Sorrento Releases Positive Results of Phase 1B Trial of Resiniferatoxin (RTX) In Reduction of OsteoArthritis (OA) Knee Pain
- Phase 1b safety data at 6 month post-administration and Day 84 efficacy data available for all patients enrolled.
- No dose limiting toxicities at any of the doses tested (up to 30 ug) at 6 months post-administration. The study is scheduled to complete the last patient follow-up (1 year) in 1Q2021.
- Dose of 12.5ug selected as the likely optimal intra-articular therapeutic dose for future clinical trials. Durable signal at 12 weeks post-injection justifies initiation of Phase 2 (dose confirmation against active drug and saline control).
- Pain control in patients with advanced disease (Kellgren-Lawrence grade 3/4) show persistence of relief beyond 6 months and composite WOMAC A+C suggests that RTX could be a promising alternative for control of refractory pain in patients candidates for elective joint replacement.
The Phase 1b trial was a placebo controlled ascending dose study with an open-label extension to assess the safety and preliminary efficacy of intra-articular administration of RTX or saline control (as placebo group) for the treatment of moderate to severe pain due to osteoarthritis (OA) of the knee. It was expanded into a dose confirmation cohort to validate the safety and efficacy of the selected therapeutic dose compared to the individual’s baseline.
An abstract presenting intermediate data was accepted for the
These strong results have prompted the Company to rapidly advance the investigational drug product into a Phase 2 clinical trial (against active drug and saline control) expected to start in 2020 and a subsequent Phase 3 clinical trial expected to start in 2021 after completing additional enabling preclinical studies.
Updated Safety Outcome (primary end-point)
Ten subjects received a single saline-control injection and 84 subjects received a single RTX injection. The majority of subjects (N=50) were dosed with resiniferatoxin at 12.5 µg. No dose limiting toxicities were observed in any of the 84 subjects dosed with RTX at any dose level studied.
Treatment-emergent adverse events (TEAEs) were expected based on the mechanism of action of the drug and included post-injection pain, tachycardia and hypertension; all of which resolved in less than a day. Mild to moderate post-procedural pain was reported as expected in nearly all subjects dosed with RTX (as well as in subjects treated with saline control) and was managed with analgesics. The pain from drug administration typically subsided within a few hours. No special requirements such as knee cooling or local anesthetics application have been used in this study.
Table 1: Subjects with Treatment-Emergent Adverse Events in Study PTVA-OA-001
|TEAE Category||Subjects dosed
|Subjects dosed with
|Any TEAE||83 (98.8%)||8 (80.0%)|
|Any Moderate TEAE||42 (50%)||1 (10.0%)|
|Any Severe TEAE||5 (6%)||0|
|Any Life-Threatening or Fatal TEAE||0||0|
|Any Serious TEAE||7 (8.3%)||0|
|Any TEAE considered related to study treatment||77 (91.7%)||7 (10.0%)|
|Any Severe TEAE considered related to study treatment||1 (1.2%)||0|
|Any Serious TEAE considered related to study treatment||0||0|
Updated Efficacy Outcomes (secondary end-point)
The magnitude of the difference in the treatment effect versus saline control (as placebo used in the ascending dose portion of the study) at 12 weeks exceeded what is traditionally considered sufficient to support regulatory approval based on greater than 2 points reduction in the WOMAC A1 10-point scale question “pain at walking on flat surface” compared to placebo.
In the RTX dose selected for upcoming clinical trials (12.5 ug), the WOMAC A1 score at day 84 showed an average of a 4.92-point reduction relative to baseline for RTX, and an average 2.59-point reduction relative to the saline control (placebo).
Fast relief (less than a week) and durability of the effect (over 84 days) confirm the clinical potential of the drug for long-term control of pain associated with OA of the knee.
The study was designed to follow patients to day 84. Patients were also given the option to be followed for a longer period of time. RTX treated patients with good initial response who were evaluated at day 168 showed pain relief to levels equivalent to their D84 response (likely persistence of effect).
Exploratory end-points: Advanced disease (Kellgreen-Lawrence Grade 3 and 4) and Womac A+C Composite Score
No difference in efficacy response was found regardless of the degree of measured OA in patients (Kellgren-Lawrence Grade 2, 3 or 4), suggesting that the strength and duration of pain relief observed following RTX treatment in this Phase 1b study may also be expected in a larger population of patients with advanced OA.
To confirm the potential of RTX to benefit patients waiting for total knee replacements, an analysis was performed applying a composite score (Womac A plus Womac C) that is traditionally used to assess a patients “qualification” for knee replacement (see Table 2).
Patients who could qualify for total knee replacement (Womac A + C over 23) showed a clear improvement following treatment (68% improved by at least 20%, versus 20% in the control group). The effect (see Figure 2) was sustained for at least 84 days with a signal that did not seem to degrade at day 84. Many patients followed through day 168 or day 365 indicate the potential of the drug effect to persist in responders for 6 months or more. These numbers, although encouraging, need to be confirmed in trials with a larger number of patients (such as Sorrento’s proposed Phase 2 and 3 trials).
Table 2: Responder* Analysis at Day 84 (Week 12). Subjects with Baseline Combined WOMAC A Pain Subscale and WOMAC C Function Subscale >=23
|Parameter||Response||12.5 ug RTX (in 5ml)||Saline Control|
|WOMAC Pain/Function||>=20% Improvement||34/50 (68.0%)||2/10 (20.0%)|
* Responder defined as combined score for WOMAC A Pain Subscale and WOMAC C Function Subscale with at least a 20% decrease from baseline at Day 84 (Week 12). Note: Subjects without Day 84 data were included as Non-Responders.
Sorrento has confirmed it will be pursuing RTX for treatment of OA pain following a traditional development program, but based on the positive results of this Phase 1b trial will also add studies focusing on demonstrating the value of RTX as an alternative to TKR surgery.
About Resiniferatoxin (RTX)
A thousand times “hotter” than pure capsaicin (16 Billion Scoville units versus 16M), and with a high affinity for afferent sensory pain nerves, resiniferatoxin binds to TRPV1 receptors present and selectively ablates the nerve endings responsible for pain signals experienced by patients1. Delivered peripherally (into the joint space) the transient nerve ending ablation effect can have profound clinical benefits lasting for months to years (as shown in canine studies2).
PTVA-OA-001 was a multicenter, placebo-controlled Phase 1b study to assess the safety and define the maximally tolerated dose of resiniferatoxin administered in the knee joint in patients with moderate to severe pain associated with osteoarthritis of the knee. The study was a dose-escalation trial in which cohorts of patients received increasing doses of resiniferatoxin until the maximum tolerated dose (MTD) was achieved. The primary objective of the study was to evaluate the safety of resiniferatoxin and identify the recommended dose for Phase 3 trials. The secondary objective was to assess the preliminary efficacy of resiniferatoxin measured by assessing changes in the intensity of pain using the A1 score from the WOMAC Index, a widely used proprietary validated pain questionnaire.
More information on this trial can be found at www.clinicaltrials.gov (NCT03542838).
Information on upcoming Phase 3 trials (Total Knee Replacement Surgery Deferment Pain and Osteroarthritis Pain) can be found under the trial references NCT04386980 and NCT04044742.
Sorrento is a clinical stage, antibody-centric, biopharmaceutical company developing new therapies to treat cancers. Sorrento's multimodal, multipronged approach to fighting cancer is made possible by its extensive immuno-oncology platforms, including key assets such as fully human antibodies (“G-MAB™ library”), clinical stage immuno-cellular therapies (“CAR-T”, “DAR-T”), antibody-drug conjugates (“ADCs”), and clinical stage oncolytic virus (“Seprehvir®”, “Seprehvec™”). Sorrento is also developing potential antiviral therapies and vaccines against coronaviruses, including COVIDTRAP™, ACE-MAB™, COVI-MAB™, COVI-GUARD™, COVI-SHIELD™ and T-VIVA-19™; and diagnostic test solutions, including COVI-TRACK™ and COVI-TRACE™.
Sorrento's commitment to life-enhancing therapies for patients is also demonstrated by our effort to advance a first-in-class (TRPV1 agonist) non-opioid pain management small molecule, resiniferatoxin (“RTX”), and ZTlido® (lidocaine topical system) 1.8% for the treatment of post-herpetic neuralgia. RTX has completed a Phase IB trial for intractable pain associated with cancer and is completing a Phase 1B trial in osteoarthritis patients. ZTlido® was approved by the FDA on
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