Novel FDA Approvals

Since the new FDA Commissioner Dr. Scott Gottlieb was sworn in on May 11, 2017, the traditionally cumbersome regulatory body has shown an unprecedented embracement for novelty in treatments and beyond.

Overarching guidelines:

Here is a roundup of those approvals

Novartis, Kymriah, first gene (transfer) therapy (first CAR-T) available in the United States

  • August 30, 2017
  • Biologics License Application (BLA) submitted on February 2, 2017
  • Approval basis: the safety and efficacy of Kymriah were demonstrated in one multicenter clinical trial of 63 pediatric and young adult patients with relapsed or refractory B-cell precursor ALL. The overall remission rate within three months of treatment was 83 percent. (FDA statement)

Pear Therapeutics, the Reset app, first mobile application to treat substance use disorders (SUD)

  • September 14, 2017
  • de novo premarket review pathway
  • Technology: the device delivers cognitive behavioral therapy to patients to teach the user skills that aid in the treatment of SUD and are intended to increase abstinence from substance abuse and increase retention in outpatient therapy programs. The system is intended to be used in conjunction with outpatient therapy and in addition to a contingency management system, a widely-used program for treating SUD that uses a series of incentives to reward patients for adherence to their treatment program.
  • Approval basis: a multi-site, unblinded 12-week clinical trial of 399 patients who received either standard treatment or standard treatment with the addition of a desktop-based version of Reset which could be accessed at the clinic or at home. The data showed a statistically significant increase in adherence to abstinence for the patients with alcohol, cocaine, marijuana and stimulant SUD in those who used Reset, 40.3 percent, compared to the patients who did not, 17.6 percent. The clinical trial did not demonstrate the effectiveness of using the Reset device in patients reporting opioids as their substance of abuse. (FDA statement)
reSET app | Source: New York Times

Memorial Sloan Kettering Cancer Center,  IMPACT test, first tumor-profiling laboratory-developed test to receive authorization through the FDA

  • November 15, 2017
  • de novo premarket review pathway
  • Technology: the IMPACT test uses next-generation sequencing (NGS) to rapidly identify the presence of mutations in 468 unique genes, as well as other molecular changes in the genomic makeup of a person’s tumor.
  • Approval basis: results indicated that the assay is highly accurate (greater than 99 percent) and capable of detecting a mutation at a frequency of approximately 5 percent (range of 2-5 percent). Additionally, detection of certain molecular changes (microsatellite instability) using the IMPACT test was concordant more than 92 percent of the time across multiple cancer types in 175 cases, when compared to traditional methods of detection.
  • Along with this authorization, the FDA is also establishing a Class II regulatory pathway for the review of other NGS-based tumor profiling tests for use in patients diagnosed with cancer. Class II designation allows these types of tests to be eligible to use the FDA’s 510(k) clearance process, either by submitting the application. (FDA statements)
Source: mskcc.org

Proteus Digital Health x Otsuka Pharma, Abilify MyCite, first drug in the U.S. with a digital ingestion tracking system

  • November 13, 2017
  • New Drug Application (NDA) dated and received June 26, 2015
  • Technology: the system works by sending a message from the pill’s sensor to a wearable patch. The patch transmits the information to a mobile application so that patients can track the ingestion of the medication on their smart phone. Patients can also permit their caregivers and physician to access the information through a web-based portal.
  • Approval basis: Abilify was first approved by the FDA in 2002 to treat schizophrenia. The ingestible sensor used in Abilify MyCite was first permitted for marketing by the FDA in 2012. (FDA statement)
Source: npr.org

Spark Therapeutics, Luxturna, first (directly administered) gene therapy approved in the U.S. to target a disease caused by mutations in a specific gene

  • December 19, 2017
  • Biologics License Application (BLA) dated April 26, 2017, and received May 16, 2017
  • Approval basis: The efficacy of LUXTURNA in the Phase 3 study was established based on the multi-luminance mobility test (MLMT) score change from baseline to one year. LUXTURNA Phase 3 clinical study results showed a statistically significant difference between the intervention group (n=21) and control participants (n=10) at one year in median bilateral MLMT score change (intervention minus control group difference of 2; p=0.001) and median first-treated eye MLMT score change (intervention minus control group difference of 2; p=0.003). (Spark press release)
  • FDA statement
Luxturna | Source: Spark Therapeutics

Loxo Oncology, Vitrakvi, first time that an entirely new treatment has received a tumor-agnostic indication at its initial approval

Source: genengnews.com

Apple, the ECG app (with Apple Watch), first FDA clearance for retail ECG watch technology

  • September 11, 2018
  • De Novo clearance from the Center for Devices and Radiological Health, classified as Class II under the generic name electrocardiograph software for over-the-counter use
  • Technology: the ECG app determines the presence of atrial fibrillation (AFib) or sinus rhythm on a classifiable waveform
  • FDA statement
  • FDA letter to Apple
  • covered in a previous blog: New Era of Medical Grade Consumer Device
Apple Watch Series 4, the ECG app | Source: Apple
  • January 17, 2019 update: Alphabet’s life sciences unit Verily received 510(k) clearance from FDA as a Class II medical device for its on-demand ECG feature
Study Watch | Source: Verily

 

Current Anti-Aging Startups Roundup

Anti-aging is a centuries-long problem and we don’t have an answer.

Here is a summary of current notable efforts that might provide some sort of solution.

Biopharma/Therapeutics Approach

Unity Biotechnology – eliminate senescent cells
Source: Unity Cellular Senescence Investor & Analyst Presentation on Dec. 11, 2018
  • Lead candidate UBX0101, a first-in-class senolytic molecule
  • UBX1967
    • January 2019, completed license agreement with Ascentage Pharma, granting Unity the exclusive worldwide development and commercialization rights and non-exclusive manufacturing rights outside of Greater China (China, Hong Kong, Macau and Taiwan) for UBX1967 in all non-oncology indications. Inside Greater China, UNITY is obligated to commercialize UBX1967 through a joint venture with Ascentage Pharma. The UBX1967 License Agreement also grants UNITY the right to continue its preclinical development efforts with respect to another Ascentage Pharma-controlled Bcl-2 inhibitor compound that will serve as a back-up to UBX1967.
    • Per the 2016 pact, should Unity choose to license at least one more products, the Chinese biotech will gain a total of 1,333,338 shares
    • plans to file an IND application for UBX1967 in the second half of 2019
Calico – A previous google company
  • Founded in 2013, Calico started within Google (later Alphabet) and soon jump-started with huge fundings – a $1.5 billion initiative/collaboration in September 2014 with Abbvie. “AbbVie and Calico will each initially provide up to $250 million to fund the collaboration with the potential for both sides to contribute an additional $500 million.”
  • In June 2018, the collaboration was extended with another $1 billion. “AbbVie and Calico will each commit to contribute an additional $500 million to the collaboration.”
  • It was also cited that “since 2014, the collaboration between the two companies has produced more than two dozen early-stage programs addressing disease states across oncology and neuroscience and yielded new insights into the biology of aging.”
samumed
Napa Therapeutics

Data Approach

Juvenescence AI
  • A subsidiary of Juvenescence, a joint effort of Juvenescence + Insilico Medicine
  • Formed in July 2017
Human Longevity
  • Was valued at $1.6 billion in 2017 with fundings from Celgene, Illumina, GE Ventures, etc.
  • Declined to a valuation of $310 million according to a WSJ report

Portfolio Approach

Juvenescence
Life Biosciences
  • Jan. 2019 Series B of $50 million
  • co-founded in 2017 by David Sinclair and Tristan Edwards
  • 8 Subsidiaries
    • Prana Biotechnology (an initial $7.5 million investment in Jan.2019)
    • Lua, HIPAA-compliant medical technology platform (acquired in Oct. 2018)
    • Senolytic Therapeutics acquired at a very early stage
    • Jumpstart Fertility acquired at a very early stage
    • the other four were formed in-house (Selphagy Tx, Spotlight Biosciences, Continuum Biosciences, Animal Biosciences)

Somehow, reminded me of Theranos… also an area that might not be reguated by FDA… (Ageing is not a disease by FDA’s definition) and some are backed by non-traditional biotech VC firms… But most seemed to be more experienced and sophisticated in biology and medicine (than Theranos’ average).

Loxo and Pan-Cancer Treatments

In the first week of 2019, besides the BMS-Celgene merger, the $8 billion acquisition of Loxo Oncology by Eli Lilly is the largest deal announced.

For a premium of 68%, what is special with Loxo?

Its approval of Vitrakvi in Nov 2018 is definitely a remarkable one, marking the second approval by the FDA based on a patient’s tumor’s molecular information (TRK fusion), regardless of the location of the tumor within the body. (pancan)

That has been the trend since targeted therapies were proved to be extraordinarily effective in certain types of cancer, usually characterized by gene mutations. EGFR is probably the most famous one.

But FDA approvals were still linked to the tumor locations until May 2017 when Merck’s Keytruda was approved upon a biomarker – microsatellite instability-high (MSI-H) or mismatch repair deficient (dMMR).

Before Keytruda became the first cancer treatment for any solid tumor with a specific genetic feature, it had been approved for the treatment of certain patients with metastatic melanoma, metastatic non-small cell lung cancer, recurrent or metastatic head and neck cancer, refractory classical Hodgkin lymphoma, and urothelial carcinoma.

Loxo’s Vitrakvi, however, received its approval solely based on biomarkers since the beginning. Also, Vitrakvi is the first targeted therapy to be approved this way.

And this big step forward for precision medicine is now acquired by Eli Lilly.

Source: Bloomberg

For Being Written In History? First Gene-edited Babies

Twin girls (Lulu and Nana) were born this month in China and they might be making a history. Applying CRISPR-cas9 to disable the CCR5 gene, which plays a key role in HIV infection, Jiankui He revealed details about the “surgery” in an exclusive interview with AP released on Monday.

At Shenzhen

According to AP, He studied at Rice and Stanford before going back to China. He opened a lab at Southern University of Science and Technology (SUST) of in Shenzhen, where he also has two genetics companies.

He has been on leave from teaching since early this year, but he remains on the faculty and has a lab at SUST.

Partner

The U.S. scientist who worked with him on this project after He returned to China was physics and bioengineering professor Michael Deem, who was his adviser at Rice in Houston. Deem also holds what he called “a small stake” in — and is on the scientific advisory boards of — He’s two companies.

All about making a headline and a history?

The motivation to prevent HIV is good, and justifiable according to George Church. But for many stakeholders in this case, other things come into play. It is political.

“Second International Summit on Human Genome Editing” was to held in Hong Kong from Nov.27 to Nov.29 (Beijing time). The He Lab uploaded videos on YouTube on Nov.26. No coincident.

Things like this could have been discussed thoroughly beforehand. Why is that related parties are “shocked” now?

The plan could have been reported months ago and open to comments/discussions. Why is that no industry associations are aware of anything?

Even the news and YouTube videos could have been written and released the day after the twin was born. Why waiting?

I believe in the future of gene editing; and it will eventually be used in humans, babies and embryos someday. But how this particular news unfolds makes me kinda uncomfortable.

It is understandable that someone (not only about He) wants to make a history, wants to be the “first”.

It is as well understandable that some others are not happy that the “first” title has been stolen.

But I would rather see science & technology less political and less about fame, making history or setting standards/principles.

When science & technology are being pursued largely for showing off, it is pathetic.


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Moderna’s Long-waited IPO Filed, Raising $500+ Million

Moderna filed S-1 with SEC last Friday and will become the largest biotech IPO in history.

The record amount of raise ($500 million in current version of documents; I will expect more) just surpassed $421 million (HK$3.3bn) IPO by Innovent. In the past years, the typical size of the largest biotech IPO is around $200-300 million.

Since October, we have seen a series of large biotech IPOs that might also contribute to the money pulled from other biotech companies.

Here is the list of ever-increase IPOs in size since October:

– Guardant Health $238 million

– Allogene $324 million

– Innovent (in HK) $421 million

– Moderna (proposed) $500 million

Guardant Health’s Liquid Biopsy Outperforming Tissue NGS

上周 Guardant Health 在 JAMA 上的一篇文章,对比了 Guardant 360 (plasma-based NGS) 和 tissue-based NGS 在 NSCLC 中检测突变的能力以指导用药。

Clinical Implications of Plasma-Based Genotyping With the Delivery of Personalized Therapy in Metastatic Non–Small Cell Lung Cancer

Guardant 360 检测出 clinical relevant mutations 的患者数接近组织 NGS 的两倍(82 vs 47)。

在多检测出的 35 例样本中,有 8 例是同时进行 plasma- & tissue- NGS 后,液体活检真正比组织多检测出的部分,另外 27 例是由于组织活检无法进行 (insufficient quantity/quality of tissue DNA)。

突出了液体活检真正的好处之一 – 肺癌晚期 (NSCLC stage IV) 的液体活检无法实施的时候 (79/207, ~38%)。

这也是液体活检努力的方向 – 在更多癌种中不要被当作 2nd line 检测。

Nobel Prize! Immunotherapy – CTLA-4 & PD-1

不得不提一下今天的诺贝尔生理/医学奖,需要把 Modern Communication (2) 往后推一天。

James P. Allison 和 Tasuku Honjo 分别发现了 CTLA-4 和 PD-1 在癌症免疫治疗中的仲要作用,共同分享今年的 Nobel Prize in Physiology or Medicine。

本身我也有一直在跟踪这个领域,对于今年的颁奖还是很兴奋的。1990s 年代的科学发现今天已经在商业上取得了很大成功,给无数癌症患者带来了缓解/治愈。

Yervoy (CTLA-4) 2011 年首次被 FDA 批准上市;Opdivo (PD-1) 2014 年 7 月在日本首次获批(melanoma, 全球第一个获批的 PD-1),随后 Keytruda (PD-1) 2014 年 9 月也在美国被批(melanoma, 美国第一个获批的PD-1,Opdivo 同年 12 月在美国获批)。

Yervoy 和 Opdivo 现都在 BMS 旗下(2009 年收购 Medarex 获得),Keytruda 现在 Merck 旗下(2009 年与 Schering-Plough合并获得,Schering-Plough 2007 年收购 Oragnon 获得)。

2018 年 6 月,Opdivo 在中国获批上市 (NSCLC);7月,Keytruda 在中国获批上市 (melanoma)。

我相信,癌症治疗就像 debug 一样。癌症本身也就是人体内代码错误。Immunotherapy 是一大步迈进,是我们不断接近 bug 源头的重要一步。或许今天我们的干预手段以后看来相当拙劣,就像是蛮力 debug,会影响其它 code 或者极其不 efficient & effective – 但我相信,(cancer) debug in a smart way 的那天并不遥远。

附上一图,来看看 commercial success from real science –

Synthetic Biology and Microbes

分享一篇New York Times的文章

Scientists Are Retooling Bacteria to Cure Disease

synthetic biology + microbes -> a novel class of medicine

随着人类对于微生物(组)在自己体内作用的理解更为深入,对于DNA engineering运用愈加熟练,这一天已经很近了。

在以后的历史书上,或许会记录下2010s是标志性的起点 – 我们掌握了CAR-T,把自己的T细胞engineer作为药物。在我看来,人类体内的微生物抑或是T细胞,本就已经是不可分割的部分,从某种角度来说,engineered microbes和engineered T-cells很是相似。

有一点区别,目前的CAR-T是自体的,需要病人提供自己的T细胞;而engineered microbes完全off-the-shelf;未来我相信会解决异体CAR-T的问题,但至少现在来说,这一点engineered microbes更有药物属性 – a difference between therapies and medicines。

未来或许会发展出一种从超市直接买的 – 营养品/保健品 or 饮料…

anyway,这是biotech/life science无比sexy的十年,在我眼里。

 

文中提到,”You can’t overestimate the impact of the microbiome work” – Then you cant’ overestimate the impact of a mix of engineered microbes。祝福相关公司,感谢所有推进人类进程、拓宽人类边界的努力。荣幸。