June Approval Outlook
Two drugs have PDUFA dates in June. Bremelanotide is a subcutaneous Injection being developed to treat hypoactive sexual desire disorder and celiprolol is a beta-blocker being developed to treat Ehlers-Danlos syndromes.
Bremelanotide from AMAG Pharmaceuticals has a PDUFA Date of Jun 23, 2019, after the FDA had delayed review by 3 months. The drug is a Melanocyte-stimulating hormone and administered as a subcutaneous injection. Bremelanotide is being developed as a treatment of hypoactive sexual desire disorder (HSDD) in women. AMAG reported increased desire and lowered distress compared to placebo in two phase III 24-week trials with more than 1,200 women with hypoactive sexual desire disorder. The most common adverse effects are nausea, flushing and headache. No interaction between bremelanotide and alcohol has been reported. We have 6 published studies for bremelanotide in our knowledgebase. Click here to subscribe and view all six studies.
Celiprolol from Acer Therapeutics has a PDUFA Date of Jun 25, 2019. The drug is an oral Beta-blocker being developed as a treatment for Ehlers-Danlos syndromes. In a trial of 53 vascular Ehlers-Danlos syndrome patients, 20% of celiprolol treated patients experienced arterial rupture or dissection, after four-years, compared to 50% with placebo in a study conducted by Greater Paris University Hospitals. Acer performed a retrospective analysis and verified the 2010 study results in 2017. The most common adverse effect reported with celiprolol is fatigue. We have 1 published study for celiprolol in our knowledgebase. Click here to subscribe and view the study.
Next week we will review May’s approvals. Click here to review previous weekly updates.
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As we reported on Friday with our special update, 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 5/24/2019to 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.
Myovant announced that results from the Phase III LIBERTY 2 trial, which is evaluating relugolix and norethindrone in women with uterine fibroids and heavy menstrual bleeding are expected in 3Q19. If like LIBERTY 1 the results are positive, Myovant plans to file an NDA in 4Q19.
Announced Research Updates
Biocryst announced that in a 24-week, 121 patient, Phase II trial, where the 150 mg dose of BCX7353 reduced angioedema attacks by 44% compared to placebo and the 110 mg dose reduced attacks by 30% compared to placebo in patients with Type I and II Hereditary Angioedema.
Lilly announced that in the 12-week, 180 patient, Phase II, SERENITY trial, more patients treated with mirikizumab had a 50% reduction in the severity in the Simple Endoscopic Score for Crohn's Disease (SES-CD) than placebo with 200 mg, 600 mg, and 1000 mg in 25.8%, 37.5%, and 43.8% of patients compared to 10.9% with placebo in patients with moderate to severe Crohn's disease.
ResTORbio announced that in a 16-week, 652 patient, Phase IIb trial, treatment with dactolisib reduced laboratory confirmed respiratory tract infections during flu season by 30.6% compared to placebo in elderly patients at high risk to develop respiratory tract infections. In a subset of 98 asthma patients who were 65 or older, 12% patients treated with dactolisib developed a respiratory tract infection compared to 40% with placebo.
Zynerba announced that in a 12-week, 20 patient, Phase II, open label trial, ZYN002 reduced the Anxiety, Depression, and Mood Scale (ADAMS) score by 15.3 points in patients with fragile X syndrome.
Published Research Updates
In a 48-week, 111 patient, open label extension of a Phase II trial, recombinant human pentraxin 2 continued to slow the decline in forced vital capacity in both patients that continued the drug from the first trial and patients that are switched from placebo.
Happy Memorial Day - Pause and Remember
On May 5, 1868, the head of an organization of Union veterans — the Grand Army of the Republic (GAR) — established Decoration Day as a time for the nation to decorate the graves of the war dead with flowers. Maj. Gen. John A. Logan declared that Decoration Day should be observed on May 30. It is believed that date was chosen because flowers would be in bloom all over the country.
The first large observance was held that year at Arlington National Cemetery, across the Potomac River from Washington, D.C., where the crowd attending the ceremony was approximately the same size as those that attend today’s observance, about 5,000 people. Then, as now, small American flags were placed on each grave — a tradition followed at many national cemeteries today. In recent years, the custom has grown in many families to decorate the graves of all departed loved ones.
By the end of the 19th century, Memorial Day ceremonies were being held on May 30 throughout the nation. State legislatures passed proclamations designating the day, and the Army and Navy adopted regulations for proper observance at their facilities. It was not until after World War I, however, that the day was expanded to honor those who have died in all American wars.
In 1971, Memorial Day was declared a national holiday by an act of Congress, though it is still often called Decoration Day. It was then also placed on the last Monday in May.
The origins of special services to honor those who die in war can be found in antiquity. The Athenian leader Pericles offered a tribute to the fallen heroes of the Peloponnesian War over 24 centuries ago that could be applied today to the 1.1 million Americans who have died in the nation’s wars: “Not only are they commemorated by columns and inscriptions, but there dwells also an unwritten memorial of them, graven not on stone but in the hearts of men.”
To ensure the sacrifices of America ’s fallen heroes are never forgotten, in December 2000, the U.S. Congress passed, and the president signed into law “The National Moment of Remembrance Act,” creating the White House Commission on the National Moment of Remembrance. The commission’s charter is to “encourage the people of the United States to give something back to their country, which provides them so much freedom and opportunity” by encouraging and coordinating commemorations in the United States of Memorial Day and the National Moment of Remembrance.
The National Moment of Remembrance encourages all Americans to pause wherever they are at 3 p.m. local time on Memorial Day for a minute of silence to remember and honor those who have died in service to the nation. As Moment of Remembrance founder Carmella LaSpada states: “It’s a way we can all help put the memorial back in Memorial Day.”
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.
An 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’s Allergenic Products Advisory Committee will review Aimmune Therapeutics’ AR101 on 9/13/2019. AR101 is an oral immunotherapy used to desensitize the patient to Peanut allergy.
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.
Announced Research Updates
Myovant announced that in the 24-week, 388 patient, Phase III, LIBERTY trial, 73.4% 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 18.9% with placebo in patients with uterine fibroids and heavy menstrual bleeding.
UniQure announced interim data from a 52-week, 3 patient, Phase IIb trial, where after 6-months treatment with a single infusion of AMT-061 had a mean increase in Factor IX (FIX) activity of 47% (individual results: 33%, 51%, 57%) and no patient required a Factor IX infusion, experienced a bleeding event or required immunosuppression.
The Medicines Company announced that in Orion-3, a 3-year extension study of ORION-1, inclisiran lowered LDL at least 50% at all doses and frequency.
Published Research Updates
The 20-month, 572 patient, Phase III SOLAR-1 trial enrolled a population of men and postmenopausal women with HR+/HER2- advanced breast cancer whose cancer progressed after at least 12 months of an aromatase inhibitor therapy. In a subset of 341 who harbored PIK3CA mutations, PFS was 11 months with alpelisib/fulvestrant and 5.7 months with fulvestrant monotherapy. In the subset whowithout PIK3CA-mutated cancer, the overall response rate was 26.6% with alpelisib/fulvestrant compared to 12.8% with fulvestrant monotherapy.
In a 28-day, 256 patient, Phase III trial, brimapitide did not improve hearing loss compared to placebo in patients with unilateral idiopathic sudden sensorineural hearing loss (ISSNHL). A post-hoc analysis found a benefit in patients with profound ISSNHL.
In a 187 patient, Phase I, open-label trial, treatment with erdafitinib resulted in a 46.2% overall response rate (ORR) in patients with urothelial carcinoma and a 27.3% ORR in patients with cholangiocarcinoma in patients with treatment resistant, pan-fibroblast growth factor receptor (FGFR) positive tumors. The ORR for all other tumor types of < 10%.
In a 560-patient trial, 31.4% of patients treated with amisulpride had no emesis or need of rescue medications compared to 21.5% with placebo in patients at low-to-moderate risk for PONV who had not received any prior prophylaxis.
Multiple myeloma is a cancer of plasma cells. While 90% of patients will survive to five years, expectancy decreases with more serious stages. Median survival is 83 months for Stage II patients and drops to 43 months for Stage 3 patients.
We are currently tracking four drugs in development for multiple myeloma
Opaganib, an oral SK2 inhibitor being developed by RedHill Biopharma and has been designated an orphan drug by the FDA. Redhill announced interim results from the Phase Ib part of a Phase Ib/II refractory or relapsed multiple myeloma trial where 2 patients had stable disease for over four months and one a partial response. Redhill has three ongoing Phase II trials evaluating opaganib for the treatment of cholangiocarcinoma, advanced liver cancer and multiple myeloma.
Isatuximab, an intravenous Anti-CD38 antibody being developed by Sanofi and has been designated an orphan drug by the FDA and EMA. In a 57 patient, Phase I, open label trial, treatment with isatuximab/lenalidomid/dexamethasone demonstrated a 56% ORR in relapsed/refractory multiple myeloma. In a 45 patient, Phase Ib, open label trial, treatment with isatuximab/lenalidomid/dexamethasone demonstrated a 62% overall response rate and 18.7-month progression-free survival in relapsed/refractory multiple myeloma. Sanofi announced that in a 307 patient Phase III trial, isatuximab added to pomalidomide and low-dose dexamethasone improved progression free survival compared to pomalidomide and dexamethasone alone in patients with relapsed/refractory multiple myeloma. Sanofi plans to submit and NDA in late 2019. Sanofi has three ongoing Phase III clinical trials evaluating isatuximab in combination with standard care for patients with relapsed/refractory or newly-diagnosed multiple myeloma.
Plitidepsin is an oral Apoptosis inducer being developed by PharmaMer and has been designated an orphan drug by the FDA and EMA. PharmaMar announced that in the 255 patient, Phase III ADMYRE trial, where multiple myeloma patients treated with plitidepsin plus dexamethasone had a PFS of 3.8 months compared to 1.9 months with dexamethasone monotherapy and OS of 11.6 months versus 6.4 months. Plitidepsin is also being evaluated for the treatment of angioimmunoblastic T-cell lymphoma.
The most advanced drug being developed for multiple myeloma is selinexor, a Selective Inhibitor of Nuclear Export/ SINE compound being developed by Karyopharm and has been granted orphan drug and Fast Track status by the FDA. Selinexor has a PDUFA date of July 6, 2019. In a 42 patient, Phase II trial, treatment with selinexor in combination with low-dose bortezomib and dexamethasone resulted in a 63% overall response rate and progression-free survival of 9 months in patients with relapsed or refractory multiple myeloma. In a 79 patient, Phase II trial, treatment with selinexor in combination with low-dose bortezomib and dexamethasone resulted in a 21% overall response rate in patients with heavily pretreated, refractory myeloma with limited therapeutic options. Karyopharm announced that in the 122 patient, Phase IIb, STORM trial, treatment with selinexor in combination with dexamethasone resulted in a 26% overall response rate in patients with highly resistant multiple myeloma. An FDA review of selinexor found limited efficacy and significant toxicity in patients with relapsed/refractory multiple myeloma treated with a combination of selinexor dexamethasone. Based on data submitted and historical studies with high-dose dexamethasone, the FDA felt it was difficult to isolate the treatment effect of selinexor. On 2/26/2019, the FDA Oncologic Drugs Advisory Committee recommend a delay in approval of selinexor-dexamethasone to treat triple class-refractory myeloma until after the results of the Phase III BOSTON trial are 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 bempedoic acid and a combination bempedoic/ezetimibe tablet in May 2019 and set a PDUFA date of 2/21/2020 for bempedoic acid and 2/26/2020 for the combination.
The FDA granted cannabidiol gel Fast Track Status for the treatment of Fragile X syndrome in May 2019.
The FDA granted leronlimab Fast Track status in May 2019 for use in combination with carboplatin for the treatment of patients with CCR5-positive metastatic triple-negative breast cancer.
The EMA approved volanesorsen as adjunct treatment of familial chyromicronemia syndrome (FCS) after diet adjustment and triglyceride therapy in May 2019.
Announced Research Updates
Voyager announced that in an open label, 1-year, 8 patient, Phase I trial, treatment with VY-AADC increased on-time without dyskinesia by 1.7 hours, decreased off-time by 2.2 hours and decreased the Parkinson's Disease Questionnaire (PDQ-39) score by 7.6 points in patients with Parkinson's disease.
Alder announced that in the 24-week, 1,072 patient, Phase III, PROMISE-2 trial, eptinezumab reduced monthly migraine days 2.1 to 2.6 days more than placebo and 57% reported much/very much improvements in their most bothersome symptom compared to 41% with placebo.
Published Research Update
In a 3.2-year, 105 patient, Phase I/II, open label, dose ranging trial, treatment with guadecitabine resulted in an overall response (a composite of complete response, partial response, marrow complete response, and hematological improvement) in 40-51% of patients with hypomethylating agent treatment-naive or relapsed or refractory patients with intermediate-risk or high-risk myelodysplastic syndromes.
In a 3-month, 46 patient, Phase I/II, dose ranging trial, RG6042 reduced mutant huntingtin protein levels in the CSF by 20-38% compared to placebo in patients with early stage Huntington's disease.
In the 27.4-month, 1,015 patient, phase III, TRINOVA-3/ENGOT-ov2/GOG-3001 trial, patients received six cycles of trebanaib/paclitaxel/carboplatin or placebo, followed by trebanaib or placebo maintenance therapy for 18 months. Median progression free survival (PFS) did not differ between trebanaib and placebo (15.9 vs 15 months).
In a 48-week, 48 patient, Phase II trial, 99% of patients treated with ublituximab achieved at least a 95% reduction in peripheral CD19+ B cells within 2 weeks after the second infusion on day 15 in patients with relapsing forms of multiple sclerosis.
In a 106 hepatorenal syndrome (HRS) patient trial, 48% of patients treated with terlipressin and albumin had a reversal of HRS type 1 (rapidly progressive loss of renal function) and 46% had a reversal of HRS type 2 (chronic ascites and more moderately elevated renal parameters).
Spinal muscular atrophy (SMA) is an autosomal recessive neurodegenerative disease. Most cases of SMA are due to the SMN1 gene not being present, which results in a deficiency of survival motor neuron (SMN) protein. A lack of the SMN protein leads to progressive muscle weakness with a rapid onset in the most severe forms of the disease.
There are five types of SMA. They are numbered from type 0 to type 4. Classification is based on the severity of the disease and the age of onset. SMA Type 0 is unique because symptoms start in utero, so the infant is born in severe distress with extreme weakness and hypotonia, and often with areflexia. The infants do not survive the neonatal period without intervention and respiratory failure leads to death in one to six months. The symptoms in children with SMA type 1 (SMA1) occur in the first six months of life. SMA1 represents 60% of SMA cases. Symptoms in patients with SMA1 progress rapidly. Muscle weakness leads to difficulty breathing and feeding and the life expectancy is less than two years. Children with SMA2 have an intermediate form of the disease with symptoms appearing before 18 months. Patients are able to sit, but not able to stand and usually survive into adulthood. SMA3 symptoms begin after 18 months and are milder than SMA2. Patients are able to stand, sometimes walk and survive into adulthood. Patients may lose some motor abilities as they age. Patients with SMA4 have an onset of disease in adulthood, are able to stand and walk, and have normal lifespans.
Because research has focused on the most severe forms of SMA the rest of the review will discuss treatment for SMA1. Before the availability of nusinersen and in patients that are not candidates for the drug, treatment consisted of intensive respiratory treatments, nutrition, physical therapy and surgery. Respiratory treatments include use of devices to improve ventilation and secretion clearing, which may include non-invasive and invasive ventilator support. Enteral nutrition is needed to maintain caloric intake. Daily range of motion exercises are used to treat joint contractures and scoliosis. Bracing is used to maintain position and surgical procedures may be used for internal support of the spine. Use of these interventions slow the course of the disease and prolong life.
Nusinersen (Spinraza) is an antisense oligonucleotide treatment for spinal muscular atrophy that was approved by the FDA in 2016. The drug binds to SMN2 pre-mRNA to displace a repressor protein leading to full-length SMN2 mRNA, which leads to a stable, and functional SMN protein. Nusinersen is administered intrathecally, because it does not cross the blood-brain barrier. It is recommended that patients be sedated during administration, therefore the drug is administered in a hospital or surgery center that provides infusion services. Treatment with nusinersen is initiated with a four-dose schedule with the first three doses given at two-week intervals, then the fourth 30 days later. After the initial loading doses, nusinersen is given once every 4 months. Because nusinersen is an antisense oligonucleotide the labeling warns of a risk for thrombocytopenia, coagulation abnormalities, and renal toxicity and recommends platelet count, coagulation testing and quantitative spot urine protein at baseline and before each dose. The WAC for each dose of nusinersen is $125,000. Therefore, the cost of nusinersen in the first year is $750,000, then $375,000 annually for the maintenance dose.
Two pivotal nusinersen trials have been published. Both trials were stopped early after interim analysis demonstrated significant positive efficacy. In the 6-month, 110 patient, Phase III, ENDEAR trial, 51% of patients (37 of 73) that received nusinersen achieved a motor-milestone response as defined by the Hammersmith Infant Neurological Examination compared to none who received placebo in SMA infants with two copies of SMN2 and onset of symptoms at 6 months of age or younger (SMA type 1). Patients in the nusinersen group also had a higher likelihood of event-free survival. In the 15-month, 110 patient, Phase III, CHERISH trial, 57% of patients that received nusinersen had an improvement in the Hammersmith Functional Motor Scale-Expanded (HFMSE) score of at least 3 points compared to 26% that received placebo in patients with late onset SMA (SMA type 2 or 3). The Children’s Hospital of Philadelphia Infant Test of Neuromuscular Disorders (CHOP INTEND) scale of motor function score was 61-62.6. Biogen announced interim results from the Phase II, open-label, NURTURE trial. NURTURE is evaluating nusinersen in 25 presymptomatic infants with SMA. Upon enrollment the infants were 6 weeks or younger, genetically diagnosed with SMA, but had not yet developed symptoms of SMA. At the time of the interim analysis all participants were alive and 14 months or older. No patient required tracheostomy or permanent ventilation and 22 patients were able to able to walk independently or with assistance.
Roche is developing risdiplam, an oral drug that increases the production of SMN by promoting inclusion of exon 7 in SMN2 mRNA. There is no indication on price, but the simplified administration may reduce total cost, when the drug is approved. Roche announced interim data from 17 patient that received the risdiplam dose for the Phase III portion of the the Phase II/III FIREFISH, open label trial, 93% of infants treated with risdiplam for at least 12 months had improved motor function by a median 17.5 points on the CHOP-INTEND scale and 64.5% were able to sit and 52.9% were able to maintain upright head control in patients with Type 1 spinal muscular atrophy. Three patients died but none were felt to be related to treatment.Roche also announced 12-month interim data from the 51 patient, Phase II/III SUNFISH trial; 71% of children age 2 to 11 and 42% of those aged 12-25 years treated with risdiplam improved motor function by at least 3 points on the MFM32 scale in patients with Type 2/3 spinal muscular atrophy. Roche also has trials in patients with SMA type 2/3 (JEWELFISH) and pre-synaptic SMA (RAINBOWFISH). Roche plans to submit an NDA for risdiplam in 2019.
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). Because the drug crosses the blood-brain barrier, it is administered as a one-time intravenous infusion. Onasemnogene abeparvovec prevents further muscle degeneration by providing a copy of the human SMN gene, allowing sustained SMN protein expression. Onasemnogene abeparvovec is a nonreplicating adenovirus (scAAV9) vector containing complementary DNA encoding the normal SMN. If long term data shows the effect of the therapy declines over time, it is likely that onasemnogene abeparvovec could not be repeated, because the patient would develop antibodies to it. The drug was approved with a black box warning regarding acute serious liver injury. 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.
In a 20-month, 15 patient, Phase I trial, treatment with onasemnogene abeparvovec 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 in patients treated with onasemnogene abeparvovec compared to a decline in the historical control. Novartis announced that 10 patients enrolled in a long-term follow-up of the Phase I START trial had maintained the motor function and milestones gained during the trial at a mean 3.7 years follow-up. Novartis announced interim data from 22 patients in the Phase III, STR1VE trial, where treatment with onasemnogene abeparvovec resulted in a 14.3 point improvement in the CHOP INTEND score at five months in patients with SMA type 1 with one or two copies of the SMN2 backup gene and who have bi-allelic SMN1 gene deletion or point mutations. 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. A second Phase III trial is being conducted in Europe called STR1VE-EU. Results are not currently available, but one death has occurred in the trial. A preliminary examination suggested the death was due to severe respiratory infection followed by neurological complications, which was deemed possibly related to treatment. Novartis announced interim data from 19 patients in the Phase I, STRONG trial, where a single intrathecal injection of onasemnogene abeparvovec improved the HFMSE score by a mean 4.2 points at a mean average follow-up of 6.5 months post-treatment in patients with SMA type 2 with three copies of the SMN2 gene. Novartis also announced interim data from 18 patients in the Phase I, SPRINT trial, where a single intrathecal injection of onasemnogene abeparvovec improved the HFMSE score by a mean 8.9 points at a mean average follow-up of one months post-treatment in in pre-symptomatic patients with SMA and two or three copies of SMN2 who are ≤6 weeks of age.
Both onasemnogene abeparvovec and nusinersen may offer more benefit if used earlier or in presymptomatic patients. All three drugs are being evaluated in presymptomatic patients: nusinersen in the NURTURE trial, onasemnogene abeparvovec in the SPRINT trial and risdiplam in RAINBOWFISH. Long term trials of all three drugs are also needed as the effects of chronic administration are not known.
The Institute for Clinical and Economic Review or ICER reviewed nusinersen and onasemnogene abeparvovec for the treatment of Spinal Muscular Atophy and developed a cost effectiveness review that was finalized in April 2019. ICER used WAC for nusinersen to calculate a quality-adjusted life year (QALY) of $1.1 million as compared to best supportive care for SMA patients. ICER estimated that nusinersen would need to cost between $72,000 and $130,000 for the first year of treatment, with a maintenance cost $36,000 to $65,000 per year to be within the cost-effectiveness thresholds of $100,000-$150,000 per QALY. In calculating the cost based on the additional number of years a person lives due to a treatment, which is referred to as the life-year gained (LYG), ICER estimated that nusinersen should cost $83,000 to $145,000 in year one, and $41,000 to $72,000 for maintenance therapy to be in a range of $100,000-$150,000 per LYG. 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 cost effective QALY thresholds and $1.2 million to $2.1 million to be cost effective as the LYG 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. AveXism said that if ICER had compared onasemnogene abeparvovec to nusinersen, instead of best supportive care, the drug would have been found to be cost effective up to $5 million. Novartis may agree to a performance-based agreement on pricing for onasemnogene abeparvovec as it has for tisagenlecleucel, where Novartis is only reimbursed for patients for whom the drug works.
Onasemnogene abeparvovec has the potential to replace nusinersen as the treatment of choice, even at a seven-figure price. An indirect comparison of the two drugs based on the 15 patient Phase I onasemnogene abeparvovec trial and the 73 patients that received nusinersen in the ENDEAR trial suggested an advantage of onasemnogene abeparvovec over nusinersen. However, with such a small patient population, a definitive conclusion should not be made. Nusinersen could eventually have competition from risdiplam. Assuming Roche submits an NDA for risdiplam in late 2019, the drug could be available in 2020.
As we reported on Tuesday, the FDA approved tafamidis meglumine (brand name: Vynaqel, from Pfizer) and tafamidis (brand name: Vyndamax from 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. Transthyretin-mediated amyloidosis is a rare, debilitating and often fatal genetic disease characterized by the accumulation of abnormal amyloid protein in peripheral nerves, the heart and other organs. Tafamidis meglumine had been granted a priority review with a July 2019 PDUFA date and the free acid of tafamidis had a standard review with a November 2019 PDUFA date.
In the 30-month, 441 patient, Phase III, ATTR-ACT trial, tafamidis reduced all-cause mortality (30% vs 43%) compared to placebo. Tafamidis 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. Tafamidis was dose at both 20 mg and 80 mg per day. The two doses were not compared, instead the authors combined the results when comparing the drug to placebo.
The recommended dosage in the approved labeling 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. Tafamidis was approved in EU for Transthyretin Familial Amyloid Polyneuropathy (hTTR-FAP) in 2011. In Europe it is dosed at 20 mg per day to treat transthyretin familial amyloid polyneuropathy (hTTR-FAP). The FDA rejected the drug in 2012 for the treatment of hTTR-FAP because of a failed U.S. trial and requested an additional clinical trial. Pfizer
Tafamidis reduces the formation of TTR amyloid by stabilizing the TTR tetramers that contain mutant amyloid, which prevents the release of amyloidogenic monomers and joins two other drugs which were approved in 2018 that decrease TTR synthesis: patisiran and inotersen.
Patisiran (Onpattro) and inotersen (Tegsedi) were approved for the treatment of hereditary hTTR-FAP. Inotersen is administered as a weekly subcutaneous injection and has a black box warning for thrombocytopenia and glomerulonephritis. Patisiran is given as an intravenous infusion every three weeks.
Both patisiran and inotersen have an annual WAC price of $450,000. The Institute for Clinical and Economic Review (ICER) estimated the discounted price to be $345,000 per year. ICER’s analysis found that compared to best supportive care inotersen would need to cost $96,103 and patisiran would need to cost $200,000 to reach a quality-adjusted life year (QALY) of $500,000/ To reach a QALY of $150,000, inotersen would need to cost $25,000 and patisiran would need to cost $46,000.
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. 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.
The FDA accepted the NDA for darolutamide on 4/29/2019 and granted a priority review suggesting a November or December PDUFA date.
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.
Novo submitted an NDA for semaglutide in March 2019 and an MAA in April 2019.
Janssen and ViiV have submitted an NDA for a once monthly injection of cabotegravir and rilpivirine.
The EMA approved sotagliflozin in April 2019 for the treatment of Type 1 Diabetes.
Eisai bought out Purdue Pharma’s stake in lemborexant in April 2019.
Announced Research Updates
VistaGen announced that in a 14-day, 19 patient, Phase II, crossover trial, AV-101 did not improve the Hamilton Depression Rating Scale (HDRS) compared to placebo in patients with treatment-resistant depression.
Lilly announced that in an analysis of 4,439 patients in the SPARTAN and SAMURAI, the most common adverse effects with lasmiditan were dizziness, paresthesia, drowsiness, fatigue, nausea, weak muscles, and hypoesthesia.
Published Research Update
In the 12-week, 21 patient, Phase II, PIONEER-HCM trial, mavacamten 10-20 mg monotherapy reduced post-exercise peak left ventricular outflow tract (LVOT) gradient by 89.5 mm Hg and mavacamten 2-5 mg plus beta-blockers reduced post exercise LVOT gradient by 25.0 mm Hg in patients with symptomatic, obstructive hypertrophic cardiomyopathy.
In a 33 patient, Phase I trial, treatment with bb2121 resulted in an objective response in 85% of patients, complete remissions in 15 (45%) patients (6 had a relapse), progression-free survival of 11.8 months in patients with relapsed or refractory multiple myeloma.
In an 8-week, 265 patient trial, blonanserin was not inferior to haloperidol with a non-significant PANSS total score of -10.3 vs -7.1.
In the 429 patient, Phase III, FORWARDS-3 trial, samidorphan/buprenorphine was no different than placebo in the treatment of major depressive disorder. The decrease in the MADRS-10 score was 4.8 vs 4.6.
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.
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