There is a gap in current formulary decision support tools: how to prepare for the annual avalanche of new drug approvals. The FDA approved 59 investigational drugs for distribution in 2018, beating the 2017 total of 46. The number of approvals in 2018 also sets a record for the number of new drug approvals in a single year. The previous highest annual total was 53 in 1996.
Almost 3/4 of the drugs (43) had priority reviews. Almost half of the priority reviews were filed as orphan drugs (34), while 58% were for rare diseases, 41% had Fast Track status and almost a quarter were designated as Breakthrough Therapies (14).
Tools are available that provide comparisons of available drug products. Such offerings may include a drug’s comparative efficacy, therapeutic role and class monographs to assist with drug therapy decisions. Clinicians can access services that detail the information, including access to past reviews, about recently released and investigational drugs. But with an average of between 3.8 and 5.9 new drugs approved every month, keeping up with their approval status is almost unviable. Additionally, current tools do not provide actionable intelligence about pending multiple drug approvals for the same indication, class or therapeutic category. For example, in 2018 three drugs were approved for migraine prophylaxis: Erenumab (Aimovig), Fremanezumab (Ajovy), and Galcanezumab (Emgality).
In May, upon the approval of erenumab we included the following advisory statement within the Pharmaceutical Pipeline Tracker’s monograph for the drug. The advisory statement was updated in the fall as ICER released a final version of its review and two additional drugs were approved.
“The FDA approved erenumab on 5/17/18 for the prevention of migraine. The drug will have an annual WAC price of $6,900. Monthly Sub-Q injection. Erenumab is available as a patient administered auto-injector. Lilly plans to offer an auto-injector for galcanezumab. Fremanezumab is a more viscous solution and will initially be offered as a prefilled syringe. So, while the drug may be approved as a quarterly subcutaneous injection, it may require a visit to a physician's office for administration, while monthly doses of galcanezumab and erenumab can be administered by the patient. Teva is working on an auto-injection system for fremanezumab, but it is not known when it will be available. Express Scripts is pushing CGRP inhibitor manufacturers to set a lower price for their drug, rather than set a high price and offer a rebate. Express Scripts also wants to set up performance contracts for the drugs based on efficacy on use of the drug in their patients. ICER released a final review of CGRP inhibitors on July 3, 2018. ICER found insufficient evidence to recommend erenumab or fremanezumab over oral preventative drugs or botulism toxin for prevention of migraine in untreated patients. ICER did find evidence of a benefit for use of erenumab or fremanezumab in patients that had previously failed preventative therapy for chronic migraine. Data was supportive but inconclusive for prevention of episodic migraine. ICER found insufficient evidence for use of galcabezumab in either indication. The drugs were found to be safe with the most common ADR of injection site reactions and upper respiratory symptoms. CGRP inhibitors were estimated to improve quality of life years (QALY) for episodic and chronic migraine patients. With an announced WAC price of $6,900/year for erenumab, ICER estimates an annual cost of $5,000/year after discounts. ICER estimated a price of $3,700 to $5,300 per year to be cost effective. Erenumab or fremanezumab were found to be cost effective in QALY gained in patients that had failed at least one preventative therapy. The estimated cost per QALY was lower for chronic migraine compared to episodic migraine. ICER felt that insurers would be justified in setting limits or restrictions on CGRP inhibitors due to insufficient long-term safety data and high cost.”
This was actionable intelligence upon which to weigh whether to wait for all three approvals before adding any of the new drugs to the formulary.
Alder Biopharmaceutials has submitted a BLA for eptinezumab. If approved, this will be the fourth member of the class. We are currently monitoring this drug and updating our advisory as new information becomes available. Eptinezumab will be dosed quarterly, but unlike the other drugs, it is administered by IV infusion.
Another gap in the current set of formulary decision support tools is the lack of ability to anticipate the timing of the introduction of budget busting drugs: those given priority review and/or priority designations. Only a select number of drugs are deemed eligible for priority review. Typically, those given priority represent significant medical breakthroughs or offer treatment where few or no other options exist. Priority review is often granted to drugs that aim to treat serious medical conditions. Between March and the end of September 2019, there are eighteen investigational drugs with PDUFA Dates. Two of those drugs were added to the list just this month. The FDA approved Caplacizumab with orphan drug priority designation on its February 6, 2019 PDUFA date for the treatment of Acquired Thrombotic Thrombocytopenic Purpura (aTTP). It was and is the only investigational drug targeted to treat the indication.
In a recent editorial, Marilyn Speedie, dean emeritus, University of Minnesota College of Pharmacy explored the widespread agreement about the importance of controlling prescription drug costs. She stated that one extremely important piece of the solution is to fully enlist pharmacists in optimizing the use of the medications the public and health plans are paying for. Being prepared for the release of expensive new drugs, their benefit and their challenges can help control the cost of drug therapy, so the right drug is used in the right patient at the right time.
Let’s get together and discuss how the Pharmaceutical Pipeline Tracker can fill the current gap in your formulary decision support suite.
FDA approved one drug and added four new PDUFA Dates
The FDA approved turoctocog alfa pegol (Esperoct from Novo Nordisk) on 2/21/2019 for the treatment of hemophilia A, however due to a contractual agreement, the drug will not launch until 2020. Esperocot is a long acting version of NovoEight (turoctocog alfa).
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. The FDA's Oncologic Drugs Advisory Committee will review selinexor on 2/26/2019.
New PDUFA dates
In the 1,509 patient, Phase III ARAMIS trial, the most common ADR with darolutamide compared to placebo was fatigue.
Reata announced that in the 12-week, 103 patient, Phase II, open-label, PHOENIX study, patients treated with bardoxolone had an increase in their mean estimated glomerular filtration rate (eGFR) from of 7.8 mL/min/1.73 m2 improvement in patients with patients with autosomal dominant polycystic kidney disease, IgA nephropathy, Focal Segmental Glomerulosclerosis, and type 1 diabetic chronic kidney disease.
Alder submitted a BLA for eptinezumab in February 2019.
Vanda is suing the FDA to lift the partial hold on tradipitant clinical trials.
On February 15, 2019, the FDA released guidance for the development of regenerative medicine therapies targeted to serious conditions and a second guidance on how the FDA will evaluate devices used with regenerative medicine advanced therapies. Draft guidance documents were issue in November 2017 and based on feedback the FDA received, the final documents were issue in February 2019.
The Regenerative Medicine Advanced Therapy (RMAT) designation was created as part of the 21st Century Cures act. A RMAT is a cell therapy, therapeutic tissue engineering product, human cell and tissue product, or any combination product that is intended to treat, modify, reverse, or cure a serious or life-threatening disease or condition. The RMAT must also have preliminary evidence that supports the drug has the potential to address an unmet medical need.
The first document describes expedited programs available for companies developing cell-based therapies and gene therapies that would qualify for RMAT status. The second document reviews the process and considerations by the FDA in evaluating devices designed for the recovery, isolation or delivery of RMATs.
The Pharmaceutical Pipeline Tracker is currently monitoring four drugs with RMAT designation.
During the week ending, 2/15/2019, the FDA approved one drug, rejected another, had a recommendation for approval by an advisory committee and set PDFA dates on two drugs. There were also eight notable clinical updates that we added to our database along with the FDA actions.
The FDA approved caplacizumab (Cablivi by Sanofi) on 2/6/2019 for the treatment of acquired thrombotic thrombocytopenic purpura (aTTP).
The FDA's Oncologic Drugs Advisory Committee will review Karyopharm Therapeutics’ selinexor on 2/26/2019.
The FDA has granted Daiichi Sankyo/Plexxikon’s pexidartinib breakthrough therapy and orphan drug designations and set a PDUFA date of 8/3/2019.
Two drugs have February PDUFA dates. The orphan drug caplacizumab and the antibiotic iclaprim.
The FDA approved caplacizumab (Cablivi by Sanofi) on its due date of February 6 as a treatment for acquired thrombotic thrombocytopenic purpura (aTTP). The drug was designated an orphan drug by the FDA. Caplacizumab was approved in Europe last August. In the 30-day, 145 patent, Phase III, HERCULES trial, treatment with caplacizumab resulted in a normalization of the platelet count in 2.69 days compared to 2.88 days with placebo. Patients that received caplacizumab were 1.55 times as likely to have a normalization of the platelet count compared to placebo.
Iclaprim has a PDUFA date of February 13. The drug is being reviewed by the FDA as a treatment of acute bacterial skin and skin structure infections. Iclaprim is also in development for the treatment of hospital-acquired pneumonia. The FDA designated iclaprim as a Qualified Infectious Disease Product and given it a Fast Track designation for the skin and skin structure infections. In the 72-hour, 600 patient, Phase III, REVIVE-2 trial, iclaprim was non-inferior to vancomycin in achieving > 20% reduction of lesion area at 48-72 hours in patients with acute bacterial skin and skin structure infections. 78% of iclaprim patients achieved > 20% lesion clearing compared to 77% of vancomycin patients. Iclaprim is being developed by Motif Bio.
Click here to review updates on seven research updates from last week.
Click here for a listing of notable 2018 approvals.
Click here to review our MONITORING POTENTIAL BUDGET BUSTERS use case about drugs with PDUFA Dates. A key use case for Specialty Pharmacy.
The FDA followed an advisory panel recommendation and rejected ALKS 5461 (samidorphan plus buprenorphine)and requested additional efficacy data. Alkermes drug had a PDUFA date of 1/31/2019.
In a 36-week open label extension of the AEGIS-CKD trial, patients originally treated with ferric maltol maintained hemoglobin levels and patients switched from placebo demonstrated a similar rise in hemoglobin. The FDA rejected ferric maltol during Shield’s first submission, but the company has resubmitted an NDA, which was accepted by the FDA in December 2018 and assigned a PDUFA date of 7/27/2019
Novo plans to submit an NDA for oral semaglutide at the end of 1Q19.
Roche discontinued the Phase III CREAD 1 and CREAD 2 trials after an interim analysis found that crenezumab was unlikely to improve Clinical Dementia Rating-Sum of Boxes (CDR-SB)scores compared to placebo in patients with prodromal or mild Alzheimer's disease. Roche has an ongoing Phase II trial evaluating crenezumab in cognitively healthy individuals in Colombia with an autosomal dominant mutation who are at risk to develop familial Alzheimer’s Disease.
Pfizer and Lilly announced that in a 24-week, 849 patient, Phase III trial, patients treated with tanezumab 5 mg had a greater decrease in the WOMAC pain subscale and WOMAC Physical Function subscale with an improvement in the patient’s Global Assessment of OA compared to placebo in patients with osteoarthritis. The 2.5 mg dose of tanezumab had a greater decrease in the WOMAC pain subscale and WOMAC Physical Function subscale, but no improvement in the patient’s Global Assessment of OA compared to placebo. In a 698 patient, Phase III trial, rapidly progressive osteoarthritis (RPOA) was observed in 1.3% of tanezumab and in an 849 patient, Phase III trial, RPOA was seen in 2.1% of patients. RPOA did not develop with any patient that received placebo in either trial. The ratio of Type 1 RPOA (joint space narrowing) to Type 2 RPOA (bone loss and joint destruction) is 2:1 in both trials.
Takeda announced that in the 15-month phase 1 portion of the 20,000 patient, Phase III, TIDES trial, two doses of Takeda’s dengue vaccine (TAK-003) demonstrated efficacy in preventing dengue fever caused by all four virus serotypes healthy in children and adolescents ages four to 16 years living in dengue-endemic areas. Part 2 of the TIDES trial will evaluate the vaccine at 21 months and include the secondary endpoints of efficacy by serotype, baseline serostatus and severity. Part 2 data is expected to be available at the end of 2019. Part 3 Orf the trial will evaluate efficacy and long-term safety for an additional three years. The BLA submission will be based on Part 1 and Part 2 data.
Two Phase III studies, ENGAGE and EMERGE, were initiated in 2015 to evaluate the safety and efficacy of aducanumab in slowing cognitive impairment and progression of Alzheimer's disease (AD). The trials should end in 2020. On 2/14/18, Biogen announced it would add an additional 255 patients to each trial to ensure a 90% chance of avoiding a false negative result. Biogen announced plans in early 2019 for a third Phase III trial that will evaluate aducanumab for the prevention or delay in the clinical onset of the disease.
In the 30-day, 632 patient, Phase III IMPACT 1 trial, cadazolid was non-inferior to vancomycin in reaching clinical cure (84% vs 85%) in patients with mild-to-moderate or severe C difficile infection. In the 30-day, 609 patient, Phase III IMPACT 2 trial, treatment with cadazolid did not reach non-inferiority to vancomycin in reaching clinical cure (81% vs 86%) in patients with mild-to-moderate or severe C difficile infection. Development of cadazolid was halted in 2018 after the failure of a Phase III trial.
Scynexis announced interim data from the 60 patient, Phase III, open-label, FURI trial where treatment with ibrexafungerp resulted in clinical benefits in 17 of 20 patients with difficult-to-treat mucocutaneous and invasive fungal infections that are refractory to or intolerant of currently available standards of care. Eleven patients achieved a complete or partial response and six patients a stable disease response.
CTI withdrew the MAA for pacritinib when CHMP indicated another Phase III trial was needed.
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