Impacting Cancer

Nextech Invest, November 2018
Is this email not displaying correctly?
View it in your browser.

Dear Reader,

In our final newsletter of 2018, we congratulate recent Nobel recipients whose discoveries form the basis of modern development of biologics and immunotherapy, announce portfolio progress and introduce you to our newest portfolio company. Specifically, we will look at four recent portfolio events in the context of the transformative science they pursue:

  • TP Therapeutics investment (drugging resistance mutations)
  • NASDAQ listing of Arvinas [ARVN] (protein degradation)
  • Revolutions Medicine’s acquisition of Warp Drive (precision medicine)
  • IDEAYA Biosiences licenses Phase I compound from Novartis (targeting oncogenes)

And finally, we provide an update on public market sentiment in the early stage biotech sector and how that impacts our investment strategy, or not.

We also proudly welcome intern Lukas Rindlisbacher to the Nextech family, and look forward to welcoming you to our new office on Bahnhofstrasse just steps from Lake Zurich and the Sprungli Chocolate Store in the New Year. 

With kind regards,

Your Nextech Team

 

Portfolio News

TP Therapeutics Investment

 

On October 19th, Nextech invested in TP Therapeutics’ USD 80 million Series D fundraising led by Foresite Capital and venBio Partners. In this article, we discuss why the Company’s strategy targeting resistance mutations is compelling. For those already convinced that resistance mutations are the next frontier, feel free to skip to ahead.

Loxo does a good job of describing the mechanisms by which mutations driving cancer occur and the need to determine which proteins are driving tumor growth (oncogenes) and which are merely bi-products here. In the late 1990s, Gleevec (which involved our Scientific Advisor Charles Sawyers) demonstrated that attacking an oncogene fueling a specific cancer with selective medicines could dramatically raise life expectancy for patients whose tumors were driven by that mutation. Many thought biotech would quickly identify all oncogenes and build a drug for each.

Funding flowed and many oncogenes were discovered, but only a subset of cancers were ripe for this strategy. Lung cancer provides a good case study: frequently occurring cancer, extensively researched. More than 35% of lung cancers are now attributed to specific mutations “oncogenes”; 20+% KRAS, 6% ALK 2% BRAF, 2% RET, 2% ROS, and others. Many of these oncogenes are also present in other tumors, so drugs which target them successfully have subsequently been utilized when the oncogene is present and not limited to one tumor location (lung, kidney etc). ALK and ROS were the first oncogenes drugged in lung cancer which expanded to become blockbusters.

Looking at the economics of drug development, oncogenes have been the best risk-reward profile for emerging biotechs. They require special knowledge or “secret sauce” and focus to map the offending protein and customize a drug for it, and can then be rapidly proven in small affordable trials showing strong responses. Success stories include portfolio companies Blueprint Medicines and Kura Oncology, in addition to Loxo Oncology, Plexxikon (acquired by Daiichi Sankyo here), Ignyta (acquired by Roche here) and others. The next oncogene wave is the development of therapies for resistance mutations which occur after a subset of patients unfortunately develop resistance to first generation therapies (as described by Charles Sawyer link).

TP Therapeutics (here) was founded by J. Jean Cui, the lead inventor of crizotinib, the first ALK inhibitor marketed by Pfizer (see interview with Jean here). The Company focuses exclusively on these resistance mutations and is developing a pipeline including a next-generation kinase inhibitor targeting genetic drivers of non-small cell lung cancer (“NSCLC”) and advanced solid tumors for which clinical data has shown profound antitumor activity and durable responses. In addition to the lead compound targeting ROS1+ NSCLC, TP Therapeutics has a pipeline of programs underway to address similarly intractable oncogenic drivers such as ALK and TRK in solid-tumor cancers. 

Read the Forbes article.

Arvinas: Protein Degradation broken down (pun intended)

Let's take a moment to celebrate the successful NASDAQ listing of Arvinas, and put in context why we spent three years venturing out to New Haven, CT (which some Boston VCs explained to us was simply too far to consider) in hopes that they might one day take our money.

In the TP article we explained that recent breakthroughs have identified disease driving oncogenes in a growing subset of tumors. Where disease driving proteins are known, the goal is simple: disable them. Unfortunately, standard small-molecule drug discovery strategies are unable to disable many identified disease driving proteins features such as intracellular location, non-enzymatic function, and surface topology etc. are barriers to therapeutic tractability. As a result, conventional therapeutic modalities can access only about 10-20% of the human proteome. A recent article in Chemical & Engineering News article notes: “If companies want to access the other 80% of the proteome, their medicinal chemists will need to forge a new set of rules for how to rationally build drugs that consistently degrade proteins.”

What does it mean to "consistently degrade proteins," and what is a protein degrader? Targeted protein degraders (also known as PROTACs) are bifunctional small molecules performing a difficult task. To be successful, protein degraders require two active ends: one binds to the protein of interest and the other binds to a protein called E3 ubiquitin ligase whose natural purpose in a cell is to identify rogue cellular material and send it for disposal to the proteasome, the cell’s waste disposal system. Protein degraders act like enzymes or catalysts, making the E3 ligases mark and send these proteins for disposal. 

The first PROTAC-like ligand was developed in the lab of Yale University chemical biologist Craig Crews, scientific founder of Arvinas, and California Institute of Technology cell biologist Raymond Deshaies,15 years ago. In 2008, Crews assembled a team of chemists and biophysicists with the goal of generating the first catalytic small-molecule drug, a modality Crews dubbed “PROTACs” for proteolysis-targeting chimeras. These efforts led to the creation of Arvinas, founded in July 2013 as the first company wholly dedicated to first-in-class protein degradation therapeutics.

Arvinas' significant partnerships with Genentech, Pfizer and Merck show that some big names in Big Pharma have come calling, highlighting the current strategic interest in this area with additional R&D efforts further evaluating the approach. Jay Bradner’s piece, suggests that Novartis is pursuing the field as a starting point for new therapeutics. The launch of C4 Therapeutics, Cedilla Therapeutics by Third Rock and Kymera Therapeutics by Atlas further validate the approach. We will be hearing more about protein degradation in the years to come. May the best drug developers win, as this innovation stands to benefit many patients. 

Revolution Medicines acquires Warp Drive Bio

On October 16th, Revolution Medicines acquired Warp Drive Bio to combine the companies’ complementary drug discovery technologies and precision oncology programs. “The merged R&D portfolio represents a rich pipeline of near- and long-term development opportunities to advance in support of our continuing commitment to translate frontier oncology targets on behalf of cancer patients,” said Mark Goldsmith, MD PhD and CEO of Revolution Medicines. WarpDrive brings an innovative drug modality (SMARTTM) based on the molecular design and optimization of compounds to engage surfaces on disease causing proteins that were previously considered undruggable. Inhibitors created using this technology exploit unique molecular contacts that have not been possible with traditional small molecules. “Mark and the team at Revolution Medicines demonstrate the rare combination of sophisticated science and internal discovery capabilities paired with a deep appreciation of the value of being first to the commercial market. In 2018, we have seen both the Sanofi partnership and the Warp Drive acquisition build upon the company’s core assets and accelerate their trajectory, and we thank the team for allowing us to partner with them in this endeavor,” said Nextech’s Thilo Schroeder.

Read the press release.

IDEAYA Licenses Phase 1 Compound from Novartis

 

On October 23th, IDEAYA Bioscience announced that it has licensed exclusive global rights with Novartis to develop and commercialize Novartis’ LXS196, a Phase 1 protein kinase C (PKC) inhibitor for the treatment of cancers with GNAQ and GNA11 mutations.
"There are no approved therapies for metastatic uveal melanoma, and continued development of promising clinical stage agents, such as IDE196, with a clear genetic biomarker rationale to treat patients that harbor GNAQ and GNA11 mutations through PKC are paramount," said Dr. Sophie Piperno‚ÄźNeumann, M.D., LXS196 Study Investigator and Medical Oncologist at Institute Curie, Paris, France. LXS196 was designed to selectively target multiple PKC isoforms in patients with metastatic uveal melanoma (MUM), an orphan disease with high unmet medical need and no current FDA approved therapies. In an ongoing Phase 1 study, LXS196 has shown early clinical activity and tolerability as a single-agent and in combination therapy with HDM201. Under the name of IDE196, IDEAYA will continue development in metastatic uveal melanoma and will also explore a tumor agnostic basket study of solid tumors with mutations of GNAQ and GNA11.
"IDE196 enhances our robust precision medicine pipeline, and we are ecstatic to develop this first-in-class therapy for cancer patients who harbor activating mutations of GNAQ and GNA11," said Yujiro Hata, Chief Executive Officer of IDEAYA. "Novartis has been an investor in IDEAYA since the Series A, so we are pleased to enter into this agreement and further enhance our strategic relationship."

Read the press release.

Nobel News

Prizes recognize advancements aiding oncology drug discovery

At Nextech, we are unapologetic about our passion for science. We watch the Nobel prize awards as others watch the Oscars, with our resident Swede Jakob Loven reveling in national pride. We scour the presentation schedule in advance of the European Society for Medical Oncology and the American Society for Hematology conferences, making predictions and bracing for the unexpected as others do for the World Cup. This photo of Jim Allison toasting the evening his Nobel was announced along with his wife and fellow scientist Pam Sharma and Nextech Scientific Advisory Board member Phil Greenberg captures the sentiment perfectly.

Congratulations to Jim Allison and Tasuku Honjo for their Nobel for Physiology and Medicine for the discovery of cancer therapy by inhibition of negative immune regulation. Nextech has invested heavily in Jim's science in recent years, counting Neon and Jounce (where he is a scientific founder), and ImaginAB (whose scientific advisory board he joined this summer) among our portfolio companies. We also congratulate Frances Arnold, Sir Gregory Winters and George Smith for the Nobel prize for Chemistry for technology related to the directed evolution of proteins and therapeutic antibodies. These discoveries are the basis for modern biologics development and immunology. 

Read the Medicine press release.

Read the Chemistry press release.

Market Musings 

To state the obvious, the public biotech market is volatile these days.

Since June, three of our portfolio companies completed NASDAQ listings which leave them very well capitalized today. Just before pricing Arvinas [ARVN] in September, Goldman published a report not quite calling a bubble but articulating that the stage at which companies were going public (sometimes prior to filing Investigational New Drug applications and beginning human testing), could make it difficult for less sophisticated investors to sift and assign probabilities of success effectively. And lackluster performance of a portion of IPOs was making some investors leery (Choi, P., Jenkins, C. (16th Sept. 2018). Americas Healthcare: SMID Biotechnology: Initiate with a Neutral view; Tightening fundamentals demand greater selectivity). Subsequently, the sector has been dragged into a broader market correction.

So what does that mean for us at Nextech? Not all that much actually. A subset of companies recently listed are holding quite strong on the valuation front. Innovation continues to accelerate, and rounds led by high quality teams with breakthrough potential continue to be over subscribed. On the margin, should the recent market reset hold, we expect to see continued pressure on B and Crossover round valuations, which is a healthy and normal calibration, and a great time to be putting a new fund to work. Stay tuned.

                                       

Revolution Medicines dosed first patients in the Phase I clinical trial of SHP2 inhibitor RMC-4630 in advanced solid tumors and published its groundbreaking work in Nature Cell Biology.

Read the press release and the published article.


Blueprint [NASDAQ:BPMC] announced updated data from phase 1 ARROW clinical trial showing broad, durable activity of BLU-667 in advanced RET-altered medullary and papillary thyroid cancers.

Read the press release.

In addition they presented preclinical data supporting the development of BLU-782, a highly selective ALK2 inhibitor, for the treatment of patients with fibrodysplasia ossificans progressiva.

Read the press release.


Neon Therapeutics [NASDAQ:NTGN] presented new data from ongoing Phase 1b NT-001 clinical trial at the European Society for Medical Oncology 2018 Congress showing response conversions by adding the personalized cancer vaccine to standard checkpoint inhibition.

Read the press release.

 


ImaginAb announced that it has entered into a multi-year, non-exclusive licensing collaboration with Merck, known as MSD outside the United States and Canada.

Read the press release.

ImaginAb announced the appointment of James Allison, Padmanee Sharma and Ramy Ibrahim to the Scientific Advisory Board.

Read the press release.

 

 


Kura Oncology [NASDAQ:KURA] appoints Marc Grasso, M.D., as Chief Financial Officer and Chief Business Officer.

Read the press release.

Kura Oncology recently presented updated data of the ongoing Phase 2 trial of tipifarnib in HRAS mutant HNSCC at the European Society for Medical Oncology (ESMO) 2018 Congress in Munich.

Read the press release.

 

 

 

Impressum
Nextech Invest Ltd.
Turnerstrasse 26
8006 Zurich, Switzerland

Web: www.nextechinvest.com
E-Mail: info@nextechinvest.com