Circle Pharma Announces Presentation at the American Associationfor Cancer Research 2022 Annual Meeting

On April 11, 2022 Circle Pharma, a pre-clinical stage company focused ondeveloping macrocycle therapeutics against targets previously considered to be undruggable, reported that it will present a poster at theAmerican Association for Cancer Research (AACR) (Free AACR Whitepaper) Annual Meeting being held April 8-13, in New Orleans, Louisiana (Press release, Circle Pharma, APR 11, 2022, View Source [SID1234611947]).

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The Company’s presentation will provide details of its progress towards structure-guided macrocycles that inhibit theprotein-protein interaction between the cyclin A:CDK2 complex and key substrates that are phosphorylated by thiscomplex. Inhibition of Cyclin A substrate binding has been postulated to be synthetic lethal in Rb mutated cancers. Thedata presented include evidence that macrocycle inhibitors of cyclin A induce G/M arrest and apoptosis in small cell lungcancer (SCLC) cell lines and have anti-tumor efficacy in SCLC xenograft animal models. Circle plans to advance its cyclinA inhibitor program to the clinic for testing in a range of cancer types, including SCLC where Rb mutations are highlyprevalent.

The presentation will be made as part of the Mechanisms of Drug Action / Experimental and Molecular Therapeuticssession at the AACR (Free AACR Whitepaper) meeting, Abstract No. 5379.

Novo Nordisk A/S – Share repurchase programme

On April 11, 2022 Novo Nordisk reported that initiated a share repurchase programme in accordance with Article 5 of Regulation No 596/2014 of the European Parliament and Council of 16 April 2014 (MAR) and the Commission Delegated Regulation (EU) 2016/1052 of 8 March 2016 (the "Safe Harbour Rules") (Press release, Novo Nordisk, APR 11, 2022, View Source [SID1234611939]). This programme is part of the overall share repurchase programme of up to DKK 22 billion to be executed during a 12-month period beginning 2 February 2022.

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Under the programme initiated 2 February 2022, Novo Nordisk will repurchase B shares for an amount up to DKK 4.4 billion in the period from 2 February 2022 to 2 May 2022.

Since the announcement 04 April 2022, the following transactions have been made:

The details for each transaction made under the share repurchase programme are published on novonordisk.com.

With the transactions stated above, Novo Nordisk owns a total of 36,748,418 B shares of DKK 0.20 as treasury shares, corresponding to 1.6% of the share capital. The total amount of A and B shares in the company is 2,310,000,000 including treasury shares.

Novo Nordisk expects to repurchase B shares for an amount up to DKK 22 billion during a 12- month period beginning 2 February 2022. As of 08 April 2022, Novo Nordisk has since 2 February 2022 repurchased a total of 4,962,250 B shares at an average share price of DKK 702.62 per B share equal to a transaction value of DKK 3,486,567,177.

Artiva Biotherapeutics Announces Agreement with Merck to Evaluate Combinations of NK Cells with Tri-Specific NK-Cell Engagers

On April 11, 2022 Artiva Biotherapeutics, Inc., an oncology company whose mission is to deliver highly effective, off-the-shelf, allogeneic natural killer (NK) cell therapies to treat cancer, reported that it has entered into an agreement with Merck, known as MSD outside the United States and Canada (Press release, Artiva Biotherapeutics, APR 11, 2022, View Source [SID1234611931]). Under the agreement, Merck will evaluate the therapeutic potential of combinations of tri-specific NK-cell engager candidates with clinical grade AB-101 NK cells generated from Artiva’s AlloNKTM platform.

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"We have established a fantastic working relationship with Merck over the last year and we are happy to expand our collaboration to include the combination of our AlloNK platform NK cells with tri-specific NK-cell engager candidates," said Peter Flynn, Ph.D., cofounder and Chief Operating Officer of Artiva.

Artiva and Merck originally entered into a collaboration and exclusive license agreement in January 2021 for the discovery, development, manufacture, and commercialization of CAR-NK cells that target certain solid tumor-associated antigens. The collaboration leverages Artiva’s off-the-shelf allogeneic NK cell manufacturing platform, along with its proprietary CAR-NK technology, and includes two CAR-NK programs with an option for a third, none of which are in Artiva’s current or planned pipeline. Artiva’s platform supports large-scale production and cryopreservation of off-the-shelf allogeneic NK and CAR-NK therapeutics.

Spectrum Pharmaceuticals Announces FDA Acceptance of BLA Resubmission for Eflapegrastim

On April 11, 2022 Spectrum Pharmaceuticals (NasdaqGS: SPPI), a biopharmaceutical company focused on novel and targeted oncology therapies, reported that the resubmitted Biologics License Application (BLA) for eflapegrastim has been accepted for filing (Press release, Spectrum Pharmaceuticals, APR 11, 2022, View Source [SID1234611930]). The U.S. Food and Drug Administration (FDA) has set a Prescription Drug User Fee Act (PDUFA) goal date of September 9, 2022. Spectrum is seeking an indication to decrease the incidence of infection, as manifested by febrile neutropenia, in patients with non-myeloid malignancies receiving myelosuppressive anti-cancer drugs associated with clinically significant incidence of febrile neutropenia.

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"The acceptance of the BLA resubmission is an important incremental step forward in the regulatory review process," said Tom Riga, President and Chief Executive Officer of Spectrum Pharmaceuticals. "We are actively working with the agency as they conduct their review and look forward to the potential approval of this novel product."

About Eflapegrastim

Eflapegrastim is a novel, long-acting granulocyte colony-stimulating factor (G-CSF), Spectrum is seeking an indication to decrease the incidence of infection, as manifested by febrile neutropenia, in patients with non-myeloid malignancies receiving myelosuppressive anti-cancer drugs associated with clinically significant incidence of febrile neutropenia. The BLA for eflapegrastim is supported by data from two identically designed Phase 3 clinical trials, ADVANCE and RECOVER, which evaluated the safety and efficacy of eflapegrastim in 643 early-stage breast cancer patients for the management of neutropenia due to myelosuppressive chemotherapy. In both studies, eflapegrastim demonstrated the pre-specified hypothesis of non-inferiority (NI) in duration of severe neutropenia (DSN) and a similar safety profile to pegfilgrastim. Eflapegrastim also demonstrated non-inferiority to pegfilgrastim in the DSN across all 4 cycles (all NI p<0.0001) in both trials.

Issues Surrounding the Development of New Chemotherapy Drugs

On April 11, 2022 Simbec-Orion reported that research is one of the most commonly investigated areas of clinical study. Oncology research has accelerated the development of advanced chemotherapy drugs, which are now generally less toxic as a result (Press release, Simbec-Orion, APR 11, 2022, View Source [SID1234611929]).

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Conventional chemotherapy drugs once primarily used cytotoxic compounds to target cancerous cells, which would also damage surrounding cells as a result.

Now, with an improved understanding of the underlying processes involved with different forms of tumorigenesis (tumour development), drug development research has resulted in non-toxic chemotherapy drugs that only interfere with specific cancer cells.

This has resulted in significant improvements in cancer patient care, with chemotherapy treatment options that have significantly less negative impact on the patient’s health and wellbeing.

Whilst there have been significant advancements in chemotherapy drug development, there is still further progress to be made. There are several issues surrounding the development of chemotherapy drugs that require careful attention from investigators and sponsors.

These issues are present across the full scope of chemotherapy drug development. From initial understandings of cancer, to the clinical pharmacology, patient care and ethical processes.

Understanding cancer as many diseases
As cancer research has progressed, our understanding of cancer as a disease has improved significantly. Insights into the processes involved in tumour development have provided researchers and medical professionals with a deeper understanding of the molecular and genomic mechanisms involved in tumorigenesis.

Such insights have proven that there are further variations of cancer types than were initially understood. For instance, lung cancer was once recognised in two different forms: non-small cell and small cell lung cancer.

Now, research has shown that there are a variety of lung cancer types, developed through different molecular and genomic processes.

These can include ALK-positive, EGFR-positive, ROS1-positive and other characteristic formations of lung cancer, all of which involve different genomic methods of tumorigenesis:

ALK-positive lung cancer is developed through the rearrangement of the ALK (anaplastic lymphoma kinase) gene and EML4 gene.
EGFR-postitive lung cancer is developed through the mutation of EGFR (epidermal growth factor receptor) proteins in cells, that when grown too much can cause cancer.
ROS1-positive lung cancer is developed through rearrangements in the ROS1 gene, whereby the gene fuses with nearby cells.
Research has shown that not all subtypes of cancer respond to the same chemotherapy treatment in the same way, making it necessary to develop targeted chemotherapy drugs. This is especially important since generalised chemotherapy treatments are significantly more damaging to patients than targeted treatments.

Developing targeted therapies
Since cancer is not simply one form of disease, patients cannot be effectively treated by generalised chemotherapy drugs. Instead, targeted chemotherapy drugs are needed.

Targeted therapies are drugs that treat the specific subtype of cancer in a specialised manner, targeting the specific molecular profiles of cells rather than damaging cells in a generalised manner.

For example, chemotherapy drugs for ALK-positive lung cancer use a different molecular compound to EGFR-positive lung cancer chemotherapy drugs.

The development of targeted chemotherapy drugs requires an individualised approach, whereby patients with specific molecular profiles are studied in order to develop specialised chemotherapy drugs for that particular subtype of cancer.

An individualised approach is essential for developing more effective targeted chemotherapy drugs, although this does come with several complexities and challenges, with many implications on clinical trial design and ethical procedures.

Limited sample groups
With many specific molecular profiles to study, this can make it difficult to find a reliable patient sample group with matching molecular profiles for clinical trials. And without successful clinical trials, chemotherapy drugs cannot proceed to market.

For instance, ROS1-positive molecular profiles occur in just 1-2% of non-small cell lung cancer (NSCLC) formations. This can present challenges with recruitment for clinical trials, since rarer molecular profiles will only be present across smaller sample groups.

For even rarer targets, there may simply not be enough patients to substantially test new development chemotherapy drugs, making it particularly difficult to enrol and retain patients for clinical trial research.

The issue of limited sample groups in chemotherapy drug development means that regulatory authorities, such as the FDA, have to approve the drug based on a limited number of trial participants.

To help overcome this issue, clinical research organisations such as Simbec-Orion take a tailored approach to clinical trial design, applying effective patient engagement and recruitment strategies to ensure the trial proceeds with a reliable sample size.

Toxicity issues in cancer drug development
Cancer chemotherapy drugs were considered cytotoxic in the earliest years of development, having potentially life-threatening side effects. Past chemotherapy drugs originally damaged or killed cancer cells in a generalised manner, having negative effects on surrounding healthy cells.

Thanks to advanced cancer drug development research, treatments are now substantially less toxic and treat the cancer in a targeted manner.

While newer chemotherapy drugs have proven to be more efficacious and much less toxic than conventional drugs, toxicity can still not be fully determined until clinical trial stages. This presents the issue of safety and toxicity risks, since this often involves testing unproven therapies on patients.

At the beginning of the clinical pharmacology process, chemotherapy drugs are tested using cell culture and animal model systems. Although, these initial testing methods are not able to provide a reliable prediction of the drug’s full toxicity.

In order to determine the chemotherapy drug’s full safety profile, it must be tested in human volunteers and patients in clinical trial research. Phase 1 will generally limit the number of cancer patients participating in the trial in order to test the safety in healthy volunteers first, and then administered to patient groups in later phases using dose escalation techniques.

The full safety profile and toxicity of newly developed chemotherapy drugs cannot be reliably determined until tested in cancer patient groups, meaning patients may be exposed to potentially toxic treatments.

Ethical issues in chemotherapy drug development
There are several ethical issues to consider surrounding the development of chemotherapy drugs. Many of these ethical concerns regard how the clinical trial process is managed in oncology research.

Risk to benefit ratio
Throughout the chemotherapy clinical trial process, the risk to benefit ratio is always an important consideration for researchers. Development chemotherapy drugs are unproven interventions, meaning it is vital that the risks and impacts on patient lives are well-understood by investigators.

Alongside understanding the potential risks, it is important to weigh up the prospective benefits. The intervention may benefit patients directly, or benefit scientific advancement generally. Although in either case, investigators must have a sufficient understanding that the drug is beneficial in order to outweigh the potential risks posed to patients.

Chemotherapy drug trials can also involve taxing procedures on patients, including biopsies, imaging and clinic visits. These procedures can be onerous and potentially distressing for patients, especially for those who are particularly unwell.

The chemotherapy drug may also prove to be ineffective, or even toxic during later stages of the trial, meaning already potentially vulnerable patients may have undergone burdensome processes for little direct benefit.

The risk to benefit ratio is a challenging ethical issue for researchers to weigh up. Because of this, it is important that patients fully understand the risks and benefits when consenting to taking part in chemotherapy drug development research.

Patient consent, communication and care
Not only should the risks and benefits be well-understood by researchers, they must also be well-understood by volunteers and patients. This raises the ethical question of whether the patient fully understands the risks and benefits of enrolling in chemotherapy drug research.

It is vital to ensure that the patient has a good understanding of the risks and benefits of taking part. Patients typically receive an informed consent document that details the potential risks, procedures and benefits involved.

This is not always the most reliable method of ensuring the patient has fully understood what’s involved. A more effective way of ensuring fully informed consent and communicating the risks and benefits is for patients to participate in a discussion with their physician. This should be encouraged across several discussions, whereby patients have time to consider the pros and cons between conversations.

This way, the patient is able to ask questions regarding any areas that are unclear, and the physician should encourage an open discussion to ensure the expectations are clear.

Patient sensitivity
Cancer can be a highly debilitating and life-threatening disease. Patients with advanced cancer, or patients who have sadly received a terminal diagnosis may be more likely to see chemotherapy drug trials as the only remaining treatment option.

This highlights the issue of patient sensitivity in chemotherapy drug development. Advanced or terminal cancer patients may feel desperate to explore new treatment options, and willing to take substantial levels of risk with unknown prospects of the benefits.

It can feel especially upsetting for patients in cases where chemotherapy drugs have proven unsuccessful or unsafe in clinical trials, making effective communication and engagement from the offset extremely important.

This issue surrounding chemotherapy drug development becomes especially complex in cases where the patient does not meet the eligibility criteria to participate in trials, although the physician may believe that the patient may benefit by taking part.

As a result of unguaranteed benefits and the chance that patients may not be eligible to participate in chemotherapy drug development trials, it is important for physicians to explain the alternative options to taking part. These may include standard therapies, or palliative care.

Addressing chemotherapy drug development challenges in clinical trial design
There are several challenges in the development of chemotherapy drugs that investigators and research organisations have to consider. From individualised approaches to targeted chemotherapy drug development, toxicity issues, sample sizing and ethical concerns, issues arise across the full scope of the drug development process.

This makes it important for research organisations to deliver a suitable clinical trial design that overcomes these challenges. There are several ways to do this, and the design will depend on the aims and type of chemotherapy research.

At Simbec-Orion, we take a tailored approach to clinical trial management, with therapeutic expertise in oncology and rare disease. Our trial designs have carefully overcome challenges using effective patient engagement strategies and centralised project management to ensure that the research meets the needs of sponsors and patients.