Tag Archives: fitness

Pullan’s Pieces #3 – January – A Corner on Market Sentiments – Seed to Series A

29 Jul

As the saying goes, “What’s in a name? That which we call a Series A by any other name would smell as sweet.” Er… something like that, right? Hmmm, maybe it went a little bit differently.

But whatever it be, or not to be😊, the Seed Round is the new Series A. Clearly. I think we’ve all felt it for sometime but the data is in and the good ‘ole Series A just don’t buy what it used to. Nahhh… the Seed round does that, and it may buy more (equity) than it used to as a Series A (more data hunting and crunching required but one gets a sense that the venture capitalists are, well, capitalizing).

Labiotech does a really nice job collecting and summarizing a variety of topics related to financings and dealmaking in the biotech sector and the 2024 breakdown of funding offers the following approximations (roughly, with some rounding made by this author):

The internal breakdowns for amounts invested look like this:


Readers of this corner will know that we keep a close eye on the XBI

As usual, the outliers can skew the numbers (more on this in a moment) but the median amounts invested into these rounds puh-rihhhty much drive the nail in the coffin of the old thinking about Series dynamics. This data could be charted in another way in which an inverted bell curve would appear and a GAPING hole between $20M and $50M would stare back at you. Think about that for a moment… if you can’t get to value inflection for ~$15-20M, you better be raising $60-75M and have multiple reasons to do so as a cursory view of the companies listed in the dataset further indicates that the lower outliers (sub-median) on the Series A were generally geared for “finding out” about a single asset in the clinic.

Back to that previously mentioned outlier that can skew the averages… it also happens to bring even more of a spotlight to those famed words from Shakespeare which began this Corner on Market Sentiments. One of the companies in the 2024 data set raised a whopping $100,000,000 … as a Seed Round!! Indeed, a rose by any other name…

The Needle Issue #11

22 Jul
Juan-Carlos-Lopez
Juan Carlos Lopez
Andy-Marshall
Andy Marshall

Haystack chat

Molecular glue degraders (MGDs) are currently having a bit of a moment. In the first half of 2025, the number of papers describing such compounds has doubled.

2025 has also witnessed a whole raft of MGD startups publish research related to their programs:

Startup (location) Scientific founders (location) 2025 paper
Ambagon Therapeutics (Eindhoven, The Netherlands) Michelle Arkin (UCSF, San Francisco, CA), Luc Brunsveld and Christian Ottman (Eindhoven University of Technology) Molecular glues of the regulatory ChREBP/14-3-3 complex protect beta cells from glucolipotoxicity
Cyrus Therapeutics (Seoul, South Korea) Keon Wook Kang (Seoul National University, Seoul, South Korea) High cereblon expression in neuroendocrine cancer confers vulnerability to GSPT1 molecular glue degrader
Matchpoint Therapeutics (Cambridge, MA) Nathanael Gray and Tinghu Zhang (Stanford University, Stanford, CA) and Edward Chouchani and Jianwei Che (Dana Farber, Boston, MA) Structure-guided design of a truncated heterobivalent chemical probe degrader of IRE1α
Monte Rosa Therapeutics (Boston, MA) Rajesh Chopra and Ian Collins (The Institute of Cancer Research and Cancer Research UK); Nicolas Thomä (Friedrich Miescher Institute, Basel, Switzerland) Structure-guided strategy for identifying human proteins predicted to be compatible with cereblon-based molecular glue degraders (see below for further details)
Oniria Therapeutics (Barcelona, Spain) Héctor G. Palmer, Esther Riambau, Isabel Puig, Josep Tabernero, Xavier Barril, and Carles Galdeano (Vall d’Hebron Institute of Oncology, University of Barcelona and ICREA) Cullin-RING ligase BioE3 reveals molecular-glue-induced neosubstrates and rewiring of the endogenous Cereblon ubiquitome
Proxygen (Vienna, Austria) Georg Winter (CeMM Research Center for Molecular Medicine, Vienna, Austria) Selective analysis of protein degradation by mass spectrometry enables degradome analysis and identification of direct protein substrates of molecular glues
Proteovant Therapeutics (King of Prussia, PA) Shaomeng Wang (University of Michigan, MI) Development of PVTX-405 as a potent and highly selective molecular glue degrader of IKZF2 for cancer immunotherapy
Sartar Therapeutics (Helsinki, Finland) Olli Kallioniemi and Harri Sihto (University of Helsinki, Finland) Pharmacokinetic profile and in vivo anticancer efficacy of anagrelide administered subcutaneously in rodents
SEED Therapeutics (King of Prussia, PA) Ning Zheng (University of Seattle, WA), Michele Pagano (New York University, NY) and Avram Hershko (Technion Institute of Technology, Haifa, Israel) UM171 glue co-opts CRL3 RING E3 ligase substrate coreceptor KBTBD4 as well as HDAC1/2, resulting in degradation of CoREST corepressors
Shenandoah Therapeutics (South San Francisco, CA) Jerry Crabtree and Nathanael Gray (Stanford University, Stanford, CA) A bivalent molecular glue linking lysine acetyltransferases to redirect p300 and CBP to activate programmed cell death genes normally repressed by the oncogenic driver, BCL6
Zenith Therapeutics (Basel, Switzerland) Daniel Nomura (UC Berkeley, CA); Nicolas Thomä (Friedrich Miescher Institute, Basel, Switzerland), and Martin Stahl (former Roche, LifeMine) Putative molecular glue niclosamide acts via ubiquitin E3 ligase CRL4AMBRA1-mediated degradation of cyclin D1 following mitochondrial membrane depolarization

On the commercial front, the march of startups receiving funding shows no sign of slowing down, with Trimtech Therapeutics and Booster Therapeutics raising substantive rounds. The first few months of the year have also seen the continuation of last year’s pharma MGD scramble to license programs from Triana Biomedicines and Neomorph, with deals based around molecular glues from Abbvie and Merck targeting Neomorph and Springworks, respectively.

In June, one of the flagship developers, Kymera Therapeutics, priced a $250.8 million follow-on offering (no mean feat in the present market) after announcing positive phase 1 safety data for KT-621, a novel MGD against STAT-6, and clinching a deal with Gilead Sciencesforanother small-molecule glue targeting cyclin-dependent kinase 2 (CDK2). All in all, we count 27 companies currently active in this preclinical space (Ambagon TherapeuticsAmphista Therapeutics, Booster Therapeutics, Captor TherapeuticsCyrus TherapeuticsDegron TherapeuticsDunad TherapeuticsF5 TherapeuticsFrontier MedicinesLifemine TherapeuticsMagnet Biomedicine,Matchpoint TherapeuticsMontara TherapeuticsMonte Rosa Therapeutics, Neomorph, Oniria TherapeuticsProxygenSartar TherapeuticsSEED Therapeutics, Shanghai Dage Biomedical Technology, Shenandoah TherapeuticsSK Biopharmaceuticals (Proteovant Therapeutics),Triana,Trimtech,Venquis TherapeuticsYDS Pharmatech, and Zenith Therapeutics). There are likely more.

Unlike their more recent cousins, the PROTACs (proteolysis targeting chimeras), MGDs have a long history. The archetypal MGD, thalidomide, was discovered back in the 1950s. From the late 1990s, a new generation of immunomodulatory imide drug (IMiD) derivatives of thalidomide were synthesized, culminating with the approvals of lenalidomide and pomalidomide for myeloma (which formed the basis for the Celgene (now BMS) franchise).

Unlike PROTACs, which use two ligands with a linker and tend to be rather unwieldy, MGDs are small, single compounds that induce conformational changes in E3 ubiquitin ligases and target proteins, reshaping both to enable binding. The vast majority of MGDs bind Cereblon (CRBN), leading to ubiquitination of the protein of interest and degradation in the 26S proteasome, although work is progressing to broaden MGD action to some of the other 600 or so E3 ubiquitin ligases (e.g., DCAF11,15 or 16DDB1SIAHKEAP1VHLβ-TrCPNedd1 and, just last week, TRIM21).

A key challenge in finding new MGDs has been a lack of understanding of the structural rules whereby MGDs turn their target proteins into CRBN ‘neosubstrates’, which has meant MGD ‘hit-finding’ is much more challenging, with fewer degrees of freedom than PROTACs.

What drug hunters have established is that many protein targets of glues contain a β-hairpin structural motif known as the ‘G-loop’. When a MGD brings a target together with CRBN, one end of the MGD interacts with a binding pocket in the C-terminal domain of CRBN, while the other end protrudes from the pocket and interacts with the G-loop (part of the so-called ‘degron’) in the neosubstrate. But how many proteins possess the β-hairpin G-loop or whether the loop is strictly necessary for MGD action have remained open questions. A recent study by Monte Rosa Therapeutics’ scientists starts to tackle these issues, disclosing a large cadre of potential new substrates for CRBN, some of which depart from the canonical β-hairpin G-loop, radically expanding MGD target space.

To map the full range of proteins potentially recruitable by CRBN through MGDs, the team led by John Castle and Sharon Townson developed computational algorithms to search for β-hairpin G-loop motifs in protein structures from two databases: Protein Data Bank and AlphaFold2. This approach resulted in 1424 candidate proteins, some of which were experimentally validated in MGD assays. The list included previously known neosubstrates, but also new proteins such as NEK7—a protein of interest as an autoimmunity target.

The researchers then wondered if the full β-hairpin structure of the G-loop is required for CRBN recognition and rescreened the structure databases looking for a minimal, structurally defined helical G-loop motif. This resulted in the identification of 184 additional potential neosubstrates, including mTOR, a well-established therapeutic target for drugs like rapamycin and sirolimus. Crystallographic data showed that the binding of this helical G-loop to CRBN is similar to that of the canonical β-hairpin G-loops.

As these protein–protein interactions have been well characterized, the team then tried to identify an even wider set of potential neosubstrates, looking now for proteins with sequences that might result in surfaces with electrostatic properties similar to known CRBN interactors, independently of secondary structure and the existence of G-loops. Using surface-matching algorithms, they identified and validated VAV1 (another autoimmune disease target) as a CRBN neosubstrate, providing compelling evidence that G-loops are not strictly necessary for the action of MGDs.

These findings show that CRBN recruitment through MGDs can be driven by a broader set of structural features than previously thought. The identification of a large number of neosubstrates potentially opens up a whole new set of previously ‘undruggable’ targets to MGDs (>1,600 proteins from many target classes, according to the Monte Rosa team).

The big questions, though, are still ahead. How will drug developers mitigate the risks of ‘off-tissue’ toxicity as this swathe of novel MGD compounds and new targets make their way into the clinic?One answer to the toxicity concern is molecular glue antibody conjugates (MACs), which can better localize glues to the tissue of interest. But that’s a subject for a whole other future Haystack Chat!

Inomagen Therapeutics: RESI Boston June IPC Winner

15 Jul

Inomagen Therapeutics, led by Chief Business Officer Eric Sandberg, is working to redefine how atrial fibrillation is treated—starting at the molecular level. A recent winner in the Innovator’s Pitch Challenge at RESI Boston June. In this interview, Sandberg shares insights into the company’s novel approach, development progress, and how RESI helped build investor momentum.

Eric Sandberg
CaitiCaitlin Dolegowski

Caitlin Dolegowski (CD): Tell us about Inomagen Therapeutics, what is your core focus, and what inspired your approach to treating atrial fibrillation?

Eric Sandberg (ES): Inomagen Therapeutics is a preclinical-stage biotechnology company developing a non-viral gene therapy to improve the treatment of atrial fibrillation (AF), the most common sustained heart rhythm disorder affecting 10M people in the US alone.  Patients with AF do not feel well and have a 4-5x increased risk of stroke, 2x risk of having a heart attack, and AF is a major cause of heart failure.  Unfortunately, current therapies, including cardiac ablation, have proven ineffective for many patients because they do not address the underlying mechanisms of the disease.

Inomagen’s approach is based on research conducted by our Founder, CEO and practicing electrophysiologist, Dr. Rishi Arora.  In his research laboratory, Dr. Arora identified major molecular mechanisms that contribute to AF in a majority of patients with AF; identified major trans-genes to selectively target these mechanisms in the atrium; utilized low energy electroporation to achieve therapeutic gene transfer and expression; and decreased AF in clinically relevant, large animal models of AF.

CD: What differentiates your platform from other therapies available to treat atrial fibrillation?

ES: Ablation is the mainstay of AF treatment. However, ablation success rates are suboptimal in patients with persistent AF. This is thought to be in large part because ablation is an anatomic procedure that is not targeted to the molecular mechanisms underlying AF. Inomagen has developed a non-viral gene therapy that targets one or more major molecular mechanisms underlying AF.  Specifically, we have demonstrated preclinical success delivering NOX2 shRNA plasmids to atrial tissue to achieve gene knockdown, to silence upstream mechanisms of AF, in order to achieve a therapeutic effect.  To be clear, our gene therapy is not replacing genes or editing genes, we are knocking down the expression of genes that are causing AF.  Based on our preclinical results, we believe that our gene therapy can potentially surpass cardiac ablation as the therapy of choice for atrial fibrillation.

To achieve safe and effective targeted gene delivery, we have developed a novel transvenous gene delivery system that uses low energy reversible electroporation to achieve high levels of gene transfection into atrial tissue.   We believe that our physical gene delivery approach overcomes the known challenges of using viral vectors which include insufficient gene transfection and well publicized off-target effects.  As such, we believe our gene delivery approach can potentially serve as a platform technology for other companies developing cardiac gene therapies, including gene therapy in the ventricles for congestive heart failure.

CD: Where are you in terms of preclinical or clinical development, and what are your near-term goals?

ES: With our recent development of a proprietary NOX2 shRNA gene plasmid and a gene delivery catheter, we have now achieved program readiness to initiate IND-enabling studies to gain FDA approval for a Phase I/IIa clinical study.  In the near term, we will be conducting IND-enabling studies in the 2nd half of the year in preparation for a pre-IND meeting with the FDA early next year prior to conducting pivotal tox and filing an IND in late 2026.  We aim to initiate our Phase I/IIa clinical study in 2027.

CD: What are you seeking in your current fundraising round, and what kind of investors or strategic partners are you hoping to connect with?

ES: We are currently raising a $5M Series Seed round and will be initiating a larger Series A round later this year to support the program through a Phase I/IIa study.  In the near term, ideal investors for Inomagen include angel groups and individuals, while we anticipate our Series A to be led by venture capital investors. Additionally, given the potential of Inomagen’s gene therapy to markedly improve the treatment of atrial fibrillation, we have several potential strategic partners who are tracking our progress.

Inomagen has multiple gene targets in our pipeline and a robust IP portfolio that includes 18 issued patents protecting genes/biologics and gene delivery.  We have an experienced team committed to bringing our gene therapy to the clinic.

CD: How did your participation in the Innovator’s Pitch Challenge at RESI Boston contribute to your visibility or investor outreach efforts?

ES: Our participation provided the opportunity to continue to share the progress that we are making with the attendees at RESI.  And being recognized as a top company in the Pitch Challenge has certainly provided increased visibility for Inomagen through Life Science Nation’s extensive readership.  We have experienced a further increase of interest in Inomagen, including a significant increase in traffic to our  website.

CD: Can you share any valuable feedback or connections that came out of the pitch sessions or RESI partnering meetings?

ES: Following our presentation in the Pitch Challenge, we added several more partnering meetings with interested investors. Given our experience at the June RESI meeting, we registered to attend the September RESI meeting as well.

CD: What advice would you give to fellow early-stage biotech founders about preparing for and participating in a RESI pitch competition?

ES: The RESI pitch competition provided a good opportunity to make sure that we are communicating the Inomagen opportunity clearly to potential investors. We appreciated the opportunity to join the many impressive companies presenting at RESI who have a passion to improve health care for patients and providers.

Applications are now open for the Innovator’s Pitch Challenge at RESI Boston this September.
New! The IPC Pitch Package now includes an optional second full RESI pass at no additional cost—bring a teammate to support investor meetings, pitch preparation, and maximize your conference presence.

Apply to Pitch at RESI Boston Sept. 2025

Pullan’s Pieces #2 – Top Drug Sellers by Geo

15 Jul

By Eric Hayes

What do analysts think will be the top 10 drugs in the year 2031 (as searched in GlobalData)?

Top 10 in the US in 2031 (USD Millions)

In the US analyst forecasts for 2031, obesity dominates (with immunology, derm and infection for other TAs). Along with the obesity peptides are 2 small molecules and 2 MAbs. The sales are in the tens of billions.

Top 10 in Europe (USD Millions)

In Europe, along with the obesity drugs and dupixent in derm, we see the oncology ADC Enhertu, the ang2 ophthalmology drug Vabysmo, a CNS CD20, and a GI integrin in the top 10. Sales are in the single digit billions.

Top 10 in Japan (USD Millions)

In Japan, obesity is not visible in the top 10. An anti-infective tops the list, followed by CNS, oncology, GI and including heme disorders. There are companies not in the top 20 for global sales. Most of the top 10 have sales below $1B.

Top 10 in China (USD Millions)

For China, obesity is back in the top 10, but Gardasil, an oncology HPV vaccine tops the list. Local company “fast followers” are apparent and most of the top forecasted drugs are not yet launched (presumably a reflection of the rapidly evolving pharmaceutical environment). To get into the top 10, sales are above $500M.

Conclusion: The marketplace for drugs shows considerable variation in different regions around the world.

Pullan’s Pieces #1 – Organ on a Chip

1 Jul

Acceleration of laboratory-based technical and computational cross-fertilization, and ethical and cost pressures on regulatory bodies and therapeutic innovators is driving advancements in preclinical human-based technologies.

Organ (Lab)-on-chip (OoC/LoC) is one of the most striking examples of new translational research technology expansion with ~35% CAGR expected over the next decade (below).  

Collaborations between academia and CRO’s are driving improvements in organoid technology for the field of oncology broadly and are expected to improve OoC adoption.  Academic innovation using commercial OoC technology is also advancing applications in specific indications in oncology.  CRO’s continue to build off established uses in ADME and toxicology to explore R&D applications in oncology space and have even combined organ systems to support elaboration of multiple drug parameters in a single assay.

DEALS

The Tara Biosystems – Valo Health deal is a nice example of how an organ-on-a-chip technology approach has driven collaborations, acquisitions and deals:

  • Tara Biosystems and GSK collaborate on CV drug profiling (2019)
  • Valo Health acquires Tara Biosystems for CV OoC platform (2022, ~$75M upfront)
  • Valo and Novo Nordisk sign CV drug discovery deal (2023, $60M upfront, $2.7B total)

EmulateTissUse and Mimetas have also been backed by strong big pharma collaborations (AstraZeneca, Bayer, Roche) and funding rounds.