It Takes Two: Tango Therapeutics Leverages Synthetic Lethality in Precision Cancer Medicines

The biotechnology company is expanding genetically targeted therapies to tumor suppressor gene loss and cancer cell immune evasion.

Although significant progress has been made in identifying and drugging the genetic origins of cancer, far too many oncology patients continue to be treated ineffectively. Existing treatments target many active oncogenes that cause tumor development. Still, they don’t address the genetic changes that feed cancer by inactivating tumor suppressor genes and allowing cancer cells to elude immune system destruction. The first wave of targeted medicines changed cancer therapy for individuals with malignancies that contain particular activating mutations. These medications target oncogenes including BRAF, EGFR, and ERBB2. However, tumor suppressor gene inactivation is equally crucial in the initiation and maintenance of cancer development and cannot be directly targeted.

Tango Therapeutics (NASDAQ: TNGX) was seeded in 2015 and eventually launched in 2017 as a precision medicine startup to fill this gap in the market and offer the next generation of targeted therapeutics. The company, based in Cambridge, Massachusetts, developed a cutting-edge CRISPR-based functional genomics target discovery platform and a robust bio-analytic pipeline that combined targets, pathways, genetic context, and functional data to identify novel synthetic lethal targets for the loss or inactivation of multiple tumor suppressor genes. Their growing pipeline consists of programs for genetically defined subsets of cancers with limited treatment options.

Tango’s global strategic collaboration with Gilead Sciences is focused on the discovery, development, and commercialization of a pipeline of innovative targeted immune evasion therapies for patients with cancer. While Tango is responsible for discovering and validating targets and advancing select programs through clinical proof-of-concept, Gilead has options for worldwide rights on up to 15 of those targets. Tango retains the option to co-develop and co-promote the lead products for up to five of those programs in the U.S. with Gilead. The collaboration, initially signed in 2018 and expanded in 2020, does not include Tango’s three lead programs. Tango retains all rights to those programs and the right to targets identified outside of the immune evasion space. The precision medicine startup is committed to advancing the programs in our wholly-owned pipeline into the clinic and beyond to deliver the next generation of transformational targeted therapies to patients in need.

In April 2021, Tango and BCTG Acquisition Corp (Nasdaq: BCTG), a special purpose acquisition (SPAC) sponsored by Boxer Capital, announced a definitive merger agreement. Leading institutional investors committed $186 million through a common stock private investment in public equity (“PIPE”) led by Boxer Capital. The total proceeds were expected to be approximately $353 million, combining funds held in trust BCTG Acquisition Corp and the PIPE financing.

GEN Edge sat down with CEO Barbara Weber, MD, to discuss the window of opportunity for tumor suppressor gene-targeted medicines and how she took Tango Therapeutics from concept to a publicly-traded company.

GEN Edge: What is Tango’s mission?

Weber: Our mission was to create a platform to identify synthetical lethal drug targets in cancer. I’m an oncologist by training with a particular interest in cancer genetics. I spent 15 years in academia studying breast cancer genetics, working on some of the teams that identified BRCA1 and BRCA2. That was back when Gleevec and Herceptin were the first precision oncology drugs. Every grant I wrote and many talks I gave started with discussing how we would identify these genes and have new drug targets for cancer. But, these are tumor suppressor genes. You can’t directly drug them because you can’t reactivate them if they’re missing or mutated.

From the beginning, I thought about how to get at an equally important group of genetic alterations in cancer. We can inactivate activated oncogenes, but we need synthetic lethality to get at tumor suppressor genes. A friend, colleague, and one of the founders of Tango is Dr. Alan Ashworth, who discovered the BRCA1/2-PARP interaction back in the early 2000s. People tried to identify synthetic lethal drug targets for specific tumor suppressor gene loss for the next ten years, but it wasn’t possible without CRISPR because the methods weren’t precise enough and scalable enough. Tango is the culmination of many years of thinking about tumor suppressor gene loss in hereditary cancer risk and targeting cancers.

For me, it’s been very exciting because I thought about being able to do this for a long time. It was a confluence of events coming together. I met the guys from Third Rock Ventures while I was at Novartis, and then CRISPR technology was discovered and made available. We’ve had great investors who believe in the story.

GEN Edge: How Is Tango’s pipeline organized?

Weber: The idea of it, in the beginning, was fairly simple. We used CRISPR-cutting libraries and druggable genome libraries in models that had a specific tumor suppressor gene loss. But our platform has evolved in two important ways. One, we use many different CRISPR-based technologies now as they have been developed and more sophisticated ways to get at synthetic synthetically with drug targets, including combinatorial CRISPR where you can knock out more than one gene at a time, allowing us to think about tumor suppressor gene combinations or whole pathways early on. Two, we’re not only thinking about cell-autonomous pathways; we’re looking at the non-cell-autonomous effects of tumor suppressor gene loss, for example, the immune system interacts with the tumor.

So, we developed an in vivo CRISPR screening system that has the ability to discover the tumor suppressor genes that may cause immune evasion in cancers when they are genetically deleted. Using those discoveries of which tumor suppressor gene loss events cause immune evasion, we then can discover drug targets to reverse that effect. We have an extensive collaboration with Gilead primarily focused on targets coming out of our immune evasion CRISPR-based platform. For the cell-autonomous targets, we retain the full rights. Our manufacturing is relatively straightforward, because are drug candidates are small molecules, and is done externally.

We make our own CRISPR libraries and do a lot of the sequencing and CRISPR discovery work in-house. But all of the in vivo work and much of the screening work is done externally at contract research organizations (CROs), as is a lot of our drug discovery. We are just getting ready to start our first clinical trial. We have a great team here at Tango, one of the best teams I’ve ever worked with. We’re almost a hundred full-time employees now. We’re just starting to build out the clinical team with head of development operations, a clinical pharmacologist and we hired a CMO last fall. We also have many people in other places, including Ukraine. But the majority  of our CROs are in China.

GEN Edge: What drove the decision to go public using a SPAC?

Weber: The announcement that we were doing a SPAC was in April of last year, and the actual closing was in August. I’d never done either an IPO or a SPAC before, but they involve similar processes in the opposite order. We first ​​​​raised the money with private investment in public equity (PIPE) investors and then filed with the SEC through an S-4 instead of writing an S-1 to file with the SEC and raising the money at the IPO.

The SPAC merger has been really good for us and even more beneficial than we realized at the time because we had no idea how bad the market would get this year. We were thinking about a traditional IPO for the fall of 2020. In late 2019 and early 2020, we were assessing the level of interest in an IPO. While there was a great level of interest from a number of sophisticated biotech investors, Aaron Davis, co-founder and chief executive officer of Boxer Capital, who had led our series B, approached me with the idea of using the Boxer SPAC to go public as opposed to a traditional IPO. After some discussion and looking at the quality of the SPAC, we agreed, one, we thought we could raise quite a bit more money between the SPAC and the PIPE than we could with an IPO, and, two, it could be done immediately.

I’m fairly new at this, but I learned one thing quickly: raise money when you can—don’t wait, since we couldn’t  know what the market would be like in the fall. It turned out it wasn’t very good, and it got worse from there. Boxer Capital brought in almost all the investors we were looking at anyway for our IPO. It was a great SPAC for us. It’s been successful, and we are very happy to be in a position of not needing to raise money even now for the next foreseeable future. Our cash runway is out to the end of 2024.

GEN Edge: What are the next steps for Tango?

Weber: A lot is going on. First of all, TNG908, which will enter the clinic fairly soon, is an unusual precision oncology target because the potential market is so big—10–15% of all human cancers, solid tumors and hematologic malignancies alike, have an MTAP (methylthioadenosine phosphorylase) deletion. We’re used to thinking about drugs like ALK inhibitors for example, that are relevant to ~ 5% of lung cancer. When you’re talking about 15% of all cancers, that’s a huge development and commercialization program.

So, we need to execute on that program, define the clinical data, and then move quickly into a full development strategy. That’s likely to include a partnership with the big company in order for us to take on a program of that size and be competitive with Mirati and Amgen. We can’t build out in 40 countries in a couple of weeks—that just isn’t going to happen. We want that to be a meaningful collaboration and partnership.

The two programs that are coming behind are also coming fairly quickly. We’ve got two more development candidates coming this year and are working on a next-generation PRMT5 program. We’ve just got a lot of clinical development coming in the next two or three years. We may partner to be able to develop such a big program as PRMT5 and then take the next one or two on ourselves. Either of the next two candidates would be somewhat more manageable for a small company.

GEN Edge: What is Tango doing with all of the leftover leads?

Weber: Some of them we’ve published, but we haven’t said which ones we’re actively working on. We’ve talked a lot about licensing out those targets But it’s a tricky proposition because validating the targets is a lot of work and then licensing out as individual validated targets is not a particularly high-value deal—it takes a lot of time. So, licensing them outside of Gilead, which is a platform partnership, is not a particularly productive thing for us to do. We’ve moved some of them forward into drug discovery, but we may partner some of them earlier than others. For undisclosed assets in our pipeline, we may well partner just because we’ve got so much going on with what we have disclosed and that we will do our best to publish as much of the rest of it as we can so that if we’re not going do it other people can.

GEN Edge: What are Tango’s immediate obstacles to getting a drug commercialized?

Weber: The first thing is clinical data. Assuming that the clinical data match  the preclinical data, it’s about finding the right partner. There’s a lot of interest in this target from many large companies because of the potential market size. So we’re looking for the right partner that would complement us the best, move the fastest, and beat out a large company. Those collaborations can be great, or they can be really contentious. Our collaboration now with Gilead is really great, and we’d like the next partnership we do to be the same.

I’ve done a lot of early clinical development. It’s always exciting when patients start responding to a new drug. It’s amazing. I never forget that every data point on those graphs is an individual with families. When I was at Novartis, I used to get letters from patients on our clinical trials. But I’ve never done it with a target from the very beginning. We built the company and the platform, picked the target, made the drug, and now we’re taking it into patients. If you do what I do, it doesn’t get more exciting than that.

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