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.
March was a busy review month for the FDA, but in April, there is only one PDUFA deadline. Risankizumab (Skyrizi, Boehringer Ingelheim and AbbVie) is an interleukin-23 inhibitor being developed for the treatment of Psoriasis and Crohn’s disease. The drug is an Orphan Drug and has a PDUFA date of 4/25/2019. Risankizumab will compete with other IL-23-targeting drugs (ustekinumab, tildrakizumab, guselkumab), IL-17 blockers (secukinumab) and TNF-blockers (adalimumab, etanercept). The drug is given as a subcutaneous injection every three months. The NDA is based on four Phase III trials. In two trials 75% of risankizumab patients achieved Psoriasis Area and Severity Index (PASI 90) compared to 42 to 48% with ustekinumab and 2 to 5% with placebo. In a third 72% of risankizumab patients achieved PASI 90 compared to 47% with adalimumab. The fourth trial was a withdrawal and re-treatment trial where 73% of risankizumab patients achieved PASI 90 compared to 2% with placebo.
The FDA approved solriamfetol (Sunosi, Jazz Pharmaceuticals) on 3/20/2019 to improve wakefulness in adults with excessive daytime sleepiness associated with narcolepsy or obstructive sleep apnea.
The FDA approved brexanolone (Zulresso, Sage Therapeutics)on 3/19/2019 for the treatment of postpartum depression.
The FDA granted Qualified Infectious Disease Product (QIDP)to the oral and IV formulations of sulopenem in March 2019.
The FDA rejected sotagliflozin on 3/22/2019.Lexicon and Sanofi are working with the FDA to determine future development of the drug.
Spectrum withdrew the BLA for eflapegrastimto provide more information to the FDA on the chemistry, manufacturing and controls process.
Two Trials Published
In a draft cost-effectiveness analysis, ICER estimated a quality-adjusted life year of $826,000 for use of siponimod in the treatment of secondary progressive multiple sclerosis, assuming the same cost for siponimod as ocrelizumab.
In a 48-hour, 389 patient, Phase III trial, 50% of Trevena’s oliceridine 0.1 mg patients, 62% of 0.35 mg patients and 65.8% of 0.5 mg patients reached the combination endpoint of a 30% or > improvement in pain (SPID-48), received no rescue drugs, completed the study period and did not reach dosing limits compared to with 15.2% that received placebo in patients with moderate-to-severe pain following bunionectomy. The 0.35 mg and 0.5 mg doses were non-inferior to morphine in reaching the primary endpoint. In a 389 patient, Phase III trial, GI ADR increased in a dose-dependent manner in oliceridine regimens; 40.8% with 0.1 mg, 59.5% with 0.35 mg and 70.9% with 0.5 mg compared to 24.1% with placebo and 72.4% with morphine.
Five Announced Investigational Drug Developments
Potential Blockbuster Approvals in 2019
Four forecast as having $1 billion in sales by 2023
ClarivateAnalytics™ in its Cortellis™ Drugs to Watch 2019 report published a forecast of four drugs that may be approved in the U.S. in 2019, which they forecast as having $1 billion in sales by 2023. All four drugs have been designated Orphan Drugs. In addition, there are three drugs with breakthrough status and two have Fast Track status. The four drugs are being developed to treat a variety of diseases, but surprisingly none are oncology drugs.
About Cortellis: Cortellis™, a suite of life science solutions from Clarivate Analytics™, curates the broadest and deepest sources of intelligence to enable precise, actionable answers to specific questions across the R&D lifecycle – from discovery and clinical development through regulatory submission and commercialization.
The FDA approved netarsudil and latanoprost ophthalmic solution (Rocklatan, Aerie Pharmaceuticals) on 3/13/2019 to decrease elevated intraocular pressure in patients with open-angle glaucoma or ocular hypertension.
In March 2019, the FDA delayed the PDUFA date for Karyopharm Therapeutics’ selinexor by three months (from April 6, 2019 to July 6, 2019).
The FDA accepted the NDA for ubrogepant on 3/11/2019. Allergan expects a 4Q19 PDUFA date of 12/27/19
The FDA accepted the NDA for lemborexant on 3/11/2019. Allergan expects a 4Q19 PDUFA date of 12/27/19
The FDA granted Orphan Drug status to Armetheon’s tecarfarin for the prevention of systemic thromboembolism of cardiac origin in patients with End Stage Renal Disease (ESRD) and Atrial Fibrillation (AFib).
Celgene filed an MAA filed for ozanimod in March 2019.
New Published Research
In a Phase III, open label, follow-up safety study, 49% completed the Alkermes samidorphan/buprenorphine study and had a mean MADRS score decrease from 22.9 at baseline to 9.8 with a remission rate of 52.5%. There were 11% of patients that discontinued due to an adverse event. The most common ADR were nausea, headache, constipation, dizziness, and somnolence. There was no evidence of an increased risk for suicidal ideation or behavior or withdrawal. There was a 1.2% incidence of euphoria-related events. No meaningful changes in laboratory values, metabolic parameters or bodyweight were found.
In a 12-week, 2,230 patient, Phase III trial, Esperion Therapeutics’ bempedoic acid lowered LDL 18% compared to a 2% increase with placebo in patients with atherosclerotic cardiovascular disease, heterozygous familial hypercholesterolemia, or both not adequately controlled on maximally tolerated statins. The frequency of ADR at 52 weeks was similar between bempedoic acid and placebo for all events (78.5% and 78.7%) or serious events (14.5% and 14.0%). Bempedoic acid patients experienced more gout (1.2% vs 0.3%). This was a non-significant increased incidence of heart failure hospitalizations and increased mortality, but the incidence was 0.5% or less.
New Announced Research
TG Therapeutics announced interim data from 69 patients in the open label, Phase II, UNITY-NHL trial. The UNITY-NHL trial is evaluating umbralisib as a treatment for multiple kinds of Non-Hodgkin's lymphoma. A cohort of 69 patients with Marginal Zone Lymphoma had an overall response rate of 40-50%. TG Therapeutics expects to file an NDA for umbralisib in late 2019.
A 35 patient, Phase II resistant renal cell carcinoma trial was stopped early due to inadequate response with Amgen’s trebananib and an anti-VEGF agent.
Akebia announced interim data at 24 weeks from a 52-week, 304 Japanese patient, Phase III, open label trial, where vadadustat was non-inferior to darbepoetin alfa in mean Hb (11.66 g/dL vs 11.93 g/dL) in patients with non-dialysis dependent CKD. Akebia also announced interim data at 24 weeks from a 52-week, 323 Japanese patient, Phase III, trial, in which vadadustat was non-inferior to darbepoetin alfa in mean Hb (10.61 g/dL vs 10 g/.65dL) in patients with hemodialysis-dependent CKD. Akebia announced that in a 24-week, 42 Japanese patient, Phase III, open label trial, treatment with vadadustat resulted in a mean Hb of 11.35 g/dL in patients with peritoneal dialysis-dependent CKD.
Arena announced that in the 12-week, 156 patient, Phase II, OASIS trial, treatment with etrasimod improved the Mayo Clinic Score (a composite of rectal bleeding, stool frequency, and endoscopic findings) 1 point more than placebo in patients with moderate to severe ulcerative colitis. Etrasimod 2 mg, but not 1 mg achieved endoscopic improvement (16.3% vs. 43.2%), histological improvement (10.2% vs. 31.7%), and histological remission (6.1% vs. 19.5%) compared to placebo. Arena also announced that in a 34-week, 118 patient open label extension of the OASIS trial 84 patients received 2 mg of etrasimod during the extension study with 79% achieving a clinical response, 39% achieving clinical remission and 51% had endoscopic at 46 weeks. Among 22 patients who also received 2 mg of etrasimod during the OASIS trial, 82% experience clinical response, 50% were in clinical remission and 55% had endoscopic improvement. In the patients that achieved a clinical response or clinical remission in OASIS, 93% experienced sustained response and 75% experienced sustained remission at both 12 and 46 weeks.
Lilly announced that in a 12-week, 249 patient, Phase II trial, treatment with mirikizumab 200 mg resulted in greater remissions than placebo in patients with moderate-to-severe ulcerative colitis who had failed at least one conventional drug. Treatment with 50 mg or 600 mg was no different than placebo. Patients that achieved a clinical response at week 12 (93 patients) were randomly reassigned to mirikizumab 200 mg subcutaneously every 4 weeks or every 12 weeks. At week 52, 46.8% of the q4w patients and 37% of the q12w patients were in clinical remission, while 57.4% of q4w patients and 47.8% of the q12w patients had endoscopic scores of zero or one.
Bayer announced that in the 52-week, 330 patient, Phase III, CHICO trial, treatment with 60 days of nifurtimox resulted in a superior serological response compared with historical placebo control in pediatric patients with acute or chronic Chagas disease.
Three FDA Actions Last Week, Celgene’s Plans and Fourteen Research Updates
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.
The FDA has granted fedratinib a priority review, with a PDUFA date of 9/3/2019. There are now twenty-five investigational drugs with PDUFA Dates between March 14, 2019 and December 25, 2019
The FDA removed the Breakthrough Therapy designation for oliceridine because current data did not support the designation. The FDA does feel the current safety data will support a refiled NDA after Trevena completes a Phase I safety study examining QT-interval prolongation.
Celgene plans to submit an NDA for ozanimod in March 2019 and a BLA for luspatercept in April.
Drugs with March PDUFA Dates
The FDA has several drugs with PDUFA Dates in March. One was approved earlier this week and six more have PDUFA Dates coming up in the coming days.
On March 5, 2019 the FDA approved esketamine nasal spray, in conjunction with an oral antidepressant, for the treatment of resistant depression. The labeling for esketamine nasal spray contains a Boxed Warning describing a risk for sedation and difficulty with attention, judgment and thinking (dissociation), abuse and misuse, and suicidal thoughts and behaviors. The drug is only available through a restricted distribution system, under a Risk Evaluation and Mitigation Strategy (REMS). Esketamine must be administered in a certified medical office where the health care provider can monitor the patient for a minimum of 2 hours and determine when the patient can leave. The patient also needs transportation to and from the visit for a dose because they are unable to drive until the day after a dose. Since the patient cannot take the spray home, the treatment sites will need to determine where patients will wait during the monitoring period and coordinate patient visit to avoid a slowdown in office workflow. WAC for esketamine nasal spray is $590 to $885 per treatment session. The drug is dosed twice a week for the initial 4 weeks, so the monthly cost will be $4,720 to $6,785. Esketamine nasal spray is dosed once weekly during the second month ($2,360 to $3,540). In the third month the patient may continue weekly dosing or have their dosing further reduced to every other week, so the WAC price for maintenance dosing is $1,180 to $3,540.
Drug with upcoming PDUFA Dates in March
Seven non-oncology development updates included below.
The FDA delayed a decision on NKTR-181 by three months to allow additional time to review preclinical data from two additional studies and set a new PDUFA date of 8/29/2019.
On 2/28/2019, 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.
The FDA accepted an NDA for diroximel fumarate on 2/25/2019 suggesting a PDUFA date of 12/25/2019.
The FDA designated AT-GAA as a Breakthrough Therapy in February 2019.
Twelve investigational drug developmental updates:
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