Pipeline News and Updates
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Regulatory Update
The FDA approved lonapegsomatropin (Skytrofa, Ascendis Pharma), on 8/25/2021, for the treatment of inadequate secretion of endogenous growth hormone in patients one year and older who weigh at least 11.5 kg (25.4 lb). The FDA accepted the NDA for asciminib for the treatment of chronic myeloid leukemia and set a PDUFA date for 4/25/2021. The EMA approved bimekizumab for the treatment of moderate to severe plaque psoriasis. Announced Research Updates Pfizer announced that in the 26-week, 728 patient, Phase III, JADE DARE trial, more patients treated with abrocitinib 200 mg achieved at least a 4-point improvement in the severity of Peak Pruritus Numerical Rating Scale (PP-NRS4) and EASI-90 at 4-weeks compared to dupilumab in patients with moderate to severe AD who were also on background topical therapy. Published Research Updates In the 12-week, 873 patient, Phase III, ADVANCE trial, monthly migraine days were reduced by 3.7 days with atogepant 10 mg, 3.9 days with 30 mg, and 4.2 days with 60 mg compared to a 2.5 days decrease with placebo in patients with 4 to 14 migraine days per month. In a 140 patient, Phase II trial, treatment with balstilimab resulted in a 15% ORR in patients with recurrent and/or metastatic cervical cancer, who had relapsed after a prior platinum-based treatment. In a 970 patient, Phase II trial, adding veliparib to carboplatin and paclitaxel did not improve OS compared to carboplatin and paclitaxel alone (5.8 vs 5.6 months) in 553 patients who smoke and have untreated, advanced squamous non-small-cell lung cancer. In the overall population adding veliparib improved OS (12.2 versus 11.2 months), but did not improve PFS (5.6 months in both arms). In a 122 patient, Phase II trial, treatment with spartalizumab did not improve progression-free survival compared to investigator’s choice of chemotherapy (1.9 versus 6.6 months) in patients with refractory, recurrent/metastatic nasopharyngeal cancer who had progressed after a prior platinum-based chemotherapy. In the 3.4 year, 7,437 patient, Phase III, FIGARO-DKD trial, 12.4% of patients treated with finerenone experienced the composite endpoint of death from cardiovascular causes, nonfatal myocardial infarction, nonfatal stroke, or hospitalization for heart failure compared to 14.2% with placebo in type 2 diabetics and stage 2 to 4 chronic kidney disease. The benefit with finerenone was primarily from a lower incidence of hospitalization for heart failure. Regulatory Update
The FDA approved difelikefalin (Korsuva, Cara Therapeutics,Vifor Pharma) on 8/23/2021, for the treatment of moderate-to-severe pruritus associated with chronic kidney disease in adults undergoing hemodialysis. The FDA approved tick-borne encephalitis vaccine (Ticovac, Pfizer), on 8/13/2021, for the prevention of tick-borne encephalitis in individuals one year of age and older. The vaccine has been available in Europe since 1976. Pfizer bought the vaccine from Baxter in 2014. The FDA accepted the NDA for mitapivat for the treatment of pyruvate kinase (PK) deficiency and set a PDUFA for 2/17/2022 The FDA and EMA have accepted the BLA for tebentafusp for the treatment of HLA-A*02:01-positive adult patients with metastatic uveal melanoma (mUM). The FDA set a PDUFA date for 2/23/2022 The EMA approved roxadustat to treat anemia in both non-dialysis-dependent and dialysis-dependent chronic kidney disease patients. Stealth BioTherapeutics submitted an NDA for elamipretide for the treatment of Barth syndrome. Announced Research Updates Coherus BioSciences and Junshi Biosciences announced interim results from 218 patients enrolled in the 465 patient, Phase III, CHOICE-01 trial, where adding toripalimab to chemotherapy resulted in PFS of 8.3 months compared to 5.6 months with chemotherapy alone in patients with advanced squamous or non-squamous non-small cell lung cancer. Published Research Updates ICER estimates an annual cost for mavacamten of $12,513 for a threshold of $100,000 per QALY and $15,451 for a threshold of $150,000 per QALY. In beginning their calculations, ICER used a placeholder price of $75,000 per year based on an analyst’s projection for mavacamten. ICER estimated the annual cost for competing therapies as $8,559 for disopyramide plus dose initiation hospitalization, $122,750 for myectomy and $55,706 for septal ablation. The cost for metoprolol and verapamil were < $70 per year. In a 38 patient, Phase II, open-label trial, treatment with camrelizumab plus famitinib resulted in an overall response rate of 60.5% in Chinese patients with advanced or metastatic renal cell carcinoma. In the 12-week, 285 patient, Phase III, JADE TEEN trial, the IGA endpoint was achieved by 46.2% of patients treated with abrocitinib 200 mg and 41.6% with 100 mg compared to 24.5% with placebo in patients 12 to 17 years of age with moderate to severe AD who also received topical therapy. EASI-75 was achieved by 72% of patients who received abrocitinib 200 mg and 68.5% with 100 mg compared to 41.5% with placebo. In a 12-week, 79 patient, Phase IIa Trial, 57.3% of patients treated with bimekizumab had a 50% or greater decrease in their Hidradenitis Suppurativa Clinical Response (HiSCR50) score compared to 26.1% with placebo in patients with hidradenitis suppurativa. HiSCR75 was achieved by 46% of bimekizumab patients and 32% achieved HiSCR90 compared to 35% and 15% with adalimumab and 10% and 0 with placebo. In the 14.9 month, 233 patient, Phase III, open-label, ASCEMBL trial, 25.5% of patients treated with asciminib achieved a major molecular response (MMR) rate compared to 13.2% with bosutinib in patients with chronic myeloid leukemia in chronic phase who were resistant or intolerant to two or more tyrosine kinase inhibitors. In a long-term follow-up, of at least 35-months, of patients enrolled in the L-MIND trial, treatment with tafasitamab plus lenalidomide resulted in an overall response rate of 57.5%, which included a complete response in 40% of patients. Overall survival was 33.5 months and progression-free survival was 11.6 months. In a 12-month, 42 patient, Phase II/III trial, patients treated with arimoclomol slowed disease progression with a 0.76 point increase in the NPC Clinical Severity Scale (NPCCSS) compared to 2.15 increase with placebo in patients, age 2-18 years with Niemann-Pick Type C disease (NPC). In patients receiving miglustat, the addition of arimoclomol reduced the increase in NPCCSS by 2.06 points. In a 29-day, 21 patient, open-label, dose-escalation, Phase II trial, treatment with a single dose of cipargamin 150 mg resulted in PCR-corrected and uncorrected adequate clinical and parasitological response (ACPR) of 75% at 14-days and 65% at 28-days, which was less than artemether-lumefantrine (> 90% at both time periods) in sub-Saharan African patients with malaria. In the 90 patient, Phase III, MAPP1 trial, patients treated with MDMA-assisted psychotherapy had a 24.4 point decrease in their Clinician-Administered PTSD Scale (CAPS-5) compared to a 13.9 point decrease with psychotherapy alone in patients with severe PTSD. In an analysis of 568 patients from the SAKURA trials, four-weeks after the first injection of daxibotulinumtoxinA, 57.9% as judged by patients and 64,8% as judged by investigors, had no static Glabellar lines (GL). After a second injection 68.1% and 75% reported no GL and 71.5% and 77.6% after the third treatment in patients with mild and moderate static Glabellar lines. In the 482 patient, Phase III SEAMLESS trial, treatment with sapacitabine plus decitabine did not improve overall survival compared to decitabine alone in elderly patients with newly diagnosed acute myeloid leukemia. Regulatory Update
The FDA approved belzutifan (Welireg, Merck), on 8/13/2021, to treat von Hippel-Lindau (VHL) disease for patients who require therapy for associated renal cell carcinoma, central nervous system hemangioblastomas, or pancreatic neuroendocrine tumors, not requiring immediate surgery. The FDA agreed with the Advisory Committee recommendation and rejected AstraZeneca’s and FibroGen’s roxadustat for the treatment of anemia in patients with chronic kidney disease and requested a new efficacy trial. The FDA rejected Sesen Bio’s oportuzumab monatox, for the treatment of BCG-unresponsive non-muscle invasive bladder cancer, and requested additional clinical and manufacturing data. In August 2021, the FDA delayed the PDUFA for Merck’s gefapixant, from December 2021 to March 2022, to allow more time for a full review of the drug. Ipsen withdrew the NDA for palovarotene to allow time for additional analyses and evaluation of data. The FDA has placed a hold for a clinical trial evaluating Aprea Therapeutics’ eprenetapopt with acalabrutinib or with venetoclax and rituximab for the treatment of lymphoid malignancies. Three trials evaluating eprenetapopt in combination with azacitidine for the treatment of myelodysplastic syndrome has also been put on hold. Announced Research Updates The Department of Veterans Affairs will not include aducanumab on its national formulary due to safety and efficacy concerns. Use of the drug is restricted to specific patients when prescribed by dementia experts. Biogen is restricted from promoting the drug to VA prescribers. Lilly announced 16-week results from the 52-week, Phase III, ADvocate 1 and ADvocate 2 trials, where more patients treated with lebrikizumab achieved an Investigator Global Assessment (IGA) score of clear or almost clear skin with a 2-point or greater improvement in the IGA score and a 75% or greater improvement in their EASI score compared to placebo in patients with moderate-to-severe atopic dermatitis. Travere announced interim results after 36-weeks from the first 280 patients enrolled in the Phase III, PROTECT trial, where treatment with sparsentan reduced the urine protein-to-creatinine ratio by 49.8% compared to a 15.1% decrease with irbesartan in IgA nephropathy (IgAN) patients with persistent proteinuria despite active ACE or ARB treatment. Travere plans to file an NDA and MAA in the first half of 2022. Published Research Updates In the 52-week, 1,444 patient, Phase III SURPASS-3 trial, treatment with tirzepatide reduced HbA1c by 1.93% with 5 mg, 2.2% with 10 mg and 2.37% with 15 mg compared to 1.34% with insulin degludec in insulin-naive patients with type 2 diabetes and inadequate glycemic control on stable doses of metformin with or without an SGLT-2 inhibitor.The reduction in HbA1c met the criteria for non-inferiority. Tirzepatide also decreased bodyweight from 7.5 kg to 12.9 kg compared to gain of 2.3 Kg with insulin degludec. In the three-month, 2,199 patient, Phase III, CONCERTO trial, treatment with laquinimod did not improve the time to confirmed disease progression compared to placebo in patients with relapsing-remitting multiple sclerosis. In an 8-week, 25 patient, open-label, phase II trial, treatment with remetinostat 1% gel resulted in at least a 30% decrease in tumor diameter in 70% of tumors and complete resolution in 54.8% of tumors in patients with basal cell carcinoma. Regulatory Update
The FDA approved avalglucosidase alfa (Nexviazyme, Genzyme), on 8/6/2021, to treat patients 1 year of age and older with late-onset Pompe disease. The FDA rejected the BLA for Spectrum Pharmaceuticals’ eflapegrastim due to deficiencies associated with the manufacturing of the drug. The FDA placed a hold on Bluebird Bio’s elivaldogene autotemcel cerebral adrenoleukodystrophy (CALD) studies in August 2021, when a clinical trial patient developed myelodysplastic syndrome. Marinus submitted an NDA for ganaxolone to treat seizures associated with CDKL5 deficiency disorder. Announced Research Updates BeyondSpring announced that in the 559 patient, Phase III DUBLIN-3 trial, treatment with plinabulin plus docetaxel improved overall survival compared to docetaxel alone in patients with non-small cell lung cancer (NSCLC) with EGFR wild type. Dicerna announced that in the six-month, 35 patient, Phase II, PHYOX2 trial, treatment with nedosiran reduced urinary oxalate excretion 57.5% more than placebo in patients with primary hyperoxaluria (PH) type 1 and 2. Reduction in urinary oxalate excretion in 29 PH1 patients (23 nedosiran and 12 placebo) was significant, but not in six PH2 patients (5 nedosiran and 1 placebo). Published Research Updates ICER provided a final evidence report for aducanumab in early August 2021. In the report ICER found the evidence to be insufficient to support a slowing of cognitive decline in patients with mild disease. The report also stated that efficacy was not shown in patients with moderate to severe disease and no previous amyloid reducing drug trials have shown a benefit in moderate to severe disease. Most of the positive benefit identified in ENGAGE and EMERGE were from post-hoc analyses, so there is a reduction in the applicability of the findings, due to loss of randomization. ICER also noted that ARIA was seen in over a third of patients and questions whether it can be adequately monitored in practice. ICER estimates the cost-effective range of $2,950 to $8,360. ICER warns that care should be taken in the promotion of aducanumab to ensure that patients and families understand that aducanumab may slow the decline in cognition, but it will not improve cognition or quality of life. In a 52-week, 119 patient extension of a 52-week, 121 patient, Phase III trial, patients treated for two-years with vosoritide achieved an increase in annualized growth velocity of 1.13 cm/year in the first year and by 1.26 cm/year after 2 years. Patients that were switched from placebo for the first year to vosoritide in the second year had a decrease in annualized growth velocity of 0.35 cm/year in the first year (on placebo), but increased growth velocity by 1.27 cm/year after 2 years (on vosoritide). Interim data from a 289 patient, Phase III, trial, suggested that 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. In the 476 patient, open label Phase III, VOYAGER trial, progression-free survival was no different with avapritinib compared to regorafenib in patients with gastrointestinal stromal tumors and a PDGFRA D842V-mutations. In the 24-week, 257 patient, Phase , GENETIC-AF trial, treatment with bucindolol resulted in cumulative atrial fibrillation burden of 24.4% compared to 36.7% with metoprolol in patients with heart failure and the ADRB1 Arg389Arg genotype. In the 428 patients, 12-week, Phase III, CREDO 1 trial, ACR20 was achieved by 63.6% of patients treated with olokizumab every two weeks and 70.4% of patients that received olokizumab every four weeks compared to 25.9% with placebo in patients with rheumatoid arthritis inadequately treated with methotrexate. In the 4-week, 57 patient, Phase II, PaTH Forward trial, 50% of patients treated with TransCon PTH achieved the composite endpoint (normal serum calcium, normal spot morning fractional excretion of calcium, not receiving vitamin D supplants and receiving less than 1000 mg/day of calcium) compared to 15% in the placebo group in patients with hypoparathyroidism. In a 24-month, 49 patient, open-label extension of the PaTH Forward trial, all patients received TransCon PTH with 71% achieving the composite endpoint. In the ARIOS follow-up study of women being treated for spontaneous preterm labor, 49 infants whose mother had received retosiban were compared to 49 infants whose mother had received placebo or atosiban from two Phase III trials that were terminated early due to poor enrollment. Infants from the retosiban group had fewer serious adverse events (12.2% vs 6.1%). Neurodevelopmental delay was also less frequent at 18 months (0 vs 31.8%) and 24 months (8% vs 14.3%). In a 608 patient, Phase III trial, entinostat plus exemestane did not improve overall survival or progression-free survival in patients with advanced hormone receptor positive, human epidermal growth factor receptor 2 negative (HR+, HER2-) breast cancer that had progressed on a non-steroidal aromatase inhibitor. Regulatory Update
The FDA approved anifrolumab (Saphnelo, AstraZeneca), on 8/2/2021, for the treatment of moderate to severe systemic lupus erythematosus (SLE). Anifrolumab will compete with belimumab (Benlysta). The FDA accepted the BLA for Roche’s faricimab for the treatment of neovascular, age-related macular degeneration (AMD) and diabetic macular edema (DME) suggesting a PDUFA date of 1/28/2022. The EMA gave PRIME status to Mustang Bio’s MB-107 for the treatment of X-linked severe combined immunodeficiency in newly diagnosed infants. Announced Research Updates A new draft report from ICER reviewing efgartigimod and eculizumab for the treatment of myasthenia gravis found moderate certainty of a comparable, small, or substantial net health benefit for efgartigimod compared to eculizumab due to uncertainties about dosing and long-term benefits. When estimating pricing ICER found the drugs to be cost effective at an estimated price of $21,800 for efgartigimod and $19,500 for eculizumab to achieve a $150,000 per quality of adjusted life year (QALY). This compares to the current list price of $653,100 with a discounted price of $470,000 for eculizumab Published Research Updates In a 14.7 month, 31 patient, open-label, Phase II trial, treatment with penpulimab plus anlotinib resulted in an objective response rate of 31% in Chinese patients with unresectable hepatocellular carcinoma. All seven members of the FDA Peripheral and Central Nervous System Drugs Advisory Committee (AdComm), which reviewed and rejected aducanumab, published a Perspective in NEJM that questioned the criteria used to justify approval of aducanumab. The AdComm pointed out that approval was based on a reduction of beta-amyloid that was measured through positron-emission tomographic brain imaging. The committee found available clinical evidence from trials to not support lowered beta-amyloid as a prediction of clinical benefit. The AdComm did not find a single positive study as justification for clinical benefit. They also reiterate the FDA’s statistical review of EMERGE and ENGAGE failed to find evidence that amyloid changes correlated with cognitive or functional changes. Aducanumab labeling does not require verification of elevated beta-amyloid despite the FDA basing approval on beta-amyloid reduction. This becomes an important issue since almost half of patients with mild cognitive impairment that are being assessed for Alzheimer’s disease do not have elevated levels of beta-amyloid.
Four FDA officials involved in the approval of aducanumab supplied a rebuttal to the Peripheral and Central Nervous System Drugs Advisory Committee Perspective in NEJM in the same issue of the journal. The FDA officials argue that use of beta-amyloid as a surrogate marker was justified due to more recent studies demonstrating that larger decrease in amyloid plaque correlates with the effect on clinical end points. They point out that while earlier studies of amyloid reducing drugs did not demonstrate a clinical benefit, the products used had little or no effects on amyloid plaque. The decision to approve aducanumab under an Accelerated Approval was justified because they judged the drug to be “reasonably likely” to predict clinical benefit”. There was no explanation for approval without requiring establishment of amyloid plaque nor the reason for disagreeing with the FDA Biostatistical Review. Data that supports a beneficial response in relation to plaque reduction is not currently published. We have updated our review of aducanumab and the revised report can be downloaded on our sample drug review web page. In addition to the information above, we have added live links for all references in our review. Our mission at Prescribe Right is to offer budget-friendly products that provide the information you need to proactively plan for budget-busting drugs. Due to the financial pressure from the pandemic, we are offering a new reduced rate to help keep our subscribers financially healthy. OUR NEW LOWER annual subscription for all searching functionality to our comprehensive, unbiased, verifiable knowledgebase is $675 and includes access to our New Drug Reviews for drugs with PDUFA dates. |
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