Rachel Meyers, PharmD

The past year has seen several new drugs for orphan diseases including 2 for Duchenne muscular dystrophy (DMD), a new combination drug for cystic fibrosis (CF), an anticonvulsant for Dravet syndrome (DS), and 2 potentially disease modifying drugs for sickle cell anemia (SCA).

ADAKVEO (CRIZANLIZUMAB) AND OXBRYTA (VOXELOTOR)

In November 2019 the US Food and Drug Administration (FDA) approved 2 therapies for SCA. Adakveo is a monoclonal antibody which binds to P-selectin, blocking interactions with its ligands including P-selectin glycoprotein ligand 1.

 The binding of P-selectin on the surface of activated endothelium and platelets prevents interactions between endothelial cells, platelets, leukocytes, and erythrocytes. Results from SUSTAIN 2 demonstrated a decreased rate of vaso-occlusive pain crises. Adakveo is approved for patients aged 16 years and older, given as a 30-minute IV infusion at weeks 0, 2, and 4, and then every 4 weeks.

Oxbryta inhibits polymerization of hemoglobin S, thus increasing its affinity for oxygen.

 a significantly higher percentage of patients in the Oxbryta group demonstrated a hemoglobin response, defined as an increase of at least 1.0 g/dL. Oxbryta is approved for patients aged 12 years and older and is an oral tablet given once daily.

VYONDYS 53 (GOLODIRSEN) AND VILTEPSO (VILTOLARSEN)

Two new medications for the treatment of DMD represent an advance in the treatment of this disease. Both Vyondys 53 and Viltepso bind to exon 53 of the dysfunctional dystrophin pre-messenger RNA, resulting in the skipping of exon 53.

 This allows for the production of a dystrophin protein, shorter than normal, but usable. The gene mutations that result in DMD vary: not all patients have mutations amenable to exon skipping. It is estimated that 8% of patients have mutations amenable to the skipping of exon 53.

 A similar mechanism is used for Exondys 51 (eteplirsen), which was approved in 2016 and skips exon 51. On the horizon is casimersen, which skips exon 45 – a new drug application is currently under consideration.

In August of 2020, a therapy for the treatment of spinal muscular atrophy (SMA) was approved, making it the third drug for this disease in less than 4 years. Evrysdi works by increasing inclusion of exon 7 in survival motor neuron 2 (SMN2) messenger ribonucleic acid transcripts, thus creating full length SMN protein. Trials in both infant-onset SMA and later-onset SMA were conducted to investigate efficacy.

 Patients in the infant-onset trial demonstrated a higher rate of sitting independently compared to typical disease progression. With this treatment, viability without permanent ventilatory assistance for children aged 23 months or older was higher than typical disease progression.

 Motor function scores compared to baseline were improved in patients with later-onset SMA.

 Evrysdi is the first oral medication for SMA.

Valtoco is an intranasal diazepam, approved for the acute treatment of seizures in patients aged 6 years and older. Devices of 5 mg, 7.5 mg, and 10 mg are available and each Valtoco device contains 1 spray; doses of 5 mg and 10 mg are given with 1 spray of the 5 mg and 10 mg device respectively. Doses of 15 mg and 20 mg are given with 1 spray from each of 2 devices of 7.5 mg (15 mg dose) and 10 mg (20 mg dose).

 A second dose may be given at least 4 hours after the initial dose.

ADVIL DUAL ACTION WITH ACETAMINOPHEN (IBUPROFEN AND ACETAMINOPHEN)

The new over-the-counter analgesic combination with ibuprofen and acetaminophen is the first of its kind in the United States. There is potential for overdose should patients use it in combination with acetaminophen or ibuprofen alone. A trial in pediatric patients aged 2-12 years is ongoing.

Fiasp, a faster-onset version of insulin aspart, was approved in 2018 for use in adults, and is now approved for patients aged 2 years and older. It is formulated with niacinamide, which increases the rate of absorption, resulting in an onset about 5 minutes earlier than the original insulin aspart formulation. Results from the onset 7 trial demonstrated non-inferiority to insulin aspart in hemoglobin A1c reduction from baseline and change in 1-hour postprandial glucose in patients aged 1 to less than 18 years.

 Fiasp is approved for use in basal-bolus regimens, subcutaneous pumps, and intravenous use under the supervision of a healthcare professional.

Originally approved in 2015 for the treatment of heart failure in adults, Entresto has now been granted approval for the treatment of symptomatic heart failure with systemic left ventricular systolic dysfunction in pediatric patients aged one year and older.

 This approval was based on 12-week results from the 52-week PANORAMA-HF trial, which compares Entresto with enalapril. Although the results were not statistically different between groups, improved outcomes were seen with Entresto.

Treatment options for COVID-19 in pediatric patients remain limited. Veklury (remdesivir) was granted an Emergency Use Authorization (EUA) for the treatment of COVID-19 in adults and children by the FDA in May of 2020.

 A clinical trial of Veklury in children is ongoing. Veklury is available in a concentrated solution and lyophilized powder, both for intravenous injection.

 The manufacturer only recommends use of the lyophilized powder for patients 3.5 kg to less than 40 kg due to the higher amount of sulfobutylether-β-cyclodextran sodium salt in the concentrated solution for injection, resulting in a higher toxicity.

Convalescent plasma has also been granted an EUA from the FDA and is being used in the treatment of children and adults with COVID-19.

 Multiple vaccines are undergoing testing, and several trials include children.

The continuing trend of new drug approvals for children and novel dosage forms is encouraging for health care providers. Expanded labeling provides practitioners with tools to treat patients safely and effectively. Several drugs in the pipeline, as well as drugs approved for adults with ongoing pediatric trials will help to continue this trend.

1. Adakveo (crizanlizumab-tmca) [package insert]. East Hanover, NJ: Novartis Pharmaceuticals Corporation; 2019.

2. Ataga KI, Kutlar A, Kanter J, et al. Crizanlizumab for the Prevention of Pain Crises in Sickle Cell Disease. N Engl J Med. 2017;376(5):429-439.

3. Oxbryta (voxelotor) [package insert]. South San Francisco, CA: Global Blood Therapeutics, Inc.; 2019.

4. Vichinsky E, Hoppe CC, Ataga KI, et al. A Phase 3 Randomized Trial of Voxelotor in Sickle Cell Disease. N Engl J Med. 2019;381(6):509-519.

5. Vyondys 53 (golodirsen) [package insert]. Cambridge, MA: Sarepta Therapeutics, Inc.; 2019.

6. Viltepso (viltolarsen) [package insert]. Paramus, NJ: NS Pharma, Inc.; 2020.

7. CureDuchenne. Duchenne Population Potentially Amenable to Exon Skipping. Accessed September 22, 2020. Available at: 

https://www.cureduchenne.org/wp-content/uploads/2016/11/Duchenne-Population-Potentially-Amenable-to-Exon-Skipping-11.10.16.pdf

8. Evrysdi (risdiplam) [package insert]. South San Francisco, CA: Genentech, Inc.; 2020.

9. US Food & Drug Administration. FDA approves oral treatment for spinal muscular atrophy. Accessed September 22, 2020. Available at: 

https://www.fda.gov/news-events/press-announcements/fda-approves-oral-treatment-spinal-muscular-atrophy

10. Valtoco (diazepam nasal spray) [package insert]. San Diego, CA: Neurelis, Inc.; 2020.

11. Bode BW, Iotova V, Kovarenko M, et al. Efficacy and Safety of Fast-Acting Insulin Aspart Compared With Insulin Aspart, Both in Combination With Insulin Degludec, in Children and Adolescents With Type 1 Diabetes: The onset 7 Trial. Diabetes Care. 2019;42(7):1255-1262.

12. Fiasp (insulin aspart) [package insert]. Bagsvaerd, Denmark: Novo Nordisk A/S; 2019.

13. Entresto (sacubitril and valsartan) [package insert]. East Hanover, NJ: Novartis Pharmaceuticals Corporation; 2020.

14. US Food & Drug Administration. New pediatric labeling information database. Accessed September 22, 2020.Available at: 

https://www.accessdata.fda.gov/scripts/sda/sdNavigation.cfm?sd=labelingdatabase

15. Novartis. Novartis Entresto receives FDA approval for pediatric heart failure, helping to address critical unmet need for treatment options. Accessed September 24, 2020. Available at: 

https://www.novartis.us/news/media-releases/novartis-entresto-receives-fda-approval-pediatric-heart-failure-helping-address

16. US Food & Drug Administration. Coronavirus (COVID-19) Update: FDA Issues Emergency Use Authorization for Potential COVID-19 Treatment. Accessed September 24, 2020. Available at: 

https://www.fda.gov/news-events/press-announcements/coronavirus-covid-19-update-fda-issues-emergency-use-authorization-potential-covid-19-treatment

17. Veklury (remdesivir) [package insert]. Foster City, CA: Gilead Sciences, Inc.; 2020.

18. US Food & Drug Administration. FDA Issues Emergency Use Authorization for Convalescent Plasma as Potential Promising COVID–19 Treatment, Another Achievement in Administration’s Fight Against Pandemic. Available at: FDA Issues Emergency Use Authorization for Convalescent Plasma as Potential Promising COVID–19 Treatment, Another Achievement in Administration’s Fight Against Pandemic. Accessed September 24, 2020.

19. Trikafta (elexacaftor, tezacaftor, and ivacaftor) [package insert]. Boston, MA: Vertex Pharmaceuticals Incorporated; 2019.

20. Koselugo (selumetinib) [package insert]. Wilmington, DE: AstraZeneca Pharmaceuticals LP; 2020.

21. Artesunate (artesunate) [package insert]. Wilmington, DE: Amivas LLC; 2020.

22. Fintepla (fenfluramine) [package insert]. Emeryville, CA: Zogenix Inc.; 2020.

23. Dojolvi (triheptanoin) [package insert]. Novato, CA: Ultragenyx Pharmaceutical Inc.; 2020.

24. Tralement (trace elements injection 4) [package insert]. Shirley, NY: American Regent, Inc.; 2020.

25. Xeglyze (abametapir) [package insert]. Princeton, NJ: Dr. Reddy's Laboratories, S.A.; 2020.

26. Lampit (nifurtimox) [package insert]. Whippany, NJ: Bayer HealthCare Pharmaceuticals Inc.; 2020.

27. Winlevi (clascoterone) [package insert]. San Diego, CA: Cassiopea Inc.; 2020.

28. Amzeeq (minocycline) [package insert]. Bridgewater, NJ: Foamix Pharmaceuticals Ltd; 2019.

29. Quzyttir (cetirizine hydrochloride) [package insert]. Deerfield, IL: Tersera Therapeutics LLC; 2020.

30. Aklief (trifarotene cream) [package insert]. Fort Worth, TX: Galderma Laboratories, L.P.; 2019.

31. Palforzia [Peanut (Arachis hypogaea) Allergen Powder-dnfp] [package insert]. Brisbane, CA: Aimmune Therapeutics Inc.; 2020.

32. MenQuadfi (meningococcal (groups A, C, Y, W) conjugate vaccine) [package insert]. Swiftwater, PA: Sanofi Pasteur Inc.; 2020.

33. SEVENFACT (coagulation factor VIIa (recombinant)-jnew) [package insert]. Les Ulis, France: Laboratoire Francais du Fractionnement et des Biotechnologies S.A.; 2020.

34. Audenz (influenza A (H5N1) monovalent vaccine) [package insert]. Summit, NJ: Seqirus USA Inc.; 2020.

35. Fetroja (cefiderocol) [package insert]. Florham Park, NJ: Shionogi Inc.; 2019.

36. Xcopri (cenobamate) [package insert]. Paramus, NJ: SK Life Science, Inc.; 2019.

37. Olinvyk (oliceridine) [package insert]. Chesterbrook, PA: Trevana, Inc.; 2020.

38. Ervebo (Ebola Zaire vaccine, live) [package insert]. Whitehouse Station, NJ: Merck & Co., Inc.; 2019.

39. Dificid (fidaxomicin) [package insert]. Whitehouse Station, NJ: Merck & Co., Inc.; 2020.

40. Anjeso (meloxicam) [package insert]. Malvern, PA: Baudax Bio, Inc.; 2020.

41. Qdolo (tramadol hydrochloride oral solution) [package insert]. Athens, GA: Athena Bioscience, LLC; 2020.

42. Advil Dual Action with Acetaminophen (ibuprofen and acetaminophen) [package insert]. Madison, NJ: Pfizer Inc.; 2020.

43. Arazlo (tazarotene) [package insert]. Bridgewater, NJ: Bausch Health US, LLC; 2019.

44. Cymbalta (duloxetine delayed-release capsules) [package insert]. Indianapolis, IN: Lilly USA, LLC; 2020.

45. Taltz (ixekizumab) [package insert]. Indianapolis, IN: Eli Lilly and Company; 2020.

46. Eucrisa (crisaborole ointment) [package insert]. New York, NY: Pfizer Inc.; 2020.

47. Epclusa (velpatasvir and sofosbuvir tablet, film coated) [package insert]. Foster City, CA: Gilead Sciences, Inc.; 2020.

48. Cleocin phosphate (clindamycin phosphate injection) [package insert]. New York, NY: Pfizer Inc.; 2020.

49. Cafcit (caffeine citrate) [package insert]. Eatontown, NJ: Hikma Pharmaceuticals USA Inc.; 2019.

50. Mycamine (micafungin sodium) [package insert]. Toyama, Japan: Astellas Pharma Tech Co., Ltd; 2019.

51. Conjupri (levamlodipine maleate) [package insert]. Hot Springs, AR: Burke Therapeutics, LLC; 2020.

52. Sorilux(calcipotriene) Foam. [package insert]. Greenville, NC: Mayne Pharma; 2019.

53. Ultomiris (ravulizumab) [package insert]. Boston, MA: Alexion Pharmaceuticals, Inc.; 2019.

54. Botox (onabotulinumtoxina injection) [package insert]. Madison, NJ: Allergan USA, Inc.; 2019.

55. Wilate (von Willebrand Factor/Coagulation Factor VIII Complex (human)) [package insert]. Hoboken, NJ: Octapharma USA Inc.; 2019.

56. Tybost (cobicistat) [package insert]. Foster City, CA: Gilead Sciences, Inc.; 2020.

57. Descovy (emtricitabine and tenofovir alafenamide) [package insert]. Foster City, CA: Gilead Sciences, Inc.; 2020.

58. Teflaro (ceftaroline fosamil) [package insert]. Madison, NJ: Allergan USA, Inc.; 2019.

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