November 2020 decisions expected from the FDA

At Prime Therapeutics (Prime), we’ve positioned ourselves to best prepare our clients to manage the new drugs that come on the market. Our clinical and trade relations teams keep a keen eye on drugs likely to be approved by the U.S. Food and Drug Administration (FDA).

11/1/2020: Bronchitol™ (mannitol for inhalation)

The FDA is reviewing Chiesi Group and Pharmaxis’ Bronchitol for the management of cystic fibrosis (CF) in patients ages six years and older to improve pulmonary function. Bronchitol is a dry powder formulation of mannitol inhaled through a small handheld device. A Phase 3 clinical trial demonstrated patients inhaling high dose Bronchitol twice a day improved FEV1 by 8.2 percent compared to baseline and 3.75 percent when compared with patients receiving the low dose.1 In January 2013, the FDA’s Pulmonary-Allergy Drugs Advisory Committee made a negative recommendation on the use of Bronchitol for CF; the FDA issued a complete response letter (CRL) due to lack of required efficacy and safety. The FDA suggested Chiesi conduct additional clinical trials. In June 2019, Bronchitol received an additional CRL detailing the remaining matters to be addressed. Similar products include Genentech’s Pulmozyme® (dornase alfa) or nebulized hypertonic saline.

11/8/2020: viloxazine hydrochloride extended release formulation

Supernus’ viloxazine is being reviewed by the FDA for the treatment of attention deficit hyperactivity disorder (ADHD) in children and adolescents aged six to 17 years of age. Viloxazine hydrochloride is a non-stimulant serotonin norepinephrine modulating agent (SNMA). Clinical trials demonstrated that viloxazine showed greater improvements in ADHD-RS-5 total score when compared to placebo as soon as week one . At six weeks, viloxazine demonstrated significantly higher CGI-I responder rate when compared to placebo (viloxazine 100mg:45%, viloxazine 200mg;51% versus placebo;30% respectively).2 Additionally, the statistically significant results were supported by two parent self-rated assessments. Parents noted improvements in their child’s ADHD symptoms and in ADHD-associated learning problems, executive functioning, defiance, peer relations and functioning in different settings. Similar products include Eli Lilly’s Strattera® (atomoxetine HCl) and its generics.

11/13/2020: sutimlimab

The FDA is reviewing Sanofi’s sutimlimab for the treatment of cold agglutinin disease (CAD). Cold agglutinin disease affects approximately 10,000 people in the U.S. and Europe combined.3 Sutimlimab is a first in class, monoclonal antibody that binds to C1s which may block downstream steps that reduce red blood cell lysis. Sutimlimab only blocks one of the three arms of the complement pathway, which ensures that the complement pathway is not totally ineffective. Sutimlimab has demonstrated in clinical trial that it rapidly halted the destruction of red blood cells and increased hemoglobin levels. Sanofi is seeking approval based on a Phase 3 clinical trial, CARDINAL, which evaluated efficacy and safety of sutimlimab in patients in two parts. The first part of CARDINAL demonstrated that 13 of 24 patients met the goal of increased hemoglobin levels. More than 70% of patients did not require blood transfusions past week five of the study.4 The second part of the study hopes to demonstrate long-term safety and tolerability with adverse events. This part of the study is set to complete fall 2020. Side effects with sutimlimab appear to be few and mild; however, they are based on limited safety data. Currently, there are no FDA-approved pharmacological treatments for CAD. Patients affected by this disease usually avoid cold temperatures. In severe cases when hemoglobin levels get very low, patients may have blood transfusions.

11/15/2020: olanzapine and samidorphan

Alkermes’ combination of olanzapine/samidorphan is being reviewed by the FDA for treatment of manic or mixed episodes associated with bipolar I disorder. Olanzapine is an antipsychotic and samidorphan is a novel opioid antagonist. Samidorphan reduces the weight gain associated with olanzapine. The ENLIGHTEN-2 study compared olanzapine/samidorphan-treated patients to patients taking olanzapine alone and found that olanzapine alone had a 57% higher weight gain from baseline when compared to patients taking olanzapine/samidorphan. Olanzapine had twice the risk of gaining 10% or more of their baseline body weight compared to patients on olanzapine/samidorphan.5 Alkermes has a tentative October 9 date with the FDA review committee to review potential drug-drug interactions (DDIs). Similar products include Lilly’s Zyprexa® (olanzapine) and its generics.

11/15/2020: AR19

Arbor Pharmaceuticals’ AR19 is being reviewed by the FDA for treatment of attention deficit hyperactivity disorder (ADHD) in adults and pediatric patients aged 3-17 years old. AR19 is an immediate-release abuse-deterrent formulation of amphetamine, with features to resist manipulation by intranasal, IV and smoking routes. Arbor Pharmaceuticals is seeking approval based on a clinical study that randomized 320 adults to receive either 20mg of AR19, 40mg of AR19 or placebo once daily for five weeks. Both doses of AR19 met the primary efficacy endpoint, improving symptoms as measured by the Adult ADHD Investigator Symptom Rating Scale. On the scale, the least square mean treatment difference versus placebo was -7.2 for the 20mg group and -7.3 for the 40mg group.6 Similar products include Teva’s Adderall® (amphetamine) and its generics.

11/16/2020: Breyanzi™ [lisocabtagene maraleucel (liso-cel, formerly JCAR017)]

Bristol-Myers Squibb (Celgene)’s Breyanzi is being reviewed for treatment of adults with relapsed or refractory large B-cell lymphoma (LBCL) after at least two prior therapies. Breyanzi is a CD19-directed autologous chimeric antigen receptor (CAR)T-cell therapy. Breyanzi uses the patient’s own healthy T-cells which are removed and re-programed to target cells that express a specific protein (CD19) commonly found on the target cancer cells. Based on the TRANSCEND NHL 001 study, 73% of patients demonstrated an objective response and a complete response (CR) in 53% of patients. Breyanzi showed a median progression-free survival of 6.8 months, and a median overall survival of 21.1 months. At 12 months, 65.5% of patients were progression free and 85.5% were alive.7 Similar products include Gilead Sciences’ Yescarta® (axicabtagene ciloleucel) and Novartis’ Kymriah® (tisagenlecleucel).

11/18/2020: Zimhi™ (naloxone pre-filled syringe)

Adamis’ Zimhi is being reviewed by the FDA as a pre-filled single-dose syringe (PFS) formulation of high-dose naloxone for treatment of opioid overdose. Zimhi was originally submitted to the FDA using pharmacokinetic studies comparing Zimhi injection to a generic naloxone comparator in 2018. However, in 2019 Adamis received a complete response letter (CRL) from the FDA with concerns about chemistry manufacturing and controls (CMC) information.8 Adamis requested a Type A meeting with the FDA. In May 2020, Adamis resubmitted the updated NDA to the FDA. According to the statistics published by the Centers for Disease Control and Prevention, drug overdoses resulted in approximately 72,000 deaths in the United States in 2017. Similar products include Kaleo’s Evzio® (naloxone) and Emergent’s Narcan® (naloxone).

11/20/2020: Zokinvy™ (lonafarnib)

The FDA is reviewing Eiger BioPharmaceuticals’ Zokinvy, a farnesyl protein transferase inhibitor for the oral treatment of Hutchinson-Gilford Progeria Syndrome (HGPS or progeria) and progeroid laminopathies. Zokinvy is seeking approval based on data from clinical studies that demonstrated a survival benefit with an 88% reduction in the risk of mortality in patients with progeria treated with Zokinvy monotherapy compared to no treatment.9 The FDA is not planning to hold an advisory committee meeting to discuss this application. There are currently no FDA-approved pharmacological therapies for progeria or progeroid laminopathies.

11/24/2020: LIQ861

The FDA is reviewing Liquidia’s LIQ861, a dry powder for inhalation of treprostinil for enhanced deep-lung delivery in patients with pulmonary arterial hypertension (PAH). LIQ861 uses the company’s PRINT technology to formulate treprostinil. LIQ861 is seeking approval via the 505(b)(2) pathway using United Therapeutics’ Tyvaso® (treprostinil) as its reference drug. In a clinical trial, INSPIRE, LIQ861 met its primary endpoint of safety and being well-tolerated in 109 patients.10 Similar products include United Therapeutics’ Tyvaso® (treprostinil), United Therapeutics’ Orenitram® (treprostinil extended release tablets), and United Therapeutics’ Remodulin® (treprostinil injection).

11/25/2020: daxibotulinumtoxinA

Revance Therapeutics’ daxibotulinumtoxinA is being reviewed by the FDA for the treatment of moderate to severe glabellar (frown) lines and lateral canthal lines commonly known as crow’s feet. It is a long-acting neuromodulator that combines a stabilizing peptide excipient with highly purified botulinum toxin. Revance Therapeutics announced two Phase 2a open-label studies that demonstrated 100% of subjects achieved a score in forehead lines at week four. In the crow’s feet study, 88% of subjects achieved a score of none or mild at week four in at least one treatment group.11 In these two Phase 2a studies, daxibotulinumtoxinA for injection was well-tolerated at all dose levels. Similar products include Allergan Botox® (onabotulinumtoxinA).

11/27/2020: setmelanotide

Rhythm Pharmaceuticals’ setmelanotide is being reviewed by the FDA for treatment of pro-opiomelanocortin (POMC) deficiency obesity and leptin receptor (LEPR) deficiency obesity. Setmelanotide is a melanocortin-4 receptor (MC4R) agonist which independently regulates energy expenditure and appetite. Setmelanotide is a self-administered subcutaneous once weekly injection. Phase 3 clinical trials have shown that one year of treatment resulted in at least a 10% weight loss, and a reduction in hunger levels and body mass index (BMI) in POMC and LEPR deficiency patients.12 Results demonstrated similar weight loss in both weekly and daily doses of setmelanotide. The mean difference in weight loss between the two formulations varied between 0.02kg and 1.71kg (0.04 and 3.77 pounds) which were not statistically significant.13 The FDA has indicated that it is not planning an advisory committee meeting. Currently, there are no pharmacologic therapies to treat these conditions, but treatment would include gastric bypass surgery.

11/30/2020: Danyelza™ (naxitamab, formerly hu3F8)

Y-mAbs’ Danyelza is being reviewed by the FDA for treatment of patients with relapsed or refractory high-risk neuroblastoma. Danyelza is a specific humanized monoclonal antibody that targets GD2. In a Phase 2 clinical trial, Danyelza demonstrated an overall objective response rate (ORR) of 78% and a complete response (CR) rate of 71% in patents with primary refractory high-risk neuroblastoma.14 In a subset of patients with relapsed neuroblastoma resistant to salvage therapy, Danyelza had an ORR of 37%. The FDA does not have plans to hold an advisory committee meeting to discuss Danyelza. Similar products include multimodality therapy that depends on the individual patient previous regimen.

While the information in this newsletter is from sources, we believe to be reliable, we do not warrant that the information in this document is free from error. Use it only as a guide. Statements regarding drugs or manufacturers are not intended as promotion; those statements should not be used to make assumptions about formulary status. Each trademarked drug name is the property of its respective owner.

References

1. https://cysticfibrosisnewstoday.com/inhaled-mannitol-mucociliary-clearance/

2. https://www.psychcongress.com/posters/extended-release-viloxazine-spn-812-100-mg-or-200-mg-treatment-adhd-children-topline#:~:text=Background%3A%20SPN%2D812%20(extended,%2Fhyperactivity%20disorder%20(ADHD)

3. https://www.hcplive.com/view/sutimlimab-demonstrates-efficacy-cold-agglutinin-disease

4. https://coldagglutininnews.com/bivv009-sutimlimab/

5. https://www.fiercebiotech.com/biotech/virtual-fda-adcomm-for-alkermes-alks-3831-adds-new-focus-drug-drug-interactions

6. https://arborpharma.com/2020/09/10/arbor-presents-data-from-pivotal-study-of-ar19-an-investigational-adhd-prescription-stimulant-treatment-specifically-designed-to-resist-physical-manipulation-for-nonmedical-misuse-or-abuse/

7. https://www.practiceupdate.com/content/lisocabtagene-maraleucel-in-relapsedrefractory-large-b-cell-lymphomas/106149

8. https://www.drugs.com/nda/zimhi_200520.html

9. https://www.prnewswire.com/news-releases/eiger-biopharmaceuticals-announces-fda-acceptance-of-nda-for-filing-with-priority-review-of-zokinvy-lonafarnib-for-treatment-of-progeria-and-progeroid-laminopathies-301062068.html

10. https://www.globenewswire.com/news-release/2020/04/30/2025110/0/en/Liquidia-Releases-Final-LIQ861-Results-from-Pivotal-Phase-3-INSPIRE-Study-in-Patients-with-Pulmonary-Arterial-Hypertension.html

11. https://www.biospace.com/article/releases/revance-announces-positive-results-in-two-phase-2a-studies-of-daxibotulinumtoxina-for-injection-for-the-treatment-of-forehead-lines-and-crow-s-feet-respectively/

12. https://ir.rhythmtx.com/news-releases/news-release-details/rhythm-pharmaceuticals-announces-fda-acceptance-new-drug

13. https://geneticobesitynews.com/2020/06/25/setmelanotides-weekly-formulation-as-safe-and-effective-as-daily-use-phase-2-trial-data/

14. https://www.onclive.com/view/fda-grants-naxitamab-priority-review-for-relapsedrefractory-highrisk-neuroblastoma