HEPH » Topics » NEUMUNE

This excerpt taken from the HEPH 8-K filed Mar 16, 2007.

NEUMUNE

Earlier this week Hollis-Eden management had the opportunity to meet face-to-face with representatives from HHS to discuss the Agency’s decision to exclude the Company’s drug candidate NEUMUNE from the competitive range in a solicitation for potential products to treat ARS and to cancel the solicitation in its entirety. In summary, HHS indicated that, while the compound is promising and met the mandatory requirements of the solicitation, the amount of data available for NEUMUNE was not sufficient to justify an advance purchase contract under Project BioShield at this time. Based on the comments made, Hollis-Eden believes the concerns of the Agency could only be satisfied with pivotal safety and efficacy trials, which, as previously indicated, the Company is not prepared to fund in the absence of an advance purchase contract. The Agency also indicated it anticipated issuing a new Request for Proposal (RFP) for potential products to treat ARS with different requirements at some point in the future. HHS encouraged Hollis-Eden to contact the National Institutes of Health (NIH) about opportunities to collaborate further on the development of NEUMUNE for ARS.

“We continue to find HHS’ actions quite confusing,” stated Richard B. Hollis, Chairman and Chief Executive Officer of Hollis-Eden Pharmaceuticals. “We believe NEUMUNE is clearly the compound farthest along in development for the acute effects of radiation injury, which the President has declared the gravest threat to our nation. By cancelling this solicitation HHS is potentially delaying the availability of an effective medical countermeasure for this critical indication by at least several years.

“In light of these actions by HHS, we have made the strategic decision to curtail further development of NEUMUNE and will focus our resources on our next-generation candidates HE3286, HE3235 and follow-on oral compounds for indications that have well-defined clinical paths and large, well-established markets. If Congressional intervention or procurement activities by the Department of Defense improve the opportunity for NEUMUNE in the very short term we may revisit this decision. We will also consider licensing or selling the compound to third parties for further development.”

This excerpt taken from the HEPH 10-K filed Mar 16, 2007.

NEUMUNE

 

NEUMUNE has been under development as a treatment for acute radiation syndrome, or ARS, a condition for which there are no approved therapeutics. ARS, also referred to as radiation sickness, is a potentially fatal acute illness caused by high doses of radiation exposure over a significant portion of the body. This exposure results in the depletion of hematopoietic stem and progenitor cells in the bone marrow, which then leads to thrombocytopenia (loss of key clotting elements known as platelets), and neutropenia (loss of white blood cells known as neutrophils). Thrombocytopenia increases the risk of uncontrolled bleeding, while neutropenia can significantly increase an individual’s susceptibility to life threatening infections. Either of these conditions can

 

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lead to death, which usually occurs in the first thirty to sixty days following radiation exposure. ARS also causes anemia (loss of oxygen carrying red blood cells) which can contribute to morbidity and mortality. If an individual can survive this initial period of insult, the bone marrow will generally return to normal production of these critical blood cell components.

 

We licensed certain patents related to NEUMUNE from Dr. Roger Loria, a professor of microbiology and immunology at Virginia Commonwealth University. We have been developing the compound in collaboration with the Armed Forces Radiobiology Research Institute, or AFRRI, an agency within the U.S. Department of Defense. AFRRI is a leader in studying the effects of radiation injury. Published studies by AFRRI with NEUMUNE in rodents have shown dramatic survival improvements in NEUMUNE-treated animals versus controls in models of radiation-induced immune suppression, leading AFRRI to identify NEUMUNE as its lead ARS candidate.

 

We have been developing NEUMUNE as a countermeasure to ARS under the FDA Animal Rule, which was adopted in 2002 for review of medical countermeasures to weapons of mass destruction. Traditional drug development programs require large-scale clinical studies to establish efficacy in humans in order for a drug candidate to be granted FDA approval. Under the Animal Rule, however, for indications in which it would be unethical to conduct efficacy studies in humans, as is the case with ARS, approval may be granted on the basis of efficacy in relevant animal species and safety in humans.

 

Pursuant to the Animal Rule, we have designed and conducted multiple efficacy studies in rhesus monkeys to assess the effect of NEUMUNE on mitigating the hematopoietic effects of ARS as well as on survival. To date, these studies indicate that NEUMUNE can provide benefit in non-human primate models across a wide range of radiation exposures, including lethal exposures, and in settings where no other medical support is administered, as well as in settings where supportive care can be provided.

 

In a sublethal model, studies conducted in rhesus monkeys exposed to 4 Gy of total body irradiation showed protection with NEUMUNE at doses ranging from 2.5 to 42.5 mg/kg. Published data from one of these studies, giving the compound once per day for 5 days by intramuscular injection at a dose of 15 mg/kg, showed the number of days of severe neutropenia were reduced from 12 to 3. In this study severe thrombocytopenia and severe anemia were eliminated.

 

High-dose radiation models were also conducted in rhesus monkeys with and without clinical support such as antibiotics, IV fluids and platelet transfusions. In the studies conducted without supportive care, 32.5% of the 40 control animals died versus only 12.5% of the 40 NEUMUNE treated animals. NEUMUNE-treated animals also required fewer platelet and blood transfusions and fewer antibiotic courses than placebo treated animals in the model where such supportive care was provided when needed. Animals receiving NEUMUNE experienced reductions in neutropenia, thrombocytopenia and anemia in both models.

 

In Phase I human safety studies conducted in the U.S. and The Netherlands, as of January 2007, a total of 129 volunteers had been enrolled including 57 in multi-dose studies designed to mimic the anticipated therapeutic regimen. One of these multi-dose studies included a separate cohort of healthy elderly subjects. An analysis of results from these studies indicates that the compound is generally well tolerated, with pain and swelling at the injection site being the most commonly reported adverse event. These healthy young and elderly volunteers also experienced a dose dependent increase in neutrophils and platelets during the multi-dose study. The magnitude of the increase in platelets and neutrophils in healthy volunteers was generally consistent with that seen in unirradiated monkeys when given doses of NEUMUNE that led to protection in radiation studies.

 

In light of the current risk of a terrorist attack with a nuclear or radiological weapon, we believe the market opportunity for a drug that could be used to ameliorate the effects of ARS could be significant. Further, because the compound could be stockpiled by government agencies, the cost of distribution could potentially be significantly less than for traditional pharmaceuticals. Our intent had been to secure procurement contracts for

 

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NEUMUNE with both the Department of Health and Human Services (HHS) and the Department of Defense (DOD). However, in March 2007, after being notified on multiple occasions that we were in the competitive range for an active Request for Proposal (RFP), we were informed by HHS that NEUMUNE did not meet the technical requirements for this RFP. HHS then cancelled the solicitation in its entirety. While we believe DOD remains interested in procuring a drug candidate like NEUMUNE for bone marrow damage from ARS, they have not yet issued a RFP for this indication. Therefore, it is uncertain whether or when a market for NEUMUNE in ARS will materialize and as a result, we have curtailed our development activities in this indication until such time as the market opportunity becomes more clear.

 

If an agency within the federal government does ultimately decide to procure NEUMUNE, we also believe state and local governments, foreign governments and civilians may be interested in stockpiling the compound, if it is approved by the FDA for this indication.

 

We believe that a successful pivotal registration efficacy study in monkeys and a successful pivotal registration safety study in humans will be required prior to the submission of a New Drug Application, or NDA, for FDA approval. Accordingly, we would plan to meet with the FDA and other appropriate government agencies to gain concurrence on final protocol design for those studies prior to initiating any such activities.

 

This excerpt taken from the HEPH 10-K filed Mar 16, 2006.

NEUMUNE

 

NEUMUNE is being developed as a treatment for ARS, a condition for which there are no approved therapeutics. ARS, also referred to as radiation sickness, is a potentially fatal acute illness caused by high doses

 

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of radiation exposure over a significant portion of the body. This exposure results in the depletion of HSPCs, in the bone marrow, resulting in thrombocytopenia, loss of key clotting elements known as platelets, and severe neutropenia, loss of white blood cells known as neutrophils. Thrombocytopenia increases the risk of uncontrolled bleeding, while severe neutropenia can significantly increase an individual’s susceptibility to life threatening infections. Either of these conditions can lead to death, which usually occurs in the first thirty to sixty days following exposure. Anemia or loss of oxygen carrying red blood cells can also contribute to morbidity and mortality from ARS. If an individual can survive this initial period of insult, the bone marrow will generally return to normal production of these critical blood cell components.

 

We are co-developing NEUMUNE with the Armed Forces Radiobiology Research Institute, or AFRRI, an agency within the U.S. Department of Defense. AFRRI is a leader in studying the effects of radiation injury. A principal AFRRI mission is the development of pharmaceutical agents that can be used to prevent injury from radiation caused by a nuclear accident or event. Over the years, AFRRI, has screened thousands of compounds in an effort to find a radioprotectant for ARS suitable for widespread use. Published studies by AFRRI with NEUMUNE in rodents have shown dramatic survival improvements in NEUMUNE-treated animals versus controls in models of radiation-induced immune suppression, leading AFRRI to identify NEUMUNE as its lead ARS candidate.

 

We are developing NEUMUNE as a countermeasure to ARS under the FDA Animal Rule, adopted in 2002 for approval of medical countermeasures to weapons of mass destruction. Traditional drug development programs require large-scale clinical studies to establish efficacy in humans in order to be granted FDA approval. Under the Animal Rule, however, for indications in which it would be unethical to conduct efficacy studies in humans, as is the case with radiation injury, approval may be granted on the basis of efficacy in relevant animal species and safety in humans.

 

Pursuant to the Animal Rule, we have designed and conducted multiple efficacy studies in rhesus monkeys to assess the effect of NEUMUNE on mitigating ARS as well as on survival. To date, these studies indicate that NEUMUNE can provide benefit in monkey models across a wide range of radiation exposures, including lethal exposures, and in settings where no other medical support is administered, as well as in settings where supportive care can be provided.

 

In a sublethal model, studies conducted in monkeys exposed to 4 Gy of total body irradiation showed protection with NEUMUNE doses ranging from 2.5 to 42.5 mg/kg. Representative data from these studies, giving the compound once per day for 5 days by intramuscular injection at a dose of 15 mg/kg, showed a reduction in the number of days of severe neutropenia were reduced from 12 to 3. In this study thrombocytopenia and severe anemia were eliminated.

 

High-dose radiation models were also conducted with and without supportive clinical support such as antibiotics, IV fluids and platelet transfusions. In the studies conducted without supportive care, 32.5% of the control animals died versus only 12.5% of the NEUMUNE treated animals. Animals receiving NEUMUNE experienced reductions in neutropenia, thrombocytopenia and anemia in both models. NEUMUNE-treated animals also required fewer platelet and blood transfusions and fewer antibiotic courses than placebo treated animals in the model where such supportive care was provided when needed.

 

In Phase I human safety studies conducted in the U.S. and The Netherlands, as of December 2005, a total of 111 volunteers had been enrolled, with 39 volunteers having completed the 5-day treatment course. An analysis of results from these studies indicates that the compound is generally well tolerated, with pain and swelling at the injection site being the most commonly reported adverse event. These healthy volunteers also experienced a dose dependent, increase in neutrophils and platelets during the study. The magnitude of the increase in platelets and neutrophils in healthy volunteers was generally consistent with that seen in unirradiated monkeys when given doses of NEUMUNE that led to protection in radiation studies.

 

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In light of the current risk of a terrorist attack with a nuclear or radiological weapon, we believe the market opportunity for a drug that could be used to ameliorate the effects of ARS could be significant. As a result of the increased terrorist threat, the U.S. government is allocating funding for the stockpiling of drugs that act as medical countermeasures to weapons of mass destruction.

 

As an incentive to industry to develop these countermeasures, the U.S. government enacted Project BioShield, legislation that provides a mechanism for placing advance orders for investigational products in this area, which are contingent on FDA approval. A total of $6 billion has been allocated to purchase medical countermeasures under this legislation. Project BioShield also contains provisions enabling the Department of Health and Human Services, or HHS, to begin purchasing new medical countermeasures for the Strategic National Stockpile, or SNS, in advance of formal FDA approval. This provision, known as an Emergency Use Authorization, or EUA, has already been implemented for other development stage medical countermeasures to weapons of mass destruction.

 

In late 2005, HHS issued an initial Request for Proposal, or RFP for therapeutics to treat ARS. The request specifically sought 100,000 treatment courses of therapies that could mitigate neutropenia sufficiently to improve survival following exposure to 2 to 6 Gy of total body irradiation. The RFP also placed an added value on candidates that could protect against additional components of ARS such as thrombocytopenia and anemia. Furthermore, the RFP requires products to be available within two years under an EUA, and gives additional consideration to products that can be supplied to the SNS within 12 months of a contract award. In February 2006, we filed our formal response to this RFP detailing the potential for NEUMUNE in this indication.

 

We believe the next step in the procurement process for countermeasures to ARS will be the awarding of advance purchase contracts. There can be no assurance when or if HHS will grant awards under this procurement process and whether we will be awarded such a contract. Our development plans and timelines may vary substantially depending on whether we receive such a commitment and the size of such commitment, if any.

 

While we responded to the initial HHS RFP for an ARS countermeasure with the objective of securing an advance purchase contract for NEUMUNE, we believe that the number of treatment courses, and the therapeutic approach inherent in the initial RFP, are insufficient to address a mass casualty nuclear scenario. A February 2002 study published in the British Medical Journal estimated that a 12.5-kiloton nuclear bomb detonated in New York City would cause 50,000 deaths immediately from the explosion, and hundreds of thousands would be potentially exposed to life threatening ARS.

 

Because the window of opportunity to treat ARS is short, we believe any drug to treat this condition will need to be stockpiled on a local level to be appropriately available for high-risk populations. High-risk areas may include any military installation or theater of operations, any metropolitan area that is at risk of a radiological attack, and a 10 to 50 mile radius around any nuclear power plant or spent fuel facility. Such a definition would encompass a large portion of the highly populated areas in the U.S., and require the procurement and stockpiling of significantly higher quantities of ARS therapies than the 100,000 treatment courses sought in the initial HHS RFP.

 

Current treatment protocols for ARS recommend hospitalization for two to three weeks, the administration of multiple platelet transfusions and the use of antibiotics, in addition to costly growth factors to replenish neutrophils. Unfortunately, such a treatment regimen is unlikely to be available for most victims of a mass casualty event. Part of the challenge with such a mass casualty scenario is the lack of hospital beds and the supply of platelets for transfusions.

 

For example, in New York State, on average there are only 20,000 to 25,000 hospital beds available on a given day, and the average hospital carries only a one-day supply of platelets. Furthermore, platelets have a very short shelf life and can not be stockpiled in large quantities. In the type of mass casualty scenario that could occur following a nuclear or radiological event, local hospitals and treatment facilities are likely to be completely overwhelmed and treatment would likely be unavailable for the vast majority of victims.

 

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The critical importance of mitigating thrombocytopenia was demonstrated in studies of victims of Hiroshima and Nagasaki showing that bleeding from ARS was a major cause of mortality. The significance of thrombocytopenia in ARS was also revealed in our studies in rhesus monkeys, where the number of days of thrombocytopenia by day 14 after total body irradiation was the strongest predictor of survival. These findings would appear to indicate that therapies to protect platelet levels are at least as important as therapies to protect neutrophils in the setting of ARS.

 

Use of a therapy such as NEUMUNE, we believe, would prove effective even without hospitalization of victims in a mass casualty scenario, offering the potential to treat a much larger percentage of victims than a hospital-based approach. As discussed above, NEUMUNE has been shown to reduce the duration of both neutropenia and thrombocytopenia following radiation exposure, and has demonstrated a survival advantage in a model of radiation injury in rhesus monkeys where similar to a mass casualty scenario, the animals were not provided any supportive care.

 

Furthermore, in a hospital setting, NEUMUNE potentially could stretch supplies of existing antibiotics and blood products across a much larger number of patients. NEUMUNE has also shown an attractive safety profile to date and is cost-effective in quantities appropriate for a mass casualty scenario, such that it could potentially be forward deployed to multiple locations across the nation and self-administered without physician supervision.

 

In addition to a possible BioShield procurement under the initial ARS RFP issued by HHS, we believe there are multiple other significant market opportunities for NEUMUNE. Among these is a potential procurement of a countermeasure such as NEUMUNE by the Department of Defense, which has been seeking an ARS therapy since the 1960s and considers NEUMUNE its lead product candidate for ARS. The Department of Defense has issued a Sources Sought Notice, or SSN, for an ARS therapy for use by U.S. forces, and we responded to that SSN in January 2006.

 

The Department of Defense also indicated in a letter to us that it will be issuing by mid-year 2006 its own RFP for an ARS therapy for the military. In that letter, we were highly encouraged by the Defense Department to respond to this RFP.

 

We also believe state and local governments, foreign governments and civilians may be interested in stockpiling NEUMUNE for ARS, if the compound is approved for this indication.

 

We believe that a pivotal registration efficacy study in monkeys and a pivotal registration safety study in humans will be required for the submission of a New Drug Application, or NDA, for FDA approval. Accordingly, we intend to meet with the FDA and other appropriate government agencies to gain concurrence on final protocol design for those studies.

 

Recent findings also show the ability of NEUMUNE to increase CD34+ HSPCs, which could lead to additional market opportunities for NEUMUNE and our other IRHs. For example, loss of CD34+ cells is implicated in many diseases of aging. We are now exploring the potential for IRHs in additional clinical indications.

 

This excerpt taken from the HEPH 10-K filed Mar 10, 2005.

NEUMUNE

 

NEUMUNE is being developed as a treatment for Acute Radiation Syndrome (ARS). ARS, also referred to as radiation sickness, is an acute illness caused by high doses of radiation exposure over a significant portion of the body in a relatively short time period. This exposure results in the depletion of hematopoietic stem cells and progenitors in the bone marrow, resulting in severe neutropenia (loss of white blood cells known as neutrophils) and thrombocytopenia (loss of key clotting elements known as platelets). Severe neutropenia can significantly increase an individual’s susceptibility to life threatening infections, while thrombocytopenia increases the risk of bleeding. Either of these conditions can lead to mortality, which usually occurs in the first thirty to sixty days following exposure. If an individual can survive this initial period of insult, the bone marrow will generally return to normal production of these critical blood cell components.

 

To date, there are no therapeutics approved to mitigate ARS. Current treatment recommendations call for hospitalization of the exposed individual during this period of vulnerability so that these critical blood elements can be monitored aggressively and supportive care can be given where necessary. Unfortunately, in the type of mass casualty scenario that could occur following a nuclear or radiological event, local hospitals and treatment facilities are likely to be completely overwhelmed and such a treatment strategy is unlikely to be available for the vast majority of victims. What is needed is an agent that could potentially be useful on an outpatient basis, without the need for hospitalization, that could protect those exposed from these life-threatening complications.

 

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NEUMUNE is being developed by Hollis-Eden and the Armed Forces Radiobiology Research Institute (AFRRI) in the U.S. military to potentially fulfill this need. Published studies by AFRRI with our immune regulating hormone NEUMUNE have shown dramatic survival improvements in NEUMUNE-treated animals versus controls in models of radiation-induced immune suppression. The ability of NEUMUNE to stimulate both neutrophils and platelets as well as other components of innate immunity is believed to be the mechanism by which NEUMUNE exerted its protective effects in these studies.

 

AFRRI is a leader in studying the short-term and long-term effects of radiation injury. A principal AFRRI mission is the development of pharmaceutical agents that can be used to prevent injury from radiation caused by a nuclear accident or event. Over the years, AFRRI, in concert with another Department of Defense project, has screened thousands of compounds in an effort to find an acute radioprotectant suitable for widespread use. Out of this screening and profiling effort, NEUMUNE has emerged as a leading candidate based on its significant efficacy in preclinical models to date, its safety profile, and the comparatively low-cost nature of its manufacturing process.

 

The FDA has informed us that NEUMUNE would qualify for review for radiation protection under a new rule adopted in 2002. Traditional drug development programs require large-scale clinical studies to establish efficacy in humans. However, pursuant to the new rule, in cases where traditional efficacy studies would be deemed unethical in evaluating a drug intended for use against lethal or permanently disabling toxic substances (such as in this situation, which would otherwise require healthy human volunteers to be exposed to potentially lethal effects of radiation), approval may be granted solely on the basis of proof of efficacy in relevant animal species and proof of safety in humans.

 

Given the accelerated potential development path for NEUMUNE and the significant and largely untapped market opportunity for compounds that can treat acute radiation injury, this program has become a top priority for us. We have demonstrated that NEUMUNE has significant activity over a range of doses in maintaining neutrophils and platelets in studies involving more than 200 non-human primates. These studies also suggest NEUMUNE can provide a survival benefit versus placebo-treated animals. We anticipate initiating clinical trials in humans with NEUMUNE in the first half of 2005. The initial studies are expected to help us establish the safety of NEUMUNE in humans and to help us determine the concentration of the compound that can be achieved in human plasma. This information can then be used in selecting the final dose for the pivotal efficacy study in non-human primates and the larger human safety study that would be required. If results from these studies are successful, we anticipate being able to file a New Drug Application (NDA) with the FDA in 2006.

 

We believe the market opportunity for a drug that could be used to ameliorate the effects of acute radiation injury would be significant. Because the window of opportunity to treat radiation injury is short, we believe any drug to treat this condition will need to be stockpiled on a local level to be appropriately available for high risk populations. In light of the current risk of terrorism, high-risk areas may include any military installation or theater of operations, any urban or metropolitan area that is at risk of a radiological attack, and a 10 to 50 mile radius around any nuclear power plant or spent fuel facility. Such a definition would encompass a large portion of the highly populated areas in the U.S. In addition, we believe similar market opportunities exist in Europe and Asia. The only drug that has been widely stockpiled for radiation injury is potassium iodide. Potassium iodide is only effective against the long-term risk of thyroid cancer, and does not protect the body from the acute effects on the bone marrow, which can lead to rapid fatalities. Despite this limitation, potassium iodide has been stockpiled broadly for years in Europe and Japan for civilians living within close proximity of nuclear power plants, and the U.S. has recently begun purchasing millions of doses of the drug for similar uses in this country. Given that NEUMUNE may be useful in protecting against the immediate life-threatening effects of radiation, we believe there may be strong interest by government agencies to adopt a similar stockpiling strategy if NEUMUNE is successfully developed.

 

As a result of the increased threat, the U.S. government is allocating significant funding for the stockpiling of drugs that act as medical countermeasures to weapons of mass destruction. As an incentive to industry to develop these countermeasures, the U.S. government recently enacted Project BioShield, legislation that provides

 

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a mechanism for placing large advance orders for investigational products in this area, even before they are approved. A total of $6 billion has been allocated to purchase the initial round of medical countermeasures under this legislation. In late 2004, the Department of Health and Human Services (HHS) issued a Request for Information (RFI) for therapeutics to treat ARS. The request was specifically targeted at therapies that could protect neutrophils and platelets from the damaging effects of radiation injury when given shortly after exposure to total body irradiation. We filed a formal response to this request detailing the potential for NEUMUNE in this indication. We believe the next step in the procurement process for countermeasures to ARS will likely be a formal Request for Proposal (RFP) process which would detail the specific requirements of any such order. There can be no assurance when or if HHS will move to the next stage of this procurement process and whether we will be able to participate.

 

Project BioShield also contains provisions enabling HHS to begin purchasing new medical countermeasures for the Strategic National Stockpile in advance of formal FDA approval. This provision, known as an Emergency Use Authorization, has already been implemented for other development stage medical countermeasures to weapons of mass destruction. In preparation for a similar potential order for NEUMUNE, Hollis-Eden has begun manufacturing scale-up activities. A decision by the U.S. Government to enter into a commitment to purchase NEUMUNE prior to FDA approval is largely out of our control. Our development plans and timelines may vary substantially depending on whether we receive such a commitment and the size of such commitment, if any.

 

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