In the history of medical science, the translation from breakthroughs in the laboratory to broadly successful clinical and therapeutic advancements is usually a bumpy road riddled with potholes and detour signs. The novel therapy just does not perform as well as one would have predicted based upon the initial understanding of the underlying biological mechanisms of the particular disease. There are numerous reasons why new therapies underperform, many of which are very complex. However, the common thread is simply the following observation - the complete understanding of the underlying biological principles for any particular disease is very difficult to achieve and often takes multiple revisions of the "disease paradigm hypothesis" over several decades before the science can translate into successful therapy.
However, there are exceptions to this divide between science and therapy. Sometimes the initial hypothesis explaining a particular disease is so elegantly sound that the therapy developed to facilitate the principles of the hypothesis result in overwhelming and immediate clinical success. These types of breakthroughs are both rare in terms of the frequency they occur and revolutionary in terms of their unprecedented impact on global health. The low-density lipoprotein (LDL) Receptor Paradigm and its hypothesized role in cholesterol metabolism/homeostasis represents one of the crowning scientific achievements of the late 20th century and quickly translated into one of the most successful therapeutic drug classes in history - HMG-CoA reductase inhibitors (statins).
However, recent laboratory and clinical evidence suggest that perhaps the LDL Receptor Paradigm is incomplete. Perhaps a new paradigm addressing different aspects of the underlying biology previously not understood might lead to improved outcomes in high-risk patients. This article briefly discusses the LDL Receptor Paradigm, its deficiencies in terms of the clinical evidence that is unsupportive, the growing body of clinical evidence in support of the new apoliprotein B (apoB) Paradigm, and the clinical trial success of novel investigational therapies that facilitate the principles of the apoB Paradigm.
What makes this story even more intriguing for investors is the fact that two small-cap biotechnology companies with vastly different products types seeking similar indications will each undergo review by the Food and Drug Administration's (FDA) Endocrinologic and Metabolic Drugs Advisory Committee (EMDAC) this October. Each product's mode of action facilitates the principles of the newly developed apoB Paradigm. Aegerion Pharmaceuticals (NASDAQ: AEGR) is developing lomitapide, a microsomal triglyceride transfer protein inhibitor (MTP-I), to reduce LDL in patients with homozygous familial hypercholesterolemia (HoFH). The new drug application (NDA) for lomitapide will be reviewed by EMDAC on October 17, 2012. Isis Pharmaceuticals (NASDAQ: ISIS) is developing mipomersen, a second-generation antisense oligonucleotide complementary to the coding region for human-specific apoB-100 messenger RNA (mRNA). The NDA for mipomersen (submitted by Genzyme Corporation who entered into a strategic alliance with Isis in 2008 and then subsequently acquired by Sanofi [NYSE: SNY]) will be reviewed by EMDAC on October 18, 2012. The Prescription Drug User Fee Date (PDUFA) action date is approximately December 28, 2012 for lomitapide and January 29, 2013 for mipomersen.
The LDL Receptor Paradigm and Cholesterol Homeostasis
In 1972, Dr. Joseph Goldstein and Dr. Michael Brown at the University of Texas Southwestern Medical Center embarked on a scientific journey to understand the genetic disease called familial hypercholesterolemia (NASDAQ:FH). At the time, it was unknown exactly what the FH genetic defect was. FH is characterized by extremely high cholesterol concentrations with very early onset of cardiovascular disease (CVD). Based upon the current understanding of other metabolic genetic defects related to enzyme deficiencies, a general hypothesis was developed that a 50% deficiency of an enzyme, as in heterozygotes for enzyme deficiencies, would not be sufficient to cause disease. In FH, the heterozygous state (HeFH) did produce disease which led Goldstein and Brown to hypothesize that the FH defect was not enzyme-related but rather a defect in regulation.
Earlier studies in rat livers had shown that HMG-CoA reductase catalyzes a rate-limiting step in cholesterol production, and its activity is reduced when rats ingest cholesterol.1 In a microassay for HMG-CoA reductase, Goldstein and Brown were able to definitively show that when cholesterol was removed from the culture medium, the activity of HMG-CoA reductase rose dramatically. Likewise, when cholesterol was added, HMG-CoA reductase activity was suppressed. When they tested separate lipoproteins separately, high-density lipoprotein (HDL) did not affect HMG-CoA reductase activity. Only LDL had an effect on HMG-CoA reductase activity. After definitively proving that the FH defect could not be related to HMG-CoA reductase in a separate experiment,2 they then developed a working hypothesis that the defect may be related to a possible LDL receptor. In 1974, an experiment3 testing radiolabeled LDL with iodine showed that LDL had high affinity binding sites for normal cells and none for HoFH cells. The evidence was now there to conclude that the genetic defect in FH was LDL receptor-related.
Over the next several years, the sequential steps in the LDL receptor pathway were elucidated.4
- LDL binds to LDL receptors
- LDL is internalized and transported to the lysosome
- LDL is hydrolyzed by the lysosome releasing LDL-derived cholesterol
- LDL-derived cholesterol interacts with sterol regulatory element-binding proteins (SREBPs) decreasing SREBP processing at the Golgi complex
- Decreased SREBP processing reduces the active fragment concentration necessary for HMG-CoA reductase translation thereby reducing HMG-CoA reductase activity
- By inhibiting the SREBP pathway, LDL-derived cholesterol also suppresses transcription of the LDL receptor gene thereby reducing the number of LDL receptors
- LDL-derived cholesterol also activates cholesterol acyltransferase (ACAT) which converts excess cholesterol into cholesteryl ester droplets in the cytoplasm
When LDL concentrations are high in the blood stream, LDL binds to LDL receptors and enters the cell where its cholesterol is released. This cholesterol inhibits the SREBP pathway and reduces HMG-CoA reductase activity and LDL receptor transcription. Cholesterol synthesis decreases and the necessary receptors for LDL internalization are decreased. As the cellular LDL concentration decreases, the SREBP pathway is no longer inhibited and HMG-CoA reductase activity increases and more LDL receptors are produced to increase the influx of LDL from the bloodstream. The control of the LDL receptor allows cells to obtain sufficient cholesterol for metabolic needs without producing cholesterol over accumulation. This concept is known as cholesterol homeostasis and is the hallmark of the LDL Receptor Paradigm. Cells keep the level of unesterified cholesterol in membranes remarkably constant despite wide fluctuations in cholesterol requirements and exogenous supply.
For their work, Goldstein and Brown were awarded the Nobel Prize in Physiology or Medicine in 1985. That same year atorvastatin (Lipitor) was first synthesized. When a statin is ingested, it binds and inhibits HMG-CoA reductase, lowering cholesterol production. The SREBP pathway is then uninhibited which increases the number of LDL receptors. Because statins inhibit HMG-CoA reductase, the feedback loop necessary to decrease the number LDL receptors is interrupted. As a result, a constant influx of LDL from the bloodstream is internalized and processed by the liver. This dramatic reduction in LDL concentration in the bloodstream facilitates the amazing therapeutic benefit from statins.5
Deficiencies of the LDL Receptor Paradigm
Despite the tremendous clinical benefit achieved through statins and the understanding of the LDL Receptor Paradigm, there are deficiencies. In HoFH, one might expect that the clearance of LDL from the bloodstream is significantly reduced because of the lack of LDL receptors. However, studies6 have shown that LDL is actually removed at a rate that is 3x that observed in normal patients. How can this be? There are two pathway for LDL clearance - receptor-mediated and non-specific pathways. In HoFH, this high rate of LDL clearance is accomplished completely by these non-specific pathways. If such a drastic influx of LDL is entering the hepatic cells in HoFH, why does cholesterol synthesis continue? Shouldn't this LDL expand the regulatory pool and trigger down-regulation of cholesterol synthesis as described above?
Finally, statin use in HoFH is much less effective leading to a mean LDL reduction of only 10-15%.7 In these HoFH patients receiving statin therapy, why is the overall LDL reduction diminished compared to the general population, especially when it is known that initial LDL clearance into the hepatic cell occurs at rate 3x that observed in normal patients? When analyzing blood stream LDL concentration as a system, when one increases the clearance (outflow) as is the case in HoFH, but the net LDL concentration remains constant or increases, the logical explanation is that a mechanism must be utilized in order to increase uptake (inflow) back into the blood stream. In HoFH patients taking statins where HMG-CoA reductase is inhibited, there must be another mechanism that accounts for this increased blood LDL concentration. Otherwise, there is no logical way for cholesterol homeostasis to be maintained.
The apoB Paradigm and Cholesterol Disequilibrium
In light of the above empirical evidence, scientists hypothesized that an in order for intracellular cholesterol homeostasis to be maintained in HoFH, a secondary pathway that shunts cellular cholesterol away from the regulatory pool and exports LDL back into the blood stream must exist. Otherwise, over accumulation of cholesterol would occur. The apoB Paradigm8 hypothesizes that LDL enters the hepatic cell primarily through LDL receptors. When that pathway is saturated, non-specific pathways for LDL clearance are increasingly utilized. In HoFH, only the latter pathways exist.
The apoB Paradigm describes separate processing of LDL-derived cholesterol depending on which pathway is utilized. For the LDL-receptor mediated pathway, the majority of LDL-derived cholesterol enters the regulatory pathway and thus follows the LDL Receptor Paradigm. However, LDL-derived cholesterol that enters via non-specific pathways is likely shunted directly to the ACAT where the majority of the LDL is esterified before it enters into the LDL-receptor/cholesterol synthesis pathway. It is also believed that some of the LDL-derived cholesterol from the LDL-receptor mediated pathway is also shunted directly to the ACAT, just to a lesser degree.
This esterified cholesterol and other triglycerides then interact with microsomal triglyceride transfer protein (MTP) where they are loaded onto apoB. Apoliproteins are an essential structural and receptor-binding component of all lipoproteins. For LDL, the apoliprotein is apoB. The resulting complex is secreted back into the blood stream as very low-density lipoprotein (VLDL), the precursor to LDL.
The apoB Paradigm claims that the rate of LDL clearance is important (the LDL Receptor Paradigm), but more critical is the rate which LDL is shunted, recycled, and then secreted. The LDL Receptor Paradigm demands tight regulation of cholesterol synthesis and preserves the equilibrium of the mass of cholesterol, whereas the apoB Paradigm allows for disequilibrium and expansion of the mass of cholesterol which is much more consistent with the pathophysiology. Therapies that reduce apoB or apoB-LDL interaction are possible therapies that would facilitate the principles of the apoB Paradigm.
Aegerion Pharmaceuticals - Lomitapide
Lomitapide is a MTP-I that prevents sufficient lipid transfer to apoB.9 When insufficient lipid is transferred, the apoB complex is degraded. In doing so, it is hypothesized that VLDL secretion will be inhibited and thus the amount of LDL in the bloodstream will be reduced. Lomitapide is also active in the intestines where it interacts with dietary cholesterol and prevents the formation of a different type of apoB-LDL complex that is secreted into the blood stream as a chylomicron.
Aegerion conducted one phase III trial in 29 patients with HoFH (NCT00730236). The design was a single-arm, open labeled dose escalation study where the dose was titrated up to 60 mg or the maximal tolerated dose. The primary efficacy endpoint was the percent change in LDL from baseline at week 26. Patients were then continued at the maximal tolerated dose for safety until week 78. Enrollment began in December 2007 and the final patient reached the 26 week time period in September 2010.
Aegerion has disclosed several snapshots of the data at different point along the study timeline. At the American Heart Association (AHA) annual meeting in 2009, an interim analysis of the results was presented. For this analysis, 14 patients had reached their 26 week and 7 had reached their 56 week. At the European Atherosclerosis Society (EAS) meeting in 2010, an additional analysis was presented where 11 patients had reached their 56 week. In May 2011, Aegerion issued a press release highlighting the top-line results for the full 56 week dataset which were also presented at EAS 2012. In January 2012, Aegerion issued a press release highlighting the final top-line results for the entire 78 week study. In March 2012, Aegerion submitted a NDA to FDA and a Marketing Authorization Application (MAA) to the European Medicines Agency (EMA) based upon the 56 week dataset. In April 2012, Aegerion announced that FDA accepted the NDA and classified the submission as a standard review with a 10-month PDUFA timetable.
A summary of the lomitapide intent-to-treat (ITT) analyses are reconstructed in the following table from the data sources provided above.
Isis Pharmaceuticals - Mipomersen
Mipomersen is an apoB protein synthesis inhibitor. Specifically, it is an antisense oligonucleotide complementary to the coding region for apoB-100 mRNA. Mipomersen has been evaluated in four randomized, double-blind, placebo-controlled, multi-center phase III studies and one phase III open label extension study. The four randomized trials were similar in design and evaluated the percent change in LDL from baseline at week 26. Patients were then followed for safety for 24 weeks or had the option to enter into the open label extension study for up to 2 years.
In July 2011, Isis issued a press release stating that a MAA was submitted to the EMA for treatment of HoFH and severe HeFH. In March 2012, Isis issued a press release stating that a NDA was submitted to FDA for the treatment of HoFH. FDA accepted the NDA and classified the submission as a standard review with a 10-month PDUFA timetable.
A summary of the efficacy results10 for the four randomized trials and the patient populations being evaluated are provided below.
In the phase III HoFH study publication,11 an adverse event table describes the incidence of transaminase (ALT) elevations.
Results from phase III open label extension study were presented at the 2012 International Symposium on Atherosclerosis (ISA) and at EAS 2012. An important efficacy slide is presented below.
An important safety slide is presented below.
Lomitapide vs. Mipomersen - Clinical & Regulatory Perspective
The clinical evidence in support of mipomersen is extremely robust. Isis has data from four randomized, controlled phase III studies and long-term follow up safety data approaching 2 years. It is important to clarify that only one is in HoFH. Lomitapide is only supported by one single-arm, open label phase III study. However, given the rarity of HoFH worldwide, it is not appropriate to simply focus on the lack of data available for lomitapide. Isis has the resources to perform an extensive clinical program while Aegerion does not. I am merely trying to commend Isis for the huge amount of data they have collected and their high-caliber clinical program rather than knocking Aegerion for not having the same.
In terms of efficacy data, I believe both lomitapide and mipomersen are highly effective at lowering LDL and are important breakthroughs in advancing the science for lipid management. Their support of the apoB Paradigm is groundbreaking. However, there are data available that lead me to conclude that mipomersen is more efficacious than lomitapide. Mipomersen has demonstrated the ability to significantly reduce the four major atherogenic lipoproteins - LDL, non-HDL, apoB, and lipoprotein(a). Lomitapide has consistently reported reductions in LDL, but the data regarding non-HDL, apoB, and lipoprotein(a) are either incomplete or not reported. At the interim analysis, significant reductions in non-HDL and apoB were reported, but I am unable to confirm these results in later disclosures. Also, there is no data disclosed that lomitapide lowers lipoprotein(a). This is potentially a huge advantage for mipomersen over lomitapide since lipoprotein(a) is an independent predictor of CVD.12 Lastly, mipomersen has shown to significantly increase HDL levels (the "good" cholesterol) while lomitapide significantly lowered HDL at the interim analysis. Later disclosures of HDL were incomplete. The effect of mipomersen on HDL is potentially another advantage over lomitapide.
In terms of safety data, I believe both lomitapide and mipomersen are safe for their intended use and have a favorable benefit/risk profile. However, there are safety issues that need to be discussed. Both lomitapide and mipomersen initially increase hepatic fat as a result of diminished secretion back into the blood stream. If you think about the apoB Paradigm, if you disrupt the pathway for secreting cholesterol back into the blood stream, it is logical that these accumulations would occur in the liver. These hepatic fat levels do decrease over time as the liver adapts to these new therapies. However, I believe the mipomersen hepatic fat data are better than lomitapide because the decrease observed in mipomersen approaches baseline while lomitapide remains elevated.
Mipomersen and lomitapide increase ALT levels which are used as a diagnostic for liver damage. The majority occur early in treatment and decrease over time similar to the hepatic fat data. However, I believe the mipomersen ALT data are better than lomitapide. When comparing the HoFH study data, 20.7% of patients taking lomitapide experience ALT elevations 3x ULN vs. 12% of patients taking mipomersen. During long-term follow-up, Aegerion has claimed that no patients experienced ALT elevations 5x ULN whereas Isis has presented robust data showing the majority of ALT elevations are below 3x ULN. The latter is a stronger statement in my opinion.
Safety issues specific to lomitapide include a high incidence of gastrointestinal (NYSE:GI) adverse events. Safety issues specific to mipomersen include a high incidence of injection-site reaction adverse events. GI events directly led to patient withdrawal in the lomitapide HoFH study whereas injection-site reaction events did not lead to patient withdrawal for mipomersen.
In terms of regulatory positioning, mipomersen is better positioned than lomitapide. Isis is seeking approval in Europe for both HoFH and severe HeFH. Aegerion is only seeking an indication in HoFH. In Europe, mipomersen has an orphan drug designation while lomitapide does not. In the United States, both mipomersen and lomitapide have orphan drug designation.
Lomitapide vs. Mipomersen - Investor Perspective
Please note that my expertise is with clinical analyses and not financial analyses. With that said, I do believe both Aegerion and Isis represent great investment opportunities. However, I believe the opportunities are quite different in terms of risk/reward as well as short/long-term value. Regarding mipomersen, I believe the strong clinical data support a high probability of EMA approval, a favorable EMDAC meeting, and subsequent FDA approval. For investors, it is important to point out that Isis share price has gone up nearly 90% year-to-date (YTD) and currently has an enterprise value (EV) of $1.2 billion. I know Isis has a diverse drug pipeline and truly disruptive technology if successful, but this is a high EV given the financial details of their 10-K and lack of current revenue generators. I think the market has most likely price-in favorable outcomes in Europe and the United States which is reflected in the current share price and valuation. Therefore in the short-term, positive regulatory news would send the share price higher, but perhaps not substantially. On the other hand, any negative regulatory news or delays would add significant pressure to the share price. I see this, however, as a low-probability event.
Regarding lomitapide, I believe the clinical data is not as strong as mipomersen. I think there is risk for investors going into the EMDAC meeting and the potential for a very close vote. Aegerion share price is down nearly 20% YTD and currently has an EV of $260 million which is low. For investors with a high-risk tolerance, I believe a favorable EMDAC meeting would cause a substantial rise in share price and bring in partnership discussions. However, Aegerion has no other drugs in their pipeline. If the EMDAC meeting is unfavorable, the effect will be disastrous.
Regarding long-term value and product adoption, I believe mipomersen has a more favorable view from the scientific community. EAS 2012 was the first major opportunity for lomitapide and mipomersen to go head to head. In my opinion, the positive response to mipomersen was substantial while lomitapide was met with some caution. There were full educational symposiums dedicated to mipomersen and the future of antisense technology in lipid management. At one of the plenary sessions, Dr. Gerald Watts had some cautious comments about lomitapide and the HoFH trial design. Dr. Watts is one of the founders of the apoB Paradigm.
Lastly, it is important to understand the different patient populations. HoFH affects approximately 1:1,000,0000. This is the indication being sought in the United States for both lomitapide and mipomersen. This is not "blockbuster" by any means. However in Europe, the indication being sought for mipomersen includes HeFH which affects approximately 1:500.13 Lomitapide is not seeking this indication. Isis is currently conducting the FOCUS Trial to expand the indication in the United States into HeFH. No such trial is being pursued by Aegerion. Finally, mipomersen has shown positive phase II clinical results in patients without FH who are not high-risk but are non-responders to statin therapy.14 Isis has laid the groundwork for growing the mipomersen franchise into larger patient populations. The same cannot be said for Aegerion with lomitapide at this time. For the long-term investor, Isis and mipomersen are better positioned in my opinion than Aegerion and lomitapide.
Disclosure: I have no positions in any stocks mentioned, and no plans to initiate any positions within the next 72 hours. 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.