On September 19, 2020 Novartis reported FDA approval for its breast cancer drug Piqray in HR-positive/HER2-negative patients with PIK3CA mutations last year, early survival data was impressive: Combining the drug with AstraZeneca’s Faslodex nearly doubled the time to disease progression or death to 11 months over Faslodex alone (Press release, Novartis, SEP 19, 2020, View Source [SID1234565372]).

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Now the final survival data from that trial, called Solar-1, is out. And while the overall survival rate wasn’t quite as dramatic, Novartis sees reason to celebrate—particularly for one subset of very sick patients.

The Piqray-Faslodex combo boosted overall survival for patients in the trial by eight months over Faslodex alone—too small a difference to reach statistical significance, Novartis announced during the virtual meeting of the European Society of Medical Oncology (ESMO) (Free ESMO Whitepaper).

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But among patients with lung or liver metastases, overall survival improved by more than 14 months, to a median of 37.2 months.

"That was really impressive and very clinically meaningful," Jeff Legos, senior vice president and global program head of Novartis Oncology, said in an interview. "Patients with advanced breast cancer who have had their disease metastasize to the lung or liver generally do much worse on available therapy. I think this further reiterates the benefit [Piqray] can provide."

The data showed that overall, patients taking Piqray plus Faslodex had a 14% lower risk of disease progression or death—a number that might not look that impressive on the surface, Legos acknowledged.

"But what’s also important for patients is their median overall survival," he said. "Here we show that patients are living on average eight months longer, which gives them that much more time to spend with family and friends and celebrate milestones."

RELATED: Novartis grabs blockbuster cancer nod for Piqray on double good news day

Novartis hopes the new data will help elucidate some key points of the marketing pitch for Piqray. One of those is quality of life. Patients in the trial taking the Piqray-Faslodex combination were able to delay chemotherapy by a median time of 23.3 months, versus 14.8 months for the patients taking Faslodex alone. Although the combination did produce some side effects—hyperglycemia was the most common complaint—toxicity overall was lower than it typically is for patients on chemotherapy, Legos said. "So they had eight-and-a-half months of a higher quality of life," he said.

Novartis was also able to parse the data from the trial using a biomarker called circulating tumor DNA. When a patient’s tumors are shedding so much of their genetic material that the cancer can be detected in blood, that’s a sign of aggressive disease and a poor prognosis, Legos said.

In patients who had detectable circulating tumor DNA at the start of the trial, Piqray plus Faslodex reduced the risk of death by 26%. "It’s just more evidence that there are patients who definitely are underserved with existing therapy and that [Piqray] does demonstrate a survival advantage," Legos said.

RELATED: Novartis, after 5 blockbuster nods in 2019, hopes for 25 more in the coming years

Novartis has often cited Piqray as a likely blockbuster. There are other PIK3 inhibitors on the market, including Verastem Oncology’s Copiktra and Gilead’s Zydelig, but Piqray was the first to gain a breast cancer nod.

Novartis has an ambitious development plan for the drug going forward. It’s preparing to file for approval in patients with a rare disorder called PIK3CA overgrowth syndrome. Novartis is also hoping to move the drug into triple-negative and HER2-positive breast cancer, as well as ovarian and head and neck cancer.

Piqray brought in sales of $79 million in the second quarter of this year, up from $74 million in the previous quarter. The European Commission approved Piqray in July, and analysts are expecting total sales to surpass $700 million in 2024, according to EvaluatePharma. Moody’s predicts sales will peak at $1 billion a year.

Piqray’s first FDA nod came courtesy of the agency’s Real-Time Oncology Review program—a boon for Novartis, Legos said. "The overall submission and review cycle was incredibly fast," he said. "As soon as data became available we were able to share it with the FDA and engage with them. It was a collaborative relationship, with the patient in mind."

On September 18, 2020, Vertex Pharmaceuticals Incorporated, a Massachusetts corporation (the "Company" or "we") reported that entered into a Credit Agreement (the "Credit Agreement"), with Vertex Pharmaceuticals (Europe) Limited, a private limited company incorporated in England and Wales and a wholly-owned subsidiary of the Company, as a co-borrower, Vertex Pharmaceuticals (Ireland) Limited, a private company limited by shares incorporated in Ireland and a wholly-owned subsidiary of the Company, as a co-borrower, certain other wholly-owned subsidiaries of the Company as subsidiary guarantors, Bank of America, N.A and the other lenders referred to therein, which is summarized below (Filing, 8-K, Vertex Pharmaceuticals, SEP 18, 2020, View Source [SID1234565429]). The Credit Agreement provides for a $2.0 billion senior unsecured revolving facility. The Credit Agreement also provides that, subject to satisfaction of certain conditions, we may request that the borrowing capacity under the Credit Agreement be increased by an additional $500 million. The Credit Agreement matures on September 18, 2022.

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Proceeds of borrowings under the Credit Agreement will be used for general corporate purposes. Loans will bear interest, at our option, at either a base rate or a Eurocurrency rate, in each case plus an applicable margin. Under the Credit Agreement, the applicable margin on base rate loans ranges from 0.500% to 0.875% and the applicable margin on Eurocurrency loans ranges from 1.500% to 1.875%, in each case, based on our consolidated leverage ratio (the ratio of our total consolidated funded indebtedness to our consolidated EBITDA for the most recently completed four fiscal quarter period). Loans under the Credit Agreement may be prepaid at par and commitments under the Credit Agreement may be reduced at any time, in whole or in part, without premium or penalty (except for LIBOR breakage costs).

Loans will be guaranteed by certain of our existing and future domestic subsidiaries, subject to certain exceptions.

The Credit Agreement contains customary representations and warranties and affirmative and negative covenants, including financial covenants to maintain (x) subject to certain limited exceptions, a consolidated leverage ratio of 3.50 to 1.00, subject to an increase to 4.00 to 1.00 following a material acquisition and (y) a consolidated interest coverage ratio of 2.50 to 1.00, in each case to be measured on a quarterly basis. The Credit Agreement also contains customary events of default. In the case of a continuing event of default, the administrative agent would be entitled to exercise various remedies, including the acceleration of amounts due under any outstanding loan.

On September 18, 2020 Baudax Bio, Inc. (NASDAQ:BXRX), a pharmaceutical company focused on therapeutics for acute care settings, reported Gerri Henwood, the Company’s President and Chief Executive Officer, will present at the Oppenheimer Fall Healthcare Life Sciences & Medtech Summit on Tuesday, September 22, 2020 at 3:20 p.m. ET (Press release, Baudax Bio, SEP 18, 2020, View Source [SID1234572274]).

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A live webcast of the presentation will be available on the "Presentations" page within the Investors section of the Baudax Bio website at View Source A replay will be available on the Baudax Bio website for a period of 30 days following the event.

On September 18, 2020 Oncologie, Inc., a precision medicine company using an innovative RNA-based biomarker platform to predict patient responses for potentially first-in-class targeted oncology therapies, announced new data and analyses from its lead clinical programs, bavituximab and navicixizumab (Press release, OncXerna Therapeutics, SEP 18, 2020, View Source [SID1234572120]). On the basis of these positive data, the company also announced its rebranding to OncXerna Therapeutics, Inc., a change that reinforces the company’s focus on using its RNA-based approach to guide novel, targeted treatments to specific people with cancer.

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"With a deep understanding of the tumor microenvironment biology at the RNA-level through our novel biomarker panel, we aim to dramatically improve clinical outcomes by matching patients to therapies with a mechanism of action that targets that specific biology," said Laura Benjamin, Ph.D., President and Chief Executive Officer at OncXerna Therapeutics. "Today’s results demonstrate a clear ability of our first panel to distinguish responders versus non-responders in our bavituximab and navicixizumab programs, and we are excited to deploy this approach in the next prospectively-defined trials that could support registration."

Interim results from Phase 2 (ONCG100) trial of bavituximab and KEYTRUDA

Trial design and background:

The Phase 2 (ONCG100) trial is a multicenter, open-label, single-arm global trial designed to assess the safety, tolerability, and antitumor activity of the investigational agent bavituximab, a chimeric monoclonal antibody that targets phosphatidylserine, in combination with KEYTRUDA, Merck’s anti-PD-1 therapy, in patients with advanced gastric and gastroesophageal cancer who have progressed on or after at least one prior standard therapy. Bavituximab previously demonstrated clinical activity in a post-hoc subset analysis in patients with non-small cell lung cancer (NSCLC) who were given a PD-1 inhibitor following bavituximab treatment, suggesting that a treatment combination of bavituximab and a PD-1 inhibitor could generate similar activity in a prospective clinical trial. In addition to measuring safety and antitumor activity in this trial, OncXerna is deploying its proprietary RNA biomarker platform (TME Panel-1) to identify patients based on their response to treatment and the dominant biology of their tumor microenvironment with the potential to dramatically improve outcomes in the next, prospectively designed trial.

Approximately 80 patients in the U.S., United Kingdom, South Korea and Taiwan are planned for enrollment in two separate groups of patients: Checkpoint inhibitor-naïve and checkpoint inhibitor-relapsed. The trial is continuing to enroll both groups with planned updates from all patients during the first half of 2021.

Interim results:

Interim results provided today, from the first 36 patients enrolled and with a post-baseline scan in the checkpoint inhibitor-naïve group, include the following:

Patient demographics: Mean age of 61 years (55% non-Asian/45% Asian) with approximately 70% and 30% of patients receiving their second-line and third-line of treatment, respectively. In terms of mutation status, known MSI-H patients were excluded (MSS included) and enrollment was PD-L1 agnostic, with 25% of patients PD-L1 negative.

Safety and tolerability: Bavituximab and KEYTRUDA treatments were well tolerated with 90% of treatment emergent adverse events considered Grade 1-3. Fourteen patients had at least one serious adverse event (SAE). All SAEs were reported as not related to bavituximab and KEYTRUDA except for pneumonitis in one patient that resolved and was considered related to the combination of bavituximab and KEYTRUDA.

Efficacy measures: Bavituximab and KEYTRUDA achieved an overall response rate (ORR) of 19% (7/36) in the evaluable population and 43% (3/7) in exploratory analyses of patients with a low neutrophil-to-lymphocyte (NLR) ratio (<4) and identified as biomarker positive using OncXerna’s TME Panel-1. In a clinical trial of KEYTRUDA that led to an accelerated approval in the third-line setting, the ORR was 13% with a 16% ORR in PD-L1 positive patients and a 9% ORR in MSS patients. Treatment with bavituximab and KEYTRUDA also generated a complete response in 20% (2/10) of patients who were PD-L1, CPS<1; a patient population where KEYTRUDA historically generates very low complete responses. In terms of response duration, all confirmed responders remain in the trial, with the longest responder approaching one-year of duration of response.

Next steps:

These data are being presented at the European Society for Molecular Oncology (ESMO) (Free ESMO Whitepaper) Virtual Congress 2020 taking place September 19-21, 2020.

OncXerna plans to conduct additional clinical trials designed to prospectively enrich for TME Panel-1 biomarker positive patients, as well as to explore additional solid tumor types.

OncXerna biomarker analysis from Phase 1b trial evaluating navicixizumab in ovarian cancer

Previously announced data and background:

OncXerna’s navicixizumab is a bispecific antibody designed to inhibit both Delta-like ligand 4 (DLL4) in the Notch cancer stem cell pathway as well as vascular endothelial growth factor (VEGF). Interim data from a Phase 1b dose escalation and expansion trial of navicixizumab plus paclitaxel in 44 platinum-resistant ovarian cancer patients who had failed more than two prior therapies and/or received prior Avastin (bevacizumab) therapy were presented virtually at the 2020 Society of Gynecologic Oncology (SGO) Annual Meeting in May 2020. Treatment with navicixizumab and paclitaxel demonstrated an ORR of 43% in all patients, and 64% and 33% in bevacizumab-naïve, and bevacizumab pre-treated patients, respectively. Treatment-related adverse events were manageable and included hypertension (58%), headache (29%), fatigue (26%) and pulmonary hypertension (18%).

Updated biomarker analyses and results:

Using its RNA-based biomarker TME Panel-1, OncXerna recently analyzed patient tissue samples obtained from 28 of the 44 patients from the Phase 1b trial. Results from this analysis revealed the following:

Clinically meaningful improvement in median progression-free survival (PFS) of 9.2 months for TME Panel-1 biomarker positive patients (n=10) compared with a median PFS of 3.5 months for biomarker negative patients (n=13), hazard ratio (0.276). The confirmed ORR for TME Panel-1 biomarker positive patients (n=10) was 70% compared to 31% ORR for TME Panel-1 biomarker negative patients (n=13).

Patients in the TME Panel-1 biomarker positive panel achieved a 70% ORR, and excluded all who had progressive disease, compared with a 31% ORR for patients in the TME Panel-1 biomarker negative panel. In Avastin-experienced patients, achievement of a 71% ORR and 100% disease control rate (DCR) in TME Panel-1 biomarker positive patients (n=7) compared with 25% ORR and 50% DCR achieved in biomarker negative patients (n=8) (Table 1).

Table 1: TME Panel-1 Results from Phase 1b trial of Navicixizumab plus placlitaxel in patients with late-stage ovarian cancer

Avastin Naïve and Experienced
Confirmed Clinical Response (%) Biomarker positive (n=10) Biomarker negative (n=13)
ORR 70% 31%
DCR 100% 69%
CR 0% 8%
PR 70% 23%
SD 30% 39%
PD 0% 31%

Avastin Experienced
Confirmed Clinical Response (%) Biomarker positive (n=7) Biomarker negative (n=8)
ORR 71% 25%
DCR 100% 50%
PR 71% 25%
SD 29% 25%
PD 0% 50%
"Biomarker" refers to TME Panel-1

Next steps:

As a result of these analyses, OncXerna plans to conduct additional clinical trials designed to prospectively enrich for TME Panel-1 biomarker positive patients with ovarian cancer who are platinum-resistant and Avastin-experienced to support registration, as well as to explore additional solid tumor types.

About Bavituximab

Bavituximab is an investigational antibody that reverses immune suppression by inhibiting phosphatidylserine (PS) signaling and is currently in Phase 2 clinical trials to treat a specific subset of patients with advanced gastric cancer to improve their response to anti-PD-1 treatment. The mechanism of action of bavituximab is to block tumor immune suppression signaling from PS to multiple immune cell receptor families (e.g., TIMs and TAMs). The dominant biology targeted by bavituximab may be relevant for patients with many types of solid tumors whose immune systems are too suppressed to benefit from currently available immune oncology therapies. Our clinical trials currently combine bavituximab with KEYTRUDA to test the hypothesis that relieving immunosuppression can enhance responses to checkpoint inhibitors. Bavituximab is an investigational agent that has not been licensed or approved anywhere globally, and it has not been demonstrated to be safe or effective for any use, including for the treatment of advanced gastric cancer.

About Navicixizumab

Navicixizumab is an investigational anti-DLL4/VEGF bispecific antibody that has demonstrated antitumor activity in patients who have progressed on Avastin (bevacizumab) in a Phase 1a/b clinical trial. The U.S. Food and Drug Administration granted Fast Track designation to navicixizumab for the treatment of high-grade ovarian, primary peritoneal or fallopian tube cancer in patients who have received at least three prior therapies and/or prior treatment with Avastin. OncXerna is targeting patients whose dominant tumor biology is driven by angiogenesis with a focus beyond VEGF to include broader anti-angiogenic pathways. Navicixizumab is an investigational agent that has not been licensed or approved anywhere globally, and it has not been demonstrated to be safe or effective for any use, including for the treatment of advanced ovarian cancer.

On September 18, 2020 LamKap Bio Group and Lonza reported that it Collaborate to Manufacture Bispecific Antibodies for Cancer Treatment (Press release, LamKap Bio Group, SEP 18, 2020, View Source [SID1234565465]).

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LamKap Bio Group develops fully human bispecific κλ antibodies targeting malignant cells in solid cancers
Lonza to provide cell line development, drug substance and drug product services and cGMP manufacturing for two programs
Lonza’s LightPath cell line development program was optimized to ensure improved process yield and throughput
Quote from Shiva Khalafpour, VP, Head of Commercial Mammalian and Microbial Development and Manufacturing, Lonza:
"Lonza’s subject matter experts enjoyed working with LamKap’s technical team to identify specific molecule needs and design a tailored work package suitable to achieve their goals. This included a customized cell line development program based on Lonza’s GS Gene Expression System and LightPath CLC methodology and optimization of the customer downstream purification approach in order to facilitate manufacturing. "

Quote from Klaus Strein, Chairman of the LamKap Bio Group:
The LamKap Bio Group together with its strategic partner Light Chain Biosciences/NovImmune have considerable experience in the R&D of T-cell bispecific antibodies and tumor targeted anti-CD47 bispecific antibodies. Technical development and GMP manufacturing of both types of bispecific antibodies were already successfully performed by Lonza in the recent years. The new collaboration with Lonza is an important pillar in the development of two Clinical Leads.

Basel and Pfäffikon, Switzerland, 17 September 2020 – LamKap Bio Group, a biotechnology group focused on the research, development and manufacturing of tumor-targeted antibody-based therapies, and Lonza announced today that the companies have a development and manufacturing collaboration in place to support their current and future product pipeline. Lonza will provide cell line and process development, drug substance manufacturing and drug product services of LamKap’s two fully human bispecific antibody products, NILK-2301 and NILK-2401.

LamKap’s therapeutic bispecific antibodies are engineered to bind to two different antigens simultaneously. The two antigens can be either located on one cell type, e.g., a tumor cell, or two different cell types, e.g., on a tumor cell and an immune effector cell. Both NILK-2301 and NILK-2401 can be used as monotherapy and/or in combination. NILK-2301 binds to a tumor-associated antigen (TAA) and CD3 on T-cells, re-targeting T cells to kill tumor cells. NILK-2401 is also targeted to a TAA and in addition to CD47 on tumor cells, thus causing increased antibody-dependent cellular phagocytosis (ADCP) and antibody-dependent cell-mediated cytotoxicity (ADCC).

Using LamKap’s fully human bispecific Kappa Lambda antibodies (κλ), consisting of two identical heavy chains, a kappa (κ) and a lambda (λ) light chain and an IgG1 Fc, helps the human body to fight cancer. This structure is nearly identical to the structure of a standard IgG antibody and lowers the risk of inducing immunogenicity while minimizing the loss of exposure. Antibodies in this format are ideally suited for therapeutic application in both benign and malignant diseases. The κλ format facilitates production/purification.

Building upon Lonza’s previous experience with the κλ body program, as well as several other bispecific antibody platforms and the extensive upstream and downstream processing know-how, Lonza will carry out cell line construction and cGMP drug substance manufacturing at its Slough, UK and Hayward, US sites. The LightPath cell line development program will start in Q3 2020, providing LamKap with material to enter phase I clinical studies. The early-stage drug product formulation and stability studies will be performed at Lonza’s Drug Product Services facility in Basel, Switzerland.

The scope of the package was tailored to ensure the program could meet the requirements of large-scale manufacturing of unique κλ body products.