acoramidis oral

Manufacturer: Bridgebio / AstraZeneca

PROPOSED INDICATIONS

Transthyretin amyloid cardiomyopathy (ATTR-CM)

CLINICAL OVERVIEW

Mechanism of action

Acoramidis is a tetrameric transthyretin (TTR) stabilizer.

Clinical trials

The randomized, double-blind, placebo-controlled, phase 3 ATTRibute-CM trial (NCT03860935) evaluated acoramidis in 632 patients with ATTR-CM and clinical heart failure. There were two co-primary endpoints. The first co-primary endpoint reported no statistically significant difference in the change in 6MWD with acoramidis compared to placebo (LS mean change, -26.51 meters versus -24.54 meters, respectively) at 12 months. The second co-primary endpoint was a four-step hierarchical analysis including (in order) death from any cause, CV-related hospitalization, the change from baseline in the N-terminal pro–B-type natriuretic peptide (NT-proBNP) level, and the change from baseline in the 6MWD after 30 months of treatment, which produced a win ratio of 1.8 (p<0.001), favoring acoramidis over placebo. In addition, the study showed that acoramidis significantly increased serum TTR levels at day 28 (p<0.001), which remained stable through month 30; an increase in serum TTR is associated with improved clinical outcomes. Acoramidis also demonstrated about a 25% relative risk reduction (RRR) in death from any cause and a 50% RRR in CV-related hospitalizations compared to placebo at 30 months. Similar safety profiles were observed with acoramidis and placebo.

Dosage and administration

In the ATTRibute-CM trial, acoramidis 800 mg was administered orally twice daily.

PLACE IN THERAPY

ATTR-CM results from the misfolding and accumulation of the tetrameric protein TTR into the extracellular space of the myocardium, which leads to progressive thickening of the ventricular wall and stiffening of the heart. Life expectancy after ATTR-CM diagnosis is about 2 to 6 years. There are two types of ATTR-CM. Wild-type ATTR-CM is due to misfolded wild-type (normal) TTR, the mechanism for which is unclear. Hereditary ATTR-CM is due to mutations in the TTR gene, which predisposes TTR to misfold. Based on limited data, an estimated 5,000 to 7,000 new cases of ATTR-CM are diagnosed each year in the U.S.; however, estimates are increasing due to advancements in diagnostic methods. ATTR-CM typically presents in individuals ≥ 60 years of age. Patients with ATTR-CM often have symptoms of chronic heart failure.

TTR is synthesized by the liver, and liver transplantation is the gold standard for treating transthyretin-related amyloidosis (ATTR). Multi-organ transplantation (heart, liver, and kidney) has been successful in slowing the natural course of the disease. Tafamidis/tafamidis meglumine (Vyndaqel®, Vyndamax®) is a TTR stabilizer approved by the FDA to treat ATTR-CM. The oral NSAID diflunisal may also stabilize TTR but is rarely used off-label for ATTR-CM due to poor tolerance and uncertain efficacy. Notably, standard treatments for CV disease such as beta-blockers, ACEIs, ARBs, diuretics or digoxin can worsen ATTR-CM symptoms.

Acoramidis leads to near-complete TTR stabilization with improved potency and stabilization compared to tafamidis. The ATTRibute-CM trial reported mixed data for acoramidis compared to placebo. While acoramidis did not significantly improve 6MWD at 12 months, significant benefit was demonstrated at 30 months in a hierarchical analysis that included all-cause mortality, CV-related hospitalization, NT-proBNP, and 6MWD. Notably, in its pivotal trial, tafamidis led to a 30% RRR in death from any cause and a 32% RRR in CV-related hospitalization compared to placebo at 30 months. If approved, acoramidis will be the second medication in the U.S. indicated to treat ATTR-CM and will directly compete with tafamidis agents.

FDA APPROVAL TIMELINE

November 29, 2024

FDA Designations: Orphan Drug

FINANCIAL FORECAST (reported in millions)

arimoclomol oral

Manufacturer: Zevra

PROPOSED INDICATIONS

Niemann-Pick disease type C (NPC)

CLINICAL OVERVIEW

Mechanism of action

Arimoclomol preserves cellular function and prevents cell death in cells experiencing lysosomal stress. It does this by amplifying the natural response to cellular stress through production of heat shock proteins (HSPs) that prevent protein misfolding.

Clinical trials

A 12-month, double-blind, phase 2/3 trial (NPC-002) evaluated arimoclomol for the treatment of NPC in addition to routine clinical care; stable miglustat therapy was allowed. Enrolled patients (n=50) were 2 to 18 years of age and were able to walk independently or with assistance. The primary endpoint was change from baseline to 12 months in NPC severity as measured by the 5-domain (5D)-NPC Clinical Severity Scale (NPCCSS) score, which includes parameters for ambulation, cognition, fine motor skills, speech, and swallowing (range, 0 to 25) with higher scores indicating greater impairment. The study demonstrated a 65% relative reduction in annual disease progression with arimoclomol based on the 5D-NPCCSS score (difference versus placebo, -1.4 point; p=0.046). Among patients also receiving miglustat, the difference in mean change in 5D-NPCCSS from baseline to 12 months with arimoclomol compared to placebo was -2.06 points (p=0.006). At 12 months, 50% and 37.5% of patients in the arimoclomol and placebo groups, respectively, had stable or improved disease (responders) (p=0.546). In addition, there was no significant difference between arimoclomol and placebo in the secondary endpoint of change from baseline to 12 months in the Scale for Assessment and Rating of Ataxia (SARA) score (LS mean difference, 0.28 points; p=0.79). Arimoclomol was well tolerated. Upper respiratory tract infection, decreased weight, and urticaria were reported more frequently with arimoclomol than placebo.

Interim data from an open-label extension (OLE) trial, in which all patients received arimoclomol, reported sustained reduction in NPC progression through 36 months. In addition, early treatment initiation with arimoclomol resulted in greater benefit compared to delayed start (in patients who switched from placebo to arimoclomol at the start of the OLE trial).

Dosage and administration

In the clinical trials, a weight-based dose (93 to 372 mg/day) of arimoclomol was administered by mouth or by feeding tube three times per day.

FDA APPROVAL TIMELINE

September 21, 2024
The FDA’s Genetic Metabolic Diseases Advisory Committee will review arimoclomol for the treatment of Niemann-Pick disease type C on August 2, 2024.

FDA designations: Breakthrough Therapy, Fast Track, Orphan Drug, RPD

FINANCIAL FORECAST (reported in millions)

N-acetyl-L-leucine oral

Manufacturer: Intrabio

PROPOSED INDICATIONS

Niemann-Pick disease type C (NPC)

CLINICAL OVERVIEW

N-acetyl-L-leucine (NALL) is a modified, acetylated derivative of the natural essential amino acid leucine that normalizes energy production, improves lysosomal function and cellular signaling, and mitigates neuronal inflammation.

A double-blind, placebo-controlled, crossover trial (NCT05163288) evaluated NALL in 60 patients ≥ 4 years of age with NPC. Enrolled patients had mild to severe NPC symptoms correlating to a Scale for the Assessment and Rating of Ataxia (SARA) score between 7 to 34 at baseline; lower SARA scores indicate better neurologic status. Patients were randomized to NALL or placebo for 12 weeks, followed by alternate treatment for 12 weeks. The primary endpoint was mean change from baseline to week 12 in the SARA total score; however, the FDA requested use of a modified SARA (mSARA) score, which did not include stance and sitting as part of the assessment. After 12 weeks, the mean change from baseline in the SARA total score was -1.97 points with NALL and -0.6 points with (LS mean difference, -1.28 points; p<0.001). Based on the mSARA, the LS mean difference after NALL and after placebo therapies was -0.96 point (p-value not reported). Exploratory data for NPCCSS (scale, 0 to 54) showed a difference in change from baseline between NALL and placebo of -0.5 point. The difference in change in the Clinical Global Impression of Improvement (CGI-I) after NALL and after placebo therapies was -0.6. No serious TEAEs occurred with NALL. One case of anal incontinence, restless legs, and rosacea were reported as transient TEAEs associated with NALL.

Dosage and administration

In the clinical trial, NALL was administered orally two to three times per day. Patients 4 to 12 years of age received 2 g to 4 g per day and those ≥ 13 years of age received 4 g per day.

PLACE IN THERAPY

NPC is a rare, inherited, lysosomal storage disorder with an estimated incidence of 1 per 100,000 live births. It is caused by mutations in the NPC1 gene (95% of cases) or NPC2 gene (5% of cases) that result in dysfunctional NPC proteins giving rise to abnormal accumulation of lipids in tissues and organs, including the brain. Signs and symptoms of NPC include hepatosplenomegaly as well as neurologic manifestations, such as impaired motor function, cognitive function, swallowing and speech. Clinical presentation and disease progression depend on the patient’s age when neurological symptoms first appear, with younger age associated with more aggressive disease.

There is no cure for NPC. Miglustat has been used off-label in the U.S. It inhibits synthesis of glycolipids and has demonstrated slowing of disease progression in clinical trials. The use of miglustat may be considered in patients with mild to moderate neurologic, psychiatric, or cognitive manifestations, ideally starting use at the time of onset of neurologic manifestations.

If approved, arimoclomol and NALL would be the first agents FDA-approved for the treatment of NPC, a disorder with high unmet medical need. In clinical trials, both oral agents demonstrated improvement in neurologic status but used different tools to evaluate symptoms of cerebellar ataxia. Phase 3 trials for arimoclomol displayed long-term data with reduction in disease progression for up to 3 years based on the validated 5D-NPCCSS score, whereas improvement in neurologic status by NALL was revealed in results from a 12-week study based on the SARA score, which is validated for evaluating effects on spinocerebellar ataxia, but not for NPC. Moreover, data revealed neurologic symptoms improved during treatment with NALL; although, neurologic status declined when the agent was stopped. Notably, there is no validated biomarker for NPC or surrogate endpoint that indicates clinical improvement.

Intrathecal and IV formulations of cyclodextrin are also in phase 3 trials for NPC.

FDA APPROVAL TIMELINE

September 24, 2024

FDA designations: Fast Track, Orphan Drug, Priority Review, RPD

FINANCIAL FORECAST (reported in millions)

The financial forecast for NALL is not currently available.

axatilimab IV

Manufacturer: Syndax

PROPOSED INDICATIONS

Chronic graft-versus-host disease (cGVHD) after failure of at least two prior lines of systemic therapy

CLINICAL OVERVIEW

Mechanism of action

Axatilimab is a monoclonal antibody targeting the colony stimulating factor 1 receptor (CSF-1R), which is expressed on monocytes and macrophages and is activated through its ligands, IL-34 and CSF-1.

Clinical trials

The randomized, open-label, phase 2 AGAVE-201 (NCT04710576) trial evaluated axatilimab in 241 allogeneic HCT recipients with recurrent or refractory cGVHD. Patients were randomized to one of three doses of axatilimab. The primary endpoint of ORR at 24 weeks (6 cycles) was 74% with 0.3 mg/kg every 2 weeks, 67% with 1 mg/kg every 2 weeks and 50% with 3 mg/kg every 4 weeks; complete response rates were 1%, 0% and 1%, respectively. In addition, 60%, 60% and 53% of patients in the respective cohorts maintaining response at 12 months. The most frequent grade ≥ 3 TEAEs reported were infection or infestations, elevated blood creatine phosphokinase and pneumonia.

Dosage and administration

In the clinical trial, axatilimab was administered IV every 2 weeks at doses of 0.3 mg/kg or 1 mg/kg, or 3 mg/kg every 4 weeks.

PLACE IN THERAPY

Chronic GVHD is a complication of allogenic HCT in which the transplanted cells attack host cells resulting in inflammation and fibrosis. Chronic GVHD can be life-threatening, affecting multiple organ systems. It is characterized by fibrosis and various clinical features like autoimmune disorders. It is estimated to occur in approximately 30% to 50% of allogenic HCT recipients. Typically, cGVHD develops within the first year after HCT, but can be present many years later.

High-dose corticosteroids are the standard first-line treatment for cGVHD, with response observed in about 50% of patients; however, more than half of patients will require second-line therapy within 2 years. The kinase inhibitors, ruxolitinib (Jakafi®; preferred), belumosudil (Rezurock®), and ibrutinib (Imbruvica®) are approved to treat cGVHD as second or later line therapy. Many other agents have been used off-label depending on organ involvement and include imatinib (Gleevec®), abatacept (Orencia®), alemtuzumab (Campath®, Lemtrada®), calcineurin inhibitors (cyclosporine, tacrolimus), etanercept (Enbrel®), hydroxychloroquine, interleukin-2, low-dose methotrexate, mTOR inhibitors, mycophenolate mofetil, pentostatin and rituximab (Rituxan® or biosimilars).

CSF-1R–dependent monocytes play a key role in profibrotic (M2) macrophage differentiation, polarization, and function and promote sustained inflammation and tissue injury during cGVHD. In addition, these cells accelerate maladaptive tissue repair and fibrosis. If approved, axatilimab will provide a new mechanism in combating cGVHD, a disorder that continues to have unmet medical need.

FDA APPROVAL TIMELINE

August 28, 2024

FDA designations: Fast Track, Orphan Drug, Priority Review

FINANCIAL FORECAST (reported in millions)

eladocagene exuparvovec (Upstaza™) intraputaminal 

Manufacturer: PTC Therapeutics

PROPOSED INDICATIONS

Aromatic L-amino acid decarboxylase (AADC) deficiency

CLINICAL OVERVIEW

Mechanism of action

Eladocagene exuparvovec is a recombinant adeno-associated virus serotype 2 (AAV2)-based gene therapy. It delivers a functional dopa decarboxylase (DDC) gene to increase AADC enzyme levels and restore dopamine production.

Clinical trials

In a study conducted in Taiwan, 26 patients were enrolled in three consecutive trials (including compassionate use, phase 1/2, and phase 2b) with similar treatment protocols and completed follow-up evaluations at 1-year. The mean age at the time of treatment was 4.1 years (range, 1.7 to 8.5 years). The mean duration of follow up was 5.4 years of age (range, 2 to 10.2 years of age). Motor ability was evaluated using the Peabody Developmental Motor Scales–Second Edition (PDMS-2) that assesses fine motor function and the Alberta Infant Motor Scale (AIMS) that assesses gross motor skills. Eladocagene exuparvovec led to a significant increase in the PDMS-2 score from baseline (10.4 ± 5.4) to 1 year (80.5 ± 43.4; n=25), 2 years (114.5 ± 55.2; n=22), and 5 years (116.1 ± 59.8; n=11) after the dose (p<0.01 for each). Likewise, the AIMS score significantly increased from baseline (1.8 ± 1.8) at 1 year (18.8 ± 11), 2 years (26.9 ± 15.5), and 5 years (24.5 ± 15) after the dose (p<0.001 for each). Secondary endpoints included change in the levels of the dopamine and serotonin metabolites, homovanillic acid (HVA) and 5-hydroxyindoleacetic acid (5-HIAA), in the cerebrospinal fluid after 12 months; significant increases in HVA were reported (p<0.001) but not in 5-HIAA. While improvements were observed in all patients who received eladocagene exuparvovec, greater improvement was associated with treatment at a younger age. Adverse events reported include post-surgery complications such as cerebrospinal fluid leakage, which were managed with SOC. No treatment-related brain injuries occurred. Mild to moderate dyskinesia was reported in most patients and resolved within a few months.

Dosage and administration

Eladocagene exuparvovec is administered as a one-time dose via intraputaminal (base of forebrain) infusion.

PLACE IN THERAPY

AADC deficiency is an ultra-rare, autosomal recessive, neurometabolic disorder. It is caused by a mutation in the DDC gene that encodes the production of AADC, an enzyme that plays a key role in the production of serotonin, dopamine, epinephrine, and norepinephrine. Impairment of these neurotransmitters leads to developmental delays, intellectual disabilities, and life-long movement disorders and autonomic nervous system dysfunction. Symptom onset usually occurs within the first six months of life. Approximately 150 to 350 cases have been identified in the literature, with it reported more often in certain Asian populations (Taiwanese, Japanese, Chinese). Symptom severity can range from relatively mild to very severe due to a broad phenotypic spectrum for the disease. Individuals with AADC deficiency are at an increased risk of early death due to complications such as infection or an acute cardiorespiratory event. Many who are affected do not live through childhood, but those with milder disease may reach adulthood.

There is no cure for AADC deficiency. Medications used to treat the condition include selective dopamine agonists, monoamine oxidase inhibitors (MAOIs) and pyridoxine. However, treatment response varies greatly among affected individuals.  Agents for symptom management, such as anticholinergics, benzodiazepines, alpha-adrenoreceptor blockers and melatonin may also be used.

If approved, the one-time gene therapy, eladocagene exuparvovec, will be the first treatment to target the underlying cause of AADC deficiency. In clinical trials, significant and durable improvement in motor skills was reported.

FDA APPROVAL TIMELINE

November 13, 2024

FDA Designations: Orphan Drug, Priority Review, RPD, seeking Accelerated Approval

FINANCIAL FORECAST (reported in millions)

tradipitant oral

Manufacturer: Vanda / Eli Lilly

PROPOSED INDICATIONS

Gastroparesis (GP)

CLINICAL OVERVIEW

Mechanism of action

Tradipitant is a neurokinin receptor 1 (NK-1R) antagonist and may treat gastroparesis by acting centrally in the nausea-vomiting centers of the brain and peripherally in the smooth muscle of the intestines.

Clinical trials

A double-blind, placebo-controlled, phase 3 trial (NCT04028492) assessed the efficacy of tradipitant in relieving GP symptoms in patients with idiopathic and diabetic GP. The primary endpoint was the change from baseline to week 12 (days 78 to 84) in average nausea severity as measured by the Gastroparesis Core Symptom Daily Diary (GCSDD) in the ITT population (n=201). The GCSDD records the patient’s rating of the worst occurrence of each cardinal symptom of gastroparesis in the past 24 hours on a scale of 0 (no symptoms) to 5 (very severe). The study demonstrated that the difference between tradipitant and placebo in the primary endpoint was not significant (-1.55 versus -1.49, respectively; p=0.741). However, exploratory analysis revealed that an unbalanced use of rescue medications (e.g., ondansetron, prochlorperazine, promethazine) may have confounded the results. Among patients who did not use rescue medication, the average nausea severity was significantly improved for patients on tradipitant compared with placebo, overcoming the large placebo effect, at week 12 (-2.01 versus -1.32; p=0.0372). In addition, average nausea severity was significantly improved at week 12 for patients in the severity adjustment population, which excluded patients with zero or the highest severity of vomiting (p=0.0276) and significant effects were seen with adequate tradipitant exposure based on a pharmacokinetic analysis. The incidence and type of adverse events reported were similar between the treatment groups and included diarrhea, urinary tract infection, sinusitis, dizziness, and headache. Discontinuation due to adverse effects occurred in 6.9% of patients in the tradipitant group and 3% of patients in the placebo group.

In a double-blind, placebo-controlled, phase 2 trial (NCT02970968), tradipitant led to a significant decrease in GCSDD score at week 4 compared with placebo (-1.25 versus -0.73, respectively; p=0.0099) and a significant increase in the percentage of nausea-free days a week 4 (28.8% versus 15%, respectively; p=0.016) among 152 adults with idiopathic or diabetic GP.

Dosage and administration

In the clinical trials, tradipitant 85 mg was administered orally twice daily.

Place in therapy

GP is a chronic disorder of delayed gastric emptying without mechanical obstruction. Its characteristic symptoms of early satiety, nausea, vomiting, bloating, and abdominal pain have a significant effect on QOL, morbidity, and mortality. Definite diagnosis of GP (based on gastric emptying scintigraphy testing) was estimated at 21.5 per 100,000 persons in the U.S. in 2018; however, actual prevalence may be much higher since many patients remain undiagnosed. GP occurs mostly in women, with causes including diabetes, medications, surgery, or unknown.

Management of GP includes a diet that promotes gastric emptying (e.g., 4 to 5 small meals per day, decreased fat and fiber, increased liquid nutrition). Use of prokinetic medications, such as metoclopramide, cisapride (investigational limited access program) and erythromycin (4 weeks, off-label), to increase gastric emptying rate, and antiemetics for symptom control are suggested based on low quality of evidence. Notably, metoclopramide is FDA-approved for acute and recurrent diabetic GP, but its use is limited to a 3-month duration due to the risk of developing tardive dyskinesia.

NK-1R antagonists are proven to be effective in reducing nausea and vomiting in chemotherapy-induced emesis. If approved, tradipitant will be the first agent of this class to treat GP symptoms and the first new mechanism for GP to be approved in over 40 years; however, in clinical trials, it demonstrated mixed results in improving nausea in patients with GP. Tradipitant is also in phase 3 trials for motion sickness.

FDA APPROVAL TIMELINE

September 18, 2024

FINANCIAL FORECAST (reported in millions)

The financial forecast for tradipitant is not currently available.

zanidatamab IV

Manufacturer: Jazz / Beigene

PROPOSED INDICATIONS

Previously treated, unresectable, locally advanced, or metastatic HER2-positive biliary tract cancer (BTC)

CLINICAL OVERVIEW

Mechanism of action

Zanidatamab is a HER2-targeted bispecific antibody that provides dual HER2 signal blockade, removal of HER2 protein from the cell surface, and immune-mediated cytotoxicity.

Clinical trials

Zanidatamab monotherapy was evaluated in the open-label, single-arm, phase 2b HERIZON-BTC-01 trial (NCT05152147) in patients with unresectable, locally advanced, or metastatic HER2+ BTC. Enrolled patients were previously treated with gemcitabine-based therapy but were naïve to HER2-targeted therapy. Cohort 1 (n=80) included patients with in situ hybridization [ISH] positive and immunohistochemistry [IHC] 2+ or 3+ disease. Long-term follow-up data confirmed an ORR (primary endpoint) of 41.3%, with a complete response rate of 2.5%. Among patients with IHC 3+ (HER2+) tumors, the ORR was 51.6%, median DOR was 14.9 months, median PFS was 7.2 months, and median OS was 18.1 months. Among patients with IHC 2+ (borderline HER2 status) tumors, the ORR was 5.6%, median OS was 5.2 months, and median PFS was 1.7 months. In the single patient with IHC 2+ disease who responded to therapy, the DOR was 7.5 months. Zanidatamab was generally well tolerated, with a manageable safety profile. A serious increase in AST and ALT was experienced by one patient, which did not lead to treatment discontinuation.

Dosage and administration

In the HERIZON-BTC-01 trial, zanidatamab was administered IV as 20 mg/kg every 2 weeks.

PLACE IN THERAPY

BTCs include gallbladder cancer and extrahepatic cholangiocarcinoma (CCA). In 2023, it was estimated that 12,220 new cases of BTC would be diagnosed in the U.S. and 4,510 deaths would occur due to the condition. BTCs are associated with a poor prognosis, as patients often have advanced disease upon diagnosis. Radiation therapy may be used in patients with unresectable disease. Systemic treatment for unresectable or metastatic BTC includes gemcitabine/cisplatin ± durvalumab (Imfinzi®; preferred) or pembrolizumab (Keytruda®). Subsequent therapy includes FOLFOX (folinic acid, fluorouracil, and oxaliplatin). HER2 overexpression or pathway activation is exhibited in about 5% to 20% of CCAs, and 15% to 30% of gallbladder cancer, for which off-label fam-trastuzumab deruxtecan-nxki (Enhertu®, for IHC 3+), trastuzumab/pertuzumab (Phesgo®) and trastuzumab + tucatinib (Herceptin® + Tukysa®) are recommended for HER2+ tumors after disease progression.

If approved, zanidatamab will be the first HER2-targeted treatment specifically indicated for patients with HER2+ locally advanced or metastatic biliary tract cancer. It demonstrated efficacy particularly in patients with IHC 3+ tumors. Zanidatamab is being evaluated in combination with first-line cisplatin and gemcitabine for the treatment of HER2+ BTC in a phase 2 trial (NCT03929666). Zanidatamab is also in phase 2 and phase 3 trials for HER2+ breast cancer and HER2+ gastric cancer, respectively.

FDA APPROVAL TIMELINE

November 29, 2024

FDA Designations: Breakthrough Therapy, Fast Track, Orphan Drug, Priority Review, seeking Accelerated Approval

FINANCIAL FORECAST (reported in millions)