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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Aurinia pharmaceuticals ($AUPH) has a likely winner in voclosporin

Aurinia Pharmaceuticals is a company putting all of their eggs into one basket. In this case, that basket is called “Voclosporin,” an immunosuppressant that hopes to treat lupus, a somewhat common – and nasty – autoimmune disease. Specifically, AUPH is hoping to treat a kidney-related complication of lupus called “lupus nephritis,” a malady that more than half of lupus patients suffer.

In the phase 2 trial, adding voclosporin to the current standard of care appeared to beat out the standard of care alone in treating lupus nephritis (LN).

Very Recent Phase 2 Trial Showed Promise

The phase 2 trial tested two doses of voclosporin (a low dose arm and a high dose arm) against the standard of care alone. The endpoints were chosen well and were actually rather stringent – the primary endpoint was complete remission of LN at the 24-week mark, and secondary endpoints were partial remission, time to response, and remission rates at the 48 week mark. As you can see in the table below, the low dose of voclosporin met the primary endpoint, with significantly more patients reaching complete remission by week 24. Voclosporin met all the secondary endpoints as well – and by week 48, significantly more patients on the high dose of voclosporin had also reached complete remission.

Significantly more patients on both doses achieved partial remission, as well – and, ultimately, the trial met every secondary endpoint.

Taken from Parikh et al., 2017

At first glance, the safety data may appear daunting. The low dose of voclosporin, in particular, had a huge number of patients die (10 out of 89). However, there are several mitigating factors. First, the high dose of voclosporin had a much lower percentage of deaths, which suggests that the drug itself was not entirely to blame – previous trials have found that voclosporin has a very dose-dependent response, so if the drug were particularly dangerous we would expect to see more deaths in the high-dose arm. Second, the sponsors and investigators of the study determined that all of the deaths were unrelated to voclosporin. Third, most of the deaths occurred within the first two months of the study, and appeared to be typical causes of death for patients with severe lupus.

As you can see below, overall, safety data from this study tracked well with safety data from the studies of other immunosuppressants.

Taken from Parikh et al., 2017

I will note, however, that there were a few things I noticed that were a little disquieting. First, AUPH has tested voclosporin on a few other immune-related diseases – with some good effect, actually – but haven’t brought any of those formulations to market. I’m not certain why (though I admit, I haven’t looked all that hard). Second, as I noted earlier, voclosporin appears to have a strong dose-dependent effect. Why, I wonder, did the lower dose see a greater and more rapid treatment effect? Given that the lower dose group also had more patients pass away, was there perhaps some issue with randomization?

Conclusion: Worth a Chance

Because volcosporin is the only drug in AUPH’s pipeline, the success or failure of the eventual phase 3 trial will be a remarkable binary event. When the final phase 2 data for volcosporin was released a few months ago, AUPH’s stock price increased more than 200%. If the phase 3 trial is a success, I’d expect an even larger price movement.

I think that AUPH have set themselves up well for the eventual phase 3 trial of voclosporin. Unfortunately, the estimated completion date for the phase 3 trial is currently December 2019 – so we have a long time to wait, which increases the odds of something weird happening, like AUPH running out of money.

I wouldn’t put a big chunk of your portfolio towards this one, but I plan on investing at least a little bit of mine in it.

Prediction: Phase 3 Success

I would take a pretty small stake, but given the data and the potential gain, I think it’s worth putting some money towards this one.

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Cytokinetics ($CYTK)’s Phase 3 Drug Tirasemtiv’s Efficacy is Questionable

Cytokinetics [$CYTK] is putting their drug Tirasemtiv through Phase 3 trials. Tirasemtiv is a drug which hopes to treat ALS (also known as Lou Gehrig’s disease). The cause of ALS is still unknown – although genetics almost certainly play a role – and the majority of patients die of respiratory failure within two to four years. As such, there’s a huge clinical need for effective ALS treatments. Of course, if developing an effective treatment was easy, somebody would already have done it, right?

ALS is a neurological disease in which the parts of the nervous system that talk to the muscles begin to die. In most cases, the disease begins in the limbs, but inexorably spreads across the body – most patients eventually die once the nervous system is no longer able to tell the respiratory muscles to keep breathing. Tirasemtiv helps muscle fibers bind to calcium, which is how muscles receive signals from the body that tell them they should be contracting. CYTK hopes Tirasemtiv will help muscle fibers stay active and keep patients alive for longer.

Unfortunately, I am skeptical about whether CYTK will be able to pull that off.

Tirasemtiv’s Phase 2 Trial

In a phase 2 trial, CYTK tested Tirasemtiv’s ability to keep patients healthy. In a fairly well-controlled study, researchers tracked changes in ALSFRS-R scores (a measure of the severity of ALS) over 12 weeks. Unfortunately, at the end of the 12 weeks, the ALSFRS-R scores of patients on Tirasemtiv were no different than the scores of patients taking placebo.

However, CYTK decided that there was a significant difference in the predicted Slow Ventilation Capacity (more on that in a moment), which is a measure of lung function. Since we know that many patients eventually die of suffocation, CTYK felt that the change in slow ventilation capacity (SVC) function was worth investigating further. Accordingly, the ongoing Phase 3 trial of Tirasemtiv is using SVC as the primary endpoint.

A note for my statistically-minded readers – the measurement of SVC was a pre-specified endpoint in the phase 2 study. For everybody else, this is important because, basically, if you collect a bunch of data and start measuring everything after the fact, you will eventually find something that’s significantly different. Because the researchers at CYTK planned to measure SVC before beginning the study, we can avoid that type of error.

So, things seem okay so far, but I’ve found something that I consider to be important. When you look at all of the patients treated by Tirasemtiv, there’s a significant effect on SVC. However, when you look more closely, it turns out that only the healthiest half of patients saw a significant effect.  

SVC was only significantly effective for a subgroup of patients (taken from CYTK’s corporate presentation)

As you can see in the table above, Tirasemtiv was only effective in patients with a baseline SVC better than the median. However, the baseline SVC was quite high at the beginning of the study – 87.8% of normal. Since the minimum entry criteria was to have a SVC at least 50% of normal, that would mean that patients with SVC between 50 to ~85% (assuming the median and mean are close) saw no benefit from Tirasemtiv.

Median SVC was already quite high (taken from CYTK’s corporate presentation)

So even though the Phase 3 study for Tirasemtiv increased the baseline SVC requirement to 70%, there will still be a significant proportion of study participants for whom the drug doesn’t work.

Finally, we see that in every measure but one, Tirasemtiv did not beat the placebo.

Taken from Shefner et al., 2016

Conclusion

Data from Tirasemtiv’s Phase 3 study is expected in Q4 of 2017. As always, it’s entirely possible that I’m wrong. However, I think I’ve demonstrated fairly convincingly that if Tirasemtiv didn’t work on the primary endpoint, didn’t work on most of the secondary endpoints, and only worked on the healthiest subgroup patients for the secondary endpoint that CYTK is excited about, it’s probably not a safe investment.

Shorting a biotechnology stock is never a good idea. My recommendation is that you simply do not buy shares of $CYTK. If you already have them, the decision, I suppose, is up to you.

Prediction: Phase 3 Failure

Tirasemtiv simply has not demonstrated enough efficacy to make CYTK worth a buy.

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Redhill Biopharma ($RDHL): Phase 3 Drug candidate RHB-105 likely to succeed, RHB-104 possible

This week I’m hoping to wrap up my two-part series on Redhill Biopharma ($RDHL). Previously I wrote about RDHL’s drug BEKINDA, which I believe is likely to pass its phase 3 trial. RDHL has two other late-stage drugs in the pipeline: RHB-105, which is designed to treat the bacteria which causes stomach ulcers, and RHB-104, which hopes to treat Crohn’s disease.

After doing some research, I believe that RHB-105 is also likely to pass the confirmatory phase 3 trial, which is scheduled to begin later this year. RHB-105 is a combination therapy designed to treat antibiotic-resistant strains of the bacteria that causes ulcers, known as Helicobacter pylori or H.pylori. Essentially, RHB-105 is a single pill containing two antibiotics and a proton pump inhibitor (acid reflux drug). The scientists at Redhill hope that the combination of drugs will be better than the current standard of care – one antibiotic and a proton pump inhibitor. It appears that they may be correct.

$RDHL’s Drug RHB-105: Likely to Pass Confirmatory Phase 3 Trial

Earlier this month, RDHL announced positive data from RHB-105’s initial phase 3 study. Redhill is planning to run a second confirmatory phase 3 study, which will probably begin sometime in June or July of this year. The initial study was well-designed: The placebo was a good match for the active intervention, they used two common methods of diagnosis to confirm the presence of H.pylori and patients who dropped out or did not complete the study were counted as failures.

In the study, RHB-105 eradicated H.pylori infection in 89% of the treated patients. This is significantly better than the standard of care’s success rate, which is roughly 70%. What’s more, at the end of the study they allowed the placebo group to be treated with the standard of care, and only 63% of that group were successfully cured of H.pylori, suggesting that 70% may have been an optimistic estimate.

So, with the first phase 3 trial RHB-105 demonstrated that it is significantly more effective than placebo (unsurprising) and significantly more effective than an estimate of the standard of care (somewhat surprising). As a follow up, the confirmatory trial will be about 4 times larger and will pit RHB-105 directly against the standard of care. There’s some room here for failure. Although I think it’s very unlikely that RHB-105 will perform worse than the standard of care, it’s possible that there won’t be a statistically significant difference between RHB-105 and the standard. I suspect that’s why the researchers are making this trial so much larger – statistically, a large trial is more likely to pick up on small differences between two conditions.

Even with that said, the strong study design and impressive results from the first phase 3 trial make me think that another pass is likely.

Prediction for RHB-105: Confirmatory Phase 3 Approval

Although it will be more than a year before we see any data from the confirmatory phase 3 trial for RHB-105, I believe that the ultimate result will be a success. I’ll update this post if something happens to change my mind.

$RDHL’s Drug RHB-104: Potential to Pass Initial Phase 3 Trial

Unfortunately, there’s not enough data for me to be certain about the third drug candidate, RHB-104. There is a strong theoretical grounding, and I believe it is highly possible that RHB-104 will pass, but I’m not quite confident enough to say “likely.” Part of the issue is the particular nature of Crohn’s disease – although we’ve identified some of the risk factors, nobody has yet proven exactly what causes Crohn’s. And because we don’t know what causes Crohn’s, nearly all of the treatments for the disease treat the symptoms, instead of the cause.

Redhill hopes to be one of the first companies with a treatment for the cause of Crohn’s. RHB-104 is, like -105, a combination therapy. In this case, the combination is of three separate antibiotics. There’s been some very recent research suggesting that combining antibiotics like this may lead to some synergistic effects; that using small doses of multiple antibiotics at the same time is better than using large doses of just one antibiotic. The sum, in effect, is greater than the parts – or at least, that’s what RDHL is hoping.

The three antibiotics in RHB-104 are all aimed at treating a particular strain of bacteria known as MAP. As you’ve probably guessed, the researchers at Redhill Biopharma believe that MAP plays an integral role in causing Crohn’s disease. It’s well-known that MAP causes Johne’s disease in cattle, which is a very similar ailment. Modern research has also conclusively demonstrated that people with Crohn’s have a much higher rate of MAP infection than people without Crohn’s.

Although none of the above is conclusive (or even demonstrates causation), there has been some research suggesting that treating MAP infection may help Crohn’s symptoms:

Effectiveness of RHB-104
Taken from Borody et al (2002), Digest Liver Dis 34:29-38

In addition, a statistical reanalysis of an Australian phase 3 study using anti-MAP therapy to treat Crohn’s disease suggested that anti-MAP therapy may be significantly more effective than placebo. However, there are some inherent issues in reanalysis, and I wasn’t able to find out whether the reanalysis was funded by RDHL.

RHB-104 Phase 3 data
Taken from Behr and Hanley (2008), Lancet Infectious Diseases 8:344

As you can see, there’s some fairly compelling evidence suggesting that MAP might be implicated in Crohn’s. If so, RDHL’s drug will probably be effective, as there’s some separate fairly compelling evidence suggesting that RHB-104 is effective against MAP. I never like to stack assumptions atop assumptions like that, though, which is why I’m ultimately going to say that this is possible, not probable.

Personally, I don’t think that MAP is exclusively responsible for Crohn’s. I suspect that Crohn’s disease is a combination of genetic susceptibility and infection from a handful of possible causes.  Even so, RHB-104 just might work. We should see interim data sometime within the next few months.

Prediction for RHB-104: Possibility for Phase 3 Approval

Unfortunately, I don’t feel comfortable putting the stamp of approval on this one. Even so, with BEKINDA and RHB-105 likely to receive approval, I think $RDHL is a buy.

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Redhill Biopharma ($RDHL)’s Drug BEKINDA will likely pass Phase 3 sometime in 2H2017

Today’s post took me much longer than normal to write. I had a lot of difficulty finding a company that fit my normal criteria – established, but not an industry leader; at least one phase 3 candidate in the pipeline; and so on. I think, however, that the effort was worthwhile. Redhill Biopharma ($RDHL) has a handful of drugs which are very intriguing to me, and I hope to cover their drug for Crohn’s Disease in a future post. Today, though, I’m writing about Redhill Biopharma ($RDHL)’s drug BEKINDA (not an acronym, just an all-caps name for some reason). As always, if you don’t care about the details, feel free to scroll to the end.

BEKINDA, formerly known as RHB-102, is an extended-release formulation of the generic drug ondansetron (commonly known under the brand name Zofran). Ondansetron is an anti-emetic (anti-vomiting) drug, and is used to prevent vomiting in patients undergoing cancer treatment or surgery. Ondansetron is also frequently prescribed off-label for children suffering from acute gastroenteritis (AGE). AGE is something of a catch-all term for “an upset stomach caused by some sort of bug.” When people say “stomach flu,” they’re talking about AGE.

Interestingly, although the use of ondansetron has been studied fairly extensively in children suffering from gastroenteritis, there is almost no data on the use of ondansetron in adults suffering from AGE. And even in children, the use of ondansetron is technically off-label. With all of that background, hopefully it makes sense that RDHL’s formulation of ondansetron, BEKINDA, is intended to be a better method of treating the stomach flu.

While I was evaluating the BEKINDA’s chances in the phase 3 trial, I decided that approval would come down to three things:

  1. Is the drug likely to be effective?
  2. Is the drug likely to be safe?
  3. Did RDHL establish a realistic study protocol?

Is BEKINDA likely to be effective in treating AGE in the phase 3 trial?

In short: yes. As mentioned above, ondansetron is already widely used to treat children with gastroenteritis. A well-designed study found that ondansetron was – in nearly every conceivable measure of effectiveness – statistically superior to both placebo and a European anti-vomiting drug known as Domperidone in treating AGE.

https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5120790/#pone.0165441.ref015
From Marchetti et al., 2016, PLOS one

The success of BEKINDA, which is simply a delayed-release pill containing ondansetron, is probably presaged by these results. Although the data above was for children, there’s no real reason why it wouldn’t hold true for adults, as well. The one caveat here – and I’ll return to this later – is that the data from the table above was taken during the emergency department (ED) visit, meaning it was short-term data.

Is BEKINDA likely to be safe in the phase 3 trial?

To summarize again: yes. There are a few contraindications for ondansetron, but the advantage of reformulating a well-known drug is that all of the kinks have mostly been worked out (or at least discovered). I forsee no significant safety issues in this trial.

Did RDHL establish a realistic study protocol? Will BEKINDA pass phase 3?

This is always the tricky one to answer. Earlier in this article I mentioned that most (if not all) of the data for ondansetron is collected over a very short time period – usually over the course of a few hours – while the study protocol is a bit longer than that. The primary outcome measures of the BEKINDA phase 3 “GUARD study” are the proportion of patients

  • without further vomiting,
  • without rescue medication, and/or
  • who were not given intravenous hydration

from 30 minutes after the first dose until 24 hours later.

The length of time might be a problem, because when the researchers from the study cited above followed up 48 hours after the emergency room visits, they found that there was no longer any difference between the three conditions.

https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5120790/#pone.0165441.ref015
From Marchetti et al., 2016, PLOS one

This isn’t really surprising, considering the nature of the drug and the fact that any kids taken to the emergency department for vomiting were likely too sick to get better in one day. The question, though, is whether BEKINDA’s extended release formulation will be enough to overcome this hurdle.

Without phase 2 data to draw on, I turned to the next best thing: a bioavailability study. The only study I could find tested RHB-102 (which became BEKINDA) against the dose of ondansetron used in chemotherapy. Over the course of 5 days, the bioavailability of BEKINDA was either equal to or better than the routine dose. And even better, when researchers tested blood concentrations 24 hours after the initial dose, BEKINDA beat out a non-extended release equivalent dose.

Ultimately, I think that yes, the GUARD study is realistic, and RDHL will likely take home a phase 3 approval.

Conclusion

If BEKINDA posts good data (expected to take place sometime in the second half of this year), it will become the first drug in its class to treat acute gastroenteritis. If the study posts particularly strong results, it may even be possible that just the one study will be sufficient for FDA approval. To summarize, ondansetron (the drug making up BEKINDA) is effective, the study protocol is achievable, and the extended-release formula appears to work.

Based on what I’ve written here, I believe that $RDHL is a buy, for at least until the BEKINDA data is released.

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Prediction: Phase 3 Approval

The drug underlying BEKINDA has already been demonstrated to be effective, and a bioavailability study suggested that the extended-release formulation works.

Paratek ($PRTK)’s Success Hinges on Oral-Only Trial for Omadacycline; Odds Look Good

As you probably know, the effectiveness of traditional “broad-spectrum” antibiotics has taken a sharp nosedive in the last decade. The widespread prescription and use of these drugs has led to a huge rise in the number of antibiotic-resistant bacteria, leaving manufacturers and researchers scrambling to formulate new versions of old medicine.

Paratek Pharmaceuticals ($PRTK) is one of these manufacturers. Their drug omadacycline is a chemical modification of an old class of antibiotics that hopes to overcome bacterial resistance.

Omadacycline has two successful phase 3 trials already on the books – once for acute bacterial skin infections (known as ‘ABSSSI’ and often caused by the poster child of antibiotic-resistant bacteria, MRSA) and once for community-acquired bacterial pneumonia (CABP). The methods, conclusions, and safety profiles of these studies all look fine, and the study design received a Special Protocol Assessment from the FDA – meaning that the FDA believes the design of the studies sufficient to warrant a new drug application. This is all good news, so why hasn’t PRTK submitted the new drug application yet?

Both of the trials of omadacycline started with an intravenous (IV) version of the drug. This is a problem because by far, the biggest commercial potential lies in oral-only antibiotics. Intuitively, this makes sense – an oral antibiotic can be prescribed and taken at home, while IV drugs require a hospital stay or expensive nursing care. Paratek, of course, is well aware of this, so a few years ago PRTK launched a third phase 3 trial testing an oral-only version of omadacycline.

The success of drug overall will, to a great degree, depend on how good the oral-only data look – data which will probably be presented sometime in the next few months.

The Study

The phase 3 trial for oral-only omadacycline is essentially an exact repeat of the IV + oral omadacycline trial which was already approved. The trials are treating the same disease and have the same “success” conditions.

Because the trials are nearly identical and the IV + Oral trial already received approval, I’m not going to look at the study design too closely for this article. The key question is this: will the oral version of the drug work as well as the IV version?

First, a fairly intricate pharmacokinetics study found that the 300mg oral dose is nearly exactly equivalent to a 100mg IV dose. That does come with a slight caveat, however: the great advantage of oral antibiotics is that they can be taken at home. This is also, of course, the great disadvantage of oral antibiotics – there’s nobody around to make sure you take them correctly. A study found that taking food with omadacycline significantly decreased the amount of the drug that went into the body. With this oral-only phase 3 design, there is a much higher risk of patients not following the protocol, which could result in the drug appearing not to work. I don’t think it’s a likely outcome, but I wanted to note it here.

I searched the previously published studies to see if any had segregated their data between IV patients and patients who had been transitioned to oral omadacycline. As far as I could tell, the only study with separate data was one of the phase 2 studies which had happened to segregate the data because they were looking at the first 72 hours of response. In that study, about a third of patients had switched to oral-only omadacycline within the first 72 hours of the study, and 96% of those patients had seen a clinical significant treatment response. That isn’t a perfect benchmark to use to evaluate the effectiveness, but it will have to be good enough.

The answer to the key question, then is yes. Previous antibiotics have been successful in moving from IV-oriented treatments to oral-oriented treatments; the oral dose appears to be equivalent to the IV dose (as long as people follow the protocol); and some fragmentary data from a phase 2 study appears to suggest that the oral drugs work effectively.

What next?

Assuming I am correct and the phase 3 trial for oral-only omadacycline is successful, expect to see Paratek submit a new drug application (NDA) before the end of 2017. Again, assuming I’m correct about omadacycline, I am confident that the NDA will be approved.

I think that $PRTK is a buy.

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Prediction: Phase 3 Approval

The oral version of omadacycline appears to work just as well as the IV version, and since the trials are functionally identical, I expect that oral omadacycline will receive a “go” just like the IV + oral version did.

PTLA Part 2: Andexanet Alfa

In Part 1, I took a look at Portola [$PTLA, currently around $40] and their drug betrixaban. In this, part 2, I’m going to look at PTLA’s other main drug candidate, andexanet alfa. Andexanet is a drug designed to reverse the effects of factor Xa inhibitors like betrixaban.

As you may recall from Part 1, factor Xa inhibitors are anticoagulants, a class of drug extremely useful for preventing dangerous blood clots. The trick, of course, is that anticoagulants prevent all blood clots; a patient on anticoagulants runs the risk of bleeding to death from even a minor injury. Imagine a small cut on your finger that just kept bleeding and bleeding, no matter what you tried to do.

Enter andexanet. PTLA calls andexanet alfa an “antidote” to factor Xa inhibitors, and in several senses, this really is the best description. As we’ll see, andexanet works rapidly, doesn’t seem to cause harmful effects, and (probably) effectively countered the factor Xa inhibitors it was deployed against. However, some concerns about the lack of a control group prevent me from recommending $PTLA as an investment.

The Data

I took the graph below from the first Phase 3 study of andexanet. It shows two groups of patients, both of which were using a factor Xa inhibitor. The “800mg bolus” group was given a large injection and IV drip of andexanet alfa, while the placebo group was not given any. The left side of the graph measures the effectiveness of the factor Xa inhibitors (anticoagulants). As you can see, the anticoagulants rapidly stopped working in the group given andexanet alfa, and stayed “off” until the end of the IV drip. There were no safety issues.

This graph shows andexanet's efficacy
Andexanet works rapidly on injection and can be sustained via an IV drip.

At this point, $PTLA asked the FDA for approval of the drug… and were denied. The FDA wanted additional data for two of the four Factor Xa inhibitors tested. As such, the researchers began a second phase 3 study which tested andexanet alfa in bleeding patients. This study is still ongoing, but in September 2016 researchers posted interim data: of 47 bleeding patients who received andexanet, 37 (79%) saw a clear clinical benefit.

This seems good, but there’s a snag – the study had no control group. Ultimately, it’s impossible to tell whether the andexanet stopped the patients from bleeding or whether it would have happened anyway.  In and of itself, this isn’t a show-stopper. I have seen drugs without control groups get FDA approval in the past. However, given that the FDA has already rejected $PTLA’s drug once, this study design makes me wonder.

Will andexanet get approved?

Given the data, I would say yes, it is likely that the application for andexanet alfa will be approved by the FDA. The lack of a control group is worrisome, but andexanet is addressing a completely unmet clinical need. Ultimately, andexanet appears to be almost entirely without side-effects, and I think that the FDA will approve the application, even given the somewhat marginal phase 3 study formulation.

That said, I cannot recommend buying stock in $PTLA at this juncture. As I mentioned in part 1 of my look at Portola, I think that the betrixaban study is going to fail. If I’m right, the share price of $PTLA could drop precipitously, and I can’t predict how much a successful application for andexanet might boost it.

Prediction: FDA Approval – but don’t invest at this time.

The unmet clinical need and safety data make me think this drug will probably receive FDA approval, but the issue with Betrixaban should keep you from investing at this time.

 

pSivida’s drug Durasert might be rejected by the FDA

pSivida [$PSDV on the NASDAQ] is conducting Phase 3 trials on a drug called Durasert. PSDV hopes that Durasert will prevent the recurrence of a disease called uveitis, which is inflammation of one of the parts of the eye. Although preliminary data from Durasert’s phase 3 trials suggests that it is effective at preventing the recurrence of uveitis, I think it’s possible that the FDA will reject the New Drug Application that PSDV sends in. The drug and delivery method that Durasert is based on has consistently been shown to increase the risk of cataracts.

Worrisome Safety Data

Whenever we talk about medications in the eyeball (which I’ve found myself doing a lot more than I expected when I started this site), there’s usually one overriding safety concern: intra-ocular pressure (IOP). Intra-ocular pressure is the pressure in the eyeball, and many medications increase it. Part of what made the Eyegate Pharmaceuticals trials so exciting is that their drug might actually decrease IOP, but pSivida isn’t so lucky. Their drug increases IOP significantly, although after an initial spike, IOP appears to be fairly stable – check out the following graph.

Phase 3 Durasert trial safety data
Durasert increases intra-ocular pressure, but pressure stabilizes after an initial spike

However, even if IOP isn’t a huge safety concern for Durasert, there’s something more ominous. At the beginning of the Phase 3 trial, 51% of the eyes had already had cataract surgery. Even so, by ~1 year into the study, 45% of the eyes treated with Durasert had to have cataract surgery, while about 10% of the control eyes had to have cataract surgery. Given that the phase 3 Durasert trials are supposed to go for about 3 years, I think it’s safe to assume that the majority of patients will have needed cataract surgery by the end of the study.

Phase 3 Durasert trials show cataract growth
50% of participants already had cataracts removed, but 45% have new cataracts

The cataract issue has been a recurring problem with PSDV’s drugs.

Cataract Issues in Previous Drugs from pSivida

Durasert is a slightly weakened dose of PSDV’s drug Iluvien (Durasert has 0.18g of the active compound, “fluocinolone acetonide,” while Iluvien has 0.19g). Iluvien was rejected three times by the FDA before finally receiving approval. Each time, the rejection came down to the same issue – taking Iluvien gave the patients increased risk of developing cataracts, with little improvement over the standard of care.

Retisert, yet another formulation of fluocinolone acetonide by PSDV, had the same issue – a study pitting Retisert against a different treatment found that 100% of the Retisert-treated eyes had cataract progression (versus 50% for the other treatment) and that eyes treated with Retisert were at 4.7 times more risk of cataract progression.

Conclusion

Durasert has absolutely shown efficacy, but I think that PSDV will struggle with the cataract issue.

Data from Phase 3 Durasert study
Durasert handily beats the placebo in preventing Uveitis recurrence. The question is: is it worth it?

Now, in fairness I should mention that cataract removal is a fairly easy procedure. Still, though, given how much Iluvien struggled, I am not confident in PSDV’s ability to get a Phase 3 pass on the first go-round.

Prediction: Phase 3 Pass on primary efficacy endpoints – but NDA rejection by the FDA

Durasert is effective, but gives patients cataracts. I can’t say whether the trade-off is worth it, but I can tell you that this company isn’t worth investing in.

Nektar Therapeutics: Old Company, New Drugs

Near the end of March 2017, Nektar Therapeutics ($NKTR) will present data from their most recent Phase 3 trial. Nektar has already brought two drugs through the entire FDA process, so this is not their first rodeo.

As I’m sure you’ve heard, prescription drug abuse is becoming a huge problem across the world. Nektar’s newest drug, under the working title NKTR-181, is supposed to be an abuse-resistant opioid. If things go well, NKTR-181 will start to take market share away from drugs like oxycodone and morphine.

The success or failure of the NKTR-181 Phase 3 trial will hinge on two things:

  1. Whether it is at less risk for abuse than other opioids
  2. Whether it can significantly decrease pain (versus a placebo)

With that in mind, let’s dive into the data.

Question 1: Is NKTR-181 less likely to be abused?

The short answer to this question is “probably.” The ultimate answer to this question can only really come from seeing how the public reacts to the drug, but the researchers have done what they can by testing rats.

In the NKTR-181 Phase 1 trials, the researchers found that NKTR-181 probably enters the central nervous system (or “CNS”) much more slowly than drugs like Oxy or morphine. The idea here is that the “high” feeling from oxycodone comes from how rapidly it hits the CNS. If NKTR-181 takes hours (instead of minutes) to hit you, you’re much less likely to feel high from it.

NKTR enters the CNS much more slowly than oxycodone
From “NKTR-181 efficacy in multiple preclinical models of pain”, Choi et al.

The researchers also found that rats will stop trying to get NKTR-181 at about the same time that they will stop trying to get saline. Graph A below shows that if you make a rat press a lever more than 25 times to get NKTR-181, the rat will give up. For oxycodone, on the other hand, the rat will keep pressing that lever. Graph B shows that if you take a rat trained to press a certain lever when it “feels” oxycodone, the rats will only start pressing the correct lever once they get a pretty high dose of NKTR-181. That’s a bit dense, but essentially it means that it takes a lot of NKTR-181 to make a rat feel like it does on just a little Oxy.

Rats are much less likely to keep self-administering NKTR-181
From “NKTR-181 efficacy in multiple preclinical models of pain”, Choi et al.

On the whole, these are all reasonable ways for researchers to say that NKTR-181 is probably less prone to abuse and addiction than oxycodone. Self-administration and drug-discrimination studies are both very common in behavioral research. On to question 2.

Question 2: Does NKTR-181 significantly decrease pain (versus a placebo)?

This is where I got a little more worried.

The Phase 2 study design was a little curious, but not unusual for opioids. Every patient in the study started by taking the drug to establish how much of the drug they needed to decrease pain. After this short “titration” period, some of the patients switched from the drug to placebo. This is called a “withdrawal” study, because the researchers withdraw the drug and replace it with a placebo.

NKTR-181 failed the Phase 2 trial. It failed because when patients withdrew to the placebo, their pain never came back. This was great for the patients, of course, but not great for the researchers at Nektar Therapeutics. Such an event is actually not uncommon in Phase 2 opioid trials, as the trials tend to be pretty short and the patients don’t have a chance to rebound.

To their credit, the researchers noted all of this and doubled the length of the Phase 3 trial. Making the trial twice as long gives patients a lot of time for their pain to come back, and should take care of the issue that tanked the Phase 2 trial. However, the Phase 3 trial is also testing a different type of pain.

Low-back pain – the type of pain being treated in the Phase 3 trial – is probably the trickiest type of pain to treat. In many cases, patients who have real, measurable lower back disorders like bulging discs will be completely pain free. In other cases, patients who have no discernable pathology will suffer from chronic lower back pain. As such, low-back pain is also one of the most responsive types of pain to placebo treatments. I can remember at least one recent study (Carvalho et al., 2016) which found that giving patients a placebo and telling them it was a placebo still had a measurable beneficial effect on lower back pain.

All of that makes me worry that the final study is going to have the same placebo problem that caused the Phase 2 trials to bomb.

Conclusion: The NKTR-181 Phase 3 study will probably be long enough

I’m a little worried about the Phase 3 study, since they are using low-back pain and following the same withdrawal design that flummoxed the Phase 2 study. However, doubling the length of the trial will probably be enough to help NKTR-181 reach significance. I’m also encouraged by the fact that – as the researchers pointed out – only 3% of the patients in the Phase 2 trial were unable to achieve pain relief.

Prediction: Phase 3 Pass

Although I still have concerns about using lower back pain for the pivotal trial, a length of 12 weeks is probably enough to eliminate the weird placebo rebound issue that buggered Phase 2. With that, NKTR-181 answered both of my questions and I think there’s better than even odds of a pass.

 

 

 

Novan’s anti-acne drug has some effect, but is not worth investing in

Summary

Novan ($NOVN) is a company focused on using nitric oxide to treat skin conditions. Nitric oxide is a curious molecule with a ton of different effects in the body. It’s an incredibly potent vasodilator and has some use in the immune system (among many, many other things nitric oxide does in the body). It’s this immune system function that researchers became particularly interested in a few years ago. Eventually, scientists discovered that immune cells were using nitric oxide to kill disease-causing microbes. Novan is hoping that they can capitalize on the anti-microbial properties of nitric oxide. Their first attempt, a gel called SB204, is in Phase 3 trials for acne.

The Phase 3 data for SB204 should be released sometime in Q1 of 2017. Based on the research I’ve done, I think that SB204 will miss one of the primary endpoints in the Phase 3 trial. Moreover, even if SB204 makes all of the endpoints, I’m not confident that SB204 warrants approval by the FDA.

SB204 is mildly effective

First, I’ll talk about the good. The nitric oxide treatment had a very clear effect on the raw number of lesions (you and I would call them “pimples”). The 4% concentration (which is the concentration that will be used in the Phase 3 trial for SB204) significantly decreased both “inflammatory” and “non-inflammatory” pimples.

This chart shows that SB204 is effective at decreasing the number of pimples.
4% concentration of SB204 significantly decreased the number of lesions (pimples)

The treatment is safe enough. Some of the subjects suffered from the side-effects which are commonly associated with topical treatments — dryness of skin and things — but nobody had serious safety issues.

However, there’s some bad news as well. In the Phase 2 study, the researchers had each subject scored on a scale of 0 to 4, where 0 was “clear skin” and 4 was “severe” acne. The subjects were scored at the beginning of the study and 12 weeks later, when the study had concluded. Only 1 subject (out of 41) who was treated with SB204 had their score drop at least 2 points to “almost clear” or “clear”.

This is critical because the severity scoring is one of the three primary outcome measures for the SB204 Phase 3 trial. The Phase 3 trial is the same length and uses the same concentration (4%) of the drug, so I see no reason how that outcome measure could be successful.

My other issue is with the treatment itself. The researchers aren’t completely positive how SB204 works, but it’s probably by killing the bacteria on the face that are causing the acne. If this is the case:

  1. the treatment is a temporary fix
  2. there are no real advantages to SB204 over the myriad of other acne treatments on the market

The study didn’t check on the patients after the treatment stopped, so we can’t tell for certain whether the drug is a temporary fix.

Not worth the investment

Ultimately, this drug from Novan ($NOVN) just isn’t worth investing in. Novan has some other drugs in the pipeline, and maybe I’ll get a chance to update this post with due diligence on one of those. NOVN should be releasing Phase 3 data sometime this quarter, but I don’t have my fingers crossed for anything too exciting.

Prediction: Phase 3 Failure

SB204’s Phase 3 trial is testing an outcome which fell flat during Phase 2. In addition, the case for the treatment itself is not compelling.