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안녕하세요 보스턴 임박사입니다.

Greg Verdine박사는 Harvard University교수이면서 VC이고 Serial Entrepreneur인 특이한 경력을 가지고 있는데요. 예를 들면 Wave Life Sciences에서 WaVe의 Ve는 Verdine의 Ve에서 따온 것입니다. 앞의 Wa는 Wada 교수의 Wa에서 따온 것이고요.

BIOTECH (8) – Wave Life Sciences의 RNA Editing 신약 가능성에 GSK가 투자하다.

Greg Verdine교수의 연구 중 가장 중요한 연구는Stapled Peptides라는 분야인데 이것은 Protein의 alpha Helix를 Chemical Bonding으로 Stapling하는 것입니다. Aileron Therapeutics라는 회사를 만들어서 RCM (Ring Closing Metathesis) 방법으로 만든 Stapled Peptides Platform을 임상에 진행시켰으나 그리 성공적이지 못했습니다.

Aileron Terminates Phase 1b Trial Evaluating ALRN-6924 in P53-mutant Breast Cancer – OncLive 2/22/2023

Despite treatment with the chemoprotective agent ALRN-6924, patients with p53-mutated breast cancer receiving neoadjuvant or adjuvant therapy with docetaxel, doxorubicin, and cyclophosphamide experienced grade 4 neutropenia and alopecia in a phase 1b trial (NCT05622058), failing to meet the trial’s primary and secondary end points of duration and incidence of severe neutropenia in cycle 1 and incidence of chemotherapy-induced alopecia, respectively.¹ Based on these results, the company has decided to terminate the trial and further development of ALRN-6924, which was also under evaluation as a chemoprotective agent in p53-mutated small cell lung cancer and non–small cell lung cancer (NSCLC).

The company announced that it is exploring strategic alternatives in conjunction with Ladenburg Thalmann & Co., Inc., which may include an acquisition, a merger, a business combination, or a sale of assets or other transactions. Further statements from the company will not be released unless or until its Board of Directors has approved a definitive course of action or it is determined that other disclosure is appropriate.

현재는 Lung Disease로 Business Model을 완전히 바꾼 상태입니다.

Aileron Therapeutics (ALRN) Announces Acquisition of Lung Therapeutics – Street Insider 10/31/2023

Aileron Therapeutics의 Stapled Peptides 임상을 통해서 그래도 배운 것이 있을 것이라 생각합니다. Aileron을 설립한지 몇년 후에 다른 Stapled Peptides Platform 회사인 Fog Pharma를 2016년에 설립했는데요 Greg Verdine 교수연구실에서 박사학위를 받고 Postdoctoral Fellow로 있던 John McGee 박사가 하던 Cysteine Stapling을 상용화하기 위한 회사입니다.

Exceptionally high-affinity Ras binders that remodel its effector domain. J. Biol. Chem. 2018, 293, 3265-3280. John H. McGee, Gregory L. Verdine et al.

De Novo Mapping of α-helix Recognition Sites on Protein Surfaces Using Unbiased Libraries. PNAS 2022, 119 (52) e2210435119. John H. McGee, Gregory L. Verdine et al.

Cysteine Stapling은 아래와 같이 Internal Cysteines을 Alkylation으로 Stapling 하는 것입니다.

이 Stapled Peptides를 Ligand로 해서 Phage display로 High throughput screening을 합니다.

Recognition and reprogramming of E3 ubiquitin ligase surfaces by α-helical peptides. Nat. Comm. 2023, 14, 6992 John H. McGee, Gregory L. Verdine et al.

이 논문에서는 1차 agnostic naive screening을 한 다음에 hit을 가지고 2차 focused screening을 거쳐서 비교적 단기간에 Lead Candidates를 찾는 방법을 보고했습니다.

$66 Million Series B를 하고 Aileron과 달리 바로 임상에 진입할 Lead를 발표했습니다.

FogPharma Secures $66 Million Series B Financing. – PR Newswire 5/16/2019

FogPharma’s drug discovery engine has been configured to deliver multiple new medicines in rapid succession, with clinical entry for the first product, a first-in-class beta-catenin antagonist, by the end of 2019, followed by a steady stream of first-in-class clinical product candidates addressing other intractable targets.

그리고 2년 후에 $107 Million Series C를 했습니다. Pipeline도 늘어났습니다.

FogPharma^® Announces $107 Million Series C Financing to Advance Direct β-Catenin Antagonist and Universal Druggability™ Platform. – Business Newswire 3/1/2021

FogPharma’s proprietary hyperstabilized α-helical peptides (Helicon™ peptides) are a new class of therapeutics that combine the targeting strength and specificity of antibodies with the broad tissue distribution, intracellular target engagement and oral dosing optionality of small molecules. The Company’s Helicon peptide drug discovery engine integrates directed evolution, proprietary helix hyperstabilization chemistry, highly multiplexed drug optimization technology, artificial intelligence including deep learning and machine learning, structure-based drug discovery, and multiscale manufacturing to rapidly discover Helicon peptide therapeutics against important, previously intractable targets with broad applicability to virtually all disease areas.

• The Company’s first-and-only-in-class direct β-catenin inhibitor. Dysregulation of the Wnt/β-catenin signaling pathway has been shown to occur in at least 20% of all human cancers, with the true patient population likely being higher. FogPharma’s lead antagonist has been shown to surgically disrupt the interaction of β-catenin with its downstream transcription factor, TCF, and thereby disrupt signal transmission thorough the oncogenic arm of the Wnt pathway.
• A first-in-class YAP/TAZ-blocker TEAD antagonist, which is the only molecule presently in development that binds the fully activated form of TEAD. The YAP/TAZ-TEAD interface is part of the hippo pathway, where dysregulation has also been shown to occur in many cancers.

다음해에 다시 $178 Million Series D를 했구요. FOG-001의 임상을 2023년 중순에 시작하겠다는 계획을 발표했습니다.

FogPharma Announces $178 Million Series D Financing to Advance Pipeline of First-in-Class Helicon Polypeptide Therapeutics Targeting Major Cancer Drivers. – Business Newswire 11/21/2022

FogPharma’s lead Helicon polypeptide development candidate, FOG-001, a first-and-only-in-class direct TCF-blocking β-catenin inhibitor with potential applicability to significant cancer patient populations, is expected to enter clinical development in mid-2023. In addition, FogPharma is advancing other first-in-class programs against important, biologically validated cancer targets that have remained elusive to other approaches including TEAD, NRAS, Pan-KRAS, ERG and Cyclin E1.

그리고 얼마전에 $145 Million Series E를 했구요. CEO를 J&J 출신인 Mathai Mammen으로 교체하면서 J&J ex-CEO Alexis Borisy가 투자자를 유치하고 BOD member로 들어오게 되었습니다.

FogPharma clears $145M series E thanks to Alexis Borisy, ex-J&J CEO Alex Gorsky. – Fierce Biotech 3/1/2024

Johnson & Johnson’s former pharma R&D chief, now the CEO of FogPharma, has brought on former J&J CEO Alex Gorsky as an investor in the company’s $145 million series E. Gorsky joins a syndicate of heavyweights like RA Capital and General Catalyst who became first-time Fog investors.

Returning investors included Arch, GV and Fidelity. Another big name on the bill is serial biotech entrepreneur Alexis Borisy, who also joined the board on behalf of Nextech, which led the round. 

FOG-001 is an intracellular TCF-blocking β-catenin inhibitor being tested in a phase 1/2 trial for solid tumors. Mutations of the Wnt/β-catenin pathway, which the drug targets, are particularly common in colorectal cancer. 

현재 Pipeline은 아래와 같습니다. FOG-001의 임상1/2상 데이타가 어떻게 나올지 궁금합니다.

(Picture: 주간동아)

안녕하세요 보스턴 임박사입니다.

실제로 조기은퇴를 해 본 사람은 현상을보는 인식이 아무래도 보다 현실적이고 다르게 볼 수 밖에 없다고 생각하는데요 최근에 경영학 박사인 최성락 박사의 주간동아의 글을 읽으면서 많이 배우게 되어 글을 남기고자 합니다. 최성락 박사는 현재 주간동아 “돈의심리”라는 칼럼을 매주 한차례씩 쓰고 있는데요 글이 정말 읽을만 하다고 생각합니다.

최성락 박사는 본래 동양미래대 교수로 재직하다가 2021년에 비트코인 투자를 통해 50억 자산가가 되면서 파이어족으로 지내고 있다고 합니다.아래는 주간동아의 인터뷰 기사링크입니다.

투자로 50억 벌어 ‘파이어족’ 합류한 최성락 전 교수 – 주간동아 7/8/2023

인터뷰 기사 내용은 그리 특이한 것은 없다고 느꼈는데요 이 분의 글은 좀 다릅니다. 가장 최근에 올라온 글을 볼까요? 그냥 이론적인 글을 쓴 것이 아닌 것을 알 수 있습니다. 상당히 세세히 피부로 경험한 바를 적고 있다는 느낌이 들었습니다. 그래서 부러우면 지는거다에 최성락 박사를 올립니다.

직장인에게 은퇴 후 화려한 생활은 그저 꿈일 뿐 – 주간동아 3/2/2024

50대 중반 친구가 퇴직을 했다. 명예퇴직이었기에 몇 년 치 연봉에 해당하는 명예퇴직금을 받고 나왔다. 정식 퇴직금과 합하면 5억 원 넘는 돈을 손에 쥐었다. 이렇게 큰돈을 평생 만져본 적 없는 친구는 먼저 퇴직한 나에게 일종의 컨설팅을 부탁했다. 이 돈을 어떻게 운용해야 화려한 노년 생활을 준비할 수 있을까에 대한 것이었다. 친구가 원하는 건 현 생활수준을 유지하면서 여생을 살아가는 것이다. 이 수억 원 퇴직금으로 그게 가능할까. 앞으로 어떻게 해야 지금처럼 계속 살 수 있을까. 내 대답은 별로 긍정적이지 않다. 5억 원 넘는 돈은 굉장히 큰돈이긴 하다. 하지만 그 돈으로 현 생활수준을 유지하면서 사는 건 쉽지 않을 것이다. 예상하지 못한 재정적 변동도 발생할 수 있다.

퇴직자가 치킨집 차리는 이유

먼저 내 경우를 이야기해보자. 나는 일정 규모의 자산을 모은 후 2021년 8월 직장을 그만뒀다. 17년간 직장에서 근무했고, 퇴직금으로 1억6000만 원이 나왔다. 퇴직금을 받고 처음 든 생각이 이것이다. “내가 파이어족으로 직장을 그만둔 게 아니라, 다른 사정으로 어쩔 수 없이 직장을 그만뒀다면 치킨집을 하는 수밖에 없었겠구나.”

내가 투자로 돈을 벌지 않고 직장만 다니다가 50대 초반 나이에 퇴직했다면 어떤 인생이 펼쳐졌을까. 연금은 65세부터 나온다. 연금이 나오기 전까지 10여 년을 먹고살아야 하는데, 가지고 있는 현금은 퇴직금으로 받은 1억6000만 원이 전부다. 이 1억6000만 원으로 연금을 받기 전까지 살아간다면 1년에 1200만 원, 1달에 100만 원으로 생활해야 한다. 중산층으로 살아왔는데 당장 사회 최하소득층이 돼버리는 것이다.

그럴 순 없다. 뭔가 일을 해서 돈을 벌어야 한다. 그런데 50대 중반에 새로 직장을 얻기는 힘들다. 자영업을 해야 하는데 1억6000만 원으로 할 수 있는 게 뭐가 있을까. 목 좋은 곳에 프랜차이즈 커피숍을 여는 것도 몇억 원이고, 세탁소 프랜차이즈도 몇억 원이 필요하다. 특별한 기술 없이 이 돈으로 할 수 있을 것이라고 떠오른 일이 세 가지였다. 치킨집, 편의점, 조그만 커피숍. 그제야 한국에서 치킨집, 커피숍이 우후죽순 생기는 이유를 알았다. 자영업을 크게 하려면 자본금이 훨씬 많이 필요하다. 일반 퇴직자의 자금 수준에서 할 수 있는 것이 치킨집, 작은 커피숍뿐이다.

그동안 나는 한국 자영업자의 어려움을 이야기하곤 했다. 그런데 알고 보니 자영업자보다 더 어려운 이는 나이 들어 직장을 그만둔 사람들이다. 이들은 제대로 자영업을 시작할 돈도 없다. 직장을 그만두고 나면 자영업자들이 그 나름 성공한 것처럼 보인다. 어쨌든 퇴직금 1억6000만 원을 손에 쥐었다. 그럼 이 1억6000만 원이 고스란히 내 돈으로 남을까. 그렇지 않았다. 은행에서 마이너스 통장 대출금을 상환하라는 연락이 왔다. 직장을 다니면서 마이너스 통장을 만들었고, 10년 넘게 아무 이상 없이 사용하고 있었다. 그사이 마이너스 통장 한도는 점점 늘었다. 직장을 그만두니 마이너스 통장을 더는 쓸 수 없다고 했다. 마이너스 통장은 1년에 한 번 연장된다. 이때 직장이 없으면 재연장이 안 된다. 그때까지 사용하고 있던 마이너스 대출금을 모두 상환해야 한다. 마이너스 통장만이 아니다. 담보대출도 직장 소득 규모에 따라 대출액 규모가 달라진다. 직장을 그만둬 더는 정기 소득이 없으면 담보대출 한도도 줄어든다.

은퇴자 생활수준 하락은 현실

나는 이전보다 자산이 훨씬 많아져 직장을 그만뒀다. 경제 상태가 퇴직 전보다 좋았다. 하지만 은행에서 중요하게 생각하는 건 안정적인 월급이 들어오는 직장이 있는지 여부였다. 아무리 자산이 있어도 직장이 없으면 마이너스 통장을 사용할 수 없다. 나는 마이너스 통장 대출금 6000만 원을 상환해야 했다. 퇴직금 1억6000만 원에서 6000만 원 대출금 상환은 크다. 내가 퇴직금만 바라보고 있었다면 예상하지 못한 큰 지출 탓에 바로 재정적 어려움에 처했을 것이다.

은행 대출금 상환 이후 발생한 일은 직장에 다닐 때보다 훨씬 오른 국민건강보험료 고지서 수령이었다. 직장가입자에서 지역가입자로 변경되면서 국민건강보험료가 크게 올랐다. 보통 사람들이 직장을 그만두면 앞으로 어떻게 할지 걱정한다. 돈 걱정을 하고, 지금 있는 돈으로 뭘 어떻게 할지 고민한다. 더는 버는 돈이 없어 살아갈 일이 걱정인데, 국민건강보험료를 더 많이 내라고 고지서가 날아온다. 넘어진 사람을 밟는 격이다. 또 일반 신용카드면 모를까, 소위 프리미엄급 신용카드도 발급이 안 된다. 나는 해외항공권 서비스 등을 목적으로 프리미엄급 신용카드를 쓰고 있었다. 15년 동안 아무 문제없이 쓴 카드였다. 그런데 직장을 그만두니 재연장이 안 됐다. 은행처럼 신용카드사도 고객의 재산 상태보다 어떤 직장에 다니는지를 더 중요시했다. 한국 금융기관은 정말 바보 같다는 생각을 하게 됐지만, 사용하는 카드를 바꿀 수밖에 없었다.

친구는 퇴직금, 명예퇴직금으로 평생 처음 ‘자기 맘대로 쓸 수 있는 큰돈’을 손에 쥐어 기분 나쁘지 않은 상태였다. 기분 좋은 은퇴 생활을 기대했다. 나는 거기에 초를 쳤다. 일단 그게 다 쓸 수 있는 돈이 아니다. 은행 신용대출이 있으면 다음 심사 때 모두 갚아야 할 것이다. 지금까지처럼 연장이 잘 되지 않는다. 그리고 담보대출도 모두 다는 아니어도 몇천만 원은 분명 갚아야 한다. 그리고 현 생활수준을 유지하는 데 소모되는 돈은 이전보다 훨씬 늘어날 것이다. 전에는 평일에 일하고 주말에만 여행을 가거나 취미활동을 했다. 하지만 은퇴하면 평일에도 뭔가 활동을 하게 되는데, 그럼 필연적으로 돈을 쓰게 된다. 과거에는 일을 했던 시간에 이제는 돈을 쓴다. 국민건강보험료뿐 아니라 생활비도 더 들어간다. 직장을 그만둔 후 평일에는 아무것도 안 하고 집에서만 시간을 보내야 생활비 지출이 같아질 것이다.

5억 원 넘는 돈도 충분한 액수가 아니다. 이 친구가 현 생활수준을 유지하려면 매달 500만 원은 써야 한다. 그럼 1년에 6000만 원이고, 10년이면 6억 원이다. 지금 있는 돈은 모두 다 써버리는 것이고, 그다음에는 월 1백 몇십 만 원 연금을 받아서 생활해야 한다. 65세가 되면 생활수준이 팍 낮아져야 하는 것이다. 그때 충격을 막으려면 지금 월 300만~400만 원을 쓰고 65세 이후에 200만~300만 원을 쓰도록 해야 한다. 지금부터 생활수준을 낮춰야 한다. 젊어서 열심히 일하고 은퇴 후 화려한 생활을 한다는 건 신화다. 실제로는 생활수준이 대폭 내려간다. 앞으로 나아지리라는 기대를 가질 수 없는 생활수준의 하락이다. 은퇴 후 생활수준을 똑같이 유지하려면 몇 배나 많은 돈이 필요하다. 그럼 새로 직장을 구하면 괜찮을까. 직장을 구하면 이 과정이 뒤로 좀 더 미뤄질 뿐이다. 그 직장을 그만두면 어차피 똑같은 상황을 겪어야 한다. 그리고 50대에 퇴직해 새로 얻는 직장은 절대 이전 직장만큼 연봉을 주지 않는다. 생활수준 하락은 피할 수 없다.

퇴직금 투자 실패 확률 높아

그럼 이 퇴직금을 기반으로 투자를 하면 되지 않을까. 연 10% 수익을 얻으면 가진 돈을 거의 까먹지 않으면서 현 생활수준을 유지할 수 있다. 하지만 이에 대한 내 대답도 ‘노(NO)’다. 그동안 계속 투자를 해온 사람이 그 돈으로 투자하면 괜찮을 수 있다. 하지만 그동안 투자를 하지 않았던 사람이 큰돈이 생겼다고 투자를 시작하면 그냥 다 잃는다고 보면 된다. 돈만 많은 투자 초보자는 이 세계에서 그냥 밥이다. 몇 년 안에 큰돈을 잃는 경험을 할 것이라고 장담할 수 있다.

어쨌든 오랫동안 일만 해온 건 사실이니, 퇴직 후 크루즈 해외여행 등에 돈을 써도 된다. 하지만 그것은 은퇴 초기 어쩌다 한 번이다. 계속해서 그런 생활을 할 수는 없다. 몇 살까지 살지 불확실한 상황이니 계속 돈을 쪼개 쓰면서 생활해야 한다. 생활수준은 계속해서 하락할 것이다. 다만 사람은 적응의 동물이다. 이 때문에 불행해하지는 않을 것이다. 안분지족하며 그 나름 만족하며 살아갈 것이다. 한 가지 분명한 건 나이 들어 퇴직하면 생활수준이 유지되거나 나아질 가능성이 거의 없다는 점이다. 대다수 직장인에게 은퇴 후 화려한 생활은 그저 꿈일 뿐이다. 안타깝지만 그게 현실이다.

안녕하세요 보스턴 임박사입니다.

Canada Toronto의 Princess Margaret Hospital의 Prostate Cancer Prevention Center의 대표였던 Neil Fleshner 박사는 2017년에 자신의 환자의 Radioligand 치료를 위해 독일로 보내야 하는 경험을 하게 되면서 Point Biopharma를 설립하고 경영진을 모으게 됩니다. Joe McCann박사를 CEO로, Neil Fleshner 박사는 CMO를 그리고 Michael Gottlieb는 CFO로 해서 Radioisotope supply와 생산기술 등을 전략적 제휴를 통해서 만들어내게 됩니다.

Toronto-founded cancer therapy maker Point Biopharma to list on Nasdaq with SPAC merger – The Globe and Mail 3/15/2021

Point was founded after Neil Fleshner, the Love Chair in Prostate Cancer Prevention at Toronto’s Princess Margaret Hospital, had to send a patient to Germany in 2017 to receive radioligand treatment. He sought to make such therapy more accessible, bringing together a corporate team.

Point Biopharma Launches With Radiopharmaceutical Development Focus – Biospace 2/25/2020

POINT Biopharma, a newly formed pharmaceutical company, is combining a seasoned management team with strategic partnerships in radio-isotope supply, manufacturing technology and novel direct to patient targeting to revolutionize radiopharmaceutical drug development and commercialization. Working closely with its scientific advisors, the Company anticipates commencement of its clinical trial programs in 2020.

Dr. Joe McCann, PhD has assumed the role of Chief Executive Officer.  An industry veteran with more than 10 years of proven radiopharmaceutical experience, Joe was most recently the CEO of Centre for Probe Development and Commercialization.  Dr. Neil Fleshner, an uro-oncologist, with more than 400 authored papers, has assumed the role of Chief Medical Officer and Michael Gottlieb, CPA, the former head of Sanofi Genzyme Canada’s Rare Disease Business joins as Chief Financial and Commercial Officer.

177Lu-PSMA Precision Radiopharmaceuticals인 PNT2002의 임상3상을 시작하면서 $20 Million Series A를 하게 됩니다.

POINT Biopharma Announces Successful USD $20M Series A Financing to Bring Precision Radioligand Therapy to Cancer Patients – Press Release 8/4/2020

“So far 2020 has been a very productive year for POINT,” Dr. McCann continued, “including the announcement of the Phase 3 clinical trial for PNT2002, our 177Lu-PSMA radiotherapeutic for the treatment of metastatic castrate-resistant prostate cancer, as well as the purchase and build-out of our 77,000 sqft radioligand manufacturing facility in Indianapolis, Indiana. Now, with the successful close of our Series A financing, POINT is well positioned to execute on our mission of making radioligands applicable to more cancers, accessible to more people, thereby improving the lives of patients and their families.”

그리고 7개월 후에 SPAC 상장에 의해 NASDAQ에 등록되고 이 때 $465 Million의 자금을 확보하게 됩니다. 이 자금으로 PNT2002의 임상3상과 Manufacturing Facility를 Indianapolis에 세우기 위한 충분한 자금이 확보된 것입니다.

Next-generation Radiopharmaceuticals Company POINT Biopharma to list on NASDAQ through merger with Research Alliance Corp. I – Globe News Wire 3/15/2021

POINT Biopharma Inc. (“POINT”), a late-stage biopharmaceutical company dedicated to bringing the many benefits of precision radiopharmaceutical therapies to patients with cancer, and Therapeutics Acquisition Corp., d/b/a Research Alliance Corp. I (Nasdaq: RACA) (“RACA”), a special purpose acquisition company, or SPAC, sponsored by RA Capital Management, today announced they have entered into a definitive business combination agreement 

A group of top-tier investors has committed to participate in the transaction through a common stock PIPE of approximately $165 million at $10.00 per share. Investors in the PIPE include lead investor RA Capital Management, an affiliate of RACA’s sponsor, as well as Johnson & Johnson Innovation – JJDC, Inc., Surveyor Capital (a Citadel company), Farallon Capital Management, L.L.C., BVF Partners L.P., Boxer Capital, Sphera Healthcare, Woodline Partners LP, Suvretta Capital, Fairmount Funds, and Perceptive Advisors. Assuming no redemptions are exercised, the Combined Company is expected to receive net proceeds of approximately $300 million at the closing of the transaction (inclusive of the trust account balance and the proceeds from the PIPE).

With the funds raised from this transaction, POINT will be well financed to complete our two Phase 3 trials for radioligands to treat prostate and neuroendocrine cancers, advance our early-stage pipeline, and complete construction on our manufacturing facility in Indianapolis, Indiana. 

SPAC 상장 1년여 후 Lantheus와 $260 Million upfront를 포함해서 $1.8 Billion까지 계약을 하고 PNT2002의 상용화 시 20% royalty, PNT2003의 경우는 15% rotyalty를 받을 수 있는 딜을 하게 됩니다.

POINT well made: Lantheus promises up to $2B for 2 of the biotech’s cancer radiopharmaceutical therapies – Fierce Biotech 11/14/2022

Lantheus is paying $260 million upfront for a double bill of licenses for two of POINT Biopharma’s radiopharmaceutical oncology candidates, with another $1.8 billion tied up in biobucks.

Under the agreements, POINT will continue to fund and complete its phase 3 SPLASH trial for PNT2002, a prostate-specific membrane antigen (PSMA)-targeting 177Lu-based radiopharmaceutical therapy for metastatic castration-resistant prostate cancer. After that, Lantheus will work with POINT to file the therapy for FDA approval.

The other candidate is PNT2003, a somatostatin receptor-targeted radioligand in development for gastroenteropancreatic neuroendocrine tumors. POINT will facilitate completion of the ongoing University Health Network-sponsored study in Canada, while Lantheus will prepare and submit the regulatory filings in the U.S.

Should the two assets secure FDA approval and then hit commercial milestones, POINT could be in line for up to $1.8 billion in biobucks plus royalties of 20% and 15% for PNT2002 and PNT2003, respectively.

그리고 1년 후에는 $125 Million의 유상증자를 하게 됩니다. PNT2002의 pivotal clinical trial 및 NDA Filing에 필요한 충분한 자금이 확보되었다고 할 수 있습니다.

POINT Biopharma Prices Public Offering of Common Stock – Globe News Wire 9/13/2022

The gross proceeds to the Company from the offering, before deducting underwriting discounts and commissions and other estimated offering expenses, are expected to be approximately $125 million.

2023년에 Eli Lilly는 준비된 Point Biopharma를 인수하기로 결정하게 됩니다. $1.4 Billion의 시총입니다. 전일 종가에 비해 87% 프리미엄의 좋은 딜이었습니다.

Lilly to Acquire POINT Biopharma to Expand Oncology Capabilities into Next-Generation Radioligand Therapies – PR News Wire 10/3/2023

POINT’s lead programs are in late-phase development. PNT2002¹ is a prostate-specific membrane antigen (PSMA) targeted radioligand therapy in development for patients with metastatic castration-resistant prostate cancer (mCRPC) after progression on hormonal treatment. Topline data from this study are expected in the fourth quarter of 2023. PNT2003¹ is a somatostatin receptor (SSTR) targeted radioligand therapy in development for the treatment of patients with gastroenteropancreatic neuroendocrine tumors (GEP-NETs). Beyond the late-stage clinical pipeline, POINT has several additional programs in earlier stages of clinical and preclinical development. Additionally, POINT operates a 180,000-square-foot radiopharmaceutical manufacturing campus in Indianapolis, as well as a radiopharmaceutical research and development center in Toronto. These facilities will be utilized alongside POINT’s extensive network of supply chain partners for sourcing radioisotopes and their precursors.

Lilly will commence a tender offer to acquire all outstanding shares of POINT for a purchase price of $12.50 per share in cash (an aggregate of approximately $1.4 billion) payable at closing. The transaction has been approved by the boards of directors of both companies. The purchase price payable at closing represents a premium of approximately 87% to POINT’s closing stock price on Oct. 2, 2023, the last trading day before the announcement of the transaction, and 68% to the 30-day volume-weighted average price. POINT’s board of directors unanimously recommends that POINT’s stockholders tender their shares in the tender offer.

현재의 파이프라인과 2023년 6월 Investor Day Presentation을 아래에 올립니다. PNT2002와 PNT2003은 임상3상에 있꼬 PNT2004는 임상1상을 진행 중에 있습니다.

PNT2002는 Novartis의 Pluvicto의 경쟁제품이 될 것인데 승인이 되어서 전립선암 환자들에게 도움이 되기를 바랍니다.

BIOTECH (104) Novartis: Pluvicto (177Lu-PSMA-617) – the First Precision Radiopharmaceuticals

안녕하세요 보스턴 임박사입니다.

Entos Pharmaceuticals는 Cananda의 Dalhousie University에 있는 Roy Duncan 교수 연구실의 Fusogenic Proteolipid Vehicle (PLV) Delivery Platform을 기반으로 한 Gene Therapy Company입니다.

Roy Duncan교수의 Fusogenic PLV Platform은 Roy Duncan 교수가 세운 Fusogenix로 IP가 이전되었다가 Innovascreen으로 합병되어 2010년대에 기술 개발이 이루어집니다. Roy Duncan 교수는 2000년에 Embo Journal에 FAST Protein에 대해 최초로 보고합니다.

Innovascreen and Saint Mary’s University Partner to Advance Novel Brain Cancer Therapeutics – Biospace 2/17/2010

Innovascreen, Inc. Release: Tumor-Targeted Nanoparticles Evaluated Using Aset Platform Featured on the Cover of Small – Biospace 6/27/2011

Roy Duncan 교수는 2010년부터 Fusogenic Reovirus를 이용하여 Fusion-Associated Small Transmembrane (FAST) Protein을 개발하였는데 이에 대해 본인이 2019년에 Annual Reviews에 기고한 논문이 있습니다.

Entos Pharmaceuticals Founder이자 CEO인 John Lewis 박사는 학회발표나 논문기고를 통해 Fusogenix FAST를 알리는데 열심히 노력을 했습니다.

COVID-19 Pandemic 기간 동안에 Entos Pharmaceuticals는 Covigenix DNA vaccine VAX-001의 임상을 진행하였습니다.

Aegis and Entos commence dosing in trial of Covid-19 DNA vaccine – Clinical Triasl Arena 4/19/2021

US company Aegis Life has initiated dosing of the first participants in a Phase I/II clinical trial with parent company Entos Pharmaceuticals’ novel DNA Covid-19 vaccine, Covigenix VAX-001, to induce immunity against SARS-CoV-2.

Entos to commence Phase II Covid-19 vaccine trial in South Africa – Pharmaceutical Technology 9/2/2021

Entos Pharmaceuticals has obtained approval from the South African Health Products Regulatory Authority (SAHPRA) to commence a Phase II clinical trial of its Covid-19 vaccine candidate, Covigenix VAX-001, in the country.

Made using the Entos’ Fusogenix proteolipid vehicle (PLV) nucleic acid delivery platform, the deoxyribonucleic acid (DNA) vaccine encodes the SARS-CoV-2 Spike protein. It also includes two genetic adjuvants to induce the innate and adaptive immune systems, offering efficient and long-term protection from Covid-19.

The Fusogenix platform leverages a new mechanism of action to carry molecules directly into the cytosol of intended cells in an intact and unaltered manner.

The latest approval is based on positive Phase I data, which showed that Covigenix VAX-001 met all the safety goals without any serious adverse events noted in the trial.

Entos Pharmaceuticals Passes Significant Enrollment Milestone in Phase 2 Clinical Trial of its COVID-19 DNA Vaccine – Financial Post 9/29/2022

이런 노력의 결과로 최근 BioMarin과 Eli Lilly와 잇달아 연구계약을 맺게 됩니다. 특히 Eli Lilly는 $50 Million Upfront 포함 $400 Million에 exclusive right을 얻게 되어 Eli Lilly가 개발 중인 Nucleic Acid Therapy에 Fusogenix PLV Platform을 사용할 계획입니다.

Entos and BioMarin Enter into Agreement for Product Candidates Incorporating Entos’ Fusogenix Drug Delivery Platform – PR News Wire 11/15/2021

“As a company committed to addressing the unmet therapeutic needs of patients living with genetic diseases, BioMarin values novel technologies that enable the development of transformative therapies,” said Brinda Balakrishnan, M.D., Ph.D., Group Vice President, Corporate and Business Development at BioMarin. “We believe that Entos’ Fusogenix platform offers potentially unique benefits for safe and effective tissue targeting compared with other lipid-based delivery systems. The Fusogenix PLV formulations generated under this agreement are a critical first step in determining how we may incorporate this promising platform into our drug development efforts.”

Eli Lilly taps Entos’ delivery tech in $50M-plus nucleic acid pact – Fierce Biotech 1/6/2022

Entos Pharmaceuticals’ star is rising. Just a few short months after the biotech’s nucleic acid delivery tech helped land a deal with BioMarin, the Edmonton, Alberta-based Canadian company has teamed up with Eli Lilly for $50 million upfront to drive its proteolipid vehicles (PLVs) toward a range of nervous system targets.

Eli Lilly has picked up exclusive right to Entos’ Fusogenix nucleic acid delivery technology, which it will use to research, develop and potentially sell nucleic acid-based therapeutics against targets in the central and peripheral nervous systems, the companies said Thursday.

The deal breaks down like this: Lilly and Entos will collaborate on multiple programs that wed Lilly-supplied therapeutic cargo to Entos’ PLVs. Entos is on deck to generate, develop and optimize those PLVs on its proprietary Fusogenix platform. Lilly will then select PLVs to take into the clinic.

Entos is in line to receive $50 million upfront from the R&D pact, which includes an equity investment in the company by Lilly. Each program under the collaboration could net Entos up to $400 million more in potential development and commercial milestones, plus royalties should any of the products reach the market.

Entos’ PLVs are formulated with so-called fusion-associated small transmembrane proteins, or FAST proteins, plus neutral lipids for better tolerability. Fusogenix, which can be used to deliver a range of therapy types, such as gene therapy, mRNA, miRNA, RNAi and CRISPR, delivers mRNA or DNA into target cells through direct fusion.

Entos Pharmaceuticals의 Pipeline은 아래와 같습니다. Fusogenix PLV가 Virus Vector나 LNP를 대체할 차세대 Gene Delivery System으로 상용화가 가능할지 주목됩니다.

안녕하세요 보스턴 임박사입니다.

Harvard University의 David R. Liu 교수는 Biotech 분야의 발전에 지금까지 수많은 업적을 남겼습니다. 중요한 업적을 든다면 아래와 같습니다. 이 분야는 모두 신약개발에 너무나 큰 공로를 갖고 있는 연구업적들이기 때문에 시간이 문제일 뿐 Liu 교수가 노벨상을 받는 날이 언젠가 올 것으로 생각합니다.

• DNA-Encoded Library
• Base Editing
• Prime Editing

Prime Medicine은 Prime Editing을 세계 최초로 보고한 2019년 Nature 논문 결과를 바탕으로 만들어진 회사입니다.

Search-and-replace genome editing without double-strand breaks or donor DNA. Nature 2019, 576, 149-157, David R. Liu et al.

2020년에 창업한 Prime Medicine은 2021년 7월에 $315 Million Series A & Series B를 하면서 알려지게 됩니다.

Prime Medicine uncloaks with $315M to push ‘search and replace’ gene-editing treatments. – Fierce Biotech 7/13/2021

After a year in the shadows, Prime Medicine is breaking cover with $315 million to develop a new kind of gene editing. It was developed by David Liu, Ph.D., and Andrew Anzalone, M.D., Ph.D., at the Broad Institute. 

Here’s how it works: “We make a prime editor that has a protein part and what’s called a guide RNA part,” Gottesdiener said. The editor carries a template for a genetic sequence that will replace the targeted mutation. Once the prime editor gets into a cell, it scans the cell’s DNA for the disease-causing sequence that needs to be edited.  

The team is about 50 strong today, and Prime hopes to grow to more than 100 employees by the end of the year. And it won’t be forging its path alone. Prime has a partnership with Beam Therapeutics, the base-editing biotech also founded by David Liu. Under the deal, Prime licensed out the rights for Beam to use prime editing in certain areas such as sickle cell disease. In return, Beam gave Prime certain rights to technology, intellectual property and so on. 

3개월 후 IPO를 하였습니다. 전광석화같은 Nasdaq 상장이었죠.

IPO Raises $175M for Prime, Developer of “Search and Replace” Gene Editing Platform – GEN Edge 10/21/2022

Gross proceeds for Prime could reach $201.25 million—just over the $200 million estimate offered earlier this month by Renaissance Capital, which tracks the IPO market. Prime is among the year’s three largest initial public offerings for a biotech company, following vision care drug/device developer Bausch + Lomb ($630 million gross proceeds) and vaccine developer HilleVax (also $200 million).

Prime projected using approximately $65 million of net proceeds for Investigational New Drug (IND)-enabling studies and potential initiation of clinical studies for some of its current therapeutic programs; and another approximately $65 million for continued advancement of its Prime Editing platform and discovery-stage research for other potential programs.

The company also projected using approximately $50 million in net proceeds to develop its early-stage manufacturing processes and build out a dedicated facility for its medicinal chemistry, process development, and analytical chemistry groups. The facility would include a non-GMP piloting lab for making guide RNA, mRNA, and synthesizing lipids.

Prime Medicine은 창업 후 4년이 지난 지금까지 아직 임상시험에 진입한 프로그램이 없습니다. 금년 상반기에 PM359의 임상진입을 기대하고 있고 FDA와의 pre-IND meeting 결과도 좋았다고 합니다.

두가지 Legal battle이 예상되는데 PASTE platform의 Tome Biosciences와의 IP infringement issue가 있습니다. Tome Biosciences에 대해서는 블로그를 쓴 바가 있습니다.

BIOTECH (97) Tome Biosciences: Programmable Genomic Integration (PGI) Platform

Prime Medicine이 Clinical-Stage로 되면 IP infringement issue가 표면화될 것으로 예상합니다. 또하나 Legal issue였던 Myeloid Therapeutics와의 공동연구계약 종료와 관련한 소송은 최근에 중재가 된 것으로 알려졌습니다.

Prime Medicine and Myeloid Therapeutics Announce Settlement of Pending Disputes – PR Newswire 1/5/2024

Prime Medicine, Inc. (Nasdaq: PRME) (“Prime Medicine”) and Myeloid Therapeutics, Inc. (“Myeloid”), today announced resolution of all of their outstanding disputes, signaling an end to the pending arbitrations and a positive outcome for both parties.

JPM: Prime Medicine Eyes 2024 IND for First Prime Editing Therapy – GEN Edge 1/9/2024

Prime Medicine is on track to file the first IND/CTA application for human trials of a prime editing therapy to the FDA during the first half of this year, with the first clinical data expected as soon as 2025, president and CEO Keith Gottesdiener, MD, told attendees at the 42^nd Annual J.P. Morgan Healthcare Conference.

Prime Medicine’s first candidate poised to enter the clinic is PM359, a blood-targeting candidate for chronic granulomatous disease (CGD) now in the IND-enabling phase. PM359 consists of autologous hematopoietic stem cells modified ex vivo using prime editing.

During 2023, Prime Medicine held pre-IND and INTERACT meetings about PM359 and its prime editing platform with the FDA, whose recommendations the company has aligned with regarding preclinical data, toxicology, CMC [chemistry, manufacturing, and controls], off-target edits, and clinical development plans.

To support its IND/CTA filing, Gottesdiener said, Prime Medicine has generated data showing:

• No off-target editing detected in healthy human donor CD34+ cells, according to a targeted in vitro analysis of 550 potential off-target sites of off-target editing.
• No large deletions or translocations in bone marrow engrafted Prime-Edited LT-HSCs, according to data from an in vivo analysis from mouse bone marrow harvested 16 weeks after engraftment was complete
• Translocation positive control: Cas9 nuclease-edited cells, generated by transfecting HEK293T cells with single guide RNA (sgRNA) targeting NCF1 and Streptococcus pyogenes Cas9 (SpCas9) mRNA

The other three pillars are:

• Liver—Programs to treat Wilson’s disease and glycogen storage disease 1b are in lead optimization phases, while a program with an undisclosed liver indication is in discovery phase. All three apply lipid nanoparticle (LNP) delivery. Other discovery programs are proceeding in Fanconi anemia and cell shielding.
• Ocular—A retinitis pigmentosa/rhodopsin candidate targeting eye tissue and using adeno-associated virus (AAV) vector delivery, is also in lead optimization phase. Other discovery programs are proceeding in retinitis pigmentosa/Usher syndrome, and Fuchs’ endothelial corneal dystrophy.
• Neuro and muscular—A candidate for Friedreich’s ataxia also delivered via AAV, also in lead optimization phase; a myotonic dystrophy type 1 program using viral and nonviral delivery is in discovery phase. Other discovery programs are proceeding in amyotrophic lateral sclerosis, Huntington’s disease, Fragile X syndrome, oculopharyngeal muscular dystrophy, and Duchenne muscular dystrophy.

He asserted that Prime Medicine has pursued an aggressive filing strategy for technological advances, and holds broad, enabling, foundational IP for all prime editing technologies—three issued and one allowed patents. “Our position is, for those that truly look like, act like, seem like prime editing, they probably are prime editing, and we’re confident that we have the foundational IP for these technologies,” Gottesdiener said.

Prime Medicine terminated the collaboration in September 2023, prompting Myeloid to file an arbitration claim seeking $17.5 million after Prime failed to pay a milestone payment in that amount. Prime countered that Myeloid breached their agreement, and filed its own arbitration claim in October seeking $43.5 million from Myeloid, according to Prime’s Form 10-Q quarterly report for the third quarter of 2023.

Prime Medicine이 올해 PM359의 IND Filing을 준비하면서 $161 Million 의 유상증자를 성공적으로 했습니다. 지금과 같은 시장상황에서 다행이라고 생각합니다. $6.25/share의 유상증자였는데 현재는 &8.74/share 로 약 40% 정도 주가가 올라온 상황입니다.

PRME – Prime Medicine Announces Closing of Upsized Public Offering and Full Exercise of the Underwriters’ Option to Purchase Additional Shares – Market Wire News 2/20/2024

The gross proceeds to Prime Medicine from the offering, before deducting underwriting discounts and commissions and offering expenses, were approximately $161.0 million.

올해 2월에 발표한 Corporate Presentation에 나타난 파이프라인은 아래와 같습니다. ex-Vivo program으로 먼저 Biology Risk를 낮추고 이후에 mRNA-LNP조합으로 간질환 rare disease와 AAV 안과 rare disease 및 Neurology rare disease 프로그램이 Lead optimization 단계에 있습니다.

PM359의 Preclinical data를 보면 아래와 같습니다.

• Prime editing을 한 LT-HSC cell은 in vivo에서 완전한 engraftment를 보여주었고
• NCF1 correction이 20% threshold를 훨씬 넘긴 85% 이상을 유지하고 있었고
• Human neutrophill을 보았을 때, ex vivo에서 NADPH oxidase activity가 >80% 교정된 것을 알 수 있었습니다.

이러한 결과는 PM359가 임상에 진입할 수 있슴을 보여주고 있습니다.

안녕하세요 보스턴 임박사입니다.

Elicio Therapeutics는 MIT의 Darrell Irvine 교수 연구실에서 2014년에 Nature에 발표한 “Amphiphile (AMP)” Platform을 기반으로 설립된 바이오텍 회사입니다.

Hitchhiking vaccines boost immunity – MIT News 2/16/2014

Now a team of engineers at MIT has developed a new way to deliver such vaccines directly to the lymph nodes, where huge populations of immune cells reside: These vaccines hitch a ride to the lymph nodes by latching on to the protein albumin, found in the bloodstream. In tests with mice, such vaccines produced very strong immune responses, the researchers report in the Feb. 16 online edition of Nature.

This approach could be especially useful for delivering HIV vaccines and for stimulating the body’s immune system to attack tumors, says Irvine, who is also a member of MIT’s Koch Institute for Integrative Cancer Research.

2019년에는 AMP platform을 이용해서 CAR-T cell therapy에 이용할 수 있슴을 보고하였습니다.

2021년에 $73 Million Series B를 하고 mKRAS cancer 대상한 ELI-002의 임상시험을 위해 노력하였습니다.

Elicio Therapeutics Secures a Total of $73 Million in Series B Financing – Business Wire 2/17/2021

Proceeds will advance Elicio’s lead program ELI-002 into clinical trials in early 2021 for mutated KRAS (mKRAS) driven cancers, estimated to be 25% of all human solid tumors. ELI-002 contains two powerful components: The company’s proprietary immune stimulating Amphiphile (AMP)-CpG, an adjuvant, and AMP mKRAS peptides which target a broad spectrum of KRAS mutations that drive 97% of all KRAS-driven cancers.

1년반 후 IPO를 하기로 하려던 계획을 취소하고 대신 $40 Million Series C를 했습니다. 이 당시 ELI-002의 phase 1가 진행 중이었습니다.

Scoop: Calling off an IPO, a cancer and Covid-19 vaccine maker raises a Series C – Endpoints News 11/4/2022

Elicio Therapeutics has secured $37 million of its planned $40 million Series C, the company confirmed in an email to Endpoints. The Boston biotech had sought to list on Nasdaq as ELTX, with a draft registration statement filed in April 2021 and subsequent SEC filings showing ambitions to price between $12 to $14 apiece. The offering would’ve brought in about the same amount of capital as Elicio now seeks in its private round.

IPO 대신 6개월 후에 Angion Biomedica와 Reverse Merger에 의해 Nasdaq에 상장합니다.

Elicio Therapeutics Announces Completion of Merger with Angion Biomedica – Globe News Wire 6/1/2023

Elicio Therapeutics (Nasdaq: ELTX), a clinical-stage biotechnology company developing a pipeline of novel immunotherapies for the treatment of cancer, today announced the closing of its previously announced merger with Angion Biomedica Corp. The combined company will operate under the name Elicio Therapeutics, and its shares will commence trading on a 1-10 reverse split adjusted basis on June 2, 2023, on the Nasdaq Global Market under the ticker symbol “ELTX”.

Hitchhiking cancer vaccine makes progress in the clinic – MIT News 2/15/2024

By 2016, Irvine was ready to begin translating the vaccine from lab bench experiments to a patient-ready treatment, spinning out a new company, Elicio. 

At Elicio, Irvine’s vaccine has evolved into a platform combining lipid-linked peptides with an immune adjuvant—no CAR T cells required. In 2021, the company began a clinical trial, AMPLIFY-201, of a vaccine named ELI-002, targeting cancers with mutations in the KRAS gene, with a focus on pancreatic ductal adenocarcinoma (PDAC). The company has initially tested a version that targets two, and Phase 1 and 2 studies of the version targeting all seven KRAS mutants are ongoing. 

Data published last month in Nature Medicine from the Phase 1 clinical trial suggests that an effective therapeutic cancer vaccine could be on the horizon. The robust responses seen in the Irvine Lab’s mouse models have so far translated to the 25 patients (20 pancreatic, 5 colorectal) in the trial: 84% of patients showed an average 56-fold increase in the number of antitumor T cells, with complete elimination of blood biomarkers of residual tumor in 24%. Patients who had a strong immune response saw an 86% reduction in the risk of cancer progression or death. The vaccine was tolerated well by patients, with no serious side effects.

2024년에 발표한 Elicio Therapeutics의 Corporate Presentation은 아래와 같습니다.

Picture from https://www.lifescienceleader.com/doc/krystal-biotech-s-side-business-gene-based-aesthetics-0001

안녕하세요 보스턴 임박사입니다.

Krystal Biotech은 저에게 Biotech에 대한 Out-of-box concept을 일깨워주는 회사입니다. 사진에 보여드리는 것과 같이 이 회사는 부부가 창업하고 펀딩해서 Nasdaq IPO를 하고 결국 FDA 승인까지 단기간에 일구기까지 신기하기도 하고 배워볼 마음에 이 글을 씁니다.

How Krystal Biotech Went From Founding To IPO In 18 Months – Smart Business Dealmakers 8/28/2019

The Pittsburgh-based company, which Krishnan co-founded with his wife and COO Suma Krishnan, is working to develop to develop treatments for rare, orphan skin diseases caused by the absence of, or a mutation in, a single gene.

“We were humming along,” he says. “We weren’t really seriously thinking of going public in 2017. We thought maybe it would be a 2018, 2019 type thing. But we had some good interest from investors on Wall Street, ones that had been in biotech and tend to be patient and long term and let the story play out.”

Krishnan was bitten by the biotech bug early in his career, when his company got a drug approved and he heard stories from friends about their children being able to take the drug and feel better.

“The real goal is not as much to go IPO, it’s to get a good treatment for a disease approved,” he says.

The Krishnans self-funded the business in April 2016. They took on two rounds of corporate venture capital, raising more than $18 million, before going public in September 2017. As a public company, Krystal has done two additional rounds of financing, a private placement in 2018 and an additional public offering in June of this year, raising another $200 million in total.

The VC market provides value in terms of guidance and experience, but in exchange they take a lot of equity, Krishnan says. That means many times, entrepreneurs, after a couple of rounds of financing, realize they’re not the bosses anymore.

“The ownership shifts from the entrepreneur to the venture capitalists pretty quickly, and then the direction and a lot of decisions do not solely exist in the hands of the entrepreneur,” he says.

“In our case, given my prior record, it was a conscious decision to stay away and try and keep as much of the ownership in the company as possible,” he says.

Obviously, the downside is it’s a lot of work to keep up with the required procedures and processes. That’s why he recommends figuring out your business strategy first as a private company. Then, when you go public, it’s more about execution of a clear marching order.

Krystal was fortunate that its two funding rounds as a public company were able to be done on the back of good data.

Krystal Biotech Announces Closing of Initial Public Offering and Full Exercise of Underwriters’ Option to Purchase Additional Shares – Globe News Wire 9/22/2017

Krystal Biotech nets $42.4mm in oversubscribed IPO – Citeline 9/22/2017

전임상 결과는 아래 논문에 보고를 했습니다.

Krystal Biotech의 Vijuvek (beremagene geperpavec)의 임상 1상과 2상 결과는 Nature Medicine에 보고하고 임상3상 결과는 New England Journal of Medicine에 발표했습니다.

Krystal Biotech Announces Publication of Phase 1 and 2 Clinical Trial (GEM 1/2 Study) of Beremagene Geperpavec (B-VEC) Data in Nature Medicine – Biospace 5/28/2022

In the Phase 1 and 2 study, matched wounds were evaluated in nine RDEB patients receiving topical B-VEC or placebo repeatedly over 12 weeks. Primary and secondary mechanistic and clinical endpoints were met. No Grade 2 or above B-VEC-related adverse events, vector shedding, or systemic drug exposure were noted.

Krystal Biotech (KRYS) Announces New England Journal of Medicine Publishes Phase 3 Data on B-VEC in Patients with Dystrophic Epidermolysis Bullosa – Street Insider 12/14/2022

In this GEM-3 trial of 31 patients, complete wound healing at 6 months occurred in 67.4% of B-VEC wounds compared to 21.6% for placebo (difference, 45.8 percentage points; 95% confidence interval [CI], 23.6 to 68.0; p=0.002). Complete wound healing at 3 months occurred in 70.6% of the wounds exposed to B-VEC as compared with 19.7% of those exposed to placebo (difference, 51.0 percentage points; 95% CI, 29.3 to 72.6; p=0.0005).

The Company received US Food and Drug Administration (FDA) filing acceptance of its Biologics License Application (BLA) for B-VEC. The BLA was granted Priority Review designation and the Prescription Drug User Fee Act action date is February 17, 2023. The Company has filed the Marketing Authorization (MA) application with the European Medical Agency (EMA) and is currently working closely with the EMA through the MA validation process.

In vivo topical gene therapy for recessive dystrophic epidermolysis bullosa: a phase 1 and 2 trial. Nat. Med. 2022, 28, 780-788. Suma M. Krishnan, M. Peter Marinkovich et al.

Trial of Beremagene Geperpavec (B-VEC) for Dystrophic Epidermolysis Bullosa. N. Engl. J. Med. 2022, 387, 2211-2219. Suma Krishnan, M. Peter Marinkovich et al.

FDA Approves First-Ever Redosable Gene Therapy for the Treatment of Dystrophic Epidermolysis Bullosa – Global Genes 5/22/2023

he FDA approval of Vyjuvek is based on two clinical studies. The GEM-1/2 trial was an intra-patient, open label, single center, randomized, placebo-controlled study showing that repeat topical applications of Vyjuvek were associated with durable wound closure, full-length cutaneous COL7 expression, and anchoring fibril assembly with minimal reported adverse events. The GEM-3 trial was an intra-patient, double-blinded, multi-center, randomized, placebo-controlled study that met both its primary endpoint of complete wound healing at six months and its key secondary endpoint of complete wound healing at three months. Vyjuvek was well tolerated with no drug-related serious adverse events or discontinuations due to treatment-related events.

“Data from our GEM-1/2 trial and our GEM-3 trial, published in Nature Medicine and the New England Journal of Medicine, respectively, demonstrated the strength of both studies showing that Vyjuvek safely and effectively improved wound healing,” said Suma Krishnan, president, Research & Development, Krystal Biotech.

이외에도 Krystal Biotech은 Jeune Aesthetics라는 subsidiary를 만들어서 KB301이라는 intradermal aesthetic injection을 개발하는 회사를 만들었습니다.

Krystal Biotech’s Side Business: Gene-Based Aesthetics – Life Science Leader 11/1/2023

In 2019, Krystal launched a subsidiary called Jeune Aesthetics to develop new applications of its STAR-D platform for the aesthetics market. Its first development candidate, called KB301, uses Krystal’s HSV vector and mechanism of action to deliver a COL31a transgene via intradermal injection, with the goal of boosting the skin’s ability to produce collogen, thereby improving the appearance of aging skin, such as the lines known as “crow’s feet.”

Picture source from Monash University

안녕하세요 보스턴 임박사입니다.

PureTech Health는 영국계 바이오텍으로서 흥미롭게도 회사 내에서 New Platform Startups Incubating을 하고 투자도 할 뿐만 아니라 기술을 사거나 팔기도 합니다. 이 회사의 CEO인 Daphne Zohar와 MIT의 Bob Langer교수가 2005년에 co-founder인 회사입니다. CEO Daphne Zohar의 창업스토리가 재미있습니다.

PureTech Health의 2024년 Corporate Presentation은 아래에 있습니다.

현재 5개의 파이프라인이 있는데 이 중 3개가 Glyph라는 Platform으로 이루어져 있습니다.

Glyph platform 기술은 2016년에 Angewandte Chemie IEE에 최초로 보고하게 됩니다.

Glyceride-Mimetic Prodrugs Incorporating Self-Immolative Spacers Promote Lymphatic Transport, Avoid First-Pass Metabolism, and Enhance Oral Bioavailability. Angew. Chem. IEE 2016, 55, 13700-13705. Christopher J. H. Porter et al.

2017년에 PureTech Health는 Australia의 Monash University Chris Porter교수로 부터 Lymphatic delivery prodrug system을 사게 됩니다.

PureTech Health Exclusively Licenses Glyph Technology from Monash University to Harness Lymphatic Biology – Controlled Release Society 8/29/2017

PureTech Health plc (“PureTech Health” or the “company”, LSE: PRTC), an advanced, clinical-stage biopharmaceutical company, today announced an exclusive licensing agreement with Monash University for a lymphatic targeting platform (the Glyph technology) based on the pioneering research of Christopher Porter, Ph.D., director of the Monash Institute of Pharmaceutical Sciences (MIPS) at Monash University in Australia. The Glyph technology is aimed at harnessing the biology of the lymphatic system to develop novel therapeutics, including those that selectively target certain lymph nodes. This program further builds on PureTech’s leadership in identifying novel approaches to address dysfunctions of the brain, immune, and GI systems.

The Glyph technology is designed to harness the biology of the lymphatic system and the endogenous trafficking of compounds through this network to develop novel drugs that bypass first-pass metabolism, improve oral bioavailability, and significantly lower the risk of liver toxicity. In particular, the mesenteric lymph nodes, proximal to the gut, are exposed to a host of microbiome-related species and serve an integral role in immune education and control. Targeting the lymphatic pathway potentially enables rational design of therapeutics to modulate the immune system, representing an innovative approach to treating a broad range of serious immunological disorders, such as cancer and autoimmune diseases. The Glyph technology will be developed by PureTech Health through its subsidiary, Glyph Biosciences, in collaboration with Dr. Porter’s laboratory.

“Through our work at Monash University, we have designed chemistries that potentially enable drugs to be preferentially and effectively transported through the endogenous pathways of lipid transport via the intestinal lymphatics in a controlled manner,” said Dr. Porter. “Our technology has been shown in preclinical experiments to achieve significant oral bioavailability of compounds through the avoidance of first-pass metabolism, and has the potential to significantly mitigate liver toxicity and to alter systemic drug disposition. I am excited to be working with PureTech Health to rapidly advance this potentially disruptive technology platform toward the development of novel therapeutics.”

“This new program builds on PureTech’s unique expertise and approach to utilize novel biology, such as the lymphatic distribution network, to treat serious diseases,” said David Steinberg, chief innovation officer and a cofounder of PureTech Health. “We look forward to a great partnership with Dr. Porter and building on his work at Monash University to drive advancements in immunomodulation.”

2년 후에 Glyph Platform 기술은 Boehringer Ingelheim에 Sub-license 하게 됩니다.

PureTech Health Announces Collaboration with Boehringer Ingelheim to Advance Immuno-oncology Product Candidates using its Lymphatic Targeting Platform – 8/17/2019

Under terms of the agreement, PureTech Health will receive up to $26 million, including upfront payments, research support, and preclinical milestones, and is eligible to receive more than $200 million in development and sales milestones, in addition to royalties on product sales. The collaboration will initially focus on applying PureTech’s lymphatic targeting technology to an immuno-oncology product candidate designated by Boehringer Ingelheim.

More specifically, the therapeutic candidates are directed to the mesenteric lymph nodes, which program as many as 70 percent of circulating adaptive immune cells. PureTech’s lymphatic targeting approach, which is based on the research of Chris Porter, PhD, Director of the Monash Institute of Pharmaceutical Sciences (MIPS) at Monash University, can potentially be applied to therapeutic molecules across a range of physiochemical properties and holds promise for the development of novel therapeutics for gastrointestinal, central nervous system, and autoimmune diseases as well as cancer.

The research collaboration with Boehringer Ingelheim will focus first on using this approach to administer an immuno-oncology candidate for gastrointestinal (GI) cancers directly to the gut lymphatics.

Targeted delivery of mycophenolic acid to the mesenteric lymph node using a triglyceride mimetic prodrug approach enhances gut-specific immunomodulation in mice. J. Control. Release 2021, 332, 636-651. Christopher J. H. Porter et al.

PureTech Health는 LYT-300을 FXTAS라는 신규뇌질환 치료제 가능성을 위해 DoD grant $11.4 Million을 받기도 했습니다. 이것은 DoD로 부터 받는 4번째 Grant로서 PureTech Health는 그동안 wholly-owned program 개발을 위해서 grant를 받는 형태로 노력해 왔습니다.

PureTech Awarded up to $11.4 Million from U.S. Department of Defense to Advance LYT-300 (Oral Allopregnanolone) for Fragile X-associated Tremor/Ataxia Syndrome – Biospace 8/1/2023

The funds will support a Phase 2 trial of LYT-300 in collaboration with the University of California, Davis (UC Davis). An exploratory, open-label trial of six men with FXTAS, evaluated IV-administration of allopregnanolone across multiple neuropsychological and emotional tests. In addition to being well-tolerated, allopregnanolone showed signals of pharmacologic benefit across multiple neurological endpoints, including the Behavioral Dyscontrol Scale, which measures executive, cognitive and motor function, and demonstrated improvement compared to baseline (p=0.009). IV administration is not feasible in most indications, especially for a chronic therapy, and there remains a need for treatments that can address this debilitating condition. PureTech plans to evaluate LYT-300 in a placebo-controlled trial to demonstrate the safety, tolerability and efficacy of the drug in people with FXTAS.

PureTech’s capital efficient strategy includes the pursuit of non-dilutive funding in the form of grants. This is the fourth DoD grant that PureTech has secured on behalf of its Wholly Owned Programs in addition to five grants secured on behalf of its Founded Entities. 

2023년 11월에 발표한 LYT-300의 임상결과는 primary end point를 모두 충족했다는 좋은 뉴스였습니다.

PureTech’s acute anxiety treatment trial meets primary endpoint  – Clinical Trials Arena 11/15/2023

Puretech Health has reported that its Phase IIa clinical trial of LYT-300 (oral allopregnanolone) to potentially treat acute anxiety met the primary endpoint. 

The proof-of-concept, placebo-controlled, randomised trial analysed the salivary cortisol response induced by LYT-300 based on the Trier Social Stress Test (TSST), an established anxiety clinical model.

The trial enrolled 80 healthy subjects who were randomised into a 1:1 ratio to receive either LYT-300 or a placebo. 

According to the trial’s topline data, oral LYT-300 offered a statistically significant decline in stress hormone response, as evaluated by salivary cortisol, compared to a placebo, meeting the primary endpoint. 

Glyph platform과 LYT-300 임상 개발에 대한 스토리는 아래 Monash University에서 잘 다루었습니다.

Drug with potential in a range of neurological conditions a step closer to being delivered as a simple oral capsule – Monash University 12/20/2022

LYT-300 was generally well-tolerated across the study, and no treatment-related severe or serious adverse events were observed. The data suggest the potential to dramatically increase practicality and usability of allopregnanolone for those with PPD, along with a broad range of neurological and neuropsychiatric conditions. Additional data will be presented in a scientific forum, and a Phase 1b/2a clinical trial is expected to begin in the first half of 2023.

The LYT-300 trial is the first clinical validation of the Glyph technology in humans.

A second candidate from the Glyph platform, LYT-310 (oral cannabidiol [CBD]), has also been nominated as a clinical candidate and is designed to greatly expand the therapeutic application and potential of cannabidiol (CBD).

Applying the Glyph technology to CBD to form LYT-310 has been shown to increase oral exposure three to fourfold versus unmodified CBD in multiple preclinical models, including large animal and non-human primate. This has the potential to translate into improved safety and reduced side effects. Lymphatic transport has also been confirmed in preclinical models, with up to 30% of LYT-310 entering the lymphatics, compared to 5% for unmodified CBD. These data further support the novel Glyph mechanism of enhancing oral bioavailability. LYT-310 is expected to enter the clinic in Q4 of 2023.