All data used in this analysis is from public sources, and is linked/ cited where possible.

INTRODUCTION/ HISTORY

Heron Therapeutics’ Zynrelef (formerly called HTX-011) represents the first novel infiltration analgesic approved by FDA since Pacira’s Exparel, which was initially approved in 2011. Heron’s clinical development pathway and regulatory process are therefore of high interest to developers of similar drugs, as they can provide insight into FDA’s current thinking on infiltration analgesics.

Exparel was granted a broad label for “administration into the surgical site to produce postsurgical analgesia”. This broad approval was based on pivotal clinical trials in bunionectomy and hemorrhoidectomy, with language deeper in the label text stating that “EXPAREL has not been demonstrated to be safe and effective in other procedures”. Pacira later circulated material containing instructions on the use of Exparel in other surgical procedures, prompting FDA to issue a Warning Letter. Pacira then sued FDA, resulting in a settlement in which FDA stated that Exparel is “approved for ‘administration into the surgical site to produce postsurgical analgesia’ for use in a variety of surgeries not limited to those studied in its pivotal trials.” For more detail see: https://www.hlregulation.com/2015/12/17/fda-settles-paciras-first-amendment-lawsuit/

Most systematically-acting novel pain drugs can obtain approval for acute postoperative pain broadly simply by demonstrating safety and efficacy in one bony and one soft tissue model (e.g. bunionectomy and abdominoplasty). But subsequent to the Pacira debate, FDA indicated in various discussions/ correspondence with Lotus’ Chief Scientific Officer, Neil Singla, that the agency would no longer provide a broad label for infiltration analgesics based on relatively limited (two models) acute pain development programs similar to Exparel’s. However, FDA did not provide definitive feedback on what types of clinical development programs could be used to successfully obtain a broad label moving forward. But based on multiple recent interactions that Lotus has had with the agency, we have developed a potential pathway that we outline below.

Developers have yet to receive definitive guidance from FDA on several key issues, but the Zynrelef development program and subsequent label provide a window into the agency’s current thinking on the following:

  1. Broad vs. Narrow Label Indications
  2. Opioid Sparing Label Claims
  3. Demonstrating Superiority vs. Active Comparator
  4. Use of Phase 2 Studies as Pivotal Trials

BROAD VS. NARROW LABEL INDICATIONS

The Zynrelef label (https://zynrelef.com/prescribing-information.pdf) is based on three randomized, double-blind, placebo- and comparator-controlled pivotal trials:

  1. Study 1: Phase 3 Bunionectomy
    1. gov: https://clinicaltrials.gov/ct2/show/NCT03295721
    2. Manuscript: https://rapm.bmj.com/content/44/7/700.long
  2. Study 2: Phase 3 Hernia Repair
    1. gov: https://clinicaltrials.gov/ct2/show/NCT03237481
    2. Manuscript: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6938470/
  3. Study 3: Phase 2b Total Knee Arthroplasty
    1. gov: https://clinicaltrials.gov/ct2/show/study/NCT03015532
    2. Manuscript: https://www.arthroplastyjournal.org/article/S0883-5403(20)30584-2/fulltext

The label explicitly states that the drug is approved “for… postsurgical analgesia for up to 72 hours after bunionectomy, open inguinal herniorrhaphy and total knee arthroplasty”. In other words, the label specifies approval only in the three models used in Zynrelef’s pivotal efficacy trials (a narrow label). Heron conducted an additional study in breast augmentation on which they published favorable safety and pharmacokinetic data (https://www.herontx.com/wp-content/uploads/2021/04/1_ASRA-2020.pdf), but this surgical model does not appear in the Zynrelef label[1].

Recently, Innocoll’s Xaracoll bupivacaine implant product received a similarly narrow label specific to “open inguinal hernia repair” after two pivotal trials in that model. We can conclude that FDA’s current inclination is to grant label indications that are specific to the models used in pivotal studies, in the absence of key evidence of generalizability across multiple surgical models. However, in discussions that Lotus has had with the agency, they have indicated that their main concern is the generalizability of safety and PK data across models, and that they would not require efficacy studies in each potential surgical model.

Based on these discussions with FDA, Lotus believes the solution to this problem is for sponsors to conduct a single large, open-label, pharmacokinetic and safety study in multiple surgical models, with 20-50 patients enrolled in each model. The range of surgical models selected will depend on the properties of each individual investigational product, but broadly FDA will require data in models that address the following concerns:

  1. Surgeries on diverse anatomical areas
  2. Large and small incisions
  3. More and less vascular areas[2]
  4. Intraperitoneal and extraperitoneal locations
  5. Soft and bony tissue, and others

Lotus is currently designing and conducting several open-label safety studies under these parameters for multiple clients. The studies are designed to systematically address FDA’s key requirements for provision of a broad label. Because each individual local anesthetic has different properties, Lotus can provide consulting on specifically tailoring this open-label design for each particular client. We have discussed and agreed upon several design specifications with FDA, which leads us to believe our designs will lead to broad labels upon approval, and we’re happy to share our findings with our clients.

OPIOID SPARING

Three potential elements/ techniques to incorporate into clinical studies in order to achieve opioid-sparing label claims are as follows:

  1. Reduced opioid consumption
    • Demonstrate a lower amount of opioid rescue consumption in subjects allocated to investigational product
  2. Reduced ORAEs (“clinical benefit”)
    • Demonstrate a lower rate of opioid-related adverse events (nausea, vomiting, respiratory depression, somnolence, constipation)
  3. Increased opioid-free patients
    • Demonstrate a higher proportion of opioid-free patients (patients who take no opioid rescue)

Lotus introduced and began advocating the opioid-free patients concept to the agency approximately 5 years ago. We also developed the experimental methodology to ensure that study designs can correctly capture opioid-free patients, and we’re very happy to see that the Zynrelef clinical trials incorporating this outcome succeeded and gave rise to a relevant label claim. This is a new and strongly positive development in the regulatory landscape.

Prior to Zynrelef, at least four drugs have achieved opioid-sparing milestone #1 and received label language stating that their drugs demonstrated reduced opioid consumption vs. placebo. However, two of these (Ofirmev and Exparel) also received a disclaimer stating that the clinical benefit of opioid sparing was not demonstrated, i.e. ORAEs were not shown to be reduced. Innocoll achieved milestones #1 and #3 (reduced opioid consumption over 24 hours and opioid-free patients over 72 hours) vs. placebo in the two pivotal hernia studies mentioned in the Xaracoll label (https://www.accessdata.fda.gov/drugsatfda_docs/label/2020/209511s000lbl.pdf):

… there was a statistically significant treatment effect for XARACOLL compared to placebo in… (total use of opioid analgesia from Time 0 through 24 hours) … The proportion of patients who did not receive opioid rescue analgesia through 72 hours in the XARACOLL and placebo treatment groups was 36% and 22%, respectively, in Study 1, and 28% and 12%, respectively, in Study 2.

The Xaracoll label does not mention ORAEs (nor does it include a disclaimer regarding undemonstrated clinical benefit of opioid sparing). No drug to date has received a label claim stating all three of the milestones above.

Zynrelef is the second analgesic agent after Xaracoll to achieve the new category of claim regarding opioid-free patients. The opioid-sparing language in the Zynrelef label is as follows:

Study 1: Bunionectomy

A significant proportion of patients treated with ZYNRELEF did not receive opioid analgesia (29%) over 72 hours compared to those treated with either bupivacaine HCl (11%) or saline placebo (2%).

Study 2: Hernia[3]

A significant proportion of patients treated with ZYNRELEF did not receive opioid analgesia (51%) over 72 hours compared to those treated with either bupivacaine HCl (40%) or saline placebo (22%). A significant reduction in total opioid consumption over 72 hours was also observed for patients treated with ZYNRELEF (median consumption 0 mg) compared to those treated with either bupivacaine HCl (7.3 mg) or saline placebo (11.3 mg).

Zynrelef achieved two of the three possible milestones (reduced opioid consumption and opioid-free patients), and while the label does not describe a reduction in ORAEs, FDA did not add the disclaimer “the clinical benefit of which was not demonstrated”. Per their published manuscripts and other public data, Heron achieved this language with the following methods:

  1. Including opioid-sparing endpoints as hierarchically-tested key secondary endpoints
  2. Utilizing a well-controlled rescue regimen (in this case oxycodone 10 mg q 4 hours, IV morphine 10 mg q 2 hours, acetaminophen 1 g q 6 hours).
  3. Systematic/ well-codified recording of ORAEs
  4. Tracking outpatient opioid consumption with take-home diaries/ follow up visits

Building on our work on the successful Heron programs, collaborations with other non-opioid analgesic developers, and extensive discussions with FDA, Lotus has developed a systematic approach to achieving success in all three opioid-sparing domains (reduced consumption, reduced ORAEs, and opioid-free patients). We have also developed a better-controlled and more refined variant of the rescue regimen detailed above in order to provide a cleaner opioid-sparing signal. We look forward to sharing these proprietary techniques as part of our complimentary consulting offering for our CRO and site clients.

SUPERIORITY TO ACTIVE COMPARATOR (BUPIVACAINE)

FDA encourages but does not require an active comparator in pivotal efficacy studies. Demonstrating superiority to a standard of care drug is obviously beneficial from a marketing perspective. But many sponsors opt to not make the attempt due to increased study cost and experimental difficulty (it’s difficult to achieve the optimal outcome: study drug beats comparator and placebo, comparator beats placebo).

Zynrelef is a combination of bupivacaine and meloxicam; Heron used plain bupivacaine as a comparator in their pivotal trials. In clinical practice, bupivacaine dosing is flexible, it’s not clear what the “standard of care” comparator dose should be.

For its pivotal trials, Heron used 50 mg bupivacaine for Study 1 (bunionectomy), 75 mg for Study 2 (hernia repair), and 125 mg for Study 3 (knee replacement). In bunionectomy and hernia bupivacaine showed efficacy for 12-24 hours, but was inferior to Zynrelef, especially at later time points. The label states Zynrelef’s superiority to bupivacaine in both models. We can conclude that 50 mg and 75 mg are good dose choices for a bupivacaine comparator in future bunion and hernia studies respectively.

Heron performed extensive work in Phase 2 testing varying doses, formulations, surgical models, administration methods and comparators/ comparator doses for Zynrelef; this iterative Phase 2 work resulted in pivotal trials where study drug outperformed a comparator that itself showed a viable efficacy signal.

USE OF PHASE 2 STUDIES AS PIVOTAL TRIALS

Heron’s pivotal knee replacement study cited in the label (Study 3) was a Phase 2 trial, yet was considered pivotal for the purpose of drug approval along with the Phase 3 bunionectomy and hernia studies. Since FDA ultimately granted a narrow, indication-specific label, it’s meaningful from a commercial perspective that Heron achieved three label indications (bunionectomy, hernia and knee replacement) instead of two. The label’s efficacy language for the knee replacement study states:

Patients treated with ZYNRELEF demonstrated a significant reduction in pain intensity compared to patients treated with saline placebo for the first 48-hour and 72-hour postoperative periods (Figure 3). There were two patients who did not receive opioid analgesia over 72 hours; one in the ZYNRELEF 400 mg/12 mg + ropivacaine treatment group and one in the bupivacaine HCl treatment group.

It is not uncommon for FDA to consider successful Phase 2 studies pivotal, provided they include the following:

The label states that Zynrelef beat placebo in knee replacement Study 3. But Study 3 has no substantive label language regarding opioid-sparing benefits or superiority to bupivacaine comparator. Reviewing the study manuscript, it’s clear that Heron gathered extensive data on both issues, and that Zynrelef both beat bupivacaine comparator and demonstrated meaningful opioid sparing. However the manuscript does not state that opioid sparing endpoints or comparisons to bupivacaine were key secondaries subject to hierarchical testing. We assume that these endpoints were not properly pre-specified and/or not properly controlled for multiplicity with either hierarchical testing or split alpha, and therefore FDA did not include this data for knee replacement in the label.

Our two main conclusions from the knee replacement portion of the label are as follows:

In addition to the above topics, there are multiple other key considerations around the Zynrelef programs and labeling that will affect ongoing and future analgesic drug development, which Lotus is happy to discuss. We’ll work to incorporate these findings into our clients’ programs in order to accelerate approvals and optimize label claims.

[1] Heron also published a Phase 2 study in abdominoplasty (https://www.herontx.com/wp-content/uploads/2020/11/150102654_ASRA_2017_Abdominoplasty_Poster_L2d_FINAL.pdf). This study utilized a different method of administration (instillation vs. infiltration) and so is not included in the drug label or in this analysis.

[2] FDA has not delineated a full list of which surgical models it considers highly vascular or less vascular. The Zynrelef label does state “Safety and efficacy have not been established in highly vascular surgeries, such as intrathoracic, large multilevel spinal, and head and neck procedures.”

[3] Heron performed an additional hernia study specifically examining opioid sparing after their Phase 3 hernia pivotal trial. This study is not mentioned in the label (https://www.surgjournal.com/article/S0039-6060(20)30430-X/fulltext)