On June 23, 2021 Tvardi reported that it launched out of Houston with the promise of finally developing the right inhibitors for the Holy Grail target of STAT3 — under the guidance of serial entrepreneur Ron DePinho and his colleague David Tweardy, a leading expert in the field. Almost three years later, they say they have the proof of concept data to keep going (Press release, Tvardi Therapeutics, JUN 23, 2021, View Source [SID1234585975]).

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It’s good enough for a $74 million Series B, a big jump from the $9 million they got in the last round and, CEO Imran Alibhai would add, a reflection of the rep his team has built.

In Phase I dose escalation studies involving patients with solid tumors who have failed all other treatments, the lead compound was shown to have downregulated the STAT3 activity of interest: blocking it from becoming phosphorylated by the receptors it typically interacts with.

"The topline news is that in over half of our patients, we’ve seen clinical benefit" in the form of tumor stabilization, shrinkage or even partial responses, he said. "That drove a lot of interest, but beyond that what’s been striking has been the safety."

He believes the secret lies in focusing on preventing the activation of STAT3, which drives the nuclear function related to disease, but not trying to remove it from the system, degrade it, or break it too much. The small window, after all, is what makes targeting STAT3 so tricky despite it being a top 5 target for cancer.

By the first half of next year, Tvardi expects to wrap up the Phase I trial and zero in on hepatocellular carcinoma in Phase II trials — while also starting to study the drug for fibrosis.

"When you think about growth and differentiation in tumors, and metastases, there’s probably three or four legs to the stool, and STAT3 is definitely one of those. Right? It is a central node," Alibhai said. "When it comes to fibrosis, there is one leg to the stool. And STAT3 modulates that pathway. And so if you could find a safe drug that actually targets STAT3, you can potentially see some really beautiful data."

Others have arrived at the same conclusion, with a small band of startups heralding new approaches such as protein degradation to target STAT3, Sanofi-partnered Kymera and Medicxi’s Janpix (now part of Centessa) among them.

For his part, Alibhai said he welcomes more options for patients and hopes Tvardi’s oral dosing small molecule treatment can set itself apart. Besides, it is not trivial to make drugs that can even get into the clinic.

"What the true test is: Can you actually get in, be safe, and be very very very targeted in the case of STAT3?" he noted. "Because there are multiple roles for STAT3 in every cell, and so we need to make sure that we’re targeting appropriately for the role that we’re interested in."

The small company is already working on a second-generation molecule that will be three to eight times more potent than the lead candidate, he said. And their new investors are in for the long game, giving them the option to either jump straight into an IPO next or raise another crossover round and, more importantly, "do something interesting."

Slate Path Capital, Palkon Capital, ArrowMark Partners and 683 Capital joined the round, with significant support from Sporos Bioventures and other existing investors.

On June 23, 2021 Rubius Therapeutics, Inc. (Nasdaq:RUBY), a clinical-stage biopharmaceutical company that is genetically engineering red blood cells to create an entirely new class of cellular medicines called Red Cell Therapeutics, reported that the first patient has been dosed in a new Phase 1 arm of the ongoing Phase 1/2 clinical trial of RTX-240 in combination with KEYTRUDA (pembrolizumab)1 for the treatment of patients with relapsed/refractory or locally advanced solid tumors (Press release, Rubius Therapeutics, JUN 23, 2021, View Source [SID1234584708]). To be eligible for the trial, patients must have disease that is relapsed or refractory to an anti-PD-1 or PD-L1 therapy.

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"RTX-240 is designed to activate and expand a patient’s own immune cells to mount a broad and potent anti-tumor response. Combining an immune agonist with a PD-1 checkpoint inhibitor has the potential to prevent the cancer from evading the immune response. The RTX-240 and pembrolizumab combination is anticipated to drive activated T cells and NK cells into the tumor microenvironment with the potential to overcome resistance to PD-1 inhibition," said Christina Coughlin, M.D., Ph.D., chief medical officer at Rubius Therapeutics. "Given the favorable emerging safety profile and promising initial clinical activity reported as part of our initial clinical results from the ongoing Phase 1 monotherapy trial of RTX-240 in advanced solid tumors, we believe that the combination with pembrolizumab has the potential to provide significant benefit to patients with disease that is relapsed or refractory to prior anti-PD-1 or PD-L1 therapy."

"Despite recent advances in cancer immunotherapy, there remains a need for new combination approaches that broaden the benefits of immunotherapy in patients with solid tumors following treatment with checkpoint inhibition," said Omid Hamid, M.D., Chief of Translational Research and Immunotherapy, Director of the Phase 1 Immuno-Oncology Program of The Angeles Clinic and Research Institute, a Cedars-Sinai Affiliate, and RTX-240 investigator. "The exciting initial safety and efficacy data from the ongoing monotherapy Phase 1 clinical trial make RTX-240 a potentially promising candidate for the treatment of cancer, and we are excited to work with Rubius to evaluate RTX-240 in combination with pembrolizumab."

RTX-240 is engineered to express a co-stimulatory molecule, 4-1BB ligand, and a cytokine, IL-15TP, on the cell’s surface, and is designed to broadly stimulate the immune system by activating and expanding both natural killer (NK) cells and T cells to generate a potent anti-tumor response. Pembrolizumab is a humanized monoclonal immunoglobulin G4 antibody (IgG4 mAb) with high specificity of binding to the programmed cell death protein-1 (PD-1) receptor, thus inhibiting its interaction with programmed cell death ligand 1 (PD-L1) and programmed cell death ligand 2 (PD-L2). Based on in vitro data, pembrolizumab has high affinity and potent receptor blocking activity for PD-1. Pembrolizumab is indicated for the treatment of patients across several indications as monotherapy and in combination with numerous therapies.

About the RTX-240 Phase 1/2 Clinical Trial
This is a Phase 1/2 open label, multicenter, multidose, first-in-human dose-escalation and expansion study designed to determine the safety and tolerability, pharmacokinetics, maximum tolerated dose and a recommended Phase 2 dose and dosing regimen of RTX-240. The trial will also assess the pharmacodynamics of RTX-240 measured by changes in T and NK cell number and function relative to baseline and anti-tumor activity. The trial has three separate Phase 1 arms: an ongoing monotherapy dose escalation arm in adults with relapsed/refractory or locally advanced solid tumors, an ongoing monotherapy dose escalation arm in adults with relapsed/refractory acute myeloid leukemia, and a combination therapy dose escalation arm with pembrolizumab in adults with relapsed/refractory or locally advanced solid tumors. The monotherapy arm of the trial in advanced solid tumors includes a Phase 2 expansion in specified tumor types.

On June 23, 2021 Portage Biotech Inc. (NASDAQ: PRTG) ("Portage" or the "Company") a clinical-stage immuno-oncology company focused on the development of therapies and treatments targeting cancer treatment resistance, reported that it has commenced an underwritten public offering of its ordinary shares. In addition, Portage expects to grant the underwriters a 30-day option to purchase up to an additional 15% of the number of the ordinary shares sold in connection with the offering (Press release, Portage Biotech, JUN 23, 2021, View Source [SID1234584321]). All of the ordinary shares in the offering are to be sold by Portage. This offering is subject to market conditions and there can be no assurance as to whether or when the offering may be completed, or as to the actual size or terms of the offering. Cantor Fitzgerald & Co. and Oppenheimer & Co. Inc. are acting as book-running managers for the offering. Portage intends to use the net proceeds from the offering primarily for the acceleration of its PORT-2 and PORT-3 clinical programs, to prepare the next products to enter the clinic, and for working capital and other general corporate purposes. The ordinary shares are offered pursuant to a shelf registration statement on Form F-3 (File No. 333-253468), including a base prospectus, filed by Portage on February 24, 2021, and declared effective by the Securities and Exchange Commission, or the SEC, on March 8, 2021. The offering will be made only by means of a prospectus. A preliminary prospectus supplement and a final prospectus supplement related to the offering will be filed with the SEC and will be available on the SEC’s website at www.sec.gov. Copies of the preliminary prospectus supplement and the accompanying prospectus relating to the offering may also be obtained from the offices of: Cantor Fitzgerald & Co., Attention: Capital Markets, 499 Park Ave., 4th Floor, New York, New York 10022, or by email at [email protected]; or Oppenheimer & Co. Inc., Attention: Syndicate Prospectus Department, 85 Broad Street, 26th Floor, New York, New York 10004, by telephone at 212-667-8055, or by email at [email protected]. This press release shall not constitute an offer to sell or the solicitation of an offer to buy, nor shall there be any sale of these securities in any state orjurisdiction in which such offer, solicitation or sale would be unlawful prior to registration or qualification under the securities laws of such state or jurisdiction.

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On June 23, 2021 Certara, a global leader in biosimulation, reported that the Japanese Pharmaceuticals and Medical Devices Agency (PMDA) has renewed its licenses of Certara’s Simcyp and Phoenix biosimulation software (Press release, Certara, JUN 23, 2021, View Source [SID1234584301]). The PMDA has been using Certara’s biosimulation software since 2014.

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The Simcyp Physiologically-Based Pharmacokinetic (PBPK) Simulator is used in drug development to determine first-in-human dose, design more efficient and effective clinical studies, and predict drug-drug interactions using virtual populations. The Phoenix Pharmacokinetic and Pharmacodynamic (PK/PD) Platform is used for pharmacokinetic, pharmacodynamic, and toxicokinetic modeling and simulation to help drug developers save time by streamlining data management.

"The continued growth in modeling and simulation approaches for new drug applications in Japan is helping to support the development of medicines for difficult-to-treat diseases and for much needed areas, including pediatrics," said Certara’s CEO William Feehery, Ph.D. "Regulatory guidance and support are critical to expand new use cases for biosimulation to ultimately bring safe and efficacious therapies to patients."

Taking into account the increase in the use of exposure-response and PBPK analyses, two guidelines were issued by Japan’s Ministry of Health, Labour, and Welfare for the use of modeling and simulation in 2020: "Guideline for Drug Exposure‐Response Analysis" and "Guidelines for Analysis Reports Involving Physiologically based Pharmacokinetic Models."

According to a report presented in March 2021 at the PMDA Public Workshop of ‘Role of Model Informed Drug Development’, an increasing number of drug approval applications have used modeling and simulation to optimize dosing regimens and establish precautions in new drug application documents submitted to the PMDA. Certara works with more than 130 biopharmaceutical companies and research institutions in Japan, including all of the top 10 Japanese biopharmaceutical companies by R&D spend.

On June 23, 2021 GlaxoSmithKline plc (GSK LSE & NYSE) reported that it will provide details of its strategy, outlook for growth and plans to create shareholder value, following the planned demerger in mid-2022 of its Consumer Healthcare business (Press release, GlaxoSmithKline, JUN 23, 2021, View Source [SID1234584300]). The resulting New GSK will be a growth company with new ambitions for patients and shareholders and an overarching purpose to unite science, talent and technology to get ahead of disease together.

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Emma Walmsley, Chief Executive Officer, said: "The benefits of the huge transformation we have driven since 2017 are now clear. We have strengthened our R&D and commercial execution, and transformed our group structure and capital allocation, while driving a profound cultural change with new leadership.

"Together, we are now ready to deliver a step-change in growth for New GSK and unlock the value of Consumer Healthcare. With world class capabilities across prevention and treatment of disease, New GSK is exceptionally well positioned to positively impact people’s health and to deliver strong performance and value to shareholders through the decade."

Key elements of the investor update are summarised below:

Strategic transformation

In 2017, GSK commenced a significant corporate transformation to address historic long-standing issues that have affected performance. Major progress has been achieved across the business to improve performance, strengthen capabilities and prepare GSK for a new future.

The company has substantially strengthened its R&D performance and productivity. Since 2017, GSK has delivered 11 major product approvals* and doubled the number of assets in Phase III and registration to 22. Commercial execution has been transformed with new and specialty products now reaching £10 billion in annual sales. Meanwhile changes to the Group’s portfolio and network within Vaccines and Pharma have led to annual cost savings delivery of £0.5 billion and proceeds from divestment of non-core brands of £1.4 billion.

Following two successful global mergers, a new world-leading consumer healthcare business, with a radically transformed portfolio and sector-leading profitability has also been created.

All of this has been achieved with acknowledged sector leadership in ESG performance.

In addition, there has been significant cultural and leadership change across the company, to improve accountability and raise levels of ambition. 85% of the top 125 leaders are new in role since 2017 and new incentives and governance have been implemented in all key areas of the company.

These changes now provide the platform for GSK to separate and create two new global companies which will have major impacts on human health and can deliver compelling performance and attractive returns and value to shareholders.

New GSK financial outlooks

2021-2026 outlook

Over the next five-year period, New GSK expects to deliver sales growth and adjusted operating profit growth of more than 5% and more than 10%, respectively, CAGR at constant exchange rates (with 2021 as the base year). Profit growth is expected to be underpinned by a combination of strong revenue growth from new vaccines and specialty medicines, improving operational performance and benefits from the transformation of recent years. These financial outlooks exclude any contribution from COVID-19 related revenues.

The company expects to improve adjusted operating margin from the mid-20s% in 2021 to over 30% by 2026. Improved sales growth, sales mix benefits and realisation of cost savings from previously announced programmes are all expected to contribute to margin improvements. GSK has identified a further £200 million of annual savings from the Separation Preparation (Future Ready) programme and has revised its cost savings target from £800 million to £1 billion with no extra costs for delivery. All restructuring programmes will complete in 2022 and no further major restructuring programmes are planned.

2026-2031 ambition

By 2031, New GSK aims to deliver sales of more than £33 billion (at constant exchange rates). Achievement of this ambition is driven by commercial execution of New GSK’s current late-stage pipeline. The company estimates that certain assets in late-stage development have the potential in aggregate to deliver peak year sales of more than £20 billion on a non-risk adjusted basis+.

The £33 billion sales ambition is before any significant revenue contribution from early-stage pipeline assets or any contribution from business development. Importantly, New GSK aims to grow sales through to 2031 despite the anticipated loss of exclusivity for dolutegravir in 2028/29.

The new outlooks and ambition will be incorporated into existing incentive plans by the remuneration committee in due course.

Maximising Vaccines and Specialty Medicines

New GSK will prioritise R&D and commercial investment in Vaccines and Specialty Medicines, which are expected to grow to around three-quarters of company sales by 2026. As part of its 2021-26 outlook, Vaccines is expected to grow sales at a high single-digit % CAGR and Specialty Medicines at a double-digit % CAGR.

The company is focused across four core therapeutic areas (TAs): Infectious Diseases, HIV, Oncology and Immunology/Respiratory. In addition, New GSK will remain open to opportunities outside these core TAs where there are scale opportunities rooted in immune science and genetic validation.

Capturing the increasing opportunities now seen across the prevention and treatment of disease offers significant scientific and commercial opportunities for New GSK. At the heart of this is the company’s R&D focus on the science of the immune system, human genetics and advanced technologies; and its world-leading capabilities in vaccine and pharmaceutical development.

The company currently has a pipeline of 20 vaccines and 42 medicines – many of which are potential best or first in class opportunities.

Optimising General Medicines

A newly defined General Medicines product group will contain all of New GSK’s primary care brands, including older established products as well as the inhaled respiratory portfolio. General Medicines will have differing performance profiles by region and brand, with growth expected most in emerging markets. Overall General Medicines is expected to show broadly stable sales over the period 2021-26 (CER).

General Medicines will be optimised for profitability and cash generation to support investment in Vaccines and Specialty Medicines. As part of this approach, further streamlining of the portfolio is expected through divestment or partnering of non-priority brands.

Strengthened balance sheet to support growth and returns to shareholders

Following separation of the Consumer Healthcare business, New GSK is expected to have a net debt/adjusted EBITDA leverage ratio of less than 2 times. This, together with expected stronger cash flow generation, will provide additional flexibility to support future investments in growth. By 2026, cash generated from operations for New GSK is expected to exceed £10 billion.

New GSK’s capital allocation priorities will be: to strengthen the pipeline, including through targeted bolt-on and in-licensing business development transactions; to invest behind successful product launches; to enhance sustainability of its operations; and to underpin its progressive dividend policy.

In 2022, GSK shareholders will receive dividends from GSK and New Consumer Healthcare due to the expected mid-year timing of the demerger. Together, these are expected to amount to approximately 55p per share for the year, assuming a New Consumer Healthcare dividend at the lower end of the previously announced 30-50% pay-out ratio range and subject to approval from the Board of New Consumer Healthcare. This pro-forma full year 2022 dividend would be a 31% reduction compared to the expected 2021 dividend of 80p per share.

New GSK will adopt a progressive dividend policy targeting a dividend pay-out ratio equivalent to 40-60%, starting at 45p per share in 2023, the company’s first full year of operation.

Strong focus on ESG performance and to impact the health of more than 2.5 billion people

Maintaining a sector leading ESG performance will be an integral part of New GSK’s strategy and a key goal for the new company.

The company intends to take a focused approach to ESG, driven by its strengths and to address the key challenges faced by the industry over the long-term. New GSK will prioritise resources across six areas it sees as material to its business: pricing/access, global health, inclusion and diversity, the environment, product governance and operating standards.

Accountabilities for these six areas will be at executive level and New GSK expects to further strengthen the alignment of incentives and remuneration to delivery of ESG performance, with increased visibility in corporate reporting.

This approach to ESG will support delivery of sustainable performance and long-term growth; build trust with stakeholders; reduce risk to operations; and enable delivery of very positive social impact.

A critical measure of success for New GSK will be health impact at scale. This is at the core of the company’s purpose and it expects to positively impact the health of more than 2.5 billion people around the world over the next 10 years.

Consumer Healthcare separation

The separation of Consumer Healthcare is expected in mid-2022 and the GSK Board’s clear priorities are to unlock the potential of New GSK and Consumer Healthcare, strengthen New GSK’s balance sheet and maximise value for shareholders.

The new Consumer Healthcare company will have a portfolio which generated annual sales of more than £10 billion in 2020 and is well-positioned for further growth. Driven by brands, innovation, leading-edge science and human understanding to deliver better everyday health, the company will have nine global power brands holding category leadership positions and major sales presences in the US and China. Altogether the business offers strong prospects for sustainable sales and profit growth, high cash generation and delivery of attractive returns for shareholders.

Subject to approval from shareholders, the separation will be by way of a demerger of at least 80% of GSK’s 68% holding in the Consumer Healthcare business to GSK shareholders, with the new Consumer Healthcare company shares expected to attain a premium listing on the London Stock Exchange, with ADRs to be listed in the US. The company intends to structure the demerger in a manner that is tax efficient for UK and US shareholders, as compared to alternative separation options, and is seeking confirmation of such treatment from the relevant tax authorities. Details of the expected tax treatment will be provided in the circular sent to shareholders in connection with the approval of the demerger.

New GSK will retain up to 20% of GSK’s holding in the new Consumer Healthcare company as a short-term financial investment, which it intends to monetise in a timely manner to further strengthen New GSK’s balance sheet and help fund certain pension benefit obligations. Prior to the demerger, New GSK is also expected to receive a dividend of up to £8 billion from Consumer Healthcare. As previously stated, the new Consumer Healthcare company is expected to have a net debt/adjusted EBITDA leverage ratio of up to 4.0 times. GSK plans to target an investment grade credit rating for the new Consumer Healthcare company.

A comprehensive update on the prospects for New Consumer Healthcare is planned for investors in early 2022.

The Board of GSK is preparing for two new independent boards following separation. A process has started to form a board of directors for the new Consumer Healthcare company, which will include the appropriate mix of skills and experience to represent and maximise the value of this business for shareholders.

In addition, and building on recent non-executive appointments, further appointments are also expected to the Board of GSK prior to the separation to increase biopharmaceuticals and scientific experience for New GSK.

*Major product approvals 2017-21

Asset

Indication(s)

Approved

Trelegy Ellipta

COPD

2017

Shingrix

Shingles vaccine

2017

Juluca

HIV

2017

Kozenis

Plasmodium vivax (P. vivax) malaria

2018

Dovato

HIV

2019

Zejula (1st line maintenance/PRIMA)

1st line maintenance ovarian cancer

2020

Duvroq

Anaemia due to chronic kidney disease

2020

Rukobia

HIV

2020

Blenrep

Relapsed or refractory multiple myeloma

2020

Cabenuva

LA HIV

2020

Jemperli[2]

Recurrent or advanced dMMR endometrial cancer

2021

+See "Basis of preparation, assumptions, and cautionary statement" section on pages 5-7. Assets in late-stage development with the potential in aggregate to deliver peak year sales of more than £20 billion on a non-risk adjusted basis

Asset

Indication(s)

cabotegravir LA

HIV PrEP

daprodustat (HIF-PHI)

Anaemia

Blenrep (BCMA ADC)

Multiple myeloma[3]

Jemperli (PD-1 antagonist)[4]

1L endometrial cancer

gepotidacin (2140944)

uUTI and GC

RSV vaccine

RSV older adults/other[5]

MenABCWY vaccine

Meningitis

otilimab (3196165, aGM-CSF inhibitor)

Rheumatoid arthritis

depemokimab (GSK ‘294, LA anti-IL5 antagonist)

Asthma

Zejula (PARP inhibitor)

1L ovarian cancer with dostarlimab

HBV ASO (GSK ‘836)

Hepatitis B

Basis of preparation, assumptions and cautionary statement

Assumptions relating to the 2021-2026 sales and adjusted operating profit growth outlooks, 2026 cash generated from operations outlook, 2031 sales ambition and 2021-2023 dividend expectations

In outlining the growth outlooks for the period 2021-2026, the 2026 cash generated from operations outlook, the 2031 sales ambition and the 2021-2023 dividend expectations (the "Relevant Statements"), GSK has made certain assumptions about the healthcare sector (including regarding possible governmental, legislative and regulatory reform), the different markets and competitive landscape in which it operates and the delivery of revenues and financial benefits from its current portfolio, its development pipeline of drugs and vaccines, its restructuring programmes and its plans for the separation of Consumer Healthcare, details of which are set out in this document.

GSK expects and assumes the next several years to be challenging for the healthcare industry with continued uncertainty related to the impact of the COVID-19 pandemic on adult vaccinations and continued pressure on pricing of pharmaceuticals. GSK assumes no premature loss of exclusivity for key products over the period. GSK also expects volume demand for its products to increase, particularly for Shingrix in the US, as healthcare systems are expected to return to normal following disruption from governments’ prioritisation of COVID-19 vaccination programmes and ongoing measures to contain the pandemic, and for Shingrix in China.

The assumptions underlying the Relevant Statements include: successful delivery of the ongoing and planned integration and restructuring plans and the planned demerger of Consumer Healthcare; the delivery of revenues and financial benefits from its current and development pipeline portfolio of drugs and vaccines (which have been assessed for this purpose on a risk-adjusted basis, as described further below); regulatory approvals of the pipeline portfolio of drugs and vaccines that underlie these expectations (which have also been assessed for this purpose on a risk-adjusted basis, as described further below); no material interruptions to supply of the Group’s products; no material mergers, acquisitions or disposals or other material business development transactions; no material litigation or investigation costs for the company (save for those that are already recognised or for which provisions have been made); no share repurchases by the company; and no change in the shareholdings in ViiV Healthcare.

The Relevant Statements also factor in all divestments and product exits announced to date as well as material costs for investment in new product launches and R&D. Pipeline risk-adjusted sales are based on the latest internal estimate of the probability of technical and regulatory success for each asset in development.

Notwithstanding the Relevant Statements, there is still uncertainty as to whether our assumptions, targets, outlooks expectations and ambitions will be achieved, including based on the other assumptions outlined above.

The statement that GSK estimates that certain assets in late-stage development have the potential to deliver peak year sales of more than £20 billion on a non-risk adjusted basis is an aggregation, across the relevant portfolio of assets, of the maximum sales that GSK considers might be achieved from each such asset (including from lifecycle innovation) in the year that that asset attains its highest sales level, in all cases before taking into account any risks that could impair GSK’s ability to reach that level of sales for that asset, including risks relating to technical and regulatory success, trial outcomes, launch dates and execution, exclusivity periods and the impact of changes in the market and healthcare landscape for that asset. The aggregation is of the peak year sales of each individual asset within the portfolio and not for one particular year. Accordingly, the statement of estimated non-risk adjusted potential peak year sales of the relevant assets in late-stage development does not comprise, is wholly different in nature to, and is subject to very significantly higher levels of uncertainty than the Relevant Statements. As such, while GSK does not expect to achieve the aggregate amount of those estimated non-risk adjusted peak year sales, a risk-adjusted assessment of sales of relevant assets during the relevant periods is (as stated above) taken into account, where relevant, within the Relevant Statements.

All outlook and ambition statements are given on a constant currency basis and use 2021 forecast exchange rates as a base, assuming a continuation of Q1 2021 closing rates (£1/$1.38, £1/€1.17, £1/Yen 152). 2021-2026 outlook refers to the 5 years to 2026 with 2021 as the base year.