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Regulatory updates
The FDA approved ferric maltol (Feraccru/Accrufer, Shield Therapeutics) on 7/26/2019 for the treatment of iron deficiency in adults. The FDA assigned a priority review for tazemetostat for the treatment of metastatic or locally advanced epithelioid sarcoma and assigned a PDUFA date of 1/23/2020. The FDA accepted the BLA for Sanofi’s isatuximab for treatment of multiple myeloma and assigned a PDUFA date of 4/30/2020. The FDA canceled an advisory committee meeting to review lumateperone as a treatment for schizophrenia due to new information provided for the NDA. No change has been made for the September 2019 PDUFA date. Vertex filed an NDA in July 2019 for VX-445 (elexacaftor, tezacaftor and ivacaftor) for the treatment of cystic fibrosis in patients with one F508del mutation and one minimal function mutation or two F508del mutations. The FDA designated La Jolla’s artesunate (LJPC-0118) an orphan drug for the treatment of malaria. Orphazyme plans to file an NDA for arimoclomol for the treatment of Niemann-Pick disease Type C (NPC) in the first half of 2020. Orphazyme plans to introduce an Early Access Program for NPC in the fall of 2019. The FDA delayed a decision on NKTR-181 to allow additional time to review preclinical data from two additional studies. In July 2019, the FDA put review of NKTR-181 on hold and canceled an advisory committee review of the drug. Some analysts expect a 1-year delay in a review. Announced Research Results Myovant announced that in the 24-week, 382 patient, Phase III, LIBERTY 2 trial, 71.2% of patients treated with relugolix, estradiol and norethindrone acetate achieved a menstrual blood loss volume of less than 80 mL and a 50 percent or greater reduction from baseline in menstrual blood loss volume during the last 35 days of the 24-week treatment period compared to 14.7% with placebo in patients with uterine fibroids and heavy menstrual bleeding. Marinus announced that in Part 2 of the 34-day, 33 patient, Phase II MAGNOLIA trial, treatment with a 6-hour infusion of ganaxolone followed by daily oral administration of the drug did not improve the HAM-D17 score compared to placebo in women with postpartum depression. Marinus announced that in the 28-day, 68 patient, Phase II, open-label, Amaryllis trial, where treatment with oral ganaxolone 675 mg decreased the HAM-D17 score by 0.8, 9.8, and 12.2 at 24 hours, 14 days and 28 days of treatment while increasing the dose to 1,125 mg after two days deceased the HAM-D17 score by 2.7, 9.3 and 14.5 at 24 hours, 14 days and 28 days of treatment in women with postpartum depression. Published Research Results In a 26-week, 256 patient, Phase III trial, roxadustat was non-inferior to epoetin in increasing hemoglobin (0.7g/dL vs 0.5 g/dL) in Chinese dialysis patients previously maintained with epoetin. In a 9-week, 154 patient, Phase III trial, roxadustat increased hemoglobin 1.9 g/dL compared to a decrease of 0.4 g/dL with placebo in Chinese patients with chronic kidney disease that were not receiving dialysis. In the 24-week, 448 patient, Phase III, FINCH 2 trial, 66% of patients treated with filgotinib 200 mg and 57.5% treated with 100 mg achieved AR20 (compared to 31.1% with placebo in patients with with moderate-to-severe rheumatoid arthritis. In a 12-week, 507 patient, Phase III trial, 57.7% of patients treated with peficitinib 100mg achieved AR20, 74.5% with 150mg and 30.7% with placebo in patients in rheumatoid arthritis patients with an inadequate response to at least one conventional DMARD. In a 12-week, 519 patient, Phase III trial, 58.6% of patients treated with peficitinib 100mg achieved AR20, 64.4% with 150mg and 21.8% with placebo in Japanese rheumatoid arthritis patients with an inadequate response to methotrexate. Regulatory Update
Announced Research Updates The bio-pharmaceutical company Orphazyme A/S has reportedly announced that it has finished enrollment in its phase 3 study assessing arimoclomol for the treatment of Amyotrophic Lateral Sclerosis (ALS) before schedule. The full analysis remains on track for the first half of 2021. J&J is testing their 6-dose, multi-antigen HIV vaccine in 2,600 sexually active women aged between 18 and 35 years in Southern Africa in the Phase IIb Imbokodo trial (results expected in 2021) and in the Phase III Mosaico trial, involving 3,800 men who have sex with men and transgender people aged between 18 and 60 years in the U.S., South America and Europe. The two trials use vaccines composed of different antigens to reflect the predominant strains in the region. Vanda announced that in the 126 patient, Phase II, Motion Sifnos trial, treatment with tradipitant decreased the percentage of participants vomiting (17.5% vs 39.7%) but did not improve the mean Motion Sickness Severity Scale (MSSS) worst score among participants on one of seven sailing voyages on the Pacific. Both a reduction in emesis and the MSSS was seen in rough seas, but no significant improvement was seen in calm conditions. Published Research Updates In a 52-week, 342 patient, Phase III, open-label trial, treatment with trifarotene cream achieved an IGA of clear/almost clear and ≥2 grade improvement in 65.1% of patients and a physician's global assessment in 66.9% of patients with moderate facial acne and moderate truncal acne. In a 59 patient, Phase II trial, levosimendan did not improve sitting slow vital capacity in patients with amyotrophic lateral sclerosis (ALS). In the 65-patient, Phase II trial, neither tremelimumab plus durvalumab nor durvalumab monotherapy appreciably improved the objective response rate (3% vs 0%) in patients with metastatic pancreatic ductal adenocarcinoma. In a 32 patient, Phase III trial, levosimendan compared to dobutamine had similar increases in renal blood flow (22% and 26%, respectively), better glomerular filtration rate, and filtration fraction was not affected by levosimendan but decreased by 17% with dobutamine in patients with heart failure and renal impairment. In a 72-patient trial, levosimendan did not reduce the occurrence rate of acute kidney injury compared to milrinone in infants after open-heart surgery with cardiopulmonary bypass. Glaxo’s Zejula Meets Main Goal in Late-Stage Study: Glaxo’s GSK phase III PRIMA study, evaluating Zejula (niraparib) for patients with ovarian cancer in first-line maintenance setting, met the primary endpoint. Data from the study showed that treatment with its PARP inhibitor, Zejula,` led to a statistically significant improvement in progression-free survival in women regardless of their biomarker status, thereby meeting the study’s primary endpoint. Zejula was added to Glaxo’s portfolio following the acquisition of Tesaro earlier this year. Regulatory Update
The FDA accepted the BLA for Sanofi’s isatuximab for multiple myeloma and set a PDUFA date for the end of April 2020. The drug has multiple mechanisms of action including direct induction of apoptosis, antibody-dependent cellular cytotoxicity, antibody-dependent cellular phagocytosis, and complement-dependent cytotoxicity. The FDA accepted the NDA for Janssen and ViiV’s once monthly cabotegravir and rilpivirine injection and set a PDUFA date for the end of 2019. Horizon submitted a BLA for teprotumumab for Graves ophthalmopathy in July 2019. Announced Research Updates ITC announced that in a 6-week, 381 patient, Phase III trial, lumateperone 42 mg reduced the Montgomery-Asberg Depression Rating Scale (MADRS) score by 16.7 points compared to a 12.1 reduction with placebo in patients with Bipolar disorder, who were experiencing a major depressive episode. ITC announced that in a 6-week, 381 patient, Phase III trial, neither lumateperone 42 or 28 mg improved the MADRS score compared to placebo in patients with Bipolar disorder, who were experiencing a major depressive episode. Amgen and Novartis discontinued two trials evaluating umibecestat in the prevention of Alzheimer's disease in pre-symptomatic patients with a genetic risk to develop the disease after an interim analysis found worsening cognitive function. A review by ICER of treatments for Duchenne’s found limited data that a slight increase in levels of dystrophin with eteplirsen and golodirsen provides a clinically significant effect. ICER concluded that if golodirsen is priced like eteplirsen, it would not meet cost benefit standards. At the current price, if either drug were able to restore perfect health in DMD patients for an additional 40 years of life, the drugs would far exceed cost-effectiveness thresholds of $100,000 and $150,000 per Quality-Adjusted Life Year (QALY) gained or $100,000 and $150,000 per Life Year Gained (LYG). Published Research Updates ICER released a review of AR101 and Viaskin Peanut in July 2019. ICER expressed concern regarding the lack of long-term data for safety and effectiveness, desensitization did not eliminate the need to be cautious with peanut exposure and increase in allergic reaction requiring epinephrine seen during clinical trials. The panel also did not find evidence to support AR101 and Viaskin Peanut to have a benefit over avoidance of peanuts or non-commercialized oral immunotherapy. In a pharmacoeconomic analysis, ICER estimated a benchmark fair-market price of $4,800-7,200 per year for AR101 and $3,000-$4,500 per year for Viaskin Peanut. In a 48-week, 294 patient, Phase II/III trial, treatment with masitinib 4.5 mg/kg/day plus riluzole 100 mg/day slowed the increase in ALSFRS-R by 27% compared to riluzole monotherapy in patients with amyotrophic lateral sclerosis. Masitinib in a dose of 4.5 mg/kg/day added to riluzole did not differ from placebo in progression of ALSFRS-R. In a 1,072 patient, Phase III trial, 19.6% of patients treated with rimegepant were pain-free and 37.6% were free of their most bothersome symptoms at two hours compared to 12% and 25.2% that received placebo in patient with migraine. In the 72-week, 419 patient, Phase II, SYNERGY trial, opicinumab failed to show improvement in disability compared to placebo in patients with relapsing multiple sclerosis. In the 12-week, 1,629 patient, Phase III, SELECT-COMPARE trial, more patients treated with upadacitinib/methotrexate improved compared to methotrexate monotherapy achieving ACR20 (71% vs 36%) and DAS28CRP<2.6 (29% vs 6%) in rheumatoid arthritis patients. At 26 weeks more, patients in the SELECT-COMPARE trial that received upadacitinib achieved low disease activity or remission compared to placebo or adalimumab. In three 13-week Phase III trial with a total of 3,864 patients, mirogabalin did not improve the weekly average daily worst pain score compared to placebo in patients with fibromyalgia. In a 176 patient, Phase II, open-label trial, 16% of patients treated with NBTXR3 added to radiotherapy achieved a pathological complete response compared to 8% with radiotherapy alone in patients with locally advanced soft-tissue sarcoma. In a 7-year, 3,084 patient, Pharmacy III trial, GSK’s malarial vaccine the incidence of severe malaria infections were 0.004 cases per person-years (PPY) with the four-dose regimen and 0.007 with the three-dose regime compared to 0.009 in the control group in children 5-7. Among children age 3-5 the incidence of severe malaria infections were 0.007 cases per person-years (PPY) with the four-dose regimen and 0.007 with the three-dose regime compared to 0.011 in the control group. Vaccine efficacy against severe malaria in both age groups did not appear to improve overall efficacy. During the first half of 2019 the FDA approved 13 investigational drugs for release to the marketplace.
Bremelanotide (Vyleesi) The FDA approved AMAG Pharmaceuticals bremelanotide on 6/21/2019 for the treatment of premenopausal women with acquired, generalized hypoactive sexual desire disorder. Press Release Polatuzumab vedotin-piiq (Polivy) The FDA approved polatuzumab vedotin on 6/10/2019 in combination with bendamustine and rituximab for the treatment of adults with resistant diffuse large B-cell lymphoma. Press Release Alpelisib (Piqray) The FDA approved alpelisib (Piqray, Novartis) on 5/24/2019 to be used in combination with fulvestrant for the treatment of postmenopausal women, and men, with hormone receptor (HR)-positive, human epidermal growth factor receptor 2 (HER2)-negative, PIK3CA-mutated, advanced or metastatic breast cancer following tumor advancement after endocrine-based regimens. The companion diagnostic test, therascreen PIK3CA RGQ PCR Kit, was also approved to detect the PIK3CA mutation in a tissue and/or a liquid biopsy. Press Release Drug Trials Snapshot Tafamidis meglumine (Vyndaqel) The FDA approved tafamidis meglumine (Vyndaqel) and tafamidis (Vyndamax) early on 5/6/2019 for the treatment of the cardiomyopathy of wild-type or hereditary transthyretin-mediated amyloidosis (ATTR-CM) in adults to reduce cardiovascular mortality and cardiovascular-related hospitalization. The recommended dosage for tafamidis meglumine is four 20 mg capsules once daily (80 mg total dose). The recommended dose for tafamidis is one 61 mg capsule taken once-daily. The annual WAC for both drugs is $225,000. Press Release Drug Trials Snapshot Risankizumab-rzaa (Skyrizi) The FDA approved risankizumab 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 in order 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. Drug Trials Snapshot Erdafitinib (Balversa) The FDA approved 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. Press Release Drug Trials Snapshot Romosozumab-aqqg (Evenity) The FDA approved romosozumab 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. Press Release Drug Trials Snapshot Siponimod (Mayzent) The FDA approved siponimod (Mayzent, Novartis) on 3/26/2019 to treat adults with relapsing multiple sclerosis. In a draft review ICER felt that compared to best supportive care siponimod reduced the risk of disability progression and decreased inflammation. ICER analysis found that siponimod lowered the risk of relapse by 46% and had an annualized relapse rate of 0.07/year compared to 0.16/year with placebo. Due to the lack of comparative trials with other disease modifying therapies and the difference in patient populations and outcome assessments with current trials, ICER analysts did not feel enough data existed to compare siponimod to those therapies. ICER estimated a quality-adjusted life year (QALY) of $826,000 for use of siponimod over best supportive care in the treatment of secondary progressive multiple sclerosis, assuming the same price as ocrelizumab. The cost per QALY dropped to $396,000 in patients with relapses within two years of the initiation of treatment. ICER reported an annual acquisition price for ocrelizumab of $64,308 after discounts. Novartis has announced an annual WAC of $88,000 for siponimod. There have been no estimates or reports of potential discounts for siponimod, during the week the drug was approved. ICER will accept comments on the draft report until April 10 and then release a final report on May 2 with a discussion of the report set for May 23. Press Release Drug Trials Snapshot Solriamfetol (Sunosi) The FDA approved solriamfetol on 3/20/2019 to improve wakefulness in adults with excessive daytime sleepiness associated with narcolepsy or obstructive sleep apnea. Drug Trials Snapshot Brexanolone (Zulresso) The FDA approved brexanolone on 3/19/2019 for the treatment of postpartum depression. Press Release Drug Trials Snapshot Triclabendazole (Egaten) The FDA approved triclabendazole (Egaten) on 2/13/2019 for the treatment of fascioliasis, a parasitic infestation caused by two species of flatworms or trematodes that mainly the affect the liver, sometimes referred to as “liver flukes”. Prior to approval, the drug has been available through the CDC. Drug Trials Snapshot Caplacizumab-yhdp (Cablivi) The FDA approved caplacizumab (Cablivi by Sanofi) on 2/6/2019 for the treatment of acquired thrombotic thrombocytopenic purpura (aTTP). Press Release Drug Trials Snapshot PrabotulinumtoxinA-xvfs (Jeuveau) The FDA approved PrabotulinumtoxinA (Jeuvea from Evolus) on 2/1/2019 for the treatment of moderate to severe glabellar lines associated with corrugator and/or procerus muscle activity in adult patients. Press Release Regulatory Update
The FDA approved Karyopharm Therapeutics’ selinexor (Xpovio), on 7/3/2019, in combination with dexamethasone for the treatment of adult patients with relapsed/refractory multiple myeloma who have received ≥4 prior therapies and whose disease is refractory to ≥2 proteasome inhibitors, ≥2 immunomodulatory agents, and a CD38-targeted monoclonal antibody. In February 2019, the FDA Oncologic Drugs Advisory Committee recommend a delay in approval of selinexor-dexamethasone until after the results of the Phase III BOSTON trial were available in the first half of 2020. In March 2019, the FDA delayed the PDUFA date for selinexor by three months. The FDA accepted the NDA for RedHill Biopharma's RHB-105 (Talicia) for the treatment of H. pylori infection and assigned a November 2, 2019 PDUFA date. RHB-105 is a combination of rifabutin, amoxicillin and omeprazole Gilead plans to file an NDA for filgotinib by the end of 2019, for the treatment of Crohn's disease, rheumatoid arthritis, and Ankylosing spondylitis Announced Research Updates Boston Biomedical discontinued a Phase III trial when an interim analysis found no improvement when adding napabucasin to nab-paclitaxel with gemcitabine compared to the two drugs alone in the treatment of metastatic pancreatic ductal adenocarcinoma. Lilly announced that a targeted investigation examining patients with cardiovascular (CV) risk factors that participated in the lasmiditan SPARTAN and SAMURAI trials found a small increase in palpitations or tachycardia as the only CV ADR, however it could not be determined if the increase was due to lasmiditan. The presence of CV risk factors did not affect efficacy. TG Therapeutics announced that in a 48-week, 48 patient, Phase II trial, 99% of patients treated with ublituximab achieved at least a 99% reduction in peripheral CD19+ B cells at 4 weeks, which was maintained through 48 weeks. At 48 weeks the annualized relapse was 0.07, down from a mean 1.45 relapses per year before the trial. 93% of patients were relapse free. Published Research Updates In a 16-week, 696 patient, Phase III trial, where compared to placebo, treatment with tanezumab decreased the WOMAC pain score by 0.6 points with 2.5mg in week 1 and 8 and a 0.73 decrease with 2.5 mg given in week 1 and 5 mg given in week 8 in patients with osteoarthritis pain of the knee and hip and an inadequate response to standard analgesics. The WOMAC Physical Function score was decreased 0.66 points with 2.5 mg and 0.89 points with 2.5/5 mg. In a 72 patient trial, levosimendan did not reduce the occurrence rate of acute kidney injury compared to milrinone in infants after open-heart surgery with cardiopulmonary bypass. Regulatory Update
In June 2019, the FDA rejected Acer Therapeutics’ celiprolol (Edsivo) for the treatment of Ehlers-Danlos syndrome and requested a new clinical trial be completed. Nabriva announced the EMA accepted the MAA for lefamulin in June 2019 for treating community-acquired pneumonia. Aimmune submitted an MAA for AR101 to the EMA in June 2019. AR101 is Aimmune’s Oral Immunotherapy used to desensitize the patient with peanut allergy. Announced Research Updates Conatus announced that in the 48-week, 217 patient, Phase IIb, ENCORE-LF trial, emricasan did not improve a composite endpoint of all-cause mortality, new decompensation events, or ≥4 points progression in the MELD score compared to placebo in NASH patients with compensated or early decompensated liver cirrhosis and severe portal hypertension. As in the original ENCORE-PF trial, there was no improvement in the hepatic venous pressure gradient after an additional 24 weeks of treatment with emricasan. Proxel announced that in the 16-week, 215 patient, Phase III, TIMES 3 trial, imeglimin in combination with insulin decreased HbA1c 0.6% in Japanese patients with type 2 diabetes Published Research Updates In a 12-week, 616 patient Phase IIb, dose ranging trail trial, more patients treated with Alder Biopharmaceuticals’ eptinezumab 300 mg achieved a 75% or > decease in migraine days compared to placebo (33.1% vs 20.7%), but there was no difference with 100mg, 30mg and 10 mg in patients with chronic migraine. In the 255 patient, Phase III ADMYRE trial, PharmaMar’s plitidepsin plus dexamethasone did not improve progression free survival or overall survival compared to dexamethasone monotherapy in patients with multiple myeloma. A lasmiditan safety analysis of 4,439 patients that participated in the Phase III SPARTAN and SAMURAI trials focused on dizziness and found that dizziness increased with dose was mostly mild or moderate in severity. Dizziness did not affect efficacy. The occurrence was 8.6% with 50 mg, 14.9% with 100 mg and 16.8% with 200 mg compared to 2.9% with placebo. The median time to onset was 30-40 minutes, with a median duration of 1.5-2 hours. Besides dose, risk factors for dizziness were non-Hispanic/Latino, mild or moderate severity of migraine attack, and lower body mass index. In a 12-week, 365 patient, Phase II trial, treatment with Daiichi Sankyo/Exelixis’ esaxerenone 1.25 mg, 2.5 mg, and 5 mg reduced urinary albumin-to-creatinine ratio 38%, 50%, and 56% compared with 7% with placebo in Japanese patients with type 2 diabetes mellitus and microalbuminuria. In a 12-week, 363 patient, Phase IIb trial, 8.6% of patients treated with Cassiopea’s clascoterone, 1% and 8.3% of patients treated with clascoterone 0.1% had at least a two-grade improvement and achieved a clear or almost clear score with the Investigator’s Global Assessment in patients with facial acne. Thirteen of the nineteen investigational drugs with PDUFA Dates prior to the end of the year are due for approval during the third quarter. Twelve different drug classes are represented in the Q3 group. Four of the Q3 potential approvals have been fast tracked while two have been designated orphan drugs by the FDA. Five of the drugs are Breakthrough Therapies and one is a Qualified Infectious Disease Product. Two of the third quarter projected approvals had their BLAs approved during Q1, and three of the Q3 projected approvals had their NDAs approved during Q1.
During the first quarter FDA approved six new drugs. There were four rejections and seven changes in priority designations. Additionally, one drug was put on a hold and three others were delayed. Stay tuned for a complete first half 2019 approvals review. Among the delays was Karyopharm Therapeutics’ selinexor which now has a 6 July 2019 PDUFA Date and Nektar’s NKTR-181 with a current PDUFA Date of 29 August 2019. |
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