Deuterization: Is it Enough to Get 5- or 7-Year Exclusivity for a 505(b)(2) Product?
As the 505(b)(2) experts, Camargo has received several enquiries about developing deuterated drugs as a means of achieving sustained-release properties for a product. The approval of Austedo (deutetrabenazine; Teva Pharmaceuticals, Inc.; NDA 208082), marked the first FDA approval of a deuterated drug. A recently shared memorandum from the CDER Exclusivity Board explains that Austedo is considered a new drug compared to the approved parent compound, tetrabenazine, and thus eligible for 5-year marketing exclusivity. Can it really be that easy to get 5 or 7 years of marketing exclusivity?
If you think back to chemistry in high school you may remember that hydrogen has only a proton in its nucleus, and that deuterium is a hydrogen atom with a neutron in its nucleus. This makes a deuterium slightly heavier than a hydrogen atom with the added property of forming stronger bonds to other atoms (more on this later). A deuterated drug is therefore one with a deuterium isotope in place of hydrogen. The parent compound is referred to as the proteo.
You may also have heard of deuterization from drug development programs in which deuterated versions of drugs are commonly generated to study the metabolism of a drug because metabolites can be identified by the increased presence of deuterium.
What are the Differences Between a Deuterized and Proteo Drug?
Adding a neutron to hydrogen is the smallest structural change that can be made to a molecule, and results in very little change to the molecule’s physicochemical properties. So a deuterated molecule can still form the same bonds as the proteo, but they are more difficult and slower to break due to the kinetic isotope effect.
The delayed breakdown of deuterium bonds can result in delayed metabolism of a compound. This can be beneficial for some drugs by extending the half-life and thereby exposure to the active metabolite. Side effects due to inactive metabolites may be reduced due to delayed formation or lowering the dose required for the therapeutic effect. But it may be less desirable for prodrugs that may experience delayed onset of action, or compounds with high toxicity such as DNA-damaging chemotherapeutic agents.
The most notable benefits for a patient may be the reduced dose or reduced dosing frequency required to achieve the same effect of the parent drug, and/or reduced side effects.
In the case of Austedo, a deuterated version of the parent compound tetrabenazine for the treatment of chorea associated with Huntington’s disease, the dosing frequency was reduced from 3 times daily to twice daily. This can be a significant benefit, especially for patients with cognitive degeneration diseases.
Development Program for a Deuterized Drug
Here we will examine the development program for a deuterated version of a parent drug that is already approved. Regular readers of our blog may already realize where we are headed here: the program will likely be appropriate for the 505(b)(2) regulatory approval pathway.
This means that much of the safety and efficacy findings of the approved drug can be used to support the approval of the deuterated drug. The key will be bridging to the approved drug via appropriate nonclinical or clinical studies, and investigating the differences between the drugs.
Like the parent drug, Austedo was approved for the treatment of chorea associated with Huntington’s disease. The approval of Austedo required only one Phase 3 study. Much of the toxicity and clinical data came from the approval of Xenazine (tetrabenazine; Valeant Pharmaceuticals LLC; NDA 021894). This 505(b)(2) program resulted in a huge time- and cost-saving benefit for a drug that may gain significant market share due to its improved dosing regimen.
Potential Pitfalls in Getting a Deuterized Drug Approved
We mentioned above the metabolic changes that may arise for a deuterated compound. These may include the generation of new metabolites, or changes to the ratio of metabolites compared with the proteo version of the drug.
In the approval of Austedo, Teva received a Complete Response Letter as they did not adequately characterize the metabolites from their deutetrabenazine product. Further studies were required before resubmission. In the end, the metabolic profile was shown to be similar enough to the approved tetrabenazine product that no new safety concerns were identified. But valuable time in getting the new drug to market was lost due to incomplete investigation of the metabolism of their product.
Obtaining Exclusivity Via Deuterization
Although the office of orphan products initially viewed tetrabenazine as the “same drug” as benazine, and therefore not eligible for orphan designation, the original Sponsor, Auspex disagreed. The FDAs Office of Orphan Products Development sought input from the CDER Exclusivity Board, which subsequently concluded that deutetrabenazine did indeed qualify for both NCE and orphan drug exclusivity (ODE). This was based on the determination that deutetrabenazine and tetrabenazine did not share the same active moiety (further detail and definitions can be found here).
In a memorandum from the CDER Exclusivity Board obtained by Hyman, Phelps and McNamara, P.C., FDA explains explains that “The Board applied FDA’s ’structure-based’ approach to determine the active moiety for each molecule and considered whether there are any structural differences between tetrabenazine and deutetrabenazine that involve non-ester covalent bonds.” As the presence of deuterium results in a structural difference, and as that difference involves a covalent bond (between carbon and deuterium or hydrogen), the Board concluded that tetrabenazine and deutetrabenazine are different active moieties, and therefore are not the “same drug” under the orphan drug regulations.
You may be wondering why 5 years of NCE exclusivity matters if the company also got 7-years or orphan drug exclusivity, to run concurrently. The answer is that both the NCE exclusivity and the ODE exclusivity for deutetrabenazine hinged on the same determination of “not the same drug.”
If it had been determined that deutetrabenazine and tetrabenazine were in fact the “same drug,” obtaining exclusivity under the orphan drug regulations would have required a demonstration that deutetrabenazine was clinically superior to tetrabenazine (or costly and time-consuming litigation to challenge this outcome, as previously blogged). In this case, Austedo would probably only have received 3-years of exclusivity as per the non-NCE or Hatch-Waxman Amendments.
So What Does it Take to Gain Exclusivity?
In the end, Austedo gets to enjoy 5-year NCE exclusivity expiring on April 3, 2022 and 7-year ODE expiring on April 3, 2024; both were dependent on the determination of “not the same drug” as tetrabenazine based on a “structure-based approach,” entailing a “non-ester covalent bond.” Changes to a compound that result in functional differences (which can have a significant clinical benefit) but not structural differences, however, do not meet the FDA’s “structure-based approach” and thus, are considered the “same drug” negating the ability to obtain NCE. For an orphan indication, the “same drug” as a previously designated drug would require a demonstration of clinical superiority to be eligible for 7 years of ODE.
At Camargo we have experts available to discuss:
- developing products with sustained-release properties
- chemistry and quality implications for deuterated drugs
- pharmacokinetic bridging studies.
Contact us to learn more.
Angela Drew, PhD, Product Ideation Consultant, Camargo Pharmaceutical Services
Stacey Ayres, PhD, Director of Research Services, Camargo Pharmaceutical Services.
Supplementary Notes and Information
New Chemical Entity Exclusivity
The definitions contained in the regulations (21 CFR 314.108) for New Drug Product exclusivity are essential to understanding why deuterated compounds are considered a “New chemical entity” (NCE). NCE means a drug that contains no “active moiety” that has been approved by FDA in any other application submitted under section 505(b) of the act. “Active moiety” means the molecule or ion, excluding those appended portions of the molecule that cause the drug to be an ester, salt (including a salt with hydrogen or coordination bonds), or other noncovalent derivative (such as a complex, chelate, or clathrate) of the molecule, responsible for the physiological or pharmacological action of the drug substance. As discussed in the main blog, the only structural difference between tetrabenazine and deutetrabenazine molecules is that the latter contains deuterium instead of hydrogen on the two methyl groups present in tetrabenazine.
Of importance, the deuterium atoms in deutetrabenazine are covalently bonded to the carbon atom. This non-ester covalent bond in dutetrabenzine makes this compound structurally different from tetrabenazine and therefore are different active moieties, and thus, not the same drug. This follows the FDA’s structure-centric interpretation of “active moiety” (rather than an activity-based interpretation). As a result, Austedo obtained a period of 5-year NCE exclusivity expiring on April 3, 2022. But remember that decisions about whether a particular drug product is entitled to 5-year NCE exclusivity are generally made at the time of approval. Interestingly, this was decided by the CDER Exclusivity Board (memorandum obtained by Hyman, Phelps and McNamara, P.C.) that was established in an attempt to assure consistency of decisions (CDERExclusivityBoard@fda.hhs.gov).
Orphan Drug Exclusivity
The regulations covering Exclusivity for Orphan Drugs (21 CFR 316.31) indicate that the FDA may designate a drug as orphan it is rare, and provide 7 years of marketing exclusivity unless the FDA has previously approved the same drug for the same use or indication.
If the same drug has been approved for the same use or indication, granting of marketing exclusivity will require the Sponsor to demonstrate that the drug is clinically superior to the previously approved drug.
For the purposes of ODE, “same drug” for small molecules is defined as a drug that contains the same active moiety as a previously approved drug and is intended for the same use as the previously approved drug, even if the particular ester or salt (including a salt with hydrogen or coordination bonds) or other noncovalent derivative such as a complex, chelate, or clathrate has not been previously approved, except that if the subsequent drug can be shown to be clinically superior to the first drug, it will not be considered to be the same drug.
Active moiety means the molecule or ion, excluding those appended portions of the molecule that cause the drug to be an ester, salt (including a salt with hydrogen or coordination bonds), or other noncovalent derivative (such as a complex, chelate, or clathrate) of the molecule, responsible for the physiological or pharmacological action of the drug substance.
Concurrent Pursuit of NCE Exclusivity and ODE
Getting back to “same drug” and “not the same drug” and the impact on ODE: the determination that deutetrabenazine is structurally different from tetrabenazine – different active moieties – “not the same drug” facilitated Teva’s ability to obtain orphan exclusivity (a period of 7-years orphan drug exclusivity expiring on April 3, 2024).
Challenges Along the Way
Let’s consider the timing involved: FDA approved Xenazine (tetrabenazine; NDA 021894) on August 15, 2008, for the treatment of chorea associated with Huntington’s disease. Xenazine received 5-year NCE exclusivity (expired August 15, 2013), and was protected by 7-year ODE until August 15, 2015. Prior to the exclusivity expiration, Auspex (original Sponsor that was acquired by Teva in May 2015) requested orphan drug designation for the use of deutetrabenazine also for the treatment of chorea associated with Huntington’s disease. In a letter dated August 15, 2013, Office of Orphan Product Development (OOPD) informed Auspex that after consultation with the Division, it considered tetrabenazine and deutetrabenazine to be the “same drug” under the Agency’s orphan drug regulations. The OOPD also informed Auspex that it would have to submit a plausible hypothesis of “clinical superiority” in order to seek and obtain orphan drug designation, and must demonstrate clinical superiority in order to receive orphan exclusivity upon marketing approval. With Auspex disagreeing (basing their argument on the “covalent bond and structure-centric definition”), Auspex submitted a request for NCE Determination (May 28, 2014). On the other side, OOPD sought advice from the CDER Exclusivity Board on June 9, 2014. The CDER Exclusivity Board made their determination in July 2015 concluding that a) tetrabenazine and deutetrabenazine are different active moieties, and b) therefore are not the “same drug” under the orphan drug regulations. Based upon this analysis, OOPD designated deutetrabenazine as an orphan drug in November 2014, without the need to advance a plausible theory of clinical superiority to tetrabenazine. Austedo was granted a period of ODE expiring on April 3, 2024. As indicated above, the value of the CDER Exclusivity Board in assuring consistency of decisions is clearly evident.