Immuno-oncology, antibody-drug conjugates, and cancer metabolism are three of the hottest and potentially most transformative approaches in cancer research today, and have occupied center stage at recent oncology meetings like ASCO and AACR (here, here).
The immuno-oncology (I/O) field has certainly hit its stride with impressive late stage clinical data and approvals around PD1/PD-L1 interventions, as well as exciting early data on engineered T-cell therapies in a variety of hematological malignancies. Antibody-drug conjugates (ADCs) have also been at the forefront of cancer R&D: over 30 ADC programs are in clinical testing today (here), building on the exciting data and approvals for both Kadcyla in metastatic breast cancer and Adcetris in NHL. And in cancer metabolism, Agios’ early but impressive data on AG-221 in IDH2 mutated cancers validates the approach of targeting key glycolytic pathway liabilities (here).
Like most early stage biotech investors, we’ve been active in all three areas. Earlier this year, Novartis acquired CoStim Pharmaceuticals, an immuno-oncology checkpoint inhibitor company backed by MPM and Atlas (here); we’ve also been supporting bispecific antibody programs in the checkpoint and I/O space at F-star (here), and have two additional soon-to-be announced I/O investments (more later!). In cancer metabolism, we’re pushing a lipid metabolism target (ACC) into the clinic over the next few months at Nimbus Discovery with a broad range of applications, including metabolic disease/NASH, but also in specific cancers dependent on de novo lipid synthesis (preclinical AACR data here). Further, Navitor is working in nutrient sensing and metabolism around the mTORC1 pathway, with clear implications in cancer research, among other applications (here).
Earlier today we announced two new financings around drug discovery platform companies targeting these cancer pathways – Raze Therapeutics and Bicycle Therapeutics – and thought (re)introducing their stories and our approach would be of interest. These were both Atlas’ seed investments that have met their initial milestones and are beginning to scale.
Cancer anabolic metabolism – specifically mitochondrial one-carbon energetics – has emerged recently as a major driver of cancer proliferation, survival, and biomass accumulation. Raze, originally seeded by Atlas and led by my partner Peter Barrett as “Project C”, has launched publicly today with a $24M financing to advance a number of therapies targeting key nodes in these pathways.
Raze’s scientific founders – Vamsi Mootha (HHMI, MGH), Josh Rabinowitz (Princeton), and David Sabatini (Whitehead/MIT) – bring extensive mitochondrial proteome, systems biology, metabolic flux, and cancer biology expertise. Their labs provided novel insights into several key nodes/targets in serine biosynthesis, glycine uptake, and related anabolic pathways.
Raze’s initial seed hypothesis was aimed at addressing the question of whether the specific set of first-in-class foundational targets were drug-able with novel chemical matter of sufficient quality to warrant a broader drug discovery campaign. After close to eighteen months, the team has more than delivered against those early hurdles, expanding our biologic insights into these pathways and establishing a compelling platform for new therapeutics creation.
Raze’s approach of antagonizing these one-carbon metabolism pathways is supported by clinical experience with anti-folates, thymidylate synthase inhibitors, and ornithine decarboxylase inhibitors that target single downstream arms of the one carbon pathway. Raze’s programs differentiate from these prior agents in two important ways: (i) potential for broader and more profound therapeutic efficacy, as Raze’s inhibitors would simultaneously inhibit all three critical one-carbon utilizing pathways, and (ii) significantly better safety properties than current metabolism-directed agents, since thymidylate synthase, dihydrofolate reductase and other enzymes are generally elevated in “normal” proliferating cells, whereas Raze’s targets are specifically upregulated only in transformed cells. Lastly, Raze and its founders have identified specific patient populations, including genetically-defined subgroups, in both solid and liquid tumors for targeting with one-carbon metabolism-based therapeutics.
In addition to Raze’s great scientific foundation, the company has built a great emerging team. In addition to our three scientific co-founders, both Keith Flaherty (MGH/Harvard) and Mike Gilman (Atlas EIR and CEO of Padlock Therapeutics) have joined the SAB. Mike was also the Acting CEO for part of the company’s formative “seed” phase. Vipin Suri and Adam Friedman, both Atlas EIRs, are currently driving the tumor biology and corporate development functions, respectively. Lastly, as of only a week ago, our newest partner Jason Rhodes has jumped in and taken the helm of Raze as the Acting CEO going forward as we ramp up lead optimization activities against a set of targets.
With today’s announcement, we’ve brought forward a $24M financing supported by great co-investors at MPM, MerckSerono Ventures, Partners Innovation Fund, Astellas Ventures, and Novartis (NIBR); this should fuel the company’s programs into development. Exciting times for Raze and cancer anabolism.
After several years of exploring different applications of their bicyclic-macrocycle platform, and perfecting the “art” around their phage-based discovery screening system, Bicycle Therapeutics has powered up with a $32M financing to focus its attention on the drug-conjugate space – aptly called our “Bicycle-Drug-Conjugate” approach (BDC).
The quick background: Atlas and Novartis Ventures co-founded Bicycle several years ago with distinguished scientific founders Sir Gregory Winter (MRC) and Christian Heinis (EPFL) around their phage-based macrocycle discovery approach (here); over the past few years, with the further support of solid co-investors SVLS, SR One, and more recently Astellas, the company has explored a variety of applications for bi-cyclic therapeutics in capital efficient manner. As described previously (here), the key with any new macrocycle platform is figuring out the true path to differentiated offerings relative to existing approaches (i.e., versus oral, cell-penetrant NCEs and parenteral, extracellular antibodies); applying a good technology to the wrong applications results in the same outcome as backing a failed technology. This is where Bicycle has been both thoughtful and disciplined.
Bicycle’s dual-loop chemical-scaffold constrained macrocycles have several key characteristics: high potency (sub-nM), robust screening fidelity, species-tunable selectivity, very high protease and metabolic stability, ease of manufacture, as well as simple and controlled conjugation of payloads.
But the real excitement comes from turning an apparent liability – their very short half-life – into a differentiated feature. One of the big problems with ADCs is that antibodies have long half-lives and expose normal tissues to toxic payloads over days if not weeks in circulation; long after dosing, ADCs can be detected in most vascularized tissues. Bystander damage to host tissues is one of the dose-limiting toxicities of these approaches.
BDCs, by contrast, rapidly extravasate with high volumes of distribution after parenteral dosing, quickly binding to cell surface tumor antigens and internalizing, and any unbound BDC is quickly cleared by the kidney within minutes. Plasma half-lives for bicycles in patients are predicted to be on the order of a few hours, not days or weeks, and yet even with these short exposures we see very potent anti-tumor activity in our in vivo xenograft models. Rather than being an Achilles heel of the platform, these short half-lives, when coupled with rapid extravasation and internalization, have the potential to be major differentiators vs conventional ADC approaches.
This financing should fuel the Bicycle platform for several years, bringing its lead program through clinical proof-of-concept studies in cancer patients (undisclosed first-in-class target), as well as advance several other programs into development. As with all drug discovery platforms, we also anticipate partnering extensively with Pharma oncology groups that have expertise in specific cell surface antigens that could be targeted by this BDC modality.
These are two oncology-focused drug discovery engines launched or seeded by Atlas over the past few years – one targeting the “big biology” around mitochondrial energetics in cancer, the other applying a novel modality to tumor-targeting of cytotoxic payloads. We have high hopes for them, and their aspirations of impacting cancer care.