TG Therapeutics [$TGTX]: Even odds in treating CLL with Ublituximab and TGR-1202

It’s a little unusual for me to discuss two drugs in the same post (in fact, I think this is only the second time I’ve ever done so). These two drugs are – unusually – being tested together in an ongoing phase 3 trial, so it made more sense to write about them together. TG-1101 – henceforth called “Ublituximab” – and TGR-1202 are both experimental treatments for a subset of cancers known as “B-cell malignancies.” TG Therapeutics [$TGTX] currently has two phase 3 trials running to treat a type of B-cell malignancy known as chronic lymphocytic leukemia (CLL):

  1. The “GENUINE” trial, which is testing ublituximab in combination with an already-approved drug (Ibrunitib). The GENUINE trial has already posted preliminary data.
  2. The “UNITY-CLL” trial, which is testing Ublituximab and TGR-1202 together as well as separately.

 There is a third phase 3 trial, as well, testing the above therapies in a separate type of cancer, but this article is long enough already and there’s much less precursor data for that one so I won’t touch on it right now.

As background, the treatment of CLL has evolved dramatically since about 2010. Initially, CLL was treated solely with chemotherapy. Recent years, however, have seen tailored antibodies and several types of B-cell inhibitors be added to – and possibly even replace – traditional chemotherapy. The latter, in particular, have revolutionized the way physicians treat CLL.

That said, room for improvement remains. Ibrutinib, the most potent B-cell inhibitor currently on the market, is not a perfect treatment – complete response is rare, and interruptions in the medication regimen can lead to rapid drug resistance and relapse. Similarly, the tailored antibodies used to fight CLL have not yet been perfected.

So, the stage is set – treatment for B-cell cancers may have been revolutionized, but the new treatments are far from perfect, and TGTX hopes that their twists on tailored antibodies (ublituximab) and B-cell inhibitors (TGR-1202) will have better effects than the current standard of care.

How TGTX’s drugs stack up against the competition: GENUINE

As I mentioned above, the GENUINE phase 3 trial is testing ublituximab (a tailored antibody) in combination with ibrutinib (the B-cell inhibitor mentioned above) in the treatment of high-risk CLL. Previous studies have suggested that ibrunitib performs poorly in the face of genetically high-risk CLL, so TGTX is hoping that adding ublituximab can improve patient outcomes.

Initially, the GENUINE study was testing both overall response rate (ORR) and progression-free survival (PFS) as the primary endpoints. However, not enough patients enrolled in the study, so the authors made the decision to cancel PFS as a primary endpoint, as they wouldn’t have had enough statistical power to effectively measure significance.

The safety profile of ublituximab was acceptable – some patients had negative reactions at the infusion site, but overall, ublituximab did not appear to cause many problems.

As you can see below, the combination therapy had a significantly greater response rate than ibrunitib alone. As a caveat, this study was not placebo controlled, which decreases my confidence in the effectiveness.

From Sharman et al., 2017 – the GENUINE study

Progression-free survival – now a secondary endpoint – was not significantly different, but this is unsurprising given the aforementioned power issues.

I suspect that TGTX will need to run another phase 3 study with PFS as a primary endpoint before seeking FDA approval for ublituximab. However, if the results from the UNITY-CLL study (which is testing ublituximab and TGR-1202) are effective enough, I can see TGTX simply moving towards an NDA for the combination of the two and not bothering to run another GENUINE.

How TGTX’s drugs stack up against the competition: UNITY-CLL

In the UNITY-CLL trial, TGTX needs to demonstrate that TGR-1202 and ublituximab – without ibrutinib, this time – can beat out chemotherapy and a different tailored antibody, Obinutuzumab. This one is a lot tougher to call.

An in vitro study  appeared to demonstrate that that obinutuzumab and ublituximab were more or less equivalent, but separate Phase 1 work by TGTX showed a synergistic effect in vitro between ublituximab and TGR-1202.

The only information directly assessing the combination of TGR-1202 and ublituximab (without any other drugs) comes from that same Phase 1 study. In that study, the drug therapy appeared to promote PFS in CLL patients, but the sample size was so small that it was difficult to tell.

There are multiple preliminary studies with impressive results, but all of them are testing the combination with at least one other drug. The combinations including ibrutinib, in particular, have been staggering.

The UNITY study, of course, does not include ibrutinib. As far as I can tell, TGR-1202 has never been tested by itself, making it very difficult for me to assess how this trial is ultimately going to go. My gut is telling me that it will likely be a success, but there isn’t nearly enough to back that up right now.

Summary

To recap:

In order to be successful, TGTX will need to demonstrate that the addition of ublituximab increases progression-free survival versus ibrutinib alone (a follow-up of the GENUINE study).  That seems achievable. Alternately or in addition, TGTX needs to demonstrate that ublituximab plus TGR-1202 can beat out chemotherapy plus tailored antibodies, and there just isn’t enough data to support a firm conclusion on that one. The third study – UNITY-DLBCL (which I didn’t discuss) has even less data backing it.

If you’re looking to take a flyer, $TGTX may be worth the investment, but I’m going to mark this one “possible” instead of “probable.”

Prediction: Possible Phase 3 Success

Ancillary data looks great, but the UNITY trial has little preliminary testing behind it, which makes it difficult to tell whether UNITY will be a success.

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