Generic Versions Of Rytary Should Meet 3 Extra Standards, Impax Says

US FDA should refrain from relying on standard PK measurements for determining bioequivalence for the extended-release Parkinson's product.

Potential generics forImpax Laboratories Inc.'s Parkinson's Disease drug Rytary (carbidopa/levodopa) should be required to meet additional testing standards because of the brand product's extended-release properties, the company argues.

In a citizen petition filed Jan. 31, Impax requested that the US FDA refuse to receive or approve any abbreviated new drug applications (ANDAs) for Rytary unless the applicants have demonstrated bioequivalence "through scientifically appropriate methods." Specifically, Impax contends that Rytary has a "unique" pharmacokinetic (PK) profile, and that approval using the standard PK measures of area under the plasma concentration-time curve (AUC) and the maximum or peak drug concentration (Cmax) are "insufficient" to demonstrate bioequivalence.

Spefically, Impax writes that there are three features of Rytary's plasma profile that are important to its clinical effect. These include:

• A timely and predictable early onset of effect following oral administration, with an initial plasma concentrations peak at about one hour;
• The low variability of plasma levels once therapeutic levels have been achieved; and
• The plasma concentrations are maintained for roughly four to five hours before declining.

Impax further requested that FDA update its bioequivalence draft guidance for levodopa-carbidopa (LD-CD) extended release (ER) capsules "to incorporate metrics to ensure that a generic product demonstrates a PK profile comparable to Rytary."

The company had submitted comments on the guidance is December 2015, criticizing the guidance's reliance on the standard PK measurements. The guidance specifically calls for "two single-dose, two-way crossover in vivo fasting and fed studies and a single-dose, two-way crossover in vivo fasting sprinkle-in-applesauce study."

Combo Of Three Kinds Of Release

Impax's argument for heightened standards for generic versions centers on what the company describes as Rytary's "unique" PK profile. According to the petition, the active components of Rytary exhibit different drug-release characteristics, "resulting in a combination of immediate release, delayed release and delayed controlled release of LD-CD."

"Rytary's unique formulation of LD-CD provides therapeutic LD plasma concentrations rapidly and maintains a relatively constant concentration over a dosing interval of approximately six hours," the petition states. "It is also clear that not all controlled-release formulations provide a LD profile that possesses the attributes characteristic of the Rytary profile."

Therefore, the standard metrics of AUC and Cmax "may not be adequate to ensure bioequivalence in that they do not ensure the same onset of effect and duration of clinical effects as Rytary under the labeled conditions of use," Impax argues.

Rytary is not the only Parkinson's drug on the market with the active ingredients of carbidopa and levodopa. Merck & Co. Inc.'s Sinemet was approved in 1975 for the treatment of Parkinson's. Rytary, however, has a sustained-release mechanism that delivers the drug more gradually. Sinemet only delivers therapeutic effects for up to two hours, compared with six hours for Rytary.

History Suggests Slim Chance For Petition

If FDA's track record on citizen petitions is any indication, Impax's chances of the agency granting the petition are slim.

According to FDA's eighth annual report to Congress on delays in approvals of applications related to citizen petitions, the agency has denied 114 505(q) citizen petitions from fiscal years 2008 to 2015, while granting only eight. Additionally, 41 were granted in-part and denied in-part. (Also see "Citizen Petitions Targeting ANDAs Recede, But Concerns Over Resources Remain" - Pink Sheet, 19 Aug, 2016.)

This trend has continued since the start of fiscal year 2016. According to the Hyman, Phelps & McNamara FDA Citizen Petition Tracker, twenty 505(q) citizen petitions have been denied, six have been denied in-part and granted in-part, and only one has been granted during that time frame.

However, the validity of testing for controlled-release generics could be an area of concern for FDA after products have been forced from the market due to performance issues, which means that Impax's recommendations could carry more weight than they would have a few years ago.

Fallback For Patent Lawsuit?

The citizen petition is not the only hurdle that potential generics must clear. Impax has an ongoing patent suit with Teva Pharmaceutical Industries Ltd., which has acquired most of Allergan PLC's generic portfolio. that Discovery in the case is ongoing, and a trial is scheduled for September 2017, Impax noted in its 2016 third quarter Form 10-Q filing.

Rytary was approved in January 2015, and shortly thereafter Allergan challenged the validity of Impax's patents by submitting an ANDA. Impax filed suit in the US District Court for the District of New Jersey on Sept. 17, 2015 seeking to prevent commercialization of the generic. Most of the drug's patents are not set to expire until 2028.

In an answer to the complaint filed on Nov. 19, 2015, Allergan invoked the defense of obviousness against six of the patents, which relate to the treatment of Parkinson's.

The subject matter of the patents "is invalid for obviousness-type double patenting in that any differences between the subject matter claimed in the patent and the subject matter claimed in any other earlier expiring patent with a common owner would have been obvious at the time the alleged invention was made to a person having knowledge of such prior art and having ordinary skill in the art to which the claimed subject matter pertains," Allergan states.

The patents, Allergan says, "do no more than combine familiar elements according to known methods to yield predictable results. Any alleged improvement over the prior art set forth … is no more than the predictable use of prior art elements according to their established functions."