Avid Bioservices Inc (CDMO)

[cjgaddy]

C3, more here on possible Animal Rule (FDA) Approval for Bavi (different than ‘EUA’ approval – see below), concentrating on Lassa Fever (one of the Viral Hemorrhagic Fevers that the DTRA is working with Peregrine on – see http://tinyurl.com/5dxpup )…

I. THE REQUIREMENTS:
Animal rule: http://tinyurl.com/yzbacxg ( 1-13-09: www.fda.gov...UCM078923.pdf )
New Drug and Biological Products: Evidence Needed to Demonstrate Effectiveness of New Drugs When Human Efficacy Studies Are Not Ethical or Feasible
FDA’s ANIMAL RULE: “Marketing approval can be granted based on efficacy in relevant Animal models with only Phase I safety trials required in humans” (Elusys 10-4-05 Anthim/Anthrax PR)
Diseases that may be affected by the ANIMAL RULE:
• Anthrax
• Botulism
• Plague
• Smallpox
• Tularemia
• VIRAL HEMORRHAGIC FEVERS (ex: Ebola, Marburg, Lassa)

II. BAVI’S PERFORMANCE TO DATE VS. REQUIREMENTS:

A. LASSA FEVER - ANIMAL EFFICACY OF BAVITUXIMAB:
• Thorpe 10-25-04:
“rodents were infected with Lassa Fever virus, a very lethal virus.. if the animals were getting Bavituximab, half the animals rejected the virus and went on to live normally. That's an extraordinary result, I don't know of any other antiviral agent that is known to protect against Lassa Fever”. http://tinyurl.com/38qjug
• BIO2005 6-22-05:
“Bavituximab provided significant protection in animals administered lethal viral loads of Pichinde virus (a model of Lassa fever) with 50% of the Bavituximab treated animals surviving and none of the animals receiving control treatment surviving.” http://tinyurl.com/avt4y
• NATURE-MED. DEC.2008, “BaviAV vs. Lassa/CMV”:
11-24-08 PR: Data Published in Nature Medicine Highlights Ability of Peregrine Pharmaceuticals' Bavituximab to Cure Lethal Virus Infections
Dr. Philip Thorpe: “By targeting a property of the host cell rather than the virus itself, anti-PS antibodies have the potential to treat a range of viral infections, and they should be less susceptible to the viral mutations that contribute to the development of drug resistance."
Dr. Melina Soares: “Recent non-affiliated research has further confirmed that exposed PS has immunosuppressive properties and is also clarifying its involvement during viral infection of cells. Our data go a step further, providing compelling evidence that exposed PS itself is a promising anti-viral drug target that is involved in the pathogenesis of multiple viruses, suggesting the possibility of achieving broad-spectrum anti-viral effects using a single anti-PS agent. We look forward to further exploring the potential of bavituximab and other anti-PS antibodies against viruses for which there are few or no effective therapeutic options." http://tinyurl.com/9ktvsb

B. HUMAN SAFETY TRIALS OF BAVITUXIMAB:
As of 10-6-09, ~252 Cancer & HepC Patients have been treated with Bavi ( see http://tinyurl.com/yclyfyt ) - generally safe and well tolerated by all subjects as reported to date.

C. PRECLINICAL BAVITUXIMAB SAFETY RESULTS:
1. 2004 MPI Research Bavituximab Monkey Safety Data:
They took monkeys up to 100 mg/kg (at least 20x expected dosage), and the worse they found were “transient dose-dependent elevations in APTT and PT”, and bleeding time that was “not significantly affected 24-hours after treatment”. Their conclusion, “Bavituximab administered as a single IV bolus is generally well tolerated in rats and monkeys with effects limited to prolonged APTT and PT”. http://tinyurl.com/lnkw9
“MPI Research helps drug developers answer a crucial question: Is it safe? The contract research organization (CRO) specializes in providing toxicology services to product development companies, as well as regulatory and other government agencies.” http://www.mpiresearch.com
2. Thorpe’s 7-23-04 Bavituximab presentation at the SRI “ANTI-CANCER Drug Discovery & Dev. Summit” in Philadelphia:
Slide: MONKEY SAFETY STUDY:
* Bavituximab was administered IV as a single bolus at up to 100mg/kg to cynomolgus monkeys (i.e. 10 to 100 times the predicted therapeutic dose)
* A transient 2-4 fold increase in APTT and 1.2 to 1.4-fold increase in PT was observed at 9mg/kg and greater
* No significant changes in blood cell counts, (white blood cells, red blood cells, platelet) or other clinical chemistries.
http://www.siliconinvestor.com/readmsg.aspx?msgid=20391939
3. Dr. Thorpe on Bavituximab Safety 10-25-04:
“…That's an extraordinary result, I don't know of any other antiviral agent that is known to protect against Lassa Fever. And we've also shown similar results in cytomegalovirus... at that dose we've never seen any sign of toxicity in mice or monkeys; about 14 species treated with the therapeutic dose. And that's thousands of mice & monkeys. And even if you increase the dose to 10 mg/kg, that's 10x the therapeutic dose.”
http://tinyurl.com/38qjug

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BIOWORLD Today - Jul. 03, 2008 (2 days after the DTRA VHF Award):
… “Solid tumors will more than likely be the first indication Peregrine seeks, he [CEO Steve King] noted. However, because of the expedited process in developing products under the govt's animal efficacy rule, the viral hemorrhagic fevers indication potentially could be the first approved use for Bavituximab”…
http://tinyurl.com/5kr6xk

Recall, the 7-2008 5-yr $44mm DTRA Award to PPHM was…
“to test & develop bavituximab and an equivalent fully human antibody as potential broad-spectrum treatments for viral hemorrhagic fever infections.”
7-1-08 PR: http://tinyurl.com/5dxpup

DR. THORPE’S AUG03-JAN08 $1.68MM NIH/NIAID GRANT FOR RESEARCH USING PPHM’S APTS (ANTI-PS/3G4) AS “NOVEL ANTI-VIRAL AGENTS FOR TREATING LASSA FEVER”:
Thorpe: “We are developing drugs to use against Lassa fever that operate on a new principle in virology. They exploit the fact that viruses coat themselves with an outer membrane where some of the lipids are inside-out. The drugs direct our immune responses to the inside-out components of the viral membrane, or envelope. These drugs potentially could be effective against numerous viruses that have similar outer membranes… We have raised mabs to PS and other anionic phospholipids that block the spread of several viruses to uninfected cells in vitro, essentially completely. The phospholipids that they recognize have the same structure & cellular distribution in different mammalian species, simplifying the transition from experimental animals into humans. The antibodies are not toxic to mice, even when administered in high doses for prolonged periods of time.”
GRANT LINK: http://tinyurl.com/5ntcm . . .11-3-03 Grant PR: http://tinyurl.com/5aulds
###8-26-09: $763k expansion NIAID grant to Dr. Thorpe for 2nd-gen. anti-PS/VHF studies: http://tinyurl.com/lxtuo3

MORE ON VHF’s:
Viral Hemorrhagic Fevers (VHFs) are a group of illnesses caused by 4 families of viruses. These include:
• EBOLA VIRUS
• MARBURG VIRUSES
• LASSA FEVER VIRUS
VHFs have common features: they affect many organs, they damage the blood vessels and they affect the body's ability to regulate itself. Some VHFs cause mild disease, but some, like Ebola or Marburg, cause severe disease and death.
http://www.nlm.nih.gov/medlineplus/hemorrhagicfevers.html

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“ANIMAL RULE” APPROVAL VS. “EUA” APPROVAL:

• Approval under “Animal Rule”
• Availability for emergency use under IND or “Emergency Use Authorization” (EUA)

“Animal Rule”
• Products to reduce or prevent serious conditions caused by exposure to lethal or permanently disabling toxic chemical, biological, radiological, or nuclear substances
• Human efficacy studies not feasible or ethical
• Use of animal data scientifically appropriate
• Not applicable if approval can be based on standards described elsewhere in FDA regulations
• Still need human clinical data - PK/immunogenicity & Safety
• Approval subject to post-marketing studies and any needed restrictions on use
• Potential limitations:
. . . . . . . No valid or comparable animal model of disease
. . . . . . . How to predictably bridge animal data to humans
. . . . . . . Confidence an issue, even with valid models

Emergency Use Authorization (EUA)
• Sec. of HHS can declare emergency after Sec.of Defense, Homeland Security, or HHS determines an emergency (or potential for one) exists, affecting national security
• Sec. of HHS (FDA) can authorize use of product:
. . . . . . . For serious or life-threatening condition
. . . . . . . No adequate, approved, available alternative
. . . . . . . Known & potential benefits outweigh known & potential risks
• EUA granted for up to 1 yr: can be renewed

EUA: CONDITIONS OF AUTHORIZATION
• Inform health care workers or recipients, if feasible:
. . . . . . . Product authorized for emergency use
. . . . . . . Significant known & potential risks and benefits
. . . . . . . Alternatives
. . . . . . . Option to accept or refuse (vs. written consent)
• Appropriate conditions for monitoring and reporting AEs, record keeping
• Authority for additional conditions, e.g., who may distribute or administer, data collection & analysis

GROUNDWORK IS NEEDED FOR BROAD EMERGENCY USE UNDER IND OR EUA
• Product may be used very widely in multiple populations
• Therefore, should have reasonable evidence of safety and support for efficacy or likely surrogate such as immunogenicity
• Primary time challenge in development is proof of principle and making product consistently - not clinical studies or review
• If product can be made, core data can be generated rapidly – example GSK Fluarix: 1 month/900 patients
• This should be done before emergency (or pre-pandemic/epidemic) wherever possible
• Managed, prioritized, funded processes needed to identify and develop candidates, assure data will be available to support use in an emergency
. . .
Per Jesse L. Goodman, MD, MPH Director, Center for Biologics Evaluation & Research (CBER), FDA CDC ICEID, March 22, 2006:
http://www.fda.gov/downloads/BiologicsBloodVaccines/NewsEvents/WorkshopsMeetingsConferences/UCM164947.pdf