Top 5 Failed Clinical Trials in April 2022: Setbacks in Oncology, Pain, and Neurology

Source: PharmaCube Med

Author: Shuye

The April 2022 issue of the "Clinical Research Monthly Report" screened out five noteworthy clinical studies that did not meet their primary endpoints.

In April, Roche's potential BIC oral Selective Estrogen Receptor Degrader (SERD) Giredestrant announced it did not meet the primary endpoint; following the failure of their study in March, Nektar and BMS, based on new pre-planned analyses of renal cell carcinoma and bladder cancer results, decided to terminate all combination studies; the failure of NYX-2925 in treating painful diabetic peripheral neuropathy led to a 50% drop in the company’s stock price. Here, we have selected the top five clinical trial failures for your reference.

1. Phase II Study of Giredestrant for the Treatment of Breast Cancer

On April 25, Roche announced its Q1 financial report for 2022, revealing that the Phase II acelERA trial of its oral Selective Estrogen Receptor Degrader (SERD) Giredestrant (GDC-9545) for the treatment of ER+/HER2- locally advanced or metastatic breast cancer did not meet the primary endpoint of progression-free survival. Detailed results of the acelERA study will be presented at a subsequent medical conference.

Giredestrant (GDC-9545) is a potential BIC SERD developed by Roche, with preclinical activity 7-15 times higher than other SERDs, including fulvestrant, camizestrant, amcenestrant, and elacestrant. In current clinical studies, Giredestrant also has the lowest dosing among SERDs. The failure of the acelERA study made Roche the second company, after Sanofi, to temporarily stumble in the SERD field.

On March 14, Sanofi announced the results of a Phase II clinical study on amcenestrant for the treatment of ER+/HER2- locally advanced or metastatic breast cancer. The data showed that the AMEERA-3 trial failed to meet its primary endpoint of improving progression-free survival (PFS). Giredestrant is the third oral SERD drug to release pivotal data, and it now appears that the preclinical advantages have not translated into clinical benefits.

The development of innovative drugs is a complex systematic project. The concept behind the development of oral SERDs is to overcome the limitations of fulvestrant, which cannot be administered orally and faces issues such as bioavailability restrictions and metabolic instability. However, as SERD data has been gradually disclosed, Elacestrant (RAD1901) is currently the only SERD with positive data. Yet, an in-depth analysis of its data released last December also caused a sharp drop in its stock price. Menarini is expected to submit regulatory applications to the FDA and EU this year. Overall, compared to fulvestrant's once-monthly injectable dosing, elacestrant’s daily oral administration improved mPFS by less than one month (0.9 months) across the entire population, and mOS data is not yet mature. In terms of safety, although it is generally well-tolerated, the incidence and proportion of grade 3/4 adverse events with elacestrant are slightly higher compared to fulvestrant.

Currently, Giredestrant is still undergoing several Phase III studies, including its combination with Palbociclib as a first-line treatment option for HR+/HER2- advanced breast cancer.

2. Clinical Study of NKTR-214 Combined with Opdivo Terminated

On April 14, Nektar and BMS jointly announced that based on the pre-planned analysis results of two clinical studies evaluating the biased IL-2 pathway agonist bempegaldesleukin (BEMPEG/NKTR-214) in combination with the PD-1 inhibitor Opdivo (nivolumab) for the treatment of renal cell carcinoma and bladder cancer, the two companies have decided to terminate the global clinical development program for NKTR-214 in combination with Opdivo.

NKTR-214 was initially developed by Nektar Therapeutics, and Bristol-Myers Squibb signed a collaboration agreement in 2018 with an upfront payment of $1.85 billion (including equity investment). Just last month, the two companies announced that the Phase III PIVOT IO-001 study, which evaluated NKTR-214 in combination with Opdivo versus Opdivo monotherapy as first-line treatment for previously untreated unresectable or metastatic melanoma, did not meet the primary endpoints of PFS and ORR. Based on these results, the two companies also decided to terminate the ongoing Phase III PIVOT-12 study investigating the combination regimen as adjuvant therapy for melanoma.

However, at that time, the two companies announced that they would continue relevant clinical explorations in renal cell carcinoma and bladder cancer, including Phase III clinical trials. Just one month later, these two studies were once again declared terminated, and all clinical development plans for NKTR-214 combined with Opdivo were simultaneously halted, including: the pivotal study for muscle-invasive bladder cancer (CA045-009), the Phase I/II study of the first-line RCC dual-drug combination with TKI (CA045-011), and a Phase I/II study for recurrent and/or refractory pediatric tumors (CA045-020), among others.

Bempegaldesleukin (BEMPEG/NKTR-214) is an immunostimulatory IL-2 cytokine prodrug engineered to selectively stimulate and expand specific anti-cancer T cells and natural killer (NK) cells by binding to the IL-2Rβγ receptor without engaging the immune-suppressive regulatory T cells via the IL-2Rαβγ trimer. Additionally, NKTR-214 is designed to increase the half-life of IL-2 (~20 hours) through the gradual release of its PEG chains, enabling sustained (over three weeks) activation of the IL-2 pathway to reduce dosing frequency.

As previously mentioned, NKTR-214 combined with nivolumab showed a higher response rate than PD-1 monotherapy in early studies. Additionally, Bristol-Myers Squibb signed a collaborative development agreement in 2018 with an upfront payment of $1.85 billion (including equity investment), which subsequently drove Nektar's stock price to soar to $110. Now, Nektar's stock price has fallen below $5, with a market value of less than $900 million.

3. Phase IIb Study of NYX-2925 for the Treatment of Painful Diabetic Peripheral Neuropathy

On April 7, Aptinyx Inc reported the results of a Phase IIb clinical study of NYX-2925 for the treatment of painful diabetic peripheral neuropathy (DPN). The data showed that NYX-2925 did not achieve a statistically significant separation from placebo on the primary endpoint of the study, which evaluated the change in average daily pain on the Numeric Rating Scale (NRS) from baseline during Week 12. Aptinyx's stock price closed down 49% at $1.19.

The prefrontal cortex (PFC) is the center for regulating goal-directed behavior, emotions, and cognitive functions, playing a crucial role in controlling the emotional and cognitive dimensions of pain. Glutamate, the primary excitatory neurotransmitter in the brain and a co-agonist of the NMDA receptor, may lead to centralized pain when reduced PFC glutamate function causes alterations in brain circuits. NYX-2925 is a novel oral positive allosteric modulator (PAM) of the NMDA receptor, which increases activity in the prefrontal cortex (PFC) and alleviates centralized pain by modulating and normalizing NMDA receptor function, aiming to treat chronic pain. Unlike other NMDAr mechanisms, NYX-2925 targets NMDAr hypofunction to restore normal CNS activity, balance calcium influx, and enhance synaptic plasticity.

This study is a randomized, double-blind, placebo-controlled Phase IIb clinical trial designed to evaluate the efficacy and safety of NYX-2925 in 229 patients with advanced painful DPN. Patients were randomly assigned to receive either once-daily oral administration of 50 mg NYX-2925 or placebo. The primary endpoint of the study was the change from baseline in average daily pain as reported on the 0 to 10 NRS during Week 12, with other pain endpoints including worst daily pain, walking pain, etc. Patients treated with NYX-2925 showed improvement in average daily pain scores but did not demonstrate differentiation from placebo, and no differences between NYX-2925 and placebo were observed in other pain endpoints.

NYX-2925 is currently still in the Phase IIb study for fibromyalgia, with preliminary results expected to be released in the third quarter of this year. In March, Aptinyx completed the recruitment of participants for the Phase IIb trial of NYX-2925 in treating fibromyalgia.

This month, Eliem Therapeutics' ETX-810 Phase IIa trial for the treatment of diabetic peripheral neuropathic pain also failed to meet its primary endpoint. ETX-810 is a non-opioid prodrug of palmitoylethanolamide (PEA) that broadly modulates neuroinflammation and pain signaling, representing a potential mechanism for treating various chronic pain conditions. Additionally, ETX-810 has no known drug interactions or potential for abuse.

4. Phase III Study of Ampreloxetine for the Treatment of Neurogenic Orthostatic Hypotension

On April 4, Theravance Biopharma announced the second-phase results of the Phase III clinical trial (Study 0170) for Ampreloxetine in treating symptomatic neurogenic orthostatic hypotension (nOH). Study 0170 is a 22-week Phase III study, including a 16-week open-label period followed by a 6-week double-blind, placebo-controlled, randomized withdrawal period. The data showed that, in the overall patient population—including those with Parkinson's disease (PD), pure autonomic failure (PAF), and multiple system atrophy (MSA)—there was no statistically significant worsening in scores on the Orthostatic Hypotension Symptom Assessment scale (OHSA) and the Patient Global Impression-Severity scale (PGI-S).

Neurogenic Orthostatic Hypotension (nOH) is a rare condition defined as a sustained orthostatic decrease in systolic blood pressure (SBP) of ≥ 20 mm Hg or diastolic blood pressure (DBP) of ≥ 10 mm Hg within three minutes of standing. Severely affected patients are unable to stand due to the drop in blood pressure, leading to cerebral hypoperfusion and syncope. nOH is caused by dysfunction of the autonomic nervous system and is associated with various underlying conditions, including Multiple System Atrophy (MSA), Pure Autonomic Failure (PAF), and Parkinson's Disease (PD).

Ampreloxetine (TD-9855) is a potent, long-acting, oral, once-daily norepinephrine reuptake inhibitor for the treatment of symptomatic neurogenic orthostatic hypotension (nOH), with patent protection until 2037. In addition to the Phase III clinical program, Theravance has conducted a comprehensive non-clinical and clinical pharmacology program. Ampreloxetine has been evaluated in more than 800 patients across clinical studies in fibromyalgia, attention deficit hyperactivity disorder (ADHD), and symptomatic nOH.

However, although the primary endpoint was not met, the odds ratio indicated that patients receiving Ampreloxetine had a 40% lower chance of treatment failure compared to placebo. Theravance stated that, given the significant unmet needs of MSA patients with symptomatic nOH, it would communicate with health authorities to confirm the pathway for further development.

5. Phase II Study of ACP-044 for the Treatment of Acute Pain

On April 18, Acadia Pharmaceuticals announced the primary results of a Phase II randomized, double-blind, placebo-controlled clinical study evaluating the efficacy and safety of ACP-044 in treating acute postoperative pain. The data showed that the cumulative pain intensity scores based on the Numerical Rating Scale (NRS) within 24 hours for the ACP-044 1600 mg (QD) and ACP-044 400 mg (QID) cohorts did not achieve statistical significance compared to the placebo group, missing the primary endpoint of the study.

ACP-044 is a non-opioid, novel FIC redox modulator under development for the treatment of acute and chronic pain, including post-surgical and osteoarthritis pain. ACP-044 is a small molecule with oral bioavailability and is believed to function as a redox modulator of reactive oxygen species such as peroxynitrite. Reactive oxygen species originate from tissue injury and inflammation and are thought to exacerbate pain through various pathways. The mechanism of action of ACP-044 is believed to modulate redox pathways involved in pain signaling by reducing the increased levels of reactive oxygen and nitrogen species, such as peroxynitrite. Redox modulation represents a new and promising approach for managing acute and chronic pain.

Unfortunately, in this study, although a trend favoring the ACP-044 400 mg every 6 hours treatment group was observed for the primary endpoint, the difference compared to placebo was -10.5 points (p = 0.1683; effect size = 0.219). At 48 hours and 72 hours, these numerical trends remained consistently better than placebo but did not reach statistical significance.

In April, in addition to the aforementioned clinical research setbacks, some drugs were terminated or had their authorization applications suspended due to unsatisfactory efficacy in clinical studies. On the 5th, Imara Inc. announced that it decided to terminate relevant studies due to disappointing interim analysis results of two Phase IIb trials on Tovinontrine (IMR-687) for treating sickle cell disease and β-thalassemia. On the 14th, Adagio Therapeutics announced that it decided to suspend the submission of its Emergency Use Authorization (EUA) application because adintrevimab (ADG20) showed significantly reduced neutralizing activity against the Omicron BA.2 variant in vitro, potentially lacking sufficient neutralizing activity against the BA.2 variant. On the 25th, Gossamer Bio announced that HIF-PH inhibitor GB004 did not meet its primary or secondary endpoints at week 12 in the Phase II SHIFT-UC clinical trial for mild to moderate active ulcerative colitis.

References:

[1] https://www.roche.com/media/releases/med-cor-2022-04-25

[2] https://ir.nektar.com/news-releases/news-release-details/nektar-and-bristol-myers-squibb-announce-update-clinical

[3] https://ir.aptinyx.com/press-releases/news-details/2022/Aptinyx-Reports-Results-from-Phase-2b-Study-of-NYX-2925-in-Painful-Diabetic-Peripheral-Neuropathy/default.aspx

[4] https://investor.theravance.com/news-releases/news-release-details/theravance-biopharma-inc-announces-results-study-0170-second

[5] https://ir.acadia-pharm.com/news-releases/news-release-details/acadia-pharmaceuticals-announces-top-line-results-phase-2-study

[6] https://ir.imaratx.com/news-releases/news-release-details/imara-announces-results-interim-analyses-tovinontrine-imr-687

[7] https://investors.adagiotx.com/news-releases/news-release-details/adagio-therapeutics-provides-update-timing-adintrevimab-eua