Pullan's Pieces #157
 
 
 
 
 
 
linda@pullanconsulting.com
1(805)-558-0361
 
 
 
 
Pullan's Pieces #157
March 2020
BD News and Analysis for  Biotech and Pharma
 
 
 
 
 
Dear --FNAME--,
 
 
 
 
Well, the world has changed since the last Pullan's Pieces.  Meetings are virtual or postponed.  About to do the first virtual BioEurope Spring!  



We hope all our friends and colleagues stay safe and that our economies recover from the shut-downs!  And that biotech innovation will be rewarded.  


Cheers,


Linda
 
 
 
 



1.  A BD perspective on choosing indications
2.  Novel targets in Phase 1
                                                             in immunology
                                                        3. Jessica:  Antiviral therapies
                                                        4.  Trevor:  The Damage is In 

 
 
        
 
 
 
A BD perspective on choosing indications
 
 
 
 
BD comparison of indications early in drug development.  

Young companies offer wonder which indications they should focus on.  At later stages, marketing research can use the drug's target product profile to interview KOL physicians about how they would use a drug compared to other alternatives.  But for early programs, there is no meaningful target product profile.  So how might we think about which indications are attractive?  

FACTORS 
  • Unmet medical need
  • Number of patients (incidence or prevalence)
  • Price per patient per year
  • Market share/fragmentation
  • Competition (including generics)
  • Number of potential partners and deal activity
  • Clinical trial size and duration
  • Clinical trial Risk
  • Scientific validation of mechanism
  • Translation of animal models

UNMET NEEDS
For unmet medical need, we at Pullan Consulting subscribe to market research from DataMonitor and GlobalData;  and for many indications can get some summary of unmet medical needs.  But we need to compare across indications.  To do that we can create a simple scoring with scoring of unmet needs ranking 

  • improving survival (especially frontline) as more important than
  • improved morbidities higher than
  • improved safety higher than
  • improved convenience. 

Let's look at some examples for a comparison. 

Pancreatic cancer = Unmet Need is Survival:  The overall five-year Overall Survival rate for PDAC patients is 8.2%, which is among the lowest across the oncology indications, and falls even further to 2.7% for those with metastatic disease (SEER*Stat Database, 2017).  The unmet need for greater efficacy is clearly high.  

Type 2 Diabetes =Unmet need is Morbidities:  The unmet need in diabetes is more subtle.  Many agents now impact glucose and glycation-end products, and offer greater duration and convenience.  About 52% of US patients are front-line (GlobalData).  However, unmet needs could include reduced obesity and cardiovascular protection, which clearly are serious co-morbidities. 

Biopolar Disorder = Unmet need is Safety:  According to GlobalData, acute mania is relatively well controlled but the depression side is treated with agents with mood stabilizers and antipsychotics with severe adverse events.  
 
 
 
 
PRICE PER PATIENT

We do not know what the price of the drug will be.  That requires much more sophistication than a survey appraisal such as this.  But we can look at the price of recently approved drugs.  Ideally, we would pick the drugs that are in the same line of treatment or same patient population, but often just looking at a couple of examples can give you a rough category of price.    Note these are US prices, probably higher than in the rest of the world.  (We could do more work and find the prices in other territories but for this simple cross indication comparison, this is enough to start the thinking process).  

  • For Pancreatic cancer, Abraxane is $45,000 per course in the US.  New cancer drugs are often higher, with $159,000 per patient per year common. 

  • For Type 2 diabetes, Trulicity is $6076 per year

  • For bipolar, Abilify is $6316 per year.  
 
 
 
 
MARKET SHARE / FRAGMENTATION. 

For an early project, how can we think about market share?  Clearly, the share will be determined by the differentiation, and by the price relatively to existing standard of care.  For a market where the standard of care has become genericized, payers have an incentive to keep using the cheap generic unless there is a compelling benefit.  Physicians become comfortable managing the existing standard of care after years of experience and may also resist changing to a new drug even if superior.  

  • For pancreatic cancer, GlobalData shows 346 marketed drugs.  Most of these are generics.  If we look at Abraxane global sales of $1.29B in 2018, then at $45,000 per course (using the US price), that is 27,311 patients, or 18% of all the patients in the major markets.  So despite the relatively small number of patients, if we had a drug that really beat Abraxane, it is not unreasonable to assume a bigger market share and a higher price, and a total peak sales of billions.  

  • For type 2 diabetes, GlobalData shows an astounding 2665 marketed drugs!  But Trulicity is forecast to have more than $5B in sales in 2020, or 822,909 patients at $6076 (US price).  That is a market share of 1.7%.  So clearly we cannot reasonably claim to get even 5% of this highly fragmented market with a new entry.  

  • For bipolar disorder, GlobalData shows 1336 drugs are marketed.  We don't see the numbers for Abilify sales in bipolar in GlobalData.  This is presumably because the antipyschotics are generic and sales are not tracked by analysts.  GlobalData reports $737M for total Risperdal Consta (ER form) sales in 2018 with $286M attributed to bipolar.  If we use the Abilify price in the US, then Risperdal Consta, the leading selling drug in bipolar captures a mere 0.9% of the patients.  For bipolar disorder, to claim you will have a really big market, you will need a pretty compelling story, despite 4.7M people with the disease.  

These numbers are all clearly very rough approximations of reality (using short courts galore) but they do begin to help us think about what we need to believe to talk about market share.  It is much easier to imagine taking market share away from 1 drug by a superior profile than getting physicians to switch from 100 different (and cheap) drugs.  That is particularly true if we are speculating that the differentiation is side effects, where the long history will have many physicians believe they can manage the side effects.  

 
 
 
 
REMAINING FACTORS

We might go and look at the number of partners with active development in each of our indications, the number of deals done in each, and how big and long the clinical trial program is for each (CV outcome trials for diabetes drugs are huge and deter many!).  We could look at the probability of success by indication and stage of development.  We could then try to think about how good the animal models are in predicting the outcomes in patients.  We certainly would want to think about the validation of the target and pathway as connected to the disease.  Generally, the best scientific argument for the target in the disease will drive which indication is chosen.  But at the very beginning, it can be helpful in thinking about what you have to show to be compelling.  

 
 
 
 
Where are we at the end?
These are all great exercises in thinking about your indication and your story.  They are not precise or accurate but they can illustrate some of the things you will need to believe.  With more details about the drug profile, the guidance gets better.  Market forecasts, valuation models are never right but sometimes they help make prioritization decisions! And the wrestling with the assumptions is good exercise.  
 
 
 
 
 
 
 
First-in-class Targets in Phase 1 in Immunology
 
 
 
 
It is exciting to see new targets being pursued.  The list below contains drugs in Phase 1 in immunology with no drug ahead at the same target for any indication.  

 
 
 
 
 
Jessica:     Anti-viral therapies
 
 
 
 
There has likely been much musing around the virtual watercooler lately about the potential value of new anti-viral medicines in development currently.  Since it seems to be front of mind for many of us, let’s take a look at the current status of marketed and pipeline anti-viral medicines.  Spoiler alert:  COVID-19 will be discussed too.


First, it’s important to recognize that the drugs targeting viruses are going to either specifically target the viral particles themselves or the immune response to the virus:
  • Virus-specific:  Targeting viral particles can lead to targeting of virus-associated molecules on the surface of infected cells (eg envelope proteins)
  • Block viral entry:  Target viral receptors to block entry
  • In the case f HIV, there are drugs that target the receptor that viruses use to enter cells, which happens to be on immune cells
  • Target Immune Response:  Targeting of the immune response to the virus will be non-specific and allow for these compounds to address different types of viruses and also, likely, can be used to address other and/or associated disease targets as well

What types of antiviral drugs are out there?  And how many are on the market already?  Below is a breakdown of all anti-viral drugs, and marketed anti-viral drugs with accounting for some of the more common molecule types:
 
 
 
 

Brand Name Drug

Viral Infection(s)

Sponsor

Molecule Type

2018 Sales (US$M)

Genvoya

HIV

Gilead

small molecule

4,690

Mavyret/Viekira Pak

HCV

Abbvie

small molecule

3,616

Triumeq

HIV

GSK

small molecule

3,531

Gardasil/ Gardasil 9

HPV

CSL

vaccine

3,151

Truvada

HIV

Gilead

small molecule

3,010

Tivicay

HIV

GSK

small molecule

2,186

Epclusa

HCV

Gilead

small molecule

1,966

Prezista

HIV

J&J

small molecule

1,955

Proquad, M-M-R Ii; Varivax

MMR;VZ

Merck

vaccine

1,798

Descovy (Withdrawn)

HIV

Gilead

small molecule

1,693



Prophylactic or Therapeutic


Prophylactic vaccines can help the inoculated persons elicit immune responses, specifically memory responses, in order to confer protection upon exposure to the infectious agent thus helping to prevent the spread of the infection.  Therapeutic products are intended to treat an active infection either by directly interfering with host cell entry or viral replication within the patient (virus-specific), or by modulating disease processes such as excessive inflammation (targeting the immune response).  It is interesting that of the top selling antiviral drugs there are more therapeutic products than vaccines (above).  Though not found in the top ten best-selling “anti-viral drugs”, another important type of drug to be used in the treatment of viral infections is anti-inflammatory drugs.  Often the collateral damage associated with the immune response to a viral infection can be more damaging (even fatal) than the infection itself.  Specifically, the hypercytokinemia or cytokine storm can be a significant underlying cause of mortality for emerging viral infections.  To that end, anti-inflammatory drugs can be an crucial component in the treatment arsenal of treating viral infections.  Importantly, we are seeing all of these types of products being actively developed to combat COVID-19. 

SARS-CoV-2/COVID-19


Several of the drugs that are being developed and/or in clinical trials for COVID-19 are drugs that were originally designed to address SARS and/or MERS.  Being of the same viral lineage, there is evidence that the same receptor, angiotensin-converting enzyme 2 (ACE2), which was used by the coronoavirus that caused SARS and MERS is also being used by the strain that causes COVID-19 Disease.  It is almost as if scientists predicted that a new SARS-CoV virus would trigger an outbreak.  Therefore, some of the drugs that are being developed to address COVID-19 are repurposed drugs that were initially designed to address SARS or MERS.  However, the swiftness with which scientists around the world have been able to study SARS-CoV-2, and the associated inflammatory responses, and develop innovative new therapeutic new agents has been unprecedented. 
 
 
 
 

Understanding SARS-CoV-2-Mediated Inflammatory Responses: From Mechanisms to Potential Therapeutic Tools


There are currently 119 drugs in development (as of 16 March 2020) or already in clinical trials already to address SARS-CoV-2.  Some high-profile, notable drugs:


Drug

Sponsor

Molecule

MOA; noteworthy actions

Furthest Stage

Remdesivir

Gilead

(FDA/CDC/NMPA/

China CDC/WHO)

Nucleotide analogue

Originally developed to address SARS and MERS; Tested in humans with Ebola; Prodrug of adenosine nucleotide analogue; blocks viral RNA replication

III

mRNA1273

Moderna

(NIH)

mRNA Vaccine

Originally designed to address MERS; quickly adapted to SARS-CoV-2; mRNA to express coronavirus spike protein to elicit immune response; not been tested in animal models

I

(FPD 3/16/2020)

COVID-19 Vaccine

CureVac

(PEI/CEPI)

mRNA Vaccine

mRNA vaccine – no further information publicly disclosed

Discovery

INO-4800

Inovio

(Gates Foundation/

CEPI)

DNA Vaccine

Relying on work with INO-4700 designed to address MERS (Ph I/IIa); optimized DNA plasmid to elicit immune response

PreClinical

(Ph I April planned)

Stem Cell Therapy for Pneumonia*

Wuhan Union Hospital

Umbilical Cord Mesenchymal Stem Cells

Undisclosed; for the treatment of severe pneumonia caused by SARS-CoV-2; improve the microenvironment in the lungs and/or promote renewal of functional cells

II

COVID-19 Vaccine

Sanofi Pasteur

(BARDA)

Recombinant DNA Vaccine

Leveraging previous development work for SARS (Protein Sciences; acquired 2017); DNA encoding viral surface proteins combined with baculovirus expression platform

Discovery

Kevzara®

Sanofi

(Regeneron)

mAb

Fully human mAb that binds and blocks the IL-6 receptor; may control excessive inflammation in the lung; supported by preliminary data on IL-6 in COVID-19 in China

II/III

BNT162

BioNTech

(Fosun Pharma; Pfizer)

mRNA Vaccine

Platform:  Uridine-containing mRNA, nucleoside modified mRNA, and self-amplifying mRNA to encode pathogen specific immunogens

Fosun:  partnership for China

Pfizer:  R&D from both companies (Germany & US); Letter of Intent for Distribution outside of China with financial terms to be decided

Discovery

(Ph I late April planned)

Global Data – Drug Database Coronavirus Disease 2019 – 16March2020

*Unclear how many sponsors/stem cell assets are under evaluation in China


The Promise Drug


Remdsivir was developed to address SARS/MERS though has not been tested in humans for those diseases due to diminished/non-existent patient pool once developed (ie, epidemic over).  It was tested in humans in The Democratic Republic of Congo (DRC) for Ebola during an active outbreak with unfavorable/inconclusive results.  Although Ebola is not a coronavirus, it was thought that the drug may still be able to function to inhibit viral replication in that disease as it is an analog of adenosine and should be effective with any RNA virus, and not be virus specific.  However, due to logistical challenges in the war-torn DRC during the trial it is unclear if the clinical protocol and/or results can be confirmed.  None-the-less, it has been tested in humans through the Ebola trial and therefore there is some safety data available. 
 
 
 
 

Unprecedented Vaccine Development


It is stunning to note how most of the newly developed, SARS-CoV-2-specific vaccines being developed are either mRNA or DNA based.  Heat-killed or live-attenuated vaccines are so last century!  First, with the virus first having been identified in December of 2019 it is astonishing that we can now describe five virus-specific vaccine products in development just three months later, with Moderna’s asset having already been tested in humans earlier this week, despite no time/ability/requirement to test it in animals models first.  This is extremely unusual.  Perhaps a result from lessons learned with Remdesivir, by the time the drug was ready for clinical trial there were no more patients as the epidemic was resolved.  Also, unusual, rumors of governments attempting to acquire exclusive access to drugs in development, directly from the sponsors.  It is interesting to opine on the potential impacts the vaccine and drug development response to this pandemic may have on shaping the post-COVID-19 future of drug development.  Maybe that should be the topic of discussion at the next virtual watercooler.  May we live in interesting times! 

We at Pullan Consulting are aware that many of you in our network are developing therapies to directly address SARS-CoV-2 or potent anti-inflammatory drugs or may be interested in partnering with those that are developing therapies to address COVID-19.  If you are looking for networking support to spur development and collaboration of these therapies, please reach out to us.  We are happy to facilitate introductions and connections always, but especially in these challenging times.
 
 
 
 
 
Trevor:  The Damage is In - Unknown how bad it will be
 
 
 
 

When the stock market over the past week-and-a-half started tripping multiple limit-down circuit breakers, things officially got wild.  We’ve all seen the empty toilet paper shelves.  Before the stock market tripped its circuit breakers, I noted that there was still a lot of 1-ply toilet paper rolls available for purchase.  After the first day we went limit down… nope, all gone, every last roll.  We had officially hit 1-ply emergency status and the stockpiling was in full swing.  I’m not sure that will be a proud memory in our history.


The public health concern is of serious import in part due to the novel nature of this pandemic infection – not knowing how bad something can be can lead to levels of unquantifiable fear as the fullness of fear searches out to fill the depths of the uncertainty.  I wonder if we’ll live to see another event so radically alter the entire social, political, financial and commercial latticework of our country – it feels epochal.  I hope we do not.

 
 
 
 

California has today become subject to an edict from its current Governor (and some of his Mayoral counterparts) that essentially seeks to shut down much of the private sector’s usual activities.  Bailouts are coming to various industries and we’re one step closer to Ben Bernanke’s (former Federal Reserve Chairman) famous solution to drop money from helicopters with the government’s proposal to stuff most everybody’s mailbox with “up to” $1,200.  Amazing to be here so quickly.  A month ago we were looking at all-time highs in the stock market, unemployment at all-time lows, full bellies and full tanks of gas.  But alas, it looks like the entire global economy is living check-to-check. 


With that, I’d like to go back to the charts from some perspective using just the Nasdaq Biotechnology Index (NBI) as our lens.  The first chart shows Feb 20 – Mar 20 of this year.  It’s a doozy and represents approximately a 25% draw down in just the past month.  But how bad is it just yet for biotech?  The next chart (below) covers October 2019 – Present and shows that we’ve just retraced the gains made in the 4th quarter of last year.


 
 
 
 


 
 
 
 

If we zoom out a little farther, we can see that we haven’t yet descended as far as we did during Q4 2018 swan dive (Dow Jones and S&P 500 are strikingly different than NBI with much more severe scarring on their charts).

 
 
 
 
Stepping back to frame the period from mid-2015 to today, we see that we haven’t been able to reclaim the all-time high set for the index back in 2015. We’ve been essentially range-bound with some fairly wide boundaries for the past 5 years.
 
 
 
 
But it’s these next two charts which make interpretation pretty tricky as patterns are present that can lead to some starkly different outcomes depending on which (if any) play out.  The first is a chart I’ve shown before (Jan 2019 Pullan’s Pieces) showing the Nasdaq Biotechnology Index from inception. The dot-com bubble and burst are clearly recognizable in the 2000-2002 time frame.  The question is obvious: are we now experiencing a much more massive version of that pattern?  If so, we’ve a long way to go down from current levels and it might take some while to get there.
 
 
 
 
But what can be easy to miss/forget when presented with a chart with such clear ramps, is this pattern from the last six months of 2008 (chart on the left) which I’ve paired with the first chart shown at the beginning of this piece.  Back in 2008 the larger indices were under intense pressure and while the NBI suffered a 33% draw-down the magical run that quadrupled its value over the next 6 years was just around the corner – thanks, in part, to Bernanke’s squadron of cash-laden helicopters.
 
 
 
 
So, the markets look like they want to find some footing here.  Whether it turns into a floor or it gives way to new levels below remains to be seen.  Either way, the damage is in.  The loss of a family member or friend is devastating.  The immediate and hard costs to those who make their living from hard-hit industries is immense.  The loss of sports not just at the collegiate and professional levels but at the T-ball level where some parents, for example, will get just 1 game of their 3rd child’s first season in a uniform… watching that child scratching out lines in the dirt while occasionally getting “baseball ready” to then dogpile teammates in search of a bouncing ball – you don’t get that year back. 


But we’ll all figure it out.  We always do.

 
 
 
 
 
 
 
www.Pullan Consulting.com

Pullan Consulting (www.PullanConsulting) provides advice and execution for biotech partnering and fund raising, with outreach to partners and investors, help with shaping of presentations, evaluations and market analysis, preliminary valuations and deal models, and negotiations from deal prep to term sheets to final agreements. 
 
 
 
 
We have extensive scientific and financial experience, with many deals signed. 

Send us an email or set up a call if you want to explore how Pullan Consulting might be of help!
 
 
 
 

Linda Pullan                     Linda@pullanconsulting.com 
Trevor Thompson             Trevor @pullanconsulting.com 
Jessica Carmen               Jessica@pullanconsulting.com 
 
 
 
 
 
 
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