Top 10 Failed Clinical Trials in July: Setbacks in Squamous Cell Carcinoma, Severe Pneumonia, and More

Text | Shuye

Based on the Industry News section of the PharmaCube website, the NextPharma database, and publicly available information, the July 2021 issue of the *Clinical Research Monthly Report* has identified 10 noteworthy clinical trials that failed to meet their primary endpoints, for your reference.

1. Phase III Study of Multikine as First-Line Treatment for Squamous Cell Carcinoma of the Head and Neck (SCCHN)

As of July 2, CEL-SCI has declined for five consecutive trading days, with a cumulative drop of over 70%. This downturn began on June 28, when CEL-SCI announced that in the full-cohort analysis of its Phase III clinical trial of Multikine for the treatment of squamous cell carcinoma of the head and neck (SCCHN)—comprising the low-risk group without concurrent chemotherapy and the high-risk group with concurrent chemotherapy—Multikine treatment failed to meet the primary endpoint of a 10% improvement in overall survival compared to the control group.

CEL-SCI Pipeline (Source: CEL-SCI Official Website)

Multikine (Leukocyte Interleukin, Injection) is an investigational cancer immunotherapy known to contain 14 natural human cytokines and human immune system modulators, including interleukins, interferons, chemokines, and colony-stimulating factors.

Multikine is the sole drug in CEL-SCI's pipeline. Despite demonstrating an overall survival (OS) benefit in the low-risk subgroup, it has failed to restore investor confidence in CEL-SCI. In the low-risk subgroup, patients with advanced primary head and neck cancer who received postoperative Multikine in combination with radiotherapy achieved a 14.1 percentage-point benefit in the 5-year OS rate (62.7% vs. 48.6%), exceeding the 10% OS benefit threshold predefined for the overall study population. Given the statistically significant OS benefit in the low-risk subgroup (p=0.0236, HR=0.68), CEL-SCI plans to seek FDA approval for the use of Multikine in this patient population.

2. Phase II Study of Avdoralimab for the Treatment of Severe COVID-19 Pneumonia

On July 6, Innate Pharma SA announced that avdoralimab, a C5aR1 antibody, failed to meet its primary endpoint across all three cohorts of the Phase II clinical trial (FORCE) for the treatment of severe COVID-19 pneumonia. Innate will terminate the development of avdoralimab for COVID-19. This decision will not affect its clinical development for bullous pemphigoid.

Overview of Avdoralimab Clinical Indications Under Development (Source: Innate Pharma Website)

Avdoralimab (IPH5401) is a therapeutic antibody that specifically binds to and blocks the C5a receptor (C5aR1) expressed on myeloid-derived suppressor cells (MDSCs) and neutrophil subsets. Targeting C5a/C5aR1 is supported by scientific evidence from clinical trials in several complement-driven inflammatory diseases, and the FORCE trial was also conducted based on preclinical data demonstrating activation of the C5a/C5aR1 pathway in patients with severe COVID-19. However, compared with best supportive care, Avdoralimab did not translate into clinical benefit; moreover, this is not the first failure of complement-targeted therapy.

In March 2021, Apellis Pharmaceuticals, a global biopharmaceutical company and a leader in targeted C3 therapies, also announced that it would no longer pursue APL-9 for the treatment of severe COVID-19. APL-9 also modulates the complement system cascade; however, unlike Avdoralimab, APL-9 targets and inhibits C3 upstream in the complement system. (APL-9 shares the same mechanism of action as APL-2 but has a lower molecular weight and a shorter half-life, making it suitable for emergency use.)

Source: Apellis Pharmaceuticals

3. Phase III Study of Mupadolimab for the Treatment of COVID-19

On July 15, Corvus Pharmaceuticals announced the discontinuation of its Phase III study evaluating mupadolimab for the treatment of COVID-19. Corvus noted that this decision was unrelated to any safety or efficacy issues observed in enrolled patients, but was primarily driven by the positive trend demonstrated by COVID-19 vaccines in reducing severe infections and hospitalization rates. Moving forward, the company will continue to advance the development of mupadolimab in oncology, with Phase I/Ib clinical trials currently underway in this therapeutic area.

Mupadolimab Oncology Indication Portfolio (Source: Corvus)

Mupadolimab (CPI-006) is a humanized anti-CD73 antibody that binds to various immune cells, including the majority of B cells. Its binding to CD73 inhibits the production of immunosuppressive adenosine in the tumor microenvironment. Additionally, mupadolimab exhibits agonistic properties, which activate B cells, promote their migration to lymph nodes, and induce their differentiation into plasmablasts and antibody secretion.

Mupadolimab is a humanized anti-CD73 antibody (Source: Corvus)

4. Phase III Study of Opdivo in Combination with Yervoy for the Treatment of Squamous Cell Carcinoma of the Head and Neck

On July 16, Bristol-Myers Squibb announced updated data from the Phase III CheckMate-651 trial evaluating Opdivo (nivolumab) in combination with Yervoy (ipilimumab) versus the EXTREME regimen (cetuximab, cisplatin/carboplatin, and fluorouracil) for the first-line treatment of recurrent or metastatic squamous cell carcinoma of the head and neck (SCCHN). The results showed that although Opdivo plus Yervoy demonstrated a notable trend toward improved overall survival (OS) in patients with PD-L1–expressing tumors and a combined positive score (CPS) ≥20, the study did not meet its primary endpoint.

CheckMate-651 is a randomized, multicenter study evaluating the efficacy of Opdivo (3 mg/kg, Q2W) in combination with Yervoy (1 mg/kg, Q6W) compared with the EXTREME regimen (cetuximab, cisplatin/carboplatin, and fluorouracil) as first-line treatment for patients with recurrent or metastatic squamous cell carcinoma of the head and neck (SCCHN). The co-primary endpoints of the trial were overall survival (OS) in the intent-to-treat population and OS in patients with tumors expressing PD-L1 and a CPS ≥ 20.

Previously, in the CheckMate-141 trial, Opdivo monotherapy demonstrated a survival benefit in recurrent or metastatic SCCHN following platinum-based therapy. Based on these results, the U.S. FDA and the European EMA approved Opdivo for this indication in 2016.

Commentary: On July 15, a Phase III study of Opdivo combined with Yervoy as second-line treatment for advanced NSCLC was published online in JAMA Oncology. Compared with Opdivo monotherapy, the combination therapy failed to meet the primary endpoint of improving overall survival (OS).

Furthermore, in the Q2 earnings report released this month, BMS disclosed that despite the success of Opdivo combined with chemotherapy as first-line treatment for metastatic gastric cancer (GC), gastroesophageal junction cancer (GEJC), or esophageal adenocarcinoma (EAC), the final analysis of the Phase III CheckMate-649 trial showed that the combination of Opdivo and Yervoy did not meet the secondary endpoint of overall survival (OS) in patients with PD-L1 CPS ≥ 5. Currently, Opdivo combined with chemotherapy as first-line treatment for metastatic GC/GEJC or EAC has received full approval from the FDA.

Looking ahead, the highly anticipated CTLA-4/PD-(L)1 combination therapy still has a long way to go. Meanwhile, the combination of Opdivo and Yervoy can be regarded as a practical foundation for the design of PD-(L)1/CTLA-4 bispecific antibodies. In disease indications where combination therapies have ultimately fallen short, the clinical advantages and superior safety profile of bispecific antibodies will undoubtedly serve as direct evidence validating this conceptual drug class.

5. Phase IIb Study of SER-287 for the Treatment of Ulcerative Colitis

On July 22, Seres Therapeutics announced that its Phase IIb trial (ECO-RESET) of SER-287 for the treatment of mild-to-moderate ulcerative colitis (UC) failed to meet the primary endpoint of improving the clinical remission rate. Additionally, no statistically significant differences were observed in endoscopic improvement, endoscopic remission, or symptomatic remission. Following this news, Seres' stock price fell by 62%, closing at $7.95.

Seres Stock Price Trend (Source: Seres Therapeutics)

SER-287 is an investigational microbial consortia therapy. In the randomized, placebo-controlled, double-blind, multicenter ECO-RESET study, a total of 203 patients with ulcerative colitis (UC) from 104 centers across the United States and Canada were enrolled to evaluate the safety and efficacy of SER-287 for the treatment of mild-to-moderate UC. The results demonstrated no clinically or statistically significant difference in clinical remission rates between the treatment and control groups. Additional efficacy and safety outcomes, along with microbiome analyses from the ECO-RESET study of SER-287, will be presented at upcoming scientific meetings.

ECO-RESET Clinical Trial Design (Source: Seres Therapeutics)

However, although the ECO-RESET trial did not meet the pre-specified threshold, Seres Therapeutics believes that the clinical research and data analysis will yield valuable insights for the development of its subsequent microbiome products, including the next-generation UC candidate therapeutic SER-301.

Next-Generation UC Candidate Drug (Source: Seres Therapeutics)

Among them, both SER-287 and SER-301 are microbial consortium products derived from microorganisms found in the gastrointestinal tracts of healthy individuals. The difference lies in that SER-287 is a donor-derived candidate product, whereas SER-301 is a rationally designed, cultured bacterial consortium product developed using Seres’ next-generation technology. The design of SER-301 leverages Seres’ reverse translation platform, which employs high-resolution analysis to evaluate how gastrointestinal microorganisms influence disease progression through their interactions with one another and with human cells and tissues.

6. ADVM-022 for the Treatment of Diabetic Macular Edema

On July 22, Adverum Biotechnologies announced that it will not further pursue the development of ADVM-022 for patients with diabetic macular edema (DME) pending a comprehensive review of data from the INFINITY study in DME and the OPTIC study in wet age-related macular degeneration (wet AMD). Study data revealed significant safety differences between the two patient populations and across different dose groups. In the high-dose arm (6 × 10^11 vg/eye) of the OPTIC study, previously unobserved dose-limiting toxicity (DLT) was observed.

ADVM-022 Drug Overview (Source: Adverum Website)

ADVM-022 utilizes Adverum’s proprietary AAV.7m8 vector capsid to carry an optimized aflibercept coding sequence. Administered as a single intravitreal (IVT) injection, ADVM-022 is designed to provide long-term efficacy while reducing the compliance burden associated with frequent anti-VEGF injections. In April 2021, safety and efficacy data presented at the Association for Research in Vision and Ophthalmology (ARVO) meeting demonstrated that 60% of patients remained injection-free at one year. Following a single low-dose injection, the annualized injection rate was reduced by 85% (n=15), demonstrating long-term durability and efficacy.

Following a single low-dose injection of ADVM-022, the annualized injection frequency is reduced by 85% (Source: Adverum website).

Wet AMD and DME have distinct pathophysiological mechanisms and risk factors. Although the underlying cause of the DLT in the OPTIC study remains unclear, Adverum stated that it will continue to advance the development of ADVM-022 in patients with wet AMD. Previously, the FDA granted ADVM-022 Fast Track designation for the treatment of wet AMD.

7. ECF843 for the Treatment of Dry Eye Disease

On July 21, Novartis announced its Q2 2021 financial results, with first-half revenue reaching $25.367 billion, up 7% year-on-year, and net profit totaling $4.954 billion, up 23% year-on-year. Notably, among the product milestones, the company disclosed plans to discontinue the development of ECF843 in a broad population of patients with moderate to severe dry eye disease (DED).

2021 Novartis Key Product Milestones (Source: Novartis Official Website)

ECF843 is a recombinant human lubricin (rh-Lubricin) protein developed by Lubris LLC in Boston, USA. In April 2017, Novartis announced it would develop ECF843 for ophthalmic indications globally (excluding Europe). As an endogenous glycoprotein, lubricin is widely expressed in areas of high shear stress and friction, including the tear film that protects ocular surface tissues.

The observed biological deficiency of lubricin in patients with dry eye disease constitutes the putative mechanism of action for ECF843 in the treatment of dry eye. Previously, in a small Phase II clinical trial, ECF843 demonstrated the potential to improve dry eye disease symptoms by enhancing lubrication across ocular and tear film surfaces and improving signs of dry eye within 28 days.

8. Roche Halts Clinical Trials for Multiple Products or Therapies

On July 22, Roche announced its financial results for the first half of 2021, with total revenue reaching CHF 30.7 billion, an 8% increase year-on-year. The Pharmaceuticals division reported revenue of CHF 21.7 billion, down 3% year-on-year, while the Diagnostics division recorded revenue of CHF 9.0 billion, up 51% year-on-year.

Meanwhile, Roche also announced updates to its pipeline products. Among them, several innovative drugs (combination therapies) have been removed from the clinical development pipeline, including gene therapy RG6247, 4DMT, bispecific antibody RG6296, anti-CD40 monoclonal antibody RG7876, and others.

Roche Pipeline Product Research Updates (Source: Roche Official Website)

9. Phase III Study of TNX-102 SL for the Treatment of Fibromyalgia

On July 23, Tonix Pharmaceuticals announced that, following a recommendation from the Independent Data Monitoring Committee (IDMC), it has decided to halt patient enrollment in its Phase III study (RALLY) of TNX-102 SL (cyclobenzaprine hydrochloride sublingual tablet) for the treatment of fibromyalgia. After completing a pre-specified interim analysis, the IDMC concluded that it is unlikely the primary endpoint—a statistically significant improvement in daily pain severity scores as measured by the Numerical Rating Scale (NRS)—would be demonstrated between the TNX-102 SL and placebo treatment groups. Following this news, Tonix's stock price plummeted, dropping 35% at Monday's open.

RALLY Clinical Study Design (Source: Tonix Website)

TNX-102 SL is a patented sublingual tablet formulation of cyclobenzaprine hydrochloride that, by bypassing hepatic first-pass metabolism, enables rapid transmucosal absorption and reduces the formation of the long-half-life active metabolite, norcyclobenzaprine. The RALLY study is a double-blind, randomized, placebo-controlled trial designed to evaluate the efficacy and safety of TNX-102 SL. The study has enrolled 514 subjects across approximately 40 sites in the United States. During the first two weeks of treatment, patients received TNX-102 SL 2.8 mg (1 tablet) or placebo; after two weeks, the dose for all participants was adjusted to 5.6 mg (2 × 2.8 mg tablets) and maintained for 12 weeks.

Tonix stated that it has not yet reviewed the detailed data and has only received the IDMC's recommendation. Preliminary blinded safety data from subjects did not reveal any new safety signals, and the decision to halt subject enrollment is unrelated to drug safety. The company plans to continue monitoring subjects currently receiving the study drug, followed by a comprehensive analysis of the unblinded data. Top-line results are expected to be reported in the fourth quarter of 2021, which will determine the next steps for the program.

This study is not the first setback for TNX-102 SL, which previously also failed in a Phase III trial for post-traumatic stress disorder (PTSD). However, Tonix plans to continue evaluating the drug's efficacy in sleep disorders.

10. Two Phase II Clinical Studies of Feiselin for the Treatment of AD and PD

On July 28, Annovis Bio presented Phase II data for Posiphen in patients with Alzheimer’s disease (AD) and Parkinson’s disease (PD) at the Alzheimer's Association International Conference (AAIC). The results showed that cognitive improvement was greater in patients receiving placebo than in those receiving Posiphen (ANVS401). Following the data release, Annovis's stock plummeted by 66%; the negative results also dragged down the stocks of several other companies that presented research data at the AAIC, including Alector (-21%) and Cassava Sciences (-23%).

Annovis Stock Trend (Source: Annovis Website)

ANVS401 is a lipophilic small-molecule compound that can be administered orally and crosses the blood-brain barrier. Pharmacokinetic analysis indicates that its brain concentration is approximately 6- to 8-fold higher than its plasma concentration. ANVS401 exhibits a unique mechanism of action, capable of reducing the levels of several key neurotoxic proteins both in vitro and in vivo, including APP, tau, and αSYN.

(Source: Annovis website)

In July, in addition to the aforementioned ten clinical setbacks, other noteworthy developments include AstraZeneca's removal of the atopic dermatitis indication for tezepelumab from its clinical development pipeline, Gilead's quiet discontinuation of the BTK inhibitor tirabrutinib for chronic spontaneous urticaria, AbbVie's abandonment of ABBV-8E12 for the treatment of Alzheimer's disease, and Gilead's halt of research on the inhaled formulation of remdesivir along with its decision to no longer pursue the injectable formulation for outpatient use.

Furthermore, Denali also announced preliminary Phase I data for DNL310, its investigational therapy for Hunter syndrome (also known as MPS II). Biomarker analysis revealed that CSF neurofilament protein levels not only failed to decrease but actually increased. According to expert estimates, a reduction of over 20% in CSF neurofilament protein levels is required to translate into clinical benefit, indicating that the clinical development of DNL310 will also not be a straightforward path.

References:

1.https://www.irdirect.net/prviewer/release_only/id/4763752

2.https://investors.innate-pharma.com/news-releases/news-release-details/update-avdoralimab-phase-2-force-trial-covid-19-patients-severe

3.https://corvuspharma.gcs-web.com/news-releases/news-release-details/corvus-pharmaceuticals-discontinues-phase-3-study-mupadolimab

4.https://news.bms.com/news/corporate-financial/2021/Bristol-Myers-Squibb-Provides-Update-on-CheckMate--651-Trial-Evaluating-Opdivo-nivolumab-Plus-Yervoy-ipilimumab-Versus-EXTREME-Regimen-as-First-Line-Treatment-for-Squamous-Cell-Carcinoma-of-the-Head-and-Neck/default.aspx；JAMA Oncol. doi:10.1001/jamaoncol.2021.2209；https://s21.q4cdn.com/104148044/files/doc_financials/quarterly_reports/2021/BMY-Q22021-Earnings-Press-Release.pdf

5.https://ir.serestherapeutics.com/news-releases/news-release-details/seres-therapeutics-announces-topline-results-ser-287-phase-2b

6.https://investors.adverum.com/news-releases/news-release-details/adverum-provides-update-advm-022-and-infinity-trial-patients

7.https://www.novartis.com/sites/www.novartis.com/files/q2-2021-investor-presentation.pdf

8.https://www.roche.com/dam/jcr:a1437516-3f73-4112-a483-40c8b1c3836e/en/irp210722.pdf

9.https://www.tonixpharma.com/news-events/press-releases/detail/1271/tonix-pharmaceuticals-announces-outcome-of-interim-analysis

10.https://irpages2.eqs.com/download/companies/annovis/Presentations/Annovis%20-%20AAIC%20Presentation%207.28.2021%20.pdf

11. Original | DNL310 Pilot Trial Setback. https://mp.weixin.qq.com/s/R_aHFzCZkpO8LaH7FdobWQ

*Disclaimer: This article was written by a contributor to Sina Pharmaceutical News. The views expressed are solely those of the author and do not represent the position of Sina Pharmaceutical News.