An FDA review of Incyte’s retifanlimab questioned whether there was enough safety and efficacy data to support approval. The FDA’s Oncologic Drugs Advisory Committee agreed and voted 13-4 to recommend the FDA delay approval of retifanlimab until additional clinical evidence is available.
The FDA accepted the NDA for Alnylam’s vutrisiran for the treatment of the polyneuropathy of hereditary transthyretin-mediated (hATTR) amyloidosis and set a PDUFA date for 4/14/2022.
EMA’s human medicines committee (CHMP) recommended approval of UCB’s bimekizumab to treat plaque psoriasis, FibroGen’s and AstraZeneca’s roxadustat to treat CKD anemia, and BioMarin’s vosoritide to treat achondroplasia.
Announced Research Updates
The FDA released documents related to the internal discussion on approval of aducanumab. The Office of Neuroscience supported accelerated approval, while the Office of Biostatistics did not. Senior FDA officials agreed with the Office of Neuroscience and approved the drug, based on the results of the higher dose cohort of the EMERGE trial and discounting the results from the ENGAGE trial. The FDA also based the decision on an analysis of six trials of Alzheimer’s drugs that reduce amyloid and demonstrated a relationship for plaque reduction and a beneficials clinical effect. That analysis has not been released and neither was the full statistical review.
UniQure announced that in the 52-week, 54 patient, Phase III, HOPE-B trial, a single dose of etranacogene dezaparvovec increased Factor IX activity from less than 2% at baseline to 39% at 26-weeks and 41.5% at 52-weeks in adult males with severe or moderate-severe Hemophilia B. The annualized rate of bleeding requiring treatment was reduced from 3.39 at baseline to 0.68 bleeding episodes. 96% of patients were able to discontinue Factor IX replacement therapy.
LSKB and Hengrui announced that in the 190 patient, open-label, Phase II, RESCUE trial, treatment with camrelizumab and apatinib resulted in overall survival of 20.1 months in previously untreated hepatocellular carcinoma patients and 21.8 months in patients receiving the combination as second-line treatment. The primary outcome of the RESCUE trial, objective response rate, was not reported.
Agios announced that in a 24-week, 20 patient, Phase II, open-label trial, 80% of patients treated with mitapivat lead to a 1 g/dL or > increase in hemoglobin in five patients with alpha thalassemia and 15 with beta thalassemia who were not transfusion-dependent.
Corbus announced that in the 28-week, 175 patient, Phase III, DETERMINE trial, adding lenabasum to standard treatment did not improve the Total Improvement Score compared to placebo in patients with active classic or amyopathic dermatomyositis.
Gilead announced that in the 120-week, 175-patient, Phase IIb, MYR204 trial, 24-weeks after the end of treatment, more patients treated with bulevirtide 2 mg plus pegylated interferon alpha 2a (PEG-IFN alpha), bulevirtide 10 mg plus PEG-IFN and bulevirtide 10 mg alone achieved at least a 2 log decrease or undetectable levels of hepatitis D (HDV) RNA and normalization of ALT levels compared to PEG-IFN alone in patients with chronic HDV. Gilead announced interim results after 24-weeks in the 48-week, 150 patient, Phase III, MYR301 trial, where 36.7% of patients treated with bulevirtide 2 mg and 28% of patients that received bulevirtide 10 mg achieved at least a 2 log decrease or undetectable levels of HDV RNA and normalization of ALT levels compared to 0% of untreated chronic HDV patients.
Fulcrum announced that in the 48-week, 80 patient, Phase IIb ReDUX4 trial, where treatment with losmapimod did not change DUX4-driven gene expression in affected skeletal muscle biopsies at 16 or 24 weeks compared to placebo in patients with facioscapulohumeral muscular dystrophy.
Madrigal announced interim results from 115 patients enrolled in the 52-week, 1,200 patient, Phase III, MAESTRO-NAFLD-1 trial, where treatment with resmetirom reduced the MRI-proton density fat fraction (MRI-PDFF) and fibrosis compared to placebo in patients with non-cirrhotic NASH.
Italfarmaco announced that in a 12-month, 51 patient, Phase II trial, treatment with givinostat did not decrease muscle fibrosis, but did decrease fat infiltration compared to placebo in patients with Becker Muscular Dystrophy. Givinostat did not demonstrate an improvement in functional status compared to placebo.
AstraZeneca and Sanofi announced that in the 150-day, 925 patient, Phase II/III, MEDLEY trial, nirsevimab was similar to palivizumab in the development of adverse events in healthy infants at high risk of respiratory syncytial virus entering their first RSV season.
Orphazyme announced interim data from an open-label extension of a 41 patent, Phase II/III Niemann-Pick disease trial, where 33 patents completed an additional 24-months of treatment. Patients that received arimoclomol for a total of 36-months had an increase in their NPC-CSS score of 3.5 points compared to an estimated 5.2 point increase in patients that received routine clinical care.
Published Research Updates
In a 70 patient, open-label Phase II trial, treatment with savolitinib for a mean 17.6 months resulted in an objective response rate of 42.9% in patients with locally advanced or metastatic METex14-positive pulmonary sarcomatoid carcinoma.
In the 831 patient, open-label, Phase III, VISION trial, patients treated with Lu-PSMA-617 plus standard of care achieved progression free survival of 8.7 months and overall survival of 15.3 months compared to 3.4 months and 11.3 months with standard of care alone in patients with advanced stage PSMA-positive metastatic castration-resistant prostate cancer previously treated an androgen inhibitor and taxane.
In a 263 patient, Phase III trial, treatment with camrelizumab plus gemcitabine and cisplatin improved progression-free survival to 9.7 months compared to 6.9 months with gemcitabine and cisplatin alone in Chinese patients with recurrent or metastatic nasopharyngeal carcinoma.
In the 40-week, 475 patient, Phase III SURPASS-5 trial, treatment with tirzepatide reduced HbA1C by 2.01% with 5 mg, 2.24% with 20 mg and 2.3% with 15 mg compared to a 1.86% decrease with semaglutide in patients with type 2 diabetes. Tirzepatide decreased body weight more than semaglutide by 1.9 kg with 5 mg, 3.6 kg with 10 mg and 5.5 kg with 15 mg.
The FDA rejected arimoclomol as a treatment for Niemann-Pick disease type C and requested additional safety and efficacy data. The FDA requested additional efficacy evidence beyond the single Phase II/III trial and data to support use of the 5-domain NPC Clinical Severity Scale (NPCCSS) as a primary endpoint.
The FDA accepted the BLA for Agenus’ balstilimab for the treatment of recurrent/metastatic cervical cancer and set a PDUFA date for 12/16/2021.
The FDA designated Lu-PSMA-617 a Breakthrough Therapy for the treatment of metastatic castration-resistant prostate cancer.
Announced Research Updates
Sage and Biogen announced that in the 15-day, 543 patient, Phase III, WATERFALL trial, patients treated with zuranolone for 15 days had a 14.1 point decrease in their HAMD-17 total score compared to a 12.3 point decrease with placebo in patients with major depressive disorder, who had a HAMD-17 score of 24 or greater. At day 42, the difference between zuranolone and placebo were no longer significant.
Biogen announced that in the 12-month, Phase III, STAR trial, treatment with timrepigene emparvovec did not improve the number of patients that achieved an improvement of at least 15 letters in best corrected visual acuity (BCVA) as measured by the Early Treatment Diabetic Retinopathy Study (ETDRS) chart compared to placebo in patients with choroideremia.
Actinium announced interim data from 113 patients in the 150 patient, Phase III, SIERRA trial, where 100% of patients treated with Iomab-B achieved successful engraftment of allogeneic hematopoietic stem cell transplant compared to 18% that received salvage chemotherapy in patients with active, relapsed or refractory acute myeloid leukemia.
Jiangsu HengRui announced that in a 67 patient, Phase II trial, treatment with pyrotinib plus trastuzumab, docetaxel and carboplatin resulted in a complete response rate of 71.4% compared to 36.7% trastuzumab, docetaxel and carboplatin alone in Chinese patients with stage 2-3 HER2-positive breast cancer and invasive carcinoma.
Aprea Therapeutics announced that in a 30 patient, Phase I/II trial, treatment with eprenetapopt plus azacitidine and venetoclax resulted in a complete response rate of 37% in patients with TP53 mutant AML.
Published Research Updates
In the 12-month, 131 patient, Phase III, PolarisDMD trial, treatment with edasalonexent did not improve the North Star Ambulatory Assessment (NSAA) compared to placebo in patients with Duchenne muscular dystrophy (DMD).
In the 24-month, 196 patient, Phase II, ADAMANT trial, treatment with AADvac1 did not differ from placebo in cognitive and functional tests in patients with mild AD. In a subgroup of patients with confirmed Alzheimer's disease biomarker profile, AADvac1 slowed the decline in cognitive and functional tests compared to placebo.
In the 26-week, 167 patient, Phase III, ADAPT trial, 68% of patients treated with efgartigimod achieved at least a 2-point improvement in their Myasthenia Gravis Activities of Daily Living (MG-ADL) score for four consecutive weeks compared to 30% with placebo in patients with myasthenia gravis on a stable drug regimen.
In the 24-week, 107 patient, Phase II, IMbark trial, 10.2% of patients treated with imetelstat achieved a ≥35% reduction in spleen volume and 32.2% achieved a ≥50% reduction in their Total Symptom Score, at in intermediate-2 or high-risk myelofibrosis patients who are relapsed or refractory to a Janus Kinase inhibitor.
After 144 patients were treated for four to seven years in the DIAN-TU trial, treatment with gantenerumab did not reduce the decline in cognitive function, but did demonstrate a reduction in amyloid plaques, cerebrospinal fluid total tau, and phospho-tau181 and attenuated increases of neurofilament light chain. The solanezumab patients had a larger cognitive decline on some measures but did not demonstrate a reduction in biomarkers.
The FDA extended the PDUFA date for lonapegsomatropin, by three months, in order to review recently submitted information. The new target date is 9/25/2021.
The FDA designated etrasimod an Orphan Drug for the treatment of eosinophilic esophagitis.
Announced Research Updates
Sanofi announced that in the 26-week, 42 patient, Phase III, CADENZA trial, 16/22 (73%) patients treated with sutimlimab achieved an increase in hemoglobin of at least 1.5 g/dL and received no transfusions or other treatment for cold agglutinin disease.
AstraZeneca announced that in the 80 patient, open-label, Phase II, EFFORT trial, treatment with adavosertib plus olaparib resulted in an objective response rate of 29% compared to a 23% rate with adavosertib alone in patients with poly(ADP-ribose) polymerase (PARP) inhibitor-resistant ovarian cancer.
Published Research Updates
In an 89 patient, open-label, Phase II trial, treatment with indoximod plus pembrolizumab, resulted in an overall response rate of 51% and progression-free survival of 12.4 months in patients with non-ocular melanoma.
In a 56-week, 137 patient, Phase III, trial, treatment with delgocitinib reduced the mEASI score compared to placebo after the 4-week blinded phase (-39.3% vs +10.9%) and the improvement was maintained during a 52-week extension in Japanese pediatric patients with atopic dermatitis.
The FDA approved the combination of olanzapine and samidorphan (Lybalvi, Alkermes), on 6/1/2021, for the treatment of schizophrenia and bipolar 1 disorder. Olanzapine and samidorphan were approved with a Black-Box warning regarding increased risk of mortality in elderly patients with dementia-related psychosis.
The FDA approved ibrexafungerp (Brexafemme, Scynexis), on 6/2/2021, for the treatment of vulvovaginal candidiasis in adults and post-menarchal pediatric females.
The FDA accepted the NDA for BeyondSpring’s plinabulin to be used in combination with a granulocyte colony-stimulating factor for the prevention of chemotherapy-induced neutropenia and set a PDUFA date for 11/30/2021.
The FDA accepted the NDA for CTI BioPharma’s pacritinib to treat myelofibrosis with severe thrombocytopenia and set a PDUFA date for 11/30/2021.
The FDA accepted the NDA for Akebia’s and Otsuka’s vadadustat for the treatment of anemia due to chronic kidney disease in both dialysis dependent and non-dependent patients and set a PDUFA date for 3/29/2021.
The FDA accepted the NDA for Amryt’s oleogel-S10 for the treatment of the cutaneous manifestations of Junctional and Dystrophic Epidermolysis Bullosa and set a PDUFA date for 11/30/2021.
AB Science is suspending clinical trials of masitinib to investigate the drug’s potential risk of ischemic heart disease, which was identified in a retrospective analysis of clinical data.
Liminal discontinued development of fezagepras for the treatment of Idiopathic pulmonary fibrosis and hypertriglyceridemia after disappointing pharmacokinetic studies.
Dermavant submitted an NDA for tapinarof cream for the treatment of plaque psoriasis.
Announced Research Updates
Santhera and ReveraGen announced that in the 24-week, 121 patient, Phase IIb, VISION-DMD trial, patients treated with vamorolone 6 mg/kg/day improved the time from supine positioning to standing by 1.4 seconds compared to a 0.1 second deterioration with placebo in boys aged 4 to 7 years with Duchenne muscular dystrophy.
Novartis announced that in the 831 patient, open-label, Phase III, VISION trial, patients treated with Lu-PSMA-617 plus standard of care achieved progression free survival of 8.7 months and overall survival of 15.3 months compared to 3.4 months and 11.3 months with standard of care alone in patients with advanced stage PSMA-positive metastatic castration-resistant prostate cancer.
Coherus BioSciences and Junshi Biosciences announced interim results from the 289 patient, Phase III, JUPITER-02 trial, where patients treated with toripalimab plus gemcitabine and cisplatin followed by toripalimab maintenance therapy achieved progression-free survival of 11.7 months compared to 8 months with gemcitabine and cisplatin alone followed by placebo maintenance treatment in Chinese patients with recurrent or metastatic nasopharyngeal carcinoma.
Biosight announced interim data from 46 patients enrolled in a Phase IIb trial, where treatment with aspacytarabine resulted in a 39% complete response rate in patients with acute myeloid leukemia who are not eligible for standard induction chemotherapy due to advanced age or comorbidities.
BeiGene announced results from the 512 patient, open-label, Phase III, Chinese RATIONALE 302 trial, where treatment with tislelizumab improved overall survival compared to investigator’s choice of paclitaxel, docetaxel or irinotecan (8.6 months vs 6.3 months) in patients with advanced unresectable or metastatic esophageal squamous cell carcinoma.
LSKB and Hengrui announced that after 10.8 months in the 596 patient, Phase II, ESCORT-1st trial, treatment with camrelizumab plus paclitaxel and cisplatin resulted in overall survival of 15.3 months and progression-free survival of 6.9 months compared to 12 months and 5.6 months with paclitaxel and cisplatin alone in Chinese patients with untreated advanced or metastatic esophageal squamous cell carcinoma.
Legend Biotech announced data after 18-months in the 97 patient, Phase Ib/II, open-label, CARTITUDE-1 trial, where ciltacabtagene autoleucel demonstrated an overall response rate of 98% and complete response of 80% in patients with relapsed multiple myeloma. Legend Biotech announced interim data from 20 patients after 5.8 months in the 120 patient, Phase II, open-label, CARTITUDE-2 trial, where ciltacabtagene autoleucel demonstrated an overall response rate of 95% and complete response of 75% in patients with progressive multiple myeloma after 1-3 prior lines of therapy, who were refractory to lenalidomide. The FDA accepted the BLA for ciltacabtagene autoleucel for the treatment of relapsed and/or refractory multiple myeloma and set a PDUFA date for 11/29/2021.
Published Research Updates
In the 24-week, 424 patient, Phase III, DOLOMITES trial, 89.5% of patients treated with roxadustat achieved hemoglobin of at least 11.0 g/dL and hemoglobin change from baseline of at least 1.0 g/dL compared to 78% that received darbepoetin in non-dialysis-dependent CKD patients with anemia.
The 58-week, 1,348 patient, Phase IIb/III, SELECTION trial evaluated filgotinib as a treatment of moderately to severely active ulcerative colitis. During the 10 week induction phase of the trial patients received filgotinib 100 mg, 200 mg or placebo. Treatment with filgotinib 100 mg did not differ from placebo in the percentage of patients achieving remission. However, compared to placebo remission was achieved in more biologic-naive patients treated with filgotinib 200 mg (26.1% vs. 15.3%) and in biologic-experienced patients (11.5% vs. 4.2%). The 664 patients that achieved remission were re-randomized to filgotinib or placebo for an additional 48 weeks. In the maintenance part of the trial, 37.2% of patients treated with filgotinib 200 mg and 23.8% that received 100 mg maintained clinical remission compared to 11.2% with placebo.
In the 24 week, 1,315 patient, Phase III MINDSET study, adding intepirdine to donepezil did not improve the ADAS-Cog or ADAS-ADL scores compared to donepezil alone in patients with mild-to-moderate Alzheimer’s disease dementia.
The FDA approved aducanumab (Aduhelm, Biogen) for the treatment of Alzheimer’s Disease. Use of aducanumab was not limited to patients with early Alzheimer’s, similar to the patient populations in the ENGAGE and EVOLVE trials. Rather it was approved for use in any patient with Alzheimer’s disease.
The prescribing information for aducanumab contains a warning for amyloid-related imaging abnormalities (ARIA). ARIA usually presents as transient, symptomatic swelling in the brain. But some patients may develop headache, confusion, dizziness, vision changes, or nausea with ARIA. In addition to ARIA, the most common adverse effects include headache, fall, diarrhea, and confusion/delirium/altered mental status/disorientation.
A review by the FDA’s Division of Neurology concluded that positive data from Emerge and a Phase II trial provided substantial evidence of effectiveness to support approval of aducanumab. However, a review by the FDA’s Office of Biostatistics concluded that a new trial was needed, because of the conflicting evidence seen in EMERGE and ENGAGE.
The FDA Peripheral and Central Nervous System Drugs Advisory Committee voted 0 yes, 10 no and 1 uncertain on whether there was enough evidence to recommend approval of aducanumab for the treatment of Alzheimer’s disease in November 2020. The FDA extended the review date for aducanumab by three months (March to June) to allow additional time to review new data Biogen had submitted to satisfy an FDA information request.
As part of the approval, the FDA is requiring Biogen, to conduct a new clinical trial to verify the aducanumab’s clinical benefit.
Biogen set the annual price for aducanumab at $56,000 a year, which is much higher than ICER’s cost effectiveness estimates of $2,500 to $8,300. ICER estimated that even in the most optimistic case, where only data from the positive EMERGE trial is used, the limited cognitive improvement would only support a price range of $11,100 to $23,100 per year.
The Prescribe Right Pharmaceutical Pipeline Tracker added drug reviews for drugs with PDUFA dates this spring. In our review of aducanumab, we give an in-depth analysis of the ENGAGE and EMERGE trials, the discontinuation of the trials after a futility analysis, their resurrection after a new analysis, the FDA review of the clinical data and the limitations of current Alzheimer’s therapy. We also include a review of adverse effects, votes by the FDA Peripheral and Central Nervous System Drugs Advisory Committee, an editorial in JAMA by three committee members, a look at the cost of other biologic drugs to treat neurological conditions and a summary of the ICER cost effectiveness analysis. As always, the source references for the review are included along with summaries of each article. As a subscriber, you will have access to these reviews, along with monographs for over 900 drugs to allow you to know what is coming, be ready to discuss controversial new drugs and plan for budget busting new therapies.
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The FDA approved sotorasib (Lumakras, Amgen), on 5/28/2021, for the treatment of non-small cell lung cancer with a KRAS G12C mutation in patients who have received at least one prior systemic therapy. Amgen has set WAC at $17,900 per month for sotorasib.
The FDA approved infigratinib (Truseltiq, QED Therapeutics), on 5/28/2021, for the treatment of previously treated locally advanced or metastatic cholangiocarcinoma harboring an FGFR2 fusion or rearrangement.
An FDA review of teplizumab found that evidence to support efficacy came from a single small trial, but supported approval given the lack of treatments for a severe and rare disease. The analysis verified available data showing a delay in the onset of Type 1 diabetes in patients treated with teplizumab. The FDA’s Endocrinologic and Metabolic Drugs Advisory Committee voted 10-7 to recommend approval of teplizumab for the delay of Type 1 diabetes in at-risk patients. The AdComm had concerns regarding the small size of the study and the lack of follow-up after patients developed diabetes.
The FDA accepted the NDA for Mezzion’s udenafil to improve exercise capacity in patients with single ventricle heart disease who have undergone a Fontan operation and set a PDUFA date for 3/22/2022.
The FDA has accepted the BLA for ublituximab to be used in combination with umbralisib in the treatment of patients with chronic lymphocytic leukemia and small lymphocytic leukemia and set a PDUFA date for 3/25/2022.
The FDA accepted the NDA for palovarotene for the prevention of heterotopic ossification in fibrodysplasia ossificans progressiva (FOP) and set a PDUFA date for 11/30/2021.
The FDA informed Travere that interim data from the Phase III DUPLEX trial was not enough to support approval. Travere hopes to file an NDA in the first half of 2022 with full data from the DUPLEX trial. Travere plans to submit an MAA by the end of 2021.
The EMA’s CHMP recommended approval of odevixibat for the treatment of progressive familial intrahepatic cholestasis.
Announced Research Updates
EQRx announced interim data from the Phase III GEMSTONE-301 trial, where treatment with sugemalimab prolonged progression-free survival compared to placebo in Chinese patients with locally advanced/unresectable Stage III NSCLC without disease progression after concurrent or sequential chemoradiotherapy.
AB Science announced that in the 60-month, 580 patient, Phase III, AB12003 trial, treatment with masitinib plus docetaxel resulted in progression free survival at 12, 18 and 24 months of 32.0%, 27.6% and 23.1% compared to 19.6%, 14.6%, and 12.0% with docetaxel alone in patients with metastatic Castrate Refractory Prostate Cancer.
NGM announced that in the 24-week 171 patient, Phase IIb, ALPINE 2/3 trial, treatment with aldafermin did not improve liver fibrosis by one or more stages with no worsening of steatohepatitis in patients with non-alcoholic steatohepatitis and stage 2 or 3 liver fibrosis. NGM discontinued development of aldafermin for the treatment of non-alcoholic steatohepatitis after failure of the ALPINE 2/3 trial.
Published Research Updates
In the 332 patient, open-label, Chinese, Phase III, RATIONALE 304 trial, treatment with tislelizumab plus pemetrexed and either carboplatin or cisplatin resulted in PFS of 9.7 months compared to 7.6 months with pemetrexed plus carboplatin or cisplatin alone in patients with advanced non-squamous non-small cell lung cancer.
In the 313 patient, Chinese, Phase III, ACTIVE trial, treatment with apatinib plus gefitinib resulted in progression-free survival of 13.7 months compared to 10.2 months with gefitinib alone in treatment-naive patients with stage IIIB/IV non-squamous non-small cell lung cancer with an EGFR-mutation.
In a six-week, 281 patient, Phase III trial, 53.9% of patients treated with sofpironium achieved a Hyperhidrosis Disease Severity Score (HDSS) score of 1 or 2 and a 50% or more reduction in total gravimetric weight of sweat compared to 36.4% with placebo in Japanese patients with primary axillary hyperhidrosis. All patients received sofpironium in a 52-week, 161 patient extension of the trial, where 57.4% of patients that switched from placebo to sofpironium achieved an HDSS score of 1 or 2 and a 50% or more reduction in total gravimetric weight of sweat compared to 58.2% that continued treatment with sofpironium.
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