The Battle for Oral Insulin
Aug 18, 2016 14:13:52 GMT -5
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Post by mannmade on Aug 18, 2016 14:13:52 GMT -5
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The Battle For Oral Insulin
Aug. 18, 2016 3:08 PM ET| About: Novo Nordisk A/S (NVO), ORMP, Includes: EMIS
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Summary
Novo Nordisk and Oramed are both working on an oral insulin diabetic treatment.
Both recently reported Phase 2 trials results that met primary endpoints.
A comparison of results indicates Novo Nordisk's treatment is far more effective, but both could find a market.
Oral insulin would be gigantic seller. With the global insulin market expected to approach a whopping $40B by 2020, an oral insulin pill could help a pharmaceutical company grab big chunk of revenue from competitors. After all, insulin is currently available only in injectable form. An oral version would likely aid compliance by ridding patients of the use of needles and offering a convenient treatment.
Coming up with an oral insulin pill is only part of the story, though. Oral insulin pills are actually simple to develop. What's hard is producing them as an effective, safe and profitable product.
You see, an oral insulin pill can be made by simply combining insulin with any one of at least a few available delivery technologies, or carriers, that aid in peptide or protein API (Active Pharmaceutical Ingredient) transport across the cells of the gastrointestinal tract and into the bloodstream.
There are two principal carrier mechanisms for this transport, transcelluar, that is through the cells, and paracellular, that is between the cells. Examples of paracellular carriers include GIPET (GastroIntestinal Permeation Enhancement Technology), which Novo (NYSE:NVO) acquired from Merrion Pharmaceuticals (who acquired it from Elan Corporation), and Oramed Pharmaceutical's (NASDAQ:ORMP) POD (Protein Oral Delivery). An example of a transcellular carrier is Emisphere Technology's (OTCQB:EMIS) SNAC. All of these carriers are FDA GRAS (Generally Regarded As Safe) additives.
Each of these carrier technologies target absorption in different regions of the gastrointestinal tract. GIPET targets absorption in the duodenum, between the stomach and the small intestine. POD targets the small intestine. SNAC targets the stomach. Consequently, GIPET and POD provide API delivery in around 1.5-2 hrs, after the stomach has emptied, and SNAC provides delivery in under 20 minutes. Also, the GIPET and POD carriers require that the pill have a protective coating to make it past the stomach without degradation while the SNAC pill requires no such coating but could potentially be coated for delivery later in the gastrointestinal tract.
Let's take a look at the Novo and Oramed trial results to glean what we can about their relative efficacies and per-treatment costs.
Novo Nordisk's Oral Insulin
Novo Nordisk has been investigating both GIPET and SNAC oral insulin formulations to treat diabetics. They have been focusing of late on the GIPET version, finding that GIPET did a better job of transporting Novo's insulin than SNAC.
Novo is using an engineered long-acting basal insulin analogue in their oral-insulin pill. This is similar in many respects to Novo's SNAC-based oral GLP-1 semaglutide, an engineered analogue that has properties conducive to survival in the gastrointestinal tract and bloodstream. Novo has tailored insulins for the oral version and potentially matched to particular carriers (SNAC or GIPET).
Novo recently presented results from their Phase 2a trial using a GIPET formulation. Their oral insulin results matched the injectable insulin results in their benefit to fasting glucose levels. Here's what they released about their data:
Phase 2a trial with oral insulin OI338GT (NN1953) completed during the first half of 2016, Novo Nordisk completed a small 8-week phase 2a trial with the once-daily oral insulin analogue OI338GT compared with subcutaneous insulin glargine U100 in 50 insulin-naïve adults with type 2 diabetes. The trial investigated the safety, tolerability as well as pharmacokinetic and pharmacodynamics profiles of OI338GT. The results were generally encouraging with a decrease in fasting plasma glucose of approximately 2.5 mmol/L for both treatment arms, and OI338GT generally appeared safe and well-tolerated.
Novo Nordisk is currently assessing the therapeutic use and investment needs of the oral insulin program, and an update will be provided in the second half of 2016.
These are really remarkable results. Novo showed that their oral insulin worked as well as injectable insulin in reducing fasting blood glucose levels, both by 2.5 mmol/L.
But the fact that Merrion recently sold their GIPET technology to Novo for $13M raises red flags for me. That is way too cheap for something with multi-billion dollar potential making good progress. Along with statements by Emisphere indicating Novo is progressing with SNAC technology in new insulin investigations, these developments indicate to me Novo is looking for something better than the current GIPET delivery method. More on why this might be is to follow when I discuss safety.
Oramed's Oral Insulin
Oramed Pharmaceuticals is developing their oral insulin using their proprietary POD formulation, which is based on research from Hadassah Medical Center in Jerusalem, Israel. Oramed is targeting both pre-diabetics and diabetics.
Oramed recently provided results from their 4-week Phase 2b trial involving patients with type-2 diabetes. Here's what they released about their data:
The primary objective of the study was to evaluate the nighttime glucose lowering effect and safety of ORMD-0801 compared to a placebo.
In the study, the mean nighttime glucose showed a significant difference in mean change from run-in (13.70 mg/dL for placebo vs. 1.66 mg/dL for the pooled ORMD-0801 arms with a p= 0.0117). Other secondary and exploratory objectives of the study included evaluating the effect of ORMD-0801 on mean 24-hour glucose, fasting glucose, and daytime glucose. The mean 24-hour glucose showed a highly significant difference in mean change from run-in (13.26 mg/dL for placebo vs. -0.32 mg/dL for ORMD-0801, p <0.0001). The mean fasting glucose showed a highly significant difference in mean change from run-in (15.95 mg/dL for placebo vs. -0.41 mg/dL for ORMD-0801, p <0.0001). The mean daytime CGM glucose showed a highly significant difference in mean change from run-in (11.88 for placebo vs. 0.88 for ORMD-0801, p= 0.0010). There was a statistically significant difference in change in HbA1c at Day 29 (0.20% for placebo vs.-0.01% for ORMD-0801, p= 0.0149). It is important to note that due to the kinetics of change of HbA1c, a four week study is insufficient to fully appreciate the potential positive impact of ORMD-0801 on HbA1c.
ORMD-0801 was safe and well tolerated, with no drug related serious or severe adverse events and no statistically significant differences in laboratory values or vital signs.
Oramed evaluated mean change from run-in relative to placebo and showed a statistically significant effect. This is very different from Novo's trial, which simply compared their new pill to a known effective treatment and showed equivalence.
That makes Oramed's candidate's results a little more difficult to interpret. A positive effect was observed but was the effect strong or weak relative to what's needed for clinical efficacy?
Comparisons
To help us understand Oramed's results, let's take a look at an example.
For a patient with a fasting glucose at or above 130 mg/dL, a common problem level, to get under 100 mg/dL, a good level (around 75 mg/dL is ideal), we have a difference of at least 30 mg/dL.
Converting Novo's fasting glucose difference results to the same units as Oramed's results, we get Novo's benefit as 2.5 x 18 = 45 mg/dL. Novo's drug reduced fasting blood glucose by 45 mg/dL. This will easily decrease the example patient's fasting glucose below 100 mg/dL, to 85 mg/dL.
Now to Oramed. Oramed's treatment had a mean patient fasting blood glucose decrease of only 0.41 mg/dL (you can barely see its yellow bar on the chart below). That's less effective than Novo's treatment by 100x! Oramed's product essentially prevented fasting glucose from increasing, which is what happened in the placebo group, but it barely reduced it in the treatment arm. In the example patient, it would hardly register, reducing the level to 129.6 mg/dL. What good is that?
Wait a minute, though. Oramed's product is being targeted toward night-time glucose levels, so let's look there instead. Note that we are to some degree now comparing apples and oranges, but we can get a rough understanding of the size of Oramed's effectiveness.
Oramed's treatment kept blood glucose levels down relative to placebo, by 12 mg/dL. Even here, though, we can see a problem. What if the initial level was high, like the example patient? Oramed's pill essentially just let the mean night-time glucose level rise a little, versus rise a medium amount on placebo, when we really wanted a large reduction.
Suppose we are trying to obtain an absolute (not relative to placebo) 25 mg/dL reduction in the night-time glucose level of a diabetic patient? It looks like we'd need to take another drug to bring it down to the level we want first. So why even bother with Oramed's treatment?
Being generous, Oramed probably needs to increase their insulin delivery by a factor of at least 10x to treat diabetics. Sure, Oramed's treatment shows an effect, but it's way too small. Their pills just don't deliver enough API to provide meaningful clinical benefit to patients with type-2 diabetes.
Let's look more closely at Oramed's treatment as it would apply to diabetics. With two 8-mg insulin pills being used with ~200U each (assumed similar to their Phase 2a study, the specific doses of Phase 2b weren't disclosed), Oramed either needs to figure out a way to get an order of magnitude better bioavailability out of their carrier or use 10x more insulin.
The former means their oral delivery technology doesn't work well enough. I think they are stuck with their technology. This means they would need to up the dosage 10x to 20 pills, which is 8000U. Since insulin costs around $50 per 100U, the Oramed treatment would cost $4000/day, a ridiculous number. So there goes both affordability and profitability for treating type-2 diabetics.
This is why Oramed is also targeting pre-diabetes.
Oramed believes it can show a prophylactic benefit for patients at high risk of becoming diabetic using a low-effective-dose pill. This is a speculative application but it is one Oramed has proffered. Oramed has stated that one of their key benefits is "slowing down the progression of diabetes." So rather than serve as a treatment for diabetics, Oramed is positioning itself for pre-diabetes and expecting their medication to delay the onset of diabetes.
Cost
Oramed has a partnership with Hefei Tianhui Incubator of Technologies Co. Ltd., who has an ownership stake in an insulin production facility in China. They may be able to manufacture large quantities of insulin for Oramed much cheaper than that $50 price, maybe by a few times. (The price would need to be reduced by 300x to make it comparable with currently marketed insulin products for treating type-2 diabetes. Also, the sheer volume needed, most of which is just wasted by digestion, might be too much to practically manufacture for that indication.) Since they are targeting the Chinese pre-diabetic market, I'd expect them to need a cost much less than the typical current U.S. diabetes treatment of approximately $350/month; so much less than $10/day.
On the other side, I have no idea how much API is in Novo Nordisk's treatment or what it costs. They very well could have a cost-of-API issue and I'm sure that is part of their consideration in moving forward with their treatment development. It was part of Novo's decision to go ahead with oral GLP-1, for which they recently invested $2B in manufacturing facilities in part to bring their oral GLP-1 production to sufficiently large scale. Regardless, Novo's treatment is clearly effective in its current formulation, so they don't have insulin up-dosing or carrier/delivery innovation issues like Oramed does for diabetes treatment.
Safety
While both treatments have been found safe in the clinical trial setting, there is a real-world risk that could doom both of these treatments. These medications are intended to be used in very large populations and will be exposed to a very wide variety of non-ideal treatment circumstances. The paracellular carrier mechanism presents a risk that toxic gut organisms or material cross the cellular barrier and enter the bloodstream even if proper treatment regimes are followed. So this risk is a concern. By the way, this is not a problem with the transcellular carrier mechanism.
Conclusion
It's clear that Novo Nordisk's oral insulin treatment has much higher efficacy than Oramed's treatment. What is unclear is the relative cost of each of these medications and whether or not their specific indications have a market large enough for them in their current forms. There are also health safety considerations that could arise with these two oral insulins.
The bottom line is that Novo has a working oral-insulin formulation for type-2 diabetes but we don't know the manufacturing cost issues. Oramed's oral insulin is only marginally effective but may be useful in treating pre-diabetes. It might be cost effective for this indication in its current form. Regardless, Oramed is far behind Novo in the practical bioavailability aspect of orally delivering treatment APIs for diabetics.
For investors, it's too early to tell if Novo's oral insulin program for diabetics will be a boon or bust, though early results look positive. Similarly, it's difficult to ascertain if Oramed will find success treating pre-diabetes. Furthermore, Oramed is likely to have the same bioavailability and health-risk problems with the other APIs they're pursuing, such as GLP-1, and so may become a one-trick pony here.
Also, who's to stop Novo from creating a cheap low-dose oral insulin product to compete on cost with Oramed. Novo appears to be well ahead in terms of bioavailability and so could use much less API in their treatments to come up with an Oramed equivalent with much lower manufacturing expenses. In my assessment, this reduces Oramed's chance of future commercial success.
Novo says they'll let us know their plans during the second half of the year. That will likely be the best near-term indication of the future for either of these treatments.
Disclosure: I am/we are long EMIS.
I wrote this article myself, and it expresses my own opinions. I am not receiving compensation for it (other than from Seeking Alpha). I have no business relationship with any company whose stock is mentioned in this article.
