In the 76-week, 1,736 patient, Phase III, TRAILBLAZER-ALZ 2 trial, treatment with donanemab resulted in a decline in the integrated Alzheimer's Disease Rating Scale (iADRS) score of 6.02 points in patients with low to medium levels of tau and 10.2 in the overall population compared to 9.27 and 13.1 point reductions in patients who received placebo in patients with early symptomatic Alzheimer disease (mild cognitive impairment/mild dementia) with amyloid and low/medium or high tau pathology based on positron emission tomography imaging. Amyloid-related imaging abnormalities of edema or effusion (ARIA-E) and amyloid-related imaging abnormalities with hemorrhage (ARIA-H) have been reported with donanemab. In the TRAILBLAZER-ALZ 2 trial, 24% of donanemab patients experienced ARIA-E with 6.9% experiencing symptomatic ARIA-E compared to 2.1% with placebo with none being symptomatic. ARIA-H was experienced by 31.4% of donanemab patients compared to 13.6% with placebo.
A lack of viable dystrophin is the cause of Duchenne muscular dystrophy (DMD). But the dystrophin gene is too large to deliver to cells using the adeno-associated virus vectors that is commonly used in gene therapy. Sarepta, Solid Biosciences and Pfizer are developing a shortened form of the gene (microdystrophin gene therapy) that stimulates a truncated form of dystrophin.
Microdystrophin was designed to resemble a protein found in patients with Becker muscular dystrophy, a milder form of the disease. However, the microdystrophin produced by delandistrogene moxeparvovec is different from what is found in patients with Becker muscular dystrophy or created with exon skipping drugs. While delandistrogene moxeparvovec has been shown to produce large amounts of microdystrophin, it is not currently known if microdystrophin has the same functional benefit as normal dystrophin in DMD patients. Limited evidence has shown a benefit compared to historical DMD data.
Sarepta announced four-year results from a four patient, Phase I/II trial (NCT03375164), where delandistrogene moxeparvovec maintained a 7-point improvement in the North Star Ambulatory Assessment (NSAA) over baseline and a 9.4-point improvement compared to a historical control group in patients with DMD.
Sarepta announced interim data from 20 patients enrolled in Part 1 of a 48-week, 41 patient, Phase II trial(NCT03769116), where delandistrogene moxeparvovec resulted in micro-dystrophin expression of 28.1% at 12-weeks. At 48 weeks, treatment with delandistrogene moxeparvovec improved the NSAA score by 1.7 points in the 20 treated patients, but the improvement was not statistically significant compared to a 0.9 point improvement in 21 placebo patients.
Sarepta announced data from 20 patients enrolled in Part 2 of a 48-week, 41 patient, Phase II trial(NCT03375164), where treatment with delandistrogene moxeparvovec improved the NSAA score by 2 points compared to a 103 patient, weighted external control group (1.3 point increase vs 0.7 point decrease).
In July 2018, the FDA placed a hold on a delandistrogene moxeparvovec trial due to the presence of a trace fragment of DNA plasmid in one lot of the drug. The hold was lifted in September 2018. A second hold was placed in August 2021 when a patient developed asthenia that required hospitalization and respiratory support after receiving delandistrogene moxeparvovec. The hold was lifted in October 2021 when additional information on risk was submitted to the FDA.
In limited patent data, the most common adverse events were vomiting, nausea, acute liver injury, fever and thrombocytopenia.
In September 2020, the FDA requested that Sarepta use a different potency assay when manufacturing delandistrogene moxeparvovec before using the drug in a Phase III trial. The Phase I ENDEAVOR trial evaluated delandistrogene moxeparvovec made by Sarepta’s commercial-scale manufacturing process. Sarepta announced one-year functional results from 20 patients enrolled in Cohort 1 of the open-label, Phase I, ENDEAVOR trial (NCT04626674), where treatment with delandistrogene moxeparvovec improved the NSAA score compared to a historical control group of patients with DMD.
An FDA review of delandistrogene moxeparvovec, in May 2023, questioned whether microdystrophin protein expression is a valid surrogate endpoint that can be used for approval, since microdystrophin has not demonstrated a pharmacologic effect on a biomarker in the pathway of the disease. The FDA failed to find a benefit for ambulatory DMD patients in a review of delandistrogene moxeparvovec trials. The FDA’s Cellular, Tissue, and Gene Therapies Advisory Committee (CTGTAC) voted 8 to 6 to recommend approval of delandistrogene moxeparvovec.
The FDA delayed the PDUFA date for delandistrogene moxeparvovec by one month in order to consider an accelerated approval for Duchenne patients ages 4-5 years old. The FDA granted an accelerated approval for delandistrogene moxeparvovec (Elevidys, Sarepta), on 6/22/2023, for the treatment of Duchenne muscular dystrophy in boys aged 4 and 5. Full approval and expansion to other age groups or withdrawal from the market will depend on the results of the Phase III EMBARK trial (NCT05096221). The EMBARK trial is forecast to report top-line results by the end of the year. Sarepta set the initial price for delandistrogene moxeparvovec at $3.2 million for the single dose gene therapy.
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The FDA approved sulbactam and durlobactam (Xacduro, Innoviva), on 5/23/2023, for the treatment of hospital-acquired bacterial pneumonia and ventilator-associated bacterial pneumonia (HABP/VABP) caused by susceptible isolates of Acinetobacter baumannii-calcoaceticus complex (Acinetobacter).
The FDA approved sotagliflozin (Inpefa, Lexicon Pharmaceuticals), on 5/26/2023, to reduce the risk of cardiovascular death, hospitalization for heart failure, and urgent heart failure in adults with heart failure or type 2 diabetes mellitus, chronic kidney disease, and other cardiovascular risk factors.
The FDA approved Pfizer’s respiratory syncytial virus vaccine (Abrysvo), on 5/31/2023, to prevent lower respiratory tract infection caused by RSV in individuals 60 and older.
The FDA is delaying the PDUFA date for delandistrogene moxeparvovec by one month in order to consider an accelerated approval for Duchenne patients ages 4-5 years old. The new PDUFA date is 6/22/2023. Full approval and expansion to other age groups or withdrawal from the market will depend on the results of the Phase III EMBARK trial. The EMBARK trial is forecast to report top-line results by the end of the year.
The FDA accepted the NDA for fruquintinib for the treatment of refractory metastatic colorectal cancer and set a PDUFA date for 11/30/2023.
The FDA accepted the BLA for lifileucel for the treatment of unresectable or metastatic melanoma and set a PDUFA date for 11/25/2023
The FDA approved beremagene geperpavec (Vyjuvek, Krystal Biotech), on 5/19/2023, for the treatment of dystrophic epidermolysis bullosa.
The FDA approved epcoritamab (Epkinly, Genmab & AbbVie), on 5/19/2023, for the treatment of relapsed or refractory large B-cell lymphoma after two or more lines of systemic therapy. Epcoritamab was approved with a boxed warning regarding Cytokine Release Syndrome and Immune Effector Cell-Associated Neurotoxicity Syndrome
An FDA review of RSVpreF for the prevention of lower respiratory tract disease caused by RSV in infants, when administered to pregnant mothers, found the vaccine to be efficacious and estimated vaccine efficacy to be 57.1% within 90 days of birth and 51.3% during the first 180 days. RSVpreF was generally safe and had an adverse effect profile similar to placebo (16.2% and 15.2%). It was noted that while there was a numerically higher occurrence of premature delivery, the difference was not significant (5.6% vs 4.7%). The FDA’s Vaccines and Related Biological Products Advisory Committee (VRBPAC) voted 14 to 0 on effectiveness and 10 to 4 on safety for RSVpreF for the prevention of lower respiratory tract disease caused by RSV in infants, when administered to pregnant mothers. Members who voted no for safety were concerned about the higher incidence of premature deliveries.
Elevar Therapeutics submitted an NDA for apatinib plus camrelizumab for the treatment of hepatocellular carcinoma.
The FDA accepted the BLA for TAK-755 for the treatment of congenital thrombotic thrombocytopenic purpura, which suggests a PDUFA date on 11/16/2023.
Mustang Bio announced it would delay initiation of Phase III trials for MB-107 and MB-207 until after a research partner completes a trial evaluating a modified version of the current lentiviral vector. Mustang Bio will initiate the Phase III trials utilizing the safest vector.
The FDA granted isaralgagene civaparvovec a Fast Track Designation for the treatment of Fabry disease.
The FDA approved pegunigalsidase alpha (Elfabrio, Chiesi, Protalix BioTherapeutic), on 5/10/2023, for the treatment of adult patients with Fabry disease. Pegunigalsidasealpha was approved with a boxed waring regarding hypersensitivity reactions, including anaphylaxis.
The FDA approved fezolinetant (Veozah,Astellas Pharma), on 5/12/2023, to treat moderate to severe vasomotor symptoms caused by menopause. Astellas priced fezolinetant a t$6,600 per year, which is higher than the $2,000 to $2,500 range recommended byICER.
The FDA rejected N-803 plus BacillusCalmette-Guerin (BCG) for the treatment of BCG-unresponsive non-muscle invasive bladder carcinoma due to manufacturing deficiencies.
The FDA rejected trastuzumab duocarmazine for the treatment of pretreated HER2-positive unresectable locally advanced or metastatic breast cancer and requested additional unspecified information.
An FDA review of delandistrogene moxeparvovec questioned whether microdystrophin protein expressionis a valid surrogate endpoint that can be used for approval, since microdystrophin has not demonstrated a pharmacologic effect on a biomarker in the pathway of the disease. The FDA failed to find a benefit for ambulatory DMD patients in a review of delandistrogene moxeparvovectrials. The FDA’s Cellular, Tissue, and Gene Therapies Advisory Committee (CTGTAC) voted 8 to 6 to recommend approval of delandistrogene moxeparvovec.
The FDA designated ampreloxetine an Orphan Drug for the treatment of symptomatic neurogenic orthostatic hypotension in patients with multiple system atrophy.
We recently added 16 new drugs to the knowledgebase:
The FDA approved omidubicel (Omisirge, Gamida Cell), on 4/17,2023, to reduce the time to neutrophil recovery and the incidence of infection. In patients with hematologic malignancies planned for umbilical cord blood transplantation following myeloablative conditioning. Omidubicel was approved with a boxed warning regarding infusion reactions, graft versus host disease, engraftment syndrome, and graft failure.
The FDA approved tofersen (QALSODY, Biogen), on 4/25/2023, for the treatment of amyotrophic lateral sclerosis (ALS) in adults who have a mutation in the superoxide dismutase 1 (SOD1) gene.
The FDA approved a fecal microbiota product (Vowst, Seres Therapeutics), on 4/26/2023, for the prevention of recurrent C. difficile infection.
The FDA approved GSK’s respiratory syncytial virus vaccine (Arexvy), on 5/3/2023, to prevent lower respiratory tract infection caused by RSV in individuals 60 and older.
The FDA rejected concizumab and requested additional information related to monitoring, dosing and the manufacturing process.
The FDA granted a Fast Track designation to VE303 for the prevention of recurrent Clostridioides difficile infection.
The FDA’s Antimicrobial Drugs Advisory Committee voted 12-0 to recommend approval of the combination of sulbactam and durlobactam for the treatment of hospital-acquired bacterial pneumonia and ventilator-associated bacterial pneumonia caused bysusceptible strains of Acinetobacter. Sulbactam/durlobactam has a PDUFA date of May 29, 2023.
The FDA has placed a hold on Sun Pharma’s deuruxolitinib 12 mg due to a report of a pulmonary embolism in a long-term Open Label Extension (OLE) study. The gold does not affect the 8 mg dose, since no thrombotic events have been reported with the lower dose.
The European Commission granted marketing authorization for vadadustat (Vafseo, Akebia Therapeutics) for the treatment of anemia in chronic kidney disease (CKD) dialysis patients.
Roche obtained zinpentraxin in February 2020, when it bought Promedior. Roche discontinued development of zinpentraxin, in February 2023, as a treatment for idiopathic pulmonary fibrosis after a futility analysis failed to find a benefit compared to placebo. In April 2023, Roche also abandoned development of zinpentraxin to treat myelofibrosis as part of a pipeline review and reprioritization.
The FDA approved retifanlimab (Zynyz, Incyte), on 3/22/2023, for the treatment of metastatic or recurrent locally advanced Merkel cell carcinoma.
The FDA approved rezafungin (Rezzayo, Cidara Therapeutics), on 3/22/2023, for the treatment of candidemia and invasive candidiasis in adults with limited or no alternative treatment options.
The FDA approved leniolisib (Joenja, Pharming), on 3/25/2023, for the treatment of activated phosphoinositide 3-kinase delta syndrome.
Iovance submitted a BLA for lifileucel for the treatment of unresectable or metastatic melanoma.
J&J discontinued development of its respiratory syncytial virus (RSV) vaccine and the Phase III EVERGREEN study to prioritize other assets.
With Chinese strict COVID-19 travel restriction being loosened the FDA has scheduled manufacturing facility inspections for 2Q23 for BeiGene’s tislelizumab and Junshi Biosciences’ toripalimab.
The FDA granted RRx-001 a Fast Track Designation for the prevention/attenuation of severe oral mucositis in chemotherapy and radiation-treated head & neck cancer patients.
The FDA accepted the resubmitted NDA for palovarotene after Ipsen provided the additional clinical data that was requested. A PDUFA date was set for 8/16/2023.
The FDA rejected the combination of foscarbidopa and foslevodopa for the treatment of motor fluctuations in patients with advanced Parkinson's disease and requested additional information about the pump used to administer the drugs.
The FDA approved zavegepant nasal spray (Zavzpret, Pfizer), on 3/10/2023, for the acute treatment of migraine with or without aura.
The FDA extended the PDUFA date for the valoctocogene roxaparvovec in order to review newly submitted three-year data from the Phase 3 GENEr8-1 study. The new PDUFA date is 6/30/2023.
The FDA accepted the resubmitted BLA for remestemcel-L to treat steroid-refractory acute graft versus host disease and set a PDUFA date for 8/2/2023.
The FDA accepted the NDA for eplontersen, for the treatment of hereditary transthyretin-mediated amyloid polyneuropathy and set a PDUFA date for 12/22/2023.
Announced Research Updates
Cytokinetics announced 10-week data from the 41 patient, cohort IV of the REDWOOD-HCM trial, where NT-proBNP was decreased by 66% with aficamten added to background therapy and 54% of patients saw at least a one-step improvement in their NYHA Functional Class in patients with non-obstructive HCM. Cytokinetics announced that in the 48-week, 19 patient,Phase II, FOREST-HCM trial, treatment with aficamten resulted in a 32 mmHg reduction in resting LVOT-G and a 47 mmHg reduction in Valsalva LVOT-G.
Aclaris announced that in a 12-week, 95 patient, Phase IIa trial, treatment with zunsemetinib did not decrease inflammatory nodule/abscess count compared to placebo in patients with moderate to severe hidradenitis suppurativa.
Incyte discontinued the Phase 3, LIMBER-304 trial when an interim analysis found that adding parsaclisib to ruxolitinib did not reduce spleen volume compared to ruxolitinib alone in patients with myelofibrosis who had an inadequate response to treatment with ruxolitinib.
Redx announced that in the 16 patient Module 2 of the Phase II PORCUPINE2 trial, treatment with RXC004 did not result in appropriate efficacy to justify development of the drug used alone to treat biliary tract cancer.
Lilly announced 10-year follow-up data from the 4.5-year, 1,100 patient, Phase III, A4 trial, where almost six years after the end of the trial, solanezumab had not slowed the decline in cognition due to Alzheimer's disease (AD) or decreased amyloid plaque in patients with amyloid plaque but no AD symptoms. Solanezumab binds only to soluble amyloid-beta protein and was not expected to significantly remove deposited amyloid plaques.
Adicet Bio announced interim data from 16 patients enrolled in the 78 patient, Phase I, GLEAN-1 trial, where treatment with ADI-001 resulted in overall response rate (ORR) of 75% and a complete response (CR) rate of 69% in patients with relapsed/refractory B-cell non-Hodgkin lymphoma.
Published Research Updates
In the 52-week, 433 patient, Phase III, ELEVATE UC 52 trial, 27% of patients treated with etrasimod achieved remission after the 12-week induction period compared to 7% with placebo in patients with moderately-to-severely active ulcerative colitis with an inadequate or loss of response or intolerance to at least one approved ulcerative colitis therapy. After 52 weeks 32% of etrasimod patients maintained remission compared to 7% with placebo. In the 12-week, 354 patient, Phase III, ELEVATE UC 12 trial, 25% of patients treated with etrasimod achieved remission compared to 15% with placebo in patients with ulcerative colitis who had an inadequate or loss of response or intolerance to at least one approved ulcerative colitis therapy.
In the 24-week, 323 patient, Phase III, STELLAR trial, patients treated with sotatercept improved their six-minute walk distance by 34.4 meters compared to 1 meter with placebo in patients with pulmonary arterial hypertension.
In a 12-week, 415 patient, Phase IIIb trial, patients treated with gefapixant achieved a Leicester Cough Questionnaire (LCQ) Total Score of 4.34 compared to 3.59 with placebo (0.75 point improvement) in patients with recent-onset refractory chronic cough or unexplained chronic cough.
In the 142 patient, Phase III, DeFi trial, treatment with nirogacestat resulted in an 88% lower risk of disease progression compared to placebo in patients with progressive desmoid tumors.
In a 30-day, 900 patient trial, the immune response for administering a yellow-fever vaccine (YF-17D) and dengue vaccine (TAK-003) sequentially or concomitantly was non-inferior in healthy patients. The immune repose reached for DENV-1 did reach non-inferiority, but titers were similar to those observed in other TAK-003 trials.
In a 95 patient, Phase Ib trial, treatment with magrolimab plus azacitidine resulted in a complete remission rate of 33% and an overall response rate of 75% in patients with untreated higher-risk myelodysplastic syndromes.
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