March 2022 decisions expected from the FDA

At Prime Therapeutics (Prime), we’ve positioned ourselves to best prepare our clients to manage new drugs. 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).

3/11/2022: Adlarity™ (donepezil, transdermal)
The FDA is reviewing Corium’s Adlarity, a once-weekly transdermal patch formulation of donepezil for Alzheimer’s dementia. Corium is applying for approval through the 505(b)(2) pathway using Pfizer’s Aricept^® (donepezil) as its reference drug.¹ Donepezil is the most widely prescribed medication in Alzheimer’s treatment. It is available as a once daily tablet or orally disintegrating tablet. Adlarity would be available as a 5mg/day and 10mg/day transdermal patch. Similar products include Pfizer’s Aricept^® (donepezil) and its generics.

3/18/2022: Tyvyt™ (sintilimab)
Innovent Biologics and Lilly’s Tyvyt is seeking approval from the FDA as a PD-1 inhibitor immuno-oncologic for use in combination with pemetrexed and platinum chemotherapy for first-line treatment of nonsquamous non-small cell lung cancer (NSCLC). Tyvyt is seeking approval based on the Phase 3 trial, ORIENT-31, which demonstrated a statistically significant improvement of progression-free survival (PFS) compared to patients who were treated with chemotherapy alone. The median PFS was 6.9 vs. 4.3 months, respectively.² Similar products include Merck’s Keytruda^® (pembrolizumab) and Sanofi/Regeneron’s Libtayo^® (cemiplimab-rwlc).

3/19/2022: relatlimab plus nivolumab
Bristol Myers Squibb’s relatlimab plus nivolumab is seeking priority review from the FDA as a fixed-dose combination for the treatment of adult and pediatric patients (12 years and older and weighing at least 40 kg) with unresectable or metastatic melanoma. Relatlimab and nivolumab is the lymphocyte-activation gene (LAG-3)-blocking antibody that is administered as a single infusion. The application was based on the efficacy and safety results of the Phase 2/3 RELATIVITY-047 trial, which demonstrated a statistically significant and clinically meaningful PFS benefit of a combination therapy over standard of care anti-PD-1 monotherapy in metastatic melanoma. Relatlimab and nivolumab demonstrated a median PFS of 10.12 months compared to 4.63 months in the control group. The 12-month PFS rate with relatlimab plus nivolumab was 47.7% vs 36.0% with nivolumab alone.³ Similar products include Bristol Myers Squibb’s Opdivo^® (nivolumab).

3/20/2022: Ztalmy™ (ganaxolone)
The FDA is reviewing Marinus Pharmaceuticals’ Ztalmy for the treatment of seizures associated with CDKL5 deficiency disorder (CDD). Ztalmy is a positive allosteric modulator of GABAA receptors being developed in both oral and intravenous (IV) formulations. Pediatric patients enrolled in the Phase 3 study who received Ztalmy demonstrated a 32.2% reduction of seizure burden compared to patients who received a placebo that demonstrated a 4% reduction. Ztalmy achieved its primary endpoint which was defined by the percentage change in 28-day frequency of major motor seizures during the double-blind phase relative to the six-week prospective baseline period.⁴ Currently there are no FDA-approved treatments for this indication.

3/25/2022: ublituximab
The FDA is reviewing TG Therapeutics’ ublituximab for treatment of patients with chronic lymphocytic leukemia (CLL) and small lymphocytic leukemia (SLL). Ublituximab is a glycoengineered anti-CD20 monoclonal antibody for use in combination with the PI3K-delta and CK1-epsilon inhibitor TG Therapeutics’ Ukoniq^® (umbralisib). The BLA submission was based on the results of the UNITY-CLL trial, a Phase 3 trial evaluating the combination of ublituximab plus UKONIQ (U2) compared to obinutuzumab plus chlorambucil in patients with treatment naive and relapsed or refractory CLL. Ublituximab met its primary endpoint by demonstrating superior progression-free survival (PFS) compared to control.⁵ Similar products include Genentech’s Gazyva^® (obinutuzumab) plus chlorambucil.

3/26/2022: udenafil
Udenafil from Mezzion Pharma is being reviewed by the FDA for oral treatment to improve the physiology of patients 12 years of age and older with single ventricle heart disease (SVHD) who have undergone the Fontan operation. Udenafil is a long-acting highly selective phosphodiesterase-5 (PDE-5) inhibitor. Udenafil’s application is supported by data from more than 200 studies completed over the last two decades, including the pivotal Phase 3 FUEL trial which evaluated the efficacy and safety.  The primary endpoint was the change in exercise capacity from baseline to 26 weeks, as measured by maximal oxygen consumption at peak exercise and results showed that treatment with udenafil was not associated with statistically significant improvements in oxygen consumption at peak exercise compared with placebo.⁷ However, analysis at ventilatory anaerobic threshold demonstrated statistically significant improvements in submaximal exercise performance. Treatment with udenafil was associated with improvement in the myocardial performance index, but not with changes in reactive hyperemia index or serum brain-type natriuretic peptide levels.⁶ Currently there are no similar products for this indication.

3/29/2022: Vafseo™ (vadadustat)
The FDA is reviewing Akebia Therapeutics’ Vafseo for treatment of anemia due to chronic kidney disease (CKD) in both adults on dialysis and adults not on dialysis. Vafseo is an oral hypoxia-inducible factor prolyl hydroxylase inhibitor (HIF-PHI). Vafseo is applying for approval based on analysis of pooled safety data from four Phase 3, open-label studies evaluating the use of Vafseo compared with darbepoetin alfa (DA). Vafseo achieved the primary efficacy endpoints in the two PRO₂TECT Phase 3 studies, which demonstrated non-inferiority of Vafseo to darbepoetin alfa as measured by a mean change in Hb between baseline and the primary evaluation period (weeks 24 to 36) and secondary evaluation period (weeks 40 to 52).⁷ Non-inferiority was achieved because the between-group difference of the mean Hb change did not fall below the pre-specified non-inferiority margin.⁷ Currently there are no approved HIF-PHIs. However, AstraZeneca and FibroGen’s roxadustat, a medication with the same mechanism of action, applying for the same indication was rejected by the FDA earlier in 2021.

3/31/2022: letibotulinumtoxinA
The FDA is reviewing Hugel America’s letibotulinumtoxinA as a botulinum toxin for treatment of moderate to severe glabellar (frown) lines in adults. LetibotulinumtoxinA met its primary endpoint of improving the facial wrinkle scale (FWS) at week four compared to baseline.⁸ LetibotulinumtoxinA is currently approved and available in 28 countries. Similar products include Allergan’s Botox^® (onabotulinumtoxinA).

3/31/2022: Ryzneuta™ (efbemalenograstim alfa, F-627)
Ryzneuta by Evive Biotech is seeking approval from the FDA for treatment of chemotherapy-induced neutropenia. Ryzneuta is a recombinant fusion protein linking granulocyte-colony stimulating factor (G-CSF) and a human IgG2-Fc fragment.

The BLA submission is supported by data from two Phase 3 trials that evaluated the efficacy and safety of Ryzneuta in adult women with Stage I-III and Stage II-IV breast cancer who were receiving chemotherapy treatment. Patients treated with Ryzneuta had a mean duration of 1.3 days of grade 4 neutropenia compared with 3.9 days for patients treated with placebo.⁹ Ryzneuta was also compared against Neulasta, however the study results have not been released yet. Similar products include Amgen’s Neulasta^® (pegfilgrastim).

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.

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References

1. https://www.biospace.com/article/corium-inc-announces-fda-filing-acceptance-of-new-drug-application-for-adlarity-donepezil-transdermal-system-for-the-treatment-of-alzheimer-s-disease/#:~:text=ADLARITY%20(donepezil%20transdermal%20system)%20is,proprietary%20CorplexTM%20technology%20platform.
2. https://www.centerforbiosimilars.com/view/sintilimab-and-bevacizumab-biosimilar-improve-pfs-in-advanced-lung-cancer
3. https://www.onclive.com/view/fda-grants-priority-review-to-relatlimab-nivolumab-for-unresectable-or-metastatic-melanoma
4. https://www.biospace.com/article/releases/ganaxolone-achieves-primary-endpoint-in-phase-3-trial-for-cdkl5-deficiency-disorder-cdd-a-rare-form-of-genetic-epilepsy/
5. https://www.biospace.com/article/releases/tg-therapeutics-announces-fda-acceptance-of-biologics-license-application-for-ublituximab-in-combination-with-ukoniq-umbralisib-as-a-treatment-for-patients-with-chronic-lymphocytic-leukemia-and-small-lymphocytic-lymphoma/
6. https://www.empr.com/home/news/drugs-in-the-pipeline/udenafil-under-review-for-single-ventricle-heart-disease/#:~:text=The%20Food%20and%20Drug%20Administration,who%20have%20undergone%20Fontan%20palliation.
7. https://www.pharmacytimes.com/view/studies-find-encouraging-safety-data-with-vadadustat-for-patients-with-anemia-due-to-chronic-kidney-disease
8. https://www.prnewswire.com/news-releases/hugel-america-inc-announces-us-fda-acceptance-of-biologics-license-application-bla-for-letibotulinumtoxina-for-injection-to-treat-glabellar-frown-lines-301312900.html
9. https://www.empr.com/home/news/drugs-in-the-pipeline/ryzneuta-efbemalenograstim-alfa-evive-fda-biologics-license-application-submission/