 total severity score with MDMA compared to placebo (MAPP1: LS mean change, -4.4 versus -13.9, respectively [p<0.001]; MAPP2: LS mean change, -23.7 versus -14.8, respectively; [p<0.001]). In MAPP1, 67% of patients treated with MDMA no longer met the diagnostic criteria for PTSD and 33% achieved PTSD remission, compared to 32% and 5% of patients, respectively, who were given placebo. A similar trend was reported based on exploratory data in MAPP2. In addition, there was a significant improvement in the key secondary endpoint of Sheehan Disability Scale (SDS) functional impairment score from baseline to week 18 with MDMA compared to placebo (MAPP-1: LS mean change, -3.1 versus -2; respectively [p=0.0116]; MAPP-2: LS mean change, -3.3 versus -2.1; respectively [p=0.03]). In MAPP1, one and three patients in the MDMA and placebo groups, respectively, did not complete therapy due to adverse effects or treatment distress. In MAPP2, the dropout rate was 1.9% in the MDMA group and 15.7% in the placebo group. Suicidal ideation was not increased or intensified by MDMA. No cardiac events indicating QT prolongation occurred with MDMA. In addition, no potential for abuse of MDMA was reported.

Patients in the phase 3 trials were allowed to participate in a long-term follow-up study and were assessed ≥ 6 months after their last therapy session with MDMA or placebo. Interim data revealed durable improvements in CAPS-5 total severity score ≥ 6 months after the last dosing session, and for over a year among those who were followed for more than a year.

Dosage and administration

The treatment period in each trial consisted of three 8-hour experimental sessions during which patients received psychotherapy in addition to oral MDMA or placebo. The sessions were conducted approximately four weeks apart. At session 1, MDMA was given as 80 mg, followed by a supplemental 40 mg dose 1.5 to 2 hours later. In sessions 2 and 3, MDMA was given as 120 mg, followed by a supplemental 60 mg dose 1.5 to 2 hours later.

PLACE IN THERAPY

PTSD is a psychiatric condition that can occur in a person of any age who experiences or witnesses a traumatic event or series of events with a threat of injury or actual injury to themselves or others. It is estimated that PTSD affects about 8 to 12 million people in the U.S. in a given year, with a higher likelihood in women and minority groups. Symptoms of PTSD are severe enough to interfere in daily life. To meet the DSM-5 diagnosis for PTSD, all of the following symptoms must be present for at least one month: re-experiencing the event (e.g., flashback, nightmares), avoidance of trauma-related stimuli, arousal and reactivity symptoms (e.g., irritability, insomnia, easily startled, engaging in risky behavior), and cognition and mood symptoms (e.g., negative thoughts and emotions, feeling isolated). PTSD symptoms typically begin within 3 months of the traumatic event, but can present at any time, even decades after the event. PTSD is also associated with comorbidities, such as depression, anxiety, substance use and abuse, dissociative disorders, and harm toward self and others.

Trauma-focused psychotherapy aids in processing and moderating memories associated with trauma using in vivo and/or imaginal exposure. Trauma-focused psychotherapy is the first-line treatment for PTSD and includes techniques such as cognitive behavioral therapy (CBT), cognitive processing therapy (CPT), cognitive therapy (CT), prolonged exposure therapy (PE), brief eclectic psychotherapy (BEP), eye movement desensitization and reprocessing (EMDR) and narrative exposure therapy (NET). While trauma-focused psychotherapy has proven to be effective, up to 50% of patients treated have lasting symptoms and nearly 25% do not complete therapy. Medication therapy (e.g., SSRIs) is an alternative first-line treatment in patients with comorbidities (e.g., depression, anxiety) or who are unable to participate in psychotherapy. Paroxetine (Paxil^®) and sertraline (Zoloft^®) are FDA-approved for PTSD; efficacy rates of ≤ 60% and remission rates of < 30% have been reported for these agents. Fluoxetine (Prozac^®) and venlafaxine (Effexor^® XR) are also recommended off-label. Evidence for combined psychotherapy and pharmacotherapy compared with psychotherapy alone is mixed.

MDMA promotes the release of monoamines and hormones in the brain that modulate emotional memory circuitry.  Neuroimaging findings suggest that MDMA acts in key neural pathways responsible for memory and emotional processing (e.g., amygdala, hippocampus, prefrontal cortex). MDMA appears to facilitate reprocessing of traumatic memories with clearer recall and empathy for oneself, and without anxiety, emotional numbing or dissociation. In clinical trials, MDMA + trauma-focused psychotherapy led to a significant and durable improvement in PTSD symptoms compared to placebo, when administered in a setting designed to enhance and support the therapeutic effects of the agent. MDMA was well-tolerated, without increase in risk in suicidality, CV effects or abuse potential of the agent.

If approved, MDMA would be the first FDA-approved psychedelic agent and will be used in combination with psychotherapy for PTSD. Also known as ecstasy, MDMA is currently a Schedule I Controlled Substance in the U.S. and will require rescheduling by the DEA to allow for prescription use. Notably, states could have unique regulations to legalize and/or govern use. Another psychedelic agent, psilocybin, is also in clinical trials for PTSD (phase 2), as well as MDD (phase 3) and eating disorders (phase 2).

FDA APPROVAL TIMELINE

August 11, 2024

FDA designations: Breakthrough Therapy, Priority Review

FINANCIAL FORECAST (reported in millions)

The projected total U.S. sales for MDMA are not available.

nemolizumab SC

Manufacturer: Galderma

PROPOSED INDICATIONS

• Prurigo nodularis
• Moderate to severe atopic dermatitis

CLINICAL OVERVIEW

Mechanism of action

Nemolizumab is a monoclonal antibody targeting interleukin-31 receptor alpha (IL-31α), which blocks signaling from IL-31.

Clinical trials

The randomized, double-blind, phase 3 OLYMPIA 2 trial (NCT04501679) evaluated nemolizumab in 274 adults with moderate to severe prurigo nodularis. The primary endpoints were itch response, defined as a reduction of ≥ 4 points on the Peak Pruritus Numerical Rating Scale (PP-NRS), with scores ranging from 0 to 10 (higher scores indicating more severe itch) and an IGA response of 0 (clear) or 1 (almost clear) accompanied by a reduction from baseline to week 16 of ≥ 2 points. At week 16, higher proportions of patients in the nemolizumab group compared to those in the placebo group achieved an itch response (56.3% versus 20.9%; p<0.001) and an IGA response (37.7% versus 11%; p<0.001). Significant improvements in itch intensity and sleep disturbance, both secondary endpoints, were seen by week 4 with nemolizumab compared to placebo. The most common TEAEs with nemolizumab were headache and atopic dermatitis. Top-line results from the OLYMPIA 1 trial (NCT04501666)  reported similar outcomes based on itch response and IGA response with nemolizumab compared to placebo (itch, 58.4% versus 16.7%, respectively [p<0.0001]; IGA, 26.3% versus 7.3%, respectively [p<0.0001]) at 16 weeks. In addition, interim data from the open-label, phase 3, long-term OLYMPIA-LTE trial (NCT04204616) demonstrated continuous improvement in skin lesions, itch, sleep disturbance, and QOL up to week 52 with nemolizumab. No new safety signals were reported at 52 weeks.

Nemolizumab was also evaluated in the identical ongoing, randomized, double-blind, phase 3 ARCADIA 1 (NCT03985943) and ARCADIA 2 (NCT03989349) trials for the treatment of moderate to severe atopic dermatitis. Combined, the trials enrolled over 1,700 patients ≥ 12 years of age who continued background topical steroid or topical calcineurin inhibitor therapy. After 16 weeks, 43.5% of patients in ARCADIA 1 and 42.1% in ARCADIA 2 who were treated with nemolizumab achieved the primary endpoint of 75% reduction in the Eczema Area and Severity Index (EASI) compared to 29% and 30.2%, respectively, of patients who received placebo (p<0.0001 and p=0.0011). In both studies, significant improvement in sleep disturbance (secondary endpoint) was also seen at 16 weeks with nemolizumab compared to placebo. Galderma has also initiated a long-term trial, ARCADIA-LTE, for nemolizumab for moderate to severe atopic dermatitis.

Dosage and administration

In the clinical trials, nemolizumab was self-administered SC at an initial 60 mg dose, followed by 30 mg or 60 mg, depending on baseline body weight, every 4 weeks.

PLACE IN THERAPY

Prurigo nodularis (PN) is a rare, chronic inflammatory skin condition characterized by raised, hyperkeratotic lesions on the arms, legs, and trunk. PN is often severely itchy and can have a marked negative effect on sleep and QOL. PN affects about 72 out of every 100,000 people in the U.S. People at increased risk for developing PN include patients ≥ 50 years of age, people who are Black, and those who have chronic conditions, such as atopic dermatitis, diabetes, ESRD, hepatitis C, untreated HIV, lymphoma, thyroid conditions, anxiety, or depression. PN treatments include topical emollients, menthol, pramoxine, capsaicin, corticosteroids, calcineurin inhibitors, and calcipotriol. Intradermal corticosteroids, cryosurgery, and phototherapy are useful in patient who fail topical agents. Systemic agents include antihistamines, as well as off-label use of antidepressants, gabapentin, methotrexate and thalidomide. In September 2022, the IL-4 receptor alpha antagonist dupilumab (Dupixent) became the first agent FDA-approved for PN in adults. In clinical trials, Dupixent led to reduction in itch (based on Worst Itch Numeric Rating Scale [WI-NRS] by ≥ 4 points from baseline) in 60% of patients and IGA of 0 or 1 in 48% of patients, compared to 18.4% of patients for each measure in the placebo group.

Atopic dermatitis (AD) is a common, chronic inflammatory skin condition characterized by persistent itch and recurrent skin lesions. It affects an estimated 31.6 million (10.1%) people in the U.S., including 9.6 million children and adolescents. Approximately 30% and 40% of cases in pediatrics and adults, respectively, are moderate to severe. Onset typically occurs before 6 years of age. While several systemic DMTs are available to treat moderate and severe AD, topical emollients, corticosteroids, and immunomodulators remain important options; however, long-term continuous use of topical steroids and immunomodulators is limited by TEAEs. The Janus kinase inhibitors abrocitinib (Cibinqo^®; oral), upadacitinb (Rinvoq^®; oral), and ruxolitinib (Opzelura^®; topical), topical PDE5 inhibitor crisaborole (Eucrisa®), injectable IL‑13 inhibitor tralokinumab (Adbry^®) and IL-4/IL-13 inhibitor dupilumab (Dupixent) are also indicated to treat AD.

Nemolizumab is a first-in-class monoclonal antibody that inhibits IL-31 and is designed to reduce burdensome itch related to chronic inflammatory skin conditions. If approved, it will be the second biologic agent approved for PN and will compete directly with Dupixent, a drug with efficacy and safety data across several immunologic conditions. Although there are no head-to-head trials, nemolizumab appears to demonstrate similar safety and efficacy to Dupixent in patients with PN, but may also gain approval in adolescents, an age group that Dupixent does not cover for PN. In addition, nemolizumab has been submitted to the FDA to treat atopic dermatitis in adults and adolescent patients. If approved, it may compete with Dupixent and Adbry in this space.

FDA APPROVAL TIMELINE

• Prurigo nodularis: August 14, 2024

FDA designations: Breakthrough Therapy, Priority Review

• Atopic dermatitis: December 14, 2024

FINANCIAL FORECAST (reported in millions)

The projected total U.S. sales for nemolizumab are not available.

tarlatamab IV

Manufacturer: Amgen

PROPOSED INDICATIONS

Advanced small cell lung cancer (SCLC) with disease progression on or after platinum-based chemotherapy

CLINICAL OVERVIEW

Mechanism of action

Tarlatamab is a bispecific T-cell engager (BiTE) that targets delta-like ligand 3 (DLL3) in neuroendocrine cancers, including SCLC.

Clinical trials

The open-label, phase 2 DeLLphi-301 trial (NCT05060016) evaluated tarlatamab in 220 patients with SCLC who had relapsed after, or was refractory to, one platinum-based treatment regimen and at least one other line of therapy. Eligible patients included those with asymptomatic, treated, stable brain metastases. Patients were randomized 1:1 to receive tarlatamab 10 mg or 100 mg doses. In the 10 mg group, at a median follow-up of 10.6 months, the ORR (primary endpoint) was 40%, with a complete response rate of 1%. In the 10 mg group, 59% and 25% of patients had a DOR ≥ 6 months and ≥ 9 months, respectively, and the PFS was 4.9 months. In the 100 mg group, at a median follow-up of 10.3 months, the ORR was 32%, with a complete response rate of 8%. Among patients who received 100 mg, 61% and 36% experienced a DOR ≥ 6 months and ≥ 9 months, respectively, and the PFS was 3.9 months. Most patients with an evaluable tumor-tissue sample (96% in each group) had DLL3 tumor expression; however, no difference in tumor reduction was seen based on DLL3 expression. The most common TEAEs reported were CRS and pyrexia. Grade 3 TEAEs occurred less often with the 10 mg dose (1%) versus the 100 mg dose (6%).

Dosage and administration

In the clinical trial, tarlatamab was administered IV over 60 minutes at a dose of 10 mg or 100 mg every 2 weeks.

PLACE IN THERAPY

Approximately 20% of all lung cancers are neuroendocrine tumors, of which nearly 14% are SCLC. Most cases of SCLC are associated with cigarette smoking. SCLC is an aggressive disease in which widespread metastases develop early in the disease course. The incidence of new cases of SCLC in the U.S. in 2023 was estimated at 33,000.

Systemic therapy is the SOC for patients with SCLC. A platinum agent + etoposide is recommended for all stages of the disease, with the addition of a PD-L1 blocker to treat extensive-stage disease, including cases in which brain metastases are present. Subsequent systemic therapies include platinum-based doublet, lurbinectedin, topotecan and irinotecan. In addition, concurrent radiation therapy may provide benefit at all stages of the disease as part of treatment and palliation; however, surgical resection is recommended only in a small proportion (5%) of patients with stage I-IIA (T1-2, N0, M0) SCLC.

Response rates to initial therapy are high, at about 70% to 90% for limited disease and approximately 60% for extensive disease. Unfortunately, most patients will relapse, and response to subsequent systemic therapy is poor and dependent on the time elapsed from initial therapy (response rate, ≤ 10% with interval ≤ 6 months and 25% with interval > 6 months).

DLL3 is highly expressed on the cell surface of neuroendocrine tumors and is present in the majority (≥ 85%) of patients with SCLC, making it a potential target in treating SCLC. Tarlatamab is a first-in-class agent that binds to both DLL3 on cancer cells and CD3 on T cells, leading to T cell-mediated lysis of the tumor cells. If approved, it will provide a new approach to combat SCLC, a disease with a large unmet need. It remains to be seen if tarlatamab will be used as second- or third-line systemic treatment. Most patients in the DeLLphi-301 clinical trial had ≥ 2 prior lines of therapy; however, the NCCN guidelines for SCLC do not distinguish between second- and third-line therapies, and instead offer recommendations based on primary and subsequent treatment options.

Amgen is also evaluating tarlatamab in phase 3 trials for SCLC, which include DeLLphi-304 comparing tarlatamab monotherapy with SOC chemotherapy (lurbinectedin, topotecan, amrubidin) for second-line treatment and DeLLphi-306 evaluating tarlatamab after chemoradiotherapy in earlier settings of SCLC.

FDA APPROVAL TIMELINE

June 12, 2024

FDA designations: Breakthrough Therapy, Orphan Drug, Priority Review, RTOR

FINANCIAL FORECAST (reported in millions)

xanomeline-trospium (KarXT) oral 

Manufacturer: Karuna

PROPOSED INDICATIONS

Schizophrenia

CLINICAL OVERVIEW

Mechanism of action

KarXT is a combination of xanomeline and trospium. Xanomeline is an antipsychotic agent with dual M1/M4 muscarinic acetylcholine receptor agonist activity and trospium is a muscarinic receptor antagonist that counteracts the peripheral muscarinic adverse effects of xanomeline.

Clinical trials

The randomized, double-blind, phase 3 EMERGENT-2 trial (NCT04659161) evaluated KarXT in 252 patients 18 to 65 years of age with schizophrenia who were hospitalized due to a recent worsening of psychosis (PANSS score ≥ 80, CGI-S ≥ 4). After a washout period of their background schizophrenia medications, patients were randomized 1:1 to KarXT or placebo. At week 5, patients treated with KarXT showed a statistically significant and clinically meaningful reduction in the PANSS total score (primary endpoint) compared to patients who were given placebo (mean change from baseline, -21.2 versus -11.6 points, respectively; difference, -9.6 points; p<0.0001). At week 5, KarXT also led to significant improvements from baseline in secondary endpoints compared to placebo including the PANSS positive subscale (-6.8 versus -3.9 points, respectively), PANSS negative subscale (-3.4 versus -1.6 points, respectively), PANSS Marder Factor negative score (-4.2 versus -2 points, respectively) and CGI-S (-1.2 versus -0.7 points, respectively) as well as the proportion of patients who experienced ≥ 30% reduction in PANSS total score (54.8% versus 28.3%, respectively) (p<0.05 for each endpoint). The most common TEAEs with KarXT (≥ 10%) were mild to moderate constipation, dyspepsia, headache, nausea, vomiting and hypertension. Discontinuation rates were similar between the two groups. KarXT was not associated with extrapyramidal or metabolic effects.

In the similarly designed randomized, double-blind, phase 3 EMERGENT-3 trial ((NCT04738123; n=256), KarXT also met its primary endpoint of reduction in PANSS total score at week 5 with an 8.4-point reduction in PANSS total score compared to placebo (p<0.0001). In addition, it demonstrated a clinically meaningful and statistically significant 3.5-point reduction in PANSS positive subscale compared to placebo (-7.1 versus -3.6 points, respectively; p<0.0001). While it showed reductions in the PANSS negative subscale, the change from baseline was not statistically significant at week 5; improvement in this subscale only achieved statistical significance at week 4 (p<0.05). The adverse event profile was generally similar to that reported in EMERGENT-2.

The PANSS total score ranges from 30 to 210 points. PANSS positive, negative and Marder Factor negative subscale scores each range from 7 to 49 points. A decrease in the PANSS score correlates with an improvement in schizophrenia symptoms. The CGI-S score ranges from 1 to 7, with 7 indicating the most severe illness.

Dosage and administration

In the clinical trials, KarXT was administered orally twice daily at xanomeline/trospium doses of 50 mg/20 mg on days 1 and 2, then 100 mg/20 mg on days 3 through 7. Beginning on day 8, KarXT dosing was flexible with an optional increase to 125 mg/30 mg and the option to return to 100 mg/20 mg based on tolerability.

PLACE IN THERAPY

Schizophrenia is a serious mental illness that affects 1% of the population. Schizophrenia manifests as positive symptoms (hallucination, delusion, and thought and movement disorder), negative symptoms (lack of emotion, pleasure, motivation and social interaction), and cognitive deficits (impaired executive function, attention and working memory). The onset of schizophrenia usually occurs between the late teens and the mid-30s. Schizophrenia can be debilitating, leading to non-fatal suicide attempts in approximately 20% to 40% of patients, and fatal attempts in approximately 4% to 5% of patients.

Psychosocial therapy, including cognitive-behavioral therapy, cognitive remediation, and social cognition training, is essential treatment for schizophrenia. Antipsychotics are the standard drugs used in patients with schizophrenia. They include first-generation antipsychotics (FGAs) (e.g., chlorpromazine, fluphenazine, haloperidol, loxapine, perphenazine, thiothixene, trifluoperazine) and second-generation antipsychotics (SGAs), also known as atypical antipsychotics (e.g., aripiprazole, asenapine, clozapine, iloperidone, lurasidone, olanzapine, paliperidone, risperidone, quetiapine, ziprasidone). Available antipsychotic agents have proven efficacy in treating positive symptoms of schizophrenia, but their efficacy for negative or cognitive symptoms is limited. FGAs work primarily by blocking dopamine (D2) receptors in the brain and are associated with extrapyramidal adverse effects, tardive dyskinesia, and hyperprolactinemia. SGAs block dopamine D2 receptors and serotonin 2A (5-HT2A) receptors and are generally more likely to cause weight gain and abnormal glucose and lipid levels. The approach to treatment of schizophrenia is largely based on trial and error due to patient variation in response and medication side effects. There is no preference between FGAs or SGAs, or between drugs within each group. However, clozapine is recommended in patients with treatment-resistant schizophrenia and in patients with a significant risk of suicide or aggressive behavior but is not recommended as first-line treatment due to serious side effects (e.g., agranulocytosis).

There are significant unmet needs in the treatment of schizophrenia, especially for the treatment of cognitive impairment and negative symptoms. In addition, side effect profiles contribute to a non-adherence rate estimated at 40% to 50%. Also, approximately 20% of patients will relapse after 1 year of being on an antipsychotic agent.

If approved, KarXT will herald in the first new mechanism of action to treat schizophrenia in several decades. Unlike FGAs and SGAs, it provides selective M1/M4 muscarinic receptor agonism through xanomeline without directly impacting dopamine D2 receptors and mitigates muscarinic TEAEs through the use of trospium. Phase 3 trials demonstrate that KarXT is effective for treating positive symptoms of schizophrenia in the short-term; however, the effects on negative symptoms and cognitive processes are inconclusive. Long-term efficacy and safety, particularly regarding tardive dyskinesia and metabolic effects, are uncertain. Due to the lack of long-term data, ICER rated the net health benefit of KarXT as promising, but inconclusive.

KarXT is also in a phase 3 trial as adjunctive therapy in schizophrenia (ARISE trial; non-hospitalized patients) and for the treatment of neuropsychiatric symptoms in Alzheimer’s disease (ADEPT program).

FDA APPROVAL TIMELINE

September 26, 2024

FINANCIAL FORECAST (reported in millions)