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  • This article addresses some misleading comparisons of MM 398 + 5FU and leucovorin to other drug regimens.
  • MM 398 + 5FU and leucovorin is the only drug regimen shown to be efficacious in a regulator-reviewed, Phase III multinational study in second-line metastatic pancreatic cancer.
  • Merrimack chose an appropriate comparator for the study based on the standard of care and the available efficacy and tolerability data in second-line metastatic pancreatic cancer.

In the past two weeks there have been a number of skeptical blogs and articles that have been written relating to Merrimack Pharmaceuticals (NASDAQ:MACK), some of which I find to be misleading to investors, prospective patients, and prescribing clinicians. This is not new; MACK has often been the subject of some confusion on its systems biology platform and pipeline prospects. Thankfully some of this has been addressed by a recent article, but there remains a great deal of dissonance. In this article I hope to provide rebuttals to a number of the arguments made about the clinical utility and proof of efficacy of MM 398, which is where skeptics appear to be hanging their hat.

On May 1, Merrimack posted top-line results of their recent Phase III NAPOLI study of MM 398 in second-line pancreatic cancer, showing a statistically significant increase in overall survival of 1.9 months (6.1 months vs. 4.2 months) of MM 398 plus 5FU and leucovorin over the control arm of 5FU and leucovorin. Skeptics would have you believe these results are not clinically relevant, or that Merrimack failed to chose the appropriate comparator.

The main claim that seems to be reiterated is that the MM 398 + 5FU and leucovorin regimen should have been compared to irinotecan plus 5FU and leucovorin (called "FOLFIRI") because MM 398 is a reformulated version of irinotecan. Let's take a closer look at this claim and the supporting data that has been provided.

Is MM 398 a reformulated version of irinotecan?

Yes and no. MM 398 is a nanoliposomal encapsulation of irinotecan that delivers a much higher payload of the active ingredient to cancer cells than normal irinotecan. Perhaps more importantly, due to nanoliposomal delivery, it reduces systemic toxicity by targeting the cancer cells better through the use of macrophage deposition. This is supported by data from several studies:

  1. A clinical imaging study recently completed that has shown targeted macrophage deposition to the tumor site.
  2. MACK has also shown that MM 398 prolongs intra-tumor cytotoxic exposure at the tumor site (area under the curve is 300x irinotecan in preclinical data).
  3. Clinical data has shown extended circulation of MM 398 vs. irinotecan (70x), as it is protected by the liposome until taken into the tumor. This is further supported by clinical data that has shown higher (5x) local activation of the active form of irinotecan (SN-38) in the tumor vs. the blood.

So you can't very well call it the same as irinotecan in terms of a drug safety/efficacy profile. For a good comparable one can look at Celgene's (NASDAQ:CELG) Abraxane. Abraxane is a reformulation of another drug (paclitaxel), is priced at a premium, and has a similar survival advantage of 1.8 months (but in first-line metastatic pancreatic cancer). Abraxane was approved and so far been successful commercially, and yet it was not compared to paclitaxel in a Phase III study in first-line pancreatic cancer.

Does irinotecan/FOLFIRI have a clinical benefit in second-line pancreatic cancer?

Some recent articles have drawn comparisons of irinotecan study data to MM 398 and stated that irinotecan efficacy "compares favorably" to MM 398, inferring that recent NAPOLI results are irrelevant, and that FOLFIRI could be just as good as the MM 398 + FU and leucovorin regimen. Below are some of the studies that have been cited in the articles. Let's take a closer look.

1. One author based his case on this study. The author stated the study "showed the use of single-agent irinotecan generated a median overall survival of 6.6 months with relatively minor adverse events." Taking a closer look at the study shows that it was a single-arm study on an asian population of 33 patients. One should be cautious citing results from a small single-arm Phase II study. These patients may have been healthier than other groups (Asian patients tend to have a better prognosis with some cancers).

2. In this cited study of FOLFIRI, there was a 12 months OS, but only 40 patients were enrolled in a single arm study in first-line pancreatic cancer, and 27% of the enrolled patients weren't metastatic (i.e., just locally advanced). This is a significantly healthier patient population compared to second-line metastatic pancreatic cancer post-gemcitabine. Not comparable at all.

3. In this cited study of FOLFIRI on 40 patients in second-line there was a six-months OS. Upon closer inspection it was a retrospective study, and also some of the population was locally advanced (i.e., not metastatic).

4. In this cited study of FOLFIRI, 50 patients were enrolled in second line, and there was a five-months OS. This study also had a portion of the population that was locally advanced (i.e., not metastatic).

5. In this cited study of FOLFIRI on 63 patients there was a 6.6-month OS, but it was a retrospective study.

Skeptics are using the above small, early stage (or retrospective) studies to compare to the MM 398 NAPOLI study, which is an international, Phase III, 72-site, randomized, controlled, prospective study on 417 patients that was reviewed by EMEA and FDA in advance, and for which they met their primary endpoint and an OS of 6.1 months. That's hardly an apples-to-apples comparison.

Retrospective studies can be fraught with bias and are usually not predictive of prospective study results (i.e., too easy to select healthier populations and there is no randomization), so we can dismiss those outright. The rest are all prospective Phase II studies, but none of them have a control arm, which could mean they were done on healthier populations than NAPOLI. Phase II studies also have inherent problems in terms of limited sample sizes, selection bias, lack of adequate comparators, and lack of diversity of sites.

This is why you need a large, controlled multi-site trial to really prove to regulators and clinicians that a drug works. Perhaps more importantly, there could be Phase I or Phase II studies done on FOLFIRI that failed or were stopped early and were not published, so it doesn't work to just cherry pick the best results. That is, unfortunately, what some of these authors have done.

Looking at broad reviews or meta analyses of all the study populations is better -- such as this one or this one -- even when the data is spotty, as is the case in second-line pancreatic cancer. These reviews give a more balanced purview across a number of studies, instead of selecting only the best or worst results. But even these reviews have a bias, because they do not account for the Phase II studies that have failed, or stopped early, because these studies are rarely published. So regulatory bodies and clinicians should always discount these meta analysis results as well.

Phase III trials are much more difficult and therefore efficacy differentials are often diminished across a broad, diverse population when compared to Phase II results or meta-analyses. This is why MM 398's Phase III results in such a difficult indication are so remarkable. As support for this, below is a list of some of the large trials in metastatic pancreatic cancer that have failed in the last few years (from

Recent large trial failures in pancreatic cancer

RigosertibOnconova (NASDAQ:ONTX)III650
CP-4126Clovis (NASDAQ:CLVS) and Clavis pharmaceuticalsIII367
SaridegibInfinity (NYSE:INFY)II122
GanibumabAmgen (NASDAQ:AMGN)III800
AxitinibPfizer (NYSE:PFE)III630
AfliberceptSanofi (NYSE:SNY) and Regeneron (NASDAQ:REGN)III546

In fact, only a few trials have been successful (Erlotinib in first line, Abraxane in first line, and FOLFIRINOX in first line), when over 30 late-stage registrational trials have failed in metastatic pancreatic cancer since 2000. These large trials would not have been initiated if there wasn't good clinical data from earlier studies. Yet more than 90% failed. This demonstrates that proving efficacy in Phase III trials is very difficult in pancreatic cancer, and drugs tend to perform worse in Phase III than Phase II or earlier studies. Importantly, these above-referenced trials were all in first-line metastatic pancreatic cancer, whereas MM 398 was tested in second line, an even sicker population of metastatic pancreatic cancer patients.

Should MM 398 have been compared against irinotecan/FOLFIRI?

Usually you want to compare a drug against the standard of care in a patient population. Irinotecan is not approved for second-line pancreatic cancer; it is used very infrequently and, as demonstrated above and in the cited review articles, the quality of the data on irinotecan in second-line pancreatic cancer is weak. So Irinotecan is not the standard of care.

What about other standards of care?

Nothing is approved in second-line metastatic pancreatic cancer because the supporting data is limited, and Phase III trials in pancreatic cancer have a high failure rate. Arguably the regimen that is used most frequently in second0line pancreatic cancer is FOLFOX (5FU, leucovorin, and oxaliplatin), but even that has poor data (small Phase III study in Germany where the protocol was altered in mid-study -- never fully published). There there is also erlotinib, and a number of other regimens. Clinicians will try a variety of regimens because there is no one regiment is supported by convincing data. Given the paucity of data the NCCN recommends, for those patients in good condition, to either do a clinical trial, do fluoropyrimidine-based chemotherapy (i.e., FU) or do gemcitabine-based chemotherapy. It does not recommend irinotecan, erlotinib, or oxaliplatin.

One can speculate what would happen if MACK had chosen irinotecan as a comparator in this study. Perhaps it would show four months overall survival vs. MM 398 at six months, but then the only thing this study would show is that MM 398 is better than irinotecan. It would not answer the question of whether the MM 398 regimen is better than 5FU and leucovorin. Merrimack may not be able to get approval of a drug on that basis, because irinotecan/FOLFIRI is rarely used and has poor data behind it. This same logic applies to other regimens used in second line as well. I suspect the reason why MACK used 5FU and leucovorin as a control is because it 5FU and leucovorin has some reasonable historical data as a control, is the only regimen listed in guidelines, and at least has a good toxicity profile. Notably, the FDA and EMEA had no objections to the study protocol or the control arm for NAPOLI.

In conclusion, when evaluating treatment options in the second-line metastatic pancreatic cancer population, I believe the question should not be, "Is MM 398 + 5FU and leucovorin better than FOLFIRI in second-line pancreatic cancer?" but rather, "Is there anything better than MM 398 + 5FU and leucovorin in second-line pancreatic cancer?" Because as of today, other than MM 398 + 5FU + leucovorin, nothing has better efficacy than 6.1 months overall survival in a large, Phase III, multinational trial. This is why if I were a patient or clinician I can be confident in MM 398's efficacy and tolerability in second-line pancreatic cancer. At the same time, I would be much less confident in other regimens based on the sometimes contradictory data from small, poorly controlled studies -- especially given the very high rate of Phase III trial failures in pancreatic cancer.

Disclosure: I am long MACK. I wrote this article myself, and it expresses my own opinions. I am not receiving compensation for it. I have no business relationship with any company whose stock is mentioned in this article.

Source: Merrimack Pharmaceuticals: Setting The Record Straight On MM 398