Stealth Biotherapeutics: Flying Under The Radar
Contributor Since 2016
Summary
- Stealth is a misunderstood developmental biotech company on the verge of a major inflection point.
- In January, topline data from the Stealth's pivotal phase 3 trial in Primary Mitochondrial Myopathy (PMM).
- Recent OLE data in Barth Syndrome supports the upcoming pivotal trial as does Alexion's recent investment of $30million.
- Upon success, Stealth is well positioned to capitalize on the rest of its pipeline as well as its preclinical compound SBT-272.
Introduction
“It’s not a good drug unless it’s failed three times.” ~ Sir James Black, Winner of The 1988 Nobel Prize for Medicine
Stealth Biotherapeutics is a small cap biotech company developing therapies to treat mitochondrial dysfunction associated with genetic mitochondrial diseases and common diseases of aging. Stealth’s lead investigational product candidate, elamipretide, is a peptide compound that readily penetrates cell membranes, and targets the inner mitochondrial membrane where it binds reversibly to cardiolipin (CL).
This elamipretide-CL association has been shown to normalize the structure of the inner mitochondrial membrane, thereby improving mitochondrial function. Functional benefit is achieved through improvement of ATP production and interruption and potential reversal of damaging oxidative stress. In both preclinical and clinical studies elamipretide increased mitochondrial respiration, improved the electron transport chain function and ATP production and reduced formation of pathogenic ROS levels.
Stealth is investigating elamipretide in late stage clinical studies in three primary mitochondrial diseases—primary mitochondrial myopathy (PMM), Barth syndrome and Leber’s hereditary optic neuropathy – as well as an earlier stage clinical study in dry age-related macular degeneration.
Figure 1: source - Stealth Biotherapeutics Investor Presentation
Despite boasting an incredible pipeline of advanced clinical studies and an abundance of data supporting Elamipretide’s MoA, Stealth remains very much under the radar, sporting a market cap of less than $250mm. We believe there exists a wide gap in the market’s understanding of these disease and elamipretide itself. To be fair, that’s not entirely the markets fault. Mistakes have been made. This undervaluation we believe is due to a number of factors:
- Novel therapy: Elamipretide is perhaps the only therapy in clinical trials that specifically targets a critical lipid in the mitochondria. Furthermore, mitochondria and their role in disease remains poorly understood.
- Difficult Disease Targets: There are no approved treatments for any of the diseases in Stealth’s pipeline.
- Poor clinical results: The clinical data generated in these pursuits has also fallen short of what investors would hope. Stealth has been forced to drop early stage trials in a number of heart related disorders. Even Elamipretide has struggled in early stage clinical trials to hit primary endpoints, including in PMM which is currently in phase 3.
- Poor read through from Barth Syndrome: Conventional wisdom would suggest that a treatment such as elamipretide that targets CL would have a large impact on a CL disorder like Barth, but initially this was not seen to be the case. Only in the last few weeks has Open Label Extension (OLE) data in Barth patients been shown to be highly impactful.
And yet despite these setbacks, we believe and will go on to show that these are but minor hiccups on the road to success. And it appears we’re not alone. With a rock bottom payment of just $30mm USD, Alexion recently acquired the option to Co-Develop and Commercialize Elamipretide for Mitochondrial diseases. With topline data in the Stealth’s pivotal phase 3 trial in PMM just weeks away we believe that Stealth’s days of being undervalued are numbered.
In order to understand why we think so highly of Stealth and its lead compound, Elamipretide, we must start with the basics. In this case, the mitochondria. As we will show, these organelles are critical to the functioning of the human body and when it comes to therapeutic targets have been over looked for far too long.
Mitochondria and the role of Cardiolipin
“Form ever follows function” ~ Louis Sullivan
While it is an oversimplification to call the mitochondria, found in almost all human cells, the “powerhouse of the cell”, it will suffice for the purposes of our report. Mitochondria produce approximately our body weight in ATP daily, providing the energy that allows cardiac muscles, for example, to beat an estimated 100,000 times every 24 hours, or 2.5 billion times by age 70, without stopping. Our skeletal muscle, heart, kidney, eyes and brains are among the highest producers and users of mitochondrial ATP in our bodies, as ATP is required for their critical functions such as the contraction of skeletal, cardiac, vasculature and lung muscle, maintenance of cell membrane potential, cellular transport and secretion of hormones and neurotransmitters. Normal mitochondrial function is essential for human life and for the proper functioning of every system in our bodies.
Mitochondria are highly specialized structures. They have their own DNA, called mitochondrial DNA (mtDNA), which is inherited only from our mothers and is separate and distinct from nuclear DNA (nDNA). Mitochondria are located within the cell, which is protected by the cell membrane, and they also have their own inner and outer membrane, which create further barriers to the effective delivery of therapeutics to these specialized organelles.
In normal healthy mitochondria, the inner mitochondrial membrane, or IMM, is highly folded, creating curves, called cristae. The cristae house the electron transport chain, or ETC, which is composed of five protein complexes responsible for mitochondrial ATP production through a process known as oxidative phosphorylation. The curved architecture of the cristae in the IMM is essential to keep the electron transport chain complexes in optimal close configuration for normal oxidative phosphorylation. An illustration of a healthy mitochondria and its curved cristae structure is shown below.
Figure 2: source – Socratic.Org
Phospholipids are the main building blocks of mitochondrial membranes. CL is a unique phospholipid which is localized and synthesized in the inner mitochondrial membrane (IMM), where it constitutes approximately 15–20% of the total mitochondrial phospholipids. CL is unusual among all phospholipid species in that it exhibits a dimeric structure with four acyl chains and two phosphatidyl moieties that are linked to the glycerol. This unique structure of CL yields a conical shape that is the origin of its curvature sensing abilities. As such, this phospholipid is essential for healthy mitochondrial cristae morphology and stability.
Figure 3: source - First-in-class cardiolipin-protective compound as a therapeutic agent to restore mitochondrial bioenergetics
In biology, a key idea is that structure determines function. In other words, the way something is arranged enables it to play its role, fulfill its job, within an organism. CL, as a regulator of mitochondrial morphology (structure) plays an essential role in determining all aspects of mitochondrial function. CL has been found to be required for optimal activity of several IMM proteins, including the enzyme complexes of the electron transport chain (ETC) and ATP production and for their organization into super complexes.
ETC complexes in the IMM are organized in higher order structures, referred generically as super complexes, rather than existing as individual complexes. This super complex organization of the ETC provides structural/functional linkages between the respiratory complexes resulting in a more efficient electron transfer, thereby preventing excessive ROS generation. CL is specifically required for association, stabilization and functioning of individual complexes into super complexes.
Figure 4: source - First-in-class cardiolipin-protective compound as a therapeutic agent to restore mitochondrial bioenergetics
Alterations in the phospholipid composition can affect the mitochondrial membrane integrity, permeability and fluidity, and hence the stability and activity of many IMM-associated proteins, including those involved in ETC and OXPHOS processes, with important implications in a variety of human diseases.
Figure 5: source – Elamipretide Effects in Adults with Primary Mitochondrial Myopathy: Phase 2 Double-Blind, Randomized, Placebo-Controlled Crossover Trial (MMPOWER-2)
Moreover, CL is involved in mitochondrial quality control and dynamics through fission and fusion, in mitochondrial biogenesis and protein import, in mitophagy, as well as in several mitochondrial steps of the apoptotic process, serving as a binding platform to recruit apoptotic factors.
Figure 6: source -Mitochondrial bioenergetics decay in aging: beneficial effect of melatonin
CL’s benefits for mitochondria extend beyond any individual mitochondrion. Proper mitochondrial morphology is also essential for mitochondrial network connectivity. Mitochondria exist in cells as connected networks. Cellular mitochondrial networks allow for sharing of metabolites and proteins as well as mitochondrial DNA. Coupled mitochondria also provide a rapid conductive path for the distribution of potential energy throughout the cell. This allows the cell to organize a united intracellular power-transmitting system. Moreover, mitochondrial networks exist not just in cells but between cells as well.
Figure 7: source - Long range physical cell-to-cell signalling via mitochondria inside membrane nanotubes: a hypothesis
This extensive connectivity enables mitochondria not just in individual cells to coordinate their activity for optimal performance but also enables entire tissues to be highly coordinated. This connectivity has been shown to be essential for proper functioning of muscle and heart tissue:
“Here we demonstrate a mitochondrial reticulum providing a conductive pathway for energy distribution, in the form of the proton-motive force, throughout the mouse skeletal muscle cell”
Energy requirements in skeletal muscle and heart muscle can nearly instantaneously increase by more than 100-fold during intense contraction. Thus, using electrical conduction as opposed to oxygen or ATP diffusion is a more effective way to quickly and uniformly distribute energy throughout these cells. The same is likely true in all other tissues of the body, though perhaps not to the same extent.
CL, as a crucial determinant of mitochondrial morphology, likely plays an important role in maintaining the dynamics of these networks. Unfortunately, due to CL’s high content of unsaturated fatty acids and its location in the IMM near to ETC complexes, the main sites of reactive oxygen species (ROS) production, CL is particularly prone to peroxidation.
When CL is degraded, it can lose its conical shape, compromising the structural integrity of the IMM by leading to a relaxation of the cristae and a drifting apart of the electron transport chain complexes. Shuttling of electrons through the electron transport chain becomes less efficient with the complexes further apart from one another, resulting in lower ATP production and higher ROS generation. Disruption of mitochondrial morphology also impairs fission and fusion, impacting signaling pathways including mitophagy. This can trigger the cellular and extra-cellular cascades (shown below) involving inflammation, fibrosis and cell death that underlie many diseases.
Figure 8: source - Pharmacologic Approaches to Improve Mitochondrial Function in AKI and CKD
The images below show healthy mitochondria, on the left, with normal CL content and cristae structure, and unhealthy mitochondria, on the right, with reduced CL content and collapsed cristae.
Figure 9: source - Stealth Biotherapeutics Investor Presentation
Various diseases alter CL composition and reduce CL content within the mitochondria. Biopsies from patients with primary mitochondrial disease (PMM) arising from mitochondrial encephalitis, lactic acidosis and stroke-like episodes, or MELAS, and multiple mitochondrial DNA deletions were found to have approximately 15% less normal CL composition than normal. Experiments in Barth patient-derived lymphoblastoid cell lines showed 50%-60% less CL than control cell lines, and work done in Barth patient-derived cardiomyocytes showed up to 75% less CL than control cardiomyocytes.
Aging has also been shown to decrease CL content in high energy-demanding organs, such as the heart, brain, liver and kidney, as well as the epidermis. Studies suggest that oxidative stress and peroxidation of CL may contribute to the overall loss of CL content in these diseases which can create a vicious cycle in which loss of CL leads to further increases in oxidation stress and peroxidation of CL.
Figure 10: source – Mitochondrial biogenetics decay in aging
“It has been shown that the rate of production of superoxide anions and hydrogen peroxide in mitochondria increases with age. Moreover, the intracellular levels of antioxidants and activities of free radical-scavenging enzymes are significantly altered in the aging process. These two compounding factors lead to an age-dependent increase in . . . free radicals that may escape the various antioxidant defense mechanisms and cause ever-increasing oxidative damage to various biomolecules in mitochondria and the cell as a whole . . . we suggest that this vicious cycle plays an important role in human aging and in the pathogenesis of age-related degenerative diseases.”
Accordingly, CL peroxidation has been found to be a common final disease pathway. From the above, it should be obvious that CL is very important and that it represents an interesting, and novel, target for therapeutic intervention in disease.
Enter Stealth Biotherapeutics
Stealth Biotherapeutics product candidates target and bind to CL, stabilizing it under conditions of oxidative stress, thereby preserving the curved architecture of the IMM. Stealth Biotherapeutics’ platform is based on SS (Szeto-Schiller) peptides which are water-soluble synthetic tetra peptides. The structural motif of these SS peptides centers on alternating aromatic residues and basic amino acids (aromatic-cationic peptides).
Figure 11: source - Stealth Biotherapeutics Investor Presentation
These small peptides contain an amino acid sequence that allows them to freely penetrate cells despite carrying a 3+ net charge at physiologic pH. It is thought that the aromatic rings serve as electron cages to shield the cationic charges via cation-π interaction. These SS peptides may be viewed as “cloaked” or “stealth” as they can evade cellular membranes, even penetrating cell barriers with tight junctions including the blood brain barrier.
Once inside cells, these aromatic-cationic peptides selectively target and localize to the IMM (these peptides concentrate >1000-fold in the inner mitochondrial membrane), in an energy-independent non-saturable manner, where they interact selectively with CL on the IMM via electrostatic interactions.
Figure 12: source - Mitochondria-Targeted Antioxidants and Skeletal Muscle Function
These compounds have been shown to have a remarkable effect in pre-clinical models (shown below):
Figure 13: source - Stealth Biotherapeutics Investor Presentation
Notably, SS peptides are the first compounds known to target specific membrane phospholipids rather than protein molecules. Upon binding to CL, they exhibit further interesting properties. The first of which is their antioxidant properties. These SS peptides can scavenge hydrogen peroxide and peroxynitrite which further inhibits lipid peroxidation. In this manner, SS peptides can act to protect CL from oxidation. It has been stated that,
“the short Szeto-Schiller (SS) peptides developed by Szeto and Schiller are the most promising mitochondria-targeted antioxidants.”
“Many publications showed and confirmed that SS peptides are the most promising tool applicable in the treatment of all diseases and impairments associated with oxidative injury such as neurodegenerative diseases.”
In addition to this ROS scavenging capacity the binding of SS-31 (Elamipretide, Stealth’s lead clinical candidate) to CL alters the interaction of CL with cytochrome c, and favors its electron carrier function while inhibiting peroxidase activity. By promoting cytochrome c reduction, SS-31 increases electron flux in mitochondria and accelerates ATP production. At the same time, SS-31 inhibits ROS generation and inhibits cytochrome c peroxidase activity, thereby preventing CL peroxidation and loss of cristae membranes. These peptides have demonstrated effectiveness in:
“remarkably diverse animal disease models, in famine or feast, support the hypothesis that these peptides act by promoting mitochondrial plasticity. With insufficient substrates and/or O2 during famine, these peptides can increase mitochondrial respiration and ATP production, and prolong survival. With excess substrates during feast, they can promote OXPHOS coupling, reduce electron leak, and prevent ROS production”
Thus, “SS-31 is a multifunctional mitoprotective compound that acts by promoting bioenergetics, reducing ROS production, scavenging excess ROS, inhibiting CL peroxidation, and preserving mitochondrial structure.”
Furthermore, SS-31 has been shown not just to protect the CL already existing in the IMM but also to upregulate the enzymes required for CL biosynthesis and remodeling. In this manner, it acts to strongly restore CL levels and quality to a healthy, youthful state.
SS-31 has also been shown to be involved in the modulation of mitochondrial quality control and mitophagy. SS-31 restores mitochondrial biogenesis and restores mitochondrial dynamics (increases mitofusion and mitophagy).
All the above has shown to have far-reaching downstream effects. For example, SS-31 has been shown to prevent cell death and inflammation, to repair cellular structure and function during aging, and to boost the body’s natural ability to heal itself.
“These compounds increase healthspan and minimize age-associated chronic diseases. 80% of adults over 65 years old have at least one chronic condition, while 68% have 2 or more chronic conditions. A wealth of preclinical studies supports the ability of these compounds to ameliorate diverse chronic conditions”.
In fact, SS-31 has also been shown to be beneficial in many models of age-associated diseases, including PD, AD, skeletal muscle aging, disuse skeletal muscle atrophy, insulin resistance, and diabetic complications.
In old vs. young mice:
Figure 14: source - Mitochondrial targeted peptide rapidly improves mitochondrial energetics and skeletal muscle performance in aged mice
In a double-blind placebo-controlled study (n=40) with healthy elderly patients:
Figure 15: source - Clinical Development of Elamipretide for Rare and Common Mitochondrial Diseases
“The numerous studies demonstrating the effectiveness of these peptides in remarkably diverse animal disease models, and in famine or feast, support the hypothesis that these peptides act by promoting mitochondrial plasticity. With insufficient substrates and/or O2 during famine, these peptides can increase mitochondrial respiration and ATP production, and prolong survival. With excess substrates during feast, they can promote OXPHOS coupling, reduce electron leak, and prevent ROS production. By selectively targeting the IMM—and by promoting mitochondrial plasticity rather than activating/inhibiting a specific target—these peptides have no effect on normal healthy mitochondria and have great safety profiles. Long-term treatment for 8 weeks revealed no safety issues in pigs, and no adverse effects were reported after 8 months of daily treatment in mice.”
In addition to the very promising preclinical results SS-31 has excellent “drug-like” properties and a promising safety profile. They are small and easy to synthesize, readily soluble in water, and resistant to peptidase degradation. As well, both the parent drug and its metabolites are excreted entirely by the kidneys within 48 hours. The pharmacokinetic results from humans have revealed an elimination half-life of ∼4 hours and a very small apparent volume of distribution - the volume of distribution (VD, also known as apparent volume of distribution) is the theoretical volume that would be necessary to contain the total amount of an administered drug at the same concentration that it is observed in the blood plasma.
“SS-31 represents the first of a class of new chemical entities that selectively target mitochondrial CL to improve mitochondrial plasticity and restore optimal bioenergetics. These compounds provide an entirely novel approach to the treatment of complex diseases that at first glance appear to be totally unrelated. Common to all of them, however, is the loss of cellular energy that accounts for their failure to function properly, and these peptides act by recharging the powerhouse of all cells. Importantly, they have no effect on normal mitochondria, which accounts for their excellent safety profile…”
“…By selectively targeting the IMM—and by promoting mitochondrial plasticity rather than activating/inhibiting a specific target—these peptides have no effect on normal healthy mitochondria and have great safety profiles. Long-term treatment for 8 weeks revealed no safety issues in pigs, and no adverse effects were reported after 8 months of daily treatment in mice.”
We have thus established that SS peptides, in particular SS-31, are very impressive in preclinical settings and have laid out the scientific basis for their effectiveness. What about clinical effectiveness in human clinical trials? After all, it is very common for drugs that seem impressive in preclinical settings turn out to be disappointing when tested for effectiveness in humans. Does SS-31 hold up?
Elamipretide in Primary Mitochondrial Myopathy (
)
“Happy families are all alike; every unhappy family is unhappy in its own way.” ~ Leo Tolstoy
Primary mitochondrial myopathies (PMM) are a group of disorders that are associated with changes in genetic material (e.g. depletions, deletions, or mutations) found within the DNA of mitochondria (mtDNA) or with genes outside the mitochondria (nuclear DNA) leading to defects of oxidative phosphorylation, affecting predominantly, but not exclusively, the skeletal muscle.
PMM is characterized by debilitating skeletal muscle weakness, exercise intolerance and fatigue accompanied by a confirmed molecular genetic diagnosis of primary mitochondrial disease. Individuals with this disease may experience muscle pain, muscle wasting, muscle cramps, rhabdomyolysis, or breakdown of muscle, progressive external ophthalmoplegia characterized by drooping of the eyelids, which often impairs vision, abnormal tilting of the head due to shortening of the neck muscles, difficulty swallowing, low muscle tone (also known as floppy infant syndrome), respiratory insufficiency and reduced deep tendon reflexes.
These symptoms can result in significant deterioration of quality of life, such that routine activities of daily living (such as walking, climbing stairs, vacuuming, reaching, driving, reading or carrying out normal job functions) are limited by poor endurance and easy fatigue. Severely impacted individuals can lose their ability to walk entirely.
As stated previously, the morphology of mitochondria in individuals with PMM is abnormal, and, unlike mitochondria in normal skeletal muscle cells, as shown below on the left, can be characterized by inclusion of abnormal rectangular-shaped, crystal-like structures, hinting at a lack of cardiolipin as shown below.
Figure 16: source -Stealth Biotherapeutics Investor Presentation
It is estimated that as many as 40,000 individuals in the United States have PMM. There are no therapies approved by the FDA, EMA or NMPA for the treatment of PMM. Stealth Biotherapeutics have received Fast Track designation and Orphan Drug designation from the FDA for the development of elamipretide in this indication.
Stealth is assessing elamipretide in subjects with primary mitochondrial myopathy irrespective of their specific primary mitochondrial disease genotype. This strategy offers Stealth the potential to treat all individuals with genetic mitochondrial disease who experience myopathic symptoms, estimated at greater than 90% of the primary mitochondrial disease population, which is a much larger target market than any specific genetic mutation or syndrome within it. To us it seems the market is underestimating the potential for elamipretide to treat the vast majority of these patients.
Stealth’s strategy may seem odd to many given that PMM is not represented by a single mutation nor even multiple possible mutations in a single genome, but rather multiple possible mutations in two separate genomes. One might then ask, “how is a single therapy that doesn’t even affect the direct product of genes (proteins) supposed to be able to treat a disorder with such a diversity of genetic causes?” Perhaps even more confounding for the uninitiated, is that elamipretide does not target a protein but a lipid.
Whenever there is mitochondrial dysfunction, inevitability there has been a change in the shape of the mitochondria, which primarily occurs due to the peroxidation of cristae. Simply put, form follows function. As we have shown, mitochondria are an extraordinary example of this axiom: they are dynamic organelles that have crucial roles in many cellular processes, including apoptosis, metabolism, reactive oxygen species (ROS) detoxification, and ATP production through OXPHOS. Such a variety of functions is coupled to a highly defined but plastic structure that continuously changes according to the needs of the cell. Bioenergetics affects shape and shape affects bioenergetics. It is a two-way street.
Because the function of cardiolipin pertains to the regulation of form of mitochondria and form and function are inextricably linked such that form determines function and functionality feeds back to affect form, any alteration in functionality due to a mutation in a mitochondrial protein inevitably affects form, i.e., cardiolipin. To misquote Leo Tolstoy, “while every PMM patient may have a unique disorder, the ways their maladies manifest themselves are all the same.”
In other words, as a treatment of form, elamipretide can affect the bioenergetic dysfunction that results from any number of the mutations that characterizes PMM. As one article titled ‘Mitochondrial Cristae: Where Beauty Meets Functionality’ concluded,
“For these reasons, this association could be the target of therapies to prevent and/or cure metabolic syndrome and genetic diseases with a mitochondrial component… This novel approach of modulating shape to correct function represents an exciting tool in the development of therapeutics against mitochondrial dysfunction in genetic and sporadic diseases.” (our emphasis in bold)
Thus, no matter what specific genetic mutation that afflicts a particular PMM patient they can inevitably benefit from the cardiolipin protection and stabilization that elamipretide offers. Stealth is currently putting this proposition to the test with their ongoing phase 3 trial (MMPOWER-3), which is the follow up to two previously completed PMM clinical trials: MMPOWER, completed in April 2016, and MMPOWER-2, completed in March 2017. MMPOWER-3 is set to read out sometime in early Q1 2020, making it Stealth’s nearest catalyst.
Elamipretide in PMM Clinical Trials
MMPOWER was a Phase 1/2, multiple ascending dose, double-blind, placebo-controlled trial with 36 subjects between the ages of 16 and 65 with genetic confirmation of mitochondrial disease and a clinical diagnosis of primary mitochondrial myopathy.
Nine subjects received a low dose of elamipretide (0.01 mg/kg hour, for an average actual drug exposure of 1.4 mg), nine subjects received a mid-dose of elamipretide (0.10 mg/kg hour, for an average actual drug exposure of 12.7 mg), nine subjects received a high dose of elamipretide (0.25 mg/kg hour, for an average actual drug exposure of 29.6 mg) and nine subjects received a placebo dose once daily by two-hour IV infusion over a treatment period of five days. The high dose of elamipretide tested in MMPOWER is slightly lower than the 40mg subcutaneous dose tested in MMPOWER-2 and currently being tested in MMPOWER-3.
The objectives of the trial were to evaluate the safety, tolerability and efficacy of elamipretide in individuals with primary mitochondrial myopathy. Subjects completed efficacy assessments, including the 6MWT (the primary efficacy endpoint) at initial screening, at baseline (prior to receiving the first dose), on the fifth day (after the last dose), and on the seventh day (two days after the last dose).
“A dose-dependent increase in six-minute walk distance (p=0.0142 by linear trend test) after five days of treatment was observed. The data showed that subjects who received the high dose of elamipretide, which was the primary dose of interest, walked an average of 64.5 meters further after five days of treatment with elamipretide than they walked before receiving elamipretide. As adjusted for the 20.4-meter improvement observed in the placebo-treated group, this represents a 44.1-meter least-squares mean improvement relative to placebo (p=0.053). A post-hoc adjustment for gender and baseline distance walked, the factors most responsible for variability within the data, as published in Neurology in March 2018, demonstrated a 51.2-meter least-squares mean improvement relative to placebo (p=0.03), as depicted below.”
Figure 17: source - Stealth Biotherapeutics Investor Presentation
The data shows that Elamipretide acts immediately to improve mitochondrial function which has rapid ramifications for the patient’s well-being and functionality. Notably, the post-hoc analysis of the data revealed that subjects’ performance on the 6MWT at baseline was predictive of how much they may improve after elamipretide treatment (a treatment by baseline interaction, with an R-squared value of 0.42, meaning approximately 42% of the variability in the data as a whole is explained by the model).
Figure 18: source - Stealth Biotherapeutics Investor Presentation
This analysis demonstrated that the more impaired subjects, walking less than 450 meters at baseline, were more likely to improve with elamipretide, whereas less impaired subjects, walking more than 450 meters at baseline, had less potential for improvement. A healthy individual can typically walk between 500 and 600 meters on the 6MWT, which suggests that those walking over 450 meters at baseline are not substantially impaired and have relatively healthy mitochondria. This is in-keeping with the MoA of elamipretide as discussed previously (see Figures 15 & 16), which does not affect already healthy and stable mitochondria. After all, the main job of elamipretide is to stabilize CL. If the CL is already stabilized, elamipretide should have almost no effect.
MMPOWER-2 was a Phase 2, double-blind, placebo-controlled crossover trial to evaluate the safety and efficacy of once daily subcutaneous administration of elamipretide in subjects previously enrolled in MMPOWER. Thirty of the 36 MMPOWER subjects enrolled in MMPOWER-2, although one subject discontinued the trial in the second four-week treatment period due to injection site pain. Subjects were randomized in a one-to-one ratio to either 40 mg once daily subcutaneous elamipretide.
Figure 19: Source - Stealth Biotherapeutics Investor Presentation
Post-hoc sequence effect among subjects walking <450 meters at baseline (p=0.047 6MWT; p=0.0006 3TUG), triggered post-hoc Treatment Period 1 analysis. In the elamipretide-treated group, there was observed a 19.8-meter improvement on the distance walked on the 6MWT relative to the placebo-treated group, although this was not statistically significant (p=0.0833).
Again, the subjects who were more impaired on the 6MWT at baseline, walking under 450 meters, derived greater benefit from elamipretide treatment, as shown below. Stealth Biotherapeutics incorporated this observation into the MMPOWER-3 trial by excluding subjects who walk 450 meters or more on the 6MWT at screening or baseline, which we believe may enrich MMPOWER-3 trial for subjects more likely to respond on this endpoint.
BASELINE WALK DISTANCE |
CHANGE (LEAST-SQUARED-MEANS DIFFERENCE)ELAMIPRETIDE VS. PLACEBO |
|
Low Walker (under 450m) (n=22) |
24.3 meters |
|
High Walker (at/over 450m) (n=8) |
8.6 meters |
While the 6MWT results weren’t stellar, the effects seen in muscle weakness, muscle pain, and fatigue were much more promising. These are the symptoms that most strongly affect the lives of PMM patients as they are severe impairments in and of themselves but also lead to emergent impairments such as the aforementioned respiratory insufficiency, impaired vision, and difficulty swallowing. Improvements in weakness, pain, and fatigue will thereby affect the aspects of PMM that most strongly affect patient’s lives. Therefore, it is incredibly significant that the treatment effect on muscle pain and muscle weakness scores garnered p values of .0079 and .0019, respectively.
That the effect should be so pronounced relative to placebo is not surprising. While there are many different complex pathways involved in pain and muscle strength, ultimately, they all lead to and from the mitochondria.
Take pain for instance. There may be many different kinds of pain and many different mediators of the pain response (e.g., prostaglandins, Il-6, TNF-alpha, substance P, etc.) these various mediators are all different aspects of an inflammatory response to presence of inflammation,
“Irrespective of the type of pain whether it is acute or chronic pain, peripheral or central pain, nociceptive or neuropathic pain, the underlying origin is inflammation and the inflammatory response. Activation of pain receptors, transmission and modulation of pain signals, neuro plasticity and central sensitization are all one continuum of inflammation and the inflammatory response. Irrespective of the characteristic of the pain, whether it is sharp, dull, aching, burning, stabbing, numbing or tingling, all pain arise from inflammation and the inflammatory response.”
Inflammation is something that’s widely misunderstood but, essentially, inflammation is an excess of positive charge (a relative increase in the ratio of protons (hydrogen ions) to electrons). In other words, inflammation is a low redox potential and a low pH. And, what play the largest role in the regulation of redox potential and pH? Indisputably, it is the mitochondria.
In health the mitochondria function properly, inflammation is kept to a minimum, and pain is absent. In disease, however, Mitochondrial dysfunction inevitably causes a low redox potential and a low pH, i.e. inflammation, which then causes the inflammatory response which can thereby result in pain. By stabilizing and protecting cardiolipin elamipretide improves mitochondrial function and thereby reduces inflammation and pain. Therefore, the strength of the reduction in muscle pain exhibited by the treatment vs placebo is a promising sign that significant positive changes in the mitochondria are occurring.
Similarly, the effects of treatment on muscle weakness also signify significant beneficial effects occurring in the mitochondria of these patients. By improving mitochondrial function you not only reduce inflammation but improve energy transduction capabilities, which have typically seen to be the main function of mitochondria, and work, e.g., muscle strength, is of course limited by the amount energy that is available. Importantly, the amount of energy available is not just a product of total amount of energy but also its accessibility. There may be energy in one part of a cell or a tissue but it may be unavailable to processes in another part of a cell or tissue and is therefore unable to perform work.
For this reason organelles, cells, tissues, organs, organ systems, etc. rely on connected networks to maintain a constant dynamic transmission of energy (in addition to information, and mass) from one area to another. The networks allow for energy in one part of the system to be shared by every other part.
As noted above, mitochondria exist in cells as connected networks. Coupled mitochondria provide a rapid conductive path for the distribution of potential energy throughout the cell. This allows the cell to organize a united intracellular power-transmitting system. Moreover, mitochondrial networks exist not just in cells but between cells as well. This network is particularly important in skeletal muscle where energy requirements can nearly instantaneously increase by more than 100-fold during intense contraction.
As cardiolipin is crucial to mitochondrial morphology and mitochondrial morphology is crucial to the dynamics and health of this network those with cardiolipin deficiencies or dysfunctions have disconnected networks and therefore are unable to effectively transmit energy across distances. This alone, in the hypothetical absence of any other mitochondrial energy deficiencies, impairs work capacity, i.e., muscle strength, of PMM patients.
In addition, these networks also allow for information propagation across distances which is essential for coordination of activity which is another crucial determinant of muscle strength.
Thus, elamipretide’s stabilization and protection of cardiolipin therefore not only increases overall energy transduction but also energy distribution, as well as coordination of muscle units, and thereby has a strong effect on muscle strength in PMM patients.
These effects on inflammation, energy, and coordination are also relevant for the effect elamipretide has on fatigue which were the most promising and are the most relevant as changes in the PMMSA total fatigue score is a primary endpoint in the phase 3 PMM clinical trial.
The PMMSA Total Fatigue score was designed to assess the fatigue and weakness that are the hallmark symptoms of primary mitochondrial myopathy. The worst (most fatigued) possible score was 16; the best (least fatigued) possible score was four. Subjects treated with elamipretide reported a clinically meaningful reduction in total fatigue from their baseline values (2.2-point, or 19%, reduction relative to baseline) and as compared to placebo (1.7-point reduction relative to placebo) (p=0.0006). Notably, subjects did not report meaningful changes in their fatigue while on placebo (0.1 points) and, for subjects on elamipretide, their fatigue levels increased toward baseline levels after withdrawal of elamipretide, as shown below.
Figure 20: source - Stealth Biotherapeutics Investor Presentation
In the trial’s open label extension, patients were able to once again achieve and maintain similar levels of response. This response is particularly relevant in light of the natural deterioration seen in patients with PMM (shown below).
Figure 21: source - Stealth Biotherapeutics Investor Presentation
Notably, improvements in fatigue are generally seen as more important than improvements seen in the 6MWT,
“The FDA may also place less emphasis on the 6MWT versus the fatigue score in the PMMSA, the former FDA official and Vockley said. The agency is increasingly focused on quality-of-life scores across all diseases, they explained. The 6MWT has been criticised in the patient community as being overused, the former FDA official said. It is hard to take the 6MWT and translate it to the real world in terms of doing errands, going to work or social activities, Frye and Vockley said…Fatigue is particularly important to measure in PMM, as patients may perform strongly in one muscle test but then get progressively weaker as their cells make less energy, a paediatric PMM expert said…As myopathies are a set of complex diseases, it is very difficult to establish reliable trial endpoints, the pediatric PMM expert and Vockley said. Thus, focusing on only one aspect, in this case muscular strength, allows for an easy measure although it does not address the condition’s comprehensive ability to affect all parts of the body, she and Vockley noted.”
Fatigue is a good measure of general potential functionality and so strong results in fatigue scores are an important measure of the overall effectiveness of the treatment. Further proof of the systemic effectiveness of the treatment comes from patients in the open-label extension who noted a number of improvements across the board. In all five categories patients reported improvements. Given the broad-based response, it would seem that elamipretide does exactly as the suggested. It successfully stabilizes the mitochondria thereby reducing RoS, improving energy production and transduction, and restoring signaling which all feed into the body’s ability to heal itself.
To the untrained eye, the early clinical data don’t scream “success”, but it’s important to understand the purpose of these trials, which is to gain valuable information about the drug as well as the disease they are attempting to treat so that the final trial is a success.
In light of the previous trials, a number of things become immediately clear:
- Elamipretide works better overtime, as the benefits for healthy mitochondria accrue to the patient. Thus, the duration on drug should improve odds of success.
- Given the incredible safety profile, Stealth should go with seemingly high dosages to ensure sufficient targeting of CL.
- Lower walk scores ensure better response to drug, as does the inclusion of a minimum score so the company doesn’t risk a patient with comorbidities.
For the phase 3 trial, Stealth has done all of the above.
MMPOWER-3
MMPOWER-3 is a Phase 3, double-blind, placebo-controlled, parallel group trial enrolling an estimated 202 subjects ranging from 16 to 80 years old, with primary mitochondrial myopathy at up to 28 sites in North America and Europe, including the United States, Canada, Denmark, Hungary, Italy, Germany and the United Kingdom to evaluate the efficacy and safety of once daily subcutaneous injections of elamipretide. Subjects are randomized in a one-to-one ratio to either 40 mg once daily subcutaneous elamipretide or placebo injection for an initial treatment period of 24 weeks, following which subjects will be eligible to participate in an open-label extension trial.
The company has been able to secure a family of primary endpoints for this trial. Either
Stealth has undertaken a number of extra measures to increase the likelihood of success in this phase three trial:
- For phase 3, baseline 6MWD was kept between 100m and 450m. As patients in the phase 2 trial who at baseline had 6MWD > 450 responded the least to drug, those patients were excluded. Stealth also removed patients who could not walk less than 100m as well owing to the increased likelihood those patients might be suffering from comorbidities. Also, Stealth hired a CRO who specializes in the 6MWT for their phase 3 trial. Combined these factors should go a long way to improve the consistency.
Figure 22: source – Stealth Biotherapeutics’ KOL Conference Call
- For phase 3, 6MW test was standardized. In the phase 2 trial, the 6MWT was not standard across participants. While some participants may have walked around a track others walked back and forth across a hallway. It’s unclear if this or how this may have biased the earlier results, since patients tried both the drug and placebo at different times throughout the study.
- Duration on drug has been increased from 4 weeks to 24 weeks. The longer trial is in Stealth’s favor, as it gives a chance for the placebo to deteriorate in line with their natural path. Furthermore, patients across a number of different diseases in Stealth’s trials have been shown to improve over time on elamipretide. In particular, the increased duration of the trial may have significant effects on the 6MWT. While great improvements were seen in fatigue, weakness and pain in the phase 2 trial these didn’t have enough time to translate into changes in 6MWT. With more time in the phase 3 trial as the patients improve and are able to move more this should allow the patients to build up muscle capacity which should enhance 6MWT capability. In support of this, in Barth Syndrome, a rare disease that specifically affects the body’s ability to produce healthy CL, elamipretide was shown to improve 6MWT over time.
When compared with historical data, this improvement in 6MWT is highly significant
Even in age-related diseases such as Dry Age Macular Degeneration (AMD), a disease for which there is no treatment and the leading cause of blindness in western countries, elamipretide was also shown to improve function overtime.
Figure 25: Source - Effects of the Mitochondria-Targeted Drug Elamipretide on Leakage-Independent Vision Loss in Fellow Eyes with Neovascular AMD in the ReCLAIM Study
When trying to treat a rare disease with no approved treatments, it takes more than just the right therapy. While PMM, being a CL disorder, makes it a great target for Elamipretide, that doesn’t guarantee success. The trial has to be designed to fit the challenges each disease offers. It would seem, that Stealth has gone above and beyond in this case. Stealth has increased the duration of treatment, while enriching the patient population, and standardizing the 6MWT. The MMPOWER-3 trial was designed with two primary endpoints, 6MWT and Total Fatigue Score. The trial will be considered a success if it hits both with statistical significance (p<0.05) or one with the p<0.025.
And while the changes made in recruitment of the phase 3 population and the additional time on treatment should positively affect the primary endpoints, 6MWT included, these changes may not even be necessary for the phase 3 trial to be a success. All that is necessary is for the PMMSA Total Fatigue score to meet a P<0.025 level of significance which was far exceeded in the MMPOWER-2 trial.
Given that the PMMSA Total Fatigue score is a purely patient reported outcome, it’s encouraging to see 95% of patient in MMPower-3 enroll into the open label extension. It’s even more encouraging when you consider the side effects that come with Elamipretide’s once daily injections.
Figure 26: source - MMPOWER-2 Open-Label Extension Trial: 6-Month Treatment Effect on Patients with Baseline 6MWT between 100-450 Meters
As such, it seems that the phase 3 MMPOWER-3 clinical trial will be successful and Elamipretide (SS-31) will have proven itself capable of enacting real positive change in human patients. We believe the trial has an 85% chance of being successful.
Conclusion: PMM is just the Beginning
With the read out of the Stealth’s first and pivotal phase 3 trial just a few months away, Stealth is on the verge of a major inflection point. There are approximately 40,000 patients in the US with PMM. The average price for an orphan drug is $140,000, which makes PMM a $6.4B market opportunity in the US alone. With no treatment available to PMM patients, and Alexion as a potential partner, Stealth should have no trouble taking a sizable chunk of this market. Given this available opportunity, and the company’s current market cap of approximately $230mm USD, we believe Stealth to be wildly undervalued.
Not only would success in PMM would read through to Stealth’s other clinical programs, especially Barth Syndrome, but the company has far more up its sleeve. Early success in dry AMD, shows Elamipretide’s potential for treating age related disorders, which arise primarily due to mitochondrial dysfunction. Mitochondrial dysfunction has been implicated as a factor in age-related neurodegenerative diseases, such as Alzheimer’s and Parkinson’s disease, rare mitochondrial diseases, such as Leigh’s syndrome and Friedreich’s ataxia, and other rare diseases, including ALS. For these Stealth, will be breaking out its discovery compounds, in particular SBT-272, which holds potentially even greater therapeutic efficacy than elamipretide in mitochondrial and age related disorders.
As illustrated below, treatment with SB-272 or its analog compounds resulted in greater reduction in plasma creatinine and blood urea nitrogen, biomarkers of kidney dysfunction, than treatment with vehicle or treatment with elamipretide. In the graph below, the sham columns represent rats that were not subjected to kidney reperfusion injury and not treated with any of the four alternatives.
Figure 27: Source - Stealth Biotherapeutics Investor Presentation
SBT-272 has shown greater than six times higher mitochondrial uptake relative to elamipretide in cell-based assays of isolated mitochondria, and has also demonstrated improved oral bioavailability in early animal studies, suggesting it may be a promising candidate for oral dosing. SBT-272 has demonstrated approximately three times greater maximum concentration, or Cmax, in the brain of rats relative to elamipretide, in each case dosed 10 mg/kg subcutaneously. SBT-272 has demonstrated more than 25 times greater area under the drug concentration-time curve in the brain of rats relative to elamipretide, in each case dosed 10 mg/kg subcutaneously, suggesting significantly higher brain exposure and residence time.
Figure 28: source – Stealth Investor Presentation
Based on SBT-272’s preferential concentration and residence time in the cerebrospinal fluid Stealth is evaluating SBT-272 for neurodegenerative indications characterized by mitochondrial dysfunction. Stealth has initiated preclinical studies in an ALS animal model and expect this data to inform further development plans for this indication. So, while it is important to note that Stealth did option away its lead compound to Alexion, it’s also worth noting that the company has a much better and more interesting compound waiting in the wings.
Disclosure: I am/we are long MITO.
Additional disclosure: The purpose of this report is to generate a discussion about mitochondrial therapies while also creating a public record of our views. This report is NOT a recommendation to buy or sell securities.