Michael Gladstone

Predicting The Next Dominoes to Fall in 2019

Posted January 31st, 2019 by Michael Gladstone, in From The Trenches, Science & Medicine

This post was written by Michael Gladstone, Principal at Atlas Venture, as part of the From The Trenches feature of LifeSciVC.

Today I will continue my time-honored January tradition of an optimistic blog post providing some bold predictions for the year ahead.

I will focus on areas where we are finally on the cusp of long-awaited breakthroughs. Of course, this is an incomplete sampling of ongoing innovation, and I mean no offense to anyone’s work that I have left out. And I promise to avoid obvious, evergreen predictions, like “The amyloid beta hypothesis will continue to stir debate!”

KRAS inhibition will produce clinical responses.

KRAS is a holy grail oncology target. It is the most frequently mutated driver oncogene and has long been considered “impossible” to drug. But “impossible” only means, “Even Tom Brady hasn’t done it yet.”

Several companies are advancing direct inhibitors of the KRAS G12C variant, and at least Mirati and Amgen plan to share preliminary clinical results in 2019. I think these drugs will have striking effect in some patients, but response durability will need to contend with:

  • Upregulation of RTK signaling, which may increase GTP-bound KRAS and overpower these drugs which work by trapping KRAS in its inactive GDP-bound
  • Mutation of the eponymous KRAS G12C cysteine. Because these drugs rely on covalently capturing this cysteine, tumors may escape if they mutate that cysteine into one of the several other oncogenic amino acids tolerated at that position (e.g., G12D, G12S, G12V). [UPDATE 2/7/2019: The author stands corrected. KRAS G12C can only mutate residue 12 to ONE other oncogenic residue with a single DNA base change (G12S, in case you were interested). Mutation to any other G12 driver mutation would require two simultaneous base changes in the same codon, and hence is quite unlikely. We thank Frances J, age 9, for her detailed review.]

Others are tackling KRAS mutant tumors in different ways. Novartis’s often-imitated allosteric SHP2 inhibitor is now also in the clinic. Other options include C-RAF inhibitors and even T cell therapy targeting the mutant KRAS epitope. And, just last week, Bayer and Evotec published on elegant inhibitors of SOS1, the enzyme that exchanges KRAS’s GDP for GTP, which may be intriguing to combine with the Shokat-inspired G12C inhibitors noted above.

While one or more of these approaches may demonstrate significant clinical utility in 2019, the greatest benefit will likely be achieved when these drugs are combined in 2020 and beyond.

Genetically-redirected T cell therapy will register a genuine solid tumor complete response.

I specified “genetically-redirected” here because unmodified T cell therapy, in the form of expanded tumor infiltrating lymphocytes (“TILs”), is already registering solid tumor cures. But TILs continue to receive all the enthusiasm of a T-bone steak at a PETA rally, so they may need to wait another year to receive the credit they deserve from the industrial cell therapy community.

But we have some new reason for hope for engineered T cell therapy in solid tumors. Two months ago at ASH, an NCI-led team announced impressive response rates (some durable) in patients with HPV+ solid tumors. With a little extra T cell “oomph,” we may be able to drive this type of solid tumor efficacy into CRs. Enough smart players are knocking on that door that I expect it to open in 2019.

A key challenge is that most solid tumor targets are expressed at a low level on some normal tissues. For this reason, I am excited about the potential for Atlas portfolio company Unum Therapeutics’ ACTR-trastuzumab combo in HER2+ tumors, given Unum’s preclinical data indicating that ACTR can differentiate between HER2-high tumor cells and HER2-low healthy tissues. Unum plans to begin clinical testing of this product in 2019.

Gene therapy will continue its march forward in numerous arenas, including “curing” at least one inborn error of metabolism.

AAV gene therapy has already made transformative contributions to diseases of the eye (RPE65), motor neurons (SMA), and vascular/blood system (hemophilia A and B). AAV is also making inroads in skeletal muscular dystrophies, including Sarepta, Solid Biosciences, and Pfizer’s work in Duchenne’s muscular dystrophy.

On the lentivirus front, Bluebird and Orchard continue to accrue data in leukodystrophies, primary immune deficiencies, and hemoglobinopathies. Meanwhile, Atlas investment AvroBio is advancing and expanding their lysosomal storage disorder franchise, with a Phase 2 program ongoing in Fabry’s disease and new clinical initiations planned for both Gaucher’s disease and Cystinosis later this year.

Another promising frontier is in inborn errors of metabolism (“IEMs”). IEMs are diverse genetic disorders resulting from a patient’s inability to process certain bio-substrates, such as specific sugars or amino acids. Clinical gene therapy progress here is already underway in 2019, given Ultragenyx’s impressive 1st clinical cohort data in glycogen storage disease Type 1a (“GSD1a”).

These data could become even stronger with higher doses, and they provide important IEM clinical proof-of-concept. Phenylketonuria may be one of the next IEMs successfully treated, with BioMarin, Homology, and Synlogic among the companies who will be in the clinic in 2019 with different approaches to reinstate the body’s ability to convert phenylalanine to tyrosine. Another Atlas company, Magenta Therapeutics, is taking multiple approaches to facilitate stem cell transplant as another potentially curative option for certain inherited metabolic disorders.

New drug candidates will emerge to treat severe neuropsychiatric conditions.

Psychiatric diseases remain an area of unfathomable unmet need worldwide. Unfortunately, for a long time this was also an area of very limited innovation. Neurotransmission was poorly understood, and we lacked translatable preclinical models and tools to guide clinical trials in these complex, heterogeneous diseases.

But recently we’ve seen important breakthroughs. Some of this progress was actually sparked by gaining better mechanistic understandings of psychoactive recreational drugs, which have provided occasionally jaw-dropping clinical benefit in severe depression and post-traumatic stress disorder. Frankly, I haven’t seen people this excited about ketamine and cannabinoids since my college roommate came back from a Skrillex concert.

Today, these learnings are guiding development of new targeted therapies for refractory depression and anxiolytic conditions. In parallel, tools like fMRI and mismatch negativity are helping to guide preclinical translation and clinical patient selection and therapeutic monitoring.

We’ve seen impressive successes for SAGE’s drugs in post-partum depression and major depressive disorder, and in 2019 we may hear more about other next-generation depression drugs, including J&J’s esketamine, Allergan’s rapastinel, Novartis/Cadent’s NMDA receptor modulator, and Navitor’s synaptogenic mTOR activator. And while depressive disorders have been the most visible recent beneficiary of these neuropsych breakthroughs, several new approaches may help address the cognitive symptoms of schizophrenia in the next 1-2 years.

2019 will be the year of (addressing) the autoantibody.

Numerous autoimmune diseases are caused or amplified by pathogenic autoantibodies (“AutoAbs”). These diseases are clinically diverse, with just a small representative sampling below:

  • Vascular/coagulation system (ITP – anti-platelet autoAbs)
  • Neuromuscular system (myasthenia gravis – neuromuscular junction autoAbs)
  • Eye (neuromyelitis optica – autoAbs to elements of the optic nerve/spine)
  • Kidney (lupus nephritis – immune complex deposition/inflammation)
  • Skin (pemphigus – autoAbs to desmosome proteins)

Many of these diseases will be responsive to modulation of autoAb production, accumulation, or effector function. Indeed, several of these conditions have been treated in the past with B cell depleting CD20 antibodies, with varying degrees of success. But often this is only partially or transiently effective and introduces risk of infection due to depletion of important protective B cells.

We’re just starting to see more nuanced approaches achieving clinical proof-of-concept in many of these settings. Below is just a subset of novel mechanisms that announced new clinical efficacy in 2018, with more to come in 2019.

  • FcRN inhibition reduces levels of circulating pathogenic IgG (efficacy in ITP, myasthenia gravis, pemphigus)
  • BTK: next-generation inhibitors may be safe enough to find a niche as oral drugs that dampen autoAb production and other pathogenic B cell activities (pemphigus)
  • Complement modulation can attenuate tissue damage imposed by auto-Abs or immune complexes. This includes both “old-fashioned” C5 inhibition (achieving new clinical breakthroughs, e.g., NMO and MG) and promising next-generation approaches to tackle the alternative or classical complement pathways further upstream.

We will almost certainly find that B cell depletion was neither the safest nor most effective approach to mitigating autoAb pathology in many of these conditions, and I expect 2019 to contribute much of that evidence.

Disease-modifying pulmonary arterial hypertension (“PAH”) drugs are on their way.

While we have three classes of effective vasodilating therapies for PAH, these are not disease-modifying and this disease is still highly progressive and fatal. At least a trio of promising new approaches are moving towards clinical proof-of-concept, though we may have to wait beyond 2019 to see the results.

Gossamer Bio is developing an inhaled PDGFR inhibitor, which may replicate the striking clinical efficacy seen previously with systemic PDGFR inhibition (via Novartis’s Gleevec imatinib) without the toxicity imposed by systemic exposure and Gleevec’s inhibitory effects on other kinases.

Acceleron is taking a different approach, binding certain BMP/TGF family proteins to restore the ability of other ones (e.g., BMP9) to activate BMPR2, a receptor whose hypoactivity is robustly linked to PAH.

Pharmacological BMPR2 activation is a great idea (and BMP modulation is no easy feat), so thankfully the industry is taking more than one shot at it. Morphogen-IX is taking the approach of administering an engineered variant of BMP9 to stimulate BMPR2 directly.

I know I said this was going to be optimistic, but …

It’s not all good news out there. When all is said and done, I predict these guys will not have achieved their stated Target Product Profile:

“Our cancer cure will be effective from day one, will last a duration of a few weeks and will have no or minimal side-effects at a much lower cost than most other treatments on the market,” Aridor said.

And I know I said I wouldn’t make obvious, evergreen predictions, but…

The Patriots are going to win the Super Bowl again.

Michael Gladstone

Michael Gladstone

Principal at Atlas
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