Praluent Sponsors Set Tone For PCSK9 Labeling, Post-Marketing Negotiations

Sanofi and Regeneron's 'extended negotiations' with FDA on requirements would later apply to Amgen's Repatha.

Praluent sponsors Sanofi and Regeneron Pharmaceuticals Inc. held negotiations with FDA over labeling language and post-marketing requirements that would set the benchmark for Amgen Inc.'s talks with the agency on Repatha a month later.

By virtue of being a few weeks ahead in the PCSK9 inhibitor approval queue – thanks to a priority review voucher – Sanofi and Regeneron had a hand in shaping what the labeled target population and post-approval safety studies would look like for others in the new class of LDL-cholesterol lowering drugs.

FDA determined that a post-marketing requirement for a pregnancy study, triggered by data from the Praluent preclinical program, should also apply to Repatha.

In a July 24, 2015 memo, Office of Drug Evaluation II Deputy Director Mary Parks said there were several issues requiring "extended negotiations with Sanofi, including the intended population for use, dosing recommendations, post-marketing requirements to further assess safety, and labeling."

Narrowing The Population

Key among these was disagreement over the broad patient population proposed for Praluent (alirocumab).

Sanofi (which was technically the applicant) and development partner Regeneron sought approval for the long-term treatment of adults with primary hypercholesterolemia (non-familial and heterozygous familial) or mixed dyslipidemia, including patients with type 2 diabetes, to reduce LDL-C, total cholesterol, non-HDL-C, apolipoprotein B, triglycerides, and lipoprotein (a), and to increase HDL-C and apolipoprotein A-1.

The companies also sought approval for use in combination with a statin, with or without other lipid-modifying therapies, as monotherapy, or as add-on to other non-statin therapy, including in statin-intolerant patients.

At a June 9 review, FDA's Endocrinologic and Metabolic Drugs Advisory Committee recommended approval of alirocumab, but panelists generally suggested the indication be narrowed to individuals with heterozygous familial hypercholesterolemia (HeFH) and those at very high CV risk who are taking maximally tolerated statins, pending completion of a cardiovascular outcomes trial (Also see "Sanofi/Regeneron's Praluent Gets FDA Panel Nod, But Not For Broad Use" - Pink Sheet, 9 Jun, 2015.).

Amgen's proposal for a similarly broad claim for Repatha elicited a similar reaction from the advisory committee at a June 10 meeting (Also see "PCSK9 'Groundhog Day': Amgen’s Repatha Gains FDA Panel Backing In High-Risk Groups" - Pink Sheet, 10 Jun, 2015.).

The advisors' recommendation found favor with FDA.

"The FDA review team has concluded that Sanofi’s proposed indication is unacceptable," Parks said, noting the "major extent of efficacy and safety data for alirocumab was derived from add-on to statin therapy trials, not monotherapy trials."

Essentially, the sponsors could not convince FDA there was a target population for the broader indications. "The attempt to carve out a population with an unmet need by defining a statin-intolerant population in whom alirocumab could serve as an alternative, possibly as monotherapy, faced some degree of criticism and skepticism internally and by several members of EMDAC," Parks said.

PCSK9s had a high bar to clear in that respect, with Parks noting committee members' uncertainty "as to whether we can appropriately identify a truly intolerant population to a class of drugs that clearly has an established history of CV benefit."

The Praluent review team "also noted that the proposed indication would include a generally broad population identified only as having primary hypercholesterolemia or mixed dyslipidemia," Parks said, adding that such a classification does not identify patients based on level of CV risk.

Praluent's Phase III program had limited data in patients with moderate or low CV risk to support an indication in this patient population, Parks said.

"Given the absence of evidence for CV risk reduction associated with alirocumab use, the clinical review staff recommended alirocumab in patients with clinical atherosclerotic cardiovascular disease (i.e., history of a CV event such as MI or stroke) who, despite maximally tolerated statin therapy, still require further LDL-lowering therapy," Parks said.

"With completion of the CVOT, FDA will have additional efficacy and long-term safety data to better assess the benefit-risk of alirocumab in a broader patient population."

In its July 24 approval, the agency also found alirocumab appropriate for reducing LDL-C in HeFH patients (Also see "Broad Enough? Sponsors Pleased With Narrower Praluent Label" - Pink Sheet, 24 Jul, 2015.).

FDA approved Repatha (evolocumab) a month later with an almost identical indication, albeit with an added claim for homozygous familial hypercholesterolemia (HoFH) patients (Also see "Amgen’s Repatha To Launch Next Week; Narrow Indication Mirrors Rival Praluent" - Pink Sheet, 27 Aug, 2015.).

Monkey Data Trigger Pregnancy Study

A concern about the risk of immunodeficiency in children exposed to alirocumab in utero, and the possibility of resulting adverse events such as poor vaccine response and increased infections in infancy, led to a late issued post-marketing study requirement (PMR) for Praluent that was similarly applied to Repatha.

The Praluent preclinical program included a T-cell Dependent Antibody Response (TDAR) study. In the offspring of treated pregnant monkeys, dose-related decreases in TDAR to a known antigen were observed from 120-180 days after birth.

"This suggests that exposure to alirocumab in utero suppressed adaptive immunity in these infant monkeys," Division of Metabolism and Endocrinology Products Deputy Director James Smith said in a July 24 review.

"It is unclear what level of humoral immune suppression would be acceptable in human infants," pharm/tox reviewer Elmore said.

In a May 4 memo, pharmacology/toxicology reviewer C. Lee Elmore said immune suppression was statistically significant at the high alirocumab dose tested, but the dose-related trend was also observed at the lower dose.

"A dose level that did not suppress humoral immunity in infant monkeys was not identified," Elmore said. "It is unclear what level of humoral immune suppression would be acceptable in human infants. Administration of alirocumab to pregnant women should only be considered when benefits outweigh the potential risks."

In a July 16 memo, Maternal Health Team Medical Officer Christos Mastroyannis said the Division of Pediatric and Maternal Health (DPMH) “has determined that the signal of humoral immune suppression, demonstrated in the offspring of pregnant cynomolgus monkeys administered alirocumab, identifies a potential safety concern for neonates and infants when a pregnant woman is administered Praluent."

"Further assessment of this potential safety concern is necessary to monitor for adverse neonatal and infant outcomes (i.e., recurrent infections with encapsulated bacteria, life-threatening enterovirus infections, failure to respond to appropriate antibiotic therapy)," Mastroyannis said.

The maternal health review suggests there was some disagreement among FDA disciplines as to whether a pharmacovigilance program would suffice or whether a vaccination study was needed.

Although some details of the maternal health team's review are redacted, it appears to have favored a post-marketing observational study of pregnancy outcomes similar to one proposed by Amgen to support European approval of evolocumab.

DPMH's Mastroyannis said the pharmacovigilance study "will not evaluate specifically the humoral immune suppression signal but rather will evaluate potential adverse events in infants that may warrant further investigation in the future (e.g., increased infections, poor response to vaccination which would lead to specific infections, etc.)."

A post-marketing requirement "would be a reasonable approach," the DPMH review states. "Further discussions about the specific study and what program should be implemented may be decided after the approval of the drug. We recommend a broadly worded PMR prior to approval. Such a PMR will allow us more time to reevaluate the options and select the best strategy."

Sanofi Tries To Avoid Study Requirement

A variety of possible PMR study designs were discussed and considered but "ultimately, there was alignment on a prospective observational study of pregnant women exposed to Praluent to evaluate fetal, infant, and childhood outcomes through the first five years of life," Smith's review notes (see box).

Pregnancy Study PMR

"Conduct a prospective observational study of pregnant women exposed to Praluent to evaluate fetal, infant, and childhood outcomes of pregnant women exposed to Praluent and their live born offspring through the first 5 years of life to estimate incidence rates for the potential safety signals of adverse pregnancy outcomes, embryo-fetal growth and development, and adverse infant and childhood outcomes related to humoral immune suppression. The study should have validated/adjudicated outcomes, a comparator group, be powered to detect the outcomes of interest, and include the justification for the proposed detectable differences in incidence rates."

On July 17, one week before the alirocumab user fee goal date, FDA sent Sanofi a PMR for a pregnancy study.

Sanofi's July 20 response proposed to list the study as a post-marketing commitment – that is, a study the sponsor was not legally bound to complete – "in order to provide the sponsor time to develop a protocol that will address the agency’s request."

"We note that this new request was communicated only recently and it will be difficult to provide accurate detail in terms of protocol and study submission dates," Sanofi said.

"Given the request, we will need to assess a number of protocol design elements including, but not limited to, appropriate 'outcomes of interest' and statistical assumptions," Sanofi said.

"Also, please note that we expect the pregnancies will be rather rare events given that Praluent will not be recommended for patients' use during pregnancy and many [health care providers] will likely take patients intending to become pregnant off all lipid-lowering therapies. In addition, the mean age of the non-FH patient population enrolled in our trials was ~60 years."

Sanofi said that if its proposal were not acceptable to the FDA, it would like a teleconference that day "to understand what the agency is specifically looking for in this study such that we can more accurately estimate the milestone dates."

FDA and the Praluent sponsors held a teleconference later that day, after which Sanofi emailed FDA a revised response to the PMR request.

Ultimately, the pregnancy study was included in the alirocumab approval letter as a PMR pursuant to the agency's post-marketing study authority in the FDA Amendments Act of 2007.

What's Good For Praluent Is Good For Repatha

Repatha was approved with an identical post-marketing requirement for a pregnancy study even though no evaluation of the infant immune system was conducted in the evolocumab preclinical program.

"Amgen failed to perform a TDAR study with the drug product Repatha. Such a study is a requirement per the ICH S8 Guidance for Industry Immunotoxicity Studies for Human Pharmaceuticals," DPMH's Mastroyannis noted in an Aug. 6 memo.

[Editor’s note: In a Jan. 19, 2016 statement to “The Pink Sheet,” Amgen said it decided not to conduct a TDAR study for Repatha “based on appropriate scientific reasons related to the difficulty in interpreting this type of data.” The company said that TDAR studies are an option, not required, only if a cause for concern is generated through standard immunotoxicity studies.]

Discussions between the nonclinical review team and DPMH "have led to the recommendation that the alirocumab experience be included in labeling for evolocumab, since this potential effect of fetal exposure to a PCSK9 inhibitor may be a class effect. Similar to Praluent, this potential safety signal will be evaluated as a PMR," Smith said in his Aug. 25 summary review of Repatha.

Amgen's European Union Risk Management Plan included a proposal for a multinational observational study to evaluate pregnancy outcomes of females diagnosed with familial hypercholesterolemia and exposed to Repatha during pregnancy.

The EU-driven study "represents an enhanced pharmacovigilance program similar to DPMH’s recommendation," FDA's review states.

Outcomes Trials Create 'Platform' For Broader Safety Evaluation

The agency imposed two additional PMRs for both Praluent and Repatha pursuant to the post-marketing study authorities in FDAAA.

The sponsors must conduct a large, randomized, controlled trial to evaluate the incidence and severity of new-onset diabetes mellitus, injection site reactions, hypersensitivity, immunogenicity, and adverse events potentially related to demyelination.

In the summary reviews for both Repatha and Praluent, FDA's Smith noted that the sponsors' ongoing CVOTs "should provide a sufficient platform to evaluate" these safety signals.

Tying the PMRs under FDAAA to the ongoing CV outcomes trials gave the agency some leverage to ensure that the outcomes trials are completed (Also see "Praluent Safety Study Requirements: A Backdoor To Ensuring Outcomes Trial Completion?" - Pink Sheet, 3 Aug, 2015.).

During the advisory committee reviews, some panelists and open public hearing speakers raised concerns that the trials would have trouble enrolling and retaining subjects once the drugs were approved and on the market (Also see "Accelerated Approval For PCSK9 Inhibitors Not Up For Discussion, FDA Tells Panel" - Pink Sheet, 15 Jun, 2015.).

At the late-cycle meeting Sanofi "noted that their clinical program included 5,300 patient years in the safety database. They felt residual issues could be handled by pharmacovigilance."

The agency also required randomized, controlled, long-term trials to prospectively evaluate changes in neurocognitive function with Praluent and Repatha. The trials must be adequately powered to exclude a clinically meaningful adverse effect, the approval letters state.

Amgen told "The Pink Sheet" it plans to fulfill the PMR through the EBBINGHAUS study, which is a substudy of the FOURIER CV outcomes trial. EBBINGHAUS is a prospective, randomized, blinded study using a validated instrument to assess neurocognitive function, the company said.

"The division will have the opportunity to review whether this substudy would be sufficient to fulfill the PMR," Smith said in his summary review of Repatha.

In contrast, Sanofi and Regeneron plan to fulfill the Praluent neurocognitive function PMR through a study separate from the ongoing ODYSSEY OUTCOMES trial.

There are indications in the review documents that the Praluent sponsors did not believe any PMRs were warranted.

In the briefing package for the late-cycle meeting, FDA listed two post-marketing commitments related to product quality microbiology but noted that the possibility of additional PMRs and PMCs was under discussion.

According to minutes from the May 28 late-cycle meeting discussion of PMRs, "the applicant noted that their clinical program included 5,300 patient years in the safety database. They felt residual issues could be handled by pharmacovigilance."

Although the issue of hepatic effects did not rise to the level of a PMR, a report of possible drug-induced liver injury with alirocumab led to a hurried search for more information by FDA and the sponsors late in the drug's review (see related story, (Also see "Liver Injury Case Sparked Flurry Of Concern Late In Praluent Review" - Pink Sheet, 18 Jan, 2016.)).