Pipeline News and Updates
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Regulatory Updates
The FDA approved risankizumab (Skyrizi, AbbVie) on 4/23/2019 for the treatment of plaque psoriasis. Risankizumab is dosed every 12 weeks after an initial 2 injections. The drug will compete with ixekizumab, tildrakizumab, guselkumab, and secukinumab. ICER has estimated an annual price of $28,800–$42,100 for risankizumab to achieve a long-term cost-effectiveness benchmark of $100,000– $150,000 per QALY. ICER suggested that step therapy approaches may not be appropriate for psoriasis. In an analysis of current data ICER found that risankizumab may be more effective than TNF-blockers, but this is based on grey literature, since risankizumab studies have not been published. AbbVie announced the annual WAC for maintenance dosing of risankizumab is $59,000. The FDA accepted the BLA for eptinezumab. Alder forecasts approval in May. If approved in 2019, Alder expects to launch the drug in 1Q20 for migraine prophylaxis. Genentech’s Risdiplam was granted PRIME status by the EMA for the treatment of Spinal muscular atrophy. Celgene and Acceleron submitted a BLA and a MAA for luspatercept in April 2019. The drug will be compared to ESA drugs in non-transfusion-dependent beta-thalassemia and in myelofibrosis. Biogen has decided not to initiate a Phase III trial of aducanumab in the prevention of Alzheimer’s disease. Fulcrum Therapeutics licensed losmapimod from GSK in April 2019 and plans to develop the drug as a treatment for facioscapulohumeral muscular dystrophy. Fulcrum has an ongoing trial evaluating losmapimod for the treatment of facioscapulohumeral muscular dystrophy. Announced Research Updates Gilead announced that in the 48-week, 803 patient, Phase III, STELLAR-3 trial, treatment with selonsertib 18 mg or 6 mg did not improve liver fibrosis by 1 stage or more without disease worsening compared to placebo in patients with stage 3 fibrosis from NASH. Published Research Update In a 24-week, 41 patient, Phase I/II, open label trial, treatment with X4P-001 (X4 Pharmaceuticals) 200 mg BID or 400 mg QD plus axitinib 5 mg BID resulted in an objective response rate of 31.8% in 22 evaluable patients with advanced clear cell renal cell carcinoma. In the 8-week, 256 patient, Phase IIb, open-label, NEW-HOPE trial, treatment with firibastat (Quantum Genomics) resulted in a 9.5 mmHg decrease in systolic blood pressure and a 4.2 mmHg decrease in diastolic blood pressure in a high-risk diverse hypertensive population. Sanofi’s dengue vaccine (Dengvaxia) has a PDUFA date of May 1, 2019. Dengvaxia is a 3-dose, subcutaneous vaccine for the prevention of malaria. The vaccine was tested in Brazil and the Philippines and was able to prevent 2/3 of cases and prevented 8/10 hospitalizations. Two large trials found efficacy of around 60%. Two Phase III pediatric trials demonstrated vaccine efficacy of 56.5% and 60.8%, respectively, against symptomatic virologically confirmed dengue. The vaccine appeared to be more effective in older children possibly due to higher baseline seropositivity and potentially a more broadly protective immune response. A four-year follow-up of two Phase II trial involving 1,378 patients found the vaccine demonstrated long-term immunogenicity. Dengvaxia is approved in 5 countries, which include Brazil, Philippines and Mexico. If that patient contracts the viral infection naturally, their immune system could process it as a second infection that is much more severe. The FDA has granted Dengvaxia a priority review. An analysis by WHO cautioned of an increased risk for severe dengue in seronegative vaccine recipients compared to seronegative non-vaccinated patients, but long-term protection in seropositive individuals is achieved. The FDA’s Vaccines and related Biological Products Advisory Committee voted to recommend approval for Sanofi’s Dengue vaccine for patients 9 to 17 years, but not in adult patients.
Novartis onasemnogene abeparvovec (Avexis) has a PDUFA date for an unspecified date in May 2019. Onasemnogene abeparvovec is a single dose, intravenous Infusion for the treatment of spinal muscular atrophy. Onasemnogene abeparvovec was evaluated In the 20-month, 15 patient, Phase I, START trial, where treatment with the gene therapy resulted in all patients being alive compared to 8% of a historical control group of patients with SMA type 1. At 3-months there was a 15.4 point improvement in the CHOP INTEND score of motor function score in patients treated with onasemnogene abeparvovec compared to a decline in the historical control. Novartis announced interim data from 22 patients in the Phase III, STR1VE trial, where treatment with onasemnogene abeparvovec resulted in a 11.8 point improvement in the CHOP INTEND score at 3 months in patients with SMA type 1. One patient died from respiratory failure, which was deemed to be unrelated to treatment. When approved onasemnogene abeparvovec will compete with nusinersen. Novartis indicated it may price the gene therapy as high as $4-5 million. Using a placeholder cost of $2 million, ICER estimated a cost per QALY for onasemnogene abeparvovec of $243,000 compared to best supportive care. ICER estimated that to be cost effective the cost of onasemnogene abeparvovec would need to be $900,000 to be in a $150,000 of QALY range, or $1.5 million if estimating the cost for each additional year of life gained (LYG) of $150,000. Regulatory Updates
The FDA approved hydrogel capsules (Plenity, Gelesis) on 4/14/2019 as a device for weight management in adults with a body mass index (BMI) of 25 - 40 kg/m2, when used together with diet and exercise. The FDA accepted the BLA and a priority voucher for Novartis’ brolucizumab in April 2019, suggesting a PDUFA date of 10/15/2019. The FDA designated Genfit’s elafibranor a Breakthrough Therapy in April 2019 for the treatment of primary biliary cholangitis. Viela Bio’s inebilizumab was designated a Breakthrough Therapy by the FDA in April 2019 for the treatment of neuromyelitis optica spectrum disorder. The FDA scheduled an Oncologic Drugs Advisory Committee (ODAC) hearing for 5/14/2019, to review Daiichi Sankyo/Plexxikon’s pexidartinib for the treatment of adult patients with symptomatic tenosynovial giant cell tumor. The FDA scheduled an Oncologic Drugs Advisory Committee (ODAC) hearing for 5/14/2019, to review Ambit Biosciences Corporation/Daiichi Sankyo’s quizartinib tablets for the treatment of adult patients with relapsed/refractory FLT3-ITD–positive acute myeloid leukemia (AML). New Trial Results Announced Alkremes announced that in the 265 patient, 28-week extension of the ENLIGHTEN-2 trial, olanzapine/samidorphan demonstrated no additional weight gain. Novartis announced interim data from 22 patients in the Phase III, STR1VE trial, where treatment with onasemnogene abeparvovec resulted in a 11.8 point improvement in the CHOP INTEND score at 3 months in patients with SMA type 1. One patient died from respiratory failure, which was deemed to be unrelated to treatment. The Phase III STR1VE is estimated to be completed in 2020. Onasemnogene abeparvovec has not been evaluated for less severe forms of SMA and long term effects are not known. Onasemnogene abeparvovec has an unspecified PDUFA date in May, 2019. GenSight announced that in the 72-week, 39 patient, Phase III, RESCUE trial, the eyes treated with birtamimab (GS010) had a loss of visual acuity of 20.6 letters in the ETDRS scale compared to a loss of 21.7 letters in the eyes that received sham injection in patients with LHON who had suffered vision loss of less than 6 months. Vision usually decreases for 3-5 months in LHON before stabilizing. This was seen in the RESCUE trial. Improvement from the nadir to week 48 was 13 letters with birtamimab and 11 letters with sham injection. Pfizer and Lilly announced that a 16-week, 3,021 patient, Phase III trial, treatment with tanezumab 5mg administered subcutaneously every 8 weeks significantly improved pain and physical function, but not an overall patient assessment compared to naproxen, celecoxib or diclofenac in patients with moderate-to-severe osteoarthritis (OA) of the hip or knee. Tanezumab 2.5mg did not differ from placebo in any of the three primary endpoints. Safety was measured at 80 weeks where treatment with tanezumab 5mg and 2.5mg resulted in a composite of rapidly progressive osteoarthritis (RPOA) type 1 or type 2, subchondral insufficiency fracture, osteonecrosis or pathological fracture in 7.1% and 3.8% of patents compared to 1.5% with naproxen, celecoxib or diclofenac in hip or knee osteoarthritis patients. The incidence of RPOA overall was 6.3% with tanezumab 5mg, 3.2% with 2.5mg arm and 1.2% with the NSAIDs. Prothera stopped the 260 patient, Phase III VITAL trial early, when an interim analysis found no improvement in a composite endpoint of all-cause mortality or cardiac hospitalizations with birtamimab compared to placebo more than 90-days after the initial infusion in treatment naive patients with AL Amyloidosis and cardiac dysfunction. New Published Trial Results Two 48-week, Phase III trials, HAWK with 1,775 patients and HARRIER with 1,049 patients compared brolucizumab to aflibercept. An intravitreal injection of brolucizumab 6mg was given monthly for 3 doses, then every month unless disease activity was present, then the drug was given every two months. Aflibercept 2mg was given as an intravitreal injection every two months. In HAWK, there was also a 3mg brolucizumab group. Brolucizumab was non-inferior to aflibercept in best corrected visual acuity (BCVA) at 48-weeks in both trials. In HAWK, treatment with brolucizumab resulted in an improvement in BCVA of 6.6 letters with 6mg and 6.1 letters with 3mg compared to 6.8 letters with aflibercept. The improvement in BCVA in HARRIER was 6.9 with brolucizumab 6 mg compared to 7.6 with aflibercept. A little more than 50% of patients were maintained on q12w dosing through Week 48 with brolucizumab (56% in HAWK and 51% in HARRIER). An extension of 251 patients in a Phase II trial found neutralizing antibodies similar for all four serotypes with a booster vaccination given 4-5 years after the 3rd dose of Sanofi’s dengue vaccine. Neutralizing antibodies were superior to levels after the third dose for 3 serotypes. In the 26-week, 1,758 patients, Phase III Pioneer-3 trial, 63% of patients treated with oral semaglutide 7mg and 14mg lowered HbA1c 0.3 and 0.5% and lowered weight 1.6kg and 2.5kg compared to sitagliptin in patients with type 2 diabetes, inadequately controlled on metformin with or without a sulfonylurea. Semaglutide, 3mg results did not demonstrate non-inferiority to sitagliptin. In an 8-week, 128 patient, Phase II trial, selopitant reduced itch visual analog scale score by 1 point at 4-weeks and 1.7 points at 8-weeks compared to placebo in patients with prurigo nodularis. In a 119-patient trial, the addition of apatinib to taxane, irinotecan and fluorouracil resulted in a total remission rate of 15.79% vs 3.23% for the drug regimen without apatinib in patients with patients with gastroesophageal junction adenocarcinoma. Progression-free survival was 3.72 months compared to 3.04 months and overall survival was 13.66 months vs 10.08 months. In a 2.2-year, 2,648 patient, Phase III trial, 6% of patients treated with atrasentan reached the primary endpoint, a composite of serum creatinine doubling, end-stage kidney disease, chronic dialysis, kidney transplantation, or death from kidney failure compared to 7.9% with placebo in patients with with type 2 diabetes and chronic kidney disease that had responded to atrasentan during an test period before randomization. The American Society of Clinical Oncology (ASCO) lists more than 120 types of cancer and related hereditary syndromes.
Tools are available that provide comparisons of available drug products. Such tools may include a drug’s comparative efficacy, therapeutic role and class monographs to assist with drug therapy decisions once a product is available. Clinicians can access services that detail the information, including access to past reviews, about recently released and investigational drugs projected for approval in the near term. But how does a formulary management team assess and prepare for perhaps eight new oncology drugs this year? FDA publications? PubMed feeds? Google alerts? Would it help to have a single source of unbiased, comprehensive clinical decision support information in one place? The Prescribe Right Pharmaceutical Pipeline Tracker contains 157 investigational cancer drugs. There are twenty-one different categories of cancer drugs in our knowledgebase. The ten most common cancers represent 85% of the cancer investigational drug universe: Bladder, Breast Cancer, Colorectal Cancer, Kidney Cancer, Lung Cancer, Lymphoma, Melanoma, Pancreatic Cancer, Prostate Cancer, and Thyroid Cancer. How does your current process provide coverage of investigational oncology drugs? Do you have a single source that is comprehensive, unbiased, with actionable intelligence? The Pharmaceutical Pipeline Tracker provides concise summaries of clinical trials that not only includes the results, but also the type of patient that was treated and any safety issues that may be present. Here’s a look at eight oncology drugs that appear to be on the approval near horizon. Comments are taken from the Pharmaceutical Pipeline Tracker knowledgebase: Quizartinib for acute myeloid leukemia with a PDUFA of May 25, 2019 has Orphan Drug, Breakthrough Therapy and Fast Track Priority Designations. Single-agent quizartinib was shown to be highly active and generally well tolerated in patients with relapsed or refractory acute myeloid leukaemia, particularly those with FLT3-ITD mutations. These findings confirm that targeting the FLT3-ITD driver mutation with a highly potent and selective FLT3 inhibitor is a promising clinical strategy to help improve clinical outcomes in patients with very few options. Selinexor for multiple myeloma with a July 6, 2019 PDUFA Date has Orphan Drug and Fast Track Priority. The combination of selinexor and dexamethasone has an ORR of 21% in patients with heavily pretreated, refractory myeloma with limited therapeutic options. Pexidartinib for tenosynovial giant cell tumor with an August 3, 2019 PDUFA Date has Orphan Drug and Breakthrough Therapy Priority Designations. Pexidartinib is also being evaluated for glioblastoma, ovarian, breast, colorectal, pancreatic and prostate cancer, malignant peripheral nerve sheath tumor, and pediatric cancers. Entrectinib for NTRK‐fusion+ solid tumors with an August 18, 2019 PDUFA Date has Breakthrough Therapy Priority Designation. Roche is seeking approval based on an integrated analysis from four Phase I and II trials that included data from 53 people with ROS1-activating gene fusions and 54 people with locally advanced or metastatic NTRK fusion-positive solid tumors. If approved, entrectinib would compete with larotrectinib to treat NTRK-fusion positive solid tumors and critzotinib to treat ROS1-mutated non-small cell lung cancer. Polatuzumab for diffuse large B-cell lymphoma with an August 19, 2018 PDUFA Date has Breakthrough Therapy Priority Designation. Current trial data display no significant safety concerns, no independent safety data are yet available. The most common ADR in an 80 patient, Phase II trial were leukopenia, thrombocytopenia and anemia. Fedratinib (Celgene, Impact Biomedicines) for myelofibrosis with a September 3, 2019 PDUFA Date has no Priority Designations. Sanofi discontinued development of fedratinib in 2013 after the FDA issued a clinical hold due to reports of Wernicke’s encephalopathy in clinical trials. Impact provided safety data to the FDA and the trial resumed. Celgene bought Impact in January 2018. Erdafitinib for urothelial cancer with a Breakthrough Therapy Priority Designation but no PDUFA date. Janssen submitted an NDA in September 2018. Janssen has the ongoing 630 patient, Phase III THOR trial evaluating erdafitinib compared to chemotherapy or pembrolizumab for the treatment of urothelial carcinoma. Darolutamide for prostate cancer has no PDUFA Date nor Priority Designations. There are direct links to three published studies in PubMed for Darolutamide in the Pharmaceutical Pipeline Tracker. Regulatory Updates
The FDA approved Amgen/UCB’s romosozumab (Evenity) on 4/9/2019 for the treatment of osteoporosis in postmenopausal women at high risk for fracture. The drug has a Boxed Warning regarding the increased risk of myocardial infarction, stroke and cardiovascular death. Amgen set WAC for romosozumab at $1,825 a month for an annual cost of $21,900. Romosozumab will likely join abaloparatide and teriparatide as a specialty drug for the treatment of osteoporosis. WAC for abaloparatide is $22,000, while the Federal Supply Schedule price is $11,800. For teriparatide, WAC is $36,000, and the Federal Supply Schedule price is $26,000. ICER estimated the cost per quality adjusted life year gained over the bisphosphonate zoledronic acid as $334,000 for abaloparatide and $942,000 for teriparatide. Due to the delay in FDA review, ICER did not include rombosozumab in its review. The FDA approved Janssen’s erdafitinib on 4/12/2019 for the treatment locally advanced or metastatic bladder cancer with fibroblast growth factor receptor (FGFR)3 or FGFR2 mutations who have progressed on platinum-containing chemotherapy. A companion lab test was also approved to identify patients with these mutations. WAC for erdafitinib will be $10,080 to $22,680 for a 28-day supply, depending on dose for an annual cost of $131,040 to $294,840. Celgene and Acceleron submitted a BLA for luspatercept in April 2019. The FDA designated FibroGen’s pamrevlumab an Orphan Drug for the treatment of Duchenne muscular dystrophy (DMD) in April 2019. Ghana has accepted 400,000 doses of GSK’s Mosquirix to pilot the malaria vaccine. Remimazolam is an investigational benzodiazepine whose effects can be reversed with flumazenil. Cosmo Pharmaceuticals licensed US marketing rights for remimazolam from Paion. Cosmo submitted an NDA for remimazolam in April 2019. New Trial Results Announced Poxel announced that in a 24-week, 213 patient, Phase III, TIMES 1 trial, imeglimin 1,000 mg lowered HbA1c 0.87% more than placebo. New Published Trial Results The Phase III APECS trial was terminated after an interim analysis showed no improvement with Merck’s verubecestat in the Clinical Dementia Rating Scale-Sum of Boxes compared to placebo in patients with prodromal Alzheimer's Disease. There were 1,454 patients enrolled in the trial at termination and 704 completed the 104-week study period. In a 12-week, 160 patient, Phase II trial, treatment with Merck’s ruzasvir and uprifosbuvir (no grazoprevir) resulted in SVR in 52/54 genotype 1a patients, 15/15 genotype 1b patients, 28/29 with genotype 2, 30/39 with genotype 3, 18/20 with genotype 4 and 2/3 with genotype 6 in patients chronically infected with HCV genotypes 1-6. The FDA accepted the NDA for Kyowa Hakko Kirin’s istradefylline in April 2019 and set a PDUFA date of 8/27/2019. Istradefylline is an A2A antagonist seeking approval for the treatment of Parkinson's Disease wearing-off phenomenon in patients on levodopa therapy.
The FDA delayed the PDUFA date for Ambit Biosciences Corporation/Daiichi Sankyo’s quizartinib from May to August 2019. This KIT Inhibitor targets acute myeloid leukemia. The FDA granted AstraZeneca’s selumetinib Breakthrough Therapy status. The drug is a MEK Inhibitor targeting differentiated thyroid cancer. The EMA accepted the MAA for Daiichi Sankyo/Plexxikon’s pexidartinib in April 2019. It’s a CSF-1R inhibitor targeting Giant cell tumors of the tendon sheath. Shionogi submitted an MAA for cefiderocol in April 2019. Immunocore’s IMCgp100 has been assigned the generic name tebentafusp and has both Fast Track and Orphan status. The drug is seeking approval for the treatment of uveal melanoma. It’s an ImmTAC which binds to cancer cells with peptide-HLA. This brings circulating T cells to the tumor site, which releases killing lytic granules, that kill the cancer cell. AZ announced interim results from two cohorts of patients in the Phase Ib, TATTON trial:
An analysis of data in two phase 3 trials for Nektar’s NKTR-181, using the MADDERS system, show a low withdrawal rate and a low risk of abuse potential, diversion or addiction. Syndax announced that an interim analysis from 53 patients with progressing melanoma on prior PD-1 blockade in a cohort of the Phase Ib/II ENCORE 601 trial, treatment with entinostat and pembrolizumab resulted in an objective response in 19% of patients and progression-free survival of 4.2 months. Allergan announced that in the 123 patient, 28 week, Phase III, open label MAPLE trial, the incidence of intraocular inflammation with a new formulation of abicipar given every two months was 8.9%. The rate of intraocular inflammation in the MAPLE trial was lower than the 15.1 to 15.7% see in the Phase III CEDAR and SEQUOIA trials. The rate of intraocular inflammation is reported as 0.01% with aflibercept, 0 to 0.6% with ranibizumab and 3-55 with brolucizumab. Allergan plans to file a BLA for abicipar in June 2019. Scynexis’ SCY-078 has been assigned the generic name Ibrexafungerp. Tonix has an ongoing Phase III trial evaluating cyclobenzaprine for the treatment of fibromyalgia. Eight Approvals
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