US Launch Of Sensipar Generics May Await Patent Case Even After FDA Approval
Executive Summary
Aurobindo remains embroiled in litigation with Amgen on a Sensipar formulation patent, while Cipla settled ahead of bench trial. Generic firms won approval of cinacalcet generics after two federal courts denied Amgen's emergency request for an injunction in dispute with FDA over pediatric exclusivity.
Despite the US FDA's approval of two generic versions of Amgen Inc.'s Sensipar (cinacalcet), competition to the branded calcium-sensing receptor agonist may await the outcome of patent litigation in a Delaware federal court.
FDA approved cinacalcet abbreviated new drug applications (ANDAs) from Aurobindo Pharma Ltd. and Cipla Ltd. on March 8. This was the same day Amgen's drug substance patent (No. 6,011,068) expired because FDA had declined to award a six-month pediatric extension – a decision that the innovator has been unsuccessful in getting reversed thus far but continues to litigate.
Neither Aurobindo nor Cipla received 180-day generic marketing exclusivity, FDA told the Pink Sheet.
However, it appears that neither product has launched due to legal wrangling over a separate formulation patent (No. 9,375,405) that expires in September 2026.
Bench Trial On Formulation Patent
In early March, Judge Mitchell Goldberg of the US District Court for the District of Delaware presided over a four-day bench trial between Amgen and a half dozen ANDA sponsors, including Aurobindo, on the '405 patent.
Before the trial began on March 5, Judge Goldberg signed a consent judgment reflecting a settlement agreement between Amgen and Cipla, the terms of which were not disclosed. However, in the consent judgment Cipla admitted that the '405 patent is enforceable and valid, and that the manufacture and sale of its generic in the US infringes the patent.
The order states that Cipla is enjoined under the '405 patent, "including any extensions and/or additional periods of exclusivity to which Amgen is or becomes entitled," from making, selling or distributing its generic cincalcet in the US "except to the extent specifically authorized in the settlement agreement."
In response to questions about the timing of its generic cinacalcet launch, Cipla said it is "in the process to clarify certain regulatory issues” and could not comment further at this stage on potential launch plans. Aurobindo did not return requests for comment.
Judge Goldberg has directed the parties in the '405 patent case to file a joint stipulation with a post-trial briefing schedule by March 16.
Three other companies – Mylan Pharmaceuticals Inc., Teva Pharmaceutical Industries Ltd. and Barr Laboratories Inc. – hold ANDA tentative approval. Amgen sued all three companies for infringing the '405 patent, but the parties subsequently stipulated to dismissal of the actions.
Ortho Tri-Cyclen Pulled Into Sensipar Dispute
FDA's grant of final approval to the Aurobindo and Cipla ANDAs followed a federal district court ruling that upheld the agency's denial of pediatric exclusivity on Sensipar. Amgen's legal challenge is not over, however, and a federal appeals court will hear oral arguments in the dispute between Amgen and FDA in May.
Amgen sued FDA in May 2017 seeking to reverse the denial of a six-month pediatric extension. FDA concluded that Amgen's pediatric study reports did not "fairly respond" to the written request for studies. That request was amended several times and ultimately included four study requirements, three of which were satisfied.
In January, Judge Randolph Moss of the US District Court for the District of Columbia ruled FDA's view that sponsors must provide "clinically meaningful information" to earn exclusivity is a reasonable interpretation of the statutory requirement that sponsors must fairly respond to written requests. However, the court remanded the case for FDA to address whether its grant of exclusivity for Johnson & Johnson's oral contraceptive Ortho Tri-Cyclen (ethinyl estradiol/norgestimate) was consistent with its decision denying exclusivity for Sensipar and, if not, whether there was a reasoned explanation for the disparate outcome. (Also see "Pediatric Exclusivity: Court Backs US On When Studies 'Fairly Respond' To Requests" - Pink Sheet, 29 Jan, 2018.)
One of the required pediatric studies for Ortho Tri-Cyclen was intended to assess the effect of bone mineral density in anorexic patients as defined by the Diagnostic and Statistical Manual of Mental Disorders, fourth edition (DSM-IV), but Amgen asserted many of the enrolled patients did not meet the required diagnostic criteria.
Two Remand Decisions
On remand, FDA reaffirmed its decision not to award pediatric exclusivity to Sensipar and said this result was consistent with its decision on Ortho Tri-Cyclen. After last-minute discovery of an additional document relating to the Ortho Tri-Cyclen exclusivity decision, FDA issued an addendum to its remand decision, again concluding that its treatment of the two products was not inconsistent.
However, Amgen asserted that FDA's explanation was inadequate and that its denial of exclusivity for Sensipar remained arbitrary and capricious.
Judge Moss rejected Amgen's arguments, and granted FDA's motion for summary judgement, in a Feb. 17 memorandum opinion.
The court noted that in FDA's initial remand decision, the agency said it did not realize that a majority of enrolled subjects in the Ortho Tri-Cyclen trial did not meet the DSM-IV criteria until after J&J's final study reports were evaluated, which occurred after the exclusivity decision.
However, the remand addendum reflects the late-discovered document, which showed that even before FDA granted pediatric exclusivity, agency reviewer Eric Colman asked J&J whether all the study subjects had body mass index (BMI) values below the 10th percentile for age. This benchmark is one way to fulfill one of the DSM-IV criteria, according to FDA.
J&J responded that 74 out of 123 patients had BMIs above the tenth percentile, but it provided a rationale purporting to explain why, in its opinion, the terms of the written request had been met, the court said.
Colman recommended granting exclusivity on the grounds that the study was conducted in agreement with the written request. Colman, who went on to become deputy director of the Division of Metabolism and Endocrinology Products, died in 2014. (Also see "Eric Colman, FDA’s Lead Obesity Drug Reviewer, Dies At Age 53" - Pink Sheet, 29 Sep, 2014.)
FDA said the new records did not alter its conclusion that it had applied the same standard to Sensipar and Ortho Tri-Cyclen. However, the agency also advanced two alternative arguments: the requirement that study subjects meet the DSM-IV criteria was not actually a requirement but rather a recommendation; and FDA may have relied on some other rationale to determine Ortho Tri-Cyclen's eligibility for exclusivity, but even if the agency was mistaken about whether the enrollment criteria were met that would not justify making a similar error when evaluating the Sensipar studies.
Judge Moss concluded that FDA had offered a reasoned explanation for why it reached different outcomes on the Ortho Tri-Cyclen and Sensipar applications for pediatric exclusivity. Even though the agency's description of the basis for the Ortho Tri-Cyclen decision may lack "crystal clarity," the court can reasonably discern the agency's reasoning and its rationale for reaching a different outcome with respect to Sensipar, Judge Moss said.
The court pointed to FDA's statement in the remand addendum that the DSM-IV "does not specify a particular BMI" for an anorexia diagnosis.
"In the FDA’s scientific judgment at the time of the relevant decisions … the Ortho Tri-Cyclen studies met the terms of the written request, and the Sensipar studies did not," Judge Moss said. "Whether the FDA was, in fact, correct in determining that the Ortho Tri-Cyclen study subjects met the DSM-IV criteria is not the relevant question. All that matters for present purposes is whether the FDA applied an interpretation of 'fairly respond' to Amgen that differed from the standard it applied to Johnson & Johnson, and the agency has reasonably explained that it did not do so."
Emergency Requests For Injunction Fail
On Feb. 22, Judge Moss denied Amgen's emergency motion for an injunction pending appeal.
Amgen appealed the summary judgment decision to the US Court of Appeals for the District of Columbia Circuit and, in the process, requested an injunction requiring FDA to temporarily refrain from approving generic versions of Sensipar pending resolution of the appeal. "If a generic enters the market before resolution of Amgen's appeal, it will flood the market in days, wiping away Amgen's exclusivity and effectively eliminating Amgen's ability to seek appellate review," the company said in its Feb. 23 emergency motion.
Oral arguments in Amgen's appeal of FDA's pediatric exclusivity decision are scheduled for May 17.
In a footnote, Amgen notes that a number of companies have filed applications to market generic versions of Sensipar. "Amgen has filed patent lawsuits involving a different patent against many of these companies, but no order or agreement in those lawsuits currently prohibits those generics from entering the market after March 8," the filing states.
In a March 2 order, the appeals court denied the motion for an injunction pending appeal, concluding that Amgen had not satisfied the stringent requirements for such an action. However, the court granted Amgen's request for an expedited briefing schedule, with briefing to be completed by April 12. Oral arguments are scheduled for May 17.
Anju Ghangurde contributed to this report.