The FDA approved AMAG Pharmaceuticals’ bremelanotide (Vyleesi) on 6/21/2019 for the treatment of premenopausal women with acquired, generalized hypoactive sexual desire disorder.
In June 2019, the FDA rejected Daiichi Sankyo’s quizartinib (Vanflyta), following the recommendation of the Oncology Drug Advisory Committee, which voted 3 to 8 against approval in May 2019.
Bluebird plans to delay its launch of beta beglogene darolentivec until 2020 to finalize a manufacturing process to support a commercial launch.
Trevena initiated a safety trial to evaluate QT-interval prolongation with oliceridine to meet an FDA requirement to refile an NDA.
Announced Research Updates
Geron announced that in the 24-week, 38 patients, Phase II/III, open label, IMerge trial, 42% of patients treated with imetelstat achieved transfusion independence at 8 weeks (primary endpoint) and 29% remained transfusion independent at 24 weeks in heavily transfusion-dependent patients with myelodysplastic syndrome.
Epizyme announced interim data from 96 follicular lymphoma patients enrolled in a Phase II trial, treatment with tazemetostat resulted in an objective response rate in 77% of 43 patients with EZH2 activating mutations and 34% of 53 patients with wild-type EZH2.
Published Research Updates
In a 16-week, 63 patient, Phase III trial, treatment with Mezzion/Allergan’s udenafil increased 6-min walking distance by 25 meters in patients with pulmonary arterial hypertension.
In a 24-month, 35 patient, Phase II, extension trial, annualized growth velocity from treatment with BioMarin Pharmaceutical’s vosoritide was maintained for up to 42 months.
The 706 patient, Phase III, ECHO-301/KEYNOTE-252 trial was stopped after the second interim analysis when Incyte’s epacadostat added to pembrolizumab did not improve progression free survival or overall survival compared to pembrolizumab monotherapy in patients with unresectable or metastatic melanoma.
In a 24-week, 56 patient, Phase III, open-label trial, AstraZeneca/FibroGen’s roxadustat maintained target hemoglobin levels in peritoneal dialysis patients who were previously treated or not treated with erythropoiesis stimulating agents.
Novo Nordisk designed the ten trial Phase III PIONEER program to support the NDA for oral semaglutide for the treatment of type 2 diabetes. If approved, semaglutide will be the first oral GLP-1 receptor agonist and will likely become a preferred treatment to add to patients that are inadequately controlled with metformin. There are links to seven published studies in the Pharmaceutical Pipeline Tracker.
Following are summaries of what we know about the ten trials.
The FDA approved polatuzumab vedotin (Polivy, Genentech/Roche) on 6/10/2019 in combination with bendamustine and rituximab for the treatment of adults with resistant diffuse large B-cell lymphoma.
In June 2019, the FDA accepted the NDA and the EMA accepted the MAA for ozanimod. Celgene estimates an FDA decision on approval of ozanimod by 3/25/2020 and approval of the MAA in the first half of 2020.
After Novavax reported a failed Phase III trial in March, the FDA recommended an additional Phase III trial evaluating their respiratory syncytial virus vaccine’s (ResVax) ability to decrease RSV disease in infants born to mothers vaccinated during pregnancy.
The FDA's Psychopharmacologic Drugs Advisory Committee will review lumateperone on 7/31/2019. The drug is an atypical antipsychotic targeting acute and residual schizophrenia.
The EMA approved beta beglogene darolentivec in June 2019. Bluebird set a price of $1.77 million in Europe, which is paid as 315,000 euros per year, over 5 years. Payments are stopped or reduced if a patient requires an infusion after receiving a treatment. However, no European country has accepted the price yet. Bluebird forecasts approval in the US in 2020.
Announced Research Updates
Lilly announced that in a 52-week, 103 patient, Phase II trial, patients received placebo or mirikizumab for 16 weeks and then all patients received mirikizumab 300 mg every 8 weeks for 46 weeks if they had not reached PSASI-90. At the end of the 16-week period only 6.5% of patients had achieved complete scalp psoriasis clearance, but at the end of 46 weeks of maintenance treatment with mirikizumab, 80.4% had achieved scalp clearance in patients with scalp psoriasis.
Karyopharm announced interim results from three arms of the Phase Ib/II, STOMP, relapsed or refractory multiple myeloma trial. In one arm, selinexor, daratumumab and dexamethasone achieved an overall response rate in 73% of patients. In the second arm, selinexor, pomalidomide and dexamethasone achieved an overall response rate in 50% of patients. In the second arm, selinexor, carfilzomib and dexamethasone achieved an overall response rate in 78% of patients.
Published Research Updates
In a 12-week, 79 patient, Phase IIa Trial, patients that received bimekizumab plus certolizumab had a 1.41 decrease in their DAS28(CRP) compared to a 0.82 decrease with certolizumab monotherapy in patients with rheumatoid arthritis that remained uncontrolled after 8-weeks of certolizumab.
In the 262 patient, Phase III, open-label, SOLITAIRE-U trial, solithromycin did not reach non-inferiority compared to ceftriaxone/azithromycin (80% eradication vs 84%) in patients infected with gonorrhea with or without chlamydia infection.
In a 69-week, 104 patient, Phase II trial, subcutaneous crenezumab lowered oligomeric forms of amyloid beta-protein by 48% compared to a 43% decrease with intravenous crenezumab and no change with placebo in patients with Alzheimer's disease.
In a 36-week, 14 patient, Phase I/II, open label trial, VTS-270 slowed decreases in cognition and adaptive behavior in patients with Niemann-Pick Type C1.
In the 24-week, 274 patient Phase III, GBT HOPE trial, 51% of patients treated with voxelotor 1,500 mg had at least a 1 g/dL increase in hemoglobin compared to 7% with placebo in patients with sickle cell disease.
In a 62 patient, Phase II trial, intermittently dosed pemetrexed added to platinum chemotherapy resulted in an objective response rate of 35%, continuous administration of pemetrexed and platinum chemotherapy resulted in an ORR of 62% and platinum chemotherapy alone resulted in an ORR of 24% in patients with non-small cell lung cancer.
In a 179 patient, Chinese trial, treatment with icotinib plus pemetrexed and carboplatin resulted in a progression-free survival of 16 months compared to 10 months with icotinib monotherapy in patients with advanced lung adenocarcinoma with sensitive epidermal growth factor receptor (EGFR) mutations.
In a 50 patient, 14-day, Phase III trial, terlipressin reduced portal venous pressure compared to placebo in patients undergoing hepatobiliary surgery.
The FDA initiated a pilot program, called Project Facilitate to help oncologists request investigational cancer treatments for patients that are not eligible for a clinical trial and who have exhausted current approved treatment options. Project Facilitate has a call center which provides help in submitting requests to FDA staff. The call center is a single point of contact for oncologists to request an experimental drug. The FDA created Project Facilitate, because of criticism that the process to request a drug through an expanded access program was too burdensome. The FDA decided to pilot enhanced help to access investigational drugs in oncology first. A pharmaceutical manufacturer still has to approve access for the patient, but if access is denied, the FDA will inquire as to why it was not granted.
Because of the perception of the difficulty in accessing investigational drugs, some states began implementing Right-to-Try laws allowing physicians to request access to an investigational drug on behalf of a patient. Federal Right-to-Try legislation was passed in May 2018. So, what is the difference between Right-to-Try and Expanded Access? Both programs are for patients with a life-threatening illness who have exhausted treatment options and are not eligible for a clinical trial or are too far away from a trial site. Insurance companies will not pay for the investigational drug or non-drug medical costs associated with treatment with either program.
Expanded Access is also known as compassionate use and has been around for 30 years beginning with access to HIV drugs. Over the years the FDA has streamlined the process to improve access. Expanded Access to a drug requires a 2-page form, submitted by a physician and approved by an IRB. Over the past 5 years there have been 9,000 EAP applications, 99% were approved and 75% were approved in a few days. Manufacturers are permitted to charge patients an FDA approved price for the investigational drug.
Right-to-Try has no FDA oversight of the treatment or treatment process. A physician makes an inquiry directly to the pharmaceutical company. Currently it is not clear how the request is made. An informed consent is also required, but it has not been defined who will create the risk and benefit description for the document. The pharmaceutical manufacturer must also provide an annual report of patients treated and safety issues. Formal guidelines for Right-to-Try have not been announced, but ERC-1671 (Gliovacfrom Epitopoietic Research Corp) became the first drug accessed through Right-to-Try in the fall of 2018.
Prescribe Right will continue to monitor these programs and provide enhancements and updates to the Pharmaceutical Pipeline Tracker as additional information becomes available. This will allow you to be prepared for patient’s questions before they happen.
The FDA accepted the BLA and the EMA accepted the MAA for Celgene/Acceleron’s luspatercept in June 2019.
The FDA granted Gilead’s momelotinib Fast Track status in June 2019.
Bluebird Bio’s beta beglogene darolentivec was approved in Europe in June 2019.
Announced Research Updates
Sierra will evaluate momelotinib in the treatment of anemia in patients with Primary Myelofibrosis (PMF), Post-Polycythemia Vera (PV) Myelofibrosis, or Post Essential Thrombocythemia (ET) Myelofibrosis who were Previously Treated with JAK Inhibitor Therapy in the Phaser III MOMENTUM trial with plans to launch the trial in 4Q19.
Allegro announced that in a 28-week, 40 patient, Phase II trial, 48% of patients with intermediate dry AMD that received two doses of risuteganib (weeks 1 & 16) gained at least 8 letters of vision at week 12 compared to 7% that received placebo.
Published Research Updates
In a 6-month, 58 patient, Phase II trial, adding AstraZeneca’s cediranib to docetaxel plus prednisone did not improve progression-free survival rate compared to docetaxel plus prednisone alone in patients with in patients with metastatic castrate-resistant prostate cancer. In a 24-week, 48 patient, Phase II trial, cediranib reduced target marker lesion diameters by 8.3% compared to a 13.4% increase with placebo in patients with in patients with metastatic alveolar soft-part sarcoma.
A 21 patient Phase II trial was stop early after an interim futility analysis found no benefit for Roche’s taselisib in the treatment of patients with PI3K pathway-activated squamous non-small cell lung cancer.
In the 24-hour, Phase III APOLLO-2 trial, treatment with PCA oliceridine (Travena) resulted in effective analgesia in 61.0% that received 0.1 mg, 76.3% with 0.35mg, and 70.0% with 0.5 mg compared to 45.7% with placebo and 78.3% for morphine in patients with acute pain following abdominoplasty. All doses of oliceridine were superior to placebo, but only the 0.35mg and 0.5mg doses were equianalgesic to morphine.
In the 26-week, 711 patient, Phase III Pioneer-4 trial, daily oral semaglutide (Novo Nordisk) HbA1c was lowered by 1.2% compared to a 1.1% reduction with daily liraglutide and 0.2% with placebo in type 2 diabetic patients. In the 52-week, 504 patients, Phase III Pioneer-7 trial, 58%of patients treated with oral semaglutide achieved an HbA1c < 7% compared to 25% with sitagliptin in patients with inadequately controlled type 2 diabetes.
Ambit announced that in the 23.5-month, 367 patient, Phase III, QuANTUM-R trial, treatment with quizartinib resulted in an overall survival of 6.2 months compared to 4.7 months with salvage chemotherapy in patients with relapsed/refractory FLT3-ITD myeloid leukemia.
In a 69-week, 104 patients, Phase II trial, subcutaneous crenezumab (Roche) lowered oligomeric forms of amyloid beta-protein by 48% compared to a 43% decrease with intravenous crenezumab and no chance with placebo in patients with Alzheimer's disease.
In a 76 patient, Phase II trial, the mean time to develop type 1 diabetes was 48.4 months in patients that received a 14-day course of MacroGenics’ teplizumab compared to 24.4 months with placebo in patients at high-risk of developing type 1 diabetes. Diabetes was diagnosed in 19 (43%) of the teplizumab patients compared to 23 (72%) with placebo.
The FDA approved Sanofi’s dengue vaccine on 5/1/2019 for patients 9 through 16 years who have previously had laboratory-confirmed dengue infection and who live in endemic areas such as the US territories of American Samoa, Guam, Puerto Rico, and the US Virgin Islands.
The FDA approved tafamidis meglumine (Vynaqel, Pfizer) and tafamidis (Vyndamax, Pfizer) 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. In the 30-month, 441 patient, Phase III, ATTR-ACT trial, tafamidis reduced all-cause mortality (30% vs 43%) compared to placebo. Tadamidis also reduced cardiovascular-related hospitalizations, decline in 6-minute walk test and decline in the Kansas City Cardiomyopathy Questionnaire–Overall Summary that measures health status.
the FDA approved onasemnogene abeparvovec (Zolgensma, Novartis) on 5/24/2019 for the treatment of patients under the age of two with bi-allelic mutations in the SMN1 gene. This would include babies with Type 1, 2 or 3 spinal muscular atrophy (SMA). Onasemnogene abeparvovec is administered as a single intravenous infusion. The drug was approved with a black box warning regarding acute serious liver injury. ICER released an addendum to the SMA review after the approval of onasemnogene abeparvovec based on additional clinical data. ICER estimated the drug cost at $1.1 to $1.9 million compared to best supportive care to reach the $100,000 to $150,000 cost effective quality-adjusted life year thresholds and $1.2 million to $2.1 million to be cost effective as the life-year gained threshold. Novartis priced onasemnogene abeparvovec at $2.125 million per dose with the total price paid over five annual installments of $425,000 The price is lower than the $4-5 million cost to treat an SMA patient for 10 years and similar to the higher ICER estimates. Onasemnogene abeparvovec will initially be available at 60 medical centers. The sites will send blood for genetic manipulation to Novartis, who will then deliver the re-engineered treatment to the center.
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.
Rejections & Delays
The FDA rejected the NDA for injectable fosfomycin due to facility inspections and manufacturing deficiencies with its contracted manufacturer for the drug.
Acacia filed an NDA for amisulpride in January 2018. The FDA rejected amisulpride's NDA in October 2018 due to manufacturing issues by it contract manufacturer. Acacia refiled an NDA in November 2018, but in May 2019, the FDA again rejected the drug due to continuing deficiencies at the contract manufacturer. Acacia is now working to get another manufacturer approved by the FDA.
The FDA informed ImmunoGen that it would not accept sub-group data from patients with high levels of folate receptor alpha enrolled in the failed FORWARD I trial evaluating mirvetuximab soravtansine for NDA approval. ImmunoGen will need to run a new Phase III trial in patients with high folate receptor alpha expression, platinum-resistant ovarian cancer before seeking approval.
An FDA review of quizartinib questioned the credibility of some clinical trial data due to inconsistencies, lack of efficacy for secondary endpoints and imbalances between the study arms. The FDA’s Oncology Drug Advisory Committee voted 3 to 8 against recommending approval of quizartinib for the treatment of relapsed or refractory acute myeloid leukemia in May 2019.
Another FDA review of pexidartinib expressed concern about data lacking for physical function, stiffness and range of motion and changes in the statistical analysis plan. The FDA’s Oncology Drug Advisory Committee voted 12 to 3 to recommending approval of pexidartinib for the treatment of giant cell tumor of the tendon sheath May 2019
The FDA has put a partial hold on an axalimogene filolisbac Phase III cervical cancer trial in January 2019, until Advaxis provided additional chemistry, manufacturing and controls information. Under the hold, no new patients could be enrolled in the trial, but current patients can continue to be treated. The FDA lifted the partial band on the cervical cancer trial on 5/15/2019.
Vertex was developing elexacaftor (VX-445) and VX-659 in parallel trials for the treatment of Cystic fibrosis caused by the F508del genetic mutation. Both drugs were used in combination with tezacaftor/ivacaftor. In May 2019 Vertex announced it would cease development of VX-659 and move forward with a combination of tezacaftor/ivacaftor/elexacaftor. Elexacaftor was chosen because it demonstrated more favorable safety and tolerability profile and could be co-administered with hormonal contraceptives. Researchers estimate the combination of elexacaftor with tezacaftor/ivacaftor could treat the underlying cause of CF in 90% of cystic fibrosis patients. Ivacaftor is estimated to treat 40% of patients and the combination of tezacaftor/ivacaftor to treat half of CF patients. Vertex plans to submit an NDA for tezacaftor/ivacaftor/elexacaftor in 3Q19 and a MAA in 4Q19.
Announced Research Updates
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