 a first-in-class acute pain treatment. Seglentis, developed by Esteve, is made up of a co-crystal form of the anti-inflammatory celecoxib and the analgesic tramadol.

The multimodal treatment approach targets four complementary pain relief mechanisms and “offers a new treatment option for acute pain management aligned with the multimodal analgesia now considered standard of care,” the company said in a press release.

The novel co-crystal structure produces a unique pharmacokinetic profile of its active pharmaceutical ingredients compared with their individual or combined administration, according to the pharma maker.

"This innovation is the result of applying a crystallization technology to improve the physicochemical properties and pharmacokinetic characteristics of its active pharmaceutical ingredients,” Carlos Plata-Salamán, M.D., chief scientific officer and chief medical officer of Esteve, said in a statement. “The FDA approval means that clinicians and adult patients in the United States now have a new treatment option for acute pain management."

Seglentis will be commercialized in the United States by KOWA Pharmaceuticals America.

Articles

Seglentis’ co-crystal formulation targets four complementary pain relief mechanisms.

FDA Clears Novel Pain Treatment

Denise Myshko is your editorial contact for the Formulary Watch. She joined Formulary Watch as editor is June 2021 from Oncology Live. Prior to that, she was managing editor of PharmaVOICE, a trade publication in the pharmaceutical industry. Email: dmyshko@mjhlifesciences.com

 the safety labeling of Cyltezo (adalimumab-adbm) with data from the trial that was used to support its application for interchangeability with Humira (adalimumab). The FDA 

 Cyltezo as the first interchangeable biosimilar of AbbVie’s Humira on Oct. 15, 2021.

“All FDA-approved biosimilars to Humira have the same label as the reference product. However, an interchangeable biosimilar is a separate, additional regulatory designation on top of the high FDA standards for a biosimilar,” a company spokesperson said in an email.

Specifically, in addition to first meeting the requirements of biosimilarity, an interchangeable biosimilar must additionally demonstrate that the risk in terms of safety or diminished efficacy of switching with the reference product is not greater than staying on the reference product in any given patient. This requirement is satisfied through an additional study of multiple switches in patients.”

 in April 2021 from the VOLTAIRE-X phase 3 trial. Results showed that in patients with moderate-to-service chronic plaque psoriasis switching several times between Cyltezo and Humira resulted in no meaningful clinical differences for pharmacokinetics, efficacy, immunogenicity, and safety. The 32-week data were presented at the American Academy of Dermatology 2021 conference. 

Related: FDA Approves First Interchangeable Biosimilar for Humira

Cyltezo’s label now includes additional information about immunogenicity, as well as pediatric use. Within the section on immunogenicity, the label now says:

“There are two assays that have been used to measure anti-adalimumab antibodies. With the ELISA, antibodies to adalimumab could be detected only when serum adalimumab concentrations were < 2 mcg/mL. The ECL assay can detect anti-adalimumab antibody titers independent of adalimumab concentrations in the serum samples.

Rheumatoid Arthritis and Psoriatic Arthritis: 

Patients in Studies RA-I, RA-II, and RA-III were tested at multiple time points for antibodies to adalimumab using the ELISA during the 6- to 12-month period.

For pediatric use, the label adds information about use in children with juvenile idiopathic arthritis and Crohn’s disease:

“A pediatric assessment for Cyltezo demonstrates that Cyltezo is safe and effective for pediatric patients in an indication for which Humira (adalimumab) is approved. However, Cyltezo is 

 approved for such indication due to marketing exclusivity for Humira (adalimumab). The safety and effectiveness of adalimumab products have not been established in pediatric patients with JIA less than 2 years of age.

The safety and effectiveness of adalimumab products for the treatment of moderately to severely active Crohn’s disease have been established in pediatric patients 6 years of age and older. Use of adalimumab products for this indication is supported by evidence from adequate and well-controlled studies in adults with additional data from a randomized, double-blind, 52-week clinical study of two dose concentrations of adalimumab in 192 pediatric patients. The adverse reaction profile in patients 6 years to 17 years of age was similar to adults.

The safety and effectiveness of adalimumab products have not been established in pediatric patients with Crohn’s disease less than 6 years of age."

Boehringer Ingelheim will make Cyltezo available when its commercial license begins on July 1, 2023. This date was the 

 with AbbVie. Boehringer Ingelheim will pay royalties to AbbVie for licensing its Humira patents once Cyltezo is available.

Cyltezo was approved by the FDA in August 2017 for the treatment of multiple chronic inflammatory diseases including rheumatoid arthritis, psoriasis and Crohn's disease.

The label now includes new data from the trial that supported Cyltezo’s application for interchangeability with Humira.

Boehringer Ingelheim Updates Safety Labeling of Cyltezo

Cigna will be removing 45 drugs covered under the pharmacy benefit from its 

 beginning in January 2022. Cigna officials said that less than 1% of customers will be impacted by these changes, and drugs are removed if there are therapeutic alternatives that are more affordable.

Formulary decisions are driven first by clinical considerations made by an independent committee of actively practicing physicians and pharmacists, a Cigna spokesperson said by email.

“We are committed to lowering drug costs for our customers and clients, so every year, we review our formularies to remove or manage certain high-priced drugs where clinically appropriate alternatives are available,” the spokesperson said.

Most of the drugs that will be removed have generic alternatives. (See table below.) 

For medications that don’t have an available generic available, Cigna recommends a different branded therapeutic. For example, among diabetes medications removed from the standard formulary are Janssen’s Invokana and Invokamet, as well as Merck’s/Pfizer’s Segluromet and Steglatro. For Invokana (canagliflozin) and Steglatro (ertugliflozin), the recommended alternative is Farxiga (dapaglifozin), which has a list price of $532 for a 30-day supply. For the combination products Invokamet (canagliflozin/metformin) and Segluromet (ertugliflozin/metformin), the recommended alternative is Synjardy (empagliflozin/metformin), which has a list price of $582 for a 60-day supply.

Among cholesterol medications removed from the standard formulary are Crestor (rosuvastatin), where there is a generic available, and Juxtapid (lomitapide). Because there is no generic for Juxtapid, Cigna recommends Amgen’s Repatha (evolocumab), where the list price is less than $500 a month. Juxtapid has a list price of almost $50,000 for 28 capsules.

Additionally, Cigna will move four therapeutics to a higher, non-preferred drug tier in 2022, and another four drugs have moved to a lower, preferred tier. Moving to the non-preferred tier are Apokyn, Remodulin, Sandostatin LAR, and Tasigna.

Apokyn (apomorphine) is indicated for the acute, intermittent treatment of hypomobility during “off” episodes in patients with advanced Parkinson’s disease. It is marketed by Supernus Pharmaceuticals. Levodopa is used to manage patients with Parkinson’s disease, but it can become less effective over time, and patients can experience a diminished clinical response marked by motor fluctuations. Cigna recommends Sunovion’s Kynmobi (apomorphine) as an alternative. The FDA approved Kynmobi in October 2020. It is a novel formulation of apomorphine that is delivered through a thin film that dissolves under the tongue.

Remodulin (treprostinil), developed by United Therapeutics, treats patients with pulmonary arterial hypertension. Cigna recommends using a generic treprostinil. Sandoz launched the first generic of trepostinil injection in 2019, and in May 2021, Sandoz launched a subcutaneous version.

Both Sandostatin and Tasigna are used by patients with cancer. Novartis’ Sandostatin LAR Depot (octreotide) treats severe diarrhea associated with metastatic tumors. Cigna recommends another Novartis therapeutic instead: Somatuline Depot (lanreotide). Tasigna (nilotinib), also developed by Novartis, treats patients with chronic myeloid leukemia. Cigna recommends Sprycel (dasatinib) from Bristol Myers Squibb as an alternative.

Moving to a lower tier are the COPD therapies Spiriva/Spiriva Respimat and Stiolto Respimat, as well as the biosimilars Udencya (pegfilgrastim-cbqv) and Ziextenzo (pegfilgrastim-bmez), which are used to prevent infection after chemotherapy.

Fourteen therapies now have coverage restrictions, including needing approval from Cigna. For several medications for age-related macular degeneration, physicians will have to show that patients have already tried Avastin (bevacizumab). These include Beovu (brolucizumab-dbll), Eylea (aflibercept), and Lucentis (ranibizumab).

Some diabetes medicines will require current patients to have approval from Cigna to continue on these therapeutics. These include Bydureon/Byetta (exenatide), Ozempic/Rybelsus (semaglutide), and Victoza (liraglutide).

Cigna plans to remove 45 drugs from its Standard Prescription Drug List and add restrictions for other therapeutics.

Cigna Releases Formulary Changes for 2022

Spending on oral therapies that treat patients with cancer without a documented overall survival benefit has increased and even surpassed spending on therapies with such clinical data, according to a 

Investigators assessed 44 new oral targeted drugs dispensed between 2011 and 2018. Most patients (97%) received drugs for which evidence of overall survival from randomized clinical trials existed. But investigators found that a growing share of patients received drugs without such data: from 12.7% in 2011 to 58.8% in 2018. Cumulative spending on drugs without overall survival data was $1.8 billion and surpassed that of drugs with documented overall survival benefit of $1.7 billion by the end of 2018.

“The results we describe in our study — increasing use of and spending on cancer drugs without documented overall survival benefit — reflect characteristics of the U.S. cancer drug ecosystem, which includes drug development, regulation, pricing, advertising, and reimbursement,” lead author Anita Wagner, Pharm.D., Dr.PH., associate professor of population medicine at Harvard Medical School and Harvard Pilgrim Health Care Institute, said in an email to Formulary Watch. She is also director of the ethics program at Point32Health, the parent company of Harvard Pilgrim Health Care and Tufts Health Plan.

Of the 44 drugs investigators analyzed, 34 (77.3%) were supported by at least one randomized clinical trial for at least one indication; 10 drugs (22.7%) were approved on the basis of single-arm studies or noncomparative trials alone. Only 11 drugs (25%) had documented, statistically significant overall survival benefit for at least one indication in FDA-approved labels by the end of 2018, and four those had overall survival as primary end point.

The investigators suggested that the increased spending on cancer drugs without overall survival data is a result of several factors, including: increasingly lenient FDA approvals, drugs advertised directly to consumers, no price regulation, fragmented purchasing and reimbursement systems, coverage mandates, and limited ability by payers to negotiate prices.

Given the U.S cancer drug ecosystem, payers have limited options to address the challenges posed by expensive drugs with uncertain benefits, Wagner said. “Nevertheless, as key actors in a complex system, payers can play a role in member and clinician education about evidence of benefits and risks. They can target drug coverage according to evidence, seek risk sharing contracts with pharmaceutical companies, and they can publicly advocate for better evidence.”

The authors suggested in the paper that value-based pricing might reduce the cost of some drugs with high spending amounts. They point to Nerlynx (neratinib), which was ranked 11th in this study in terms of spending. Developed by Puma Biotech, this therapy was approved in 2017 as adjuvant treatment of adult patients with early stage HER2-positive breast cancer. One 

 suggested Nerlynx’s price would need to be reduced by 85% for it to be cost-effective at a willingness-to-pay threshold of $150,000 per quality-adjusted life-year gained.

Wagner said policy changes in this complex ecosystem likely need to be multi-pronged. “They are likely challenging and controversial as most require cooperation of stakeholders with different priorities,” she said. “They include, for example, validated surrogate end points with pre-defined thresholds predictive of clinically meaningful benefit.”

But she indicated that some changes may be more readily feasible than others. Among those may be FDA efforts to make explicit and easily accessible for patients, their clinicians, and others what is known and what is not known about the clinical benefits of newly approved highly priced cancer drugs.

“Such efforts could start with consistent documentation of overall survival information in FDA-approved labeling as we have suggested based on another recent study and clear visual alerts in labels of limited evidence underlying accelerated approvals akin to black box warnings as colleagues at Institute for Clinical and Economic Review have suggested.”

Cumulative spending on drugs without overall survival data was $1.8 billion in 2018 and surpassed that of drugs with such data.

Study: Spending Increasing for Cancer Therapies Without Evidence of Overall Survival

 Xipere (triamcinolone acetonide injectable suspension) for suprachoroidal use for the treatment of macular edema associated with uveitis, a form of eye inflammation. Developed by Bausch + Lomb, and Clearside Biomedical, Xipere provides a targeted delivery to the retina and choroid.

Macular edema is the buildup of fluid in the macula, which causes retinal swelling and distorted vision, and if left untreated, may lead to permanent vision loss.

The FDA approval was based on results from PEACHTREE, a phase 3 clinical trial of 160 patients with macular edema associated with uveitis. The primary efficacy end point was the proportion of patients in whom BCVA (Best Corrected Visual Acuity) had improved by at least 15 letters from baseline after 24 weeks of follow-up. In the trial, 47% of patients achieved at least a 15-letter improvement in BCVA compared with 16% of patients in the control arm.

The most common adverse reactions reported by greater than or equal to 10% of patients and at a rate greater than control included elevated intraocular pressure and eye pain.

“The safety and efficacy data of Xipere were demonstrated in multiple clinical studies and its unique suprachoroidal administration approach provides exceptional access and high bioavailability to the posterior segment of the eye,” Steven Yeh, M.D., professor of ophthalmology and director of retinal disease and uveitis, Stanley M. Truhlsen Eye Institute, University of Nebraska Medical Center, and principal investigator in PEACHTREE study, said in a statement.


Xipere is delivered via an injection to the back of the eye to treat macular edema associated with uveitis, a form of eye inflammation.


FDA Approves Targeted Therapy for Macular Edema

Although the FDA’s Vaccines and Related Biological Products Advisory Committee voted 17 to 0 to recommend the use of Pfizer and BioNTech’s COVID-19 vaccine for children ages 5 to 11, some organizations have expressed concerns, especially about the risk of myocarditis and unknown longer-term side effects.

While there were no myocarditis cases in Pfizer and BioNTech’s clinical trials in the vaccine for children, the rare cases seen in real-world settings — predominantly in males under 30 years after the second dose of mRNA vaccine — are causing concern, according to an American Academy of Pediatrics 

Around 42% of children may have already had COVID-19, which likely means they have some protection, H. Cody Meissner, M.D., FAAP, chief of the Division of Pediatric Infectious Disease at Tufts Medical Center, said in the AAP article. “We’re getting down to a very small percent of otherwise healthy 5 to 11-year-old children who might derive some benefit, and we simply don’t know what the side effects are going to be.”

Members of the FDA panel noted the low incidence of myocarditis in adolescents after vaccination. Additionally, the vaccine given to children would be a lower dose, they said.

Myocarditis historically is less common in this age group than in older groups and more data won’t be available until the vaccine is more widely used, according to Mark H. Sawyer, M.D., FAAP, professor of clinical pediatrics in the Division of Infectious Diseases at the University of California San Diego School of Medicine.

“I do think we need [the vaccine] as a tool in our armamentarium for high-risk children, for equity issues, for parents who really would like to protect their children and because of the long-term very profound implications of schools being disrupted and the social and educational impact that that’s having,” Sawyer said in the AAP article.

Some vaccine committee members expressed a preference for limiting the vaccine to children with high-risk conditions, which CDC data showed were present in about two-thirds of hospitalized children ages 5 to 11, AAP said.

Prior to the advisory committee meeting, Robert F. Kennedy, Jr., chairman of Children’s Health Defense (CHD), and Meryl Nass, M.D., highlighted recent peer-reviewed research demonstrating that children have a low risk hospitalization and death from the COVID-19 virus, CHD said in a 

Safety data from the trials found the most common reactions were pain at the injection site, fatigue and headache. Reactions were mostly mild or moderate. There were no serious adverse events related to the vaccine, including myocarditis or anaphylaxis, AAP said.

The U.S. government has purchased 50 million more doses of the companies’ COVID-19 vaccine, to prepare for the pediatric vaccine rollout after FDA grants EUA, Pfizer and BioNTech said in a 

. The companies expect to deliver all of these doses by April 30, 2022.

Separately, Pfizer and BioNTech have agreed to provide a total of 1 billion doses to the U.S. government at a not-for-profit price for donation to low- and lower-middle-income countries.

Since the start of the pandemic, about 1.9 million children ages 5 to 11 have been infected, and account for around 9% of all U.S. cases, the AAP said. More than 8,300 have been hospitalized and 94 have died.

Some have expressed concerns about the risk of myocarditis and unknown longer-term side effects.

Concerns About Childhood COVID-19 Vaccines Persist, Despite FDA Committee OK

 dexamethasone, 4 mg and 6 mg, a generic version of Decadron, an anti-inflammatory glucocorticoid steroid used to treat several medical conditions, including respiratory complications associated with COVID-19.

 by the NIH and the World Health Organization for treating COVID-19. In the 

, dexamethasone was shown to reduce mortality in hospitalized patients with COVID-19 who required supplemental oxygen. This study was 

 in the New England Journal of Medicine in February 2021.

But dexamethasone tablets can produce reversible hypothalamic-pituitary adrenal (HPA) axis suppression with the potential for glucocorticosteroid insufficiency. The HPA is complex system of neuroendocrine pathways that function to maintain physiological homeostasis. Changes in this system can potentially lead to a disruption in neuroendocrine, behavioral, autonomic, and metabolic function

Elevated blood pressure, sodium and water retention, and increased excretion of potassium, have also been reported.

Mild-to-severe infection with exacerbation may occur with the use of dexamethasone tablets alone or in combination with other immunosuppressive agents. Dexamethasone is contraindicated in patients hypersensitive to any components of this product.

Dexamethasone is recommended by the NIH and the World Health Organization for treating COVID-19.

Generic of Decadron is Launched to Treat COVID-19

The utilization of higher cost medications for rare diseases is driving higher spend on prescription drugs. In fact, nonspecialty drug utilization has remained relatively flat but specialty drug utilization is forecasted to increase, according to a 

“Almost every new chemical entity to the market is a specialty drug; they are coming to market faster through various programs, such as orphan drug and other pathways through the FDA,” Nick Taylor, R.Ph., VP, national pharmacy practice leader consulting services at Segal, said in an interview.

Specialty drug prices are rising as these therapeutics replace lower-cost therapies, and the majority of the pipeline is specialty or orphan drugs, the Segal study found. Specialty drugs now account for 53% of spending, according to IQVIA Institute for Human Data Science. Segal analysts project a cost trend for specialty drugs in 2022 of 14.4%, up from the projected 11.5% for 2021.

That pressure could ease a bit in 2023, when Boehringer Ingelheim’s interchangeable biosimilar of AbbVie’s Humira is expected to launch. The FDA approved Cyltezoz) adalimumab-adbm) on Oct. 15, 2021, but it won’t launch until July 1, 2023. This date was the result of a patent ligation with AbbVie. Boehringer Ingelheim will pay royalties to AbbVie for licensing its Humira patents once Cyltezo is available.

Related: FDA Approves First Interchangeable Biosimilar of Humira

“It'll be interesting to see what happens with negotiation of price and rebates,” Taylor said. “We will continue to see the uptick in the use of biosimilars, particularly on the medical side with infused products in the cancer category.”

Biosimilar utilization has increased 60% over the last two years, according to IQVIA. Taylor said that biosimilars are expected to provide some savings, especially in the oncology categories. “But it's not going to be like the traditional brand-generic type situation where you have 60%, 70% or 80% savings. Biosimilars are still quite expensive to produce and market. I think it’s going to become a price game with rebates and price concessions if pharma companies want to status of these drugs.”

The Segal report found that the average impact of rebates was a 2.4 percentage point reduction in prescription drug spend. Additionally, other plan strategies, such as prior authorization and step therapy, Taylor said, are effective in managing specialty drug spend, and he predicts health plans will continue to adopt these strategies.

Taylor said health plans are also starting leverage manufacturer coupon programs to maximize the value of these coupons. “Unless there's regulatory change where coupons are not available, or manufacturers decide to go a different route and not offer coupons, we can see them continuing going forward.”

Beyond plan design, member cost-sharing also can have an impact on drug spend, often influencing patient behavior. “Members with plans that have lower cost sharing choose differently from members who have plans that have higher cost share. The idea of a high deductible health plan is that people shop for price.”

Specialty drug prices are rising as these therapeutics replace lower-cost therapies.

Segal: Specialty Drugs Driving Cost Trend 

 Novartis’ supplemental biologics license application (sBLA) and for Kymriah (tisagenlecleucel) in adult patients with relapsed or refractory (r/r) follicular lymphoma (FL) after two prior lines of treatment. The agency has also granted priority review for this application.

If approved, this would be the third indication for Kymriah, which is an autologous, immunocellular cancer therapy that involves reprogramming a patient's own T-cells with a chimeric antigen receptor (CAR) to identify and eliminate CD19-expressing cells. It is administered as intravenous infusion.

The submission is based on positive data from the pivotal phase 2 ELARA trial, which investigated the efficacy and safety of Kymriah in adult patients with r/r FL. The trial met the primary endpoint with robust responses observed in heavily pretreated patients. The majority of patients treated (66%) achieved a complete response; the overall response rate was 86%.

In the trial, no patients experienced grade 3 or higher cytokine release syndrome related to Kymriah within the first eight weeks following infusion.

Novartis also submitted an application for this indication to the European Medicines Agency. The European Commission has granted Kymriah an orphan drug designation for relapsed or refractory follicular lymphoma.

Kymriah is currently approved by the FDA, EMA and other regulatory authorities for the treatment of r/r pediatric and young adult (up to and including 25 years of age) acute lymphoblastic leukemia, and r/r adult diffuse large B-cell lymphoma.

Follicular lymphoma is the second most common form of non-Hodgkin lymphoma and represents about 22% of non-Hodgkin lymphoma cases.

Novatis is seeking approval for Kymriah in adult patients with advanced follicular lymphoma.

FDA Accepts Novartis’ Application for New Indication for Kymriah 

The FDA’s Vaccines and Related Biological Products Advisory Committee voted 17 to 0, with one abstention, to recommend the agency grant an emergency use authorization (EUA) for the Pfizer and BioNTech’s COVID-19 vaccine in children 5 to 11 years of age.

The committee reviewed the totality of scientific evidence shared by the companies, including results from a 

 trial that included about 4,500 children 5 to 11 years of age.

The dose used was one-third of the dose given to people 12 years and older. The study enrolled 2,268, as well as 2,379 from a supplemental safety group. Participants received a two-dose regimen of 21 days apart. Pfizer leaders indicated the dose level was selected based on safety, tolerability and immunogenicity data evaluated as part of a dose-ranging study.

The phase 2/3 trial showed a favorable safety profile, robust immune responses and a vaccine efficacy rate of 90.7% in participants without prior SARS-CoV-2 infection, measured from seven days after the second dose.

If authorized, the vaccine will be the first COVID-19 vaccine available for use in children 5 to 11 years of age in the United States. The companies expect to then begin shipping pediatric vaccine doses immediately.

“COVID-19 is an ongoing threat for the more than 28 million young children in this age group in the United States, as they remain at risk for this infection. About 10% of all weekly U.S. cases occur in children 5 to under 12 years of age with a potential risk of complications,” Kathrin U. Jansen, Ph.D., senior vice president and head of vaccine research & development at Pfizer, said in a statement.

Pfizer and BioNTech have submitted requests for authorization of their COVID-19 vaccine in this age group to other regulators around the world, including the European Medicines Agency.

The phase 2/3 trial showed a favorable safety profile, robust immune responses and a vaccine efficacy rate of 90.7% in children 5 to 11 years of age.



Concerns About Childhood COVID-19 Vaccines Persist, Despite FDA Committee OK

Generic of Decadron is Launched to Treat COVID-19

Segal: Specialty Drugs Driving Cost Trend

FDA Accepts Novartis’ Application for New Indication for Kymriah

FDA Advisory Committee Recommends Pfizer Vaccine for Children