On April 13, 2022 GlaxoSmithKline plc (LSE/NYSE: GSK) and Sierra Oncology, Inc (Nasdaq: SRRA) reported that the companies have entered into an agreement under which GSK will acquire Sierra Oncology, a California-based, late-stage biopharmaceutical company focused on targeted therapies for the treatment of rare forms of cancer, for $55 per share of common stock in cash representing an approximate total equity value of $1.9 billion (£1.5 billion) (Press release, GlaxoSmithKline, APR 13, 2022, View Source [SID1234612115]).

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Myelofibrosis is a fatal cancer of the bone marrow impacting the normal production of blood cells. Anaemia represents a high unmet medical need in patients with myelofibrosis. At diagnosis, approximately 40% of patients are already anaemic, and it is estimated that nearly all patients will eventually develop anaemia.[1],[2] Patients treated with the most commonly used JAK inhibitor will often require transfusions, and more than 30% will discontinue treatment due to anaemia.[3] Anaemia and transfusion dependence are strongly correlated with poor prognosis and decreased overall survival.[4]

Momelotinib has a differentiated mode of action with inhibitory activity along key signalling pathways. This activity may lead to beneficial treatment effects on anaemia and reduce the need for transfusions while also treating symptoms. In January 2022, Sierra Oncology announced positive topline results from the MOMENTUM phase III trial. The study met all its primary and key secondary endpoints, demonstrating that momelotinib achieved a statistically significant and clinically meaningful benefit on symptoms, splenic response, and anaemia.

Luke Miels, Chief Commercial Officer, GSK said: "Sierra Oncology complements our commercial and medical expertise in haematology. Momelotinib offers a differentiated treatment option that could address the significant unmet medical needs of myelofibrosis patients with anaemia, the major reason patients discontinue treatment. With this proposed acquisition, we have the opportunity to potentially bring meaningful new benefits to patients and further strengthen our portfolio of specialty medicines."

Stephen Dilly, MBBS, PhD, President and Chief Executive Officer, Sierra Oncology said: "Uniting with GSK creates the best opportunity for Sierra Oncology to realise its mission of delivering targeted therapies that treat rare forms of cancer while also delivering compelling and certain value for our stockholders. Now we have a partner with a global infrastructure and oncology expertise that enables us to deliver momelotinib to patients as quickly as possible and on a global scale."

Momelotinib complements GSK’s Blenrep (belantamab mafodotin), building on GSK’s commercial and medical expertise in haematology. The proposed acquisition aligns with GSK’s strategy of building a strong portfolio of new specialty medicines and vaccines. If the transaction is completed and momelotinib is approved by regulatory authorities, GSK expects momelotinib will contribute to GSK’s growing specialty medicines business, with sales expected to begin in 2023, with significant growth potential and a positive benefit to the Group’s adjusted operating margin in the medium term.

Financial considerations

Under the terms of the agreement, the acquisition will be effected through a one-step merger in which the shares of Sierra Oncology outstanding will be cancelled and converted into the right to receive $55 per share in cash. Subject to customary conditions, including the approval of the merger by at least a majority of the issued and outstanding shares of Sierra Oncology, and the expiration or earlier termination of the waiting period under the Hart-Scott-Rodino Antitrust Improvements Act of 1976, the transaction is expected to close in the third quarter of 2022 or before.

The per share price represents a premium of approximately 39 per cent to Sierra Oncology’s closing stock price on 12 April 2022 and a premium of approximately 63 per cent to Sierra’s volume-weighted average price (VWAP) over the last 30 trading days. Sierra Oncology’s Board of Directors has unanimously recommended that Sierra’s stockholders vote in favour of the approval of the merger. Additionally, stockholders of Sierra Oncology holding approximately 28 per cent of Sierra’s outstanding shares, have agreed to vote their shares in favour of approval of the merger.

GSK will account for the transaction as a business combination and expects it to be accretive to adjusted EPS in 2024, the expected first full year of momelotinib’s sales. New GSK reaffirms its full-year 2022 guidance, the medium-term outlook for 2021-2026 of more than 5% sales and 10% adjusted operating profit CAGR* at CER**, and long-term sales ambition.

The value of the gross assets of Sierra Oncology to be acquired (as of 31 December 2021) is $109 million (£83 million at the rate of £1 = $1.312, being the 31 March 2022 spot rate). The net losses of the business were $95 million for the 12 months ended 31 December 2021 (£70 million, at the rate of £1 = $1.38, being the average rate for the period).

* CAGR: Compound Annual Growth Rate; **CER: Constant Exchange Rate

Advisors

PJT Partners is acting as financial advisor and Cleary Gottlieb Steen & Hamilton LLP is serving as legal counsel to GSK in connection with the transaction. Lazard is acting as financial advisor and Wilson Sonsini Goodrich & Rosati, is serving as legal counsel to Sierra Oncology.

On April 13, 2022 EORTC-SPECTA reported that New results from three research projects are being presented at this year’s annual meeting of the American Association for Cancer Research (AACR) (Free AACR Whitepaper), the world’s foremost cancer research organisation (Press release, EORTC, APR 13, 2022, View Source [SID1234612113]). This year’s annual meeting takes place in New Orleans from 8 – 13 April.

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SPECTA is a collaborative European platform, under the sponsorship of EORTC, that aims to develop translational1 research projects in cancer, including biomarker discovery. The first two presentations report results from studies investigating the enhanced use of molecular screening to identify ‘best fit’ treatments. Notwithstanding important advances in the personalisation of treatments, many patients are still unable to benefit from them because there is limited knowledge of the molecular characterisation of their cancer and/or poor access to screening platforms.

Rare cancers, defined as having an incidence lower than 6 per 100,000 cases per year, are a particular victim of these factors, mainly because rare cancers are so heterogeneous. To address this, EORTC, in collaboration with EURACAN2, has developed a project within the SPECTA platform to evaluate the molecular situation of rare cancers in Europe. By providing rare cancer patients with access to molecular screening, SPECTA can relate their potentially treatable alterations to possible therapies, and therefore advise clinicians on potential trials or new treatments for their patients.

In the SPECTA Arcagen trial3, researchers analysed the genetic material of tumour samples from patients with rare cancers via biopsies of paraffin-embedded samples or blood. At the cut-off date, molecular alterations that are involved in cancer initiation and proliferation were found in the tumours of 629 patients, of whom 421 were theoretically treatable by an existing therapy. Approved treatment in the right tumour type could be proposed in 58 cases. The researchers will now follow up the patients to see if the treatment was suitable and understand the clinical care for rare cancer in Europe.

Another SPECTA project4 set out to look for clinically relevant molecular alterations in adolescent and young adult (AYA) cancer patients. Each year there are around 45,000 new diagnoses of cancer in this age group in Europe; these cancers are also categorised as rare. Despite the great progress that has been made in the understanding the molecular landscape of cancer in children and adults, AYA cancer biology is still poorly understood.

The researchers studied tumours from 48 patients aged between 12 and 29 who had a newly diagnosed high risk sarcoma, or one that had relapsed. They identified treatable molecular variations in 81.2% of them thus, they say, confirming that there is an unmet clinical need among AYA sarcoma patients. Encouragingly, they were also able to identify ways of reducing quality control failures in the tumour samples, thus enabling more to be screened.

The third study5 presented forms part of a European project called IMMUcan, which seeks to enhance understanding of the tumour microenvironment. IMMUcan researchers report on their creation of a single cell RNA sequencing database, a cutting-edge technology to study gene expression at single cell level. While single cell RNA sequencing has been invaluable in helping to understand the cells, molecules, and blood vessels that surround a cancer cell (referred to as the tumour microenvironment), this has generated a massive amount of dispersed information which is not always presented consistently. The new database will bring it all together in one place in a user-friendly format.

Dr Marie Morfouace, an EORTC senior translational research scientist, who presented the SPECTA projects at the meeting, said: "These studies are another step along the road to making precision cancer medicine available for all patients. By understanding the molecular landscape of the tumour and its microenvironment, we can not only advise clinicians on potential targeted therapy for their patients, but we also build scientific hypotheses for the next generation of clinical trials, based on the strong molecular and cellular data generated in those projects."

1.Translational research aims to convert basic research results into results that will benefit humans directly.

2.EURACAN is the European reference network (ERN) for rare solid tumour cancers in adults. ERNS are virtual patient-centred networks bringing healthcare providers and patient representatives across Europe. Working together, they tackle complex or rare diseases and conditions that require highly specialised care and concentrated knowledge and resources.

3.View Source!/10517/presentation/16354

4.View Source!/10517/presentation/12148

5.View Source!/10517/presentation/17468

Funding:

The EORTC SPECTA platform is supported by Alliance Healthcare, a member of the AmerisourceBergen group

Arcagen is a collaboration between EORTC and Euracan and is funded by F. Hoffman-La Roche.

The AYA project is supported by the Walgreen Boots Alliance.

The IMMUcan project has received funding from the Innovative Medicines Initiative 2 Joint Undertaking under grant agreement No 821558. This Joint Undertaking receives support from the European Union’s Horizon 2020 research and innovation program and EFPIA.

On April 12th, 2022 NanoMab Technology Limited, a privately held biopharmaceutical company focussing on cancer precision therapies is delighted to reported that over the course of the last two quarters it has taken the next steps forward in its commitment to developing next generation pharmaceuticals by forming exclusive licensing agreements with Radiopharm Theranostics (ASX: RAD) and Full Life Technologies (HK) Ltd (Press release, NanoMab, APR 12, 2022, View Source [SID1234645316]).

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The agreements grant RAD full rights to develop three of NanoMab’s single-domain antibody assets: NM-02, NM-03, and NM-04; respectively targeting HER-2 (breast cancer), TROP-2 (triple negative breast cancer), and PTK7 (multiple solid tumours) biomarkers. RAD is an ASX-listed company led by a strong global team with world-class experience, who aim to develop radiopharmaceutical products for both diagnostic and therapeutic uses in areas of high unmet medical needs. RAD is the latest venture of Australian bioentrepreneur, Paul Hopper, who is behind numerous successful companies developing oncology drugs.

Additionally, an agreement issuing the full IP right to develop NM-05 (sdAb targeting FAP) has been established with Full-Life Technologies (HK) Ltd. Full-life is a global nuclear health company seeking to tackle two core issues experienced in the radiopharmaceuticals sector; the ability to produce primarily alpha- and beta- medical radioisotopes in quantity, and the development of an innovative translational research platform for Targeted-Radiotherapy.

NanoMab believes these exclusive licensing agreements have formalised the strategic collaborations between the respective parties, which will speed up the development and commercialisation of our unique platform of immuno-oncology theranostic drugs to aid patients in the battle against aggressive cancers.

On April 12, 2022 Erasca, Inc. (Nasdaq: ERAS), a clinical-stage precision oncology company singularly focused on discovering, developing, and commercializing therapies for patients with RAS/MAPK pathway-driven cancers, reported preclinical data from six poster presentations at the American Association for Cancer Research (AACR) (Free AACR Whitepaper) Annual Meeting in New Orleans, Louisiana (Press release, Erasca, APR 12, 2022, View Source [SID1234639379]). The posters are available online at Erasca.com/science/#presentations.

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"To shut down the highly oncogenic RAS/MAPK pathway, we are targeting multiple nodes and cooperative mechanisms using a data-driven clinical development effort that identifies single agent and combinations with potential to significantly prolong survival in patient populations with high unmet needs," said Jonathan E. Lim, M.D., Erasca’s chairman, CEO, and co-founder. "This year, we were pleased to present six posters at the AACR (Free AACR Whitepaper) annual meeting highlighting preclinical data supporting the clinical development of three of our best-in-class programs, including our ERK1/2 inhibitor ERAS-007, our SHP2 inhibitor ERAS-601, and one of our CNS-penetrant KRAS G12C inhibitors ERAS-3490, as well as our choice of combination partners for these product candidates."

Poster Presentation Highlights
Abstract 2672: ERAS-007 is a selective ERK1/2 inhibitor with preclinical activity across RAS/MAPK pathway-driven CRC models
ERAS-007 demonstrates promising preclinical activity across a wide range of RAS/MAPK pathway-driven CRC models as a monotherapy and in combination. Over 50% of patients with colorectal cancer (CRC) have activating mutations in the RAS/MAPK signaling pathway, with available targeted therapies demonstrating limited overall response rates and duration of response.

ERAS-007 is a highly potent and selective small molecule ERK1/2 inhibitor with long target residence time that promotes sustained RAS/MAPK pathway inhibition
ERAS-007 demonstrates promising preclinical activity across a wide range of RAS/MAPK pathway-driven CRC models both as a monotherapy and in combination
ERAS-007 + encorafenib and cetuximab in BRAF V600E CRC, and ERAS-007 + palbociclib in KRAS/NRAS mutant CRC are currently being evaluated in the HERKULES-3 Phase 1b/2 master protocol clinical trial in patients with advanced gastrointestinal malignancies (NCT05039177), with initial data expected between the fourth quarter of 2022 and the first half of 2023
Abstract 2671: ERAS-601, a potent allosteric inhibitor of SHP2, demonstrates compelling single agent anti-tumor activity in RAS/MAPK-driven tumor models
ERAS-601 blocks growth signals from multiple receptor tyrosine kinases (RTKs) to help prevent cancer growth. SHP2 acts as a convergent node for RTK signaling, relaying growth and survival signals from RTKs to intracellular signaling pathways. ERAS-601 inhibits SHP2, blocking oncogenic signal transduction through SHP2, which helps delay development of therapeutic resistance.

ERAS-601 inhibits loading of RAS-GTP and demonstrates anti-proliferative activity in KRAS mutant, BRAF Class III, NF1 loss of function (LOF), and EGFR-activated cell lines
ERAS-601 achieves substantial systemic exposure and inhibits tumor growth in multiple RAS/MAPK-activated CDX and PDX models harboring EGFR, KRAS, BRAF Class III, and NF1 LOF mutations
ERAS-601 is being investigated in the ongoing FLAGSHP-1 Phase 1/1b trial in patients with advanced solid tumors (NCT04670679), with initial data expected in the second half of 2022
Abstract 2670: ERAS-601, a potent allosteric inhibitor of SHP2, synergistically enhances the efficacy of sotorasib/adagrasib and cetuximab in NSCLC, CRC, and HNSCC tumor models
ERAS-601 can serve as a backbone of combination therapy to enhance efficacy of other targeted therapies. Treatment durability with KRAS G12C inhibitors in non-small cell lung cancer (NSCLC) and with EGFR antibodies in CRC is limited due to RAS and RTK reactivation. ERAS-601 + sotorasib/adagrasib and ERAS-601 + cetuximab were evaluated for enhanced efficacy or prevention of resistance in advanced solid tumor models.

ERAS-601 + KRAS G12C inhibitors synergistically inhibits cell viability in KRAS G12C cells and achieves tumor inhibition superior to either agent alone in KRAS G12C NSCLC and CRC CDX and PDX models
ERAS-601 + cetuximab enhances anti-proliferative activity and achieves tumor growth inhibition superior to respective monotherapies in RAS/RAF wildtype HPV-negative head and neck squamous cell carcinomas (HNSCC) and triple wildtype (KRAS/NRAS/BRAF wildtype) CRC CDX and PDX models
ERAS-601 + sotorasib is being investigated in the ongoing HERKULES-2 Phase 1b/2 master protocol in patients with advanced NSCLC (NCT04959981)
ERAS-601 + cetuximab is being investigated in the FLAGSHP-1 Phase 1/1b trial in patients with advanced solid tumors, including RAS/RAF wildtype CRC and HPV-negative HNSCC tumors (NCT04670679), with initial data expected between the fourth quarter of 2022 and the first half of 2023
Abstract 3345: ERAS-601, a potent allosteric inhibitor of SHP2, synergistically enhances the activity of a FLT3 inhibitor, gilteritinib, in FLT3-mutated AML tumor models
ERAS-601 works synergistically with gilteritinib to inhibit RAS/MAPK signaling and cell viability of FLT3-mutated acute myeloid leukemia (AML), achieving more durable tumor inhibition than either agent alone. AML is dependent on RAS/MAPK pathway signaling, with prevalent mutations across multiple nodes of this pathway. Gilteritinib, a FLT3 inhibitor, has demonstrated clinical activity, but resistance limits the benefit of gilteritinib monotherapy. ERAS-601 + gilteritinib was evaluated non-clinically in FLT3-mutated AML models to assess potential for improvement with co-suppression of the RAS/MAPK pathway.

ERAS-601 + gilteritinib inhibits oncogenic RAS/MAPK pathway signaling as measured by ERK1/2 phosphorylation and synergistically inhibits cellular viability of FLT3-mutated AML cells in vitro
ERAS-601 + gilteritinib achieves more durable tumor growth inhibition in vivo than either agent alone in multiple FLT3-ITD mutant models
ERAS-601 + gilteritinib in FLT3-altered AML is being investigated in the HERKULES-4 Phase 1b/2 master protocol trial in patients with hematologic malignancies (NCT05279859)
Abstract 2669: ERAS-007 (ERK1/2 inhibitor) + ERAS-601 (SHP2 inhibitor) exhibit nonclinical combination activity across KRAS mutated NSCLC, CRC, and PDAC tumor models
Erasca’s first MAPKlamp, ERAS-007 + ERAS-601, demonstrates combination activity in KRAS mutant tumor models by inhibiting both an upstream node of the RAS/MAPK pathway, SHP2, and the most distal node, ERK1/2. KRAS mutations occur in approximately 25% of all cancers and promote oncogenesis via constitutive activation of the RAS/MAPK pathway. Rapid emergence of resistance, often mediated by reactivation of RAS/MAPK signaling, limits monotherapy activity. Erasca’s first MAPKlamp (ERAS-007 + ERAS-601) was evaluated for the potential to prevent RAS/MAPK pathway reactivation more robustly than inhibition of a single node alone.

The ERAS-007 + ERAS-601 MAPKlamp combination inhibits colony growth more potently than either agent alone in KRAS mutant NSCLC, CRC, and PDAC cell lines in vitro
The ERAS-007 + ERAS-601 MAPKlamp combination achieved superior tumor growth inhibition and regression over either agent alone in KRAS mutant NSCLC, CRC, and PDAC xenografts in vivo
These data support the clinical development of the ERAS-007 + ERAS-601 MAPKlamp combination
Abstract 2675: Discovery of potent CNS-penetrant covalent KRAS G12C inhibitors
Erasca has discovered multiple central nervous system (CNS)-penetrant KRAS G12C inhibitors (ERAS G12Ci’s) with robust systemic and CNS activity, highlighting these inhibitors’ potential to address systemic cancers with CNS involvement. The KRAS G12C mutation occurs in 14% of lung adenocarcinoma tumors, with brain metastases in up to 40% of patients. ERAS-3490, an ERAS G12Ci, is designed to address the high prevalence of CNS metastases in KRAS G12C mutant lung cancer.

ERAS G12Ci’s achieve 11-68% brain/plasma concentration ratios in intravenously infused rats, with brain concentrations between 91-290 ng/g, and potently inhibit cell proliferation and RAS/MAPK signaling in KRAS G12C cell lines
ERAS-3490 has robust anti-tumor activity in KRAS G12C mutant MIA PaCa-2, NCI-H1373, and NCI-H2122 CDX subcutaneous models
ERAS-3490 shows robust anti-tumor activity and dose-dependent survival benefit in the KRAS G12C NSCLC intracranial model NCI-H1373-luc, a nonclinical model of NSCLC CNS metastasis
IND filing for ERAS-3490 in KRAS G12C mutant NSCLC is expected in the second half of 2022

On April 12, 2022 – Ribonexus, a biotechnology start-up developing new therapies that can overcome resistance to current targeted therapies in cancer patients, reported it has received €2 million ($2.19M) in funds from the French public investment bank Bpifrance (Press release, Ribonexus, APR 12, 2022, https://ribonexus-project.com/wp-content/uploads/2022/11/220412_Ribonexus-Deeptech-Funding-NR-EN.pdf [SID1234628864]).

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This financing, which has been granted in connection with the French government’s ‘Deeptech Plan’, will enable Ribonexus to select the best drug candidate to enter preclinical development and leverage its proprietary platform based on a key selective pathway.

The company will receive two instalments via the French government’s ‘Future Investments Program’: €1.4M ($1.53M) in the form of a repayable advance and €600k ($658k) in grants.

Ribonexus, whose R&D programs focus on the treatment of melanoma, is developing a pipeline of molecules targeting the eukaryotic translation Initiation Factor-4A (eIF4A). This target is highly active in a variety of solid and hematologic cancers, including melanoma, and is associated with resistance to many current therapies. Inhibiting eIF4A appears therefore to be a promising therapeutic approach.

"Following our recent partnership with the leading pharmaceutical group Pierre Fabre, this funding is a clear recognition of the high potential of our pipeline, aiming to restore sensitivity and avoid resistance to current targeted therapies to dramatically improve the standard of care in cancer patients," said Alejo Chorny, COO at Ribonexus. "Thanks to this strong pipeline, our experienced team of drug developers, scientists and investors, and this financing, we are well positioned to prepare our Series A funding round and proceed with IND-enabling studies."

Ribonexus’ long-term strategy includes reinforcing its early-stage oncology pipeline and expertise to assess and expand its programs beyond melanoma to treat other cancer indications. The company is also looking to establish a licence agreement with a pharmaceutical / biopharma company based on the clinical data generated through the eIF4A inhibitor program.

The deep tech financing provided by Bpifrance is intended to fund the research and development phases of innovative, breakthrough projects prior to their industrial and commercial launch. Established in 2019, the Deeptech plan is comprised of funds worth €2.5Bn ($2.72Bn) over five years, with the objective of financing the creation of 500 startups each year.

Targeting the eIF4A protein to overcome resistance to cancer therapies
While targeted therapies have clearly improved cancer patient outcomes, global efficacy of these treatments decreases over time, with patients rapidly developing resistance to therapies. Moreover, even with therapies that lead to a complete response, small populations of cancer cells often survive treatments, driving cancer relapse, which remains one of the most challenging obstacles to effective treatments.

EIF4A, an RNA helicase, is one of the three proteins composing the eIF4F complex, essential for the cap-dependent translation initiation of many oncogenic proteins.

The abnormal activity of this complex, observed in many cancers, leads to the synthesis of proteins involved in tumor growth and metastasis. In addition, the selective translation of cellular mRNAs, controlled by this eIf4F complex, also contributes to the resistance to cancer treatments such as targeted therapies and checkpoint inhibitors.

Ribonexus aims to avoid resistance to BRAF and MEK inhibitors and restore sensitivity to these inhibitors in patients that become resistant to treatment.