On June 20, 2024 Jazz Pharmaceuticals plc reported top-line results from the Phase 2b clinical trial (NCT05122650) evaluating the efficacy and safety of suvecaltamide (JZP385), an investigational, highly selective and state-dependent modulator of T-type calcium channels, in adult patients with essential tremor (ET) (Press release, Jazz Pharmaceuticals, JUN 20, 2024, View Source [SID1234644460]). Suvecaltamide did not achieve statistical significance at 30mg versus placebo on the primary endpoint of change from baseline to week 12 on the Essential Tremor Rating Assessment Scale (TETRAS) modified composite outcome score and key secondary endpoint of Clinical Global Impression-Severity (CGI-S) scale.

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While not statistically significant, numeric improvements were observed on the primary endpoint and key secondary endpoint at 30mg versus placebo. The improvement in placebo from baseline to week 12 also exceeded the Company’s expectations and was higher than what was observed for placebo in the prior T-CALM trial of suvecaltamide.

"We are disappointed that the trial did not meet its primary endpoint. We recognize the significant unmet need for people living with ET, and we are grateful to the patients, their families and the investigators that participated in the trial," said Rob Iannone, M.D., M.S.C.E., executive vice president, global head of research and development of Jazz Pharmaceuticals. "We are evaluating the data to better understand the trial results and await the results of the suvecaltamide trial in Parkinson’s disease tremor to determine next steps for the program. The Phase 2 Parkinson’s disease tremor trial is ongoing with results expected first quarter 2025."

Suvecaltamide was well tolerated and the overall safety profile was consistent with previous studies with no new safety signals observed. The most common treatment-emergent adverse events (TEAEs) were dizziness, headache, paresthesia, diarrhea and insomnia. These were predominately mild to moderate in severity. One participant experienced a serious adverse event considered treatment related by the investigator.

About the Phase 2b Trial
The Phase 2b clinical trial (NCT05122650) is a 12-week, multicenter, double-blind, randomized, placebo-controlled trial evaluating the efficacy and safety of suvecaltamide in a once-daily oral dose of 10, 20 and 30mg or placebo. The primary endpoint (modified TETRAS composite outcome score) represents items 1-11 from the TETRAS-ADL combined with items 6+7 (spiral and handwriting assessments, respectively) from the TETRAS-PS with scoring modifications. The key secondary endpoint in the trial measured the percentage of participants with ≥1 point improvement on CGI-S. The trial randomized 420 participants from four countries.

About Suvecaltamide
Suvecaltamide (JZP385) is an investigational, highly selective and state-dependent modulator of T-type calcium channels (Cav3). T-type calcium channels play a role in the brain’s control of muscle movement.1 Suvecaltamide preferentially binds to stabilize a specific conformation of the channel and reduce activity. The suvecaltamide Phase 2 proof-of-concept trial in Parkinson’s disease tremor is ongoing (NCT05642442).

On June 20, 2024 Kanvas Biosciences, a full-stack spatial biology company, reported its newest drug candidate in its Immuno-oncology Program: KAN-003 (Press release, Kanvas Bioscience, JUN 20, 2024, View Source [SID1234644459]). The Kanvas platform provides the unique ability to map host-microbiome interactions and leverage the resulting data to design live biotherapeutic products (LBPs), which can be used to create novel microbiome-based therapies that complement existing therapies and provide a safe method for targeting underlying disease processes with greater efficacy. The company’s lead drug candidate, KAN-001, is an LBP demonstrating significant potential to improve outcomes for cancer patients who have been resistant to immune checkpoint inhibitors (ICIs). KAN-003 will be a consistent dose regimen that cancer patients can take just before and with ICI treatment.

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ICI treatment is a type of immunotherapy that can help fight a variety of cancers, including malignant melanoma, non-small cell lung cancer, classical Hodgkin lymphoma, head and neck squamous cell carcinoma, urothelial carcinoma, and renal cell carcinoma. ICIs block checkpoint proteins from binding with their partners, which prevents the "off" signal from being sent to T cells and allows T cells to kill cancer cells. However, only 20 – 40% of patients respond to ICI therapy. For patients whose cancers don’t respond to ICI treatment, intervening with a fecal microbiota transplant (FMT) is an alternative option. FMTs involve transferring a microbial ecosystem from a healthy individual into another person, often by colonoscopy. Still, FMT treatments are not commercially scalable, risk the transfer of pathogens and in most cases provide only a single dose.

To improve upon the effectiveness of FMTs, Kanvas has developed its own microbiome-based drug pipeline. With KAN-003, the company’s goal is to dramatically increase the percentage of patients who respond to ICI therapy across all ICI-approved cancer types. Both KAN-001 and KAN-003 are currently undergoing preclinical studies in collaboration with The University of Texas MD Anderson Cancer Center and the institution’s Platform for Innovative Microbiome and Translational Research (PRIME-TR). While KAN-003 is different from KAN-001 in terms of donor source and the microbial ecosystem, the two candidates’ manufacturing strategies are identical, allowing Kanvas to synergize its learnings and scale to drug production quickly.

"As we’ve learned time and again, there’s no single cure for cancer, but every cancer patient deserves safe and effective options. Designed as an earlier treatment option, KAN-003 may generate an earlier response and the chance to stabilize or send cancers into remission for ICI-naive patients," said Matthew Cheng, co-founder and CEO of Kanvas Biosciences. "We believe that the complex interaction of the gut microbiome with human health can be unlocked with a series of discrete, solvable steps, and FMT treatments have already revealed what’s possible for microbiome-based therapeutics. With KAN-001 and now KAN-003, we’re working to transform Immuno-oncology and patient lives."

Kanvas is currently preparing a pre-Investigational New Drug (IND) filing for KAN-003 for Q3 of 2025 and actively seeking additional partners interested in supporting rigorous clinical studies over the next few years. To learn more, contact the company directly.

On June 20, 2024 AstraZeneca reported that Truqap (capivasertib) in combination with Faslodex (fulvestrant) has been approved in the European Union (EU) for the treatment of adult patients with estrogen receptor (ER)-positive, HER2‑negative locally advanced or metastatic breast cancer with one or more PIK3CA, AKT1, or PTEN-alterations following recurrence or progression on or after an endocrine-based regimen (Press release, AstraZeneca, JUN 20, 2024, View Source [SID1234644458]).

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The approval by the European Commission follows the positive opinion of the Committee for Medicinal Products for Human Use and is based on results from the CAPItello-291 Phase III trial published in The New England Journal of Medicine.1

In the trial, Truqap in combination with Faslodex reduced the risk of disease progression or death by 50% versus Faslodex in combination with placebo in patients with tumours harbouring PI3K, AKT or PTEN alterations (based on hazard ratio of 0.50, 95% confidence interval 0.38-0.65; p=<0.001; median progression-free survival (PFS) 7.3 versus 3.1 months).1

In Europe, breast cancer remains the leading cause of cancer death, with more than 140,000 deaths in 2022 and more than 550,000 patients diagnosed in the same year.2 Hormone receptor (HR)-positive breast cancer (expressing estrogen or progesterone receptors, or both), is the most common subtype of breast cancer with 70% of tumours considered HR-positive and HER2-negative.3 More than 97% of HR-positive breast cancer tumours are ER-positive.4,5 Collectively, mutations in PIK3CA, AKT1 and alterations in PTEN occur frequently, affecting approximately 50% of patients with advanced HR-positive breast cancer.6-8

Mafalda Oliveira, MD, PhD, Vall d’Hebron University Hospital, and Senior Clinical Investigator of the Vall d’Hebron Institute of Oncology’s Breast Cancer Group in Barcelona, Spain, said: "Patients with advanced ER-positive breast cancer typically experience tumour progression or resistance with widely used endocrine-based treatment regimens, and there is an urgent need to provide them more time with their disease under control. Today’s approval is welcome news for approximately half of ER-positive breast cancer patients in Europe who have tumours with these biomarkers, and it is important for clinicians to test and identify eligible patients who may be able to benefit from this combination."

Dave Fredrickson, Executive Vice President, Oncology Business Unit, AstraZeneca, said: "Truqap is now the first and only AKT inhibitor approved in the European Union for patients with ER-positive breast cancer who have tumours harbouring these specific biomarkers. Breast cancer continues to be the leading cause of cancer-related death in Europe, and today’s news represents a significant step forward in providing an important new treatment option for patients in need of new, innovative therapies."

In the CAPItello-291 trial, the safety profile of Truqap plus Faslodex was similar to that observed in previous trials evaluating this combination.1

Regulatory applications are currently under review in China and several other countries. Similar indications for Truqap in combination with Faslodex are already approved in the US, Japan and several other countries based on the CAPItello-291 trial.

Financial considerations
Following this approval in the EU, Astex Therapeutics is eligible to receive a milestone payment from AstraZeneca on first commercial sale of the drug in the EU as well as royalties on future sales in line with the agreement between the two companies.

Notes

HR-positive breast cancer
The growth of HR-positive breast cancer cells is often driven by estrogen receptors, and endocrine therapies that target ER-driven disease are widely used as 1st-line treatment in the advanced setting, and often paired with CDK4/6 inhibitors.9-11 However, resistance to CDK4/6 inhibitors and current endocrine therapies develops in many patients with advanced disease.10 Once this occurs, treatment options are limited – with chemotherapy being the current standard of care – and survival rates are low with approximately 35% of patients anticipated to live beyond five years after diagnosis.3,10,12

The optimisation of endocrine therapy and overcoming resistance to enable patients to continue benefiting from these treatments, as well as identifying new therapies for those who are less likely to benefit, are active areas of focus for breast cancer research.

CAPItello-291
CAPItello-291 is a Phase III, double-blind, randomised trial evaluating the efficacy of Truqap in combination with Faslodex versus placebo plus Faslodex for the treatment of locally advanced (inoperable) or metastatic HR-positive (ER-positive and ER-positive, progesterone receptor-positive), HER2-low or negative (immunohistochemistry (IHC) 0 or 1+, or IHC 2+/in-situ hybridisation (ISH)-negative) breast cancer.

The global trial enrolled 708 adult patients with histologically confirmed HR-positive, HER2-low or negative breast cancer whose disease has recurred or progressed during or after aromatase inhibitor therapy, with or without a CDK4/6 inhibitor, and up to one line of chemotherapy for advanced disease. The trial has dual primary endpoints of PFS in the overall patient population and in a population of patients whose tumours have qualifying alterations in the PI3K/AKT pathway (PIK3CA, AKT1 or PTEN genes). In the trial, approximately 40% of tumours had these alterations and approximately 70% of patients received a prior CDK4/6 inhibitor.

Truqap
Truqap is a first-in-class, potent, adenosine triphosphate (ATP)-competitive inhibitor of all three AKT isoforms (AKT1/2/3). Truqap 400mg is administered twice daily according to an intermittent dosing schedule of four days on and three days off. This was chosen in early phase trials based on tolerability and the degree of target inhibition.

Truqap is approved in the US, EU, Japan and several other countries for the treatment of adult patients with HR-positive (or ER-positive), HER2-negative locally advanced or metastatic breast cancer with one or more biomarker alterations (PIK3CA, AKT1 or PTEN) following recurrence or progression on or after an endocrine-based regimen based on the results from the CAPItello-291 trial. Truqap is also approved in Australia for the treatment of adult patients with HR-positive, HER2-negative locally advanced or metastatic breast cancer following recurrence or progression on or after an endocrine based regimen based on these trial results.

Truqap is currently being evaluated in Phase III trials for the treatment of breast cancer (CAPItello-292) and prostate cancer (CAPItello-280 and CAPItello-281) in combination with established treatments.

Truqap was discovered by AstraZeneca subsequent to a collaboration with Astex Therapeutics (and its collaboration with the Institute of Cancer Research and Cancer Research Technology Limited).

Faslodex
Faslodex is an endocrine therapy indicated for the treatment of ER-positive, locally advanced or metastatic breast cancer in postmenopausal women not previously treated with endocrine therapy, or with disease relapse on or after adjuvant anti-estrogen therapy, or disease progression on anti-estrogen therapy.

In the US, EU and Japan, Faslodex is also approved in combination with CDK4/6 inhibitors for the treatment of women with HR-positive, HER2-negative advanced or metastatic breast cancer, whose cancer has progressed after endocrine medicine. Faslodex represents a hormonal treatment approach that helps to slow tumour growth by blocking and degrading the estrogen receptor – a key driver of disease progression.

Faslodex is approved as monotherapy or in combination with medicines from various drug classes including CDK4/6, PI3K and AKT inhibitors for the treatment of patients with HR-positive advanced breast cancer and is being evaluated in combination with medicines from other drug classes.

On June 20, 2024 Medigene AG (Medigene, the "Company", FSE: MDG1, Prime Standard), an immuno-oncology platform company focusing on the discovery and development of T cell immunotherapies for solid tumors, reported that it has selected its lead candidate for MDG2021, a T cell receptor engineered T cell (TCR-T) therapy targeting Kirsten rat sarcoma viral oncogene homologue (KRAS) G12D with human leukocyte antigen (HLA)-A*11 being developed in combination with the Company’s PD1-41BB costimulatory switch protein (CSP) technology (Press release, MediGene, JUN 20, 2024, View Source [SID1234644457]).

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With its proprietary End-to-End (E2E) Platform, the Company has successfully generated an optimal KRAS G12D-HLA-A*11 TCR that meets the Company’s selection criteria for highly specific, sensitive and safer (3S) TCRs as the lead that will now advance into the pre-clinical stage. The Company’s evaluation criteria for TCR selection included sensitive and precise tumor cell recognition combined with simultaneous display of a high safety profile demarked by lack of recognition of panels of healthy cells and tissues, matched and mismatched for HLA.

"We are delighted to announce that we have successfully generated a novel 3S TCR targeting KRAS G12D-A*11 that meets our rigorous selection criteria of high specificity, heightened sensitivity, and promising potential for enhanced safety," said Dr. Selwyn Ho, Chief Executive Officer at Medigene.

"The selection of this KRAS G12D lead-TCR expands our library of TCRs against neoantigens and cancer-testis antigens. Further, with the addition of our armoring & enhancement technology, PD1-41BB CSP to our TCR-T therapies, we are confident that our approach will yield best-in-class TCR-T therapies, providing improved outcomes for patients with to date, difficult-to-treat solid tumors such as colorectal cancer and pancreatic cancer. We are looking forward to presenting initial pre-clinical data on MDG2021 at upcoming scientific conferences in the second half of 2024."

The Company’s E2E Platform continues to generate 3S TCRs with unique and distinctive attributes that will be utilized across multiple therapeutic modalities, including TCR-T therapies, TCR-guided T cell engagers and TCR natural killer cell therapies. The new 3S TCR is designed for co-expression with Medigene’s PD1-41BB CSP to enhance the proliferation, persistence, and cytotoxic function of TCR-T cells, while simultaneously mitigating immunosuppressive effects of the tumor microenvironment.

Following the lead announcement of Medigene’s first KRAS program MDG2011 (KRAS G12V-A*11) in June 2023, MDG2021 is the latest program now in preclinical development within Medigene’s library of neoantigens that comprises multiple KRAS mutations and HLAs. The MDG20xx program is dedicated to further develop the Company’s TCR library, exploring other KRAS neoantigen mutations and HLAs.

On June 20, 2024 Tempest Therapeutics, Inc. (Nasdaq: TPST), a clinical-stage oncology company developing first-in-class1 therapeutics that combine both targeted and immune-mediated mechanisms, reported new positive data from the ongoing global randomized Phase 1b/2 clinical study in which amezalpat2 (TPST-1120), Tempest’s PPAR⍺ antagonist, delivered a six-month improvement in median overall survival ("OS") advantage when combined with atezolizumab and bevacizumab in a comparison to atezolizumab and bevacizumab alone in the first-line treatment of patients with unresectable or metastatic hepatocellular carcinoma ("HCC") (Press release, Tempest Therapeutics, JUN 20, 2024, View Source [SID1234644456]).

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"We are thrilled by these new survival data that build on the already meaningful data released in the fall showing the improvement of the amezalpat arm over atezolizumab and bevacizumab control across all study endpoints," said Stephen Brady, president and chief executive officer of Tempest. "These new data come after 10 more months of follow-up since the last data analysis and show not only a strong hazard ratio of 0.65 favoring the amezalpat arm, but also a six-month improvement in the median overall survival with half the patients still in survival follow up, as well as observation of a survival advantage across key populations – results that we believe put amezalpat in a strong position for a successful pivotal Phase 3."

At the cutoff date of February 14, 2024, the new data from 40 patients randomized to the amezalpat arm and 30 patients randomized to the control arm show:

21 month median OS for the amezalpat arm versus 15 month for the control arm, a six-month survival advantage
20/40 patients remain in survival follow up in the amezalpat arm, compared to 9/30 patients in the control arm
0.65 hazard ratio ("HR") for OS, revealing a stable HR since the top-line analysis 10 months earlier when the HR was 0.59
Manageable safety profile consistent with Phase 1 data
The earlier top-line data analysis, dated April 20, 2023, had a median follow up of 9.2 and 9.9 months for the amezalpat and control arms, respectively, and showed:

Confirmed objective response rate ("cORR" or "confirmed ORR") of 30% for the amezalpat arm versus 13.3% for the control arm;
Biomarker subpopulation findings were consistent with the mechanism of action of amezalpat
Patients with b-catenin activating mutations (21% in this study (n=7)) showed a cORR of 43% and a disease control rate ("DCR") of 100% in the amezalpat arm
The amezalpat arm was consistently active across both PD-L1 positive and PD-L1 negative tumors, with a cORR of 27% in the amezalpat arm compared to 7% for the control arm in PD-L1 negative tumors
Amezalpat remains well tolerated, with safety data comparable between the two arms
The randomized arms were generally well balanced at baseline
ORR was determined by RECIST v1.1, and confirmed responses included at least two scans. Tempest retains all product rights to amezalpat.

Conference Call & Webcast Information

Tempest will host a webcast conference call today, June 20, 2024 at 8:30am ET.

To join the conference call via phone and participate in the live Q&A session, please pre-register online here to receive a telephone number and unique passcode required to enter the call. The live webcast and audio archive of the presentation may be accessed on the investor section of the Tempest website at View Source The webcast will be available for replay for 30 days.

About the Randomized Clinical Trial

The Phase 1b/2 global randomized HCC study is part of Roche’s Morpheus program and evaluates amezalpat in combination with atezolizumab and bevacizumab versus atezolizumab and bevacizumab, the standard of care, in patients with unresectable or metastatic HCC not previously treated with systemic therapy. The trial randomized 70 patients to receive either amezalpat with atezolizumab + bevacizumab or a contemporaneous control arm of atezolizumab + bevacizumab alone at approximately 25 sites worldwide, including in the United States, Europe, and Asia. The primary efficacy endpoint was confirmed objective response rate, and key secondary endpoints including PFS and OS. Under the terms of the clinical collaboration agreement, Roche is managing the study operations for this global, multicenter trial and Tempest retains all product rights.

About Amezalpat (TPST-1120)

Amezalpat is an oral, small molecule, selective PPAR⍺ antagonist. Tempest’s data suggest that amezalpat treats cancer by targeting tumor cells directly and by modulating immune suppressive cells and angiogenesis in the tumor microenvironment. In an ongoing global randomized phase 1b/2 study of amezalpat in combination with atezolizumab and bevacizumab in first-line patients with advanced HCC, the amezalpat arm showed clinical superiority across multiple study endpoints when compared to atezolizumab and bevacizumab alone, the standard of care. These randomized data were supported by positive results observed in the Phase 1 clinical trial in patients with heavily pretreated advanced solid tumors.

About Hepatocellular Carcinoma

HCC is an aggressive cancer with rising mortality and is projected to become the third leading cause of cancer death by 2030.3 Every year, more than 900,000 people worldwide are diagnosed with HCC.4 Incidence and mortality are highest in East Asia and are increasing in parts of Europe and the US.5 In the US, HCC represents the fastest-rising cause of cancer-related death.3

Nine out of ten cases of HCC are caused by chronic liver disease, which includes chronic hepatitis B and C infection, non-alcoholic fatty liver disease (NAFLD), non-alcoholic steatohepatitis (NASH), alcohol-related liver disease (ALD) and cirrhosis resulting from these conditions.6

Even if diagnosed in the early stage, an estimated 70-80% of people with early-stage HCC experience disease recurrence following surgery.7 Early recurrence is associated with poorer prognosis and shorter survival.5,8 Tumor size, number of tumors, and portal vein invasion are associated with an increased risk of recurrence.