Dr. Sud Agarwal and Darryl Davies on IRX211 – A Breakthrough in Managing Breakthrough Cancer Pain (BTcP)


Introduction

Breakthrough cancer pain (BTcP) is a sudden and severe pain episode that interrupts the background pain relief provided by long-acting analgesics. Historically, immediate-acting fentanyl-based drugs such as Abstral or Fentora (fentanyl buccal tablets) and Actiq (fentanyl lozenges) were widely used for BTcP. These treatments demonstrated significant pain relief in clinical trials, but their withdrawal due to safety concerns and misuse potential has left patients with no approved BTcP-specific therapies.

IRX211, an innovative inhaled synthetic THC formulation developed by InhaleRx, addresses this gap by offering rapid-onset, predictable pain relief through its novel cold-delivery pMDI technology. With an ethics committee-approved Phase 2 trial set to launch in early 2025, IRX211 has the potential to redefine BTcP management.

Pain Relief Benchmarks: Fentora, Actiq, Abstral

Fast-onset fentanyl drugs were the standard treatments for BTcP before their withdrawal in the USA in October 2024. This was principally due to the FDA-mandated Risk Evaluation and Mitigation (REMs) programs imposed on all fast-acting fentanyl therapies, making them uneconomical and therefore, withdraw from the market.

However, their clinical trial data results are still visible and provide a clear benchmark for evaluating the efficacy threshold for new therapies seeking FDA approval, targeting the same indication (BTcP), including IRX211.

For BTcP the most common endpoints used to approve previous drugs was the Pain Intensity Reduction at 30 minutes (SPID₃₀ – Sum of Pain Intensity Differences at 30 minutes)

Fentora (Fentanyl Buccal Tablet)

• Pain Intensity Reduction: SPID₃₀ was 3.0 compared to 1.8 for placebo, reflecting an improvement of 1.2 points above placebo.

• Time to Relief: Significant pain reduction was observed by 15 mins and sustained through to 60 mins.

Actiq (Fentanyl Lozenge)

• Pain Relief Score: Actiq achieved a mean pain relief score of 2.5 at 30 minutes compared to 1.0 for placebo, therefore, an improvement of 1.5 points above placebo in pain relief scores.

These efficacy results highlight the substantial pain relief these drugs provided. For IRX211 to establish itself as a viable alternative, its pivotal trials should demonstrate similar or greater improvements in pain intensity and relief.

IRX211: Predicted Efficacy Based on Plasma THC

IRX211’s efficacy predictions can be extrapolated from its Phase 1 pharmacokinetics data and pK data from another inhaled THC study¹, which correlated plasma THC levels achieved via an inhaler with the resultant pain reduction that occurred . The device was a vaporising inhaler which used THC dominant cannabis to achieve target plasma levels in patients with chronic pain. The results demonstrated a clear positive correlation between plasma THC concentration and reduction in pain score in chronic pain.

Results of plasma THC ng/ml versus Pain Reduction at 30 mins¹

The IRX211 achieved similar plasma THC doses without heating/ vaping/ smoking and with no significant adverse events.Based on these THC results via a pMDI, it could have the potential to provide comparable or superior efficacy to fentanyl-based drugs:

While these estimates are preliminary, it is expected that increasing the number of actuations with IRX211 (up to the seven permitted in the Phase 2 trial) would result in progressively higher plasma THC levels, leading to increased analgesic efficacy.

Advantages Over Historical and Current Therapies

The management of Breakthrough Cancer Pain (BTcP) has long relied on rapid-onset fentanyl-based medications. However, concerns over safety, misuse, and legal issues have led to the withdrawal of several key products, creating a significant gap in effective treatment options for patients.

Withdrawn Fentanyl-Based Medications for BTcP:

Note: Market share percentages are approximate and based on available data prior to each product’s withdrawal.

*There are no current FDA approved products making a label claim for BTcP on the market today in the USA today*

Impact on BTcP Treatment Landscape:

The withdrawal of these medications has left a substantial “sales gap” in the BTcP market, limiting options for rapid-onset pain relief, specifically making a label claim for BTcP. Peak sales for BTcP fentanyl drugs exceeded USD$2Bn prior to the FDA introducing restrictions on fentanyl-based drugs.

This underscores the urgent need for new, effective, and safer treatments to address this unmet medical need.

Advantages of IRX211

• Safety in Overdose and Abuse
  • Unlike fentanyl-based drugs, which carried a high risk of misuse and overdose, IRX211 offers a safer alternative. A non-opioid mechanism of action and synthetic THC reduces the risk of dependency and abuse.
  • Cold-Delivered Technology: Unlike vaporized THC products, IRX211’s pMDI avoids the generation of harmful volatile compounds.

• Rapid, Customised, “Just-in-Time” Relief
  • IRX211’s ability to allow up to seven actuations per episode provides flexible and patient-specific dosing. This aligns with the episodic nature of BTcP, delivering rapid and titratable pain relief when it is needed most.
  • IRX211’s rapid Tmax (~3-4 minutes) further supports its alignment with the acute needs of BTcP management which is far superior to the fentanyl-based drugs which recorded Tmax of around 15 minutes. (Tmax is the time taken to achieve maximal plasma concentration).

“We believe IRX211 has the potential to offer a safe and effective alternative for patients suffering from BTcP. The IRX211 Phase 2 trial is designed to rigorously evaluate its efficacy and safety profile, with the hope of providing a much-needed solution for this highly, challenging condition.” – Dr. Sud Agarwal, CEO of iNGENū CRO.

Phase 2 Trial: Setting New Standards

The upcoming, ethics approved, Phase 2 trial, scheduled to launch in early 2025, will assess IRX211’s efficacy and safety in BTcP patients. The endpoints will be the same as the other BTcP drugs (Reduction in SPID₃₀) and from the excellent transfer of THC from inhaler to the blood stream seen in the IRX211 Phase 1 trial, it would be hopeful that the THC levels seen would correlate with significant pain reduction in the target population.

By aiming to meet or exceed the efficacy benchmarks set by Fentora and Actiq, IRX211 could redefine the standard of care for BTcP.

Conclusion

IRX211 represents a promising solution for BTcP, offering rapid-onset, tailored pain relief with a safer profile than historical fentanyl-based treatments. By aiming to achieve similar or superior efficacy to Abstral, Fentora and Actiq in their pivotal trials. IRX211 has the potential to fill the void left by these withdrawn drugs and provide a much-needed option for cancer patients experiencing breakthrough pain. With its innovative delivery technology and an upcoming Phase 2 trial, IRX211 is poised to transform BTcP management and set a new standard of care in oncology pain relief.

The discontinuation of key fentanyl-based BTcP treatments has created a critical need for alternative therapies. Innovative solutions like IRX211 represent a hopeful advancement in providing effective and safer options for patients suffering from breakthrough cancer pain.

Additionally, it is likely that the FDA may consider this a major unmet need due to the fact there are no marketed therapies in the USA with proven efficacy and a specific therapeutic claim for Break Through Cancer Pain.