On June 3, 2024 AstraZeneca reported that Tagrisso (osimertinib) with the addition of pemetrexed and platinum-based chemotherapy has been recommended for approval in the European Union (EU) for 1st-line treatment of adult patients with locally advanced or metastatic epidermal growth factor receptor-mutated (EGFRm) non-small cell lung cancer (NSCLC) whose tumours have exon 19 deletions or exon 21 (L858R) mutations (Press release, AstraZeneca, JUN 3, 2024, View Source [SID1234644036]).

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The Committee for Medicinal Products for Human Use (CHMP) of the European Medicines Agency (EMA) based its positive opinion on the results from the FLAURA2 Phase III trial, which were also published in The New England Journal of Medicine.

Results showed Tagrisso with the addition of chemotherapy reduced the risk of disease progression or death by 38% compared to Tagrisso monotherapy, which is the 1st-line global standard of care (hazard ratio [HR] 0.62; 95% confidence interval [CI] 0.49-0.79; p<0.0001). Median progression-free survival (PFS) by investigator assessment was 25.5 months for patients treated with Tagrisso plus chemotherapy, an 8.8-month improvement versus Tagrisso monotherapy (16.7 months).

While overall survival (OS) remained immature at the second interim analysis (41% maturity), an encouraging trend towards an OS benefit was observed with Tagrisso plus chemotherapy versus Tagrisso alone (HR 0.75; 95% CI 0.57-0.97). The trial continues to assess OS as a key secondary endpoint.

Each year in Europe, there are more than 450,000 people diagnosed with lung cancer.1 Among those with NSCLC, the most common form of lung cancer, about 10-15% of patients in Europe have tumours with an EGFR mutation.2,3 Additionally, the majority of patients with NSCLC are diagnosed with advanced disease.4

David Planchard, MD, PhD, thoracic oncologist at Gustave Roussy Institute of Oncology and principal investigator for the trial, said: "The FLAURA2 results build on the established efficacy of osimertinib monotherapy in patients with EGFR-mutated lung cancer, demonstrating a meaningful nine-month improvement in progression-free survival with the addition of chemotherapy. Today’s positive recommendation is a vital step towards providing patients in Europe with an additional treatment option capable of extending the time before their disease progresses. This expands on the already approved use of osimertinib as monotherapy, providing physicians with options to tailor treatments that best suit their patients’ specific disease needs."

Susan Galbraith, Executive Vice President, Oncology R&D, AstraZeneca, said: "Today’s news reinforces the importance of Tagrisso as the backbone therapy in EGFR-mutated lung cancer. If approved in Europe, patients will have the option to be treated with Tagrisso alone, or with chemotherapy, which is especially important when caring for patients whose disease has spread to the brain or those with L858R mutations."

The safety profile of Tagrisso plus chemotherapy was generally manageable and consistent with the established profiles of the individual medicines. Adverse event (AE) rates were higher in the Tagrisso plus chemotherapy arm, driven by well-characterised chemotherapy-related AEs. Discontinuation rates of Tagrisso due to AEs were 11% for Tagrisso plus chemotherapy and 6% for monotherapy.

Tagrisso is approved as monotherapy in more than 100 countries including in the US, EU, China and Japan. Approved indications include for 1st-line treatment of patients with locally advanced or metastatic EGFRm NSCLC, locally advanced or metastatic EGFR T790M mutation-positive NSCLC, and adjuvant treatment of early-stage EGFRm NSCLC. Tagrisso with the addition of chemotherapy is also approved in the US and several other countries for the 1st-line treatment of patients with locally advanced or metastatic EGFRm NSCLC.

Notes

Lung cancer
Lung cancer is the leading cause of cancer death among both men and women, accounting for about one-fifth of all cancer deaths.5 Lung cancer is broadly split into NSCLC and small cell lung cancer.3 Each year there are an estimated 2.4 million people diagnosed with lung cancer globally, with 80-85% of patients diagnosed with NSCLC, the most common form of lung cancer.3,5-6 The majority of all NSCLC patients are diagnosed with advanced disease.7

Approximately 10-15% of NSCLC patients in the US and Europe, and 30-40% of patients in Asia have EGFRm NSCLC.8-10 Patients with EGFRm NSCLC are particularly sensitive to treatment with an EGFR-tyrosine kinase inhibitor (EGFR-TKI) which blocks the cell-signalling pathways that drive the growth of tumour cells.11

FLAURA2
FLAURA2 is a randomised, open-label, multi-centre, global Phase III trial in the 1st-line treatment of patients with locally advanced (Stage IIIB-IIIC) or metastatic (Stage IV) EGFRm NSCLC. Patients were treated with Tagrisso 80mg once-daily oral tablets with the addition of chemotherapy (pemetrexed (500mg/m2) plus cisplatin (75mg/m2) or carboplatin (AUC5)) every three weeks for four cycles, followed by Tagrisso with pemetrexed maintenance every three weeks.

The trial enrolled 557 patients in more than 150 centres across more than 20 countries, including in the US, Europe, South America and Asia. The primary endpoint is PFS. The trial is ongoing and will continue to assess the secondary endpoint of OS.

Tagrisso
Tagrisso (osimertinib) is a third-generation, irreversible EGFR-TKI with proven clinical activity in NSCLC, including against central nervous system (CNS) metastases. Tagrisso (40mg and 80mg once-daily oral tablets) has been used to treat nearly 800,000 patients across its indications worldwide and AstraZeneca continues to explore Tagrisso as a treatment for patients across multiple stages of EGFRm NSCLC.

There is an extensive body of evidence supporting the use of Tagrisso in EGFRm NSCLC. Tagrisso is the only targeted therapy to improve patient outcomes in early-stage disease in the ADAURA Phase III trial, locally advanced stages in the LAURA Phase III trial and late-stage disease in the FLAURA Phase III trial and FLAURA2 Phase III trial.

As part of AstraZeneca’s ongoing commitment to treating patients as early as possible in lung cancer, Tagrisso is also being investigated in the neoadjuvant setting in the NeoADAURA Phase III trial with results expected later this year and in the early-stage adjuvant resectable setting in the ADAURA2 Phase III trial.

The Company is also researching ways to address tumour mechanisms of resistance through the SAVANNAH and ORCHARD Phase II trials, and the SAFFRON Phase III trial, which test Tagrisso plus savolitinib, an oral, potent and highly selective MET TKI, as well as other potential new medicines.

On June 3, 2024 Beyond Cancer, Ltd., a clinical-stage biotechnology company developing ultra-high concentration nitric oxide (UNO) as an immunotherapeutic for solid tumors, reported encouraging first-in-class clinical data demonstrating evidence of immune system activation via biomarker response in a heavily pretreated population in the ongoing Phase 1a trial (Press release, Beyond Air, JUN 3, 2024, View Source [SID1234644035]). The single agent treatment in relapsed or refractory unresectable, primary or metastatic cutaneous and subcutaneous malignancies represents an unprecedented use of UNO as an immunotherapeutic up to 50,000 parts per million. These data were presented at the American Society of Clinical Oncology (ASCO) (Free ASCO Whitepaper) Key Opinion Leader Event held in conjunction with the 2024 Annual Meeting in Chicago, Illinois.

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The Company also reported a case of relapsed/refractory Triple Negative Breast Cancer (TNBC) in which the subject showed no evidence of malignancy in a satellite lesion 21 days following UNO treatment and a corollary, rapid and durable clinical resolution of radiation-induced dermatitis.

The immune biomarker data at Day 21, following a single 5 minute dose of UNO 50,000 ppm, demonstrated increases in dendritic cells, cytotoxic T-cells, central memory T-cells and a favorable increase in the M1/M2 ratio. Myeloid Derived Suppressor Cells (MDSCs) also showed a 54% decrease. In the 25,000 ppm cohort, the same stimulatory immune biomarkers were upregulated. UNO was generally well tolerated with primarily Grade 1 related toxicities. One Grade 3 adverse event was deemed a dose limiting toxicity in the 50,000 ppm cohort resulting in the expansion of the cohort to six total subjects.

The Phase 1b trial has been submitted to the Israeli Ministry of Health (IMOH) and upon regulatory approval will enroll up to 20 subjects with prior exposure to anti-PD-1 antibody that have either progressed, not achieved a response, or have prolonged stable disease ( 12 weeks) on single agent anti-PD-1 without radiographic evidence of continued tumor reduction. Subjects enrolled in the Phase 1b trial will be treated with the UNO + anti-PD-1 combination upon completion of the Phase 1a trial.

"We are excited to present first-in-class data that demonstrate the potential of UNO to induce a clinically meaningful response in a subject with triple-negative breast cancer who was highly refractory to standard of care therapy, with complete resolution of the radiation-induced dermatitis. The safety profile and promising anti-tumor activity observed in this Phase 1a study provide a strong foundation to advance UNO in the clinical setting," said Jedidiah Monson, MD, Chief Medical Officer of Beyond Cancer. "We look forward to future results of the planned Phase 1b trial in combination with PD-1 inhibitor therapy and potentially expand its application to other cancer types."

About UNO Therapy for Solid Tumors
Cancer is the second leading cause of death globally, with tumor metastases responsible for approximately 90% of all cancer-related deaths. Current cancer treatment modalities generally include chemotherapy, immunotherapy, radiation, and/or surgery. Ultra-high concentration Nitric Oxide (UNO) therapy is a completely new approach to preventing relapse or metastatic disease. In vitro murine data show that local tumor ablation with UNO stimulates an anti-tumor immune response in solid tumor cancer models. Beyond Cancer, Ltd. believes that UNO has the potential to prevent relapse or metastatic disease with as little as a single 5-minute treatment and with limited toxicity or off-target effects.

About Nitric Oxide
Nitric Oxide (NO) is a potent molecule, naturally synthesized in the human body, proven to play a critical role in a broad array of biological functions. In the airways, NO targets the vascular smooth muscle cells that surround the small resistance arteries in the lungs. Currently, exogenous inhaled NO is used in adult respiratory distress syndrome, post certain cardiac surgeries and persistent pulmonary hypertension of the newborn to treat hypoxemia. Additionally, NO is believed to play a key role in the innate immune system and in vitro studies suggest that NO possesses anti-microbial activity not only against common bacteria, including both gram-positive and gram-negative, but also against other diverse pathogens.

On June 3, 2024 Adaptimmune Therapeutics plc (NASDAQ: ADAP), a company working to redefine the treatment of solid tumor cancers with cell therapy, reported data from its pivotal IGNYTE-ESO trial of lete-cel (letetresgene autoleucel), an engineered cell therapy targeting NY-ESO-1, in synovial sarcoma (SyS) and myxoid/round cell liposarcoma (MRCLS) at the American Society of Clinical Oncology (ASCO) (Free ASCO Whitepaper)’s (ASCO) (Free ASCO Whitepaper) annual meeting (Press release, Adaptimmune, JUN 3, 2024, View Source [SID1234644034]). Dr. Sandra D’Angelo of the Memorial Sloan Kettering Cancer Center will present "Lete-cel in patients with synovial sarcoma or myxoid/round cell liposarcoma: Planned interim analysis of the pivotal IGNYTE-ESO trial" in an oral session at 11:30 a.m. CDT, Monday, June 3rd, in Hall D2 as part of the Developmental Therapeutics-Immunotherapy track.

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Dennis Williams, PharmD., Senior Vice President, Late-Stage Development, Adaptimmune: "We’re encouraged by the findings from the IGNYTE-ESO trial and the potential of our sarcoma franchise. Our lead cell therapy product, afami-cel, targets MAGE-A4 in synovial sarcoma and the ability to now also target the NY-ESO-1 cancer antigen with lete-cel will enable us to reach a greater number of people impacted by advanced sarcomas. We are eager to continue advancing lete-cel to further realise the promise of engineered TCR T-cell therapies for patients and healthcare providers. We look forward to sharing the full results of the IGNYTE-ESO trial in late 2024. We continue to work toward commercializing afami-cel later this year and lete-cel in 2026."

Dr. Sandra D’Angelo M.D., Sarcoma Medical Oncology, Memorial Sloan Kettering Cancer Center, lead author and presenter: "Data from this planned interim analysis support the potential of lete-cel to serve as a novel therapy for people with advanced or metastatic MRCLS or synovial sarcoma. As the current treatment options in these two indications are significantly limited, both represent a greatly unmet medical need for novel, innovative therapies."

Lete-cel data at ASCO (Free ASCO Whitepaper)

At the planned interim analysis, 18/45 patients who received a single dose of lete-cel had clinical responses (previously reported). The overall response rate (ORR) of 40% was consistent across both SyS and MRCLS, and markedly greater than historical standard of care outcomes in these indications. The primary endpoint success criterion for efficacy was met by the interim analysis 40% ORR. Responses to lete-cel are durable, with the median duration of response (mDOR) at ~11 months, with 9/18 patients censored from mDOR calculation as their responses were ongoing at the time of the interim analysis. The complete primary analyses from IGNYTE-ESO, including more mature duration of response, are currently in progress with a full dataset anticipated in late 2024.

Given the success of the pivotal IGNYTE-ESO trial, Adaptimmune plans to initiate a rolling Biologics License Application (BLA) submission for lete-cel for the treatment of advanced or metastatic MRCLS and synovial sarcoma during 2025. Lete-cel will allow Adaptimmune to bolster its sarcoma franchise by expanding the addressable patient population to NY-ESO-1 positive MRCLS and synovial sarcoma solid tumors.

About lete-cel

Lete-cel is an engineered TCR T-cell therapy targeting the solid tumor antigen NY-ESO-1. Lete-cel is being investigated for the treatment of synovial sarcoma and myxoid/round cell liposarcoma (MRCLS) in the pivotal IGNYTE-ESO (NCT03967223) trial in patients who received prior anthracycline treatment.

About Synovial Sarcoma

There are more than 50 different types of soft tissue sarcomas which are categorised by tumors that appear in fat, muscle, nerves, fibrous tissues, blood vessels, or deep skin tissues.1 Synovial sarcoma accounts for approximately 5% to 10% of all soft tissue sarcomas (there are approximately 13,400 new soft tissue cases in the U.S. each year).2 One third of patients with synovial sarcoma will be diagnosed under the age of 30.2 The five-year survival rate for people with metastatic disease is just 20% and most people undergoing standard of care treatment for advanced disease experience recurrence and go through multiple lines of therapy, often exhausting all options.3

About Myxoid/round cell liposarcoma (MRCLS)
Myxoid/round cell liposarcoma (MRCLS) is a type of soft tissue sarcoma that is predominantly found in the limbs. MRCLS accounts for approximately 5% to 10% of all soft tissue sarcomas.4 One-third of MRCLS cases will become metastatic with tumors spreading to unusual bone and soft tissue locations. MRCLS commonly presents at an age ranging from 35-55 years and has a poor prognosis because it recurs locally and tends to metastasize quickly and widely. The 5-year survival rate for metastatic MRCLS is only 5%.

On June 3, 2024 Merus N.V. (Nasdaq: MRUS) (Merus, the Company, we, or our), a clinical-stage oncology company developing innovative, full-length multispecific antibodies (Biclonics and Triclonics), reported the publication of a poster regarding MCLA-129 presented at the 2024 American Society of Clinical Oncology (ASCO) (Free ASCO Whitepaper) Annual Meeting taking place in Chicago May 31-June 4, 2024 (Press release, Merus, JUN 3, 2024, View Source [SID1234644033]).

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"These data continue to support our view that MCLA-129 is a very active drug, and that our Biclonics platform really can create clinically active drugs for patients with cancer. We plan to start a cohort investigating MCLA-129 in combination with chemotherapy in 2L+ EGFRm NSCLC later this year," said Bill Lundberg, M.D., President, Chief Executive Officer of Merus. "We continue to evaluate MCLA-129 with a focused investment and remain interested in a partnership to resource the further development of this asset."

Poster presentation title: Efficacy and safety of MCLA-129, an anti-EGFR/c-MET bispecific antibody, in non-small-cell lung cancer (NSCLC) with Hepatocyte Growth Factor Receptor (c-MET) exon 14 skipping mutations (METex14)

Observations in the presentation include:

As of a February 16, 2024 data cutoff date, 22 patients (pts) were treated and 14 pts (64%) were continuing treatment
All the pts received MCLA-129 in monotherapy at the dose of 1500 mg, every 2 weeks
Pts received a median of 2 lines of prior therapy
10 pts (45%) were tyrosine kinase inhibitor (TKI)-naïve and 12 (55%) had received prior TKIs
7 pts were excluded from the efficacy population. 4 discontinued due to AEs <2 cycles of treatment and did not experience progressive disease while on study; 3 were ongoing as of the cutoff date with <2 treatment cycles
15 pts were evaluable for response having received ≥2 treatment cycles, measurable disease at baseline and ≥1 post-baseline scan
Response rate overall: 3 partial responses (PRs) and 6 unconfirmed PRs (uPRs) were observed by Response Evaluation Criteria in Solid Tumors v1.1 per investigator assessment; 5 of the 6 uPRs were confirmed and 1 uPR progressed after the data cutoff (8/15 confirmed PRs [53%])
6 of 8 TKI-naïve cancers responded, one of which was an initial uPR that progressed after data cutoff
3 of 7 cancers with prior MET TKI responded
Reduction in target lesion tumor size from baseline was demonstrated in 12 pts (80%)
Early safety assessment in 22 pts treated with MCLA-129 monotherapy included
Infusion related reactions (composite term) in 86% (18% ≥ Grade (G)3)
One pt had treatment-related interstitial lung disease (G2)
Venous thromboembolism was recorded in 2 pts (1 G3 possibly treatment-related, the other G2 and not related to treatment)
The full presentation is available on the Publications page of our website.

MCLA-129 is subject to a collaboration and license agreement with Betta Pharmaceuticals Co. Ltd. (Betta), which permits Betta to develop MCLA-129 and potentially commercialize exclusively in China, while Merus retains global rights outside of China. An abstract sponsored by Betta entitled: Efficacy and safety of MCLA-129, an EGFR/c-MET bispecific antibody, in advanced non-small cell lung cancer (NSCLC) was accepted for poster presentation at 2024 ASCO (Free ASCO Whitepaper).

On June 3, 2024 Scholar Rock (NASDAQ: SRRK), a late-stage biopharmaceutical company focused on advancing innovative treatments for spinal muscular atrophy (SMA), cardiometabolic disorders, and other serious diseases where protein growth factors play a fundamental role, reported encouraging data from its Phase 1 DRAGON proof-of-concept trial of SRK-181, a selective inhibitor of latent TGFβ1 activation, in combination with pembrolizumab in patients with advanced solid tumors (Press release, Scholar Rock, JUN 3, 2024, View Source [SID1234644031]). The results show encouraging responses in heavily pretreated and anti-PD-(L)1 resistant patients across multiple tumor types. Data were shared in an oral presentation during the American Society of Clinical Oncology (ASCO) (Free ASCO Whitepaper) Annual Meeting on June 3 in Chicago.

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"These new data from our SRK-181 program show promising response to treatment with SRK-181 across multiple tumor types and represent further evidence of the value of our highly selective TGFβ platform," said Jay Backstrom, M.D., MPH, President and Chief Executive Officer of Scholar Rock. "The anti-tumor activity we observed in heavily pretreated cancer patients, most notably in ccRCC and melanoma gives us confidence that SRK-181 could be part of a treatment strategy to overcome immune checkpoint inhibitor-associated resistance. In addition, our new finding that baseline CD8+ infiltration status and elevated baseline regulatory T-cell levels in ccRCC correspond with the twofold increase in response rate has the potential to inform a patient selection strategy. We are very encouraged by these new data and are committed to engaging with the FDA in an end of Phase 1 meeting, while also continuing to evaluate opportunities to partner this important program."

Safety data continued to show SRK-181 was generally well tolerated

Safety data from all cohorts in the dose expansion phase (Part B; n=78 patients; 1500 mg q3w) continued to show SRK-181 was generally well tolerated when used in combination with pembrolizumab. One Grade 4 treatment-related adverse event (AE) of generalized dermatitis exfoliative was observed in one patient. No Grade 5 treatment-related AEs occurred. The only treatment-related serious adverse event related to SRK-181 or pembrolizumab that occurred in at least 2% of patients was pemphigoid. The most common AEs were rash, pruritis, fatigue, and diarrhea.

Data presented continues to provide objective evidence of anti-tumor activity

Encouraging responses were observed in multiple tumor types, continuing to support proof-of-concept for SRK-181. The response was assessed by principal investigators based on RECIST 1.1 for patients across five cohorts: clear cell renal cell carcinoma (ccRCC), head and neck squamous cell carcinoma (HNSCC), melanoma (MEL), urothelial carcinoma (UC), and non-small cell lung cancer (NSCLC). A summary of anti-tumor activity is presented in the table below; results for NSCLC (n=11) are not included because no response was observed.

Summary of Response Rate in Multiple Tumor Types

ccRCC (n=30)

HNSCC (n=11)

MEL (n=11)

UC (n=11)

Objective response rate (ORR)

7 (23.3%)

2 (18.2%)

3 (27.3%)

1 (9.1%)

Durability of response (DoR); median (range), months

7.7+ (2.5+, 20.9+)

2.2+ (0.1, 4.3+)

4.9 (1.8, 7.1)

12.9 (12.9, 12.9)

Biomarker findings continue to support proof of mechanism

Tumor infiltration by CD8+ T-cells was measured in multiple tumor types for which paired biopsy samples (i.e., samples before and after treatment for individual patients) were available. The analysis included patients with ccRCC, melanoma, non-small cell lung cancer (NSCLC), head and neck squamous cell carcinoma (HNSCC) or urothelial carcinoma (UC). In 6 out of 9 paired biopsies analyzed, the combination of SRK-181 and pembrolizumab was associated with an enhanced proinflammatory microenvironment, with activated CD8+ T-cells in responding patients across multiple cohorts and the number of activated T-cells correlating with tumor shrinkage.

New biomarker findings in ccRCC could inform patient selection strategy

Notably, the baseline immune contexture unique to ccRCC amongst the cohorts examined has been identified, predictive of clinical response.

An analysis in ccRCC patients showed a positive correlation between baseline CD8+ infiltration status and response rate, with an increase in ORR from 23.3 to 40%, and an improvement in median durability of response (mDoR) from 7.7 to 9.3 months if enrollment had been limited to patients whose tumors were infiltrated by CD8+ T-cells at baseline.

In addition, an independent analysis showed a positive correlation between elevated regulatory T-cell (Treg) levels in ccRCC patients pre-treatment and response rate, with an increase in ORR from 23.3 to 50% and improvement in mDoR from 7.7 to 9.8 months if enrollment had been limited to patients whose tumors had elevated Treg levels at baseline. Together, these results suggest that baseline CD8+ status and Treg levels should be further investigated as a potential future patient selection strategy, aimed to predict ccRCC patients who are likely to respond to SRK-181 and anti-PD-(L)1 combination therapy.

The presentation is available in the Publications & Posters section of Scholar Rock’s website.

For conference information, visit View Source

Conference Call Information

Scholar Rock will host a conference call on June 4 at 8 a.m. EST that can be accessed from Events and Presentations page of Scholar Rock’s website. Members of Scholar Rock’s executive management team will be joined by Dr. Toni Choueiri, M.D., Director of the Lank Center for Genitourinary (GU) Oncology at Dana-Farber Cancer Institute (DFCI). The audio of the conference call can be accessed by registering in advance at the following link: https://register.vevent.com/register/BIca0060fe57734207b3fc21ce38d84a63

About SRK-181

SRK-181 is a selective inhibitor of TGFβ1 activation being developed to overcome primary resistance to checkpoint inhibitor therapy, such as anti-PD-(L)1 antibodies, in advanced cancer. TGFβ1 is the predominant TGFβ isoform expressed in many human tumor types. Based on analyses of various human tumors that are resistant to anti-PD-(L)1 therapy, data suggest that TGFβ1 is a key contributor to the immunosuppressive tumor microenvironment, excluding and preventing entry of cytotoxic T cells into the tumor, as well as suppressing T cell activity, thereby inhibiting anti-tumor immunity.

SRK-181 specifically targets the latent TGFβ1 isoform in a context-independent manner, designed to enable complete inhibition of TGFβ1 in all compartments within the tumor microenvironment. Scholar Rock believes that SRK-181 has the potential to overcome this immunosuppressive tumor microenvironment and induce tumor regression when administered in combination with anti-PD-(L)1 therapy while potentially avoiding toxicities associated with non-selective TGFβ inhibition. Enrollment of the DRAGON Phase 1 proof-of-concept clinical trial (NCT04291079) was completed in December 2023, and patients who remain on the study continue to be treated. The trial enrolled patients in multiple proof of concept cohorts conducted in parallel, including urothelial carcinoma (UC), cutaneous melanoma (MEL), non-small cell lung cancer (NSCLC), head and neck squamous cell carcinoma (HNSCC), and clear cell renal cell carcinoma (ccRCC). SRK-181 is an investigational product candidate and its efficacy and safety have not been established. SRK-181 has not been approved for any use by the FDA or any other regulatory agency.