A look at the latest and upcoming pharmaceutical patents

January 15, 2019
Michael S. Cooper, OD
Volume 11, Issue 2

Recent mergers, acquisitions, and drug patent battles in the pharmaceutical space have led to changes in the ocular pharmaceutical pipeline.
These dynamics have led to a strain on the larger pharmaceutical segment in which new chemical entities have been slower to reach the marketplace. But this does not mean eyecare professionals are not seeing new products. 

Innovative chemistry
Start-up pharma companies with and without venture capital backing have given rise to a bumper crop of innovative chemistry. Check the news feed or peruse the stock market quotes to find these organizations. They are everywhere-domestic and international.

I have been trained by my father-an electrical engineer by trade-to always keep my ear to the ground. He instilled this spirit of opportunistic ingenuity that drives my curiosity, especially in the allergy field.
I am sharing updates on drugs in development that are readily available in the public domain, so there are no concerns of trade infringements or secrets.

Reproxalap (Aldeyra Therapeutics)Aldeyra Therapeutics has found a niche in aldehyde chemistry (see “How palynology and aldehydes affect allergy treatment” in the June 2016 issue ).

Clinically, antihistamine/mast cell stabilizers deliver on reducing itch and redness over a 12- to 24-hour period, yet they still suffer from some level of tachyphylaxis or a plateau in efficacy over time.

The premise for this developmental drug is to lower free aldehyde (malondialdehyde) levels by creating a “trap” mechanism to bind to the molecule, which downregulates cytokine release as part of the extended inflammatory cascade.1,2 

Previously by Dr. Cooper: Propolis may help treat ocular disease

With this innovative therapeutic approach, human clinical trials were initiated after animal models illustrated reproxalap effective in diminishing ocular redness. An additional caveat showed equivalence to that observed with corticosteroids.1

A randomized double-masked, parallel-grouped single-center Phase 2a study enrolled 100 healthy men and women with at least a two-year history of allergic conjunctivitis to grass, tree, or ragweed pollen.3
The work demonstrated statistically significant activity (P=0.009) of the target drug over vehicle in reducing ocular itching and tearing.2,3 

Following up on this success, a Phase 2b study was initiated with a randomized, dose-ranging, parallel-group, double-masked, vehicle-controlled, conjunctival allergen challenge (ORA-CAC) comparative of 0.1% and 0.5% solutions.4

The trial enrolled 154 patients (approximately 50 per arm) with allergic conjunctivitis, including subjects with seasonal and perennial allergies.4,5

While the higher concentration did not meet the one point over placebo primary endpoint, it was found to have a preferable dose specific response and tolerability profile, specifically in late-phase inflammation.4,5 
Aldeyra recently completed a Phase 3 clinical trial called “A Multi-Center, Double-Masked, Randomized, Parallel-Group, Vehicle-Controlled, Phase 3 Clinical Trial to Assess the Safety and Efficacy of Reproxalap Ophthalmic Solutions (0.25% and 0.5%) Compared to Vehicle in the Conjunctival Allergen Challenge (Ora-CAC) Model of Acute Allergic Conjunctivitis.”

Known as ALLEVIATE, the trial results are expected to be announced in 2019.6
 

PRO-13 (Realm Therapeutics)
PRO-13 relies on a higher concentration of hypochlorous acid to act as an immunomodulatory agent rather than the anti-microbial component in order to down regulate inflammation.7,8

In preclinical trials there was a significant reduction in cytokines, includingIL-4, IL-13, TNF-α, IL 1β, IFN-γ, IL-6, IL-8, IL-12, and TARC (thymus and activation-regulated chemokine), as well as IL-31 and TSLP (thymic stromal lymphopoietin) in the mediation of itch.7,9,10

In a multi-center, double-masked, randomized Phase 2 study comparing 0.045% and 0.06% concentrations to vehicle for ocular itch and redness in 90 patients, PR0-13 failed to show efficacy as of March 2018.11,12

The company has since scrapped further work on this formulation in favor of PR0-22, shifting its focus to atopic dermatitis.12PRT-2761 (Portola Pharmaceuticals)
One of the best examples of collaborative work taking place on a regular basis in the ocular allergy sector is Ora, Inc.

For over 40 years, Ora has assisted industry partners of all sizes-from preclinical to pivotal to commercialization of more than 1,600 projects with 46 U.S. Food and Drug Administration (FDA)-approved products.13
ORA-CAC (conjunctival allergen challenge), has set the standard with its model for clinical allergy research.

Ora inked a deal with Portola Pharmaceuticals in 2015 to build PRT-2761 (Syk[spleen tyrosine kinasae] inhibitor) and focus on the ophthalmic segment. The compound has additional value to the parent company in the other key areas outside of allergy in thrombosis and hematological cancer.14

A growing interest in Syk chemistry, which includes cytosolic non-receptor protein propagates B-cell receptor signaling along with immune and adhesion receptor signal transduction, has encouraged the move.15
This particular compound has the potential to provide a more robust prevention of mast cell activation. 

One single-center, randomized, double-masked, vehicle and active-controlled, dose-ranging Phase 2 trial looked at 0.5% and 1% concentrations with active comparators in Patanol (olopatadine, Novartis) and Pred Forte (prednisolone acetate, Allergan).

A 10-Q investor filing illustrated statistical significance in one of two primary endpoints studying ocular itch and conjunctival redness.16,17

Ora is currently exploring the potential to pursue an indication for PRT-2761 in dry eye and other ocular inflammatory diseases in a Phase 3 study.17What’s next?
Time will tell if these drugs make it through the rigor of studies and the FDA approval process. However, clearly unmet needs on a global scale still await new solutions.

Read more by Dr. Cooper

References:

1. Aldeyra Therapeutics. Allergic conjunctivitis: A common disease with suboptimal therapy. Available at: https://www.aldeyra.com/allergic-conjunctivitis/. Accessed 12/26/18.
2. American Academy of Ophthalmology. Aldehyde trap drug rapidly improves signs, symptoms of dry eye disease. Available at: https://www.aao.org/headline/aldehyde-trap-drug-rapidly-improves-signs-symptoms. Accessed 12/26/18.
3. Aldeyra Therapeutics, Inc. Aldeyra Therapeutics reports positive results from Phase IIa clinical trial in subjects with allergic conjunctivitis. Available at: http://ir.aldeyra.com/news-releases/news-release-details/aldeyra-therapeutics-reports-positive-results-phase-iia-clinical?ReleaseID=957653. Accessed 12/26/18.
4. U.S. National Library of Medicine. A study of ADX-102 in subjects with allergic conjunctivitis Clinicaltrials.gov. Available at: https://clinicaltrials.gov/ct2/show/NCT03012165?cond=adx-102&rank=1. Accessed 12/26/18.
5. Aldeyra Therapeutics, Inc. Aldeyra Therapeutics announces results from allergic conjunctivitis Phase 2b clinical trial and plans for Phase 3 clinical testing | Aldeyra Therapeutics, Inc. Available at: http://ir.aldeyra.com/news-releases/news-release-details/aldeyra-therapeutics-announces-results-allergic-conjunctivitis?ReleaseID=1030137. Accessed 12/26/18.
6. U.S. National Library of Medicine. ALLEVIATE Trial - A Phase 3 trial in subjects With allergic conjunctivitis. Clinicaltrials.gov. Available at: https://clinicaltrials.gov/ct2/show/NCT03494504?recrs=abd&cond=Allergic+Conjunctivitis&rank=1. Accessed 12/26/18.
7. Realm Therapeutics.Technology: Realm Therapeutics, Inc. Available at: http://www.realmtx.com/technology. Accessed 12/26/18.
8. Stroman DW, Mintun K, Epstein AB, Brimer CM, Patel CR, Branch JD, Najafi-Tagol K. Reduction in bacterial load using hypochlorous acid hygiene solution on ocular skin. Clin Ophthalmol. 2017 April 13;11: 707-714. doi: 10.2147/OPTH.S132851.
9. Kataoka Y. Thymus and activation-regulated chemokine as a clinical biomarker in atopic dermatitis. J Dermatol. 2014 Mar;41(3): 221-229. doi: 10.1111/1346-8138.12440.
10. Ziegler SF, Roan F, Bell BD, Stoklasek TA, Kitajima M, Han H. The biology of thymic stromal lymphopoietin (TSLP). Adv Pharmacol. 2013; 66: 129-155. doi: 10.1016/B978-0-12-404717-4.00004-4.
11. U.S. National Library of Medicine. Effectiveness of PR013 topical ophthalmic drops compared to vehicle for the treatment of allergic conjunctivitis. Clinicaltrials.gov. Available at: https://clinicaltrials.gov/ct2/show/NCT03368339?cond=pr013&draw=1&rank=1. Accessed 12/26/18.
12. Taylor NP. Realm scraps eye drug after midphase flop, sinking stock. FierceBiotech. Available at: https://www.fiercebiotech.com/biotech/realm-scraps-eye-drug-after-midphase-flop-sinking-stock. Accessed 12/26/18.
13. Ora Clinical. About Ora- Our customized approach to guiding your ophthalmic contract product development. Ora. Available at: https://www.oraclinical.com/about/about-us/. Accessed 12/26/18.
14. The Pharma Letter. Portola inks deal with Ora for PRT2761 in ophthalmic diseases. Available at: https://www.thepharmaletter.com/article/portola-inks-deal-with-ora-for-prt2761-in-ophthalmic-diseases. Accessed 12/26/18.
15. Liu D, Mamorska-Dyga A. Syk inhibitors in clinical development for hematological malignancies. J Hematol Oncol. 2017 July;10(1): 145. doi:10.1186/s13045-017-0512-1.
16. U.S. National Library of Medicine. Study evaluating the efficacy and safety of PRT-2761 for the treatment of acute and chronic allergic conjunctivitis. Clinicaltrials.gov. Available at: https://clinicaltrials.gov/ct2/show/NCT03320434. Accessed 12/26/18.
17. Portola Pharmaceuticals, Inc. Portola Pharmaceuticals Inc field this form 10-Q on 09/09/2018. Available at: http://investors.portola.com/mobile.view?c=198136&v=202&d=3&id=aHR0cDovL2FwaS50ZW5rd2l6YXJkLmNvbS9maWxpbmcueG1sP2lwYWdlPTEyNDAwNDc3JkRTRVE9MSZTRVE9MzQmU1FERVNDPVNFQ1RJT05fUEFHRSZleHA9JnN1YnNpZD01Nw%3D%3D. Accessed 12/26/18.

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