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Tuesday, January 10, 2023

Top Marine General In Japan Bluntly Describes US "Setting Theatre" For Future War With China

 The top Marine Corps General for Japan this week issued some very revealing statements in an interview focused on countering China in the Financial Times. Despite Chinese leadership insisting that the Taiwan and Ukraine situations are not comparable, this is precisely how Lieutenant General James Bierman presented the situation, even going so far as to admit the Pentagon is preparing a counter-China "theatre" by cultivating military ties with southeast Asian allies.

"The US and Japanese armed forces are rapidly integrating their command structure and scaling up combined operations as Washington and its Asian allies prepare for a possible conflict with China such as a war over Taiwan, according to the top Marine Corps general in Japan," the FT report begins.

While it's no secret that Tokyo has been more and more openly siding with the US stance on arming Taiwan over the past year, also abandoning its historic post-WWII neutrality by drastically ramping up defense spending, Gen. Bierman confirmed "exponential increases" over the past year in joint US-Japan operations. 

The interview itself is explosive enough to provoke the ire of Beijing officials, given how explicit the theme of the 'Ukraine-ification of Taiwan' is throughout Bierman's statements, especially given it's coming from the commanding general of Third Marine Expeditionary Force (III MEF) and of Marine Forces Japan.

Speaking in an unusually open and detailed manner regarding ongoing preparations to defend Taiwan, the US general said the following:

"Why have we achieved the level of success we’ve achieved in Ukraine? A big part of that has been because after Russian aggression in 2014 and 2015, we earnestly got after preparing for future conflict: training for the Ukrainians, pre-positioning of supplies, identification of sites from which we could operate support, sustain operations," he said.

"We call that setting the theatre. And we are setting the theatre in Japan, in the Philippines, in other locations."

Again, this kind of talk itself constitutes a brazen shot across China's bow. FT admits Bierman's comments are an "unusually frank comparison" between potential conflict with China and the Ukraine crisis.

Of course, as applied to Ukraine itself the comments are highly revealing, given the casual admission that US defense planners were busy inside Ukraine years ago "earnestly preparing" for war with Russian, even down to the "pre-positioning of supplies" and readying the battle space.

And more frank comments from the top Marine general in Japan, per the interview: 

"When you talk about the complexity, the size of some of the operations they would have to conduct, let’s say [in] an invasion of Taiwan, there will be indications and warnings, and there are specific aspects to that in terms of geography and time, which allow us to posture and be most prepared," he said. As part of those preparations, the Philippines plan to allow US forces to preposition weapons and other supplies on five more bases in addition to five where the US has already access.

"You gain a leverage point, a base of operations, which allows you to have a tremendous head start in different operational plans," Bierman said. "As we square off with the Chinese adversary, who is going to own the starting pistol and is going to have the ability potentially to initiate hostilities . . . we can identify decisive key terrain that must be held, secured, defended, leveraged."

Another interesting part of the interview comes in him cautioning regional US allies, including Taiwan, not to overestimate the Chinese military, asserting that the Chinese People’s Liberation Army (PLA) should not be fearfully seen as as being "10 feet tall".

The general's remarks were published at the very moment China is continuing its threatening drills aimed at Taipei, which since Nancy Pelosi's provocative August trip to the self-ruled island has featured PLA fighters and navy ships breaching the Taiwan Strait media line on frequent occasions, including dozens of times on Sunday. It was the second major exercise within less than two weeks into 2023, which the PLA Eastern Command described as "joint combat readiness patrols and actual combat drills."

If Pentagon leadership continues down this path of casting the Taiwan-China standoff in terms directly relatable to the Russian invasion of Ukraine (and correspondingly, the Unites States' arming of Kiev to the teeth... comparable to arms transfers to Taipei), we can fully expect Beijing to steadily ramp up its aerial and naval threatening drills aimed at Taiwan.

SCMP: PLA Navy Type 52D guided-missile destroyer "Yinchuan" sails in the Pacific

China's longstanding official policy, including that which is consistently articulated by President Xi, has been that it only seeks peaceful unification, and that it remains only Washington "playing with fire" in falsely stoking pro-independence forces. Yet Beijing is certainly not naïve, and appears busy paving the way of setting its own theatre looking ahead to a potential clash.

For example, a fresh report in South China Morning Post cites evidence of recent PLA Navy maneuvers that strongly suggest it's seeking to expand warfighting capacity in Pacific waters:

A People’s Liberation Army warship’s solo trip deep into the South Pacific is believed to have been a test of the Chinese navy’s refueling and supply capacity at sea.

The PLA Navy’s guided-missile destroyer Yinchuan (hull number 175) had been sailing near the exclusive economic zone of New Caledonia, a French overseas territory in the South Pacific, about 1,500km east of Australia, according to a French defence ministry tweet on December 29.

French navy jets tracked and photographed the warship’s activities, it said.

The same warship had only last month been spotted sailing close to French Polynesia, causing SCMP to point out that "The area it appeared in was tens of thousands kilometers away from the Chinese coast, and far beyond the range the 7,500-tonne destroyer could sustain without resupply, leaving aside the requirements for the return journey."

Meanwhile, China also necessarily finds itself in a position where it must utilize strong diplomacy - or else soft power - with its neighbors as it seeks to mitigate the effects of America's significant and growing regional presence. As but the latest clear example, last week Philippine President Ferdinand Marcos visited Beijing. He met with his Chinese counterpart Xi Jinping on Wednesday, and the two agreed to "friendly consultation to appropriately resolve maritime issues," according to state media.

* * * 

War-gaming a China-US war over Taiwan: a hypothetical invasion would exact "high costs on the island and the US Navy," according to a new think tank study...

Activist Bluebell builds stake in Bayer, pushes for company breakup

 

Activist investor Bluebell Capital Partners has built a stake in Bayer AG and is pushing for a breakup of the German pharmaceutical and agriculture company, Bloomberg reported on Tuesday, citing sources.

UK-based Bluebell is also seeking an overhaul of Bayer's corporate governance, the report added.

A Bayer spokesperson, who declined to comment on the report, said: "Generally speaking we are always open for a constructive dialogue with our stakeholders."

https://www.marketscreener.com/quote/stock/BAYER-AG-436063/news/Activist-Bluebell-builds-stake-in-Bayer-pushes-for-company-breakup-Bloomberg-42704541/

Kymera: 2023 Goals for Evolution into Fully Integrated Degrader Medicines Company

 Kymera Therapeutics, Inc. (NASDAQ: KYMR), a clinical-stage biopharmaceutical company advancing targeted protein degradation (TPD) to deliver novel small molecule protein degrader medicines, today announced its research, development and corporate goals for 2023.

“2022 was a pivotal year for Kymera, as the Phase 1 trial of our lead program, KT-474 (SAR444656), demonstrated fidelity of translation from healthy volunteers to patients, an encouraging safety profile, and clinical impact in complex inflammatory diseases such as hidradenitis suppurativa (HS) and atopic dermatitis (AD), highlighting the superior clinical potential of an IRAK4 degrader over a small molecule inhibitor and validating our platform, molecule design and target selection capabilities and strategies,” said Nello Mainolfi, PhD, Founder, President and CEO. “With our oncology pipeline advancing through dose escalation, we look forward to sharing data on the clinical activity of our STAT3 (KT-333) and IRAKIMiD (KT-413) programs in their target patient populations later this year, as well as initial proof-of-mechanism data on our MDM2 degrader (KT-253). More broadly, we have demonstrated the ability to effectively translate pharmacokinetic (PK), pharmacodynamic (PD) and safety from preclinical models into patients, as well as validation of our target selection strategy, allowing us to leverage and extend these learnings as we continue to expand our pipeline with differentiated and potentially best-in-class programs in large immunology and oncology franchises.”

“Kymera ended 2022 with a cash balance of approximately $560 million, providing the company with an anticipated cash runway into the second half of 2025 that is expected to take us past the proof-of-concept Phase 2 data for KT-474, as well as early proof-of-concept data for KT-413, KT-333 and KT-253.” Continued Dr. Mainolfi. “In addition, we are well-positioned to advance our wholly-owned clinical programs while continuing significant investments in our platform and robust discovery pipeline, additional details about which we look forward to sharing in 2023.”

Kymera’s 2023 Objectives

Kymera is a leader in the discovery and development of novel small molecule therapeutics designed to selectively degrade disease-causing proteins by harnessing the body’s natural protein degradation system. The company’s data, generated in healthy volunteers and patients with HS, AD, hematological malignancies and solid tumors, has provided industry leading, proprietary know-how in TPD and enabled Kymera to focus on applications in areas with significant patient need and large commercial opportunities, including immunology and oncology.

Key objectives include:

  • Collaborate with Sanofi to Initiate KT-474 Phase 2 trials
  • Publish results of KT-474 Phase 1 trial, including the HS/AD patient cohort
  • Demonstrate KT-413 clinical anti-tumor activity in target patient populations
  • Demonstrate KT-333 clinical anti-tumor activity in target patient populations
  • Initiate KT-253 Phase 1 trial in solid and hematological tumors and demonstrate KT-253 clinical proof-of-mechanism in patients
  • Deliver at least 2 new development candidates (DC)/Investigational New Drugs (IND) from the preclinical pipeline in areas of large clinical and commercial opportunity and pathways where TPD has potential to provide either the only or the best-in-class solution
  • Further expand the capabilities of Kymera’s Pegasus™ platform and continue to leverage Kymera’s E3 Ligase Whole-Body Atlas of over 600 unique E3 ligases, with a focus on tissue restricted E3 ligases
  • Expand novel molecular glue franchise in areas of unmet medical need, exploiting a newly identified degron motif
  • Advance existing collaborations, or execute additional strategic partnerships, that support the company’s evolution into a fully integrated, global biopharmaceutical company

Program Background

IRAK4 Degrader Program (KT-474/SAR444656)

KT-474 is a potent, highly selective, orally bioavailable IRAK4 degrader, in development for the treatment of IL-1R/TLR-driven complex inflammatory diseases where there is an opportunity to significantly advance the standard of care in a broad variety of diseases. In 2021, Kymera completed dose escalation in the single ascending dose (SAD) and multiple ascending dose (MAD) portions of its KT-474 Phase 1 trial, with the data demonstrating near complete IRAK4 degradation in peripheral blood mononuclear cells (PBMC) and skin, robust inhibition of multiple ex vivo-stimulated disease-relevant cytokines, and was generally well tolerated.

In the recently completed patient cohort of the Phase 1 trial, KT-474 showed evidence of robust IRAK4 degradation in the blood and active skin lesions of HS and AD patients, and was generally well tolerated. Treatment with KT-474 was associated with a systemic anti-inflammatory response and meaningful improvement in skin lesions and symptoms in both HS and AD patients, with internal consistency between the effect on inflammatory biomarkers and impact on clinical endpoints. KT-474 was generally safe and well-tolerated, with no serious adverse events, no drug-related infections, and no dose interruptions or discontinuations due to adverse events. Sanofi, which is collaborating with Kymera on the development of KT-474 (SAR444656) outside of the oncology and immune-oncology fields, has notified Kymera of its commitment to advance KT-474 into Phase 2 clinical studies. Initial Phase 2 clinical trials of KT-474 will investigate its potential in HS and AD, with the first study initiating in 2023.

STAT3 degrader program (KT-333)

KT-333 is designed as a potent degrader of STAT3, a transcriptional regulator that has been linked to numerous cancers and inflammatory and autoimmune diseases. KT-333 is being developed for the treatment of STAT3-dependent hematological malignancies and solid tumors. The Phase 1 clinical trial of KT-333 is designed to evaluate the safety, tolerability, PK/PD and clinical activity of KT-333 dosed weekly in adult patients with relapsed and/or refractory lymphomas, leukemias and solid tumors.

The Phase 1a dose escalation portion of the trial is ongoing. In December 2022 Kymera announced that Dose Level (DL) 1 had been completed with a total of 4 patients enrolled. All patients were heavily pretreated with multiple prior regimens and included 3 with solid tumors and 1 with cutaneous T-cell lymphoma. Plasma PK and PD translated as expected in humans, with mean maximum STAT3 degradation in PBMC following the first 2 doses averaging 66%, with maximum STAT3 knockdown of up to 86% as measured by mass spectrometry. There were no dose-limiting toxicities or treatment-related serious adverse events reported at this dose.

IRAKIMiD degrader program (KT-413)

KT-413 is a novel heterobifunctional degrader targeting both IRAK4 and the IMiD substrates Ikaros and Aiolos. Designed to address both the IL-1R/TLR and Type 1 IFN pathways synergistically with a single molecule, KT-413 is in development for the treatment of MYD88-mutant B cell malignancies. The Phase 1 clinical trial of KT-413 is designed to evaluate the safety, tolerability, PK/PD and clinical activity of KT-413 administered as an IV infusion once every 3 weeks to adult patients with relapsed and/or refractory B-cell non-Hodgkin's lymphomas.

The Phase 1a dose escalation portion of the trial is ongoing. In December 2022, Kymera announced that the first two dose levels had been completed. Patients were heavily pretreated with multiple prior regimens and included follicular lymphoma and DLBCL, which were both wild-type for MYD88. Plasma PK and PD translated as expected in humans with both dose levels showing dose-dependent degradation of IRAK4, Ikaros and Aiolos in PBMC, with up to 95/100% knockdown of Ikaros/Aiolos and 40% knockdown of IRAK4 at the second dose level. Serial tumor biopsies at Cycle 3/Day 4 in the patient treated at DL1 showed comparable knockdown of Ikaros/Aiolos and IRAK4 as in plasma. There were no dose-limiting toxicities or treatment-related serious adverse events and no neutropenia observed in the two patient cohorts.

MDM2 degrader program (KT-253)

The FDA has cleared the IND for KT-253, an investigational degrader that targets MDM2, the crucial regulator of the most common tumor suppressor, p53, which remains intact (Wild Type) in close to 50% of cancers. Unlike small molecule inhibitors, KT-253 has been shown preclinically to have the ability to suppress the MDM2 feedback loop and rapidly induce apoptosis, even with brief exposures. Kymera plans to commence the KT-253 Phase 1a dose escalation study in the first quarter of 2023, with IV doses of KT-253 administered every 3 weeks to patients with solid tumors and hematological malignancies, including acute myeloid leukemia (AML).

https://www.biospace.com/article/releases/kymera-therapeutics-shares-key-2023-goals-to-support-its-evolution-into-a-fully-integrated-degrader-medicines-company/

Merck Highlights Growth Strategy at J.P. Morgan

 Powered by its oncology and cardiovascular pipeline, Merck is eying significant revenue growth of more than $20 billion within the next decade.

At the 41st J.P. Morgan Healthcare Conference, Merck CEO Robert M. Davis outlined the company’s growth strategy that banks on the continued expansion of Keytruda and other oncology assets, as well as growth for its human papilloma virus vaccine, Gardasil. Key highlights from Merck’s presentation are:

Revenue Growth

Merck remains on track for significant revenue growth for the whole of 2022. In the third quarter, the company reported year-to-date revenue of $45.5 billion, a 29% increase from the previous year. In the same quarter in 2021, Merck reported $35.2 billion in year-to date revenue. Overall sales for 2021 were $48.7 billion, a 17% increase over 2020 earnings of $41.5 billion.

The primary growth driver for Merck is its checkpoint inhibitor, Keytruda, which generated $15 billion by the end of the third quarter. Other products contributing significant revenue include Gardasil, which  generated $5.4 billion for Merck through the first nine months of the year.

Surgical drug Bridion added another $1.2 billion in sales by the end of the third quarter. PARP inhibitor Lynparza, co-developed with AstraZeneca, provided $825 million and cancer drug Lenvima generated $660 million by the end of the third quarter for 2022.

Full year results for 2022 are expected to be announced in February.

Vaccines

Merck’s vaccines business will be a key growth driver over the next 10 years. Gardasil will continue to play an important role in Merck’s vaccines business. In its presentation, Merck said sales of the HPV vaccine are expected to double by 2030. The significant revenue boost will be driven by “strong global demand and increased ability to supply,” the company announced.

Other vaccine assets for Merck include a promising pipeline of vaccines for RSV and Dengue. Merck partnered with Instituto Butantan on the development of a Dengue vaccine. Earlier this year, IB posted positive topline results from a Phase III study of the vaccine candidate. The data is expected to inform next steps, Merck said.

Merck also has a suite of population-specific pneumococcal conjugate vaccines. In 2022, V116, a Phase III vaccine for the prevention of invasive pneumococcal disease in adults received Breakthrough Therapy designation.

Merck also intends to leverage its established presence in pediatric vaccines, the company noted in its presentation. One of its key pediatric vaccines is Vaxneuvance, a pediatric pneumococcal vaccine approved in June. The vaccine was approved for invasive pneumococcal disease in 2021.

Pipeline Advancements

In 2022, Merck continued to make significant progress with Keytruda. The drug racked up additional approvals, including receiving the green light for advanced endometrial cancer. Keytruda is also potentially in-line for additional approvals in non-small cell lung cancer and HER2- gastric or GEJ adenocarcinoma based on positive clinical data.

Lynparza received an approval for adjuvant treatment of adults with gBRCAm, HER2- high-risk early breast cancer.

The company also posted positive Phase IIb topline data for MRNA-4157/V940, a potential therapeutic for adjuvant melanoma.

Merck also saw progress with its cardiometabolic disease pipeline. The company announced positive topline data from the Phase III STELLAR trial assessing sotatercept for treatment of pulmonary arterial hypertension. Merck gained the drug through its $11 billion acquisition of Acceleron. That data is expected to lead to multiple regulatory filings.

Additionally, Merck’s MK-2060 received Fast Track designation in August for the reduction in risk of major thrombotic cardiovascular events in patients with end-stage renal disease. MK-2060 is an experimental monoclonal antibody designed to inhibit Factor XI.

M&A

Merck will continue to augment its pipeline through “the best external science.” Over the past five years, Merck spent more than $36 billion on business development deals. Noted activity over the past 12 months includes a collaboration with Moderna to evaluate a personalized cancer vaccine across multiple tumor types, as well as a collaboration with PeptiDream to discover and develop novel peptide drug conjugates.

Merck also acquired Imago BioSciences in November to expand its hematology presence with the LSD1 inhibitor, bomedemstat. The $1.3 billion deal provided Merck with a pipeline of myeloproliferative neoplasms therapeutics.

https://www.biospace.com/article/merck-highlights-growth-strategy-at-j-p-morgan/

Amgen Boasts Lucrative Acquisitions, Drug Updates, Burgeoning Biosimilars at JPM

 Not even a month after purchasing rare disease company Horizon Therapeutics Amgen came to the 41st J.P. Morgan Healthcare Conference in San Francisco to tout more than just this feather in its hat.

In a presentation led by Robert J. Bradway, Amgen chairman and chief executive officer, the company covered recent acquisitions, Repatha and Lumakras updates, biosimilars and its broader financial outlook.

Acquisitions

  • In December, Amgen acquired Horizon Therapeutics for $26.4 billion, emerging as the winner of a three-way bidding contest to acquire the sought-after company in biopharma’s most significant acquisition of 2022.

Bradway said the acquisition stood to:

  • Strengthen Amgen’s portfolio of first-in-class / best-in-class innovative therapeutics
  • Leverage Amgen’s decades of commercial and medical leadership in inflammation and nephrology
  • Besides Horizon, Amgen completed the integration of ChemoCentryx in October 2022, a biopharma company focused on orally-administered therapeutics for $52 per share in cash, an aggregate merger of $3.7 billion. Bradway reported the integration of the portfolio is going well.

Repatha and Lumakras

  • Repatha, for use adults with atherosclerotic cardiovascular disease, posted 52% volume growth in 2022.
  • Lumakras, part of Amgen’s oncology portfolio--here in lung cancer, specifically, posted 11% gains in year-end growth (for the oncology grouping as a whole).

Bradway said global sales of their top nine products, covering inflammation, oncology and general medicine, showed 16% volume growth by the third quarter of 2022, totaling $10.5 billion.

Biosimilars

Bradway said Amgen’s biosimilars continue to show gradual but stable growth.

  • Amjevita (Humira) will launch in the U.S. on January 31st.
  • More broadly, Amgen expects additional biosimilars to launch within the decade with potentially lucrative results.
  • Five biosimilars launched in 2021 racked up $2.2 billion in revenue. By 2030, Bradway projected at least 11 biosimilars to be at play and predicted Amgen to see more than double the 2021 revenue as a result.

Financial Outlook

Though it’s “disciplined capital allocation,” Bradway projected a bountiful future for Amgen through 2030.

Here’s how:

  • Executed strategic transactions to invest in external innovation
  • Acquired ChemoCentryx and Horizon Therapeutics
  • Invested $4 billion in research and development
  • Expect $1 billion in capital expenditures (manufacturing facilities in Ohio and North Carolina)
  • Increased dividend by 10%
  • Repurchased $6 billion in shares

AbbVie, Anima Strike mRNA Deal Worth Up to $582M

 Tuesday, AbbVie partnered with Anima Biotech to discover and develop mRNA modulators in a collaboration of up to $582 million. The partnership will focus on three oncology and immunology targets.

Under the agreement, AbbVie will put down an upfront payment of $42 million and, in return, will gain access to Anima’s mRNA Lightning technology and exclusive rights to license and further develop any resulting programs. AbbVie will also have the option to add three more targets under the same terms, potentially increasing the overall partnership value.

Meanwhile, the New Jersey-based private firm will be eligible for up to $540 million in option fees and research and developmental milestones across the three targets. The collaboration also leaves room for further commercial milestones and tiered royalties.

“Modulating mRNA biology with small molecules is a new approach,” said Jonathon Sedgwick, Ph.D., vice president and global head of discovery research at AbbVie, in a statement. This … “has the potential to address ‘undruggable’ targets with implications across multiple therapy areas.”

Tuesday’s partnership will combine this cutting-edge approach with AbbVie’s extensive expertise and global footprint in oncology and immunology.

Anima’s mRNA Lightning platform uses automated high-scale phenotypic screening combined with artificial intelligence to identify small molecule mRNA drugs and elucidate their mechanisms of action. This technology has won young biotech high-value partnerships.

In 2018, Anima signed a discovery and development deal with Eli Lilly worth at least $1 billion, focused on undisclosed targets. Three years later, the New Jersey biotech gained another partner in Takeda Pharmaceuticals, which bought into Anima’s tech in a potential $1.2 billion deal.

AbbVie Continues to Pick Up Partners

Anima is the latest partner in AbbVie’s quest to deepen its pipeline. Last week, they entered a multi-year collaboration with Immunome to identify up to 10 target-antibody pairs across three solid tumors. The deal is valued at $30 million upfront, with potential additional transfers of $70 million in platform access payments and $120 million per target in development and first commercial sale milestones.

Last month, AbbVie picked up Canadian company AbCellera in a discovery and development collaboration focused on identifying novel antibody candidates for up to five targets across several undisclosed indications.

The deal will give AbbVie access to AbCellera’s discovery and development engine, while the latter will be entitled to research payments as well as clinical and commercial milestones and royalties.

In October, AbbVie dropped $225 million in cash to acquire British biotech DJS Antibodies, adding the latter’s lead program DJS-002 into the AbbVie fold.

DJS-002 is a lysophosphatidic acid receptor one antagonist antibody being studied for idiopathic pulmonary fibrosis and another fibrotic disease.

Last year, in May, AbbVie signed another partnership with Massachusetts biotech Eugene, paying $48.5 million upfront for the latter’s CUG252, a Treg-selective IL-2 mutein with best-in-class potential. The pact also includes other novel IL-2 muteins across the autoimmune disease and cancer spaces.

https://www.biospace.com/article/abbvie-anima-strike-mrna-deal-worth-up-to-582/

Halozyme drops following weak 2023 outlook

 Halozyme Therapeutics Inc. (HALO) stock fell in the extended session Tuesday after the biotech drug maker's 2023 forecast disappointed Wall Street. Halozyme shares fell as much as 8% after hours, following a 1.2% gain to close the regular session at $55.70. The company forecast annual adjusted earnings of $2.50 to $2.65 a share on revenue of $815 million to $845 million with royalties of $445 million to $455 million. Analysts surveyed by FactSet had forecast $2.55 a share on revenue of $892.5 million with royalties of $478.2 million.

https://www.morningstar.com/news/marketwatch/20230110963/halo-therapeutics-stock-drops-following-weak-2023-outlook