NCRx Pipeline Report 10.1.21

National CooperativeRx constantly monitors the pharmaceutical pipeline. As treatment options change, it’s important to know how those changes could impact your plan and which drugs bring the highest value. Our quarterly NCRx Pipeline Reports highlight some of the newest therapies coming to market and are not intended to imply formulary placement or coverage by CVS Caremark.

Xywav (oxybate salts): On August 12, Xywav® became the first drug approved for idiopathic hypersomnia (IH), a condition which literally translates to excessive sleepiness of unknown origin. Xywav® is Jazz Pharmaceuticals’ follow-on product to Xyrem®, which is set to face generic competition in 2023. Both drugs are approved to treat daytime sedation and/or cataplexy in patients with narcolepsy, but Jazz has only sought approval for IH for Xywav®. The marketing for Xywav® has focused on the drug’s reduced sodium content compared to Xyrem® and on how patients can be screened for symptoms of IH. The study through which Xywav® gained approval had an interesting and somewhat confusing design.¹ Patients with IH initiated Xywav® during a ten-week open-label dose titration period. Once a stable dose was attained, patients were randomized in a double-blind fashion to placebo (i.e., withdrawal of Xywav®) or continued Xywav® for two weeks. Patients in the treatment group saw symptom improvements, while those on placebo saw their symptoms worsen during the withdrawal period. Even though most of the efficacy data in the trial was obtained during open-label treatment and used subjective measures of success, the efficacy of the drug would likely still be significant if the trial had been designed a different way. The safety and tolerability of the drug is more concerning; the drug is related to gamma-hydroxybutyrate, a drug formerly used during childbirth and illicitly as a “date rape drug.” The potential for abuse and significant side effects led to the implementation of a risk mitigation program for the drug, requiring prescribers of Xywav® to be certified and restricting the network of dispensing pharmacies. In the clinical trial for IH, 11% of patients withdrew from the study due to side effects; the most common reason for withdrawal was anxiety. The most common side effects in the study overall were nausea (21%), headache (16%) and anxiety (12%). Given the significant safety and toxicity issues, it will be important that Xywav® be used only in patients who meet a strict, objective diagnosis of IH and for whom the benefits of the drug clearly outweigh the risks. While Xywav® is now the only FDA-approved drug for IH, there are several others that are commonly accepted treatments for the disorder, such as modafinil (Provigil®), armodafinil (Nuvigil®), methylphenidate (e.g., Ritalin®) and amphetamines (e.g., Adderall®) which are not subject to the REMS and come at significantly lower cost.

Anticipated Launch: Already available for narcolepsy; launch expected for IH by end of 2021.

Impact: High. IH is considered a rare condition but the cost of Xywav® therapy can impact plan spend significantly even with low utilization.

Price: $186,500* annually.

Opzelura® (ruxolitinib) topical: On September 22, the FDA approved a topical formulation of ruxolitinib, Opzelura®, for atopic dermatitis (AD, also known as eczema). The drug is one of several products for AD submitted to the FDA for review in 2021. Opzelura® belongs to a class of drugs known as Janus Kinase (JAK) inhibitors, of which most are oral agents used for autoimmune conditions. Opzelura® cream would be the first in the class of drugs to be used for AD. The JAK inhibitor class has been plagued by safety concerns, including heart problems and cancer, prompting scrutiny by the FDA that resulted in restrictions and warnings to the drugs’ labels. Further, the FDA has delayed decisions for several JAK inhibitors while additional safety data from phase three trials is reviewed. The FDA did apply a black box warning to Opzelura’s® label, similar to the oral JAK inhibitors, regarding risk of infection, death, cancer, heart-related events and blood clots.  However, a summary of information presented at the Revolutionizing Atopic Dermatitis conference provided some reassurance around safety: there was no link between use of Opzelura® and serious safety events in a year-long trial.² Furthermore, a separate analysis measuring blood levels of ruxolitnib following exposure to the cream concluded that the cream is not expected to produce blood levels high enough to elicit adverse effects of concern in oral JAK inhibitors.³ Along with this safety data, the efficacy data for Opzelura® cream is encouraging. In the two landmark trials submitted to the FDA, 39-54% of those in the treatment group had clear or almost clear skin after eight weeks of treatment compared to 8-15% of those in the placebo group.⁴ For perspective, Elidel®, another cream commonly used for atopic dermatitis, produced clear to almost clear skin in 35% of users after six weeks.⁵ Opzelura® cream will be a welcome addition to the selection of topical treatments available for AD. The last major approval in this arena came in 2016 with the approval of Eucrisa®, a PDE-4 inhibitor.

Anticipated Launch: September 2021.

Impact: Moderate. 32 million people in the U.S. have AD⁶ and most need to try several treatments before finding one that works.

Price: Currently unknown, but likely to be similar to other brand-name topical products for AD at around $10 to $12* per gram of cream.

Saphnelo® (anifrolumab): Saphnelo® was approved by the FDA in early August for the treatment of lupus. The drug is administered intravenously every four weeks and blocks the action of interleukin-1 (IL-1), a chemical involved in the inflammatory pathway in lupus. It is the second drug approved in 2021 for lupus, following the approval of Lupkynis® in January for the treatment of lupus nephritis, but still leaves lupus patients with few treatment options. Saphnelo® was studied in two major phase III clinical trials in patients with moderate to severe lupus who were receiving standard of care. The first trial, dubbed “TULIP-1,” did not meet its primary endpoint for efficacy. It did, however, meet several secondary endpoints, which led researchers to change the way efficacy was measured in the second trial. In “TULIP-2”, significantly more patients in the Saphnelo® group saw a response to therapy than in the placebo group (47.8% versus 31.5%).⁷ Patients in the treatment group also saw improvements in skin-related lupus symptoms, and they were more likely able to reduce their oral steroid doses.  In terms of safety, the adverse effect rate in the trials was high for both Saphnelo® and placebo, at 88-89% and 78-84% respectively. The most notable side effects were upper respiratory infections and shingles infections, which occurred more often in patients treated with Saphnelo®; there were two deaths from pneumonia as well: one in each of the TULIP trials, both in the treatment groups. All things considered, however, Saphnelo® fills a void as an option for patients with treatment refractory disease. Saphnelo® will be under New-to-Market Block with CVS until a formulary analysis is completed. It’s likely the drug will be restricted to patients with documented lupus antibodies and have treatment-resistant disease.

Anticipated Launch: August 2021.

Impact: Low overall, because only 1.5 million people in the U.S. have lupus⁸ and Saphnelo® is not a first-line treatment. In addition, intravenous administration will make it a less attractive option to patients.

Price: $59,800 annually, in addition to administration fees.

Kerendia (finerenone): In July, the Food and Drug Administration (FDA) approved Kerendia® (finerenone) to slow the decline in kidney function and reduce the risk of end-stage kidney disease, cardiovascular death, nonfatal heart attack and heart failure hospitalization in adults with chronic kidney disease (CKD) and type 2 diabetes (DM2). Kerendia® blocks a key receptor in the kidney, ultimately preventing the fibrosis and inflammation that are so damaging in CKD. Compared to other drugs that are considered the standard of care for CKD, it is less effective in preventing progression to end stage kidney disease and other adverse outcomes like death from cardiovascular disease.^9,10 In the clinical trial which won the drug its FDA approval, significantly fewer patients in the Kerendia® group experienced significant decline in kidney function, kidney failure or death from CKD compared to the placebo group (17.8% vs 21.1%, respectively). However, there was not a statistically significant difference between Kerendia® and placebo in preventing heart attack, stroke, hospitalization for heart failure or death (13% vs 14.8%, respectively).¹¹ In the safety analysis, high blood potassium was the most significant adverse effect leading to treatment discontinuation. Existing therapies for CKD, SGLT-2 inhibitors and ACE inhibitors, have safety problems of their own, though; for example, SGLT-2 inhibitors are known to increase the risk of acid build-up in the blood and genital yeast infections. Bayer, the Kerendia®’s manufacturer, is touting the drug as the “first and only [drug of its kind] which is proven to reduce the risk” of adverse kidney disease outcomes, providing an additional therapy modality with a different mechanism of action. While it certainly provides an additional therapy modality which may prove helpful for some patients, it’s likely that ACE inhibitors and SGLT-2 inhibitors will continue to be used as first-line treatments; Kerendia® will likely be reserved for patients who don’t tolerate first-line treatments or as an add-on therapy when needed. The drug is currently on New-to-Market Block with CVS and is available only via medical exception.

Anticipated Launch: Third Quarter 2021.

Impact: Low. While there are an estimated 8 million people in the U.S. with CKD and DM2,¹² Kerendia® is not expected to be a first-line treatment.

Price: $570* for a 30 day supply; a 30 day supply of Farxiga®, an SGLT-2 inhibitor, is $530*

Other Recent/Pending FDA Approvals:

Trudhesa (dihydroergotamine mesylate): Trudhesa®, a nasal spray for the treatment of migraine headaches, was recently approved as follow-on product to Migranal®. Both products contain dihydroergotamine mesylate and Trudhesa was approved in part using Migranal’s® clinical studies. The main differentiator is the device used to deliver the drug to the nasal passage. The Trudhesa® device may be more user friendly, but there are no apparent differences in efficacy or safety data between the Migranal® and Trudhesa®.^13,14 Trudhesa is expected to cost between $300-$425,* while generic Migranal® costs $119** per treated migraine.

Jardiance® (empagliflozin): Jardiance®, a popular diabetes drug, was recently approved to reduce risk of death and hospitalization in heart failure patients.  Jardiance cut relative risk of death or hospitalization by 25% and was relatively well-tolerated.¹⁵ Jardiance belongs to a class of drugs known as sodium-glucose co-transporter 2 (SGLT-2) inhibitors. Farxiga®, another SGLT-2 drug, also has the indication for heart failure patients with or without diabetes.

AXS-05 (dextromethorphan/bupropion): The FDA recently notified Axsome Therapeutics that a decision on its combination product for major depressive disorder (MDD), AXS-05, would be delayed. The product performed well in MDD¹⁶ but failed to meet the primary endpoint in a phase III trial for treatment-resistant depression.¹⁷ The company intends to initiate a new phase III trial in treatment resistant depression; AXS-05 is also under investigation for Alzheimer’s agitation and smoking cessation.

YCANTH® (cantharidin): A decision on YCANTH® for the treatment of molluscum is expected by the end of the year, after multiple delays by the FDA over manufacturing, training and distribution. Administration of YCANTH® resulted in clearance of molluscum skin lesions in about half of the treatment group versus 13-18% of the placebo group.¹⁸ There are no FDA-approved treatments for the viral skin disease; currently, physicians rely upon compounded versions of cantharidin which are applied in clinic. Verrica Pharmaceuticals is also studying YCANTH® for use in common warts and external genital warts.

Semglee® (insulin glargine): On July 28, 2021, Semglee® became the first interchangeable biosimilar insulin, meaning there are no clinically meaningful differences between the biosimilar and the reference product, Lantus® (insulin glargine). All 50 states have enacted rules around substitution at the pharmacy, with most states allowing a pharmacist to substitute an interchangeable biologic without prior approval of the prescriber.¹⁹ Semglee® is under New-to-Market Block with CVS, pending a formulary analysis, and available only via medical exception.

*Wholesale acquisition cost (WAC)

**WAC and NADAC, respectively

1. Xywav (oxybate salts) Prescribing Information. Palo Alto, CA:  Jazz Pharmaceuticals.; 2021
2. Topical Ruxolitinib Found Safe, Effective in 52-Week AD Study – Medscape – Jun 25, 2021
3. Gong, X., Chen, X., Kuligowski, M.E. et al. Pharmacokinetics of ruxolitinib in patients with atopic dermatitis treated with ruxolitinib cream: data from phase II and III studies. Am J Clin Dermatol 2021; 22: 555–566.
4. Papp K, Szepietowski JC, Kircik L, et al. Efficacy and safety of ruxolitinib cream for the treatment of atopic dermatitis: Results from 2 phase 3, randomized, double-blind studies. J Am Acad Dermatol 2021 Oct;85(4):863-872.
5. Elidel® (pimecrolimus) cream 1% Prescribing Information. Bridgewater, NJ: Valeant Pharmaceuticals.; 2014
6. National Eczema Association: Eczema Stats.  https://nationaleczema.org/research/eczema-facts/.  Accessed September 21, 2021.
7. Morand EF, Furie R, Tanaka Y, et al. Trial of anifrolumab in active systemic lupus erythematosus. N Engl J Med 2020; 382(3): 211–21.
8. Lupus Foundation of America: Lupus Facts and Statistics.  https://www.lupus.org/resources/lupus-facts-and-statistics.  Accessed September 23, 2021.
9. Perkovic V, Jardine MJ, Neal B, et al. Canagliflozin and renal outcomes in type 2 diabetes and nephropathy.  N Engl J Med 2019; 380:2295-2306.
10. Heerspink HJL, Stefánsson BV, Correa-Rotter R, et al. Dapagliflozin in patients with chronic kidney disease.  N Engl J Med 2020; 383:1436-1446.
11. Bakris GL, Agarwal R, Anker SD, et al. Effect of finerenone on chronic kidney disease outcomes in type 2 diabetes.  N Engl J Med 2020; 383:2219-2229.
12. New drug review:   IPD analytics.  August 2021
13. Migranal® (dihydroergotamine mesylate) nasal spray 4mg/mL Prescribing Information. Bridgewater, NJ: Valeant Pharmaceuticals.; 2019
14. Smith TR, Winner P, Aurora SK, Jeleva M, Hocevar- Trnka J, Shrewsbury SB. STOP 301: A phase 3, open- label study of safety, tolerability, and exploratory efficacy of INP104.  Headache 2021; 00:1–13.
15. Packer M, Anker SD, Butler J, et al. Cardiovascular and renal outcomes with empagliflozin in heart failure. N Engl J Med 2020; 383:1413-1424.
16. O’Gorman C, Feliz S, Jones A, Streicher C, Thomas Z, Tabuteau H. Effects of AXS-05, an oral NMDA receptor antagonist with multimodal activity, on patient reported depressive symptoms in major depressive disorder: results from the GEMINI phase 3 double-blind, placebo-controlled trial.  Presented at American Society of Clinical Psychopharmacology [ASCP]; June 2021.
17. Axsome therapeutics announces topline results of the STRIDE-1 phase 3 trial in treatment resistant depression and expert call to discuss clinical implications.; 2020. Available at: https://axsometherapeuticsinc.gcs-web.com/node/9176/pdf. Accessed September 24, 2021.
18. Eichenfield LF, McFalda W, Brabec B, et al. Safety and efficacy of VP-102, a proprietary, drug-device combination product containing cantharidin, 0.7% (w/v), in children and adults with molluscum contagiosum:  two phase 3 randomized clinical trials.  JAMA Dermatol 2020; 156(12): 1315-1323.
19. Cardinal Health. Biosimilar interchangeability laws by state.  July 2021.  https://www.cardinalhealth.com/content/dam/corp/web/documents/publication/Cardinal-Health-Biosimilar-Interchangeability-Laws-by-State.pdf.  Accessed September 24, 2021.