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(Picture: Ugur Sahin, PhD, Co-Founder & CEO and Özlem Türeci, PhD, Co-Founder & CMO, BioNTech SE)

BioNTech Acquires Neon Therapeutics to Bolster Immuno-Oncology Pipeline – Biospace 1/17/2020

Mainz, Germany-based BioNTech announced it was acquiring Cambridge, Massachusetts-based Neon Therapeutics in an all-stock deal valued at about $67 million.

Neon’s focus is on neoantigen therapies that have the potential to be both vaccines and T-cell therapeutics. Neoantigens are immune targets generated by mutations inherent in tumors. Its most advanced program is NEO-PTC-01, a personalized neoantigen-targeted T-cell therapy. It is derived of multiple T-cell populations that target the most relevant neoantigens from each patient’s cancer. The company is also working on a precision T-cell therapy program that targets shared neoantigens in specific, genetically defined patient populations. The lead program from that endeavor is NEO-STC-01, which targets shared RAS neoantigens.

Neon Therapeutics was founded in 2015 by Third Rock Ventures. The company was one of BioSpace’s NextGen Class of 2017 biotech startups to watch.

“This acquisition fits with our strategy to expand our capabilities and build our presence in the U.S. and further strengthens our immunotherapy pipeline,” said Ugur Sahin, co-founder and chief executive officer of BioNTech. “I am particularly excited about the adoptive T-cell and neoantigen TCR therapies being developed by Neon, which are complementary to our pipeline and our focus on solid tumors.”

Under the terms of the deal, after the acquisition Neon will merge with Endor Lights, a wholly-owned subsidiary of BioNTech incorporated in Delaware. It will then become a wholly-owned subsidiary of BioNTech. At the close of the deal, BioNTech will issue 0.063 American Depositary Shares (ADS) to Neon shareholders in exchange for each of their Neon shares. This exchange ratio implies a deal value of $67 million, or $2.19 per Neon share, based on BioNTech’s ADS closing price of $34.55 on Wednesday, January 15, 2020.

The deal has been approved by both companies’ boards of directors. It is expected to close in the second quarter of 2020.

BioNTech was founded in 2008 and focuses on personalized cancer treatments. Earlier this month the company announced publication in the journal Science data from preclinical research on its first-in-kind CAR-T cell therapeutic approach to solid tumors. The therapeutic, BNT211, is an autologous CAR-T cell therapy that targets the oncofetal antigen Claudin 6 (CLDN6). It is suggested that the company’s CARVac is a broadly applicable RNA vaccine.

CAR-T has been shown to be effective in blood cancers, but much more limited in solid tumors. BioNTech is focused on developing CAR-T therapies in multiple solid tumors in combination with an RNA vaccine.

In the published data, the therapy was studied in mice with human ovarian cancer transplants. In the research, CLDN6-CAR-T showed complete tumor regression of transplanted large human tumors within two weeks after treatment initiation. The combination with CARVac improved engraftment, proliferation and CAR-T cell expansion, all of which is promising for human studies, which the company plans to launch this year, with ovarian, testicular, uterine and lung cancer.

Of the merger with BioNTech, Hugh O’Dowd, chief executive officer of Neon, said, “We are very proud of all we have accomplished since we founded Neon and look forward to joining forces with BioNTech to continue to build a business that provides life-changing immunotherapy products to patients battling a variety of cancers.”

BioNTech Buys Kite TCR Cell Therapy Plant to Boost US Trials – Biospace 7/19/2021

Germany’s BioNTech announced it is acquiring Kite’s solid tumor neoantigen T-cell receptor (TCR) research-and-development platform and its clinical manufacturing plant in Gaithersburg, Maryland. Kite is a Gilead company.

The company is best known for its mRNA COVID-19 vaccine it developed with Pfizer. However, much of BioNTech’s pipeline is focused on using mRNA for cancer applications. 

BioNTech indicates the acquisition will add production capacity in support of U.S. clinical trials. It already has a cell therapy manufacturing site in Idar-Oberstein, Germany. 

The company’s pipeline includes cancer product candidates built on its CAR-T cell amplifying mRNA vaccine (CARVac) and NEOSTIM platforms in addition to the newly acquired individualized neoantigen TCR program.

“The development of individualized cancer therapies is at the core of our work at BioNTech,” said BioNTech CEO and co-founder Ugur Sahin. “It also strengthens our presence in the U.S., building on our successful integration of adoptive T-cell and neoantigen TCR therapies as part of our acquisition of Neon Therapeutics last year.”

BioNTech picked up Neon Therapeutics in an all-stock deal worth $67 million in January 2020. Neon’s focus is on neoantigen therapies for both vaccines and T-cell therapies. 

Neoantigens are immune targets created by mutations inherent in tumors. Neon’s most advanced program was NEO-PTC-01, a personalized neoantigen-targeted T-cell therapy.

BioNTech’s pipeline includes BNT111 for advanced melanoma, currently in Phase II studies; BBNT112 in Phase I/II for metastatic Castration Resistant Prostate Cancer (mCRPC); and BNT113, also in Phase I studies for HPV16+ head and neck cancer, and approximately 11 others in clinical trials and more in preclinical development. 

On June 18, BioNTech treated the first patient in its BNT111 Phase II trial. It is testing BNT111 in combination with Libtayo (cemiplimab) in anti-PD1-refractory/relapsed unresectable Stage III or IV melanoma. It is being run in collaboration with Regeneron Pharmaceuticals. BNT111 is an intravenous cancer vaccine that uses mRNA to encode four cancer-specific antigens. Libtayo is Regeneron and Sanofi’s anti-PD-1 checkpoint inhibitor.

“Our vision is to harness the power of the immune system against cancer and infectious diseases,” said Özelm Türeci, co-founder and chief medical officer of BioNTech at the time. “We were able to demonstrate the potential of mRNA vaccines in addressing COVID-19. We must not forget that cancer is also a global health threat, even worse than the current pandemic.”

“BNT111 has already shown a favorable safety profile and encouraging preliminary results in early clinical evaluation. With the start of patient treatment in our Phase II trial, we are encouraged to continue on our initial path to realize the potential of mRNA vaccines for cancer patients,” she continued.  

Any Kite staffers working at the Gaithersburg facility will be offered employment with BioNTech. The company also indicates it plans to invest more in the location, including hiring more people. Kite has a new manufacturing site in Frederick, Maryland, to manufacture CAR T-cell therapies that are not part of this deal.

“In order to serve more patients that need cell therapy today, Kite is rapidly growing both through global expansion and seeking new indications for our existing approved CAR T-cell therapies,” said Christi Shaw, chief executive officer of Kite. “This transaction will enable us to focus our energies and investment on accelerating the reach of our current CAR-T-cell therapies and midterm pipeline.”

JPM 2022: BioNTech builds to a Crescendo with $750M biobucks pact for immunotherapies – Fierce Biotech 1/10/2022

After signing yet another deal with COVID-19 vaccine partner Pfizer last week, BioNTech is not stopping anytime soon on the deal front. This time, the vaccine maker is partnering with Crescendo Biologics for a $40 million upfront deal to work on immunotherapies.

BioNTech will provide the upfront fee to the Cambridge, U.K.-based biotech and a potential $750 million in biobucks for immunotherapies against cancer and other undisclosed diseases. The biotech, emboldened and lined with cash from its pandemic vaccine, will choose the targets for the mRNA-based antibodies and engineered cell therapies, the company said on the first day of the annual J.P. Morgan Healthcare Conference.

The German biotech will also provide research funding and handle development in exchange for exclusive worldwide rights on any products that come out of the discovery collaboration, which has an initial timeline of three years.

The deal gives BioNTech access to Crescendo’s “Humabody” platform, which is being used to generate multi-specific therapies. The company has developed CB213, which is not part of the deal, using the platform to target T cells expressing both PD-1 and LAG-3. Humabodies retain the binding and specificity of traditional antibodies but have a smaller size with better tumor penetration and stability, BioNTech said.

The platform is aimed at retaining the binding and specificity of traditional antibodies but utilizing a smaller size with better tumor penetration and stability, BioNTech said.

“Crescendo’s platform provides excellent properties for exploiting novel targets and target combinations which we believe has great potential for the development of multi-specific mRNA and engineered cell-based therapies in a variety of disease areas,” said BioNTech CEO Ugur Sahin, M.D., in a statement.

BioNTech will join Amgen in the multi-specific game, which is a type of medicine that attacks cancer in several different ways. Several bi-specifics have been approved and are in waiting at the FDA or in clinical trials. 

This is the second deal for BioNTech in five days. The company linked arms again with its Cominarty partner Pfizer last week to work on an mRNA-based shingles vaccine. Pfizer dished out $225 million upfront and will pay up to $200 million in biobucks. 

BioNTech jumps into PRAME game, paying Medigene $29M for preclinical T-cell therapy program – Fierce Biotech 2/22/2022

BioNTech, flush with COVID-19 cash, has struck another deal. The latest agreement will see the German biotech pay 26 million euros ($29 million) for a preclinical T-cell receptor (TCR) program from its compatriot Medigene.

Through the deal, BioNTech will take control of a preclinical program targeting PRAME, an antigen that is highly expressed in several solid tumors but largely limited to the testis in healthy tissues. The expression profile of PRAME led Medigene to genetically modify T cells to express both a TCR against the antigen and a PD1-41BB switch receptor designed to prevent inhibition in the tumor microenvironment.

BioNTech is acquiring the program as part of a deal that also gives it exclusive options on other TCRs. The partners will collaborate on the development of TCRs, with Medigene applying its discovery platform to multiple solid tumor targets selected by BioNTech under the terms of a three-year partnership.

In return, BioNTech is paying 26 million euros upfront, plus research funding for the collaboration, and committing to milestones that could top 100 million euros per program. The outlay also gives BioNTech licenses to Medigene’s PD1-41BB switch receptor and precision pairing library for use across its cell therapy programs.

Those cell therapies have played second fiddle as BioNTech’s mRNA capabilities have put it on the map, but they are a key area of focus for the biotech. Last year, BioNTech struck a deal to buy a solid tumor neoantigen TCR R&D platform and clinical manufacturing facility from Gilead’s Kite Pharma to add to its existing capabilities in Germany. The Medigene deal fits into the same strategy. 

BioNTech has also used its cash reserves, which came in at 2.4 billion euros and climbing at the end of the third quarter, to enter into a collaboration with Crescendo Biologics to develop engineered cell therapies as well as mRNA-based antibodies. The string of cell therapy deals was only broken up by the takeover of antibacterial biotech PhagoMed Biopharma for 50 million euros upfront in October.

The addition of Medigene to BioNTech’s list of cell therapy deals sent investors into overdrive. Shares in Medigene soared more than 90% to around 4 euros in early trading. While Medigene’s stock has hovered around the 4-euro mark for much of the past year, it fell to below 2 euros earlier this month. The BioNTech deal marks a rare moment in the spotlight for a biotech now perhaps better known for spawning Adaptimmune and Immunocore than it is for its internal achievements. 

BioNTech sets sights on oral mRNA vaccines with deal to access Matinas delivery technology – Fierce Biotech 4/12/2022

BioNTech has struck a deal to explore oral delivery of mRNA vaccines. Working with Matinas BioPharma, the German mRNA specialist will study the potential for a lipid nanocrystal (LNC) platform to enable new vaccine formulations.

The pandemic catapulted BioNTech into the biotech big leagues as the vaccine it discovered and then developed with Pfizer became a cornerstone of vaccination COVID-19 campaigns around the world. From that position of strength, BioNTech has identified Matinas as a company that can help it build a business beyond the Comirnaty windfall.

BioNTech is paying $2.75 million for exclusive access to Matinas’ LNC platform in the delivery of mRNA vaccines, and will fund some of its new partner’s research expenses related to the collaboration. Talks about a potential licensing agreement are underway.

The deal gives BioNTech a chance to take a closer look at the value the platform could bring to its mRNA vaccines. Matinas, which also has a LNC partnership with Genentech, licensed the platform from Rutgers University to enable the targeted intracellular delivery of a range of molecules, including mRNA.

In the context of mRNA vaccines, the stability of LNC structures has potentially significant implications. According to Matinas, the highly stable structure “allows for the avoidance of extreme cold chain storage temperatures required for maintaining the integrity of [lipid nanoparticles],” such as those used in the administration of Comirnaty. The Pfizer-BioNTech COVID-19 vaccine is stored at -90°C to -60°C.

If the LNC platform can enable mRNA vaccines to be stored at higher temperatures, it would be easier to get the products to people in the developing world, although the pandemic has already increased access to ultracold chain freezers. 

The stability of the LNC structure also opens the door to oral administration. Matinas is already using the platform to enable oral administration of its own molecules and BioNTech wants to assess whether it can open up a new route of delivery of mRNA vaccines. 

BioNTech adds STING to oncology portfolio in €40M small molecule licensing deal with Ryvu – Fierce Biotech 11/30/2022

It may have become a household name during the pandemic, but the drumbeat of announcements from BioNTech this year are a reminder that the German company has far more varied ambitions. With infectious disease and cancer vaccines in various stages of development, the biotech has now licensed a variety of small-molecule programs from Poland’s Ryvu Therapeutics.

Under the multi-target agreement, BioNtech will pay Ryvu 20 million euros ($20.7 million) upfront along with an equity investment of the same amount. Split into two parts, one side of the deal will see BioNTech secure an exclusive global license to develop and commercialize Ryvu’s STING agonist portfolio as standalone small molecules, including as monotherapies and in combination with other therapies.

The stimulator of interferon genes (STING) pathway is an immunity pathway that plays a key role both in responding to infections and autoimmune diseases as well as providing antitumor immunity. Preclinical studies have shown that Ryvu’s STING agonists were able to activate proinflammatory cytokine production and long-lasting immune responses, BioNTech said in a release.

The second part of the agreement will see the two companies jointly undertake drug discovery and research projects to develop multiple small-molecule programs for targets selected by BioNTech. The primary focus of these targets will be immune modulation for oncology, but the biotech has the option to push into other disease areas. Once candidates have been singled out for development, BioNTech will have the option to license them.

BioNTech will fund all discovery, research and development activities, with Ryvu also in line for undisclosed milestone payments and low single-digit royalties.

“Small molecules targeting novel immune signaling pathways have a great potential to increase the efficacy of cancer immunotherapies,” said BioNTech CEO Ugur Sahin, M.D., in a Nov. 30 release. “The collaboration with Ryvu provides us with the opportunity to complement our immunotherapy pipeline with a portfolio of potent immunomodulatory molecules.”

BioNTech’s oncology pipeline is already well underway. The company has 19 candidates across a total of 24 clinical trials, including CAR-T cell therapy candidate BNT211. The furthest developed are phase 2 trials of melanoma vaccine BNT111 and BNT113 for HPV16-positive cancers—which both use the biotech’s FixVac platform—plus a pancreatic cancer hopeful called autogene cevumeran and the bispecific antibody immune checkpoint modulator BNT311.

A number of drug developers have been stung in their attempts to chase the STING pathway. In 2019, Novartis ended work on an intratumoral STING pathway activator candidate developed by Aduro Biotech, while Nimbus Therapeutics also pivoted away from the pathway the following year.

BioNTech isn’t the only one who still sees potential, however. AstraZenecasnagged the global rights to research, develop and bring to market STING inhibitor compounds for $12 million upfront from F-star Therapeutics last year.

BioNTech’s cancer push continues, coughing up $200M for OncoC4’s CTLA-4 antibody – Fierce Biotech 3/20/2023

While BioNTech is still keeping one foot in the COVID-19 arena that made its name, the German company has made a concerted push toward treating cancer in recent months.

That effort took another leap forward Monday as the biotech announced a licensing deal with OncoC4, taking on the latter’s mid-stage CTLA-4-targeting monoclonal antibody, ONC-392, for $200 million in upfront cash. The exclusive licensing and collaboration agreement also includes an undisclosed amount of commercial and clinical milestones.

The deal is evidence of BioNTech’s fervor to keep its foot on the clinical gas pedal, particularly in cancer. ONC-392 is currently being assessed in a phase 1/2 trial in patients with solid tumors as both a monotherapy and combination treatment alongside Merck & Co.’s blockbuster Keytruda. Another phase 2 trial is looking at the same combo treatment in patients with platinum-resistant ovarian cancer. 

The data accrued from the ongoing phase 1/2 trial supports the launch of a phase 3 trial testing ONC-392 as a monotherapy in patients with PD-L1-resistant non-small cell lung cancer, BioNTech said in the release. 

The company believes the newly-acquired antibody has a “differentiated safety profile,” CEO Ugur Sahin, M.D., said. “Despite being a prime target for more than a decade, we believe that targeting CTLA-4 has not reached its full potential in cancer immunotherapy.”

The knock on the target in the past has been a significant level of immune-related adverse events. One systemic review from 2015 concluded that the tradeoff of anti-CTLA4 antibodies was “atypical immune toxicity.” 

ONC-392 slots into an ever-growing cancer pipeline for BioNTech, which includes nearly two dozen clinical-stage assets, five of which are antibodies. Four of the antibodies are part of a collaboration with Genmab, including phase 2 BNT311 currently targeting patients with metastatic non-small cell lung cancer. 

Much of the star power still rests with BioNTech’s cancer vaccine research, particularly after the U.K. government partnered with the company to deliver 10,000 personalized therapies by 2030. As part of the agreement, BioNTech will build a new R&D hub in the country, expanding its European footprint. 

BioNTech moves into ADCs with Duality deal – Biopharmadive 4/3/2023

Dive Insight:

Armed with cash earned from sales of the COVID-19 vaccine it developed with Pfizer, BioNTech has been investing in cancer drug research and development — its primary focus prior to the pandemic.

While BioNTech specializes in messenger RNA, it also has built a pipeline of antibody drugs, too. Most recently, it spent $200 million for rights to a cancer immunotherapy from the biotechnology company OncoC4.

The deal with Duality adds ADCs to BioNTech’s pipeline, taking the company into a fast-growing field. ADCs pair a cell-killing toxin with a targeting compound designed to home in on tumors while sparing healthy tissue. The complex drugs have a long history, but pharmaceutical companies’ interest in them has grown over the past several years, buoyed by clinical trial successes.

The Food and Drug Administration has approved eight ADCs since 2019, including AstraZeneca and Daiichi Sankyo’s breast cancer drug Enhertu. Dramatic study results for that treatment led the agency to expand its approval last summer to include people whose tumors have low levels of a protein called HER2.

Still, while ADCs have shown promise, they can cause severe side effects as well.

Duality’s lead candidate, dubbed DB-1303, also targets the HER2 protein, which is overexpressed in breast cancer and a number of other tumors. The drug is currently in a Phase 2 clinical trial for advanced solid tumors that are positive for HER2.

The other candidate BioNTech gains, DB13-11, is in preclinical development for “multiple cancer types.”

BioNTech isn’t the first Western drugmaker to turn to China-based biotechs for ADC technology. In 2021, Seagen — a pioneer in the field — struck a similarly sized deal with the Yantai, China-based biotech RemeGen to gain access to a HER2-targeting ADC.

BioNTech swiftly axes oral mRNA vaccine project after tech flunks early test – Fierce Biotech 5/11/2023

BioNTech has swiftly rejected an oral mRNA delivery technology. Barely one year after signing up to work with Matinas BioPharma, BioNTech found an initial mouse study failed to show preclinical activity—leading it to join Gilead Sciences on the list of companies to dump the biotech in recent months.

In April 2022, Matinas revealed BioNTech had paid $2.75 million for exclusive use of a lipid nanocrystal (LNC) platform in the delivery of mRNA vaccines. BioNTech agreed to fund Matinas’ research related to the collaboration, which covered formulation, optimization and in vitro testing, and entered into talks about a potential licensing agreement. 

The collaboration made it as far as a study in mice. Thursday, Matinas revealed that the study of the oral mRNA candidate failed to show activity. With the single study now over, BioNTech and Matinas have ended their collaboration.

Matinas’ summary of the collaboration offers insights into the challenges of delivering mRNA orally. The April 2022 statement about the deal said the collaboration would “evaluate the combination of mRNA formats and Matinas’ proprietary LNC platform technology.” However, the mouse study tested a non-LNC formulation of a BioNTech-supplied reporter mRNA.

As Matinas explained, it developed a “nano-formulation, distinct from traditional LNCs” to cope with the “physical complexity and biological fragility of mRNA.” The formulation worked in vitro, Matinas said, “and because of the timelines required under the BioNTech collaboration was brought forward for oral in vivo evaluation.”

While BioNTech is walking away, Matinas made the case that its approach may work, stating that internal in vivo studies of similar non-LNC mRNA formulations “showed activity when administered systemically.” The formulations are stable for at least 17 weeks at 4 degrees Celsius, suggesting they may be easier to ship and store than existing mRNA vaccines based on lipid nanoparticles.

The conclusion of the BioNTech deal comes five months after Gilead pulled out of a deal with Matinas to develop an oral COVID-19 antiviral to focus on its internal candidate. Roche’s Genentech unit recently extended its alliance with Matinas for another year, although, with the biotech completing its obligations related to a third and final molecule in the first quarter, the longer-term prospects remain uncertain.

BioNTech acquires tech company InstaDeep for $549m – Pharmaceutical Technology 8/1/2023

BioNTech has acquired all the remaining shares of technology company InstaDeep in a deal valued at €500m ($549m) in cash. The total deal value excludes the shares BioNTech already owns.

In January 2023, the parties signed an agreement for the acquisition.

UK-based InstaDeep is a technology provider in the fields of artificial intelligence (AI) and machine learning (ML). The takeover follows a collaboration between the two parties since 2019 and an equity investment by BioNTech in InstaDeep through a Series B funding round held in January 2022.

BioNTech expects that the deal will help it establish robust expertise in AI-powered drug discovery and the development of advanced vaccines and immunotherapies for conditions with high unmet medical needs.

BioNTech pays Autolus $250M for manufacturing, CAR-T expertise in wide-ranging collab – Fierce Biotech 2/8/2024

BioNTech has already been tinkering with its manufacturing processes in the run up to CAR-T BNT211 entering pivotal trials. Now, the German biotech has brought British company Autolus Therapeutics on board in an intriguing $250 million upfront collaboration.

The deal means BioNTech can use Autolus’ manufacturing and clinical site network across the U.K. to help efficiently develop BNT211 for pivotal trials in CLDN6+ tumors, the companies said in a Feb. 8 release.

In addition, BioNTech gains an exclusive license to use certain target binders identified by U.K.-based Autolus as well as the option to license additional binders or cell programming technologies to support the German biotech’s own in vivo cell therapy and antibody-drug conjugate (ADC) candidates. Autolus will be eligible to receive milestone payments from any resulting drugs.

In return, BioNTech will support the launch and expansion of Autolus’ lead autologous CD19 CAR-T, dubbed obe-cel, which is awaiting an FDA decision for patients with B-cell acute lymphoblastic leukemia.

BioNTech will also gain co-commercialization options for Autolus’ AUTO1/22 program, which has undergone a phase 1 study for relapse in patients who have received a CAR T-cell therapy for B-cell acute lymphoblastic leukemia, as well as AUTO6NG, which was expected to enter the clinic late last year for children with neuroblastoma.

BioNTech described the agreement as a “strategic collaboration aimed at advancing both companies’ autologous CAR-T programs towards commercialization, pending regulatory authorizations.”

While it appears that both biotechs will benefit from the collaboration, Autolus’ bank balance definitely wins out. BioNTech is not only handing over $50 million cash but will also buy $200 million of Autolus’ American depositary shares (ADSs) in a private placement. In return, BioNTech gets the right to appoint a director to Autolus’ board and is eligible for up to mid-single digit royalties on obe-cel sales.

To coincide with the BioNTech announcement this morning, Autolus said it was making a public offering of a further 58.3 million ADSs, which are expected to bring in gross proceeds of $350 million.

Autolus CEO Christian Itin said the deal with BioNTech was “a remarkable opportunity to leverage our core capabilities, accelerate pipeline programs, realize cost-efficiencies and expand opportunities beyond autologous cell therapies.”

Back in August, BioNTech executives attributed part of the success of the CLDN6 CAR-T program BNT211 in a solid tumor clinical trial to the company’s new manufacturing process. In today’s release, the biotech said it plans to have “10 or more ongoing potentially registrational clinical trials in the pipeline by the end of 2024,” which include BNT211 in relapsed or refractory germ cell tumors.

“The collaboration with Autolus enables us to expand our BNT211 program into trials for multiple cancer indications in a cost-efficient way,” BioNTech’s CEO Ugur Sahin, M.D., said in today’s release. “Autolus’ state-of-the-art manufacturing facilities’ set-up for clinical and commercial supply will enhance our own capacities in addition to our existing U.S. supply network and the ongoing expansion of our site in Gaithersburg, Maryland.”

(Picture: Mark C. McKenna, Founder & CEO of Mirador Therapeutics)

안녕하세요 보스턴 임박사입니다.

작년 6월에 Merck는 Prometheus Biosciences를 $10.8 Billion에 All-cash deal로 인수합니다. Merck의 Presentation을 보면 Prometheus의 Pipeline 중 PRA023 (MK-7240, Potential Best-In-Class & First-in-Class TL1A Antibody)에만 관심이 있습니다.

Prometheus에는 PRA023 말고도 PRA052 (CD30 ligand mAb)를 비롯한 다양한 Early-Stage Programs이 있었습니다. Merck는 이들 프로그램에는 관심이 없는 것 같습니다.

Merck Finalizes $10.8B Prometheus Buy – Biospace 6/19/2023

Merck finalized its acquisition of immune-focused Prometheus Biosciences for approximately $10.8 billion, scoring five clinical and pre-clinical candidates for inflammatory bowel and immune-mediated diseases on Friday.

Merck announced that Prometheus would now function as a fully-owned subsidiary. The leading candidate under Prometheus, originally designated for the treatment of ulcerative colitis and Crohn’s disease, has now been rebranded as MK-7240. This therapy serves as a catalyst, moving Merck further into the immunology space, an area in which the company has previously had limited involvement.

Original story published April 17:

Merck Acquires Prometheus Biosciences for Nearly $11 Billion

As per the terms of the all-cash agreement, Merck will buy all of Prometheus’ outstanding shares for $200 a piece, representing a 75% premium to Prometheus’ Friday closing price of $114. The companies expect to close the deal in the third quarter of 2023.

At the center of the transaction is Prometheus’ investigational monoclonal antibody, PRA023, which is set to enter late-stage studies later this year for ulcerative colitis (UC) and Crohn’s disease (CD). The drug targets and inhibits the action of tumor necrosis factor (TNF)-like ligand 1A (TL1A), a key immune factor that plays a role in both inflammation and fibrosis in intestinal immune-mediated disease.

In December, Prometheus announced results from Phase II and IIa studies that showed promising efficacy and safety in both inflammatory bowel diseases.

In the Phase II ARTEMS-UC study, 26.5% of patients with moderately-to-severely active UC reached clinical remission 12 weeks after receiving PRA023, as opposed to 1.5% of placebo comparators. Prometheus’ candidate also demonstrated superior endoscopic improvement and met all of the trial’s secondary endpoints.

PRA023 also performed well in the Phase IIa APOLLO-CD study, eliciting a 49.1% clinical remission rate in patients with moderately-to-severely active disease, compared with a 16% historical placebo rate. The candidate also led to higher endoscopic response and improved several markers of fibrosis and inflammation.

Both trials enrolled patients who had failed prior lines of therapy.

Prometheus is also evaluating PRA023 in systemic sclerosis-associated interstitial lung disease in Phase II assessments. In March 2022, the company kicked off the Phase II ATHENA-SSc-ILD study in this indication, with topline results expected in the first half of 2024.

Aside from PRA023, Prometheus is advancing four other candidates for immune-mediated indications, all of which will join Merck’s fold after the buyout.

Prometheus’ stock soared 70% in pre-market trading Monday, while Merck’s fell 1%.

Merck의 Prometheus Biosciences 인수가 마무리되고 나서 Mark C. McKenna를 비롯한 ex-Prometheus Biosciences Team은 다시 Mirador Therapeutics를 설립합니다. Arch Ventures, Orbimed와 같은 좋은 투자자들이 든든히 뒤를 받쳐준 덥분에 $100 Million Series A를 하려던 계획은 실제로 4배 규모의 시리즈 A로 마무리짓게 됩니다.

On the Lookout: Prometheus Veterans Launch Mirador Therapeutics With $400 Million – GEN Edge 3/21/2024

After being bought out by Merck in June 2023 for nearly $11 billion, some of the ex-brass from Prometheus Biosciences headed to a spear-shaped peninsula in Mexico surrounded on three sides by white sand beaches, Pacific Ocean waters, and lush tropical flora for some rest and relaxation. But playing golf and taking in the sea breeze in the coveted hideaway of Punta Minta wasn’t enough to keep Mark C. McKenna, the former chairman, president, and CEO of Prometheus Biosciences, from getting back into the game of making medicines. 

“The transaction with Merck was bittersweet,” McKenna told GEN Edge. “They were the right buyers, and it was the right time to do it… But there was a lot of unfinished business at Prometheus. There was a realization that we could all go work for different companies, or we could come back together and finish the mission. The field of data science is evolving so rapidly, so we were only scratching the surface.” 

About three-quarters of a year after the buy-out, McKenna, with some Prometheus veterans and new additions, unveiled Mirador Therapeutics with the vision to bring “end-to-end” precision medicine into immunology and inflammation. Behind a $400 million Series A and their proprietary platform, Mirador360, Mirador plans to leverage open-source human genetics data and cutting-edge data science, which, according to McKenna, will enable the company to file for investigational new drugs (INDs) by 2025. 

“We believe that based on our experience in this category, we have a unique vantage point,” said McKenna, alluding to the company’s name, which directly translates to viewpoint in Spanish. 

Prometheus veterans Olivier Laurent, PhD, Allison Luo, MD, Tim Andrews, Vika Brough, Nori Ebersole, and Jordan Zwick will join McKenna at Mirador Therapeutics in San Diego, CA. As for new faces, Mirador has brought on William J. Sandborn, MD, who previously served as a professor of medicine and chief of the division of gastroenterology at the University of California, San Diego, for ten years and co-founded Santarus and Shoreline Biosciences. 

작년 3월에 발표된 Prometheus Biosciencs 팀 Executive Team 8 명 중 4명이 Mirador에 조인을 합니다.

그리고 UCSD의 William J. Sanborn 박사가 조인을 하기로 되어 있습니다. 그는 IBD 등 Gastroenterology MD 입니다.

“It’s what you do with the data.” 

For Prometheus, that surface consisted of a clinical database and associated biobank exclusively licensed from Cedars-Sinai Medical Center. It included more than 200,000 samples linked to extensive clinical data from 20,000+ patients collected over 20 years. According to McKenna, the problem with that is that technology changes.  

Prometheus360이라고 불리던 지난 20년간 모은 2만개 이상의 환자 시료를 포함한 20만개 이상의 샘플이 있습니다.

이것들을 이용한 Data Science와 Genetics를 통해 새로운 표적을 발굴하는 것이 Prometheus Biosciences의 Platform Engine이었습니다. Patients Samples로 Inflammatory Diseases의 Genetics를 해독하고 새로운 표적을 발굴했는데 이런 과정에서 발굴된 것 중 하나가 PRA023 (MK-7240) 이었습니다. 검증된 플랫폼인 것이죠. McKenna는 소화기 (Gastrointestinal), 폐 및 피부 질환에 관심이 많다고 말했습니다. 이를 위해 학계와 파트너쉽도 하고 좋은 Asset이 있으면 Licensing-In 하려는 계획도 밝혔습니다.

McKenna said, “One of the things that big pharma, whether Regeneron or others, is realizing is that sequencing techniques and data science are evolving so quickly, and we need them to continue to invest in democratizing data and sequencing patients. Thank you, George [Yancopoulos] from Regeneron, for all you do at the UK Biobank and other places because that allows for innovation. I don’t believe the data itself is what’s proprietary. I think that what you do with the data is. The technologies allowing these data sets to be interwoven and translated more rapidly than ever weren’t available months ago.” 

Mirador’s scope of indications will go much broader than just inflammatory bowel disease. McKenna said Mirador is building a data cohort that straddles the disease areas they’re interested in—gastrointestinal tract, lung, and skin diseases—from a combination of open-source data and proprietary academic partnerships. 

End-to-end precision medicine 

According to McKenna, end-to-end means Mirador will discover and validate genetic associations with immuno-fibrotic diseases, identify novel therapeutic targets and optimal target-target pairs for potential combination therapies, develop diagnostics, and stratify heterogeneous patient populations for precise clinical development. 

“No one’s been able to do this before,” said McKenna. “We can put this on steroids and move the field further. It’s not the beginning but certainly not the end either.” 

In the last twenty years, McKenna said that he’s learned several lessons, none more important than properly managing and stratifying risk. This is particularly applicable to committing to using a single therapeutic modality. McKenna said that Mirador will not be afraid to try novel approaches from a modality perspective, but it will not be at the core of what they do.  

“If you think about the evolution here… [In the early days, you started] with an entrepreneur or scientist with one idea and a biased binary outcome,” said McKenna. “Then we shifted to this platform-focused idea: create all this data and then ask, is there actually a product? In version 3.0, it is more like a pipeline and a drug. We are focused on and have expertise in biologics. But we’re agnostic to what it is once it’s in the clinic, and we will have approaches with biologics working on targets that we find interesting and can be best-in-class. You have got to think about this for stratification very carefully.” 

Momentum-gaining investments 

The massive $400 million round of funding began through discussions with six investors, some of whom had previously worked with Prometheus; some were new relationships. 

“I wanted to work with people who had a big vision for doing transformational stuff and had a track record doing so, and I’m not sure you could have found better leads than ARCH [Venture Partners], OrbiMed, and Fairmount [Partners],” said McKenna. “Each of them brings different things to the table. At ARCH, [co-founder and managing director] Bob Nelson has big visionary ideas. [Managing director] Kristina Burrow understands how companies operate. You have OrbiMed’s public-market understanding. You have Fairmount and their ability to build companies. Then you have these different investors, like Fidelity—when was the last time Fidelity entered a Series A? So, we hand-selected these investors.”  

McKenna said the $400 million will go to multiple programs, INDs, and clinical data. It will allow Mirador to in-license external innovation that would benefit from our platform.

“We never went out and said, We want to raise $400 million,” said McKenna. “We said we will raise [$100 million], which started as a snowball. This is more dilution than necessary in the early days. We want to have a war chest to go in, create value, and build a pursuing medicine engine that people just haven’t been able to do.”

McKenna also said that Mirador will engage in external innovation, finding programs and companies that benefit from its platform, expertise, and know-how to accelerate the company’s pace.  

“Time is the new currency, particularly in biotech, and you see a lot of companies spending years and years to figure it out and burning a lot of cash to get there,” said McKenna. “One of the most remarkable things about the journey from Prometheus was that, in three and a half years, we created value, and the goal was never to build something to sell—the goal was to build a great company. If we build a great company and focus on inputs, the output will come. That’s exactly what we’re doing here [at Mirador]. This team is fired up, and it’s not about the money; it’s about what kind of impact we can actually have.” 

Merck와의 딜로 인수는 되었지만 Merck가 관심이 없는 임상1상 중인 약물 PRA052 (CD30 ligand mAb)이 있습니다. 최근 발표 자료에 의하면 만성 IBD 질환에 드는 약물입니다. 이 약물을 Merck로 부터 인수할지 여부도 궁금하고 향후 Mirador가 어떤 행보를 할지 궁금합니다.

(Picture: John “Jack” C. Bogle, Sr – Founder of Vanguard Group)

안녕하세요 보스턴 임박사입니다.

저와 같은 주알못도 주식투자로 돈을 벌 수 있도록 길을 열어준 故John Cliffton Bogle, Sr를 부러우면 지는거다에 초대합니다. 인덱스펀드는 주식시장 전체의 인덱스에 연동하도록 만든 뮤추얼펀드로서 거의 비용이 들지 않는 0.03%의 Management Fee 만을 붙이는 펀드입니다. 이것이 얼마나 적은 돈이냐 하면 소위 CFA/CFP라고 하는 사람들은 0.5 ~ 2%의 Management Fee를 붙이기 때문입니다.

그가 한 유명한 말이 있습니다.

“When a door closes, if you look long enough and hard enough, if you’re strong enough, you’ll find a window that opens.- John Cliffton Bogle, Sr” (기회의 문이 닫혔을 때 그 문을 오랜동안 아주 열심히 보다보면 새로운 창문이 열리고 있다는 사실을 볼 수 있을 것이다)

그는 그런 사람이었습니다. 미국 프린스턴 대학교를 졸업하고 1965년Wellington Fund에 입사한 Jack Bogle은 자신이 맡긴 펀드매니저들의 터무니없는 펀드 관리로 인해 1974년 해고를 통보받습니다. 그러나 그는 굴하지 않고 끝까지 남겠다는 주장을 관철시켜서 당시 맡고 있던 뮤추얼펀드의 대표직을 계속할 수 있다는 결정을 끌어냅니다. 그는 자신이 프린스턴 대학교에서 연구했던 논문과 노벨경제학상 수상자인 Paul Samuelson의 글을 읽고 인덱스 펀드를 만들기로 결정합니다. 처음에는 반대가 많았지만 관리비가 들지 않는다는 말에 결국 결정은 받아들여지게 됩니다. 그리고 이 펀드의 커미션을 모두 없애 버립니다.

제가 2000년대 중반부터 401(k)에 투자를 시작했는데 처음에는 뮤추얼펀드를 어떻게 고를지 몰라서 그냥 수익률이 좋은 펀드에 투자를 하는 식으로 했지만 수익률이 좋지 않았습니다. 그러다가 인덱스펀드가 가장 수수료가 싸고 좋은 투자라는 것을 알게 되어 2010년대부터 인덱스펀드에 100%로 투자하고 있는데 그 이후에 이 펀드가 가장 수익률이 좋았습니다. 지금도 저의 최애 펀드는 VOO 라는 Vanguard Group이 운영하는 Standard & Poors 500 Index Fund입니다.

직장에 다니면서 주식투자를 전문가처럼 하기는 불가능합니다. 이기는 것도 불가능하지만 그렇다고 투자를 하지 않을 수도 없습니다. 그래도 다행히 저에게 뱅가드의 인덱스 펀드가 있으니 얼마나 다행인지 모릅니다. 요즘은 피델리티도 뱅가드와 같이 최저가 관리비 (expense ratio)로 운영하는 인덱스펀드가 많이 생겨서 얼마나 즐거운 고민을 하고 있는지 모릅니다.

2019년에 89세의 일기로 작고하셨지만 Jack Bogle의 Legacy는 지금도 Bogleheads.org 라는 잭 보글을 따르는 커뮤니티에 영원히 살아계십니다.

The Worth Of A Man: A Tribute To John C. Bogle – Forbes 1/16/2019

You cannot measure the quality of a man by the size of his bank account, but in John Bogle’s case, you can measure it by the size of your bank account. No one on this planet has done more to increase the lot of individual investors in the last 50 years than John C. Bogle, founder and former chairman of the Vanguard Group and creator of the world’s first index mutual fund.

Throughout his legendary career, Jack Bogle, as he is fondly known to everyone who has had the pleasure to meet his confident smile and piercing blue eyes, has helped millions of investors build wealth the right way. His repetitive lessons of low fees, broad diversification, and Stay the Course! are engrained in the minds of “Bogleheads” near and far and have made their way into every personal finance book published in the past two decades.

I was fortunate to get an hour of John Bogle’s time last September to record an interview for “The Bogleheads on Investing” podcast. If you haven’t heard of the Bogleheads, they’re a group of like-minded individual investors who meet on Boglehead.org to discuss the general investment and business beliefs of Jack Bogle. It is a conflict-free community where individual investors reach out and provide education, assistance and relevant information to other investors of all experience levels at no cost.

Sensible investing isn’t all that Jack was about. Until his last day, he led a tireless campaign to restore common sense to the investment industry and instill words like honor and duty. Bogle championed restoring integrity in industry practices and believed that a trustworthy business and financial complex is essential to America’s continuing leadership in the world and to social and economic progress at home.

It is an uphill battle to bring integrity to the financial system. In my last conversation with Jack, he expressed frustration with our leaders in Washington who struggle with the concept of imposing a fiduciary duty on all financial advisers who guide individual investors. The so-called fiduciary rule is something he truly believed in and championed for. In Jack’s honor, I propose we rename this effort “The Bogle Rule“.

One of my favorite books Jack Bogle wrote was titled “Enough, True Measures of Money, Business, and Life”. It reveals Jack’s unparalleled insights on money and what we should consider as the true treasures in our lives. He details the values we should emulate in our business and professional callings and provides thought-provoking life lessons regarding our individual roles in society. Jack examined what it truly means to have “enough” in a world increasingly focused on status and score-keeping.

Most people choose a career in the investment business to make money; Jack Bogle chose to use that career to make a difference. Rest in peace, Jack. You’ve done enough.

Jack Bogle died peacefully at his home on Wednesday afternoon, January 16, 2019. He was 89 years old.

Bogle was never shy about expressing his views or talking about his life. He did so again in an essay for Forbes‘ 2017 centennial issue, which is republished here.

Jack Bogle Dies At 89—Here Is His Timeless Advice – Forbes 1/16/2019 by Abram Brown

Jack Bogle, the founder of the Vanguard Group who pioneered the idea of low-cost investing and index funds, has died. He was 89. His ideas have grown into the cornerstone of investing advice for average Americans, and Bogle was never shy about expressing his views or talking about his life. He did so again in an essay for Forbes‘ 2017 centennial issue, which is republished below.

“Reinvention”

By Jack Bogle

In 1965, my mentor, Walter L. Morgan, the founder of Wellington Management Co., called me into his office. It was the go-go era, and we only had a conventional, balanced mutual fund. “I want you to do whatever it takes to fix the company. You’re in charge now.” I was 35. So I merged with a very aggressive equity fund out of Boston with managers younger than I was. It seemed like an act of genius, until it wasn’t. The go-go era fell apart, and they turned out to be terrible money managers. In January 1974, the board of Wellington Management, controlled by that Boston group, fired me.

Except that the mutual funds themselves had a separate board controlled by independent directors, and I persuaded that board not to fire me. So there was a big fight, and it was resolved with a terrible deal: I would continue as chairman and CEO of the funds, which would be responsible for their own legal, compliance, administration and record keeping. (And I had to come up with a new name —that was the start of Vanguard Group.) My rivals, the people who fired me, would continue to oversee distribution, marketing and investment management. The scheme was totally irrational.

I had to find a way for Vanguard to take on the investment management and distribution of our funds. I had done some work on index funds in my senior thesis at Princeton in 1951. I had experienced the failure of active management firsthand. And I had just read an article by Nobel Laureate Paul Samuelson, saying, in essence, “Somebody, somewhere, please start an index fund.” I took the idea to the board and they said “You can’t get into investment management,” and I said, “This fund has no investment management.” They bought it, and there’s where the index revolution began. Then I decided we couldn’t allow Wellington and its sales force to continue to distribute the funds so we eliminated all sales commissions and went no-load overnight. The directors said “You’re not allowed to take over distribution,” and I said “We’re not taking it over; we’re eliminating it.” They bought it, again.

When a door closes, if you look long enough and hard enough, if you’re strong enough, you’ll find a window that opens.

안녕하세요 보스턴 임박사입니다.

인덱스 펀드의 창시자 고 Jack Bogle (John C. Bogle) 이 만든 Vanguard에서는 주알못을 위한 Target Retirement Funds를 2003년부터 판매하고 있습니다.

The Worth Of A Man: A Tribute To John C. Bogle – Forbes 1/16/2019

일반적으로 Target Retirement Funds의 구조는 아래와 같은 개념을 바탕으로 만들어져 있습니다.

20대에는 90% 주식 : 10% 채권으로 구성을 합니다.

40대까지도 이 비율은 거의 유지가 됩니다. 주식 90% : 채권 10% 입니다.

은퇴 준비 연령인 60세가 되면 주식 60% : 채권 40% 로 채권비율이 높아지도록 비율을 조정합니다.

Medicare를 받는 나이이면서 은퇴연령인 65세가 되면 주식 50% : 채권 50% 로 채권의 비율이 더 늘어납니다.

401(k), IRA의 RMD 나이인 72세가 되면 주식 30% : 채권 70% 로 채권의 비율이 월등하게 높아지게 됩니다.

Expense ratio는 0.08%로 Low-Cost Mutual Fund입니다.

1963-1967년생들에게 맞는 펀드는 “VTHRX – Retirement 2030 Fund”가 해당하는 펀드입니다.

• 미국 주식 (VSMPX, 0.03% expense ratio, 1.35% dividend yield): 37.8%
• 해외주식 (VGTSX, 0.08% expense ratio, 3.12% dividend yield): 24.9%
• 미국채권 (VTBIX, 0.02% expense ratio, 3.22% dividend yield): 24.1%
• 해외채권 (VTILX, 0.07% expense ratio, 4.22% dividend yield): 11.2%

포트폴리오 구성은 주식 61.9% : 채권 36.1% 입니다.

2006년에 창설된 이래 연평균 복리수익률이 6.63%이고 배당수익률은 2.54% 입니다.

1968-1972년생들에게 맞는 펀드는 “VTTHX – Retirement 2035 Fund”가 해당하는 펀드입니다.

• 미국주식 (VSMPX, 0.03% expense ratio, 1.35% dividend yield): 43.0%
• 해외주식 (VGTSX, 0.08% expense ratio, 3.12% dividend yield): 20.8%
• 미국채권 (VTBIX, 0.02% expense ratio, 3.22% dividend yield): 27.3%
• 해외채권 (VTILX, 0.07% expense ratio, 4.22% dividend yield): 8.9%

포트폴리오 구성은 주식 70.3% : 채권 29.7% 로 되어 있습니다.

2003년에 펀드가 창설된 이래 연평균 7.4% 복리수익률로 수익률이 좋습니다. 배당률도 현재 2.41%입니다. 2030 펀드에 비해 주식비중이 높다보니 배당률은 0.14% 정도 낮게 되어 있지만 그래도 나쁘지 않은 수익률입니다.

(Picture: Bert Vogelstein, MD, Professor of Johns Hopkins University)

(Picture: Drew M. Pardoll, MD, PhD, Professor of Johns Hopkins University)

안녕하세요 보스턴 임박사입니다.

면역항암제에 대한 환자들의 반응은 좀 극단적인 경향을 띄어서 반응을 하는 환자들은 완치가능성이 높아지는 반면 반응하지 않는 환자들의 경우는 독성만 높아서 환자들이 고통을 받기 일쑤입니다. Johns Hopkins University의 Drew M. Pardoll교수와 Bert Vogelstein교수는 이것을 찾기 위해 MANAFEST (Mutation-Associated Neoantigen Functional Expansion of Specific T Cells) Assay를 개발하고 2018년 Cancer Immunology Research에 발표를 합니다.

2021년에는 MANAFEST를 이용해서 anti-PD-1 면역항암제 치료를 받은 폐암환자들 중 반응을 하는 환자들 (Responders)와 반응하지 않는 환자들 (Nonresponders)를 조사해서 MANA (Mutation-Associated Neoantigen)을 발견하고 Transcriptional programming을 통해 반응하지 않는 환자들이 반응할 수 있도록 했다고 2021년에 Nature지에 발표를 했습니다. MANAFEST Assay를 이용한 이러한 효과를 바탕으로 2020년말에 ManaT Bio라는 회사를 창업했습니다.

Right Program Could Turn Immune Cells into Cancer Killers – Johns Hopkins University Newsroom 9/9/2021

Cancer-fighting immune cells in patients with lung cancer whose tumors do not respond to immunotherapies appear to be running on a different “program” that makes them less effective than immune cells in patients whose cancers respond to these immune treatments, suggests a new study led by researchers at the Johns Hopkins Kimmel Cancer Center Bloomberg~Kimmel Institute for Cancer Immunotherapy.

The findings, published in the August 5 issue of Nature, could lead to new ways to overcome tumor resistance to these treatments.

“Cancer immunotherapies have tremendous promise, but this promise only comes to fruition for a fraction of patients who receive them,” says study leader Kellie N. Smith, Ph.D., assistant professor of oncology and Johns Hopkins Bloomberg~Kimmel Institute of Immunotherapy investigator. “Understanding why patients do or don’t respond could help us raise these numbers.”

Cancer immunotherapies have gained traction in recent years as a way to harness the immune system’s inherent drive to rid the body of malignant cells, Smith explains. One prominent type of immunotherapy, known as checkpoint inhibitors, breaks down molecular defenses that allow cancer cells to masquerade as healthy cells, enabling immune cells known as CD8 T cells to attack the cancer cells. Different populations of these immune cells recognize specific aberrant proteins, which prompt them to kill malignant cells as well as cells infected by various viruses.

Although checkpoint inhibitors have shown tremendous success in some cancer types — even sometimes eradicating all evidence of disease — the portion of patients with these dramatic responses is relatively low. For example, only about a quarter of patients with non-small cell lung cancer (NSCLC) have significant responses to these treatments.

Searching for differences between responders and nonresponders, Smith and her colleagues turned to results of a previous immunotherapy study. They gathered blood, tumor and healthy tissue samples taken from 20 early-stage NSCLC patients who took part in the previous study, which tested the effects of administering immune checkpoint inhibitors before surgery to remove tumors. Nine of the patients had a dramatic response to checkpoint inhibitors, with 10% or less of their original tumors remaining at the time of surgery. The other 11 patients were nonresponders and had either significantly lower responses or no response at all.

After isolating CD8 T cells from each of these samples, the researchers used a technology developed at Johns Hopkins called MANAFEST (Mutation Associated NeoAntigen Functional Expansion of Specific T cells) to search specifically for those cells that recognize proteins produced by cancerous mutations (known as mutation-associated neoantigens, or MANA), influenza or Epstein-Barr, the virus that causes infectious mononucleosis. They then analyzed these cells using a commercially available technique called single cell transcriptomics to see which genes were actively producing proteins in individual cells — the “program” that these cells run on.

The researchers found that responders and nonresponders alike had similarly sized armies of CD8 T cells in their tumors, with similar numbers of cells in both populations that respond to MANA, influenza and Epstein-Barr. However, when they compared the transcriptional programs between responders and nonresponders, they found marked differences. MANA-oriented CD8 T cells from responders showed fewer markers of exhaustion than those in nonresponders, Smith explains. Responders’ CD8 cells were ready to fight when exposed to tumor proteins and produced fewer proteins that inhibit their activity, she says. In one patient who showed a complete response to checkpoint inhibitors — no evidence of active cancer by the time of surgery — the MANA-oriented CD8 T cells had been completely reprogrammed to serve as effective cancer killers. In contrast, nonresponders’ MANA-oriented CD8 T cells were sluggish, with significantly more inhibitory proteins produced.

Both responders and nonresponders’ MANA-, influenza- or Epstein-Barr-oriented CD8 T cells had significant differences in their programming as well. The MANA-oriented cells tended to be incompletely activated compared with the other CD8 T cell types. The MANA-oriented cells were also significantly less responsive to interleukin-7, a molecule that readies immune cells to fight, compared with influenza-oriented cells.

Together, Smith says, these findings suggest numerous differences in MANA-oriented cells between checkpoint inhibitor responders and nonresponders that could eventually serve as drug targets to make nonresponders’ CD8 T cells act more like responders’ — both for NSCLC and a broad array of other cancer types.

“By learning how to reprogram these immune cells, we could someday facilitate disease-free survival for more people with cancer,” says Smith. She adds that “an important and interesting finding was that nonresponders had cells that recognized the tumor. So there is ‘hope’ for developing treatments for patients who don’t respond to single agent immunotherapy. We just need to figure out the right target to activate these cells to help them do what they were made to do.”

Other Johns Hopkins researchers who contributed to this study include Justina X. Caushi, Jiajia Zhang, Zhicheng Ji, Ajay Vaghasia, Boyang Zhang, Emily Han-Chung Hsiue, Brian J. Mog, Wenpin Hou, Richard Blosser, Ada Tam, Valsamo Anagnostou, Tricia R. Cottrell, Haidan Guo, Hok Yee Chan, Dipika Singh, Sampriti Thapa, Arbor G. Dykema, Poromendro Burman, Begum Choudhury, Luis Aparicio, Laurene S. Cheung, Mara Lanis, Zineb Belcaid, Margueritta El Asmar, Peter B. Illei, Rulin Wang, Jennifer Meyers, Kornel Schuebel, Anuj Gupta, Alyza Skaist, Sarah Wheelan, Jarushka Naidoo, Kristen A. Marrone, Malcolm Brock, Jinny Ha, Errol L. Bush, Matthew Bott, David R. Jones, Joshua E. Reuss, Victor E. Velculescu, Kenneth W. Kinzler, Shibin Zhou, Bert Vogelstein, Janis M. Taube, Julie R. Brahmer, Patrick M. Forde, Srinivasan Yegnasubramanian, Hongkai Ji, Drew M. Pardoll.

This work was funded by grants from the Lung Cancer Foundation of America, the Mark Foundation for Cancer Research, the SU2C/Mark Foundation Lung Cancer Dream Team Convergence Award, the SU2C INTIME and SU2C-LUNGevity-American Lung Association Lung Cancer Interception Dream Team, Bristol-Myers Squibb, the SU2C DCS International Translational Cancer Research Dream Team, The IASLC Foundation, Swim Across America, The LUNGevity Foundation, the Commonwealth Foundation, the Banks Family Foundation, Subsidies for Current Expenditures to Private Institutions of Higher Education from the PMAC, through a subaward from Juntendo University, the Dr. Miriam and Sheldon G. Adelson Medical Research Foundation, the Virginia and D.K. Ludwig Fund for Cancer Research, the Ludwig Center for Cancer Immunotherapy at Memorial Sloan Kettering, Cancer Research Institute, the Parker Institute for Cancer Immunotherapy, the Lustgarten Foundation for Pancreatic Cancer Research, the Conquer Cancer Foundation of ASCO, Bloomberg Philanthropies, the Maryland Cigarette Restitution Fund, the V Foundation, the Allegheny Health Network–Johns Hopkins Research Fund, the Damon Runyon Cancer Research Foundation, U.S. National Institutes of Health grants (R37CA251447, R01HG010889, R01HG009518, R01CA121113, R01CA217169, R01CA240472, CA62924, T32 CA193145, T32 CA009110, and T32 GM136577), and National Institutes of Health Cancer Center Support Grants (P30 CA008748 and P30 CA006973).

Anagnostou receives research funding from Bristol-Myers Squibb and AstraZeneca. Taube receives research funding from Bristol-Myers Squibb and serves a consulting/advisory role for Bristol-Myers Squibb, Merck, and AstraZeneca. Illei receives research funding from Bristol-Myers Squibb and Erbe Elektromedizin GmbH and serves a consulting/advisory role for AstraZeneca and Veran Medical Technologies. Naidoo receives research funding from AstraZeneca, Bristol-Myers Squibb, and Merck, and serves a consulting/advisory role for AstraZeneca, Daiichi Sankyo, Bristol-Myers Squibb, Merck, and Roche/Genentech. Marrone is a consultant for Amgen and AstraZeneca. Jones is a consultant for More Health and AstraZeneca and a steering committee member for Merck. Park is a consultant for AstraZeneca and Regeneron and has received honoraria from Intuitive Surgical. Chaft is a consultant for AstraZeneca, Genentech, Merck, Flame Bioscience and Novartis. Velculescu is a founder of Delfi Diagnostics and Personal Genome Diagnostics, serves on the board of directors and as a consultant for both organizations, and owns Delfi Diagnostics and Personal Genome Diagnostics stock, which are subject to certain restrictions under university policy.

Additionally, The Johns Hopkins University owns equity in Delfi Diagnostics and Personal Genome Diagnostics. Velculescu is also an adviser to Bristol-Myers Squibb, Genentech, Merck, Takeda Pharmaceuticals, Daiichi Sankyo, Janssen Diagnostics and Ignyta. Hellman receives research support from Bristol-Myers Squibb; has been a compensated consultant for Merck, Bristol-Myers Squibb, AstraZeneca, Genentech/Roche, Nektar, Syndax, Mirati, Shattuck Labs, Immunai, Blueprint Medicines, Achilles, Arcus, and Natera; and has received travel support/honoraria from AstraZeneca, Eli Lilly and Bristol-Myers Squibb. He also has options from Shattuck Labs, Immunai and Arcus and has a patent filed by his institution related to the use of tumor mutation burden to predict response to immunotherapy (PCT/US2015/062208), which has received licensing fees from PGDx. The Johns Hopkins University is in the process of filing patent applications related to technologies described in this paper on which Hsiue, Vogelstein, Kinzler and Zhou are listed as inventors. Vogelstein and Kinzler are founders of Thrive Earlier Detection. Kinzler is a consultant to and was on the board of directors of Thrive Earlier Detection. Vogelstein, Kinzler and Zhou own equity in Exact Sciences; are founders of, hold or may hold equity in, and serve or may serve as consultants to manaT Bio, manaT Holdings, Personal Genome Diagnostics and NeoPhore. Zhou has a research agreement with BioMed Valley Discoveries. Kinzler and Vogelstein are consultants to Sysmex, Eisai and CAGE Pharma and hold equity in CAGE Pharma. Vogelstein is a consultant to and holds equity in Catalio. The companies named above, as well as other companies, have licensed previously described technologies related to the work from this lab at The Johns Hopkins University. Licenses to these technologies are or will be associated with equity or royalty payments to the inventors as well as to The Johns Hopkins University. Merghoub is a co-founder and holds equity in IMVAQ Therapeutics; is a consultant for Immunos Therapeutics, ImmunoGenesis and Pfizer; receives research funding from Bristol-Myers Squibb, Surface Oncology, Kyn Therapeutics, Infinity Pharmaceuticals, Inc., Peregrine Pharmaceuticals, Inc., Adaptive Biotechnologies, Leap Therapeutics, Inc. and Aprea; and holds patents on applications related to work on oncolytic viral therapy, alpha virus-based vaccines, neoantigen modeling, CD40, GITR, OX40, PD-1 and CTLA-4. Brahmer serves an advisory/consulting role for Amgen, AstraZeneca, Bristol-Myers Squibb, Genentech/Roche, Eli Lilly, GlaxoSmithKline, Merck, Sanofi and Regeneron; receives research funding from AstraZeneca, Bristol-Myers Squibb, Genentech/Roche, Merck, RAPT Therapeutics, Inc. and Revolution Medicines; and is on the data and safety monitoring board of GlaxoSmithKline, Janssen and Sanofi. P.M.F. receives research support from AstraZeneca, Bristol-Myers Squibb, Novartis, and Kyowa; has been a consultant for AstraZeneca, Amgen, Bristol-Myers Squibb, Daichii Sankyo, and Janssen; and serves on a data safety and monitoring board for Polaris. Yegnasubramanian receives research funding from Bristol-Myers Squibb/Celgene, Janssen and Cepheid, has served as a consultant for Cepheid, and owns founder’s equity in Astra Therapeutics and Digital Harmonic. Smith, Pardoll, Vogelstein and Kinzler have filed for patent protection on the MANAFEST technology described herein (serial no. 16/341,862). K.N.S., D.M.P., J.E.C., B.V., E.H.-C.H. D.M.P., K.W.K. and S.Z. have filed for patent protection on the p53 R248L mutation-specific TCR described herein (serial No. 63/168,878). Pardoll is a consultant for Compugen, Shattuck Labs, WindMIL, Tempest, Immunai, Bristol-Myers Squibb, Amgen, Janssen, Astellas, Rockspring Capital, Immunomic and Dracen, and owns founder’s equity in manaT Holdings, LLC, WindMIL, Trex, Jounce, Anara, Tizona, Tieza and RAPT, and receives research funding from Compugen, Bristol-Myers Squibb and Anara. Smith has received travel support/honoraria from Illumina, Inc., receives research funding from Bristol-Myers Squibb, Anara and Astra Zeneca, and owns founder’s equity in manaT Holdings, LLC. The terms of all these arrangements are being managed by the respective institutions in accordance with their conflict of interest policies.

그리고 2023년부터 $153 Million 규모의 Series A를 시작합니다. 당시에는 KRAS, BRAF, p53와 같은 유전자의 Mutated Neoantigen에 대한 치료제를 계획하고 있었습니다.

ManaT Bio, a KRAS biotech from Bert Vogelstein and Catalio, targets $153M with Third Rock partner as CEO – Endpoints News 10/26/2023

A new immunotherapy biotech from famed Johns Hopkins oncology researchers Bert Vogelstein and Drew Pardoll is in the works, with a sizable $153 million financing round underway.

Vogelstein, who has founded cancer detection companies like Thrive and Haystack Oncology, has been working on a “multi-year collaboration” with Pardoll to find mutation-associated neoantigens (hence MANAs) that show up on the cell surface, according to the company’s incubator, Catalio Capital Management.

Vogelstein is a venture partner at Catalio, the life sciences investment firm that his son, Jacob Vogelstein, co-founded with George Petrocheilos. Private equity firm KKR recently bought a minority stake in Catalio, the firms said last week.

An SEC filing from this week indicates Baltimore-based ManaT has reeled in about $72 million of an anticipated $153 million funding round.

Cary Pfeffer
The company is currently led by Cary Pfeffer, a Third Rock Ventures partner who’s been at the biotech investment firm since it was founded in 2007 and has helped launch other portfolio startups like Faze Medicines and Tango Therapeutics. He’s CEO and president of ManaT, per the SEC paperwork.

Pfeffer declined to comment Thursday morning.

ManaT’s goal is to create biologics or cell therapies that target mutations in KRAS, BRAF and p53, among other genes commonly found in cancers, per Catalio’s website, and the startup’s website notes it’s developing off-the-shelf therapies based on insights into genetics.

KRAS, one of the most frequently mutated cancer drivers, has drawn more attention in recent years thanks to the race between approved KRAS drugmakers Amgen and Mirati Therapeutics, which is being bought by Bristol Myers Squibb for $4.8 billion.

Alongside Pfeffer on the board are fellow Third Rock partner Andrea van Elsas, Vivo Capital managing partner Jack Nielsen and Raymond Camahort, a partner in Novo Holdings’ venture investments group.

ManaT was formed in late 2020 and initially led by co-founder Eileen McCullough, who then went on to lead AI-driven protein synthesizer Amide Technologies, per her LinkedIn profile.

그리고 금년 3월에 총 $150 Million Series A를 받았다고 발표를 했습니다. 개발 중인 파이프라인은 MANA (Mutation-Associated NeoAntigen)을 통한 Modular T Cell Engagers (TCEs)입니다.

Third Rock, Novo Holdings-backed Clasp Tx hooks $150M series A for next-gen cancer treatments – Fierce Biotech 3/20/2024

A new immuno-oncology biotech has emerged, clasping $150 million that will go toward developing next-generation T cell engagers (TCEs) targeting a range of hard-to-treat tumors.

Clasp Therapeutics unveiled March 20, touting a series A co-led by Catalio Capital Management, Third Rock Ventures and Novo Holdings, the latter of which manages the Novo Nordisk Foundation’s assets.

The newly launched biotech is built on advances made by scientific founders Bert Vogelstein, M.D., and Drew Pardoll, M.D., Ph.D., both of whom are professors at Johns Hopkins University. The company’s platform is designed to help develop modular TCEs that are tailored to each patient’s oncogenic driver mutations. 

Clasp’s TCEs are bispecific-antibody-like molecules that can bind to both a T cell and a tumor-specific mutant peptide at the same time. The approach aims to ensure immune activation against the tumor while sparing normal tissue, which lacks the tumor-specific mutated peptide.

The resulting treatment should be a highly specific, off-the-shelf medicine that ditches toxicities commonly associated with on-target, off-tumor binding, CEO Robert Ross, M.D., said in the March 20 release.

“We have the ability to redirect T cells to kill cancer cells while sparing healthy cells throughout the body,” Andrea Van Elsas, Ph.D., chief scientific officer at Clasp and partner at Third Rock Ventures, said in the release.

“Clasp’s proprietary technology enables immune targeting of intracellular oncogenic driver mutations to achieve durable tumor killing, even with low levels of surface presentation,” Elsas added. “Furthermore, the modularity of Clasp’s TCE platform gives it potential to address unmet need across a broad range of hard-to-treat tumor types.”

회사 홈페이지에 나온 것을 보면 전형적인 TCE를 개발한다는 그림이 있는데 이 중 특정 HLA molecule T cell receptor peptide를 표적합니다.

따라서 Clasp의 TCE는 MANA와 HLA type을 결합해서 Allogeneic TCEs를 개발하겠다는 것으로 보입니다. 임상에 진입을 할 것 같은데 임상 PoC가 어떻게 나올지 기대가 됩니다.

(Picture: Steven M. Albelda, MD, PhD, Professor of University of Pennsylvania School of Medicine)

(Picture: Jonathan A. Epstein, MD, Professor of University of Pennsylvania School of Medicine)

안녕하세요 보스턴 임박사입니다.

In vivo CAR-T 치료제를 개발하는 회사 중에 Umoja Biopharma에 대해 블로그를 적은 적이 있습니다.

BIOTECH (60) – Umoja Biopharma’s in vivo CAR-T Platform

Penn Medicine의 Steven M. Albelda교수와 Jonathan A. Epstein 교수팀에서는 2019년 Nature에 CD8+ T cell을 이용해서 Cardiac Fibrosis를 치료할 수 있다는 가능성에 대해 논문을 발표했습니다.

그리고 2022년에는 Science에 노벨상 수상자인 Drew Weissman교수와 함께 CD5-targeted LNP-mRNA를 이용한 In Vivo CAR-T에 의해서 Cardiac Fibrosis를 치료할 수 있다는 것을 Mouse Proof of Concept Data로 발표했습니다.

(Picture: Drew Weissman, MD, PhD, Professor of University of Pennsylvania School of Medicine)

이러한 연구결과를 바탕으로 Novartis Venture Fund와 OrbiMed에 의해 2021년에 Capstan Therapeutics가 시작되었고 2022년에 Pfizer, BMS, Bayer, Eli Lilly 등이 함께 참여하여 총 $165 Million Series A를 했습니다.

Capstan Therapeutics의 특징은 Immune-targeted LNP를 Delivery System으로 사용한다는 것입니다.

Science 논문에서는 CD5-targeted LNP를 사용한 연구결과를 발표했고 2023년에 SITC 학회에서 발표를 했습니다.

Capstan Therapeutics Launches with $165M for Precise in Vivo Cell Engineering – Biospace 9/14/2022

Backed by industry giants, Capstan Therapeutics launched Wednesday with $165 million to combine the potency of cell therapy with the precision of genetic medicines against various difficult-to-treat diseases.

Capstan’s core technology is in vivo cell engineering. By injecting lipid nanoparticles targeted to immune cells, the biotech is looking to deliver a piece of mRNA that can induce the transformation of T lymphocytes into transient therapeutic CAR T cells inside the body. This approach can be applied to many therapeutic areas, such as cancer, blood disorders and autoimmune diseases.

The scientific basis for Capstan’s platform was first characterized in a study published in Science in January. The study tested the technology in mice with cardiac fibrosis–the scarring of heart tissue.

The research team, which included several Capstan founders, encased engineered mRNA in lipid nanoparticles designed to seek out the CD5 surface protein of T cells.

When injected in mice models, they found that these complexes could reprogram T lymphocytes into CAR T cells targeting the FAP protein, a fibrosis-related target. Cardiac function was eventually restored in the treated mice.

Capstan plans to use the proceeds from Wednesday’s launch to further develop this platform and its three modules: the targeted lipid nanoparticles, the targeting molecules to ensure specificity and the disease-related mRNA payload. 

The company’s goal is to maximize the clinical promise of cell therapies by accomplishing the precise and in vivo engineering of cells.

Capstan is prioritizing diseases ripe for transforming the standard of care in terms of therapeutic targets. Initially, the company will leverage its already-demonstrated approach of producing therapeutic CAR T cells in vivo. Its goal is to make such treatments administrable in the outpatient setting. 

Monogenic blood disorders are also in the company’s sights.

“We are conducting research across oncology, autoimmune disorders, fibrosis, as well as monogenic blood disorders and optimizing the components of our platform with the goal of nominating lead candidates and progressing towards IND-enabling activities,” Laura Shawver, president and CEO of Capstan, told BioSpace.

Backed by Industry and Scientific Heavy-Hitters

The promise of Capstan’s platform has earned it the support of several industry giants. The young company’s initial funding includes $102 million from a recently closed Series A financing round led by Pfizer Ventures. Leaps by Bayer, Eli Lilly and Company and Bristol Myers Squibb, among other investors, also participated.

The remaining $63 million came from Capstan’s seed funding, led by Novartis Venture Fund and Orbi Med.

Aside from industry backers, Capstan is also built on a solid scientific foundation. Among the company’s founders are Jonathan Epstein, M.D. and Haig Aghajanian, Ph.D., both experts in preclinical translation, as well as Carl June M.D. and Bruce Levine, Ph.D., leading figures in cell engineering.

Lending Capstan with their mRNA and lipid nanoparticle expertise are Drew Weissman, M.D., Ph.D. and Hamideh Parhiz, Pharm.D., Ph.D., while Ellen Puré, Ph.D. and Steven Albelda, M.D. provided insight on immunology and fibrosis. Helming the company is Laura Shawver, Ph.D., who will serve as its president and chief executive officer. Shawver has more than 20 years of executive leadership experience.

시리즈 A를 한지 채 2년이 되지 않아 $175 Million Series B를 했습니다. 이번 증자에는 Johnson & Johnson이 참여를 했습니다. CPTX2309라는 CD19-CAR-T를 Autoimmune Disease 치료제로 임상에 적용하려는 것이 이번 펀딩의 목적입니다.

Capstan heats up ‘in vivo’ cell therapy chase with $175M fundraise – Biopharmadive 3/20/2024

Capstan Therapeutics, a biotechnology startup developing medicines that reprogram cells inside the body, has raised another $175 million to bring its first prospect into clinical testing. 

The high-profile startup, formed by a group of pioneering cell therapy and messenger RNA researchers, secured the financing from a wide range of investors led by RA Capital and including five pharmaceutical companies, it said Wednesday. Johnson & Johnson is one of Capstan’s new backers, joining existing investors Pfizer, Bristol Myers Squibb, Eli Lilly and Bayer, among others. The startup has now raised $340 million since 2021.  

Capstan will use the funds to advance its work developing cell therapies designed to be administered through a single infusion, rather than via a laborious process that involves genetically manipulating cells in a lab. If successful, these “in vivo” cell therapies could help broaden the reach of so-called CAR-T therapy, and be more convenient and accessible to patients. 

The startup is one of a handful of young drugmakers to emerge in the last three years to pursue in vivo cell therapy research and attract funding. Multiple pharmaceutical companies have shown interest, investing in Capstan as well as others like Asgard Therapeutics and Ensoma. Another well-funded in vivo cell therapy startup, Umoja Biopharma, signed a collaboration deal with AbbVie in January. 

Capstan’s goal is to use messenger RNA technology to coax the body into making its own CAR-T cells. Early research published in Science and Nature showed the feasibility of the approach in animals, but it’s nonetheless a daunting task that’s never been attempted in humans. 

“Our immune system is primed to attack anything that’s delivering RNA. So the main challenge is, how do you make it stealth and get it into cells without causing a lot of immune activation?” said CAR-T innovator and University of Pennsylvania scientist Carl June, one of Capstan’s co-founders, in an interview with BioPharma Dive in 2022. 

Since then, the company has progressed to the point that it now has a lead program. Called CPTX2309, it is being developed for autoimmune diseases and delivers an mRNA payload that redirects T cells to cells with the protein CD19. 

That particular protein is found on the antibody-making B cells that malfunction in a variety of autoimmune diseases. It’s also the target of a number of cell therapies in clinical testing for lupus and other inflammatory conditions, all of which aim to induce a “reset” of a patient’s disease. Many of those programs involve “ex vivo” approaches, however. 

Capstan said the funds will get its lead program to early proof-of-concept studies and help advance the rest of its pipeline. 

“We are grateful for the support of both new and existing investors as we enter a critical phase of execution, with the ultimate goal of bringing new therapeutic modalities to patients,” said CEO Laura Shawver, in a statement. 

2023년 SITC와 2024년 PNAS 논문에서는 CD5-targeted LNP-mRNA를 이용한 In Vivo CAR-T로 IL7이 T Cell에서 선택적으로 증가함을 보고했습니다. CD5-targeted LNP가 Spleen과 Lymph Node로 잘 전달되어서 T 세포에서 잘 발현된다는 결과입니다. 아직 초기단계이기는 하지만 빅파마들의 관심이 뜨겁군요. 펀딩이 벌써 $340 Million이나 되었습니다. 요즘 바이오텍 펀딩시장은 상당히 살아나는 것으로 보입니다. 임상에 진입해서 Human PoC Data가 동물실험의 결과와 유사하게 나올지 궁금합니다.

오늘은 막내딸의 생일이었다.

한국식으로는 고3, 미국식으로는 Senior in High School로 어려운 인내의 시간을 잘 버텨준 딸에게 사랑의 마음을 보내고 싶다. 돌아보면 이 아이를 가질 때부터 우리 가족은 경제적으로나 영적으로 그리고 가정적으로 안정되기 시작했던 것 같다. 내가 미국에서 포스닥 생활을 마치고 첫 직장을 보스턴에 얻어서 이사를 오게 되었고 1년이 채 되지 않아 새집을 장만했었다. 그렇다보니 우리 딸은 보스턴이 자기가 평생 기억하는 유일한 고향이었고 이곳에서 초등학교부터 고등학교까지 같은 친구들과 내내 잘 지내었다.

어릴 때는 애교도 많고 항상 사랑받고 자라서 사랑을 줄줄도 아는 아이였는데 사춘기를 지나면서 변화가 생기고 차츰 소원해진 적도 없지 않았다. 큰딸과 나이차가 있다보니 어떤 마음에서는 새롭게 다시 양육을 배우는 과정이었던 것 같기도 하고 모든 면에서 처음인 것이 많았던 것 같다. 언니가 항상 학교를 가니 자기도 가고 싶었는지 장난감 가방을 지고 애기때부터 학교 가는 시늉을 하곤 해서 우리 부부에게 웃음을 안겨주던 딸이었다. 그게 습관이 되어서 항상 공부만큼은 나무랄 것 하나없이 잘했다. 자동차 운전도 운전할 수 있는 가장 어린 나이인 15살 9개월이 되자마자 Permit 받고 운전 연수를 시작했고 이제는 자기 차를 가지고 매일 등하교를 스스로 한다.

엄마가 잠시 한국을 방문하게 되어 단둘이 있는 시간이 많아졌는데 매일 저녁식사를 함께 하고 무빙 (Moving)이라는 20개의 에피소드를 함께 하루에 한두개씩 같이 보는게 유일한 낙이 되었다. 곧 칼리지 투어를 가야할 것 같은데 이 순간들이 딸 아이와 나 사이에 좋은 추억이 되기를 기대해 본다.

오늘 저녁 큰아이가 자기 집에 초대를 해서 저녁을 먹고 막내는 학교에 아카펠라 공연으로 다니러 갔다가 늦게 다시 큰아이 집에 모여서 작은 생일 케이크와 선물 교환을 하고 한국에 있는 엄마와 카톡으로 영상통화도 함께 했다.

이제 성인이 된 우리 딸.

하나님의 뜻을 깨닫기 시작한 우리 막내가 어엿한 어른으로 나아가는 새로운 세상에서 자신의 아이덴티티를 잘 붙들고 꿋꿋이 나아가기를 기대해 본다.

Happy Birthday!!

안녕하세요 보스턴 임박사입니다.

이곳이 투자를 얘기하는 곳이지만 투자에는 꼭 주식, 채권, 부동산만 있는 것이 아니라 연금도 있다고 생각합니다. 그 중에서 장수연금 (Longevity Annuity)는 장수 리스크를 해결할 수 있는 가장 좋은 방법이라고 생각하고 특히 401(k)나 IRA를 이용해서 들 수 있는 QLAC (Qualified Longevity Annuity Contract)을 60세가 되면 가입을 하려고 생각을 합니다.

Longevity annuities: Why clients should consider them. Journal of Accountancy 5/30/2023

Frank and Jenna, both 65 and in good health, have roughly $2 million saved for retirement, but Frank is reluctant to take the extended European vacation they had long promised themselves. “What if we live into our 90s and the markets tank?” he says. “We might run out of money.” Perplexed by his hesitation about spending, Jenna suggests they speak with their CPA financial planner, who explains that one option would be to buy a longevity annuity.

After further consultations, the hypothetical couple take 10% ($200,000) of their retirement nest egg and purchase an annuity that will pay $65,000 each year beginning when they reach age 85 for as long as either of them is alive.

Longevity annuities are a type of annuity that will “kick in if you’re still alive at a given age to ensure that no matter what’s happened in your portfolio, you have some amount of money to live,” said David Blanchett, Ph.D., who heads retirement research at PGIM DC Solutions, the global investment management business of Prudential Financial Inc.

Low-cost longevity protection

Blanchett observed in an interview that longevity annuities are “a relatively low-cost way to provide longevity protection.” While single-premium immediate annuities are expensive because the annuity payments begin right away, longevity annuities “cost a lot less because the guarantee starts at some point in the future.” In addition, because actuaries can predict that a certain percentage of the annuity purchasers won’t live long enough to receive a payout (to age 80 or 85, say), those who do survive receive correspondingly greater monthly annuity payments (calculated using the concept of “mortality credits”).

This makes longevity annuities “a very economically efficient way to create income that’s guaranteed for life,” Blanchett said.

Michael Finke, Ph.D., professor of wealth management at The American College of Financial Services, who will speak about annuities at this year’s AICPA & CIMA ENGAGE 2023 conference, concurred in this positive opinion of longevity annuities. He and others who research retirement view longevity annuities as “the ideal solution to getting rid of longevity risk in a tax-efficient fashion,” he said. He especially highlighted qualified longevity annuity contracts, or QLACs, which are purchased with qualified funds such as those in a 401(k) or an IRA.

Which clients they’re best for

Longevity annuities are ideal for clients whose worries about outliving their money are preventing them from enjoying their retirement years, like the hypothetical couple Frank and Jenna above. In Blanchett’s view, whether to buy a longevity annuity is “very much a conversation about how someone feels about spending their portfolio.”

“Even if you’re radically overfunded for retirement, if you’re not willing to go on cruises or do things that you enjoy because you’re worried about outliving your resources, OK, we can fix that” with a longevity annuity, Blanchett said.

“What annuities do, behaviorally,” Finke said, “is give the client a pathway to spending down the money that they’ve saved without the fear that they’re going to run out.”

It almost goes without saying that longevity annuities — also referred to as deferred income annuities or delayed income annuities — are best for healthy clients who are optimistic about living long enough to collect the annuity payments when they begin, typically at age 80 or 85.

Generally, high-wealth people are the ones who purchase longevity annuities, Finke said. The product might not be as worthwhile for average-wealth clients because, for one thing, longevity annuities “are priced based on the type of person who has enough money to buy one of these” — typically, wealthy Americans, who tend to live longer. In other words, the mortality tables reflect the longer-lived person who tends to buy an income annuity. But for certain clients of average wealth, a QLAC may be a sensible purchase.

For clients in general, the primary strategy to consider for increasing their guaranteed stream of lifetime income is to spend down savings, if necessary, as a bridge to delay claiming Social Security until age 70, both Finke and Blanchett said. Maximizing one’s monthly government check in this manner is advantageous especially because Social Security, which is essentially a government-funded annuity, comes with an annual cost-of-living adjustment.

Why clients hesitate to buy them

While academic researchers laud them, longevity annuities have yet to catch on widely with clients. They “are very behaviorally difficult to buy,” Blanchett said, noting that clients may think: “What do you mean? I’m going to allocate $100,000 to buy this annuity where if I’m alive in 15 years, it starts paying me?” Agreeing, Finke described these annuities as “probably the most difficult financial product to sell.”

In addition, some financial advisers have a negative perception of annuities in general, which may be partly because of some poor products on the market or their price, but, Finke said, they should rethink these negative views. Perhaps in some cases, too, advisers may be reluctant to remove money from their assets under management, he said.

Worries about insurance company solvency may be another reason clients hesitate to buy longevity annuities. “You really do need to pay attention to credit quality of the insurance company,” Finke said, because the payout does not begin for 15 or 20 years.

Also, some clients may be reluctant to buy a longevity annuity because of concern about future inflation eroding the value of the annuity payments. While a client can pay extra for an annuity the payments of which will increase annually by a fixed percentage (such as 2% or 3%), this does not truly protect against inflation, both Finke and Blanchett said.

Tax aspects

Longevity annuities have certain tax advantages. If one is purchased through a qualified retirement plan or an IRA, “you get the QLAC opportunity,” Finke noted. This includes being able to buy the QLAC with pretax funds. Also, the investment in the QLAC is not counted in calculating current required minimum distributions (RMDs) from qualified retirement plans, which may save substantially on taxes.

The maximum amount an individual can invest tax-deferred in a QLAC is $200,000 (indexed for inflation). If a workplace retirement plan doesn’t offer QLACs, a client could roll over funds to an IRA to buy the QLAC, Blanchett said.

Purchasing a longevity annuity through a taxable investment account has significant tax benefits, too. Blanchett highlighted that you won’t be taxed on the annuity income until you begin receiving payments (say, 15 or 20 years in the future), and the tax is only on the amount of income above the premium paid. “There is a little bit of ‘tax alpha’ that you get from buying these in taxable accounts versus qualified accounts, given the way that annuities structure the income,” he said.

Finke commented: “I think that annuities are chronically underused in financial planning as a way of sheltering nonqualified tax-inefficient investments such as bonds.”

In addition, “you may be able to get a tax arbitrage benefit if your client is in a lower marginal tax bracket environment in retirement, or if they move to a lower-tax state then,” he said.

But whether your client chooses to buy a longevity annuity through a qualified or a taxable account, Finke and Blanchett agreed that it may not make sense to pay extra for an optional “return of premium” rider that gives back the premium, or some of it, to your beneficiaries if you die early. The rider cuts into the size of the annuity payments.

Blanchett suggested that it is best to think about longevity annuities as longevity insurance: “OK, just say, ‘You know what? I’m going to buy this, and if I’m still alive in 20 or 25 or however many years, I’ll get the income. If not, I’m not going to worry about it.’ Right?”

Both Blanchett and Finke will be giving presentations on retirement planning at the upcoming AICPA & CIMA ENGAGE 2023 conference, which is being held June 5–8 in Las Vegas and live online. They also have a podcast together called Wealth, Managed.

Members of the AICPA’s Personal Financial Planning Section can learn more about annuities in chapter 8 of the Guide to Financial and Estate Planning, Vol. 2.

— Dave Strausfeld, J.D., is a JofA senior editor. To comment on this article or to suggest an idea for another article, contact him at David.Strausfeld@aicpa-cima.com.

은퇴자금 바닥나는 만년에 수입 보장 – 미한국일보 3/6/2017

‘자격있는 장수 어누이티 계약’(qualified longevity annuity contracts·QLACs)라는 고령에 대비한 은퇴 저축 플랜에 대해 아는 한인들이 많지 않다. 3년전 버락 오바마 행정부가 장수시대를 맞아 은퇴 자금이 말년에 모두 고갈 되는 것을 막기 위한 새로운 연금상품 방식으로 출범했다. 주요 골자는 이렇다.

401(k), 403(b)와 같은 직장 은퇴저축플랜과 전통 IRA와 같은 개인 은퇴저축플랜을 가진 경우 돈의 일부를 ‘롱지비티 어누이티’(장수시대 대비 은퇴연금보험)에 투자한 후 일정 기간이 지나면 죽을 때까지 매달 고정금액을 받는 것이다. 이들 은퇴저축플랜은 세금을 내기전 수입에서 적립하므로 감세 효과는 물론이고 말년에 보장된 수입을 올릴 수 있는 저축 상품으로 환영을 받아왔다.

많은 보험회사들이 뛰어 들어 QLAC 상품을 선보이고 있지만 적지 않은 사람들이 구입할지를 놓고 고심하고 있다. 사실 완벽한 은퇴 저축플랜은 없다. QLAC 역시 새로운 상품이기 때문에 아직 장단점이 완전히 파악되지는 않았다.

65세 여성의 예를 들어 설명해 보자. 이 여성은 IRA에 50만 달러를 가지고 있다. 4%규칙에 따라 65세부터 매년 4%씩 찾는다고 가정하면 한달 수입이 1,666달러이고 그 금액은 매년 줄어들어 30년 후에는 모든 저축금이 고갈된다.

이 여성이 어누이티(은퇴연금보험) 옵션을 사용한다면 이야기는 달라진다. IRA에서 최대 12만5,000달러까지 인출해 QLAC에 투자한다. 85세까지는 찾아 않아도 된다. 이후 매달 3,300달러, 또는 연간 4만 달러를 받는다. 이 금액은 여성이 120까지 산다고 해도 죽기 전까지 계속 동일한 금액으로 받을 수 있다.

이 여성은 IRA에 남은 37만5,000달러를 여유 있고 공격적으로 투자해 돈을 더 불려나갈 수 도 있고 또 여유 있게 돈을 지출할 수 있다. QLAC에 투자한 돈으로 85세 이후 은퇴 수입을 보장받기 때문이다.

▲QLAC

QLAC는 401(k), 403(b) 또는 전통 IRA와 같은 세금 유예 은퇴저축플랜에서 구입할 수 있는 은퇴연금보험 계약이다. 상품의 목적은 말년까지 은퇴 수입을 만들 수 있도록 하자는데 있다. 물론 세금은 찾아 쓸 때까지 유예된다.

은퇴 유예저축플랜은 59½세부터 벌금 없이 찾아 쓸 수 있지만(세금은 내야 함) 70½세까지는 한푼도 찾지 않아도 된다. 하지만 70½세가 지나면 의무적으로 정부가 정한 계산법에 따라 최소한의 돈을 찾아 써야 한다. 이를 최소분배금(Required Minimum Distribution) 또는 RMD라고 부른다.

그런데 QLAC에 적립되는 돈은 RMD 계산 때 적용되는 은퇴 플랜 총액에서 제외된다. 이에따라 RMD가 줄어들 것이고 소득세도 그만큼 줄어들게 된다. 그러나 QLAC 적립금에도 한계가 있다. QLAC 적립금은 은퇴저축플랜에 있는 총액의 최고 25%까지 또는 12만5,000달러중 적은 쪽을 택해야 한다.

▲QLAC 혜택

세금 혜택 외에의 장점은 QLAC는 일반적으로 즉시 지불 은퇴연금보험 상품(single premium annuity product)보다 비싸지 않다는 점이다.

70세의 나이에 8만 달러를 투자했다면 80세에 찾을 경우 남성은 매년 1만2,850달러, 여성은 매년 1만1,500 달러를 받을 수 있다. 반대로 보험료를 일시불로 다 낸 후부터 즉시 매년 돈을 받는 즉시 은퇴연금보험(immediate annuity)에 같은 금액을 투자했다면 남성은 연간 6,150달러, 여성은 5,750달러를 찾아 쓸 수 있다. 거의 절반 수준이다.

은퇴 자금이 거의 동날 시점인 만년에 적당한 은퇴 수입을 지속적으로 받을 수 있는 매우 유익한 상품이다. QLAC는 또 일반적으로 직접 투자 관리를 하지 않아도 된다. 투자가 필요 없어 연례 관리비를 내지 않아도 된다.

▲부부 공동 가능

QLAC은 부부 또는 누군가와 공동으로 오픈할 수 있다.

다시말해 평생 보장된 수입을 죽을 때까지 부부 또는 공동으로 어카운트를 오픈하는 사람과 받을 수 있다는 의미다. 물론 매달 받는 수입은 혼자 받을 때 보다 줄어든다. 만약 공동 어카운트가 부부가 아닌 경우에는 별도의 제약이 따른다.

부부가 별도의 QLAC를 구입해도 된다. 이 경우 각각 IRA등 은퇴 저축플랜이 있어야 한다. 이런 경우 배우자 사망했을 때 생존한 배우자는 자신이 받는 돈을 그대로 유지할 수 있다.

▲유산 가능

가입자가 QLAC 페이먼트를 받기 전에 죽거나 돈을 받는 도중에 죽었고 구좌에 원래 지불했던 보험금이 남아 있다면 이 돈은 유산으로 물려 줄 수 있다.

페이먼트가 시작되기 전에 죽었다면 처음 냈던 보험금 100%를 일시불로 상속자에게 물려 줄수 있다. 페이먼트를 받는 동안에 죽었다면 남은 금액을 물려 줄 수 있다는 말이다.

얼핏 듣기에는 보험금을 모두 돌려 받을 수 있어 좋은 것으로 들리지만 사실은 그렇지 않다. 돈이 묶여 있는 동안에 불어난 수입은 찾지 못하고 원금만 돌려 받는다. 다른 투자상품들과 다른점이다.

▲QLAC 단점

장점도 많지만 그만큼 단점도 많은 상품이다.

우선 QLAC의 가장 큰 단점은 은퇴 자산의 일부를 한 투자처에 묶어 놓는다는 점이다. 앞서 말한대로 QLAC는 말년의 평생 수입을 보장해 주지만 일찍 죽을 경우 투자에 따른 수익은 지불이 되지 않는다. 원금은 보장되지만 수익까지 돌려받지는 못한다.

인플레이션 역시 우려할 문제다. 일부 어누이티 상품은 지불이 시작될 때 인플레이션에 따라 조절하는 조건을 붙인다. 하지만 일반적인 QLAC는 인플레이션으로부터 보호받지 못한다. 현금 가치가 줄어들 수 있다.

요즘같이 저금리 시대에서 과연 QLAC가 그만큼 이익을 내 줄 수 있는지에 대해 의문을 갖는 사람들도 많다. 그 돈을 다른 곳에 투자 했을 때 얻는 수익이 QLAC 투자수익보다 더 많다는 것이다. 따라서 이 상품을 구입할 때는 자신의 건강상태 등을 종합해 구입 여부를 판단하는 것이 좋다.

 장수연금보험(QLAC) 요약

▲세금 감면
IRA 또는 401(k) 세금유예 은퇴구좌 적립금의 25% 또는 12만5,000달러까지(둘 중 작은 금액) QLAC 구좌에 이채할 수 있다. 이 돈은 최소분배금(RMD) 계산 때 제외된다. RMD 금액이 줄어들기 때문에 RMD 이상을 찾을 때 내야 하는 소득세 금액이 줄어든다.

▲RMD
금액 줄어RMD 금액이 많으면 소득세를 그만큼 많이 내야 한다. 예를들어 IRA 세금유예 은퇴 구좌에 50만달러가 있다면 최고 12만5,000달러까지 QLAC에 돈을 옮겨 놓을 수 있다. 이에따라 70½세 이후에 찾아야 하는 연 RMD는 50만달러가 아닌 37만5,000달러로 계산한다.

▲미래의 수입
계획QLAC는 입금 후 최대 15년 또는 85세까지 불려 나갈 수 있고 죽기 전까지 평생 수입을 보장해 준다.

▲배우자 또는 비배우자 혜택
모든 돈은 배우자 등 상속자에게 물려준다. 어누이티 보험회사가 갖는 것이 아니다.

▲원금 보장
QLAC는 장수은퇴연금 구조다. 고정금을 평생 받는다. 원금이 100% 보장된다.

▲COLA
추가보험사에 따라 생계비 조정(COLA)을 붙일 수 있고 도시 생활자 기준 소비자 물가지수(CPI-U)를 붙일 수 있다.

▲연 수수료 없음
QLAC는 고정을 돈을 지급하는 어누이티이며 연 수수료가 없다. 에이전트가 받는 커미션은 상품 판매 때 지불되며 변동 또는 인덱스 어누이티와 비교해 매우 낮다.

▲인덱스 또는 변동 투자 불허
변동 및 인덱스 어누이티는 QLAC로 사용할 수 없다. 오직 장수 어누이티 구조만이 QLAC로 인정된다.

▲인플레이션 적용
QLAC 규정에 따라 보험료를 인플레이션 수준에 맞출수 있다. 일시불 금액은 1만 달러이고 매 3~4년에 한번씩 올릴 수 있다.

<김정섭 기자>

(Picture: Vikram Sudarsan, Ph.D., CEO and president of Engrail Therapeutics)

안녕하세요 보스턴 임박사입니다.

Engrail Therapeutics는 Neuroscience Drug Discovery를 전문으로 좋은 Asset을 Acquisition을 통해서 성장하는 것을 목적으로 하는 회사입니다. Vikram Sudarsan 박사는 Cipla Technologies의 CEO 였는데 Pulmatrix에 2019년에 인수되었습니다.

Pulmatrix and Cipla Technologies LLC enter into Definitive Agreement for the Development and Commercialization of Pulmazole™ – 4/15/2019

그리고 Engrail Therapeutics를 창업했는데 중국의 Nan Fung Life Sciences (NFLS) 이라는 VC Firm의 전폭적인 지원 속에 현재까지 왔습니다. 1년 후 $32 Million Series A를 받았습니다. ENX-101이라는 GABA-A Modulator를 개발하는 중이었습니다.

Engrail Therapeutics nabs $32M series A for CNS work – Fierce Biotech 6/19/2020

San Diego-based biotech Engrail Therapeutics has raised $32 million as it looks to kick-start its first clinical work for its central nervous system med.

Nan Fung Life Sciences (NFLS), the global investment platform of the Nan Fung Group, led the round, which will see the cash funneled into its first pipeline asset, ENX-101, a sub-type selective GABA-A modulator. On top of this, it’s also looking to beef up its pipeline with more asset deals penciled in for the future.

The biotech, which launched last year, says it wants to buy up more assets with “validated mechanisms, ultimately catalyzing a diverse portfolio of therapies to treat diseases of the nervous system.” Its business model includes licensing, co-development and company buyouts—big ambitions for such a young startup.

Vikram Sudarsan, Ph.D., CEO and president of Engrail, said the cash should be there for its ambitious plans. “With these resources and a long-term commitment from NFLS to invest $1.5 billion in the life sciences sector, we will leverage our unique, flexible transaction model to build a world-class neuroscience company,” he said in a release.

Neuroscience is a notoriously tough R&D area, however, with billions of research dollars spent and lost on projects that simply couldn’t make the grade, especially in areas like Alzheimer’s disease.

Sudarsan, former chief at Cipla Technologies before it was bought by Pulmatrix last year, is confident the industry may be past the peak of these failures.

“Neuroscience is making massive strides. As the brain’s complexities and molecular mechanisms have become clearer, we are better able to identify disease targets, which has also a supported a resurgence in funding neuroscience drug development,” he said.

“These factors have contributed to recent clinical and commercial success across the industry. However, significant unmet needs persist, placing immense disease burden on patients. Our goal is to build a leading neuroscience company fueled by a robust pipeline. We are focused on the acquisition, development and commercialization of patient-centric neuroscience therapeutics. ENX-101 represents the first milestone in this effort.”

Just what it will be leading is being kept under wraps; Its MAO, GABA, is however the major inhibitory transmitter controlling synaptic transmission and neuronal excitability. It is present in a high percentage of neurons in the CNS and also present in the peripheral nervous system, and it acts to maintain a balance between excitation and inhibition.

A number of targets have been in development using this approach including epilepsy, anxiety and sleep disorders.

그리고 2021년에 NeuroCycle Therapeutics를 인수했는데 ENX-101과 같은 기전의 Drug candidate를 가지고 있는 회사였습니다.

Engrail Therapeutics Acquires NeuroCycle Therapeutics – Press Release 2/2/2021

Engrail Therapeutics™ (Engrail) today announced that it has acquired NeuroCycle Therapeutics, a company focused on sub-type selective GABA-A modulation. The acquisition strengthens Engrail’s presence in the GABA-A space and provides a strong platform for initiation of clinical trials with multiple assets in 2021.

“We believe Engrail represents the ideal company to carry on the work NeuroCycle started given their focus and experience in the GABA-A space. We look forward to seeing them bring novel medicines to patients that need them.”

“Our flexible transaction model and science-first approach allows us to acquire high-quality assets with a lower-risk path to market where significant patient need still exists,” said Vikram Sudarsan, Ph.D., CEO and president, Engrail Therapeutics. “We combine a comprehensive view of clinical development strategy, regulatory considerations and intellectual property to find differentiated assets with validated mechanisms of action. GABA-A is a well validated target and modulators of this receptor have therapeutic effect across a broad range of neurological and psychiatric conditions. We now have multiple sub-type selective GABA-A modulators with strong profiles and look forward to rapidly advancing development.”

Dr. Sudarsan continued, “We remain committed to building a leading, patient-centric neuroscience company with a growing pipeline through licensing, co-development and acquisitions. Our goal is to build a diverse pipeline of neuroscience therapeutics over the next several years, and the acquisition of NeuroCycle represents another important step on this path. We expect 2021 to be a busy year as we consider additional transactions to expand our portfolio.”

Jed Hubbs, Ph.D., CEO and president, NeuroCycle Therapeutics said, “We believe Engrail represents the ideal company to carry on the work NeuroCycle started given their focus and experience in the GABA-A space. We look forward to seeing them bring novel medicines to patients that need them.”

NeuroCycle을 인수한 이후에 Series A extension으로 총 $64 Million을 받게 됩니다. ENX-101은 임상1b에 있었고 ENX-102는 임상1a에 있는 상태였습니다.

Engrail Therapeutics Extends Series A Financing to $64 Million – Press Release 8/3/2021

Engrail Therapeutics™ (Engrail) (the Company), a neuroscience company focused on the acquisition, development and commercialization of patient-centric therapies, today announced the close of a $32 million extension of its Series A financing round, which brings the total round to $64 million. Nan Fung Life Sciences (NFLS), the global investment platform of the Nan Fung Group, led this round following their leadership of the original Series A raise. The Company will use the proceeds to finance the advancement of their diverse pipeline, including its lead assets, ENX-101, ENX-102 and internal preclinical programs. Engrail’s lead compounds are subtype-selective GABA-A modulators with compelling pharmacological profiles that possess wide ranging therapeutic utility.

“We are excited to support this team as it continues acquiring high-quality assets and advances them through clinical development.”

“Earlier this year, we initiated a Phase 1b study for ENX-101 and Phase 1a study for ENX-102. This funding will help advance these assets, as well as our earlier-stage pipeline, as rapidly as possible while continuing to build out our clinical development capabilities,” said Vikram Sudarsan, Ph.D., CEO and president of Engrail Therapeutics. “Additionally, NFLS has made a long-term commitment to invest $2 billion in the life sciences sector, enabling us to continue leveraging our flexible transaction model to acquire assets with validated mechanisms to treat diseases of the nervous system through licensing, co-development and company acquisitions. We continue to pursue transactions that will grow our pipeline and cater to major unmet needs in the neurosciences.”

Engrail has assembled a diverse portfolio of assets with validated mechanisms through its dynamic model for advancing drugs aimed at treating life-limiting diseases of the nervous system. By adopting a ‘science-first’ approach, combined with a comprehensive view of clinical development strategy, regulatory considerations and intellectual property, the Company can find differentiated assets with validated mechanisms of action for diseases where significant patient need still exists.

“Engrail has demonstrated impressive progress in the past year since its founding with the initiation of two Phase 1 studies for its lead candidates,” said Peter Bisgaard, managing director of NFLS and chairman of Engrail’s board of directors. “We are excited to support this team as it continues acquiring high-quality assets and advances them through clinical development.”

About Engrail Therapeutics

Founded in 2019, Engrail is forging a new direction to reduce the enormous burden of diseases that impact the nervous system. We unite biological insights with clinically meaningful solutions to build and catalyze a diversified portfolio of transformative medicines. Harnessing our rigorous scientific approach to identify the most promising therapies, we leverage our flexible transaction model to advance assets with validated mechanisms and efficiently move them through development to commercialization. Engrail is supported by a long-term capital commitment from Nan Fung Life Sciences. For more information, visit www.engrail.com.

About Nan Fung Life Sciences

Nan Fung Life Sciences is a global life sciences investment platform with a long-term capital commitment from the Nan Fung Group. Our team possesses diverse experience with long track records in company formation, venture capital, growth/buyout investments, and drug discovery and development. Through direct investments via Pivotal bioVenture Partners US and Pivotal bioVenture Partners China as well as fund investments, we cover the full spectrum of the life sciences industry including therapeutics, medical devices and diagnostics and across all development stages. To learn more, visit www.nanfunglifesciences.com.

2022년에 ENX-101 임상1b 결과를 발표했습니다. 대체적으로는 긍정적인 발표였는데 어떤 이유인지 파이프라인에서는 결국 사라졌습니다.

Engrail Therapeutics Announces Positive Results of ENX-101 Phase 1b Clinical Study and Prepares for Initiation of ENACT Phase 2 Trial in Focal Epilepsy – 6/7/2022

ENX-101 exhibited a favorable safety and pharmacokinetic profile in healthy volunteers
• ENX-101 was well tolerated following once-daily oral administration with no dose titration
• Translational biomarker data indicated target engagement consistent with anti-seizure activity
• Engrail plans to initiate the ENACT phase 2 trial in epilepsy

SAN DIEGO – June 7, 2022 – Engrail Therapeutics™ (Engrail) (the Company), a precision neuroscience company focused on the acquisition, development, and commercialization of transformational therapies, has announced positive results from a phase 1b clinical trial of ENX-101, a subtype-selective GABA-A positive allosteric modulator (PAM). The phase 1b clinical trial data were presented on June 6, 2022, at the 2022 Epilepsy Pipeline Conference in Santa Clara, California. Following these results and recent interaction with the US FDA that included alignment on the phase 2 development program, Engrail plans to initiate the ENACT Trial, an international multi-center phase 2 clinical trial to evaluate the efficacy and safety of ENX-101 in patients with focal epilepsy.

“We are excited to announce that repeated administration of ENX-101 showed a highly favorable safety and tolerability profile in healthy volunteers across a wide range of doses,” said Kimberly Vanover, Ph.D., chief scientific officer of Engrail Therapeutics. “Moreover, translational biomarker data provided strong evidence of target engagement by ENX-101 that we believe are predictive of positive clinical benefit in patients with epilepsy as well as other disorders of the central nervous system.”

ENX-101, administered orally once daily for ten days, was safe and well tolerated in healthy volunteers. There were no dose-related, clinically meaningful changes in vital signs, electrocardiograms, physical exams, or clinical laboratory values. Treatment-emergent adverse events (TEAEs) were generally mild and transient. There were no serious adverse events or severe adverse events reported. The most frequent TEAE associated with ENX-101 administration was mild and transient somnolence that occurred primarily during the first few days of dosing. ENX-101 exhibited predictable dose-related exposure with a half-life of approximately 20 hours.

ENX-101 exhibited activity across pharmacodynamic biomarkers confirming target engagement. Notably, ENX-101 decreased saccadic peak velocity, consistent with centrally acting GABA-A PAM pharmacology, and increased beta power of quantitative electroencephalogram (qEEG) recordings. ENX-101 exhibited little to no adverse effect on alertness, psychomotor function, or sustained attention with repeated administration. Additionally, ENX-101 did not show a sedative-like increase in qEEG delta power, rather, ENX-101 decreased delta power. Moreover, there was no evidence of tachyphylaxis to functional target engagement or tolerance to the central nervous system inhibitory effects of ENX-101 with repeated administration. Taken together, the data are consistent with a GABA-mediated pharmacodynamic profile that is distinct from sedative benzodiazepines and other non-selective GABA-A PAMs.

“The data generated to date with ENX-101 are highly encouraging. I look forward to seeing the translation of these results into outcomes in patients suffering from therapy resistant epilepsy – an inherently tough disease in need of better treatment options,” said Jacqueline French, M.D., professor of Neurology at NYU Langone Health’s Comprehensive Epilepsy Center.

Vikram Sudarsan, Ph.D., chief executive officer and president of Engrail added, “the positive ENX-101 phase 1b clinical results are just one of many important outcomes we expect to see from the organization over the coming years. We founded Engrail in 2019 with the aspiration of becoming a leading neuroscience company. Our stellar and experienced team has built a deep and differentiated pipeline spanning six unique programs, including two programs rapidly advancing to phase 2. We built this pipeline through thoughtful business development as well as internal drug discovery efforts and are now focused on advancing our entire portfolio.”

About the ENX-101-004 Phase 1b Trial

ENX-101-004 was a randomized, placebo-controlled multiple ascending dose trial conducted in healthy volunteers. ENX-101 or placebo was administered orally once daily in the morning for 10 days. Five cohorts (N=9; 6:3 active:placebo in each cohort) evaluated doses of 5, 10, 15, 25, and 50 mg ENX-101. The primary objective of the study was to evaluate the safety and tolerability of ENX-101 following repeated administration. Secondary objectives included the evaluation of the effects of ENX-101 on electrocardiogram (ECG) parameters, pharmacokinetic (PK) parameters, and a battery of pharmacodynamic biomarkers such as saccadic eye movement, quantitative electroencephalographic (qEEG) parameters, visual analog scales, and cognitive performance.

Following a Screening Period (Day -28 to Day -3), healthy volunteers meeting inclusion criteria were admitted to an inpatient clinical research center for a Baseline Period (Day -2 to Day -1). Study treatment was administered on Days 1 through 10 and participants were followed for an additional three days following the cessation of treatment and discharged on Day 13. The extensive biomarker battery was collected at Baseline and on Days 2 and 9. Safety and tolerability were assessed daily.

About ENX-101

Targeting the gamma-aminobutyric acid A (GABA-A) receptor is a well-validated pharmacological approach for the treatment of epilepsy, anxiety, pain, and other centrally-mediated disorders. However, conventional, non-selective GABA-A modulators, such as benzodiazepines, have several liabilities limiting chronic use, primarily driven by GABA-A α1 subunit containing channels. ENX-101 is an investigational precision targeted GABA-A PAM that enhances neurotransmission in receptors containing α2, α3, and α5 subunits while blocking α1. This profile is thought to contribute to anti-seizure efficacy and a favorable safety profile while minimizing the undesirable effects associated with α1-mediated GABAergic neurotransmission. ENX-101 has been well-tolerated in clinical trials with once daily oral dosing and does not require dose titration.

2023년 7월에 ENX-102의 임상2상을 시작했다고 발표를 했습니다. 아마도 ENX-101 임상을 중단하고 ENX-102로 바뀐 것 같습니다.

Engrail Therapeutics Initiates the ENCALM Phase 2 Clinical Trial of ENX-102 in Patients with Generalized Anxiety Disorder – Press Release 7/18/2023

Engrail Therapeutics™ (Engrail) (the Company), a precision neuroscience company focused on the acquisition, development, and commercialization of transformational therapies, today announced initiation of a multi-center phase 2 clinical trial, the ENCALM Trial, to evaluate the efficacy and safety of ENX-102 in patients with generalized anxiety disorder (GAD). ENX-102 is an investigational, highly selective GABA-A α2,3,5 positive allosteric modulator (PAM) and antagonist at α1-containing GABA-A channels. ENX-102 represents a first-in-class approach to the treatment of GAD.

“Translational and phase 1 clinical data indicate central target engagement with a highly differentiated safety and tolerability profile for ENX-102 vs. non-selective GABA-A PAMs such as benzodiazepines. ENX-102 exhibits a long half-life and can be dosed once daily without titration. These data support further evaluation of ENX-102 for efficacy in generalized anxiety disorder,” said Kimberly Vanover, PhD, chief scientific officer of Engrail.

“While there are a variety of options for treating GAD, they all have significant drawbacks – particularly limiting safe and tolerable long-term use. Engrail’s approach of selectively targeting GABA-A α2, α3, and α5 subunits holds promise for providing strong anxiolytic effect while reducing the risk of sedation and abuse potential,” said Charles Nemeroff, MD, PhD, chair and professor with the Department of Psychiatry and Behavioral Sciences at the Dell Medical School, University of Texas at Austin.

Vikram Sudarsan, Ph.D., chief executive officer and president of Engrail added, “We are excited by the best-in-class profile of ENX-102 and look forward to further elucidating its efficacy and safety profile in phase 2. The initiation of phase 2 and further advancement of the rest of our precision neuroscience pipeline makes 2023 a hallmark year for the organization.”

For more information on the ENCALM Trial, visit clinicaltrials.gov.

About ENX-102

Targeting the gamma-aminobutyric acid A (GABA-A) receptor is a well-validated pharmacological approach for the treatment of anxiety and other centrally-mediated disorders. However, broad-spectrum GABA-A modulators, such as benzodiazepines, have several liabilities limiting chronic use, primarily driven by GABA-A α1 subunit containing channels. ENX-102 is an investigational subtype-selective GABA-A PAM acting to enhance GABA neurotransmission in receptors containing the α2, α3, and α5 subunits while blocking α1. This profile is thought to contribute to anxiolytic efficacy and result in a favorable safety profile without the undesirable effects associated with α1.

얼마전에 $157 Million의 펀딩을 받았습니다. ENX-102의 임상을 더 집중할 수 있는 규모일 것같습니다.

Engrail Raises $157M in Oversubscribed Series B to Move Neuro Pipeline Forward – Biospace 3/19/2024

San Diego-based Engrail Therapeutics has closed a $157 million oversubscribed Series B funding round to support the development of its therapeutic assets for the treatment of anxiety disorders, depression, post-traumatic stress disorder and rare neurodegenerative diseases.

New investors, including Forbion, F-Prime Capital, and Norwest Venture Partners, led the funding. Other participants included RiverVest Venture Partners, Red Tree Venture Capital, Ysios Capital, Longwood Fund, Eight Roads Ventures and Pivotal Life Science.

Proceeds from the financing round will be used to support the advancement of Engrail’s pipeline through clinical development.

“With strong financial backing from highly sophisticated and dedicated life science investors, we are well-positioned to deliver multiple value-creating milestones. Notably, we look forward to completing our ongoing ENX-102 Phase II study in generalized anxiety disorder and advancing the rest of our pipeline into clinical development,” Engrail CEO Vikram Sudarsan said in a statement. “Engrail was fortunate to have been incubated under a tremendous commitment from Pivotal Life Sciences. We are excited to start the next chapter of our journey with some of the best thought partners in neuroscience and life sciences investing in our success.”

Engrail emerged in 2020 with a $32 million Series A financing round singularly funded by Nan Fung Life Sciences, which was designed to advance its first pipeline asset. Known as ENX-101, the drug was a sub-type selective GABA A modulator but the drug has since been removed from the company’s website. The Series A was extended to $64 million in 2021. Since 2019, the biotech has raised over $220 million.  

“We see tremendous potential in Engrail’s pipeline and management team and are excited to participate in their development of transformative therapies for patients,” Stacie Weninger, board member and president of F-Prime Biomedical Research Initiative, said in a statement.

Engrail is among several biotechs that have recently secured funding. ProfoundBio, a Seattle-based antibody-drug conjugate company, raised $112 million in its Series B round in February 2024 to move four candidates forward.  

In January 2024, Beijing Avistone Biotechnology, which is focused on precision oncology treatments, also completed a 1 billion yuan ($140 million) Series B round.  

2024년 1Q의 Corporate Presentation은 아래에 링크합니다.

안녕하세요 보스턴 임박사입니다.

저는 어려서부터 가장 존경하는분들이 여기저기 기웃거리지 않고 한 분야에서 오랜 기간 한우물을 파는 분들이라고 여겼습니다. 오늘 소개할 분은 1980년대부터 시작된 Antisense Oligonucleotide라는 한 분야를 지난 40여년간 개척하신 Stanley T. Crooke 박사님입니다.

Stanley 박사님은 1989년에 Isis Pharmaceuticals (현재 Ionis Pharmaceuticals)를 설립하시고 2020년에 퇴직하실 때까지 31년간 Ionis의 Founder이자 Chairman & CEO로 일하셨습니다. 이 분이 은퇴하신 건 아닌 것이 Ionis Pharmaceuticals에서는 퇴직을 하셨지만 희귀병을 위한 n-Lorem Foundation 을 설립하시고 이곳의 Chairman으로 이제는 환자들을 위해 일하고 계시기 때문입니다.

Stanley 박사님이 n-Lorem Foundation에 대해 팟캐스트에 나와서 설명하시는 영상이 있습니다. Ionis Pharmaceuticals에 대해서도 잠깐 설명을 하십니다.

그리고 본인의 연구인생을 적은 글이 있습니다. 하나는 아래에 있는 5-페이지의 글입니다.

또한 Nucleic Acids Research 2022년에 8페이지로 비교적 상세히 Ionis Pharmaceuticals를 설립하시고 Antisense Oligonucleotides 분야에서 일하며 발견한 Milestone에 대해 얘기하시는 것이 나옵니다.

저도 Stanley 박사님을 Role Model로 해서 회사를 위해, 환자를 위해, 사회를 위해 일하는 과학자가 되고 싶은 마음이 있습니다. 기회가 되면 이 분이 최근에 발견하신 Science에 대해서도 나누겠습니다.